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ID Statement Reference ID
1 The effect of peppermint oil resembled that of the dihydropyridine calcium antagonists. It is concluded that peppermint oil relaxes gastrointestinal smooth muscle by reducing calcium influx 1646142
2 Ceramide and sphingomyelin decreased only slightly in the mice ,,teated with PDMP alone, but inclusion of CS - which slows the synthesis of all sphingolipid., - produced a marked decrease in ceramide level and augmented the effect of PDMP on LacCer, 1827738
3 Ceramide and sphingomyelin decreased only slightly in the mice teated with PDMP alone, but inclusion of CS - which slows the synthesis of all sphingolipid., -produced a marked decrease in ceramide level and augmented the effect of PDMP on LacCer 1827738
4 Similar decreases in CMH and synergistic action were seen in liver after subcutaneous injection of DPDMP and CS as the stearate salts together with Myrj (unpublished data). In one such experiment, the concentration of total lipids in liver also decreased (10% with o-PDMP, 217~ with PDMP + CS, 23% with CS alone). The opposite effect on total liver lipids was produced by elevating the organ's GIcCer level, especially when the GIcCer was protected against glucosidase action by conduritol B epoxide [201 1827741
5 Similar decreases in CMH and synergistic action were seen in liver after subcutaneous injection of DPDMP and CS as the stearate salts together with Myrj (unpublished data). In one such experiment, the concentration of total lipids in liver also decreased (10% with o-PDMP, 21% with PDMP + CS, 23% with CS alone). The opposite effect on total liver lipids was produced by elevating the organ's GIcCer level, especially when the GIcCer was protected against glucosidase action by conduritol B epoxide [201 1827749
6 Ceramide and sphingomyelin decreased only slightly in the mice teated with PDMP alone, but inclusion of CS - which slows the synthesis of all sphingolipid., produced a marked decrease in ceramide level and augmented the effect of PDMP on LacCer 1827755
7 At the dose levels used (Table llb, the treated mice lost weight and the dosages were accordingly reduced each day. By the end of the fifth day, the average decreases in body weight were 18% in the PDMP group (B), 22% in the PDMP-CS group (C) and 14% in the CS group (D), significant differences when compared with the control mice. 1827761
8 Cycloserine produced no significant changes (Table V) but PDMP produced distinct increases in the sphingolipid hydrolases and a decrease in glucuronidase. 1827771
9 significant decreases in enzyme level but this normalized by 24 h. Liver also showed a significant loss of enzyme by 3 h and also normalized. Brain did not show any significant differences. 1827776
10 By two-way analysis of variance and Scheffe’s paired t tests, there were no significant differences in either CHDL or triglyceride levels for any of the five metabolic diet, alcohol substitution diet periods 7435407
11 Levels of diastolic pressure were lowest in those consuming 2 to < 3 drinks per day 7737723
12 systolic pressure was higher by 4.0 mm Hg (95% confidence interval [CI], 0.5 to 7.6 mm Hg) in abstainers, 3.6 mm Hg (95% CI, 0.5 to 6.6 mm Hg) in those who drank < 1 drink per day, 0.4 mm Hg (95% CI, -4.7 to 5.5 mm Hg) in those who drank 2 to < 3 drinks per day 7737723
13 Under these conditions, the net accumulation in the medium of triglycerides, unesterified cholesterol, cholesteryl esters, apoA-I, and apoE was stimulated by 75%, 41%, 43%, 19%, and 39%, respectively. 8732781
14 ApoA-I and apoE mRNA levels increased by 15% 8732781
15 secretion of newly synthesized apoA-I without significantly affecting that of apoB-100. The increase in apoA-I secretion was evident at 0.05% ethanol and reached a maximum of 77% at 0.5%ethanol 8732781
16 Under these conditions, apoB mRNA abundance was elevated by 17-26% 8732781
17 Advanced atherogenesis and alcohol consumption showed a U-shaped relation (Figure 3d). ORs were generally shifted toward protection and were not influenced by LDL levels 9596232
18 Excess risk of atherosclerosis observed among heavy alcohol consumers (adjusted OR, 3.41) 9596232
19 decrease in fibrinogen, antithrombin III, and, eventually, lipoprotein(a). 9596232
20 regular alcohol intake was associated with multiple changes in vascular risk factors, including an elevation of HDL cholesterol, apolipoprotein A1, systolic and diastolic blood pressures 9596232
21 The association between regular alcohol intake and 5-year progression of carotid atherosclerosis was J-shaped, with light drinkers facing a lower risk than either abstainers or heavy alcohol consumers (n5780, Figure 3a and 3b). 9596232
22 Differential effects of regular alcohol consumption on various stages of atherogenesis are visualized in Figure 3c and 3d. Notably, effects of low alcohol intake on early atherogenesis were apparently different in subjects with high ($66th percentile53.88 mmol/L; 150 mg/dL) and low-to normal LDL cholesterol levels (adjusted ORs, 0.39 versus 1.07, P50.009 for effect modification, Figure 3c) 9596232
23 Only LacCer stimulated the expression of ICAM-1. Other GSLs and their constituents or gangliosides did not stimulate ICAM-1 expression (Fig. 3A). LacCer stimulated ICAM-1 expression in a time-dependent (Fig. 3B) and concentration- dependent (Fig. 3C) manner. 9852101
24 However, unlike LacCer, TNF-a also stimulated the expression of VCAM-1 and E-selectin in addition to ICAM-1 (Fig. 3, D and E). 9852101
25 As shownin Fig. 4, LacCer exerted a concentrationdependent increase in the mRNA levels of ICAM-1 in HUVECs. A maximum stimulation of ICAM-1 mRNA level occurred following incubation of cells with 5 mM LacCer for 2 h. 9852101
26 LacCer (5 mM) markedly stimulated the adhesion of green fluorescencestained neutrophils to the orange fluorescence-stained endothelial cell monolayer (Fig. 9). 9852101
27 However, in cells infected with Ad-SOD, LacCer-induced ICAM-1 expression was proportionally decreased with an increase in MOI and SOD xpression. This finding suggests that the LacCer-induced stimulation of ICAM-1 expression was mediated by the intracellular generation of O2 . . 9852101
28 Three-fold stimulation of NADPH oxidase activity was observed at 5 mM LacCer, as compared with nonstimulated cell membrane preparations (Fig. 6A). 9852101
29 LacCer stimulated O2 . Production in HUVECs in a concentration-dependent (Fig. 5A) and time-dependent (Fig. 5B) manner. 9852101
30 On the other hand, allopurinol, a specific inhibitor of xanthine oxidase (23), failed to inhibit LacCer-induced O2 . generation (data not shown). 9852101
31 Preincubation of LacCerstimulated/ nonstimulated cell membrane preparations with DPI, a potent NADPH oxidase inhibitor (23), attenuated the LacCer induced increase in NADPH-dependent oxidase activity in the membrane preparations (Fig. 6A). 9852101
32 Moreover, this phenomenon was abrogated by preincubation of cells with N-acetyl-L-cysteine, an antioxidant and a scavenger of free oxygen radicals, as well as DPI, an inhibitor of NADPH oxidase. 9852101
33 LacCer (5 mM) markedly stimulated the adhesion of green fluorescencestained neutrophils to the orange fluorescence-stained endothelial cell monolayer (Fig. 9). 9852101
34 This phenomenon was abrogated by anti-human ICAM-1 antibody in a concentration-dependent fashion (Fig. 10B) 9852101
35 However, exogeneously added SOD did not inhibit the LacCer-induced O2 . levels in endothelial cells and ICAM-1 expression (Fig. 7, A and B). 9852101
36 Preincubation of cells with D-PDMP decreased the synthesis of LacCer ;0.4-fold compared with the control. D-PDMP effect was not altered significantly after stimulation of cells with TNF-a. 9852101
37 Within 5 min, about 1.5-fold stimulation of GalT-2 activity was observed compared with the control. Thereafter, the activity of GalT-2 continued to rise in cells stimulated with TNF-a. 9852101
38 For example, 5 min after the stimulation with TNF-a, a 1.5-fold increase in LacCer synthesis was observed and continued to increase 60 min after stimulation 9852101
39 Preincubation of HUVECs with D-PDMP inhibited TNF-a-induced ICAM-1 expression in a concentrationdependent manner (Fig. 2A). 9852101
40 but not by exogeneous ceramide or glucosylceramide (Fig. 2B), 9852101
41 Moreover, this inhibition by D-PDMP was reversed upon incubation with exogeneous LacCer 9852101
42 In addition, we found that very heavy alcohol consumption—7 or more drinks per day—was associated with an increased risk of ischemic stroke. 9892451
43 In a quadratic model of stroke risk, increased risk of ischemic stroke was statistically significant among those consuming 7 or more drinks per day (OR, 2.96; 95% CI, 1.05-8.29). 9892451
44 The protective effect of alcohol consumption in our subjects was not explained by an elevation in HDL levels.The independent protective effect of moderate alcohol use remained afterHDL was added to our model in an analysis 9892451
45 Moderate alcohol consumption, up to 2 drinks per day, was significantly protective for ischemic stroke after adjustment for cardiac disease, hypertension, diabetes, current smoking, body mass index, and education (odds ratio [OR], 0.51; 95% confidence interval [CI], 0.39-0.67). 9892451
46 In our analyses, much of the protective effect of alcohol on stroke risk was independent of HDL. 9892451
47 These novel inhibitors resulted in the inhibition of glycosphingolipid synthesis in cultured cells at concentrations that did not significantly raise 1ntracellular ceramide levels or inhibit cell growth. 10329660
48 These inhibitors have two identified sites of action: the inhibition of glucosylceramide synthase, resulting in the depletion of cellular glycosphingolipids, and the inhibition of 1-O-acylceramide synthase, resulting in the elevation of cell ceramide levels. 10329660
49 77 ± 13% of the alcohol cleared from plasma was converted directly to acetate entering plasma. Acetate flux increased 2.5-fold after alcohol consumption. 10539756
50 The fractional contribution from DNL to VLDL-triacylglycerol palmitate rose after alcohol consumption from 2 ± 1% to 30 ± 8 %; 10539756
51 Adipose release of nonesterified fatty acids into plasma decreased by 53% 10539756
52 whole-body lipid oxidation decreased by 73%. 10539756
53 The average individual consuming 30 g of alcohol a day showed an 8.82 mg/dl (7.79 to 9.86) increase in apolipoprotein A I concentrations (6.5% increase over baseline; fig 2). 10591709
54 If high density lipoprotein cholesterol, fibrinogen, and triglycerides act independently to raise or lower the risk of coronary heart disease the overall benefit projected from consuming 30 g of alcohol a day would be 24.7% after adjustment for measurement error (table). 10591709
55 The average individual consuming 30 g of alcohol a day would expect an increase in high density lipoprotein cholesterol concentration of 3.99 mg/dl (95% confidence interval 3.25 to 4.73) compared with an individual who abstains—an 8.3% increase from pretreatment values (fig 2). 10591709
56 From 35 data records we found that triglyceride concentrations increased by 0.19 mg/dl per gram of alcohol consumed a day (P = 0.001) and 5.69 mg/dl (2.49 to 8.89) per 30 g consumed a day (5.9% increase over baseline; fig 2). 10591709
57 Clinical trials in patients with and without coronary heart disease and with and without high cholesterol have demonstrated consistently that statins reduce the relative risk of major coronary events by approximately 30% and produce a greater absolute benefit in patients with higher baseline risk. 10637210
58 Complete inhibition of gall-bladder emptying was caused by both oils and n-butylscopolamine. 10641042
59 Peppermint oil and caraway oil show a relaxing effect on the gall-bladder and the former slows small intestinal transit. 10641042
60 Peppermint oil and caraway oil show a relaxing effect on the gall-bladder and the former slows small intestinal transit 10641042
61 The apoA-I concentrations increased by 10% (P50.048) 11067787
62 apoA-II concentrations increased by 17% (P50.005) 11067787
63 There were no significant changes in total cholesterol (P50.30), triglyceride (P50.93), VLDL-C (P50.14), or LDL-C (P50.25) concentrations with alcohol consumption. 11067787
64 As expected, HDL-C concentrations were 18% higher on the EtOH diet than on the control diet (P50.002). 11067787
65 HDL particle size did not change (P50.23) 11067787
66 In contrast, native LDL had no effect on expression of these genes 11149950
67 We found that treatment of phorbol 12-myristate 13-acetate-differentiated human THP-1 macrophages with either acetylated LDL or highly oxidized LDL led to a coordinate induction of apoE, ABCA1, and ABCG1 expression (Fig. 1). 11149950
68 As shown in Fig. 2, treatment of these cells for 48 h with the RXR ligand LG268 (50 nM) 11149950
69 Consistent with the in vitro data presented above, treatment of wild-type mice with either LG268 or the synthetic LXR agonist T0901317 induced expression of apoE 2.5- to 4-fold in adipose tissue but had aminimal effect on expression of this gene in liver (Fig. 6 B and C) 11149950
70 As shown in Fig. 2, treatment of these cells for 48 h with the RXR ligand LG268 (50 nM) or with the LXR ligands 20(S)- or 22(R)- hydroxycholesterol (2 mgyml) resulted in a significant induction in ApoE RNA expression. 11149950
71 A similar induction of apoE expression was observed after treatment of peritoneal macrophages derived from wild-type mice with 22(R)-hydroxycholesterol, lanosterol, or T0901317 (Figs. 6A and 7) 11149950
72 Induction of apoE in adipose tissue by LG268 and T0901317 was abolished in Lxra2y2 Lxrb2y2 mice (Fig. 6B). 11149950
73 In contrast, loss ofLXRexpression had no effect on apoE expression in liver (Fig. 6C). 11149950
74 VSMCs were stimulated with 50 mol/L GM1, GM2, and GM3. As shown in Figure 1B, stimulation of VSMCs with 50 mol/L GM1 and GM2 resulted in a 4.3-fold and 6-fold increase in DNA synthesis, respectively, whereas treatment of the cells with 50 mol/L GM3 caused a 42% reduction of the DNA synthesis. 11711493
75 When VSMCs were treated with 50 mol/L GM1 (Figure 2A) and GM2 (Figure 2B), a marked time-dependent phosphorylation of ERK1/2 was observed, with maximal stimulation at 15 minutes. 11711493
76 Control experiments were performed after stimulation of the PD 098,059–treated cells with 50 ng/mL PDGF-BB. GM1, GM2 (each 50 mol/L), and PDGF-BB caused a 66 12%, 44 6%, and 99 11% increase in cell number, respectively (mean SD, 3 separate independent experiments). 11711493
77 As seen in Figure 7, the Ras inhibitor FTI did not affect the GM1- or GM2- induced ERK1/2 phosphorylation. 11711493
78 To investigate whether GM3 exerts an antagonistic effect on the GM1- and GM2- induced ERK1/2 stimulation, the effect of GM1 and GM2 on ERK1/2 stimulation was examined in VSMCs pretreated with GM3. As demonstrated in Figure 3B, treatment of VSMCs with 50 mol/L GM3 had no effects on the ERK1/2 stimulation induced by GM1 or GM2. 11711493
79 we investigated the effect ofgangliosides on the phosphorylation of ERK1/2 in VSMCs treated with the selective MEK1 inhibitor 2-(2 -amino-3 - methoxyphenyl)-oxanaphthalen-4-one (PD 098,059).30 As shown in Figure 2A and 2B, the ganglioside-induced phosphorylation of ERK1/2 was abolished, whereas the effect of PDGF-BB was remarkably attenuated. 11711493
80 the GM1-induced and the PDGF-BB–induced increase in cell number was markedly reduced from 66 12% and 99 11% to 23 5% and 28 8%, respectively (Figure 8). 11711493
81 Pretreatment of VSMCs with PD098,059 resulted in a complete inhibition of the effect of GM2 and PDGF-BB on JNK activation. GM1 (50 mol/L) also stimulated the phosphorylation of JNK after 15 minutes. 11711493
82 Interestingly, treatment of the VSMCs with 100 nmol/L PTX resulted in an almost complete inhibition of the GM1- and GM2-induced phosphorylation of ERK1/2 (Figure 5). 11711493
83 Control experiments were performed after stimulation of the PD 098,059–treated cells with 50 ng/mL PDGF-BB. GM1, GM2 (each 50 mol/L), and PDGF-BB caused a 66 12%, 44 6%, and 99 11% increase in cell number, respectively (mean SD, 3 separate independent experiments). 11711493
84 Treatment of cells with 20 mol/L PD 098,059 resulted in a complete inhibition of the GM2-induced increase in cell number. 11711493
85 Pretreatment of VSMCs with PD 098,059 resulted in a complete inhibition of the effect of GM2 and PDGF-BB on JNK activation. GM1 (50 mol/L) also stimulated the phosphorylation of JNK after 15 minutes. 11711493
86 EC preincubation with the antioxidant N-acetylcysteine (NAC; 20 mM for 2 h) completely abolished the shear-induced O2(-.) production and significantly inhibited ICAM-1 expression. 11740154
87 EC preincubation with D-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of the GSL glycosyltransferases GlcT-1 and GalT-2, abrogated the shear-induced activation of GalT-2 11740154
88 D-PDMP also abolished the shear-induced O2(-.) production and ICAM-1 expression. 11740154
89 We observed that exposing cultured human umbilical vein ECs (HUVECs) to fluid shear stress (20 dyn/cm(2) for 30 min) activated GalT-2. 11740154
90 Shear stress also increased EC O2(-.) generation, that peaked at 30 min, and surface ICAM-1 protein expression at 6 h post-shear. 11740154
91 Ezetimibe had dramatic inhibitory effects on the development and progression of atherosclerosis in the apoE-/- mice fed all 3 diets. 11742881
92 Changes in body weight and food consumption were similar between the control and ezetimibe-treated groups fed the cholesterol-containing diets (Table). 11742881
93 Ezetimibe was found to significantly inhibit cholesterol absorption in wild-type and apoE-/- mice at 0.3 m-/-g per day. Cholesterol absorption was inhibited by 90% at 3 m-/-g per day in apoE-/- mice and by ?90% at 10 m-/-g per day in C5-/-L -/- and apoE-/- mice (Figure 1). 11742881
94 Figure 3. Effect of ezetimibe on hepatic cholesterol levels in apoE -/- mice. 11742881
95 Figure 2. Effect of ezetimibe on plasma cholesterol and lipoprotein profiles in apoE-/- mice. 11742881
96 When THP-1 macrophages were treated with 200 mM CBE for 4 days, cellular apoE levels were decreased by 10% and this was associated with a 34% increase in cellular cholesterol concentration 11820771
97 Figure 3C shows that both LacCer and CBE decrease the apoE to cholesterol ratio significantly. This is exacerbated by the paradoxical increase in cellular cholesterol levels that accompany the reduced apoE levels (i.e., apoE levels would be expected to increase as cholesterol levels increase). 11820771
98 Cholesterol-loaded foam cells were generated by exposing THP-1 macrophages to acLDL for 36 h. This resulted in a significant increase in cellular apoE 11820771
99 Lactosyl Ceramide Decreases the Levels of apoE Present in THP-1 Cells and Tissue Culture Supernatants 11820771
100 depletion of glucosylceramide-based glycosphingolipids in cultured ECV304 cells with D-t-EtDO-P4 resulted in significantly increased formation of inositol 1,4,5-trisphosphate above base line, and an increased sensitivity of phospholipase C- to bradykinin stimulation. 11886852
101 No significant differences were observed in the cellular expression of phospholipase C- 1, phospholipase C- 1, phospholipase C- 1, annexin II, eNOS III, c-Raf-1, PDGF-R , and Ras between control cells and cells treated with EtDO-P4. 11886852
102 At concentrations where D-t-EtDO-P4 was highly effective in depleting glucosylceramide and lactosylceramide, cell ceramide levels were not significantly elevated in ECV304 cells (Fig. 2). 11886852
103 treatment of cells with 100 nM D-t-EtDO-P4 resulted in maximal decrements of 99.9% glucosylceramide mass and 99.7% lactosylceramide mass, respectively. 11886852
104 100 nM D-t-EtDO-P4 induced a significant increase in the tyrosine phosphorylation of phospholipase C- (Fig. 5A). 11886852
105 No changes in sphingomyelin content were detected in cells treated with D-t- EtDO-P4 (data not shown). 11886852
106 When ECV304 cells were simultaneously incubated with D-t-EtDO-P4 and exogenously added glucosylceramide (1 M), the effect of D-t-EtDO-P4 on the induction of tyrosine phosphorylation of phospholipase C- was abrogated (Fig. 5B), 11886852
107 Cooling of gastrointestinal smooth muscle preparations induces graded myogenic contractions inversely proportional to the temperature. 11903504
108 The presence of CD14 in lipid rafts after LPS stimulation was also investigated. CD14 was found to be present in lipid rafts after LPS stimulation (Fig. 2B). Other LPS receptors such as hsp70 and hsp90 that were associated with lipid rafts prior to LPS stimulation were still present in microdomains after LPS treatment (Fig. 2C,D). 12045230
109 The presence of CD14 in lipid rafts after LPS stimulation was also investigated. CD14 was found to be present in lipid rafts after LPS stimulation (Fig. 2B). Other LPS receptors such as hsp70 and hsp90 that were associated with lipid rafts prior to LPS stimulation were still present in microdomains after LPS treatment (Fig. 2C,D). 12045230
110 In contrast CXCR4, GDF5 and TLR4, which were not associated with lipid rafts prior to LPS stimulation, were recruited in microdomains following LPS treatment (Fig. 2E,F,G) 12045230
111 we found that JNK/SAPK was concentrated in lipid rafts only following LPS stimulation (Fig. 8E), lending more support to the idea that LPS signalling occurs within lipid rafts. 12045230
112 We found that we could detect MyD88 in fractions two to three of LPS-stimulated MonoMac-6 cells, suggesting that it is indeed associated with lipid rafts (Fig. 8A), whereas MyD88 was not detected in fractions isolated from non-stimulated MonoMac-6 cells (Fig. 8B). 12045230
113 MCD was found to inhibit CD14 (Fig. 5B), hsp70, hsp90, CXCR4, GDF5 and TLR4 association with lipid rafts. Similar results were obtained when MonoMac-6 cells were used. 12045230
114 Pre-incubation of monocytes with either nystatin or MCD dramatically inhibited LPS-induced TNF-a secretion (Fig. 6D) 12045230
115 While further investigation is necessary, the results in this case suggest one of the mechanisms by which ECPO improves IBS symptoms is antimicrobial activity in the small intestine. 12410625
116 Plasma C-reactive protein and fibrinogen levels were decreased by 35% (P ¼0.02) and 12.4% (P 0.001), respectively, after 3 weeks’ consumption of beer, as compared to no-alcohol beer consumption. 12428180
117 After 3 weeks’ daily beer consumption serum HDL-cholesterol concentrations were significantly increased by 11% (P 0.001), as compared to no-alcohol beer consumption (Table 2). 12428180
118 Serum triglyceride levels were not affected (Table 2). 12428180
119 Specifically, the lowest baseline CRP levels were observed among participants who reported moderate alcohol use (group 4: 5 to 7 drinks weekly; CRP, 1.60 mg/L; IQR, 0.80 to 3.30 mg/L). 12551869
120 cells were treated with 50 uM CBE, an inhibitor of lysosomal glucocerebrosidase (25), for 24 h. This resulted in approximately a 2-fold increase in endogenous GlcCer levels (Table I), 12657626
121 HSFs were incubated for 5 h with exogenous LacCer, globoside, GM1, or SM, similar to that seen when cells were incubated in LPDS medium, whereas little SREBP-1 cleavage was seen in control samples that were not incubated with exogenous SLs. 12657626
122 FIG. 1. Exogenous SLs elevate cholesterol levels in normal HSFs 12657626
123 LDLR Expression but Not LDL Internalization Is Increased in SL-treated Cells 12657626
124 Finally, upon triggering of HT1080 cells with FasL, neither Fas nor any of the molecules involved in the early steps of the apoptotic signaling pathway, such as FADD and caspase-8, translocated to lipid rafts (Figure 2B). 12753742
125 TNF -induced phosphorylation of I B was observed 2 min after stimulation of HT1080 cells, whereas FasL stimulation had noeffect (Figure 6A). 12753742
126 In contrast, FADD and caspase-8, which are involved in the apoptotic pathway, were not found in lipid rafts upon TNF stimulation (Figure 2A). 12753742
127 Early events occurring after TNFR1 activation are the recruitment of the adaptors TRADD and TRAF2, as well as the kinases RIP, IKK , All these proteins translocated to microdomains after 2 to 10 min of TNF stimulation (Figure 2A). 12753742
128 Association of TNFR1 with lipid rafts was greatly inscreased upon receptor engagement (Figure 2A). A significant translocation was already observed as early as 2 min after TNF addition 12753742
129 TNFR1 and RIP Are Ubiquitylated in Lipid Rafts 12753742
130 Similarly, DPPE that blocks activation-induced recruitment of signaling molecules to lipid rafts also impaired I B phosphorylation (Figure 6A). 12753742
131 Lipid Rafts Are Essential for Ubiquitylation, and Translocation Precedes Ubiquitylation 12753742
132 As demonstrated in Figure 6A, disruption of lipid rafts by MCD mediated cholesterol depletion completely abrogated TNF -induced phosphorylation of I B . 12753742
133 Moderate alcohol consumption may have a beneficial impact on the long term prognosis following successful coronary stenting. The extent of this effect is positively related to preprocedural inflammatory status 15020518
134 Statins can lower LDL cholesterol concentration by an average of 1.8 mmol/l which reduces the risk of IHD events by about 60% and stroke by 17%. 15125495
135 ABCA1-dependent cholesterol efflux from J774 mouse macrophages was increased by 17.5% ( P 0.027) compared with water consumption. 15231854
136 Plasma capacity to induce cholesterol efflux from Fu5AH cells increased by 4.6% (P 0.002). 15231854
137 ABCA1 and ABCG1 mRNA levels were significantly increased by LXR agonist treatment in bone marrow cells from C57Bl/63 LDLR / and LDLR / 3 LDLR / mice, 15539622
138 LXR agonist treatment for 6 weeks significantly reduced atherosclerosis in mice with macrophages that express LXR (57% reduction in C57Bl/63LDLR / and 68% reduction in LDLR / 3 LDLR / , Figure 4B 15539622
139 whereas bone marrow cells from LXR / 3 LDLR / mice showed no induction of these mRNA transcripts (Figure 4C and 4D). 15539622
140 LXR agonist treatment for 6 weeks significantly reduced atherosclerosis in mice with macrophages that express LXR (57% reduction in C57Bl/63LDLR / and 68% reduction in LDLR / 3 LDLR / , Figure 4B 15539622
141 In contrast, LXR agonist treatment had no inhibitory effect on atherosclerosis in mice with macrophages devoid of LXRs (LXR / 3 LDLR / , Figure 4B). 15539622
142 LXR agonist treatment resulted in a 70% reduction of lesion area in comparison to vehicle-treated controls (Figure 1B, middle versus bottom, and 1C), demonstrating a preventive effect of the LXR agonist on lesion development. 15539622
143 LXR agonist treatment resulted in significant 62% reduction in lesion areas compared with mice assessed at baseline (Figure 1B, top versus middle and bottom, and 1C), demonstrating that the LXR agonist induced regression of preexisting atherosclerotic lesions. 15539622
144 There were no significant alterations in plasma total or HDL cholesterol levels in any of the BMT conditions treated with the LXR agonist, relative to their vehicle-treated controls, 15539622
145 LXR agonist treatment significantly reduced plasma total cholesterol levels by 28% (Figure 3C) 15539622
146 In this BMT condition, mice treated with the LXR agonist had significantly lower plasma cholesterol levels than did their vehicle-treated LDLR / 3 LDLR / controls 15539622
147 There were no significant alterations in plasma total or HDL cholesterol levels in any of the BMT conditions treated with the LXR agonist 15539622
148 along with a nonsignificant reduction of HDL cholesterol after 6 weeks of treatment (Figure 3D) 15539622
149 In addition, LXR agonist treatment significantly increased ABCA1 mRNA levels in atherosclerotic lesions by 67% (Figure 3A) 15539622
150 There was also a slight ( 10%) increase in ABCG1 mRNA levels in the atherosclerotic lesions, which did not attain statistical significance (data not shown). 15539622
151 Expression of the macrophage marker CD68 in these aortic lesions was significantly reduced by 45% in LXR agonist–treated mice compared with vehicle-treated controls (Figure 3A) and consistent with the reduction in macrophage-positive immunostaining (Figure 2A and 2B). 15539622
152 This effect was accompanied by a 34% increase in collagen content of lesions in LXR agonist–treated mice (Figure 2C versus 2D and Table 1). 15539622
153 Immunostaining of aortic root lesions with the macrophagespecific antibody MOMA-2 showed a significant 48% reduction of macrophage-positive areas in LXR agonist–treated mice (Figure 2A versus 2B and Table 1). 15539622
154 As expected, the LXR agonist increased plasma triglyceride concentrations (Figure 3E) 15539622
155 Oil red O staining of en face aortas revealed that myriocin treatment reduced atherosclerotic lesion coverage in Western diet–fed apoE-KO mice by 93% (Figure 6). Growth of atherosclerotic lesions in the brachiocephalic artery and aortic valve area was also significantly inhibited (Figure 7). In the brachiocephalic artery, myriocin treatment led to a 76% decrease in lesion area and a 74% decrease in macrophage area. 15545514
156 On the other hand, myriocin treatment reduced ceramide levels by 60%, which is comparable to the standard chow–fed group (Figure 3B). 15545514
157 Myriocin lowered plasma cholesterol and TGs by 41% and 45%, respectively (Figure 4). 15545514
158 Myriocin lowered plasma cholesterol and TGs by 41% and 45%, respectively (Figure 4). In addition, myriocin lowered -VLDL and LDL cholesterol levels by 51% and 35%, respectively. 15545514
159 In contrast, HDL cholesterol content was increased by 54% (Figure 5). 15545514
160 In addition, myriocin lowered plasma apoB levels, which were comparable to those in the standard chow–fed group (T.-S. Park, unpublished data, 2004). Because plasma apoB levels, especially apoB100 levels, 15545514
161 Myriocin treatment lowered SM accumulation in the liver by 45% compared with Western diet–fedapoE-KO mice (Figure 2C). 15545514
162 Myriocin decreased SM levels by 20% (Figure 2E) 15545514
163 The present evidence from observational studies suggests an 30% reduced risk of type 2 diabetes in moderate alcohol consumers, whereas no risk reduction is observed in consumers of 48 g/day. 15735217
164 Similar to the effect of LacCer, treatment of fibroblasts with CBE under conditions shown previously to promote accumulation of both GSLs and cholesterol (2, 4) significantly inhibited apoA-I-dependent cholesterol efflux (Fig. 1B) 15890646
165 Similar to the effect of CBE on fibroblasts, treatment of MDMs with 50 M CBE inhibited subsequent cholesterol efflux to apoA-I (7.1 0.82% versus 3.7 0.38%, mean S.E., n 3; p 0.05) as assessed at the 8-h time point 15890646
166 To examine whether LacCer inhibits fibroblast cholesterol efflux specifically, we analyzed apoA-I-mediated phospholipid efflux. LacCer significantly inhibited phospholipid efflux to apoA-I, although the magnitude of this inhibition was not as marked as that seen for cholesterol (Fig. 2A). 15890646
167 When the SLSD and control fibroblasts were compared, we found no correlation between the levels of ABCA1 mRNA expression and the rate of cholesterol efflux 15890646
168 Treatment of fibroblasts with 40 M LacCer did not significantly reduce ABCA1 mRNA levels (n 4) overall 15890646
169 The level of cellsurface ABCA1 expression was reduced, however, by as much as 50% after LacCer treatment (Fig. 3B) 15890646
170 Treatment of human fibroblasts with 40 mM LacCer inhibited apoA-I-mediated cholesterol efflux while having no effect on the low levels of basal efflux observed in the presence of albumin (Fig. 1A). 15890646
171 LacCer did not inhibit cholesterol efflux to either PLVs or MBCD, 15890646
172 it did not significantly promote apoA-I-dependent cholesterol or phospholipid efflux (Fig. 11). 15890646
173 Although NB-DNJ reduced cellular GSL levels and also increased cholesterol solubilityto an extent even greater than observed with PDMP treatment, it did not significantly promote apoA-I-dependent cholesterol or phospholipid efflux (Fig. 11). 15890646
174 50 M NB-DNJ reduced GSL levels by 43% (Fig. 11A). This level of GSL depletion was more effective than that achieved using PDMP 15890646
175 At 10 M, PDMP increased ABCA1 mRNA levels by up to 2.7-fold (2.1 0.3-fold, mean S.E., n 3; p 0.05) 15890646
176 The levels of cell-surface ABCA1 expression were increased to a similar degree by PDMP, indicating that PDMP acts primarily by regulating ABCA1 expression and not by modulating trafficking to the cell surface (Fig. 9C). 15890646
177 At 10 M, PDMP increased cholesterol efflux to apoA-I by up to 6-fold (2.8 0.8-fold increase above apoA-I alone, mean S.E., n 7) as assessed at the 8-h time point while having no effect on basal efflux (Fig. 7). 15890646
178 PDMP Promotes ApoA-I-dependent Cholesterol Efflux from Human Monocyte-derived Macrophages 15890646
179 At 10 M, PDMP increased cholesterol efflux from MDMs and MDM foam cells to apoA-I by 2-fold as assessed at the 8-h time point (Table I) 15890646
180 Interestingly, although PDMP did not significantly promote basal cholesterol efflux from fibroblasts 15890646
181 it did increase basal efflux from both MDMs and acLDL-loaded MDMs (Fig. 7; cf. Table I 15890646
182 Confirming previous studies, treatment of fibroblasts with PDMP for 72 h inhibited cellular GSL levels as determined by binding of fluorescently labeled CTxB to cell-surface GM1 (Fig. 6) 15890646
183 At 10 M, PDMP did not affect cholesterol efflux to either PLVs or MBCD (Fig. 8). These data indicate that PDMP promotes cholesterol efflux through an ABCA1-dependent pathway 15890646
184 Eight out of 12 placebo controlled studies show statistically significant effects in favor of PO. Average response rates in terms of "overall success" are 58% (range 39-79%) for PO and 29% (range 10-52%) for placebo. 16121521
185 Optimal pH triggered enteric coated formulations start releasing PO in the small intestine extending release over 10-12 h thus providing PO to the target organ in irritable bowel syndrome, i.e. the colon. 16121522
186 With one exception, which show an unexplained potentiation of neostigmine stimulated colon activity, all other studies result in effects, indicating a substantial spasmolytic effect of PO of the smooth muscles of the gastrointestinal tract. 16121522
187 Statin therapy can safely reduce the 5-year incidence of major coronary events, coronary revascularisation, and stroke by about one fifth per mmol/L reduction in LDL cholesterol, largely irrespective of the initial lipid profile or other presenting characteristics. 16214597
188 Thisindicated that a homozygous Sptlc1 deficiency caused embryonic death, as expected 16216550
189 We found that liver Cer and Sph but not S1P were significantly decreased in both Sptlc1+/ and Sptlc2+/ mice, compared with WT animals 16216550
190 We found that plasma Cer, S1P, and Sph were significantly decreased in both Sptlc1+/ and Sptlc2+/ mice, compared with WT animals (Table 2) 16216550
191 Sptlc1 and Sptlc2 deficiency had no significant effect on phospholipids, cholesterol, or triglyceride 16216550
192 Sptlc1 and Sptlc2 deficiency had no significant effect on phospholipids, cholesterol, or triglyceride 16216550
193 liver total SM did not change 16216550
194 while plasma total SM did not change (Table 3) 16216550
195 Furthermore, liver SPT activity and Sptlc1 protein mass in Sptlc1+/ mice were decreased by 45% and 50%, respectively 16216550
196 Real-time PCR analysis demonstrated that there was a 44% reduction of Sptlc1 mRNA in heterozygous Sptlc1-deficient (Sptlc1+/ ) mouse liver, in comparison with WT mice. 16216550
197 This indicated that a complete Sptlc2 deficiency also caused embryonic death 16216550
198 Sptlc2+/ mouse liver has 60% less SPT activity and 70% less Sptlc2 mass and than the WT 16216550
199 Real-time PCR analysis also showed that Sptlc2+/ mice have about 57% less Sptlc2 mRNA in their livers than the WT 16216550
200 These samples present a reduction of the activity similar to that obtained with NB-DNJ treatment. 16959503
201 Cells transfected with shRNA11 showed a 58% GCS activity compared to that of wild-type, while those transfected with shRNA-68 had a GCS activity of 50% wild-type. Cells transfected with the vector alone (psiRNA) showed an activity of 75% wild-type. 16959503
202 2 of the 4 siRNAs tested, siRNA-11 and siRNA-68, were able to considerably reduce the expression of GCS in HeLa cells (3- and 4-fold, respectively). siRNA-34 and siRNA-48 showed no effect. 16959503
203 We decided not to continue using WEHI-3B cells for the rest of the study based on the lack of consistent results they provided. siRNA 16959503
204 Fig. 3A shows GCS activity from HeLa cells transfected with different amounts of siRNA-11 (8–80 nM final concentration). Any amount of siRNA-11 used reduces GCS activity. The transfection of 8 or 16 nM of siRNA reduces control activity in approximately 1.7-fold (56%±0.9 and 60%±7.5 respectively), while transfections of 24 or 32 nM produce a 3.2-fold reduction of GCS activity (32%±1.7 and 31%±4.0, respectively). These samples present a reduction of the activity similar to that obtained with NB-DNJ treatment. The activity shown by cells transfected with 40, 56 or 80 nM of siRNA is negligible. 16959503
205 siRNA-34, which has 16 out of of 20 nucleotides homologous to the mouse sequence, was used as a negative control. This siRNA was unable to reduce Ugcg expression in RAW264.7 cells (data not shown) as expected. 16959503
206 RAW264.7 were transfected with different amounts of siRNA-68 and Ugcg RNA levels were quantified by Real Time PCR, 24 h after transfection (Fig. 5). A reduction of about 60–70% was obtained for all siRNA concentrations. Similar levels of inhibition were still observed after 48 h (data not shown). 16959503
207 After adjustment for a series of coronary risk factors, alcohol consumption $15.2 g/d was associated with a 39% reduction in the 13-y risk of IHD [relative risk (RR) of IHD ¼ 0.61, P ¼ 0.02]. 17116715
208 At 20 weeks, FTY720 treatment dramatically reduced atherosclerotic lesion volume by 61.5% in male (0.04 0.01 mm3 compared with 0.11 0.02 mm3 in controls, P 0.05) and 45.7% in female mice (0.03 0.01 mm3 compared with 0.06 0.01 mm3 in controls, P 0.05) (Figure 1). FTY720 also reduced the atherosclerotic lesions in the aortic root: the volume fraction of the lesion was reduced by 46.3% (0.16 0.02 mm3 in FTY-treated mice compared with 0.36 0.04 mm3 in controls, P 0.05; Figure 2) 17158351
209 Chronic FTY720 treatment significantly reduced peripheral blood lymphocyte counts by 56.6% in FTY-treated mice compared with controls (0.9 0.13 103/mm3 versus 2.0 0.3 103/mm3) without an effect on circulating levels of other blood cells or cholesterol levels 17158351
210 Collagen content was 63.5% lower in lesions of FTY-treated mice (12.60 1.30%) compared with controls (34.58 2.06%). Altogether, treatment of ApoE / mice with FTY720 resulted in a dramatic reduction of lesion size, monocyte/macrophage content and collagen deposition. 17158351
211 Real time PCR did not reveal any differences in IL-10 or IL-12 gene expression (Table). The expression of two other important cytokines, IL-4 and IFN , in elicited peritoneal macrophages was not affected either (Table). 17158351
212 Chronic FTY720 treatment significantly reduced peripheral blood lymphocyte counts by 56.6% in FTY-treated mice compared with controls (0.9 0.13 103/mm3 versus 2.0 0.3 103/mm3) 17158351
213 41.8% reduction of macrophage content in lesions of FTY-treated mice (18.44 1.69%) compared with controls (31.70 1.88%). 17158351
214 Stimulation of deendothelialized rat aortae with thrombin (4U/mL) for 24 hours induced a robust secretion of MCP-1 into the supernatants (Figure 5A). Coincubation with the phosphorylated, biologically active form of FTY720 (FTY720P) dose-dependently inhibited the MCP-1 release (Figure 5A) 17158351
215 In cultured rat VSMCs, FTY720P also inhibited thrombin-induced MCP-1 release (data not shown) 17158351
216 Using aortae from mice deficient for the S1P3 sphingolipid receptor, we identified it as responsible for mediating the effect of FTY720P: in these ,FTY720P did not attenuate thrombin-induced MCP-1 secretion while it still inhibited MCP-1 release in wild-type controls (Figure 5C). 17158351
217 Using aortae from mice deficient for the S1P3 sphingolipid receptor, we identified it as responsible for mediating the effect of FTY720P: in these, FTY720P did not attenuate thrombin-induced MCP-1 secretion while it still inhibited MCP-1 release in wild-type controls (Figure 5C) 17158351
218 Stimulation of deendothelialized rat aortae with thrombin (4U/mL) for 24 hours induced a robust secretion of MCP-1 into the supernatants (Figure 5A). Coincubation with the phosphorylated, biologically active form of FTY720 (FTY720P) dose-dependently inhibited the MCP-1 release (Figure 5A) 17158351
219 In cultured rat VSMCs, FTY720P also inhibited thrombin-induced MCP-1 release (data not shown) as well as MCP-1 mRNA expression levels: the 12-fold induction of MCP-1 mRNA after 4 hours of thrombin 17158351
220 as well as MCP-1 mRNA expression levels: the 12-fold induction of MCP-1 mRNA after 4 hours of thrombin stimulation was potently inhibited by FTY720P with an IC50 of 8.4 0.2 log mol/L (Figure 5B) 17158351
221 Vasodilation in response to acetylcholine in aortae from FTY720-treated mice was unaffected (maximal dilatation: 94.21% in FTY720-treted mice versus 90.90% in controls, and EC50: 7.3 0.1 log mol/L in FTY720-treated mice versus 7.2 0.1 log mol/L in controls; data not shown) 17158351
222 In contrast, SMC content did not differ significantly between the two groups (9.00 0.90% in FTY-treated mice compared with 6.43 0.67% in controls) 17158351
223 The T-lymphocyte content of the lesions was low and indistinguishable between the groups (17.39 2.51 cells/mm3 in FTY-treated mice compared with 11.3 2.04 cells/mm3 in controls) 17158351
224 Interestingly, aortae of mice chronically treated with FTY720 exhibited a similar vasodilator response to FTY720P as the controls: maximal dilatation was 53.26% in FTY720-treated mice (EC50: 7.2 0.2 log mol/L) and 50.87% in controls (EC50: 7.1 0.1 log mol/L; Figure 5D) 17158351
225 high doses of FTY720 (approximately 0.4 mg/kg per day) led to significant reductions in lesion area compared with control mice. A similar pattern was observed for the brachiocephalic artery plaques 17242282
226 No significant changes (by repeated-measures ANOVA) in the plasma lipid profile were observed between treatment groups (Figure 3D). 17242282
227 As shown in Figure 4, the relative amount of lymphocytes was markedly decreased, whereas that of neutrophils was relatively increased in LDL-R / mice treated with high doses of FTY720 17242282
228 The hepatic ceramide content of C57Bl/6J mice was not changed by the AMP-DNM diet. 17287460
229 Similar effects on sphingolipids were observed in muscle tissue (Table 2). 17287460
230 Two weeks’ treatment of ob/ob mice with 25 mg AMP-DNM kg 1 day 1 did not result in any significant changes in ceramide concentrations in muscle or liver. In sharp contrast, glucosylceramide content of muscle and liver from ob/ob mice decreased by 45 23 and 45 11%, respectively, with AMP-DNM, reaching values similar to those in wild-type animals (Table 2) 17287460
231 In muscle tissue of ob/ob mice, glucosylceramide was again elevated compared with wildtype mice (P 0.031); however, ceramide concentrations were similar (Table 2). 17287460
232 Table 3 shows that treatment with a dose of 25 mg AMP-DNM kg body wt 1 day 1 resulted in a clear reduction in hepatic concentrations of glucosylceramide and gangliosides but did not change ceramide level 17287460
233 Similar observations were made for muscle (not shown). 17287460
234 Quantification by HPLC revealed that ceramide and gangliosides were elevated by TNF- . The increase of the gangliosides GM3 and GM2 induced by the cytokine, but not that of ceramide, was counteracted by the iminosugar AMP-DNM (Table 1). 17287460
235 Similar effects on shingolipids were observed in muscle tissue (Table 2). 17287460
236 Table 3 shows that treatment with a dose of 25 mg AMP-DNM kg body wt 1 day 1 resulted in a clear reduction in hepatic concentrations of glucosylceramide and gangliosides but did not change ceramide levels. 17287460
237 liver glucosylceramide was reduced by 41 5%. 17287460
238 led to a pronounced reduction in blood glucose concentrations (P 0.008) (Fig. 3B) 17287460
239 Marked improvements in fasted and nonfasted blood glucose became already apparent within 1 week of treatment (Fig. 4A and B). Around 3 weeks of treatment, the ZDF rats receiving 25 mg AMP-DNM kg 1 day 1 showed close to normal fasted and nonfasted blood glucose concentrations, but, subsequently, blood glucose levels gradually rose 17287460
240 Comparable treatment of normal C57Bl/6J mice with AMP-DNM did not result in reduction of blood glucose or A1C 17287460
241 Quantification of the ganglioside GM3 by HPLC revealed that the lipid was reduced by 28 6% in liver of AMP-DNM–treated mice 17287460
242 The A1C concentration was 4.82 0.85% in the treated ob/ob mice compared with 6.82 0.88% in the untreated animals and 4.31 0.66% in corresponding wild-type mice. 17287460
243 Triglyceride concentrations in livers of AMP-DNM–fed ob/ob mice were significantly decreased from 107 13 to 80 11 nmol/mg liver (P 0.035) 17287460
244 Analysis of glycosphingolipids revealed that the hepatic concentration of glucosylceramide was higher in ob/ob mice (115 16 nmol/liver) compared with matched wild-type animals (85 15 nmol/liver; P 0.045) (Table 2) 17287460
245 A 4 weeks treatment with peppermint oil improves abdominal symptoms in patients with irritable bowel syndrome 17420159
246 There were no changes in atherosclerotic lesions in early and established atherosclerosis 17761943
247 However, there was a 2.4-fold increase in total serum cholesterol levels (supplemental Table I) with a marked elevation of the VLDL fraction (Figure 1A).Triglyceride levels were unaltered 17761943
248 Figure 1C and 1D illustrates that HMGCoA reductase transcript levels normalized to -actin were upregulated (1.8-fold) in liver tissue of FTY720-treated animals (1.20 0.15 versus 0.68 0.05; P 0.03 17761943
249 FTY720 administration caused a 70% reduction in peripheral blood lymphocyte counts but did not influence other blood cells such as monocytes (supplemental Table I). 17761943
250 Administration of FTY720 was associated with a significant increase in plasma levels of the natural analogue of FTY720-P— sphingosine-1-phosphate (S1P)—in the treated group (1318 39.0 ng/mL versus 1158 54.9 ng/mL, P 0.0476; Figure 1B) 17761943
251 Figure 1C and 1D illustrates that HMGCoA reductase transcript levels normalized to -actin were upregulated (1.8-fold) in liver tissue of FTY720-treated animals (1.20 0.15 versus 0.68 0.05; P 0.03 17761943
252 Figure 1C and 1D illustrates that HMGCoA reductase transcript levels normalized to -actin were upregulated (1.8-fold) in liver tissue of FTY720-treated animals (1.20 0.15 versus 0.68 0.05; P 0.03 17761943
253 These data show a discoordinate modulation of lymphocyte populations with a preserved overall balance of pro-and antiatherogenic T cells 17761943
254 The likelihood of having extensive coronary calcification on computerized tomography scanning was reduced in those who consumed 1 to 2 drinks daily. Data from Vliegenthart et al. (17). 17825708
255 Alcohol was associated with a reduction in C-reactive protein (CRP), particularly at 5 to 7 drinks per week. Reproduced with permission from Albert et al. (31). 17825708
256 The relationship of daily alcohol consumption to the relative risk of all-cause mortality in men and women. Reproduced with permission from DiCastelnuovo et al. (2). 17825708
257 A large meta-analysis of 370,000 individuals followed for 12 years showed a 30% reduction in new diabetes in people who consumed 1 to 2 drinks per day (Fig. 7) 17825708
258 In a recent study of 1,966 men followed for 13 years, alcohol intake of approximately 1 drink daily was associated with a 40% decreased risk of having the metabolic syndrome (39). 17825708
259 Moderate alcohol intake (1 to 2 drinks per day) reduced the rate of myocardial infarction (MI) in this group of 8,867 middle-aged males already following healthy lifestyle recommendations (6). 17825708
260 Relationship between daily alcohol and ischemic stroke. This was fully adjusted for the usual stroke factors. OR odds ratio. Reproduced with permission from Sacco et al. (12). 17825708
261 Together with the lipopolysaccharide- detecting receptor TLR4, activation of the nucleic acid sensors TLR7 and TLR9 in DCs were particularly potent in stimulating iNKT cells to produce IFN-g, but not IL-4. 17950005
262 iNKT cell activation in response to TLR9 stimulation required combined synthesis of type I interferon and de novo production of charged b-linked glycosphingolipid(s) by DCs 17950005
263 whereas apoB and ABCA1 mRNA levels were unaltered (Fig. 5A) 17978313
264 Hepatic apoA-I mRNA expression was increased significantly (2.6-fold) by myriocin 17978313
265 hepatic and plasma apoA-I concentrations were increased significantly (45% and 38%, respectively) in the myriocin-treated mice 17978313
266 whereas apoB and ABCA1 mRNA levels were unaltered (Fig. 5A) hepatic and plasma apoA-I concentrations were increased significantly (45% and 38%, respectively) in the myriocin-treated mice 17978313
267 Myriocin treatment did not completely halt the progression of atherosclerosis over this time; however, the increase in relative lesion area observed in mice fed regular chow for 60 days was inhibited by 60% with oral myriocin treatment (Fig. 3A) 17978313
268 TABLE 1. Plasma lipid and glucose concentrations 17978313
269 In addition, statistically significant reductions in hepatic cholesterol (10%) and TG (30%) concentrations were also observed in the myriocin treated mice compared with the control animals 17978313
270 Most notably, compared with the mice switched to regular chow alone, the myriocin-treated group showed significant decreases in cholesterol, TG, SM, and GSL concentrations (57, 18, 54, and 21%, respectively) 17978313
271 The demonstration that oral delivery of myriocin also significantly reduced plasma GSL levels confirms and extends our recent work showing that intraperitoneally administered myriocin reduces plasma GSL levels in apoE2/2 mice fed a HF diet 17978313
272 Myriocin treatment (group III compared with group II) reduced hepatic SM concentration by 39% (Fig. 4) 17978313
273 coating apoptotic murine carcinoma cells from the colon and kidney with SM4s promoted their phagocytosis by murine macrophages up to 3-fold ex vivo and in vivo. 17982067
274 This increased capacity was specifically inhibited by preincubation of macrophages with oxidized or acetylated low density lipoprotein and maleylated albumin, indicating involvement of scavenger receptors in this interaction. 17982067
275 The uptake of SM4s-coated apoptotic cells significantly enhanced macrophage production of TGF- 1, expression of P-selectin, and secretion of IL-6. 17982067
276 Atherosclerotic lesions were detected at all four sites. However, no significant difference in lesion size was observed between the control and EtDO-P4-treated groups (Fig. 3) 18467744
277 EtDO-P4 administration did not result in significant changes in plasma cholesterol or TG levels, whereas plasma SM levels were reduced by 23.7% 18467744
278 Although we have focused on plasma GSL levels in this study, previous work has shown that EtDO-P4 administered as a PLV complex (10 mg/kg intraperitoneally every 12 h for 8 weeks) also reduced tissue GSL levels in murine liver, kidney, heart, and brain by 34%, 49%, 40%, and 16%, respectively 18467744
279 plasma GlcCer and LacCer concentrations were reduced by 49% and 56%, respectively, in the EtDO-P4-treated mice 18467744
280 Induction of apoAI and lecithin:cholesterol acytransferase (LCAT) in the liver by myriocin was associated with an increased HDL 18611440
281 Lesion area and macrophage area were also diminished in the cuffed femoral artery of ApoE KO mice 18611440
282 myriocin reduced the atherosclerotic lesion area in aortic root by ∼37% compared with the regression (24weeks) and progression controls (36weeks) 18611440
283 Downstream products in sphingolipid biosynthesis, ceramide and SM levels were also lowered by myriocin significantly (Table 1) 18611440
284 Myriocin treatment lowered plasma cholesterol and TG levels in a dose-dependent manner 18611440
285 Myriocin significantly lowered plasma levels of cholesterol and TG than those of 24- and 36-week-old control group (Table 2). 18611440
286 However, in our preliminary rat study, 0.3 mg/kg/day myriocin administration by I.P. injection or oral gavage for 4 weeks resulted in a similar lipid-lowering effect without gastrointestinal toxicity (K. Zimmerman and S. Karathanasis, Eli Lilly, unpublished observations) 18611440
287 in contrast, LDL- and VLDL-cholesterolwere lowered dramatically by myriocin (Table 2). 18611440
288 myriocin treatment reduced cholesterol contents in VLDL and LDL and elevated HDL-cholesterol 18611440
289 Myriocin raised HDL-cholesterol by 34% which is comparable to the progression control (24weeks). 18611440
290 in contrast, LDL- and VLDL-cholesterol were lowered dramatically bymyriocin (Table 2). 18611440
291 The synthesis of PC was reduced in myriocin-treated apoE KO mice and the plasma SM/PC ratio, a risk factor for atherosclerosis 18611440
292 myriocin dramatically lowered plasma SM levels in a dose-dependent manner (Table 1). At the highest dose of myriocin (1 mg/kg/day), plasma SM levels were reduced by 70% when compared with no-myriocin control 18611440
293 Myriocin decreased precursor SREBP-1 and mature SREBP-1 protein levels (Fig. 3A). mRNA analysis by RT-PCR showed decrease in SREBP-1 protein levels was due to suppression of SREBP-1c in the liver (Fig. 3B). In contrast, expression of SREBP-1a (data not shown) and SREBP-2 was not significantly affected by myriocin LDLR +/- mouse 18611440
294 In the liver, ABCG1 and CYP7A1 mRNA expression levels were significantly increased by 2.3- and 2.8-fold, respectively, whereas ABCA1, ABCG5, and ABCG8 mRNAs remained unchanged (Fig. 8A). 18812595
295 No significant differences were observed in ABCA1 and ABCG1 mRNA levels (Fig. 8B) 18812595
296 In the ileum, ABCA1, ABCG1, and ABCG5 mRNAs remained unchanged upon DMHCA administration (Fig. 8C), while SREBP1c was significantly decreased by 53%. 18812595
297 Administration of DMHCA to chow and WTD increased ABCA1 mRNA levels in the aortae by 1.4- and 1.7-fold, respectively 18812595
298 MPM isolated from C57Bl/6 mice and foam cells were incubated in the absence or presence of 2.5 mM DMHCA for 24 h. As expected, DMHCA was found to stimulate ABCA1 mRNA expression in MPM and in aggregated LDL-laden foam cells in vitro by 7.0- and 4.8-fold, respectively, compared with untreated macrophages and foam cells (Fig. 1) 18812595
299 Additionally, the expression levels of ABCA1, ABCG1, ABCG5, and ABCG8 were significantly increased by 1.9-, 2.1-, 3.5- and 2.8-fold, respectively. 18812595
300 Additionally, the expression levels of ABCA1, ABCG1, ABCG5, and ABCG8 were significantly increased by 1.9-, 2.1-, 3.5- and 2.8-fold, respectively. 18812595
301 Additionally, the expression levels of ABCA1, ABCG1, ABCG5, and ABCG8 were significantly increased by 1.9-, 2.1-, 3.5- and 2.8-fold, respectively. 18812595
302 LDLR and acetyl- CoA carboxylase (ACC) were markedly decreased by 34% and 24%, respectively (Fig. 8B) 18812595
303 Quantification of Oil Red O-stained aortic valve sections revealed that treatment with DMHCA resulted in a significant 45.9% and 48.4% decrease in lesion area in male (Fig. 7B) and female (Fig. 7C) apoE-deficient mice when compared with controls. To further document positive effects of DMHCA on atherosclerosis, Oil Red O-stained lesions in en face preparations of aortas were quantified. Treatment with DMHCA led to a significant reduction in lesion area of male and female apoE-deficient mice compared with controls (27.7% and 29.5%, respectively) (Fig. 7D, E). 18812595
304 plasma TC levels were significantly reduced by 32% in mice fed chow diet plus DMHCA but remained unchanged in mice fed WTD plus DMHCA when compared with controls. 18812595
305 Hepatic TC concentrations were markedly decreased on both diets by DMHCA (54% and 56%, respectively). 18812595
306 Hepatic SREBP1c, fatty acid synthase (FAS) and ChREBP mRNA quantities were unaltered upon DMHCA treatment. 18812595
307 treatment with DMHCA led to a significant 2.5-fold increase of CYP7A1 mRNA expression (Fig. 4A). 18812595
308 LDLR and acetyl- CoA carboxylase (ACC) were markedly decreased by 34% and 24%, respectively (Fig. 8B) 18812595
309 In MPM, mRNA expression of SREBP1c was slightly but significantly reduced by 13%, 18812595
310 In accordance, DMHCA treatment resulted in only 1.6-fold increased SREBP1c mRNA (Fig. 2B) and there were no changes in nSREBP1 protein levels 18812595
311 DMHCA does not induce liver steatosis or hypertriglyceridemia in apoE-deficient mice 18812595
312 Oil Red O staining of liver specimens from DMHCA-treated animals revealed minimal steatosis (Fig. 2A) 18812595
313 Plasma TG concentrations were not significantly altered by DMHCA on both diets suggesting that a high dose of DMHCA fed for more than 2 weeks does not induce hypertriglyceridemia in wild-type animals (Table 1). 18812595
314 slightly increased hepatic TG levels (24.5 64.8 mg/g) when compared with controls (19.7 6 1.6 mg/g)(Fig. 2, inset) 18812595
315 In contrast, liver weight remained unchanged (1.15 6 0.04 g) and the liver color appeared normal in DMHCA fed mice (Fig. 2A) 18812595
316 but also enhanced SREBP1c, FAS, and ChREBP mRNA by 4.7-, 3.4-, and 1.3-fold, respectively (Fig. 4A). 18812595
317 T0901317 treatment significantly enhanced SREBP1c mRNA levels by 4.4-fold (Fig. 2B). increased mature, transcriptionally active hepatic nuclear SREBP1 (nSREBP1) protein by 2.9-fold (Fig. 2C). 18812595
318 Macroscopically, administration of T0901317 resulted in a yellow-brown change in color of the liver and moderate tosevere steatosis (Fig. 2A). 18812595
319 TG concentration, which was significantly increased by 2.4-fold when compared with controls (Fig. 2, inset) 18812595
320 liver weights were significantly increased in T0901317-fed animals (1.5460.24 g) when compared with controls (1.12 6 0.12 g) (Fig. 2A). 18812595
321 Table 1. Effect of AMP-DNM on Expression of Key Genes in Cholesterol Homeostasis in Liver and Intestine 19072830
322 AMP-DNM Increases Biliary Lipid Secretion 19072830
323 The excretion of bile salt was unchanged, signifying that the capacity of the enterohepatic uptake and recycling system of bile salt was sufficient to cope with the increased bile production in AMP- DNM–treated animals. 19072830
324 and cholesterol content increased slightly 19072830
325 Interestingly,AMP-DNM also robustly lowered plasma cholesterol, TG, phospholipids, and FFA levels (Fig. 1C) 19072830
326 Indeed, we found that neutral sterol excretion was strongly increased in AMP-DNM–treated mice, demonstrating enhanced RCT 19072830
327 AMP-DNM prevented phosphorylation of both FRS2 and ERK induced by FGF19, indicating very early interaction in the pathway 19072830
328 Interestingly,AMP-DNM also robustly lowered plasma cholesterol, TG, phospholipids, and FFA levels (Fig. 1C) 19072830
329 There was a decrease in liver GSLs of 4.8% and 27.9% in mice treated with 25 and 100 mg/kg bw AMP-DNM, respectively 19072830
330 There was amodest but significant decrease in blood glucose levels, not resulting in hypoglycemia (Fig. 1B) 19072830
331 There was no effect on liver phospholipids 19072830
332 In the liver, the expression of the scavenger receptor class B type 1 was upregulated 19072830
333 TG levels were strongly decreased in a dose dependent manner 19072830
334 The compound was well tolerated but a slight decrease in food intake was observed in the mice treated with 100 mg/kg bw/day AMP-DNM during the first 2 weeks, resulting in a 10% decreased body weight gain. This was restored in the last 3 weeks of the treatment period, and consequently food intake and body weight gain no longer differed between the treatment group 19072830
335 A comparable pattern was also observed for CCAAT/enhancer binding protein (C/EBP)a and adipocyte fatty-acid-binding protein, aP2/(FABP4). 19305508
336 AMP-DNM treatment significantly increased (1.3-fold) adiponectin in adipose tissue (Fig. 3B). 19305508
337 Interestingly, all these markers showed a significant increase when compared to untreated LepOb mice upon inhibition of glucosylceramide synthesis; Pparc (2-fold), adipsin (6-fold) and GLUT-4 (3-fold), suggesting that adipogenesis is normalizing 19305508
338 A comparable pattern was also observed for CCAAT/enhancer binding protein (C/EBP)a and adipocyte fatty-acid-binding protein, aP2/(FABP4). 19305508
339 two important proteins involved in the recruitment of ATM to adipose tissue and local inflammation, Ccl2 and OPN, were down-regulated in adipose tissue after treatment with AMP-DNM. 19305508
340 CD11c gene expression, which is found on recruited proinflammatory ATM, normalized following treatment with AMP-DNM (Fig. 4F) 19305508
341 Glucosylceramide, but not ceramide, was reduced in plasma from inhibitor treated animals (see table 1). 19305508
342 In adipose tissue we observed a significant reduction of GM3 (4.5560.32 pmol/mg versus 1.9360.57 pmol/mg), again without affecting ceramide (52.4268.61 pmol/mg versus 62.97624.2 pmol/ mg) (Fig. 2A) 19305508
343 Real time PCR showed a consistent reduction in F4/80 mRNA in the AMP-DNM fed LepOb mice. F4/80 mRNA was approximately 4-fold increased in LepOb adipose tissue and normalized in treated LepOb mice (Fig. 4E). 19305508
344 Treated LepOb mice showed (near) normal HbA1c, nonfasted blood glucose concentrations and glucose clearance upon oral challenge in an oral glucose tolerance test (OGTT) 19305508
345 Fasted insulin levels and the homeostatic model assessment (HOMA) index, which is clearly increased in LepOb animals, were significantly reduced upon treatment. 19305508
346 When adipocytes were stimulated ex-vivo with insulin for 10 min no phosphorylation of Akt/PKB was observed in LepOb derived adipocytes, whereas in the case of cells from treated animals clear phosphorylation of Akt/PKB was detected (Fig. 2B). 19305508
347 AMP-DNM reduces macrophages in adipose tissue 19305508
348 On the other hand adipogenesis inhibiting Pref1 was undetectable in lean and AMP-DNM treated animals, but was detected in LepOb mice (data not shown). 19305508
349 Following treatment with AMP-DNM a reduction of the median adipocyte size was observed in LepOb mice (green curve), mainly due to a shift to the left of the 2nd and 3th quartiles of the distribution, reflecting reduced numbers of the large adipocytes. 19305508
350 Treatment with GW3965 or WAY-252623 (15 mg/kg) resulted in a significant reduction of atherosclerosis (28% and 37% for GW3965 and WAY-252623, respectively) ( Fig. 2A ). 19318684
351 Significant increases in ABCA1 mRNA observed at 7- and 14-day time points returned to control levels later in the fi rst study ( Fig. 5A , right panel) 19318684
352 There was a dose-dependent increasein ABCG1 expression starting on day 7 that was sustained throughout the length of each study ( Fig. 5A , B , left panels). 19318684
353 As shown in Table 2 , dose-dependent increases in plasma drug levels for WAY-252623 had no effect on serum cholesterol, triglyceride, hepatic enzymes (ALT and AST), or liver weights 19318684
354 Liver triglyceride and cholesterol concentrations were not increased in hamsters treated with WAY-252623 (supplementary Fig. II). 19318684
355 WAY-252623 caused a time- and dose-dependent decrease in serum total cholesterol of 28–34 and 45–57% for the 15 and 50 mg/kg/day doses, respectively. In the second study, reductions were observed as early as 7 days following the initiation of dosing. 19318684
356 It appears that LXR activation may provide an additional means for increasing plasma FGF19 protein levels and for triggering signaling through its hepatic receptor FGFR4. (Fig 6) 19318684
357 FPLC analysis confi rmed that VLDL, LDL, and HDL cholesterol fractions were unchanged in treated samples (data not shown). 19318684
358 Total HDL cholesterol concentrations were largely unaltered with two exceptions that refl ect significant reductions as indicated ( Fig. 4C, D ) 19318684
359 Decreases in LDLc followed a similar temporal pattern to total serum cholesterol ( Fig. 4A , B ). Maximal reductions in LDLc of 42 and 77% with 15 and 50 mg/kg/day treatments, respectively, were reached by the end of the study on day 28 ( Fig. 4A ). 19318684
360 Simvastatin by itself did not have any effect on ABCG1 or ABCA1 expression ( Fig. 5B ). The gene expression profi le for combination treatment was very similar to that obtained for WAY-252623 alone, indicating a compound specific effect on LXR-mediated target gene transcription. 19318684
361 Figure 6 19318684
362 Plasma triglyceride measurements were not consistently elevated over the course of either study following WAY- 252623 administration ( Fig. 3C, D ). 19318684
363 WAY-252623-mediated effects exceed those observed for simvastatin and the combination treatment provided no additional lipid lowering benefit over WAY-252623 monotherapy ( Fig. 3B ). 19318684
364 Signifi cant LDLc reductions were observed for WAY-252623 and the combination treatment in the second study whereas simvastatin at the dose tested (20 mg/kg) failed to produce signifi cant LDLc lipid lowering. 19318684
365 Treatment with any cholesterol biosynthesis inhibitor notably decreased the cholesterol content in raft and non-raft domains (Table 1). 19433058
366 Similarly, in cells treated with AY 9944, supplementing the medium with cholesterol prevented the reduction in membrane cholesterol but only reduced in part the incorporation of intermediate sterols into membrane domains. 19433058
367 Just for comparison, in our system methyl β-cyclodextrin practically abrogated insulin-stimulated glucose transport, which is in accordance with previous results reported by others 19433058
368 Inhibition of cholesterol biosynthesis resulted in a loss of both caveolin and GM1 staining at the cell surface and, interestingly, they no longer colocalized (Fig. 2B), confirming the decrease in lipid rafts/caveolae as a result of cholesterol starvation. 19433058
369 In cells treated with SKF 104976, simultaneous supplementation with cholesterol prevented the reduction of cholesterol levels in membrane domains but did not impedethe incorporation of substantial amounts of lanosterol and dihydrolanosterol into raft and non-raft fractions (Table 1). 19433058
370 In cells treated with SKF 104976, simultaneous supplementation with cholesterol prevented the reduction of cholesterol levels in membrane domains but did not impede the incorporation of substantial amounts of lanosterol and ihydrolanosterol into raft and non-raft fractions (Table 1). 19433058
371 As shown in Fig. 5, insulin caused a stimulation of glucose transport in 3T3-L1 preadipocytes, and all of the cholesterol biosynthesis inhibitors, SKF 104976, AY 9944 and triparanol, produced significant inhibition of the ability of insulin to enhance glucose uptake. 19433058
372 This effect was markedly lower in cells treated with cholesterol biosynthesis inhibitors than in control (+insulin) cells. 19433058
373 Coincubation with cholesterol restored IR activation to control values (Fig. 4B and C). Moreover, Fyn levels decreased in treated cells, an effect that was prevented by adding cholesterol to the incubation medium (Fig. 4B). 19433058
374 Genz-123346 treatment resulted in a trend toward decreased mRNA levels of SREBP-1c and several genes involved in fatty acid synthesis, including ATP citrate lyase (ACL), acyl-CoA carboxylase- 1 (ACC1), fatty acid synthase (FAS), and stearoyl-CoA desaturase-1 (SCD-1). 19444873
375 Drug treatment also decreased the serum levels of the liver transaminase ALT (Fig. 2B), albeit not to normal levels. 19444873
376 In contrast, in the drug-treated group the increases in ALT levels were significantly abated. 19444873
377 Genz-123346 treatment decreased the levels of ALT, indicating a reversal of liver pathology 19444873
378 The livers of animals treated with Genz-123346 exhibited a significantly reduced ratio of fat mass to lean mass compared to the livers of animals treated with placebo (water) (Fig. 4A). 19444873
379 Genz-123346 exhibited a significantly reduced ratio of fat mass to lean mass compared to the livers of animals treated with placebo (water) (Fig. 5A) 19444873
380 The levels of GM3 trended lower but were not significantly altered as a result of drug treatment, and the levels of ceramide and GL2 were unchanged (data not shown). 19444873
381 Drug treatment reduced GL1 levels by 40% (P 0.05) compared to the placebo (water) treated animals. 19444873
382 Glucose levels in the group treated with Genz-123346 declined within the first week of treatment, and remained within the range of 200-250 mg/dL for the next 4 weeks. 19444873
383 after 6 weeks of treatment we consistently observed a significant reduction in HbA1c levels in the animals treated with Genz-123346 (Fig. 1D) 19444873
384 Total liver triglycerides were also determined, and reduced triglyceride levels were observed in the drug-treated ob/ob mice relative to the placebo-treated group (Fig. 2E). 19444873
385 There was a significant (P 0.05) decrease in vacuole area fraction in the ob/ob mice treated with Genz-123346 (Fig. 2D). 19444873
386 Morphometric analysis confirmed this reduction in fractional lipid vacuole area from 0.098 (placebo) to 0.025 (Genz-123346) at 12 weeks, representing a 74% decrease, and from 0.139 (placebo) to 0.032 (Genz-123346) at 20 weeks, a 77% decrease (Fig. 4D). 19444873
387 animals treated with Genz-123346 exhibited decreased liver weights (Fig. 2A). 19444873
388 There was no significant adverse reaction. 19507027
389 Colpermin is effective and safe as a therapeutic agent in patients with IBS suffering from abdominal pain or discomfort. 19507027
390 a marked increase of apoE, by 3.5-fold (p 0.0001), but no changes in apoB or apoA-I (Fig. 6, A and B) 19648608
391 a marked increase of apoE, by 3.5-fold (p 0.0001), but no changes in apoB or apoA-I (Fig. 6, A and B) 19648608
392 Liver Sptlc2 deficiency also significantly decreased ceramide and sphingosine in the liver by 39 and 32%, respectively (p 0.01) 19648608
393 Moreover, plasma ceramide levels were also significantly decreased by 54% (p 0.001) 19648608
394 There were no significant changes in total cholesterol, phospholipid, or triglyceride levels (data not shown). 19648608
395 HDL and non-HDL cholesterol were increased (Fig. 4B), 19648608
396 hydroxymethylglutaryl-CoA reductase mRNA levels do not change (data not shown) 19648608
397 plasma phosphatidylcholine (PC) levels were significantly increased by 19% (p 0.01) 19648608
398 PC/SM ratio was increased by 77% (p 0.001), compared with controls 19648608
399 There were no significant changes in total cholesterol, phospholipid, or triglyceride levels (data not shown). 19648608
400 Plasma from Liver-specific Sptlc2-deficient Mice Promotes Cholesterol Efflux from Macrophages 19648608
401 and increased sphingosine 1-phosphate contents by 38% (p 0.01) 19648608
402 whereas there was no change in sphingosine 1-phosphate 19648608
403 plasma SM levels were again significantly decreased by 36% (p 0.01), 19648608
404 In accordance, the expression of LXR, ABCA1, ABCG5, and ABCG8 were decreased 20167657
405 AMP-DNM treatment had a spectacular inhibitory effect on the development of atherosclerosis in this model. Mice receiving the dose of 50 mg of AMP-DNM showed a reduction of 86% in the amount of lesions compared to control animals. At 100 mg of AMP-DNM, no lesions were detectable in the aortic sinus of the mice. 20167657
406 AMP-DNM treatment inhibits the development of atherosclerosis and ameliorates hyperlipidemia in LDLR -/- mice 20167657
407 At the end of the experimental period, the mice treated with AMP-DNM showed a dose dependent reduction of the amount of GlcCer and a 20167657
408 As expected, by inhibiting GlcCer synthase, AMP-DNM dose-dependently lowered the amount of hepatic GlcCer without a change in the amount of Cer (Table). 20167657
409 The cholesterol and triglyceride contents were also decreased significantly in the liver of treated animals 20167657
410 lipids were more significant in the LDLR / mice than in the APOE*3 Leiden mice, also in this model AMP-DNM inhibited lesion formation (Figure 5A and 5B). Drug treatment resulted in a reduction of plasma cholesterol (Figure 5C) and triglycerides (Figure 5D) and an amelioration in the lipoprotein profile (Figure 5E). 20167657
411 lipids were more significant in the LDLR / mice than in the APOE*3 Leiden mice, also in this model AMP-DNM inhibited lesion formation (Figure 5A and 5B). Drug treatment resulted in a reduction of plasma cholesterol (Figure 5C) and triglycerides (Figure 5D) and an amelioration in the lipoprotein profile (Figure 5E). 20167657
412 As a consequence of lowered hepatic cholesterol levels,26 expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (5.1-fold) and one of its main regulators, SREBP-2 (2-fold), were increased 20167657
413 In accordance, the expression of LXR, ABCA1, ABCG5, and ABCG8 were decreased, whereas the expression of the very low density lipoprotein receptor and the LDLR were upregulated 20167657
414 AMP-DNM treatment induced an increase of cholesterol secretion from 5.0 nmol/min/ 100 g bw at 50 mg of AMP-DNM to 8.8 nmol at 100 mg of AMP-DNM 20167657
415 AMP-DNM treatment induced an increase of cholesterol secretion from 5.0 nmol/min/ 100 g bw at 50 mg of AMP-DNM to 8.8 nmol at 100 mg of AMP-DNM 20167657
416 The amount of sphingomyelin determined in a pool of plasma also decreased at the end of the treatment: 68% and 83% of reduction with 50 and 100 mg of AMP-DNM, respectively 20167657
417 Theamount of sphingomyelin determined in a pool of plasma also decreased at the end of the treatment: 68% and 83% of reduction with 50 and 100 mg of AMP-DNM, respectively 20167657
418 Bile acids showed a slight but significant increase within the HF-Ath treated mutant Ugcgflox/flox//AlbCre mice (Fig. 6E). 20432257
419 Fig. 8. Sterol secretion in bile and feces. (A/A0,B/B0) Determination of total cholesterol concentration in bile (A, TLC; A0, densitometry; amount loaded on TLC 1 lL bile) and feces (B, TLC; B0, densitometry; corresponding to 1 mg feces dry weight) did not reveal significantly increased levels in mutant mice. (C-E) 20432257
420 Within the free ceramides, only nonhydroxy- lated fatty acids could be detected by TLC (Fig. 3B). No quantitative difference between Ugcgflox/flox controls and Ugcg-deficient mice were seen (Fig. 3B0). 20432257
421 No significant dif- ferences could be seen between control liver- and GSL- depleted liver total cholesterol content (Fig. 3C,C0) and phospholipid patterns (Supporting Fig. 2). 20432257
422 GSL-deficient animals under HF-W and HF-Ath had no significantly differ- ent plasma cholesterol concentrations (Fig. 6C), tri- glycerides (Fig. 6D), and blood glucose levels (Fig. 6A) when compared to their respective controls. 20432257
423 Also, measurements of bile flow (C), bile acids in bile (D), and bile acids in feces resulted only in marginal changes in mice with GSL-depleted hepatocytes 20432257
424 Measurements of lipoprotein profiles in plasma did not reflect a significant difference in HDL, LDL, and VLDL lipoprotein levels in plasma from GSL-deficient mice and controls with chow (C; controls/ mutant n ¼ 4, males) or HF-W (D; controls/mutant n ¼ 8, males) (shown are mean values 6 SEM). 20432257
425 Total body weight (BW) and liver-to-BW ratios were unaffected for all three diets applied comparing mutant with control mice 20432257
426 As consequence of GSL depletion, theoretical accruing ceramides generated a shift in the GSL/SM pathway (Fig. 1A) and led to increased sphingomyelin produc- tion in mutant mice (Fig. 2E). 20432257
427 Livers of Ugcgflox/flox//AlbCre mice showed a modest but significantly increased sphingomy- elin concentration compared to their respective controls (Fig. 3A,A0). 20432257
428 Feeding of HF-Ath led to extreme lipid storage, but again with no difference comparing control with mutant livers (Fig. 4A). 20432257
429 confirmed by GSL analysis. In the neutral fraction of Ugcgflox/flox ‘‘wildtype’’ mouse total liver lipid extract solely a marginal amount of GlcCer could be detected 20432257
430 These results almost copy the analysis of extracts from liver and hepatocytes, suggesting that plasma GSL are derived from hepatocytes 20432257
431 Using a 48 h treatment period, we found that the IC50 values for the inhibition of Aβ secretion by PDMP, PPMP and EtDO-P4 were 15.8 μM, 5.8 μM and 1.0 μM, respectively (Fig 4). 20599631
432 EtDO-P4 also inhibited Aβ production by human neurons (Fig 8). In this case the IC50 for Aβ secretion was found to be ~ 3 μM and, under these conditions, total cellular GSL levels were reduced by ~ 50% (Fig 8). 20599631
433 Gross morphological changes and overt cytotoxicity were only observed when the compounds were used at concentrations ~ 2-fold greater than their IC50 values for Aβ secretion. 20599631
434 Significant decreases in cellular MTT reduction were detected for all three ceramide analogues when tested at concentrations that inhibit Aβ secretion by ~50% (Fig 6) 20599631
435 a significant reduction of atherosclerotic lesions in the aortic arch and root; and 20814016
436 However, in this study, we found that plasma ceramide levels in Sms2/Apoe DKO mice are increased, so that ceramide-level changes could not be a reason for the reduction of atherosclerosis in the DKO mice. 20814016
437 More important, we also found that SM and ceramide levels in the BCA were significantly decreased (by 35% and 32%, respectively; P 0.01) in Sms2/Apoe DKO BCA compared with Apoe KO mice (Table 3). 20814016
438 the DKO mice had significantly lower free cholesterol and cholesteryl ester levels in the BCA than the Apoe KO mice (by 58% [P 0.01] and 60% [P 0.01], respectively) (Table 3) 20814016
439 in Sms2/Apoe DKO mice, finding that there was a significant decrease in SM levels (30%, P 0.01), but not in other lipids (Table 1), 20814016
440 PC levels were not statistically distinguishable between the 2 groups of mice (Table 3). 20814016
441 However, BCA dihydroxyl ceramide sphingosine and sphingosine-1-phosphate levels showed no significant changes (supplemental Table II). 20814016
442 significant decrease in plasma SM levels (35%, P 0.01) and in the SM/PC ratio (46%, P 0.01) 20814016
443 However, BCA dihydroxyl ceramide sphingosine and sphingosine-1-phosphate levels showed no significant changes (supplemental Table II). 20814016
444 Apoe / S1pr2 / mice showed greatly attenuated atherosclerosis compared with the Apoe / mice. Bone marrowtransplant experiments indicate that S1PR2 function in the hematopoietic compartment is critical. S1PR2 isexpressed in bone marrow– derived macrophages and in macrophage-like foam cells in atherosclerotic plaques 20947824
445 Lipoprotein profiles, plasma lipids, and oxidized low-density lipoprotein uptake by bone marrow– derived macrophages were not altered by the S1pr2 genotype 20947824
446 Immunohistochemistry for Sphk1 of atherosclerotic lesionsof ApoE / mice showed that the enzyme was abundantly expressed there and colocalized mainly with macrophages (Figure 6D) 21164103
447 S1P3 Deficiency Has No Effect on Atherosclerotic Lesion Volume but Dramatically Reduces Monocyte/Macrophage Content in Atherosclerotic Lesions of S1P3 / /ApoE / Mice 21164103
448 Neointima Formation After Carotid Ligation Is Increased in S1P3 / Mice 21164103
449 We found MCP-1 and tumor necrosis factor (TNF) gene expression to be reduced by 70% to 80% in S1P3 / macrophages (Figure 5C), 21164103
450 In agreement, protein levels of MCP-1 were reduced more than 150-fold in the peritoneal exudates of S1P3 / mice compared to controls as measured by ELISA (Figure 5C, inset) 21164103
451 We found MCP-1 and tumor necrosis factor (TNF) gene expression to be reduced by 70% to 80% in S1P3 / macrophages (Figure 5C), 21164103
452 S1P3 in Both Hematopoietic and Nonhematopoietic Cells Is Required for Monocyte/Macrophage Accumulation in Atherosclerotic Lesions 21164103
453 Sudan III showed a substantial and significant increase in the number of atherosclerotic plaques in the group of mice treated with high-dose ethanol (AngII/High-ET) compared with those receiving low-dose ethanol (AngII/Low-ET). 21757824
454 The plasma CXCL12/SDF-1 level was significantly increased in mice treated with low-dose ethanol compared with mice treated with a high dose 21757824
455 Ethanol regulated the secretion of SDF-1 and vascular endothelial growth factor from fibroblasts in a dose-dependent and bimodal fashion. 21757824
456 and the plasma concentration of transforming growth factor-β1 was significantly increased in mice treated with high-dose ethanol compared with control mice 21757824
457 Therefore, our results point to the possibility that Archaea may play a role in the pathogenesis of IBD, particularly in patients with ulcerative colitis and large bowel Crohn’s. 21815901
458 Similarly, when we assessed the d- and lthreo enantiomers of EtDO-P4 at a concentration of 1 μM, only the d-EtDO-P4 (which was the more potent GSL synthesis inhibitor) significantly inhibited Aβ production 22103431
459 whereas both d- and l-EtDO-P4 inhibited ERK phosphorylation (Figure 3) 22103431
460 Furthermore, only the d-enantiomer inhibited Aβ production, whereas both the d- and l-enantiomers inhibited ERK phosphorylation (Figure 5). 22103431
461 In contrast, both d- and l-PPMP significantly inhibited ERK phosphorylation (Figure 2) 22103431
462 MAPK pathway inhibitors, PD98059 or U0126. Both PD98059 and U0126 strongly inhibited pERK formation; however, Aβ production was not suppressed (Figure 7). In fact, for reasons that remain unknown, PD98059 stimulated Aβ production by 20% 22103431
463 GCS siRNA treatment of CHO-APP cells did not result in any detectable changes in either Aβ production or ERK phosphorylation (Figure 9). 22103433
464 Targeting of GCS using a 40 nM concentration of siRNA duplex for 48 h reduced GCS mRNA levels by 82% (Figure 8). This resulted in a 77%decrease in CHO-APP cellular GSL levels (Figure 8). 22103434
465 A cardioprotective association between alcohol use and ischaemic heart disease cannot be assumed for all drinkers, even at low levels of intake. 22229788
466 In three small early-phase trials, REGN727 significantly reduced LDL cholesterol levels. This effect was significant both in healthy volunteers and in subjects with familial or nonfamilial forms of hypercholesterolemia. 22435370
467 Although REGN727 and atorvastatin both lower LDL cholesterol by increasing hepatic LDL-receptor activity, atorvastatin does so primarily by enhancing the production of receptors, whereas REGN727 decreases the degradation of receptors. 22435370
468 In addition, the demonstration of a good correlation between a reduction in free PCSK9 levels and a reduction in LDL cholesterol levels after the administration of REGN727 in humans supports previous reports from studies involving rodents and nonhuman primates that PCSK9 in the circulation, not intracellular PCSK9, is primarily responsible for regulating hepatic LDL receptors.10,11 22435370
469 Also the intestinal cholesterol transporters Abcg5 and Abcg8 as well as the short chain peptide transporter Pept1 and the glucose transporters Sglt1 and Glu5 were not significantly altered. 22851168
470 Secretion of bile acids (Fig. 7D) and pancreatic lipases (Fig. 7E) into the gut lumen were unaltered indicating that their production and release into the gut limen were not affected in mutant mice. 22851168
471 Niether the intestinal fatty acid-binding proteins Fabp2 and CD36 nor enzymes important for triglyceride synthesis and transfer such as were statistically significantly changed. 22851168
472 and ceramide increased ~20% in mutant tissue at P7 22851168
473 The intestinal cholesterol concentrations were slightly but not significantly reduced in mutant jeju- num at P7 22851168
474 Fatty acids (Fig. 7, A and B) and cholesterol (Fig. 7, A and C) significantly accumulated in feces. 22851168
475 Consequently, all investigated intestinal parts of mutant mice showed GSL depletion (Fig. 1F). 22851168
476 Although Ugcg-deficient mice were able to absorb glucose (Fig. 7L), the extent was less than in wild type animals (Fig. 7, K and M, quantification). 22851168
477 The total sphingomyelin con- tent in mutant intestine appeared almost unaltered (Fig. 2C), 22851168
478 In concordance, plasma triglyceride concentrations significantly decreased in mutants (Fig. 7J). 22851168
479 AMP-DNM treatment resulted in a dose-dependent reduction of expression of each of these markers. At the dose of 100 mg AMP-DNM, the reduction was even larger. It suggests that the highest dose of AMP-DNM completely corrected the effect of the western-type diet on liver inflammation. 23056165
480 AMP-DNM treatment induced a dose-dependent decrease of plasma GlcCer and ceramide (table 1). 23056165
481 Whereas the amount of GlcCer was dose dependently decreased in the livers of treated animals, ceramide amounts were not changed (table 1). 23056165
482 AMP-DNM also dose dependently decreased plasma triglycerides, FFA, and cholesterol (fig. 1A–C). 23056165
483 we observed that the western-type diet induced an up-regulation of SREBP1 (fig. 4) and some of its target genes, i.e. fatty acid synthase (FAS) and stearoyl-CoA desaturase (SCD1). AMP-DNM treatment normalized expression of these genes. 23056165
484 Moreover, we observed that the western-type diet induced expression of PDK4 and glucose-6-phosphatase. Animals treated with AMP-DNM showed corrected expression of both genes. 23056165
485 The homeostasis model assessment (HOMA) index was significantly reduced in treated animals (fig. 3C). As a consequence of the improved glucose homeostasis, the percentage of glycated haemoglobin was notably reduced as well (fig. 3D). 23056165
486 At the dose of 100 mg AMP-DNM, Kuppfer cells looked even closer to normal, almost equal in size to those in animals on chow diet. 23056165
487 AMP-DNM showed a dramatic reduction in the amount of hepatic lipid droplets, whereas at the dose of 100 mg AMP-DNM, virtually no lipid droplets were present. 23056165
488 AMP-DNM also corrects hepatic steatosis in APOE*3 Leiden 23056165
489 Newborn mutants demonstrated a drastic reduction of lipid absorption indicated by reduced intracellular lipid depots in enterocytes as compared to newborn control littermates 23473748
490 Sptlc2 haploinsufficiency significantly increased protein levels of ABCA1 (2.2-fold; P < 0.05), but not ABCG1 or SR-B1 23549085
491 Sptlc2 haploinsufficiency in myeloid cell lineage reduces atherosclerosis in Ldlr–/– mice. 23549085
492 Sptlc2 haploinsufficiency in hematopoietically derived cells reduces atherosclerosis in Ldlr–/– mice 23549085
493 whereas ceramide, phosphatidylcholine, diacylglycerol, sphingosine, and S1P showed no significant differences between the groups 23549085
494 Sptlc2 haploinsufficiency impairs macrophage inflammatory responses 23549085
495 Sptlc2 haploinsufficiency induces cholesterol efflux in macrophages and promotes macrophage-mediated reverse cholesterol transport in mice 23549085
496 Sptlc2 haploinsufficiency results in decreased SPT activity, leading to reduced macrophage SM content 23549085
497 After 16 weeks of a high-fat diet, mice transplanted with Apoe-/- Abca12 El12/El12 FLCs exhibited double the number of the plaques in comparison to Abca12+/+counterparts (Figures 6D and 6H; p < 0.002). 23931754
498 With cholesterol loading, Abca12 deficiency led to a significant accumulation of cholesterol, cholesteryl esters, ceramides, sphingomyelins, triglycerides, and phosphatidyl- choline (Figure 5E). 23931754
499 Figure 2. Involvement of Lxrb in the Impairment of Cholesterol Efflux in Abca12-Deficient Cells 23931754
500 Figure 1. Cholesterol and Phospholipid Efflux from Abca12-Deficient Cells 23931754
501 we found colocalization of PAFR and CD36 in macrophages from human atherosclerotic plaques 24130805
502 The IL-10 production was significantly reduced by the previous treatment of macrophages with PAFR antagonists, an anti-CD36 blocking antibody, or a combination of PAFR antagonists with anti-CD36. 24130805
503 Figure 1B shows that the uptake was reduced by pre-treatment of macrophages with antibodies to CD36 (62% inhibition compared to untreated group). 24130805
504 The combination treatment with anti-CD36 and WEB2170 or anti-CD36 and CV3988 further reduced the oxLDL uptake (71% and 79% inhibition, respectively). 24130805
505 Pre-treatment with PAFR antagonists (WEB2170 or CV3988) also reduced the oxLDL uptake (42% and 61% inhibition, respectively). 24130805
506 We found that βCD caused a significant reduction (70%) in FITC-oxLDL uptake (Figure 2A and 2B). 24130805
507 OxLDL induces IL-10 mRNA expression only in HEK293T expressing both receptors (PAFR and CD36). 24130805
508 OxLDL does not induce IL-12 production 24130805
509 OxLDL induces co-immunoprecipitation of PAFR and CD36 with the constitutive raft protein flotillin-1, and colocalization with the lipid raft-marker GM1-ganglioside 24130805
510 Reversibly inhibits glucosylceramide synthase, the enzyme that catalyzes the primary step in glycosphingolipid synthesis, 24338084
511 Real-time PCR showed that the expression level of the CD36, SRB-1, and ABCA1 genes were significantly upregulated by D-PDMP treatment (Figure 5B) 24710030
512 The most unexpected result was the observation that treatment with 10 mg/ kg D-PDMP completely prevented atherosclerosis in these mice at 36 weeks of age (Figure 2D). Notably, coronary artery disease, the principal cause of morbidity and mortality resulting from atherosclerosis, was drastically prevented by the treatment 24710030
513 Blood pressure did not change significantly with treatment, the increase in arterial stiffness is largely independent of blood pressure. 24710030
514 At 36 weeks, the mice fed 5 and 10 mg/kg D-PDMP plus an HFHC diet showed a dose-dependent increase in body weight (36.53±1.77 and 41.03±0.55 g) compared with the other groups. The main reason was an increase in bone mass density and muscle mass 24710030
515 Rabbits fed an HFHC diet showed a marked increase in aortic lactosylceramide levels (Figure 7A), accompanied by extensive aherosclerosis, and a 17-fold increase in serum cholesterol (Figure 7B). In contrast to rabbits fed an HFHC diet alone, rabbits treated with D-PDMP showed a prevention of atherosclerosis as measured by lactosylceramide and cholesterol levels, which were similar to levels in controls (Figure 7) 24710030
516 Similarly, the serum levels of LDL cholesterol (Figure 4B) and triglycerides (Figure 4C) were increased in serum from mice fed a Western diet. This was also decreased to baseline values in mice fed D-PDMP. 24710030
517 The level of Cyp7A1 was also significantly upregulated by drug treatment (Figure 5D), indicating cholesterol catabolism and bile acid synthesis on drug treatment. 24710030
518 D-PDMP dose-dependently decreased the activity of both GlcCer synthase and LacCer synthase in 36-week-old mice, as indicated by the mass of LacCer (Figure 3E) and GlcCer (Figure 3F) 24710030
519 High activity of glucosylceramide synthase and lactosylceramide synthase in the aorta in ApoE−/− mice was observed in 20-week-old mice fed an HCHF diet (Figure 3A and 3B). When these mice were given a daily supply of D-PDMP by oral gavage during this period (at 20 weeks of age), it dosedependently decreased the activity of these enzymes 24710030
520 Interesting, although feeding the Western diet decreased the serum levels of HDL cholesterol (Figure 4D), treatment with D-PDMP raised HDL cholesterol level in the serum 24710030
521 As shown in Figure 5A, treatment with 10 mg/kg D-PDMP increased the mRNA levels of 3-hydroxy-3-methylglutarylcoenzyme A reductase and sterol regulatory element binding transcription factor 2 up to ≈5.2-fold (P<0.0001) and 3.6-fold 24710030
522 Similarly, the serum levels of LDL cholesterol (Figure 4B) and triglycerides (Figure 4C) were increased in serum from mice fed a Western diet. This was also decreased to baseline values in mice fed D-PDMP. 24710030
523 The mRNA level of LDL receptor was also elevated by D-PDMP respectively 24710030
524 Western immunoblot assays revealed that placebo mice liver tissue had significantly lower expression of SREBP2 protein and LDL receptor protein mass (Figure 6A and 6B). In contrast, treatment with D-PDMP markedly increased the expression of these proteins 24710030
525 treatment with D-PDMP dose-dependently increased the mRNA levels of lipoprotein lipase and very-low-density lipoprotein (VLDL) receptor to ≈4.8-fold (P<0.0001) and 2.4-fold (P<0.0001) in liver samples of drug-treated mice 24710030
526 Feeding an HFHC diet markedly increased the serum level of oxidized LDL measured with an ELISA assay. In contrast, feeding the glycosyltransferase inhibitor dose-dependently decreased the serum levels of oxidized LDL to below baseline levels in the ApoE−/− mice serum (Figure 4A) 24710030
527 Likewise, PWV measurement revealed a similar pattern, that is, suggesting that the thickening of the aortic wall was associated with arterial stiffening. This was lowered to control levels on treatment with 5 and 10 mg/kg D-PDMP in a dose-dependent manner (Figure 1H). 24710030
528 About 20% of caveolin-1 was distributed to raft domains in HEK293 cells, but only 5 and 8% of caveolin-1 was detected in raft domains of HEK/ABCG1 and HEK/ABCG4 cells, respectively (Fig. 7B), suggesting that ABCG1 and ABCG4 reorganize membranes and disrupt raft domains. 25302608
529 ABCA1 was recovered from a soluble fraction when it was treated with Triton X-100 (Fig. 2A and Fig. S3). Similarly, most of ABCA1 was detected in the soluble fraction when cells were treated with Brij 96 (Fig. 2B 25302608
530 ABCA1 is localized to non-raft domains, ABCG1 to Triton X-100 raft domains, and ABCG4 to Brij 96 raft but not to Triton X-100 raft domains. 25302608
531 In contrast to ABCA1, ABCG1 was preferentially recovered from an insoluble fraction when HEK/ABCG1 cells were treated with Triton X-100 or Brij 96 25302608
532 These results suggest that ABCG1 localized to raft domains containing flotillin-1, and that ABCG1 and ABCG4 localized to distinct membrane domains on the plasma membrane. 25302608
533 This observation indicates that cellular SM levels do not affect cholesterol efflux by ABCG4, in contrast to ABCA1 and ABCG1 (Table 1). 25302608
534 The amounts of cholesterol exported by ABCG4 from LY-A and LY-A/CERT cells did not differ significantly (Fig. 1B), although the SM levels in LY-A cells have been found to be reduced by about 36% compared with that in LY-A/CERT cells 25302608
535 Enterocyte-specific Ugcg-deficient mice were generated by crossing floxed Ugcg mice with mice expressing Cre recombinase under the control of the villin promoter induced either in the embryo (using VilCre-expressing mice) or during adult life (using VilCre-ERT2-expressing mice) [28]. GlcCer- derived GSLs were profoundly absent in the intestines of the VilCre-Ugcg pups. Although undistinguishable from control littermates at birth, VilCre-Ugcg pups did not gain weight and died by postnatal day 8. 25351657
536 Floxed Ugcg mice were crossed with a keratin K14 promoter-driven Cre line to produce mice lacking Ugcg expression in keratinocytes (K14Cre-Ugcg KO mice) [24].K14Cre-UgcgKOpupsshowedprofounddesqua- mation and epidermal dehydration and died at about 4 days of age. 25351657
537 Global deletion of the Ugcg gene in mice, which con- sequently eliminates all GlcCer-based GSLs, caused early embryonic lethality [14]. 25351657
538 No other phenotype was detected in the AlbCre-Ugcg mice, even after challenge with a high-fat diet, arguing against a vital role of hepatic GlcCer synthesis in glucose control, liver steatosis, or cholesterol metabolism. 25351657
539 A liver-specific knockout of Ugcg was generated by crossing floxed Ugcg mice with mice expressing Cre recombinase under the control of the albumin promoter (AlbCre-Ugcg mice) [27]. The mice had greatly reduced GSL levels in liver and plasma, pinpointing liver as the major source of plasma GSLs. 25351657
540 These reports show that GlcCer-based GSL synthesis is expendable for embryonic development of the nervous system, but is required for its proper development, stability, and function after birth. 25351657
541 However, episodic and chronic heavy drinking do not provide any beneficial effect on IHD. 25567363
542 Epidemiological evidence for a beneficial effect of low alcohol consumption without heavy drinking episodes is strong, corroborated by experimental evidence. 25567363
543 A relatively frequent consumption pattern in Russia is episodic heavy to very heavy consumption with sometimes prolonged binges (‘zapoi’, an episode of continuous drunkenness lasting two or more days in combination with withdrawal from normal social life 25567363
544 Gb3 is the only GSL reduced on the cell surface of almost all investigated cell lines (n = 4) and for both inhibitors. The only exception was observed in case of PDMP treatment on T47D (Figure 2B) 25715344
545 the expression of the other globo series GSL SSEA3 was only affected in BG1. 25715344
546 While PPMP significantly reduced LacCer expression in BG1 cells, PDMP did not affect LacCer expression in all cell lines 25715344
547 Myriocin treatment increased ABCA1 protein levels and reversed WD-induced changes in ABCA1 and SR-B1 gene expression. The WD produced no significant changes in the expression of hepatic mRNA levels of ATP-binding cassette transporters Abcg5 and Abcg8, the half-transporters involved in hepatobiliary cholesterol elimination. However, myriocin treatment caused a 45% induction of ABCG8 compared to the WD (Fig 4F) 25993337
548 Myriocin treatment stabilized ApoB levels and significantly increased ApoAI levels resulting in a normalized ApoB/ApoA1 ratio 25993337
549 The WD, but not the SD resulted in substantial aortic root lesions as assessed by Oil Red-O staining. Myriocin supplementation significantly reduced aortic root atherosclerosis by ~50 fold, compared with a WD-fed mice (Fig 7A and 7B). Combined together with the liver histology data, these results indicate that pharmacological inhibition of ceramide production prevents diet-induced NAFLD and associated atherosclerosis 25993337
550 Myriocin partially normalized the hepatic ceramide levels (reduced long-chain ceramides and increased C24:0) resulting in lower total ceramide levels compared to both SD and WD groups. 25993337
551 Myriocin normalized both total and individual ceramides in plasma 25993337
552 Myriocin reduced total plasma cholesterol and triglycerides and increased HDLc 25993337
553 Myriocin reduced hepatic and plasma ceramides and sphingomyelin, and decreased atherosclerosis, hepatic steatosis, fibrosis, and apoptosis without any effect on oxidative stress 25993337
554 The high fasting glucose and insulin levels (Table 1) and abnormal glucose tolerance test (Fig 1A and 1B) caused by theWD were normalized by myriocin 25993337
555 myriocin significantly reduced hepatic cholesterol accumulation, increased the cholesterol PR and partially upregulated the expression of SREBP2 and HMG-CoA Reductase compared to WD 25993337
556 Myriocin significantly reduced the weight gain in the WD group These observations demonstrate that myriocin prevents WD-induced obesity and systematic insulin resistance in LDLR-/-mice 25993337
557 myriocin increased biogenesis and selective hepatic uptake of HDL and hepatobiliary elimination of cholesterol, all suggesting increased RCT 25993337
558 The increased levels of hepatic SM were also normalized by myriocin (Fig 2E) 25993337
559 Myriocin treatment significantly reduced plasma SM as compared to theWD group, but it did not completely eliminate WD-induced alterations (Fig 2F) 25993337
560 Myriocin treatment increased ABCA1 protein levels and reversed WD-induced changes in ABCA1 and SR-B1 gene expression. The WD produced no significant changes in the expression of hepatic mRNA levels of ATP-binding cassette transporters Abcg5 and Abcg8, the half-transporters involved in hepatobiliary cholesterol elimination. However, myriocin treatment caused a 45% induction of ABCG8 compared to the WD (Fig 4F) 25993337
561 Fig. 7. Effect of D-PDMP on the expression of hepatic genes that play roles in cholesterol and lipid metabolism and cardiac genes implicated in hypertrophy. 26111596
562 Fig. 4. Polymer-encapsulated D-PDMP was more effective in ameliorating atherosclerosis in ApoE / mice compared to unencapsulated D-PDMP 26111596
563 Fig. 6. Treatment with polymer-encapsulated D-PDMP (PE D-PDMP) prevents the onset of cardiac hypertrophy 26111596
564 Fig. 5. Encapsulated D-PDMP is more effective in mitigating lipid accumulation than unconjugated D-PDMP. Levels of triglycerides (A), cholesterol (B), and oxidized LDL (C) were measured by ELISA. Glucosylceramide (D) and lactosylceramide (E) were measured by MSMS. In all cases, placebo-treated animals fed a HFHC diet experienced dramatic increases in each type of lipid and lipid accumulation was significantly reduced following treatment with D-PDMP (each condition is given in the Legend). Furthermore polymer-encapsulated D-PDMP was always equally or more effective than unencapsulated drug even at one tenth the dose (e.g., 1.0 mpk compared to 10 mpk) n ¼ 3 (***p < 0.0001, **p < 0.001, *p < 0.01). 26111596
565 Polymer-encapsulated D-PDMP is more effective than unconjugated D-PDMP in reducing aortic intima media thickening 26111596
566 Pre-exposure of monocyte-derived macrophages to T0901317 reduced susceptibility of these cells to HIV infection in vitro. This protective effect lasted for up to 4 days after treatment termination and correlated with upregulated expression of ABCA1, reduced abundance of lipid rafts, and reduced fusion of the cells with HIV 26126533
567 T0901317 pretreatment also reduced HIV-induced dyslipidemia in infected mice 26126533
568 When eight humanized mice were pretreated with LXR agonist prior to HIV infection, five animals were protected from infection, two had viral load at the limit of detection, and one had viral load significantly reduced relative to mock-treated controls 26126533
569 Pre-exposure of peripheral blood leukocytes to T0901317 provided only a short-term protection against HIV infection. 26126533
570 Treatment of HIV-exposed humanized mice with LXR agonist starting 2 weeks post-infection substantially reduced viral load. 26126533
571 Quantitative RT-PCR measurements of these genes (Fig. 3A) showed that treatment with DPDMP reversed the expression of ANP and BNP mRNAs 26253472
572 Feeding a HFHC diet significantly increased Mean arterial pressure (MAP) (Fig. 1E), which was improved upon treatment with D-PDMP 26253472
573 In contrast, in mice fed D-PDMP (Fig. 1A, C, top right panel), the wall thickness was comparable to the control. Masson's-Trichrome staining (Fig. 1G) of thin sections of the left ventricle revealed extensive collagen deposition (white arrow) in mice fed with HFHC diet (Fig 1G, B) compared to control and this was reversed and/or prevented upon treatment 26253472
574 Quantitative RT-PCR analysis revealed that several genes encoding the proteins implicated in anti-oxidant defense were induced by 10 mg/kg D-PDMP (Fig. 3B). For example, the mRNA levels of superoxide dismutase I and II (SOD1, SOD2), catalase (CAT) were increased by treatment 26253472
575 Additional details of our echocardiography study parameters are presented in supplement (Table S1) 26253472
576 As shown in Fig. 2, feeding 5 mg/kg and 10 mg/kg of D-PDMP 36 weeks old mice dose-dependently decreased the mass of lactosylceramide and glucosylceramide compared to placebo mice heart tissues. 26253472
577 The results show that treatment for 6 months (36 week old mice) not only mitigated cardiac hypertrophy due to HFHC feeding, but also maintained cardiac contractility/heart function to the same level as 12 weeks old mice, thus mitigating the aging effect in these mice 26253472
578 While, the HFHC diet substantially increased LV mass further. In contrast, treatment with varied DPDMP doses dependently decreased LV mass. 26253472
579 The heart weight to body weight ratio (Fig. 1F) and cardiomyocyte size (Fig. 1G) were also increased in placebo mice fed HFHC compared to control and were dosedependently decreased upon treatment 26253472
580 In contrast, mRNA levels of hypoxia inducible factor-A was markedly decreased in these tissues. Collectively, treatment with D-PDMP accelerated the anti-oxidant defense in mice heart 26253472
581 Fig. 2. D-PDMP inhibits the mass of glycosphingolipids in the heart tissue in apoE/ 26253472
582 Western immunoblot of phospho p44MAPK in left ventricle tissue extracts showed that 10 mg/kg D-PDMP decreased the expression of p44MAPK compared to the placebo mice heart tissues (Fig. 4) 26253472
583 mice. At 36 weeks, the mass of lactosylceramide (A) and glucosylceramide (B) was also 26253472
584 decreased, as measured by RP-HPLC 26253472
585 Functional analysis demonstrated a negative correlation between cholesterol efflux capacity of HDL and viral load in the ART-naive HIV-infected group (R2 = 0.26, p = 0.026). 26343868
586 Proteomic profiling revealed decreased levels of paraoxonase (PON) 1 and PON 3 in HDL from HIV patients relative to HDL from uninfected controls (p < 0.0001) 26343868
587 Lipidomic profiling uncovered a negative correlation between CD4 T cell counts and particle sphingomyelin, lyso-phosphatidylcholine and ether-linked phosphatidylserine content in the ART-naive (R2 = 0.2611, p < 0.05; R2 = 0.2722, p < 0.05; and R2 = 0.3977, p < 0.05, respectively) but not treated HIV-infected subjects. 26343868
588 PON activity of HDL from control group (0.13 ± 0.01 U/μl) was significantly higher than PON activity of HDL from HIV-infected untreated subjects (0.12 ± 0.01 U/μl, p = 0.0035),subjects treated with non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy (0.11 ± 0.01 U/μl, p < 0.0001), subjects treated with protease inhibitor (PI)-based therapy with detectable viral load (0.11 ± 0.01 U/μl, p < 0.0001), and PI-treated patients with undetectable viral load (0.12 ± 0.01 U/μl, p = 0.0164). 26343868
589 Plasma triglyceride levels were elevated by LXR agonist treatment in all 3 BMT groups (Table 2). 155396232
590 WAY-252623 dosed alone or in combination with simvastatin was associated with robust increases in intestinal ABCA1, ABCG1, SREBF1, INSIG1, and SCD mRNA. (Fig 6) 193186854
591 These findings suggest that there may be a difference in anærobic intestinal flora between patients with cancer of the large bowel and those without the disease.  70691
592 The most common cause of "idiopathic" pruritus ani is coffee, including decaffeinated coffee. 832560
593 There are at least six common foods that unequivocally cause "idiopathic" pruritus ani: coffee, tea, cola, beer, chocolate, and tomatoes (ketchup). 832560
594 Figure 1 1541601
595 Short-chain fatty acid production by caecal contents was up to eight-fold higher than contents from the sigmoid/rectum. 1541601
596 Host-produced substances includ- ing glycoproteins (Macfarlane et a!. 1989a), exfoliated epi- thelial cells (Wolin & Miller 1983) and pancreatic secretions 1541601
597 Methanosphaera stadtmaniae, however, occurs in some individuals and obtains energy by reducing CH30H with H2 (Miller & Wolin 1983b). 1541601
598 Their principal substrates are dietary residues that have escaped digestion in the small bowel, such as resistant starch, non-starch polysaccharides, proteins and peptides (Cummings et al. 1989). 1541601
599 These carbohydrates and proteins are broken down through a variety of intermediates to short-chain fatty acids (SCF A) (Cummings 1981), ammonia (Macfarlane et a!. 1986), H2 and C02 (Gibson et a!. 1988a) and, in some individuals, CH4 (Bond et a!. 1971 ). 1541601
600 These results indicate that protein breakdown and amino acid fermentation are quantitatively more dominant processes in the distal than in the proximal colon. 1541601
601 Total production of butyrate, a fatty acid with the potential to regulate cell growth and differentiation (Roediger 1980), is thus greater in the right colon. 1541601
602 Since abso- lute H2 production presumably is constant, this increase in H2 observed at low initial PH2 is attributable to the inability of bacteria, at low PH2, to consume this gas as rapidly as it is produced. 1556190
603 The lower fasting breath H2 concentration reported for CH4-producing subjects (22) can be explained by the more efficient H2 con- suming ability of methanogenic bacteria. 1556190
604 Thus, it seems likely that fermentation by fecal bacteria involves some metabolic pathways that do not liberate H2. 1556190
605 Thus, slowly fermentable substances that are metabolized along the extent ofthe colon might be expected to yield far less net H2 per gram than substrates that are completely fermented in the right colon. 1556190
606 Our results (Table III) showed that high H2 tensions had little, if any influence on H2 liberation by pure cultures of two typical colonic bacteria (B. fragilis, E. coli). While an effect on H2 production cannot be totally excluded, it seems likely that the major effect of PH2 is on the rate of H2 consumption. 1556190
607 Our results demonstrate that, despite comparable rates of H2 production, the amount of H2 released from well-stirred fecal contents would be many-fold greater than from poorly stirred feces. 1556190
608 Such in- creased consumption could result from decreased fecal stirring, an increase in numbers and/or efficiency of H2 consuming fecal organisms, or a migration of methanogens from the left to the right colon. 1556190
609 The marked day-to-day variations in an individ- ual's breath H2 response to a given dose of non-absorbable carbohydrate and the sudden increase in H2 excretion reported during periods of stress (25) more likely are attributable to vari- ations in colonic stirring than to acute alterations in the colonic flora. 1556190
610 The present study demonstrated that at high PH2, human feces are able to oxidize H2 at an extremely rapid rate. 1556190
611 Thus, we conclude that the site of lactulose fermentation is physically separated from that of CH4 formation, a concept supported by studies in CH4 producers showing that CH4 pro-duction occurs mainly in the left colon (26, 27) while the right colon should be the primary site of lactulose fermentation. 1556190
612 While there are no quantitative data on stirring of colonic contents, it is tempting to speculate that efficient co- lonic mixing explains why some subjects have symptoms of excessive gas such as abdominal distention and flatulence in spite ofdelivery of normal quantities of fermentable substrate to the colon. 1556190
613 1556190
614 Furthermore it is possible to stop methanogenesis in some subjects fed inorganic sulphate. 1855683
615 By contrast, the high dietary sulphate consumed by the British population is associated with the carriage of significant sulphate reducing bacteria. 1855683
616 In the present studies sulphate absorption paralleled sulphate losses in urine, with absorbed sulphate being largely excreted within 24 hours in urine 1855683
617 Our results show that ileal infusion of a trigly- ceride, free fatty acids of different chain length and saturation, aphospholipid, detergents, and a deconjugated bile acid all delayed stomach to caecum transit time. 2128071
618 The fact that all of the 'active' substances are lipid soluble suggests that the ability to partition into cell membranes may be a prerequisite for interacting with receptor mechanisms. This suggestion is supported by the observation that the more water soluble substance taurocholic acid that interacts with a membrane bound receptor did not delay stomach to caecum transit time, but actually caused a small but significant acceleration in stomach to caecum transit time. 2128071
619 DPDPE (i.c.v.) was equipotent in inhibiting diarrhea and in eliciting analgesia, but did not effect the rate of transit. 2540324
620 The mu agonists, morphine and PLO17, given i.c.v, inhibited diarrhea at doses much lower than those needed to produce analgesia or to inhibit gastrointestinal transit.  2540324
621 U50,488H (i.c.v.) inhibited diarrhea only at extremely high doses which also caused profound postural-motor incapacitance. 2540324
622 When administered i.c.v., morphine, PLO17 and DPDPE inhibited diarrhea in a dose-related fashion 2540324
623 When given peripherally, morphine, PLO17, DPDPE and U50,488H all inhibited diarrhea in a dose-related fashion. 2540324
624 All four compounds inhibited diarrhea at doses much below those needed to cause analgesia. Morphine s.c. and PLO17 s.c. both inhibited diarrhea at doses lower than those required to inhibit transit. DPDPE s.c. and U50,488H s.c. had no effect on transit at any dose. 2540324
625 A history of allergy (allergic rhinitis, sinusitis, or asthma) was noted frequently in the study population and more commonly in those with chronic giardiasis. 2578921
626 An increased frequency of constipation and upper gastrointestinal complaints in patients with chronic giardiasis was noted. 2578921
627 Immunologic abnormalities have long been linked to giardiasis, and a secretory IgA deficiency has been reported (16). 2578921
628 We also found milk intolerance to be more common in chronic giardiasis than acute. 2578921
629 Fever was substantially more common in patients with acute giardiasis. 2578921
630 Multiple doses of MDMA, cules resulting from a structural change may be a methamphetamine or fenfluramine can induce degeneration of serotonin nerve termi- nals, as evidenced by a decrease in the number of central 5-hydroxytryptamine (5-HT) uptake sites and an irreversible loss of brain TPH activity and 5-hydroxyindole content 2714371
631 Seven patients with hypercholesterolaemia were treated for 4 weeks with activated charcoal at a dose of 8 g three times a day. Plasma total cholesterol and LDL-cholesterol decreased by 25% and 41%, respectively, whereas HDL-cholesterol increased by 8%. Side-effects were negligible. 2874369
632 Its lack of effect in these patients suggests that excessive opioid activity does not contribute to slow colonic transit. 2979677
633 Neither nalmefene nor naloxone appeared to have any effect on slow-transit constipation. 2979677
634 Recently Kaufman et reported that parenteral naloxone does not effect colonic transit in normals suggesting that opioids do not regulate colonic transit in the normal bowel. 2979677
635 Exogenous opioids (both alkaloids and peptides) have been shown to depress the peristaltic reflex 3070578
636 In the rabbit isolated ileum, opioids inhibited, and naloxone stereospecifically enhanced propulsive peristaltic contractions (232). 3070578
637 It displayed high affinity to opioid mu-receptors (485) and has been proposed from in vivo studies to block mu- and kappa-receptors but to activate sigma-receptors (274 3070578
638 N-allyl-normetazocine (SKF 10.047). This opioid alkaloid inhibited the longitudinal muscle contraction in a naloxone reversible fashion, but enhanced both reflex peristalsis and rhythmic penistaltic contractions elicited by acetylcholine (240). 3070578
639 Schang et al. (371) concluded from their human studies that morphine promoted stationary spiking activity (mixing segmentations) and suppressed propagating spike bursts (which may relate to propulsive circular muscle contractions) in the colon of healthy volunteers 3070578
640 Since naloxone probably mmrors the action of endogenous opioids, these results support the notion that gastrointestinal opioids might inhibit acetylcholine release and thereby penistalsis at least partially by decreasing the concentration of intracellular free calcium at that particular site, where it is required for stimulus-release coupling. 3070578
641 The amplitude of ascending contractions (145a) and the frequency of expulsive peristaltic contractions (234) were increased or decreased by opioids, respectively. 3070578
642 This contrasts with an earlier report showing that opioids are at their highest concentration in the duodenum (417). 3070578
643 This gradient describes the phenomenon, from oral to aboral, of decreasing frequency of peristaltic waves and decreasing sensitivity to the distension stimulus. 3070578
644 Dahl et a!. (75) reported very recently that partial chemical ablation of myentenic neurons increased [Leu5J-enkephalin concentrations in the rat jejunum. Thus, there may be a more than compensatory increase in opioid biosynthesis in the surviving neurons. 3070578
645 However, a high concentration may well correspond to a low functional significance of that pool. 3070578
646 In vitro, spontaneous nonpropulsive contractions were also enhanced upon opioid application in the rat (301, 133, 186, 377), mouse (114), and cat large intestine (475), although contractions elicited by electrical or chemical stimulation were inhibited as expected 3070578
647 It was an important finding, therefore, that naloxone was able to enhance the electrically stimulated release of acetylcholine in the longitudinal muscle myenteric plexus preparation of the guinea-pig ileum (467). 3070578
648 Opioid withdrawal in the guinea-pig ileum in vitro results in a dramatic increase of peristaltic waves per mm (242), suggesting that enhanced motility plays a significant role in withdrawal diarrhea. 3070578
649 The gradient in the excitatory influence of naloxone, which probably mirrors an inhibitory role of endogenous opioids, from oral to aboral might partially explain the well-known “gradient of the intestine” (8, 446). 3070578
650 The gradient in the excitatory influence of naloxone, which probably mirrors an inhibitory role of endogenous opioids, from oral to aboral might partially explain the well-known “gradient of the intestine” (8, 446). This gradient describes the phenomenon, from oral to aboral, of decreasing frequency of peristaltic waves and decreasing sensitivity to the distension stimulus. 3070578
651 A decrease in bile flow has been observed in the isolated rat liver perfused with an endotoxin-containing solution [JO.JI] and resembles the cholestasis seen in patients during infections with gram-negative bacteria. 3235801
652 LPS is predominantly taken up by Kc early after injection [7-10]. 3235801
653 This and the other experiments clearly show that the lethal toxicity of LPS is inhibited in the presence of bile, in particular by bile acids. 3235801
654 We have never detected endotoxin in the portal blood of normal rats. The same was found for humans 3235801
655 Highly significant differences in the proportion of subjects with detectable methane in breath were found; % producers--rural black 84, urban black 72, white 52, Indian 41 (chi 2 121 p less than 0.001 3 df). 3396948
656 Studies from this laboratory (5) found that, in addition to HDL, low density lipoproteins (LDL) markedly reduced the cytotoxic effects of LPS added to bovine aortic endothelial cell cultures compared to cells that did not have lipoproteins present in the medium. 3517876
657 Fecal lipid elimination was significantly increased (P < 0.05) in each cocoa butter group when compared with the corresponding corn oil group, resulting in lower digestibility coefficients for cocoa butter (59—72%) than for corn oil (93—97%) 3585514
658 Fecal lipid elimination was significantly increased (P < 0.05) in each cocoa butter group when compared with the corresponding corn oil group, resulting in lower digestibility coefficients for cocoa butter (59%-72%) than for corn oil (93%-97%) 3585514
659 The absence of methane excretion with inflam- matory bowel disease and pneumatosis cystoides intestinalis may result from an altered epithelial mucosa. 3965369
660 The absence of methane excretion with inflammatory bowel disease and pneumatosis cystoides intestinalis may result from an altered epithelial mucosa 3965369
661 The finding of negative correlations be- tween the concentrations of H2 and H2S, and H2 and CH4 presumably reflects the importance of disposal of H2 via methanogenesis or H2S production. 3965369
662 The similarity in methane production after faecal fermentation both in healthy breath methane excretors and non-excretors may indicate that methane is produced by all subjects but in varying concentrations, and that only when the production reaches a threshold level does methane appear in the breath. 3965369
663 A group of patients with conditions associated with possible reduced colonic blood flow have been shown to have an increased incidence of breath methane. 3965369
664 A group of patients with conditions associated with possible reduced colonic blood flow have been shown to have an increased incidence of breath methane.25 3965369
665 In sharp contrast, we have observed that H2S, methanethiol, and dimethylsulfide (as opposed to dimethyl disulfide) were the predominant sulfur gases in the flatus (unpublished data). 3965369
666 It has been demonstrated that methanogens exist in high concen- tration only in the left colon, whereas sulfate-reducing bacteria may be present throughout the colon (7). 3965369
667 It has been demonstrated that methanogens exist in high concen- tration only in the left colon, whereas sulfate-reducing bacteria may be present throughout the colon (7). Hence, sulfate-reducing bacteria (which exist in the 3965369
668 It is possible that methane producing bacteria colonise the mucosa of the distal intestine where there is a complex microbial ecology.2 3965369
669 Such wild swings were not observed, suggesting that a sizable fraction of Nz was derived from a more constant source of delivery, i.e., diffusion from the blood. 3965369
670 The positive correla-tion between the flatus volumes of H2 and C02, (r = 0.56, P < 0.001) suggests that CO2, like H2, was derived predominantly from bacterial fermentation. 3965369
671 The positive correlation observed between H2S and methanethiol concentrations in flatus could reflect the common origin of both gases from H2S or some environmental factor(s) that independently en- hances the production of each of these gases. 3965369
672 Whereas the sole source of H2 in the gut is bacterial fermentation, CO2 may be derived from fermentation, diffusion from the blood, or the interaction of bicarbonate and acid. 3965369
673 Diffusion from the blood could not have been an appreciable source of flatus CO2 because the CO2 concentration of rectal gas averaged 34.7% (285 Torr), well in excess of the roughly 50 Torr present in venous blood. 3965369
674 Haines et a120 found that 80% of patients with large bowel carcinoma (n=30) excreted methane compared with 40% of non-gastrointestinal patients, whereas other workers,"1 showed that only 42% of patients with unresected large bowel carcinoma (n=55) excreted breath methane. 3965369
675 Large amounts of CO2 may be released in the upper gastroin- testinal tract from the interaction of bicarbonate and acid or from ingested carbonated beverages. However, this gas is very rapidly absorbed during passage through the small bowel and thus does not contribute to rectal gas. 3965369
676 The flatus samples of all individuals contained H2S, and the concentration of this gas was not influenced by the presence or absence of CH4. 3965369
677 A common factor in all cases of this type is the simultaneous occurrence of relatively high concentrations of fat, bacteria, and bile salts at a particularsite,either in the small intestine as above or in the colon. 4418840
678 The finding of significant amounts of 10-hydroxy- stearic acid in the faecal fat ofpatients with steatorr- hoea is of more than academic interest as hydroxy acids occur in a number of purgatives (Table V). Thus, the presence of this fatty acid could be a factor in producing the diarrhoea which, in the great majority of cases, is associated with steatorr- hoea. 4418840
679 The main site of formation of OHSA in ileal resection patients is therefore in the colon. This is probably true also in patients with chronic pancreatic insufficiency: in the one patient with this condition who also had an ileostomy, low faecal OHSA excretion was observed in the face of gross steator- rhoea. 4418840
680 These facts suggest that the major differences in composition of dietary fat and faecal fat are due to transformation of unabsorbed fat by the micro- organisms in the gut, e.g., by reduction of linoleic acid, oxidation of stearic acid, and syntheses of oleic acid isomers, probably from stearic acid. 4418840
681 Ingestion of lactulose, a nonabsorbable disaccharide, did not influence the breath CH~ excretion of individuals studied over a 5 hr period (see Fig. 7). 5111441
682 Ingestion of lactulose, a nonabsorbable disaccharide, did not influence the breath CH4 excretion of individuals studied over a 5 hr period (see Fig. 7). 5111441
683 It follows that the major alteration in the composition of the unabsorbed dietary fat must occur in the colon. 5771672
684 The previous dietary study (Webb et al, 1963) in intact subjects showed that the composition of the dietary fat made little difference to the composition of the faecal fat; the present study has shown that in the small intestine only minor changes occur in the nature of the dietary fat, mostly attributable to the addition of non-dietary fat, possibly from desquamation of intestinal epithelium. 5771672
685 Opiates have pronounced effects on gastrointestinal motility and can reverse diarrhoea. 6130292
686 These findings support our hypothesis that a relative or absolute excess of endogenous opioids or an altered opiate receptor affinity may contribute to or cause hypomotility in severe idiopathic constipation, and that a specific opioid antagonist can effectively reverse this state. 6130292
687 Table 1. Polysaccharide content of some cereal products (g 100 g-1 dry matter) 6319817
688 No triglyceride is found in normal feces. 6342528
689 There is no evidence for absorption of long-chained lipids in the colon. 6342528
690 During transit, several bacterial modifications occur. These include hydrol­ ysis of glycerides, phospholipids, wax esters, and cholesterol esters by vari­ ous bacteriallipases (160, 161), hydroxylation of double-bonds of fatty acids (160), and dehydrogenation, epimerization, and deconjugation of bile salts (162, 163). 6342528
691 Every strain grew well on each complex medium examined, with the exception of Balch medium 3, which is essentially Balch medium 1 plus 1.5% NaCl (Table 3). 6798932
692 Every isolate grew with H2-CO2 or formate as the energy source (Table 2). Growth with for- mate was poorer than it was with H2-CO. 6798932
693 These results suggest that Methanobrevibacter smithii is the dominant methanogen in the hu- man large intestine. 6798932
694 In addition manni- tol has little affinity for facilitated transport systems, is non-toxic, and very small metabolic losses occur after it is injected intravenously. 6818037
695 All subjects in the present study excreted mannitol naturally, even four subjects who had fasted for 2 days. 6818037
696 Permeabilitv characteristics of the gastrointestinal tract are of interest since abnormalities have been shown to occur in pathological states such as coeliac disease [1-31. 6818037
697 Since mannitol did not disappear after 2 days fasting the possibility of an additional source, such as endogenous production, or release from dietary fibre by the action of colonic bacteria, cannot be excluded. 6818037
698 Sufficient is absorbed after ingest- ing 2-75 mmol orally to give easily measured plasma and urinary levels, although the optimum dose and samples to be taken for assessing gastrointestinal permeability should be established. 6818037
699 The present study does not support this conclusion since stool cultures caused breakdown of mannitol to acid and carbon dioxide. 6818037
700 In most subjects the amount of mannitol excreted was too small to signifi- cantly affect calculations of the amount excreted. 6818037
701 In contrast with previous studies we have shown that lactulose ingestion can increase methane pro- duction. This should not be surprising, as hydrogen and carbon dioxide are end-products of bacterial metabolism of lactulose and may be substrates for methane production by methanogenic bacteria.7 7450560
702 It is of interest, however, that half the subjects did not increase breath methane levels when given lactulose, despite rises in hydrogen production and the presence of baseline levels of methane. This indicates that available substrate does not ensure methane production in the presence of methano- genic bacteria. 7450560
703 The present results suggest that the adenosine A1-receptor antagonist selectively enhances the lower gastrointestinal propulsion, resulting in defecation without diarrhea. 7494374
704 Incubating human granulocytes ( I07/ml), demonstrated to contain a highly selective opiate alkaloid receptor (μ3; Makman et al. 1995), with authentic morphine caused spontaneously active cells (ameboid conformation and moving) to become inactive and round, an action that can be antagonized by naloxone (Fig. 2; Makman et al. 1995). 7556563
705 We surmise these opiate alkaloid substances produced by the worm are used to downregulate host immune responsiveness so as to prevent a host-mediated immune attack (Stefano and Scharrer 1994). 7556563
706 (5) coincubation with PMN increases the endogenous level of this material found in the worm, indicating the presence of a positive feedback loop; 7556563
707 The present study demonstrates the following: (I) Morphine- and codeine-like molecules are present in S. mansoni 7556563
708 It was found that non-survivors were more likely to have low endogenous levels of IgG which failed to recover. 7561138
709 Human liver bile inhibited methanogenesis at all concentrations tested (03-30/o v/v), and this effect was reversed by cholestyramine. 7590441
710 (ii) Even in methanogenic humans, caecal production of methane is small compared with faecal production of methane.” 8003641
711 (iii) There is a virtual absence of methanogenesis in Crohn’s patients. l8 8003641
712 Bile acids are detergents which, if present in sufficiently high concentrations, inhibit all bacteria. 8003641
713 Black Africans have quick colonic transit times relative to Cau~asians,~ yet have a methano- genesis prevalence of 8S%, compared with prevalences in Indian and Caucasian populations of 25-509’0.~ 8003641
714 However, it is reasonable to suppose that increased bile acid losses into the colon might occur in humans who ingest high fat diets. (iv) This could explain the variations in the prevalence of methanogenesis among different ethnic groupsS4 (v) This could also explain the finding that breath methane correlates inversely with 0be~ity.l~ 8003641
715 Nitrate, however, does not reach the human colon in significant amounts 8003641
716 On the other hand, others have reported that Methanobrewibacter smithii from hu- man faeces is inhibited by bile.z1 8003641
717 Second, Oxoid bile acid inhibits methanogenesis in the in vitro faecal cultures in a dose related manner (Figs 1-3). 8003641
718 Therefore, in such environments, sulfate-reducing or nitrate-reducing bacteria outcompete methanogens for hydrogen. 8003641
719 Thus, bile acid losses into the colon may be an important determinant of net hydrogen production in the colon. 8003641
720 With efficient removal of hydrogen by hydrogen-consuming bacteria, oxidation of substrate can proceed more fully to acetate.2 8003641
721 (i) colonic transit time. This has been found to be longer in methanogenic humans than in ‘non-methanogenic’ humans in a homogeneous Western population. l6 8003641
722 Certain incompletely oxidizing reactions proceed only at low hydrogen concentrations so that without removal of hydrogen, there is more production of the reduced bioproducts, proprionate and butyrate. 8003641
723 The terminal ileum and its function are commonly impaired in Crohn’s disease, and thus bile acid losses into the colon are considerably > 0.5 g/day. 8003641
724 This is probably an important mechanism for maintaining the relative sterility of the normal small intestine. 8003641
725 This argues against retention time in itself being a significant controlling factor in human methanogenesis. 8003641
726 As well, elevated opioid peptide levels were reported in schistosome infected mice and were correlated with the decreased levels of gonadal steroids and the lower reproductive potential of the infected mice 8221115
727 The chronic opioid activation in E. vermiformis infected mice may be associated with changes in immune and inflammatory responses. 8221115
728 Hamsters infected with the blood fluke, Schistosoma mansoni, displayed analgesic responses that were reduced by the prototypic opiate antagonist, naloxone, along with altered locomotory responses sensitive to opiate antagonists 14'15 8221115
729 It is likely, therefore, that the centrally mediated analgesic responses observed in the present study are primarily associated with a differentially increased activity of the hosts endogenous opioid systems. 8221115
730 Recently, we demonstrated that a sub-clinical infection with the enteric sporozoan, Eimeria t,ermiformis, had naloxone sensitive analgesic effects in male mice 5 8221115
731 Interleukin 10 Reduces the Release of Tumor Necrosis Factor and Prevents Lethality in Experimental Endotoxemia 8426124
732 Interlukin 10 Reduces the Release of Tumor Necrosis Factor and Prevents Lethality in Experimental Endotoxemia 8426124
733 LPS activation similarly enhanced CE accumulation almost 3-fold from two CE-rich lipoproteins, βVLDL and LDL, as compared with controls. 8457252
734 Thus, activation of RAW 264.7 macrophages enhanced their ability to accumulate lipid from a variety of lipid particles and to become foam cells. 8457252
735 Thus colonic perfusions of Ensure (Fig. 7) and casein significantly prolonged the cycle length (P < 0.05) of duodenal MMCs, but perfu- sion of maltose and oleate did not. 8572226
736 In this study, we have shown that fat confined to the proximal half of the small intestine also inhibited intestinal transit via a jejunal brake. 8601377
737 A similar gastric relaxation was observed in response to colonic infusion of SCFAs, the products of carbohydrate fermentation. 8690193
738 Our findings show that in healthy subjects, disac- charide delivery into the proximal colon (either by ingestion of the nonabsorbed lactulose or by direct colonic infusion of lactose) induces a significant inhibition of proximal gastric tone. 8690193
739 The pro-glucagon molecule is processed in the intestine into several structurally related peptides, such as oxyntomodulin, glucagon, glucagon-like peptide (GLP) 1, and GLP-2.17 Some of these peptides and PYY inhibit gastric and pancreatic secretions.18–20 8690193
740 However, a sig- nificant increase of the average plasma PYY concentra- tion was observed with respect to the basal level in every group 8690193
741 In addition, several peptides with sequence homology to glucagon are colocalized and probably co-released with PYY in the endocrine L cells of the distal intestine, possibly participating in this control. 8690193
742 In animals, colonic infusion of SCFAs or fermentable nutrients has been shown to release peptide YY (PYY),13,14 which is present in the ileocolonic mucosa. 8690193
743 Lactose infusion increased H2 concentration in exhaled air, whereas SCFA infusion did not. 8690193
744 Several data suggest fatty acids that SCFAs participate in the ileal inhibition of gastric motility induced by nonabsorbed starch; inhibition of starch digestion induces intracolonic fermentation and is associated with slowed gastric emptying. 8690193
745 The incidence va- ries with the ethnic origin of the populations studied: 30-50% for Western subjects (Bjor- neklett and Jenssen, 1982; Bond et al., 1971; McKay etal., 1985; Doré et al., 1995) and 80% or more in rural Africans (Segal et aL, 1988). 8841038
746 An altered intestinal permeability was found in 9 of the 21 (43%) autistic patients, but in none of the 40 controls. 8888921
747 We speculate that an altered intestinal permeability could represent a possible mechanism for the increased passage through the gut mucosa of peptides derived from foods with subsequent behavioural abnormalities. 8888921
748 The results of this study showed that ivermectin therapy is effective against both parasites at a dose of 200 micrograms/kg. 8918027
749 After brief ( < 30 min) treatment of DRG neurons with GM1 ganglioside, the threshold concentration of the opioid peptide, dynorphin A-(l-13) required to prolong the APD in many DRG neurons is markedly decreased from nM to fM levels ([38]; see also [33]) and the opioid antagonist, naloxone unexpectedly prolongs the APD of GMl-treated cells [10]. 8974633
750 We have recently demonstrated that very low (pM) concentrations of naloxone or naltrexone can selectively antagonize excitatory opioid receptor functions in naive DRG neurons [49], similar to the action of pM etorphine or diprenorphine on these cells [11,35]. 8974633
751 Since naloxone accelerated intestinal transit during fat induced jejunal (32) and ileal (33) brakes, the inhibitory response to fat may also depend on a naloxone lockable opioid pathway. 9009111
752 Patients with chronic back pain consume over twice as much caffeine as patients without chronic back pain. 9014959
753 The finding of negative correlations be- tween the concentrations of Hz and H2S, and H2 and CH4 presumably reflects the importance of disposal of Hz via methanogenesis or H2S production. 9176210
754 Although bacterial metabolism would be expected to liberate H2 and COZ in a roughly constant ratio, the volume of gas passed correlated positively with the concentration of CO2 but not HZ; i.e., COZ production appeared to rise out of proportion to that of Hz. 9176210
755 Hence, sulfate-reducing bacteria (which exist in the right colon of virtually all subjects) could account for the H2S observed in the flatus of all subjects. 9176210
756 It has been demonstrated that methanogens exist in high concen- tration only in the left colon, whereas sulfate-reducing bacteria may be present throughout the colon (7). 9176210
757 Given that methanogens and sulfate-reducing bacte- ria usually are mutually exclusive in human feces, we expected to find a strong negative correlation between the CH4 and H2S concentrations of flatus. Surprisingly, no such negative correlation was observed. The flatus samples of all individuals contained H2S, and the concentration of this gas was not influenced by the presence or absence of CH4. 9176210
758 Large amounts of CO2 may be released in the upper gastrointestinal tract from the interaction of bicarbonate and acid or from ingested carbonated beverages. However, this gas is very rapidly absorbed during passage through the small bowel and thus does not contribute to rectal gas. 9176210
759 In conclusion, the evidence presented in this report clearly shows that the intestinal transport of undegraded, nondenatured proteins (here exemplified by bromelain) can take place to a small but significant extent in the healthy adult male. 9252520
760 Recently, it was noted that beta-endorphin infusion increased glucagon and decreased insulin levels at 60 and 90 minutes of exercise in rats, compared with saline infusion,l72 9257407
761 Exercise of sufficient intensity and duration has been demonstrated to increase circulating beta-endorphin levels. 9257407
762 These findings suggest that the regulation of secretion and absorption by μ receptors involves a regulation of blood flow in the intestinal wall especially in the submucosal and mucosal layers. 9300443
763 This result leads to the hypothesis that μ receptors are involved in neuroimmune interactions via nerve endings mechanisms. Under certain circumstances such as inflammation,59 μ receptor sites might be activated by endogenous μ agonists released by intestinal immune cells. 9300443
764 Infusion of U50488, a selective kappa-agonist (33 nmol), into the third cerebroventricle in sated rats, potently stimulated the intake of HF only in the OM rats, whereas it induced a significant but moderate stimulation of intake of both HF and LF diets in the S5B/P1 rats. 9437746
765 Of the commonly used agents, mupirocin (pseudomonic acid) ointment has been shown to be 97% effective in reducing S. aureus nasal carriage. 9475834
766 S. aureus nasal carriers have a two- to tenfold increased risk of developing S. aureus surgical site or intravenous catheter infections. 9475834
767 Bismuth Subsalicylate Markedly Decreases Hydrogen Sulfide Release in the Human Colon 9558280
768 Fecal homogenates showed a dose-dependent relationship between the concentration of bismuth subsalicylate and H2S release.  9558280
769 Treatment of subjects with bismuth subsalicylate produced a >95% reduction in fecal H2S release. 9558280
770 In our population-based prospective study, the association between regular alcohol intake of various quantities and 5-year progression of carotid atherosclerosis was J-shaped, with light drinkers facing a lower risk than either heavy drinkers or abstainers (Figure 3a). 9596232
771 Figure 3c 9596232
772 Occasional drinking, ie, alcohol intake less than once a week, had essentially no effect on incidence and progression of atherosclerotic lesions. 9596232
773 Epicatechin, a flavonoid that is a major component of cocoa and dark chocolate, is a well-known antioxidant associated with a lower risk of stroke and heart failure (8, 24, 30). 9643451
774 Flavonoids Reduce Morphine Withdrawal In-vitro 9643451
775 Furthermore, these studies show an inverse correlation between the intake of flavonoid-rich cocoa products and mortality because of coronary heart disease  9643451
776 Other groups have concluded that antinociception induced by flavonoids underlies the activation of the opioid system since this observed analgesic effect was reversed by naloxone (15).  9643451
777 Studies show that 6.3 g (30 kCal) per day of dark chocolate containing 30 mg of polyphenols are sufficient to reduce blood pressure in hypertensive patients (31). 9643451
778 In conclusion, we show that subantioxidant doses of epicatechin produce cardiac protection via δ-opioid receptor stimulation and activation of downstream survival and antiapoptotic pathways, thus defining a receptor-mediated mechanism for epicatechin action. 9643451
779 Of these 511 subjects, 285 (56%) showed significant im- provement while taking 5-HTP. 9727088
780 Tryptophan hy- droxylase can be inhibited by numerous fac- tors, including stress, insulin resistance, vita- min B6 deficiency, and insufficient magne- sium. 9727088
781 5-HTP acts primarily by increasing levels of serotonin within the central nervous system. Other neurotransmitters and CNS chemicals, such as melatonin, dopamine, nor- epinephrine, and beta-endorphin have also been shown to increase following oral admin- istration of 5-HTP.7-10 9727088
782 Casein triggers strong intestinal braking - refer other claims 9770556
783 In young children, chronic constipation can be a manifestation of intolerance of cow's milk. 9770556
784 The charcoal lined cushion effectively limits the escape of these sulphur-containing gases into the environment 9771412
785 Sulphur-containing gases are the major, but not the only, malodorous components of human flatus. 9771412
786 For example, in an earlier study, reducing the resistance to cholesterol flow by overexpressing CETP in the mouse lowered the HDL-C concentration from 59 to 15 mg/dl, yet the rate of centripetal cholesterol movement from the peripheral organs remained constant at about 89 mg/day per kg (2). 9799800
787 In hamsters, the concentration of cholesteryl esters carried in HDL was nearly twice as high in animals fed a Western-style diet as in those receiving psyllium in the diet, yet the absolute flux of these sterol esters to the liver was essentially the same (32). 9799800
788 Similarly, the HDL-C concentration was increased from about 28 to 121 mg/dl when LCAT was overexpressed in the rabbit (31). 9799800
789 However, in 32 individuals subjected to external sterol balance, the rate of whole body cholesterol synthesis remained remarkably constant in the face of a 4- fold variation in the plasma HDL-C concentration (33, 34). 9799800
790 These studies provide direct evidence that in the mouse, the concentrations of HDL-C and apoA-I in the plasma play no role in maintenance of cholesterol homeostasis in any peripheral organ and do not regulate the rate of net centripetal flux of sterol from these tissues to the liver. 9799800
791 Thus, in this situation, there is no accumulation of cholesterol in the peripheral organs, no change in the net flux of cholesterol to the liver, and no change in the excretion of this sterol as neutral fecal sterols or as bile acids. 9799800
792 Administration of leptin was found to reduce food intake in both normal and ob/ob mice (17, 18). 9874578
793 The protective role of leptin reminds us of another class of TNF-induced hormones, namely glucocorticoids. Also in this case, mice devoid of a functional glucocorticoid system (by adrenalectomy or administration of a receptor antagonist) are highly sensitized to the toxic effects of TNF (27, 28). 9874578
794 A single injection of TNF into animals causes acute anorexia, weight loss, metabolic derangement, hypotension, and, at very high doses, shock and death as a result of a widespread systemic inflammatory reaction (2, 3). 9874578
795 After bisacodyl infusion, about 90% of patients showed a motor response characterized by the appearance (within on average 13 +/- 3 min) of one or more high-amplitude propagated contractions, the manometric equivalent of mass movements, and about 75% of these were followed (mean 18.5 +/- 4 min) by defecation. 9892801
796 An additional potential problem with the chronic ingestion of megadoses of activated charcoal is that such doses might decrease the availability of essential nutrients as well as concurrently administered medications. 9934757
797 Given that the binding sites of the activated charcoal in feces would be exposed to sulfur gases (as well as a variety of other compounds) during passage through the gut, it is not surprising that all binding sites had been filled by the time the feces reached the rectum. 9934757
798 In initial studies, we found that dry powdered charcoal rapidly bound sulfur-containing gases 9934757
799 Thus, we conclude that administration of activated charcoal does not provide a practical means of reducing fecal gas release. 9934757
800 Addition of colostrum to drinking water (10% vol/vol) prevented villus shortening in the mouse model of small intestinal injury. 10205201
801 Colostrum increased proliferation and cell migration of RIE-1 and HT-29 cells. 10205201
802 It is unclear, for instance, if a lysosomal preparation from T84 cells does contain an enzyme equivalent to the acyloxyacyl hydrolase of neutrophils required for detoxification of lipid A (Luchi and Munford, 1993). 10330399
803 It was recently shown that lipopolysaccharide (LPS)1 deposited at the apical surface of cultured polarized epithelial cells was recovered at the opposing basolateral side of the epithelium (Beatty and Sansonetti, 1997). 10330399
804 Morphine and fentanyl (i.c.v. and s.c.) inhibited GIT and PER in a dose-related manner 10385239
805 Pretreatment with ABs or ODN to μ-OR, blocked the central effects of μ (but not δ) agonists on GIT and PER. 10385239
806 These findings demonstrate that signaling via MyD88 is essential for LPS response, but the inability of MyD88 knockout mice to induce LPS-dependent gene expression cannot simply be attributed to lack of the activation of MAP kinases and NF-κB. 10435584
807 They demonstrated that 165 mL of strong regular or decaffeinated coffee increased CCK levels and decreased gallbladder volume by approximately 30%, whereas the control solution did not show an effect (55). 10499460
808 They studied the effects of 240 mL of regular coffee, decaffeinated coffee, water and a 1000 kCal meal on colonic motility. Regular coffee, decaffeinated coffee and the meal induced more colonic activity and more propagated contractions than water. 10499460
809 As anticipated, subjects with various chronic and recurrent bacterial infections constitute a second large population in which high ETX predicts a markedly elevated risk of incident carotid atherosclerosis. 10588212
810 This finding fits well into the concept that it is not smoking itself (exposure to nicotine and other smoke ingredients) but chronic bronchial infections and/or bacterial colonization that represent the actual atherogenic culprit. 10588212
811 The significance of chronic minor infections in the mediation of smoking effects on atherosclerosis is substantiated by our finding that the incidence of carotid atherosclerosis was no higher in current and ex-smokers with ETX concentrations lower than 50 pg/ml than in non-smokers (Fig. 4). 10588212
812 For example, the inflammatory effects of endotoxin are blocked by the cytokine IL-10 (13) and antioxidants (14). 10588213
813 24.0% of atherosclerotic cases (A) and 52.3% of controls (C) were negative for C. pneumoniae lipopolysaccharide antibodies (p = 0.00002). 10611843
814 The results show that a persistent C, pneumoniae infection with evidence of lipopolysaccharide immunoglobulin G and A is equally associated with the atherosclerotic alteration of coronary arteries, carotid arteries and peripheral arterial occlusive disease, irrespective of the severity of atherosclerosis and with no predisposition to any particular vascular region. 10611843
815 Immunofluorescent staining of T84 cells demonstrated the cell-surface presence of the TLRs 10623846
816 Thus, IEC may play a frontline role in monitoring lumenal bacteria. 10623846
817 TLR4 protein was expressed in all cell lines; however, TLR2 protein was absent in HT29 cells. 10623846
818 Cocoa butter, consumed as black chocolate within a normal mixed diet, has a high digestibility, similar to that of corn oil, and a digestible energy value of 37 kJ=g in man. Thus, cocoa butter cannot be considered to be a low-calorie fat 10694782
819 Proximal colonic filling at 6 hours, a measure of orocecal transit, was accelerated by tegaserod (70.4% ± 1.3% [mean ± SEM] vs. placebo, 46.4 ± 1.9; P = 0.015). 10702196
820 Gastric emptying was unaltered by tegaserod 10702196
821 Proximal colonic emptying half-time and geometric center at 48 hours were also accelerated by tegaserod compared with baseline, but not compared with placebo. 10702196
822 Atherosclerosis in germ-free animals was not measurably different from that in animals raised with ambient levels of microbial challenge 10770809
823 To determine if responses to gram-negative bacteria are necessary for atherogenesis, we first bred atherosclerosis-prone apolipoprotein (apo) E-/- (deficient) mice with animals incapable of responding to bacterial lipopolysaccharide. Atherogenesis was unaffected in doubly deficient animals 10770809
824 After 6 weeks of supplementation with 600 mg emulsified oil of oregano daily, there was complete disappearance of Entamoeba hartmanni (four cases), Endolimax nana (one case), and Blastocystis hominis in eight cases. 10815019
825 Caffeine increases spike activity in the colon, and its effect may be dose-dependent. 10831259
826 Furthermore, secretion from the small intestine may also be involved in this mechanism, since caffeine increases small-intestinal secretion dose-dependently (8). 10831259
827 This hypothesis is based on the finding that colonic motility was significantly increased by both gastrin and cholecystokinin (7). 10831259
828 Gastric and jejunal slow waves are not affected by caffeine. 10831259
829 Like many receptors that utilize Gi subfamily members for signal transduction, the opioid receptors have long been known to inhibit adenylyl cyclases (17) and Ca2` channels (18, 19), as well as to stimulate K` channels (20) and to increase intracellular Ca2` levels (21). 10836142
830 Opioid receptors are known to suppress the release of neurotransmitters in many pharmacological preparations by preventing Ca2` influx. 10836142
831 Opioid receptors are prototypical ‘‘Gi/Go-coupled’’ receptors because opioid signals are efficiently blocked by pertussis toxin (PTX), a bacterial toxin produced by Bordetella pertussis that ADP-ribosylates and inactivates the a subunits of Gi/Go proteins (Gai/o subunits). 10836142
832 This result suggests that the morphine from Ascaris can act on immune cells to enhance its survival. 10861070
833 Thus, Ascaris may secrete this opiate alkaloid to diminish its “flushing” from the host because a secondary effect on gastrointestinal motility is to induce constipation. 10861070
834 Complementing the present study are reports that Schistosoma synthesize a morphine-like compound inhibiting immunocytes in a naloxone-reversible manner (22). 10861070
835 These two pieces of data suggest that, in Ascaris, morphine is secreted into the microenvironment where it could be used as a signaling molecule. 10861070
836 Using another approach, organisms such as the Ascaris worm produce opioids such as morphine, ostensibly to impair peristalsis and thereby avoid mechanical elimination [4]. 10861070
837 Our previous studies have shown that stimulation of mu-opioid receptors within the nucleus accumbens preferentially enhances intake of palatable food containing sucrose and fat; thus, opioids in this brain area may mediate the rewarding characteristics of food by modulating taste and macronutrient preference. 10938432
838 Activation of the ileal brake requires the presence of end products of nutrient digestion such as fatty acids [5]. This brake initiates a distal-to-proxi- mal intestino-intestinal and intestino-gastric feedback loop that inhibits upper gut motility (to slow gastric emp- tying and intestinal transit) in response to nutrients in the distal small intestine [3•]. 10980979
839 In this setting, transit is no longer tightly regulated, and the luminal content can move freely through the gut. When partially digested nutrients that cannot activate inhibitory feedback provide an osmotic load, fluid shifts further worsen the resultant diarrhea. 10980979
840 Gut glucagon-like immunoreactivity (gGLI), specifi- cally glucagon gene products GLP-1 and GLP-2, may also be important in mediating the ileal brake [9,17••,18]. 10980979
841 In contrast, when insoluble fibers like cellulose or undigested starches reach the colon, bacterial fermentation may pro- duce sufficient quantities of SCFA to trigger the release of PYY [31], resulting in the slowing of transit by triggering the colonic brake [17••]. 10980979
842 The critical reader must bear in mind important species differences among triggers for the ileal brake when evaluating models and studies of its action. In dogs and humans, fat is the most potent trigger [1•,3•,7••], with protein and carbohydrate also triggering the ileal brake [8]; in rats, fat [5] and protein are active triggers [9]. 10980979
843 The role of PYY in the fat-induced ileal brake was confirmed when the slowing of intestinal transit by distal gut fat was abolished by intravenous administration of polyclonal PYY antibody [7••]. 10980979
844 This slowing effect was can- celed when the formula was not allowed access to the ileal brake, which supports the idea that the addition of fiber intensifies nutrient-triggered inhibitory feedback by displacing nutrients to the ileal brake (Fig. 5). 10980979
845 Whereas the role of endogenous neurotensin and enteroglucagon in the ileal brake remains poorly estab- lished [1•], an association between slowing of transit and peptide YY (PYY) release triggered by ileal fat perfusion has been shown repeatedly [11,12]. 10980979
846 A female bias (p = 0.012) for methanogenesis (63% females vs 37% males), which has been found in most studies (6, 17, 21, 22, 32), is unlikely to be a chance finding. 11051362
847 For example, males have on average faster colonic transit (22, 23) that would dilute methanogens, which are extremely slow growing anaerobes whose carriage is favored by slow transit. 11051362
848 Once established, the microbial ecology is remarkably stable and prevents colonization of other species or subspecies 11051362
849 In several studies β-oxidation was found to be significantly reduced and sulphur-reducing bacteria were increased in colonocytes of acute and quiescent ulcerative colitis [2, 9]. 11079736
850 It is postulated that ulcerative colitis is due to either exogenous (decreased luminal availability) or endogenous (impaired intracellular oxidation of butyrate) starvational factors limiting fattyacid oxidation in colonocytes [2, 7]. 11079736
851 One possible explanation for the impaired butyrate metabolism could be the presence of reducing sulphur substrates, produced by sulphur reducing bacteria in the colon [8]. These sulphur substrates might inactivate fatty-acid dehydrogenases or butyryl-CoA synthetase [2]. 11079736
852 One possible explanation for the impaired butyrate metabolism could be the presence of reducing sulphur substrates, produced by sulphur reducing bacteria in the colon [8]. These sulphur substrates might inactivate fatty-acid dehydrogenases or butyryl- CoA synthetase [2]. 11079736
853 Antagonistic activity was produced byNCFM against foodborne disease agents, Staphylococcus aureus, Salmonella typhimurium, enteropathogenic Escherichia coli, and Clostridium perfringens (Gilliland and Speck, 1977a). 11233016
854 In vitro tests of inhibition indicated a range of activity only against other Lactobacillus strains and Enterococcus faecalis, not against pathogens (Barefoot and Klaenhammer, 1983). 11233016
855 NCFM was reported to take up cholesterol in the presence of bile and in the absence of oxygen, both conditions present in the intestinal tract. 11233016
856 Studies conducted on rats consuming a meat-based diet showed a lower incidence of colon cancer after a 20-wk experimental period, suggesting that the NCFM supplement increased the latency period for colon cancer in experimental rats (Goldin and Gorbach, 1980). 11233016
857 These studies suggest that NCFM inhibits the populations or activities of dimethylamine- and nitrosodimethylamine-producing overgrowth bacteria, and can positively influence colonization of the small bowel. 11233016
858 Bacterial overgrowth is accompanied by production of toxic metabolites, including nitrosodimethylamine and dimethylamines. These compounds can be measured in the blood of the patients. 11233016
859 Fermentation results in 34% D- and 66% L-lactic acid. 11233016
860 In vitro studies have shown that the majority of strains of Lactobacillus frequently (but not always), produce bacteriocins that kill closely related species. 11233016
861 Inhibition resulted from organic acids, hydrogen peroxide, and perhaps other antimicrobial products. 11233016
862 L. acidophilus NCFM was found to produce a bacteriocin, designated lactacin B (Barefoot and Klaenhammer, 1983). 11233016
863 The authors concluded that among Sweet Acidophilus milk, yogurt, and buttermilk, none had a significant effect on serum cholesterol. The levels of viable L. acidophilus NCFM were not reported in the study, although typical Sweet Acidophilus milk formulation levels would have provided ~2 × 108 cfu of viable L. acidophilus per day in this study. 11233016
864 These studies show that not all uses of NCFM resulted in an improved digestion of lactose. However, given in adequately high levels, some symptom relief and improved digestion of lactose may occur in lactose maldigesters when they consumeNCFM. Presumably, these effects result from the bacterium’s ability to metabolize lactose during digestion and transit through the GI tract. 11233016
865 2) Reduction of Gram-negative bacteria in the intestines (i.e., sources of endotoxin) with antibiotics (5) or lactobacillus administration (6) minimized early alcoholic liver injury. 11254735
866 3) Early ethanol-induced liver injury can be prevented by gadolinium chloride, a selective Kupffer cell toxicant (7). 11254735
867 4) Early alcohol- induced liver injury was attenuated with TNF-a Abs and was prevented in TNF receptor-1 knockout mice (8, 9). 11254735
868 However, ethanolinduced hepatic injury was minimized significantly here in CD14-deficient mice (Fig. 4). 11254735
869 It was very recently reported that alcohol-induced liver injury, using the same model used in this study, is blunted in the Toll-like receptor 4 mutant C3H/HeJ mouse (36). 11254735
870 TNF-a is increased in alcoholics with hepatitis and levels correlate with survival (35) and appears to be the principle mediator of early alcohol-induced liver injury since injury was blocked in mice lacking the TNF receptor- 1 (9). 11254735
871 1) Ethanol increases permeability of the isolated small bowel to endotoxin in a dose-dependent manner (3) and elevates circulating endotoxin (4). 11254735
872 Elevated circulating endotoxin most likely activates Kupffer cells to release many potent effectors and cytokines, thus leading to tissue injury. 11254735
873 Recent studies show that alcohol exposure increases the expression of CD14 in Kupffer cells (18) and estrogen sensitizes Kupffer cells to LPS via increases in CD14. 11254735
874 The binding of LPS to CD14 triggers the release of endogenous inflammatory mediators including cytokines and free radicals (15, 30–33), leading to inflammation and requires additional molecules for signal transduction, including Toll-like receptors (34, 35). 11254735
875 TLR4 is not present in epithelium from children with inflammatory bowel disease. 11396812
876 Flatus with hydrogen sulfide concentrations > 1 parts per million could be detected by the odor judge, and severity of malodor was highly correlated with hydrogen sulfide concentration. 11453473
877 IEC expressed low levels of TLR4 compared with HMEC and none expressed MD-2. 11466383
878 No IEC line responded to LPS, whereas human dermal microvessel endothelial cells (HMEC) did respond to LPS. 11466383
879 Consistent with their CD14 negative phenotype, lamina propria macrophages displayed markedly reduced LPS-induced cytokine production and LPS-enhanced phagocytosis. 11509607
880 Here we show that resident macrophages isolated from normal human intestine lack CD14 and CD89. 11509607
881 In addition, IgA-enhanced phagocytosis was sharply reduced in lamina propria macrophages. 11509607
882 Thus, the absence of CD14 and CD89 on resident intestinal macrophages, due to down-regulated gene transcription, causes down-modulated LPS- and IgA-mediated functions and probably contributes to the low level of inflammation in normal human intestinal mucosa. 11509607
883 egaserod, 2 mg b.d. and 6 mg b.d., showed a statistically significant relief of overall irritable bowel syndrome symptoms, measured by a weekly, self-administered questionnaire. At end-point, treatment differences from placebo were 12.7% and 11.8% for 2 mg b.d. and 6 mg b.d., respectively 11564007
884 Adenosine suppresses the interdigestive migrating motor complex, cholinergic giant migrating contractions, propulsive motility and morphine withdrawal diarrhea (Suzuki et al., l995; Hancock and Coupar, 1995a). 11579381
885 Thus, nasal carriage of S.aureus takes hold in nasal fluid that is permissive for colonization and induces a local inflammatory response that fails to clear the colonizing bacteria. 11687441
886 Basal PYY was increased in untreated celiac patients (N = 13) compared to patients on a gluten free diet (N = 9) [15.6 (11.8–27.0) pM vs 12.2 (10.1–13.1) pM; P < 0.05] and compared to control subjects (N = 15) [9.5 (8.3–10.4) pM; P < 0.001]. 11713961
887 Furthermore, it confirms that fasting plasma PYY concentrations in untreated celiacs are in- creased compared to normal subjects and that these basal PYY levels decrease when patients follow a gluten-free diet with normalisation of the small intes- tinal mucosa. 11713961
888 In malabsorption syndromes the feedback regula- tion through PYY may be enhanced as a possible compensatory mechanism in reaction to the acceler- ated passage of nutrients (26, 27). In disease states as Crohn’s ileitis, chronic pancreatitis, and tropical and gluten-sensitive sprue, basal plasma PYY levels were found to be elevated (26, 28). 11713961
889 Increased basal and postprandial plasma PYY concentrations were also observed in patients with malabsorption due to tropical sprue and to chronic pancreatitis (26). 11713961
890 Other possible explanations for the in- creased plasma PYY levels are an increased number of (immature) PYY-producing cells in the intestinal mucosa, analogous to the increased amount of CCK producing cells in the proximal small bowel in celiacs (37), or an increased amount of fermentation prod- ucts of unabsorbed nutrients in the colon stimulating release of PYY (38). 11713961
891 Studies in animals indicate that PYY release is not only stimulated by direct effects of stimulating sub- stances acting at or near the PYY-producing cells in the distal gut, but also by activation of mechanisms originating in the proximal gut (22). Release of CCK from endocrine cells in the mucosa is one of the candidate mechanisms originating in the proximal small bowel that has been proposed to play a role (8). 11713961
892 The hormone peptide YY (PYY) is released from endocrine cells in the distal ileum, colon and rectum (1–8). 11713961
893 There- fore, it seems more likely that the increased PYY response to predigested fat is related to the presence of products of fat digestion such as free fatty acids, which are generated by lipolysis of triglycerides in the corn oil meal. 11713961
894 The supposition that generation of free fatty acids is im- portant for appropriate release of PYY is supported by the finding that PYY is stimulated by digestible fat in which the fatty acids can be split off by pancreatic lipases, but not by the undigestible fat sucrose poly- ester (olestra) in which the fatty acids cannot be split off (30). 11713961
895 Due to the significant risk of decreasing analgesic efficacy of the opioids, a better agent would be an opioid antagonist that does not cross the blood–brain barrier. 11779668
896 In addition, opioids contribute to decreased bowel motility by decreasing the release of acetylcholine, resulting in a decrease in parasympathetic activity. 11779668
897 Oral naloxone has some efficacy for relief of constipation in divided doses. 11779668
898 CD14 Expression and Up-Regulation in Response to LPS. The absence of CD14 expression in gastrointestinal tissue was recently suggested to explain the unresponsive phenotype in respect to the normal intestinal flora (12, 13) 11877479
899 The central role of CD14 and TLR4 during this process in vivo is illustrated by the fact that deficient mice are highly resistant to septic shock and that endotoxin hyporesponsiveness in humans is associated with genetic polymorphism in the TLR4 locus (8, 9). 11877479
900 These results indicate that TLR4 is not on the plasma membrane of m-ICcl2 cells during LPS-induced cell activation, but rather in an intracellular compartment 11877479
901 Although macrophages reached significantly higher levels of total chemokine production, both the maximal stimulatory LPS concentration and the time kinetic of MIP-2 secretion in m-IC cl2 cells and RAW 264.7 cells were similar. Both cell types produced maximal MIP-2 secretion at 1 ng/ml LPS (Fig. 1, A and C), and highest chemokine productions were achieved after 6 h of stimulation with LPS (Fig. 1, B and D). 11877479
902 CD14 expression was confirmed by immunohistochemistry, demonstrating a weak surface staining on untreated m-ICcl2 cells and an increasingly intense staining signal after LPS exposure (Fig. 2 B). 11877479
903 However, the response of m-ICcl2 cells was limited to the production of the chemokine MIP-2. 11877479
904 Thus, m-ICcl2 cells synthesize CD14 and seem to enhance rather than diminish their LPS-binding capacity in response to LPS exposure 11877479
905 No secretion of the proinflammatory cytokines TNF-, or IL-6 was detected. 11877479
906 In a preliminary placebo-controlled double-blind study, however, pyridoxine was found to increase cortical arousal during REM sleep and to increase the vividness of the dreams of 12 college students [71], thus demonstrating some influence on sleep 11883552
907 In short, the role of increased permeability in initiation of CD is uncertain; however, there is ample evidence suggesting that it is an important factor in disease perpetuation and reflects an early change in the course of disease. 11907349
908 Several experimental studies strongly suggest that endotoxin is essential in causing alcohol-related liver injury. 11907349
909 These examples suggest that increased intestinal permeability and endotoxemia play a role in either initiation of liver injury or in the progression of liver disease. 11907349
910 This is especially intriguing when occurrence of flare ups of CD after NSAID consumption are considered and suggests that other stressors may have similar effects. 11907349
911 Data presented demonstrate that in a dose-dependent manner, LPS is able to down regulate the mRNA expression of the two primary high-density lipoprotein (HDL) receptors, scavenger receptor B1 (SR-B1) and ATP binding cassette A1 (ABCA1), with a 50% inhibitory concentration of less than 0.2 ng/ml, as well as to decrease SR-B1 protein expression by 80%. 12010990
912 We also found that LPS treatment resulted in a significant decrease (to 20% of the control level) of the specific 125I-HDL binding as well as in 50% inhibition of the HDL-mediated cholesterol efflux compared to untreated cells. 12010990
913 Twenty-eight patients entered the study, which was completed by 25. 'Adequate symptomatic relief' was recorded in six of 14 on naloxone and three of 11 on placebo. Whilst the differences were not significant, improvements in severity gradings and mean symptom scores for pain, bloating, straining and urgency to defecate were greater with naloxone than placebo for all parameters. 12197844
914 Peptides with opioid activity derived from dietary sources, in particular foods that contain gluten and casein, pass through an abnormally permeable intestinal membrane and enter the central nervous system (CNS) to exert an effect on neurotransmission, as well as producing other physiologically-based symptoms. 12223079
915 Moreover, other recent results in rats show that medium chain TAG would protect against lipotoxicity and insulin resistance induced by high fat diet, compared to long chain saturated TAG that are usually reported to be deleterious [100]. 12427787
916 Moreover, the increase in plasma LPS is lower when mice are submitted to a diet containing 35% energy as fat compared 34 with mice fed a high-fat diet [7]. 12427787
917 Our initial studies also suggests that siRNA-induced knockdown of NF-kB and/or p65 prevents the LPSinduced increase in Caco-2 TJ permeability. 12427787
918 Rotaviruses have been shown recently to associate with LDs and the inhibition of LD formation negatively affects viral replication [104]. 12427787
919 The data of this study led us to the hypothesis that the interaction of LPS with TLR4/ MD2 contributes to the perpetuation of the inflammatory epithelial cell injury via TNFa induced alterations of enterocyte turnover in an autoparacrine/paracrine manner. 12427787
920 The time course of TLR-4 expression paralleled the increase in Caco-2 TJ permeability; targeted knockdown of TLR-4 expression or pharmacological inhibition of the TLR-4 signal transduction pathway prevented the LPS-induced increase in Caco-2 TJ permeability, demonstrating the requirement of TLR-4 and the activation of the signal transduction pathway in mediating the LPS-induced increase in Caco-2 TJ permeability. 12427787
921 As compared to water, ingestion of glucose leads to a lower intracellular TG content and increased chylomicron secretion, suggesting that carbohydrate and fat influence each other’s metabolism [47]. 12427787
922 Consistent with our data, previous studies have also shown low or undetectable levels of TLR-4 in healthy human intestine and markedly elevated TLR-4 expression in patients with IBD or NEC 12427787
923 Defective intestinal epithelial TJ barrier has been shown to be an important pathogenic factor of inflammatory bowel disease (IBD) and necrotizing enterocolitis (NEC) by allowing paracellular permeation of luminal antigens that elicit and promote inflammatory response.1,2 12427787
924 For example in mice, it was shown, that a high saturated fat and cholesterol diet increased the sensitivity of mice to LPS, and the release of Il-6 and TNFa [65]. 12427787
925 Furthermore, systemically circulating endotoxin and increased titres of anti-endotoxin antibodies are found in patients with Crohn’s disease (CD) or ulcerative colitis (UC).6 12427787
926 Herein, we show for the first time that physiologically and clinically relevant concentrations (0 to 10 ng/mL) of LPS cause an increase in intestinal epithelial TJ permeability in vitro and in vivo, when present in the interstitial fluid or basolateral membrane compartment. 12427787
927 In humans, Amar et al. found a link between food intake and 35 plasma endotoxin, with a positive correlation between energy intake and endotoxemia [7]. 12427787
928 Intestinal apoB48 lipoprotein overproduction was demonstrated for the first time in an insulin resistant animal model, the fructose fed hamster [14]. 12427787
929 Most recently, we have shown in healthy non-smoking humans that the digestion of a mixed breakfast, containing various types of lipids (animal, vegetal) in emulsified and non-emulsified forms, results in a transient elevation of endotoxin in plasma and an increase of sCD14 [9]. 12427787
930 The different results suggest that a chronic fat-rich diet could result in increased endotoxemia and low-grade inflammation due to the repeated endotoxin absorption from the gut during the digestion of lipids, which in turn could increase the risk of insulin resistance and atherosclerosis. 12427787
931 The intestinal tissue and circulating LPS levels are markedly elevated in IBD and NEC, and play an important role in mediating inflammatory response. 12427787
932 These studies suggest that the LPS-induced increase in TLR-4 expression leads to an activation of NFkB. 12427787
933 This can explain the significant peak of inflammatory cytokine IL-6 that we observed 2 h after the mixed meal (Figure 2A). 12427787
934 Because these authors considered that smoking could 4 contribute to elevation of plasma endotoxin via the absorption of LPS by lung [67], they examined 5 endotoxemia for 4 hours in men receiving no meal, a high-fat meal, no meal and 3 cigarettes, or a 6 high-fat meal and 3 cigarettes [8]. Fat was found to be the only significant parameter impacting on 7 postprandial endotoxemia [8]. 12427787
935 Consistent with the presence of high concentrations of bacteria and LPS in the gut lumen, LPS in the apical membrane surface did not affect the intestinal barrier function. 12427787
936 Importantly, Shi et al. have also shown that TLR4-KO mice are protected from NFkB-induced inflammation and development of insulin resistance [66]. 12427787
937 Importantly, Shi et al. have also shown that TLR4-KO mice are protected from 31 NFkB-induced inflammation and development of insulin resistance [66]. 12427787
938 In turn 29 CD14-KO mice resisted to increased weight gain, endotoxemia and insulin resistance induced by 30 a high fat diet [4]. 12427787
939 In turn CD14-KO mice resisted to increased weight gain, endotoxemia and insulin resistance induced by a high fat diet [4]. 12427787
940 The possibility of TLR-2 or TLR-5 involvement was also considered, but LPS did not affect the expression of TLR-2 or TLR-5, and siRNA-induced silencing of TLR-2 or TLR-5 did not prevent the LPS-induced increase in intestinal TJ permeability, confirming that the LPS effect is regulated specifically by the TLR-4 signal transduction pathway. 12427787
941 Meta analysis has demonstrated that in a large variety of patients, including patients suffering from pancreatitis, ulcerative colitis, Crohn’s disease, surgery, trauma, or multiorgan failure, enteral feeding was associated with a lower risk of infection compared with starvation and parenteral nutrition (38). 12538700
942 Our data suggest that LBP and chylomicrons cooperate in the detoxification of LTA. 12538700
943 This LBP-induced interaction of LPS with chylomicrons prevented endotoxin toxicity, as demonstrated by reduced cytokine secretion by PBMC. 12538700
944 LBP was demonstrated to associate with chylomicrons and enhance the amount of LPS binding to chylomicrons in a dose-dependent fashion 12538700
945 We found a significant reduction (19%; P < 0.001) in the occurrence of nasal PPB in the group who consumed the probiotic drink but not in the group who consumed yogurt. 12540416
946 Our results show that a 4-week course of either VSL#3 or anti–TNF- antibodies improves hepatic histology, serum alanine aminotransferase (ALT) elevations, and several biochemical measures of hepatic insulin resistance. 12540784
947 Thus, several centers have recently begun to evaluate anti-TNF antibodies as therapy for patients with severe alcoholic hepatitis. 12540784
948 Our previous studies showed that the intestinal flora of ob/ob mice produce excessive EtOH16 and that ob/ob fatty liver disease can be improved by insulin-sensitizing agents, such as metformin,17 that inhibit hepatic TNF- activity. 12540784
949 Constipation severity also differed significantly among the breath test patterns (P < 0.05), with higher severity scores reported by sub- jects who produced methane. 12645795
950 The pre-dominant gas excreted by patients with IBD was hydrogen alone, detected in 47 of 49 subjects (95.9%) with Crohn's disease and 29 of 29 (100%) of subjects with ulcerative colitis (Figure 5). 12645795
951 When IBS subgroups were compared, constipation- predominant IBS was reported by 91 (37%) of the hydrogen-excreting subjects, 23 (52.3%) of the hydrogen- and methane-excreting subjects, and 6 (100%) of the methane-excreting subjects. 12645795
952 Evidence of a genetic role for MOR in the control of gut inflammation was provided by showing that MOR-deficient mice were highly susceptible to colon inflammation, with a 50% mortality rate occurring 3 days after TNBS administration. 12727924
953 The mechanistic basis of these observations suggests that the anti-inflammatory effects of MOR in the colon are mediated through the regulation of cytokine production and T cell proliferation, two important immunologic events required for the development of colon inflammation in mice and patients with inflammatory bowel disease (IBD). 12727924
954 These data provide evidence that MOR plays a role in the control of gut inflammation and suggest that MOR agonists might be new therapeutic molecules in IBD. 12727924
955 To evaluate whether MOR may also be involved in controlling gut inflammation, we first showed that subcutaneous administration of selective peripheral MOR agonists, named DALDA and DAMGO, significantly reduces inflammation in two experimental models of colitis induced by administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) or peripheral expansion of CD4+ T cells in mice. 12727924
956 A naloxone-antagonizable prolongation of gastrointestinal transit time has also been observed upon oral administration of gluten hydrolysate in humans [139]. 12769741
957 In particular, a reduction of intestinal motility upon oral or intragastric administration of b- casomorphins or casein has been observed in adult humans [116], in calves [117], in dogs [123], in steers [124] and in rat pups [122]; it may have been caused by b-casomorphins demonstrated to be present in the gastrointestinal lumen of humans [132] or animals [86] after milk or casein ingestion. 12769741
958 POMC gene mutations just led to early onset severe obesity, red hair pigmentation and adrenal insufficiency [47] 12769741
959 Table 3. Characterization of Food Protein Derivatives with Opioid Agonist or Antagonist Activity 12769741
960 Collectively, several steps in RCT are impaired during the APR that may contribute to the increased risk of atherosclerosis. 12777468
961 In J774 murine macrophages, endotoxin and cytokines decrease levels of ABCA1 and ABCG1. 12777468
962 In the present study, we report that endotoxin decreases mRNA levels of ABCG5 and ABCG8 in mouse liver. 12777468
963 Mutations in ABCG5 or ABCG8 are the cause of sitosterolemia, a disorder characterized by xanthomatosis and premature atherosclerosis due to uncontrolled absorption of sterols and failure to excrete them into the bile. 12777468
964 Previously, our laboratory has shown that in rodents, hepatic mRNA levels of liver X receptor (LXR) and retinoid X receptor (RXR) were rapidly decreased in response to endotoxin (33). 12777468
965 The reduction in cholesterol excretion could help retain cholesterol in the body for use during infection. 12777468
966 Treatment of mouse peritoneal macrophages with interferon-gamma caused a decrease in ABCA1 mRNA levels and cholesterol efflux (56). 12777468
967 During the APR, multiple alterations in lipid and lipoprotein metabolism occur (5). Plasma triglyceride levels increase, and there is an increase in small, dense LDL (6). 12777468
968 In the small intestine, the ABCG5-ABCG8 heterodimers efflux plant sterols as well as dietary cholesterol out of the intestinal cells, whereas in hepatocytes, they efflux those sterols into the bile (31, 32, 50). 12777468
969 While a decrease in LXR may mediate the decrease in levels of these proteins in the liver, the down-regulation of ABCA1 by endotoxin in macrophages is not likely to be mediated by LXR. 12777468
970 Fasting and postprandial plasma levels of PP have been found to be high and postprandial PYY level to be low in patients with ISTC [52]. 12814404
971 Constipation increases with age [4] and is more common in women [5,6]. 12814404
972 It has been proposed that ISTC arises as a consequence of pelvic autonomic dysfunction [36]. 12814404
973 It is difficult to distinguish these patients from patients with irritable bowel syndrome (IBS) according to Rome II criteria [10], however, patients with ISTC have a slow colonic transit. 12814404
974 PYY is colocalized with enteroglucagon [40]. 12814404
975 Radio-opaque markers method (Fig. 1) with single plain abdominal X-ray is simple safe and reproducible [24,32]. The methods reported by Mecalf [21] and Abrahamsson et al. [23] are the most popular. 12814404
976 This dysfunction would arise after pelvic surgery such as hysterectomy, tubovarian and even appendectomy as well as after child birth[36] 12814404
977 This may explain the contradictory results obtained in separate investiga- tions on the neuroendocrine system in different groups of ISTC patients. 12814404
978 This study has shown that all patients had a disturbance in the colonic neuroendocrine peptides. The nature and the neuroendocrine peptides affected were, however, different in different individuals. 12814404
979 Consistent with the hypothesis, we found that individuals with the linked 1976T/T and the 2592 Tins/Tins variants in the A2a adenosine receptor gene reported greater increases in anxiety after caffeine intake than did individuals in either of the other two genotypic groups. 12825092
980 We did not find any evidence for an association between A1 adenosine receptor gene polymorphisms and caffeine-induced anxiety. 12825092
981 Eight cases with ulcerative colitis and diarrhoea were examined; the small intestine transit time was found to be normal or slightly delayed. Thus the diarrhoea appears to be due only to the inability of the colon to absorb water and to store the solid contents; as the colon is successively filled it empties at the same rate, and only relatively small amounts of contrast medium remain in its lumen. 13768329
982 In fact two of these four patients might have been classified as suffering from steatorr- hoea when on the corn oil diet if the limit of normality is taken as an excretion of 5 g. of fat per 24 hours. 13999335
983 it is known from many studies with labelled fats that most of the faecal fat in patients with steatorrhoea is unabsorbed dietary fat. 13999335
984 These experi- ments were confirmed by Pessoa, Kim, and Ivy (1953) who found that ligation of the pancreatic duct also increased the faecal fat loss. 13999335
985 The present studies in patients without steatorrhoea show that the nature of the dietary fat appears to have little influence on the composition of the faecal fat. 13999335
986 An even stronger effect was observed with the doubled stranded RNA mimetic poly I:C, a specific ligand for TLR3. 14580333
987 Consistent with their effects on LXR-dependent gene expression, TLR3/4 ligands potently inhibit the ability of macrophages to efflux excess cholesterol. 14580333
988 Loss of bone marrow LXR expression leads to a marked increase in atherosclerotic lesion formation, whereas treatment of mice with a synthetic LXR agonist ameliorates the disease (Joseph et al., 2002; Tangirala et al., 2002). 14580333
989 LXR ligands reduce atherosclerosis in animal models, whereas loss of macrophage LXR expression dramatically accelerates the disease (Joseph et al., 2002; Tangirala et al., 2002). 14580333
990 Remarkably, IRF3 was able to inhibit LXR even in the absence of TLR ligands. 14580333
991 Surprisingly, among these agents, only lipid A exhibited the ability to inhibit LXR targets genes 14580333
992 The TLR4 ligand lipid A effectively inhibited macrophage expression of ABCA1 and apoE (Figure 2C). 14580333
993 TLR4 is required for survival during lethal oxidant stress resulting from hyperoxia (1, 2) or bleomycin- induced injury (3). 14580333
994 We have previously reported that ligand activation of LXR in macrophages inhibits the expression of NF-kappaB-dependent inflammatory gene expression induced by LPS, IL-1, and TNFalpha (Joseph et al., 2003). 14580333
995 Activation of LXR induces expression of genes involved in cholesterol efflux including ABCA1, ABCG1, apoE, and PLTP (Repa and Mangelsdorf, 2002; Tontonoz and Mangelsdorf, 2003). 14580333
996 C. pneumoniae LPS, a ligand for TLR4, has been shown to promote macrophage foam cell formation (Kalayoglu and Byrne, 1998). 14580333
997 In addition, recent studies cholesterol metabolism and determinants of athero- have shown that C. pneumoniae and herpesvirus accelsclerosis susceptibility. Viral and bacterial pathogens erate the development of atherosclerosis in mice (Alber have long been suspected to bemodulators of athero- et al., 2000; Moazed et al., 1999). 14580333
998 In the absence of TLR4, lung tissue as well as endothelial cells expressed increased levels of Nox3. 14580333
999 Macrophage uptake of oxidized LDL leads to increased cellular concentration of oxysterols, the physiologic ligands for LXRs (Janowski et al., 1996; Lehmann et al., 1997). 14580333
1000 Recently, enhanced expression of several TLRs has been detected in human atherosclerotic lesions, and polymorphisms in the TLR4 locus have been associated with atherosclerosis risk (Boekholdt et al., 2003; Edfeldt et al., 2002; Kiechl et al., 2002). 14580333
1001 To our surprise, the lungs of Tlr4–/– mice exhibited age-related changes that resembled pulmonary emphysema in humans both histologically and functionally. 14580333
1002 Our findings provide evidence for a susceptibility locus for panic disorder, and possibly including agoraphobia, either within the ADORA2A gene or in a nearby region of chromosome 22, and serves as the first successful candidate gene replication study in panic disorder. 14666117
1003 Colostrum and mature human milk have significant lethal effect on E. histolytica and protect against its infection in breast fed children. 14991951
1004 Follow-up work also shows that methane gas itself slows small intestinal transit (17). 14992440
1005 Specifically, this has led to new approved therapeutic agents acting as an agonist (11) and antagonist (12, 13) on serotonin receptors. 14992440
1006 Recent findings reveal that IBS subjects with predominantly diarrhea have ele- vated postprandial serotonin compared to controls (10). 14992440
1007 Serotonin is a neurotransmitter predominantly secreted by enterochromaffin cells of the gut located in the crypts of the intestinal villi (5). After release, the predominant function of this product is peristaltic stimulation of the gut (6–9). 14992440
1008 Whereas the MyD88-deficient mice evinced a marked reduction in early atherosclerosis, mice deficient in CD14 had no decrease in early lesion development. 15034566
1009 Although diarrhea was the most frequent symptom in untreated celiac disease, steatorrhea occurred in only one-fifth of patients. 15051613
1010 Many patients had alternating diarrhea and constipation, both of which were responsive to the gluten-free diet.  15051613
1011 However, no definitive cases of toxicity have emerged despite the worldwide usage of 5-HTP for last 20 years, with the possible exception of one unresolved case of a Canadian woman. 15068828
1012 The use of l-Trp as a dietary supplement was discontinued in 1989 due to an outbreak of eosinophilia–myalgia syndrome (EMS) that was traced to a contaminated synthetic L-Trp from a single manufacturer. 15068828
1013 It has previously been shown that bacterial DNA has anti-inflammatory and immunostimulatory properties when administered subcutaneously in a number of animal models of colitis.18 15082588
1014 The results of this study confirm that systemic administration of L salivarius 118 had an anti-inflammatory effect on colitis in IL-10 KO mice, demonstrating that the oral route is not mandatory for its effect. 15082588
1015 We have previously shown that oral consumption of the probiotic Lactobacillus salivarius 118 can attenuate colitis seen in interleukin 10 knockout (IL-10 KO) mice. 15082588
1016 By using these nociceptive responses to the hot plate at 52°C and a low dose of morphine (Sung et al. 2000), we found that instant coffee extract reversed the anti-nociceptive effect of morphine. 15088081
1017 Further, high caffeine intake from coffee (500 mg/day) has been shown to cause 11% delay in time of conception in fertile European women (Bolumar et al. 1997). 15088081
1018 The results of this study further demonstrate that cinnamoyl-1,5-quinides in instant coffee have anti-opioid properties in vivo. 15088081
1019 Apolipoprotein E-deficient mice that also lacked TLR4 or MyD88 demonstrated reduced aortic atherosclerosis that was associated with reductions in circulating levels of proinflammatory cytokines IL-12 or monocyte chemoattractant protein 1, plaque lipid content, numbers of macrophage, and cyclooxygenase 2 immunoreactivity in their plaques. 15249654
1020 Electrophysiological recording in enteric neurones reveals that opiates and opioid peptides have a universal action ) suppression of neuronal excitability 15357848
1021 Exposure to morphine or opioid peptides suppresses gallbladder contractile responses to fatty meals and to CCK.65–67 This occurs in humans, and animal models, and might also be a contributing factor in the association between morphine administration and biliary stasis, bile saturation and cholelithiasis. 15357848
1022 In view of the evidence for central opiate/opioid activation of sympathetic outflow to the bowel,35,38 a presynaptic inhibitory action of noradrenaline might be a factor in opioid suppression of gallbladder contractility. 15357848
1023 Measurements of continuous release of the inhibitory neuromuscular transmitters (e.g. VIP and NO) from the small intestine in vivo, reflects ongoing firing of inhibitory motor neurones.18 Inhibition of the ongoing firing by opioids or opioid peptides or locally acting anaesthetics is reflected by decreased release of inhibitory neurotransmitters.19 15357848
1024 Medications that selectively block opiate receptors in the ENS could benefit some patients suffering from functional constipation. 15357848
1025 Small intestinal bacterial overgrowth and bacterial translocation are associated with morphine- induced suppression of the migrating motor complex in rats.32 15357848
1026 Suppression of excitability in excitatory musculomotor neurones to the longitudinal muscle and to segments of circular muscle requiring excitatory input is therefore expected to reduce contractile 15357848
1027 Suppression of neuronal excitability accounts for most of the actions of opiates, synthetic opioids and endogenously released opioid peptides on gastrointestinal motility and secretion. 15357848
1028 As endogenous opioid peptides also act at opiate receptors to cause constipation, it is reasonable to speculate that overactivation of the endogenous opioid systems in the gastrointestinal tract might contribute to functional constipation in some patients 15357848
1029 Increased occurrence and amplitude of rhythmic contractions of the circular muscle coat is best explained by suppression of excitability of inhibitory musculomotor neurones and disinhibition of the autogenic musculature. 15357848
1030 Unlike the circular muscle, the longitudinal muscle receives little inhibitory input; its primary input is excitatory. responses. 15357848
1031 Endotoxin bound to lipoproteins is preferentially shunted to hepatocytes for clearance, rather than hepatic macrophages, and is ultimately excreted in bile.32 15472123
1032 In particular, high-density lipoprotein (HDL) is believed to play a major role in clearance of circulating endotoxin (see Endotoxin and Lipoproteins). 15472123
1033 In support of this hypothesis, intraperitoneal injection of LBP protected mice from LPS-induced cytokine release and hepatic failure, resulting in significantly decreased mortality.52 15472123
1034 Of note, a human CD14 promoter polymorphism has been shown to be associated with reduced incidence of myocardial infarction in a population of low-risk patients, although the effects of this polymorphism on CD14 expression and on LPS responsiveness were not determined 15472123
1035 Our laboratory has demonstrated that lovastatin and atorvastatin block endotoxin-induced proinflammatory cytokine release, monocyte adhesion, and ROS production in human saphenous vein explants, as well as cultured HCAEC and HCASMC. 15472123
1036 Recently, mutations in human TLR-4, particularly the Asp299Gly polymorphism, which is relatively common in the Caucasian population, have been shown to be associated with a reduced incidence of atherosclerosis and other cardiovascular diseases,62–64 as well as acute coronary events and decreased plasma fibrinogen and soluble vascular cell adhesion molecule-1 levels.65 15472123
1037 Recently, our laboratory reported that LPS-induced activation of human coronary artery endothelial cells (HCAEC) and HCASMC is modulated in a biphasic manner by the LBP/sCD14 ratio 15472123
1038 These findings are consistent with recent clinical reports that statin therapy may be beneficial in sepsis.150,151 15472123
1039 A recent study of 2355 apparently healthy individuals revealed that elevated basal levels of IL-8 were associated with increased risk of future coronary artery disease.132 15472123
1040 Although Chlamydia pneumoniae has recently been identified in atherosclerotic lesions79–82 and has been implicated as a risk factor for atherosclerosis by some researchers,83–85 its role as a causal agent for atherosclerosis is still unclear. 15472123
1041 Although markers of chronic inflammation, such as C-reactive protein, are clearly predictive of clinical atherosclerosis,9,10 the sources of inflammatory responses, and the mechanisms by which inflammation leads to vascular disease, remain to be elucidated. 15472123
1042 Among primates, chimpanzees share the generally high endotoxin sensitivity of humans, although baboons are insensitive, with a responsiveness comparable to that of rodents.164 15472123
1043 Data from the Bruneck study indicate that blood endotoxin levels in an ambient population of 516 apparently healthy volunteers, with no clinical evidence of infection, ranged from 6 to 209 pg/mL, with a median of 14.3. Individuals with levels of 50 pg/mL or greater were identified to have an increased risk for development of atherosclerosis. 15472123
1044 Endotoxin modulates this process at multiple steps, including activation of 2-integrins, upregulation of selectins and CAMs, and increased phosphorylation of PECAM-1. 15472123
1045 However, during the acute inflammatory response, whereas sCD14 levels increase slightly (2-fold), LBP levels increase by 10- to 30-fold.49 15472123
1046 IL-8 release in response to endotoxin has been demonstrated in a wide variety of experimental models. 15472123
1047 In animal studies, weekly injections of endotoxin accelerated the development of atherosclerotic lesions in rabbits on hypercholesterolemic diets22 and in apolipoprotein E-deficient mice.23 15472123
1048 In human coronary artery and saphenous vein, TLR-4 immunostaining was detected throughout the vessel wall, rather than being restricted to a specific location or cell type. 15472123
1049 In this 5-year prospective study, in subjects without atherosclerosis at baseline, approximately 40% of newly developed carotid atherosclerosis was estimated to be attributable to chronic infection, making it a leading atherogenic risk predictor.20 15472123
1050 Individuals with levels of 50 pg/mL or greater were identified to have an increased risk for development of atherosclerosis. 15472123
1051 It has been known for many years that tetra-acylated LPS or lipid A (lipid IVA) and Rhodobacter sphaeroides lipid A are LPS antagonists in human cells but display LPS mimetic activity in murine169 and hamster cells.170 15472123
1052 MCP-1 is highly expressed in human atherosclerotic plaques and is believed to play a crucial role in monocyte recruitment into subendothelial lesions.114,126 15472123
1053 More recently, in a population-based study, levels of soluble CD14 (sCD14) were positively correlated with aortic stiffness and carotid plaque formation,43 thus supporting a proatherosclerotic effect of CD14 in humans. 15472123
1054 Our laboratory has recently demonstrated that very low levels of endotoxin (1 ng/mL) cause significant increases in MCP-1 release by HCAEC, HCASMC, and human saphenous vein explants.28,29 15472123
1055 These observations support the hypothesis that chronic exposure to endotoxin may be pathogenically linked to atherosclerosis. 15472123
1056 TLR-4 expression has been detected in murine and human atherosclerotic plaques, preferentially localized to macrophages and perhaps endothelial cells.60,61 15472123
1057 Although bovine aorta, pulmonary artery, and mesenteric artery endothelial cells are responsive to LPS, bovine aortic smooth muscle cells fail to respond even in the presence of 100-fold higher endotoxin levels (up to 100 g/mL).168 15472123
1058 These findings suggest that TLR-4–mediated inflammatory responses may contribute to ischemic myocardial damage, although Wright et al reported that there was no difference in the magnitude of aortic root atherosclerosis in TLR-4/apoE double knockout mice as compared with control apoE knockout mice.69 15472123
1059 In the 10 men and women with repeated measurements, BMI increased significantly and small bowel transit accelerated after treatment and was 3.6 h (1.7-5.5) before treatment and 2.3 h (0.7-4.0) after treatment, and p= 0.007. 15571592
1060 In untreated male patients BMI was significantly reduced compared to healthy males, and small bowel transit time (SBTT) was significantly longer compared with healthy males, 3.9 (1.2-5.5) versus 2.5 h (1.4-4.3), median and percentile 10 and 90, respectively, and p= 0.04. 15571592
1061 Indeed, activation of NF-jB is sufficient to induce resistin expression, and loss of NF-jB function abolishes LPS induction of resistin. 15578112
1062 Furthermore, several studies, though not all, have reported increased serum resistin levels in patients with obesity, insulin resistance, and/or type 2 diabetes [19,20,21,22,23,24,25,26]. 15578112
1063 Here we show that the endotoxin lipopolysaccharide (LPS), a potent inflammatory stimulant, dramatically increases resistin production by inducing secretion of inflammatory cytokines such as TNFa. 15578112
1064 In rodents, resistin is produced exclusively by adipocytes, regulates normal glucose homeostasis, and causes insulin resistance at high circulating levels [11,13]. 15578112
1065 Translation of resistin’s metabolic effects from rodents to humans has been problematic because peripheral blood mononuclear cells and macrophages appear to be a primary source of resistin in humans [15,16]. 15578112
1066 We have demonstrated that, in human macrophages, an inflammatory cascade with secretion of cytokines, including TNFa and IL-6, is sufficient and necessary for the induction of resistin. 15578112
1067 We observed that, when we gave nonobese and obese subjects a 50 000 IU dose of vitamin D2 orally or exposed them to simulated sunlight in a tanning bed for the same periods of time, the obese subjects exhibited increases in blood vitamin D concentrations of no more than 50%, compared with nonobese individuals (24). 15585788
1068 Both dietary calcium and 1,25(OH)2D3 are important regulators of autoimmune responses in the gastrointestinal tract and central nervous system. 15585793
1069 Dietary calcium has independent effects on IBD severity. 15585793
1070 However, the best results for IBD were observed when the calcium concentration was high and 1,25(OH)2D3 was administered.  15585793
1071 In the absence of vitamin D signaling, the T cell compartment has a potentially stronger Th1 phenotype. 15585793
1072 The active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], has been shown to inhibit the development of autoimmune diseases, including inflammatory bowel disease (IBD). 15585793
1073 The evidence suggests a model in which the effectiveness of 1,25(OH)2D3 treatment of autoimmune diseases results from inhibition of the development and function of Th1 cells and the induction of other Th cells, including Th2 cells (33). 15585793
1074 The Th2 cell-driven disease experimental asthma failed to develop inVDRKOmice (Figure 2) (31). 15585793
1075 Vitamin D-deficient IL-10KOmice began to die at 6 wk of life; by 9 wk of age,50% of the vitamin D-deficient IL-10 KO mice had succumbed to a wasting disease that was confirmed as IBD in the necropsy (Figure 1) (23). Vitamin D-sufficient IL-10KOmice remained without symptoms until  12 wk of age (Figure 1). 15585793
1076 Vitamin deficiencies in general and vitamin D deficiency in particular have been shown to occur among patients with inflammatory bowel disease (IBD) (7). 15585793
1077 T cells that preferentially produced the Th1 cytokines (IL-2, IFN-, and tumor necrosis factor ) were shown to transfer Crohn’s disease-like symptoms to naive mice (19, 20), and the production of Th1 cytokines is associated with IBD among humans subjects (21). 15585793
1078 The hormonally active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], is known to increase bone mineralization when administered to experimental animals (12) and human subjects (13). 15585793
1079 In the kidney, methylxanthines induce diuresis and natriuresis, an effect first described by Davis and Shock (1949). 15590766
1080 Moreover, both nonselective and selective A1 receptor antagonists have been shown to increase renal fluid and Na excretion in animal studies (Knight et al., 1993; Wilcox et al., 1999), healthy volunteers (Brater et al., 1983; Balakrishnan et al., 1993, 1996), and in hypertensive patients (van Buren et al., 1993). 15590766
1081 Consistent with this notion, the present study revealed that caffeine significantly increased urinary glucose excretion in wild-type mice. 15590766
1082 Furthermore, rats treated with selective A2A receptor antagonists as well as A2A receptor knockout mice displayed an elevated blood pressure and heart rate (Ledent et al., 1997; Monopoli et al., 1998). 15590766
1083 Moreover, both nonselective and selective A1 receptor antagonists have been shown to increase renal fluid and Na excretion in animal studies (Knight et al., 1993; Wilcox et al., 1999), healthy volunteers (Brater et al., 1983; Balakrishnan et al., 1993, 1996), and in hypertensive patients (van Buren et al., 1993). 15590766
1084 Since methylxanthines are nonselective adenosine receptor antagonists (Fredholm et al., 2001), it is conceivable that the changes in urine excretion are the result of inhibition of the renal actions of endogenous adenosine 15590766
1085 The main observation of the present study is that mice lacking the A1 receptor do not exhibit the diuresis and natriuresis typically elicited by the application of the methylxanthines caffeine or theophylline. 15590766
1086 While Ruminococcus sp. and Enterococcus sp. ferment crystalline cellulose with concomitant production of H2[10], Bacteroides sp. metabolised more amorphous celluloses without production of H2(unpublished data). 15621457
1087 15790844
1088 Data obtained from this study demonstrate thatwhen given to normal, opioid-naive subjects for 3 consecutive days,methylnaltrexone alone causes a statistically significant reduction in transit time, suggesting that endogenous opioids exert an effect in regulating human gut motility. 15831777
1089 Our observations suggest that methylnaltrexone may possess therapeutic value in treating hypomotility disorders associatedwith an increase in endogenous opioid effects. 15831777
1090 These findings suggest that the pharmacokinetics of methylnaltrexone are unchanged at steady state and, consistent with the absence of significant toxicity in study subjects, support the presumption that a q6h regimen at this dose level is safe. 15831777
1091 Epithelium-associated counts of bifidobacteria in active [median 15/mm of epithelial surface (range, 4-56), n = 14] and quiescent ulcerative colitis [26/mm (range, 11-140), n = 19] were lower than in controls [56/mm (range, 0-144), n = 14; P = 0.006 and P = 0.03, respectively]. 15867588
1092 Conversely, epithelium-associated Escherichia coli counts were higher in active [82/mm (range, 56-136)] than inactive ulcerative colitis [6/mm (range, 0-136), P = 0.0001] or controls [0/mm (range, 0-16), P < 0.0001] 15867588
1093 Epithelium-associated clostridia counts were also higher in active [3/mm (range, 0-9)] than inactive colitis [0/mm (range, 0-9), P = 0.03] or controls [0/mm (range, 0-1); P = 0.0007]. 15867588
1094 Epithelium-associated E. coli counts were higher in Crohn's disease [42/mm (range, 3-90), n = 6] than controls (P = 0.0006). 15867588
1095 Numbers of Lactobacillus and Bacteroides showed no differences between patient groups 15867588
1096 Adiponectin levels are significantly reduced in patients with type II diabetes (see below). 15867843
1097 In vivo overexpression of adiponectin in apolipoprotein E–deficient mice suppresses atherosclerosis, in part by downregulating adhesion molecules.39 On the basis of all the above-mentioned effects, adiponectin appears to act as an anti-inflammatory molecu 15867843
1098 Leptin-deficient mice are protected from inflammation in some, although not all, experimental models of inflammatory bowel disease (IBD),22,79 suggesting a possible involvement of leptin in maintaining high cytokine production and low rates of apoptosis in intestinal lymphocytes of patients with IBD. 15867843
1099 Nevertheless, the general consensus is that leptin exerts a proinflammatory role, while at the same time protecting against infections. 15867843
1100 On the other hand, adiponectin reduces the production and activity of TNF-a.33 15867843
1101 Furthermore, administration of endotoxin to human volunteers is associated with dramatically increased circulating resistin levels.44 15867843
1102 However, leptin deficiency is also associated with increased susceptibility to the toxicity of proinflammatory stimuli, such as endotoxin and TNF-a, an effect that might be mediated by leptin’s activity on the kidney.25-27 15867843
1103 However, recent data indicate that stimulation of macrophages in vitro with endotoxin or proinflammatory cytokines leads to a marked increase in resistin production.44 15867843
1104 IL-6 and TNF-a are the 2 best-studied cytokines in obesity and have been consistently found to be increased in the serum, WAT, or both of obese subjects.8 15867843
1105 TNF-a can directly lead to insulin resistance by inducing serine phosphorylation of the insulin receptor, which inhibits insulin signaling.55 15867843
1106 However, despite initial promising results in animal studies, neutralization of TNF-a activity has proved ineffective in ameliorating insulin sensitivity in diabetic patients.56 15867843
1107 Butyrate enemas induced a sustained, concentration-dependent colonic hypersensitivity and, to a lesser extent, a referred cutaneous mechanical hyperalgesia, particularly in female rats, but no macroscopic and histologic modifications of the colonic mucosa, as observed in patients with IBS. 15940632
1108 Altogether, our data demonstrate that sulfide inhibits cytochrome c oxidase activity, reduces cell respiration and proliferative activity without affecting the cell viability nor ATP cell contents. 15996823
1109 It has been proposed that the inhibitory effect of H2S upon butyrate h-oxidation in the colon epithelial cells would participate to some extent to the development of ulcerative colitis [18,19]. 15996823
1110 The sulfide fecal concen- tration in humans receiving a high meat diet can represent as much as 3.4 mM [3]. 15996823
1111 This molecule which is a toxicant known to disturb lung and brain functions [7,8] has been implicated in the etiology of ulcerative colitis from the following observations. First, it has been documented that hydrogen sulfide has a number of potentially adverse effects that could play a part in the pathogenesis of ulcerative colitis (for a review see [9]). Secondly, fecal sulfide was found to be elevated in patients with active ulcerative colitis [10,11]. Thirdly, in exper- imental colitis animal models, it is possible to induce a pathological state similar to the one observed in ulcerative colitis using two forms of undigestible sulfates, i.e., dextran sulfate sodium [12,13] and sulfate-containing carraghenan [14]. 15996823
1112 Stimulation of these enzymes by proinflammatory cytokines, in particular interferon-g (IFN-g), enhances the catabolism of tryptophan, making less tryptophan available for conversion to 5-HTP and serotonin (Taylor & Feng, 1991; Myint & Kim, 2003). 16023217
1113 To our knowledge, however, serotonin syndrome has not been reported in humans in association with 5-HTP, either as monotherapy or in combination with other medications. 16023217
1114 Cannabinoids enhanced epithelial wound closure either alone or in combination with lysophosphatidic acid through a CB1—lysophosphatidic acid 1 heteromeric receptor complex. 16083701
1115 Two G-protein—coupled cannabinoid receptors, termed CB1 and CB2, have been identified and several mammalian enteric nervous systems express CB1 receptors and produce endocannabinoids 16083701
1116 Also, Oslin et al (2003) showed that alcoholdependent persons carrying the G allele are more likely to respond to treatment with the opioid antagonist, naltrexone, than those homozygous for the A allele. 16123758
1117 Hypothalamic corticotropin-releasing hormone (CRH) neurons, which effect glucocorticoid release by stimulating pituitary adrenocorticotropin (ACTH) secretion, are directly and indirectly inhibited by b-endorphin-producing neurons via the MOR (Johnson et al, 1992). 16123758
1118 Our findings, as far as we know, are the first to demonstrate that the G allele of the A118G MOR polymorphism is associated with a blunted HPA response to psychosocial stress in humans. 16123758
1119 An in vitro study demonstrated that the expression of the Asp40 allele causes a three-fold increase in binding affinity to b-endorphin and enhances G protein-coupled potassium channel activation. 16123758
1120 For instance, we previously showed that this polymorphism is associated with enhanced cortisol response to opioid blockade by naloxone (Wand et al, 2002). 16123758
1121 Prior to these findings, it had been shown that higher cortisol responses to naloxone are more likely in those with a family history of alcoholism (Hernandez-Avila et al, 2002; Wand et al, 2001). 16123758
1122 Several human studies have suggested that the 118A allele may be a risk factor for opiate and other drug addiction. 16123758
1123 Apart from the regulatory effect of MOR activation on various immune/inflammatory cells40–43 and within the gastrointestinal mucosa,16 novel MOR agonists are currently in development. 16299031
1124 At the physiological level, β‐endorphin downregulates inflammatory responses in a MOR dependent manner. 16299031
1125 Further work should establish whether an unbalanced ligand/receptor ratio is essential in IBD pathogenesis and whether oral administration of opioid agonists can have therapeutic effect. 16299031
1126 Herein, we showed ex vivo that DALDA can dampen the production of TNF-a mRNA by more than 60% and with a higher efficiency in IBD patients compared with controls, suggesting the importance of the physiological availability of MOR agonists. 16299031
1127 Impaired release of β‐endorphin by the gastrointestinal tract and/or by peripheral blood leucocytes have been associated with IBD,37,38suggesting that chronic inflammation may lead to an exhausted release of β‐endorphin or alternatively that MOR activation is somehow critical in IBD development. 16299031
1128 The increased availability of MOR and its agonists at the intestinal interface of IBD patients and demonstration of their anti-inflammatory effects would promise the development of innovative drugs, such as by upregulating endogenous opiates and/or opioid receptor expression and/ or by using new opioid compounds with topical antiinflammatory effects. 16299031
1129 Consistent with our preliminary RT‐PCR data, the pattern of stained cells was significantly different in the inflamed intestine of IBD patients with increased MOR staining limited to LPMC reaching approximately 4–10% and 11–15% of stromal cells, respectively, in the inflamed tissues of patients with CD and UC (fig 2B–D) and was undetectable in LPMC from controls. 16299031
1130 Herein, we showed that MOR mRNA and protein expression were induced similarly by TNF-a, IFN-gamma, and IL-1b in THP1 and Jurkat cell lines. 16299031
1131 The regulatory mechanisms of increased MOR expression by mononuclear cells in IBD patients remain speculative. In cell lines, MOR mRNA production is regulated by activator protein 1 and IL-4 through binding of STAT-6 transcription factors to the MOR gene promoter.17 39 16299031
1132 This enhancement of MOR transcription was associated locally with an increase in the number of MOR immunoreactive cells infiltrating the mucosa. 16299031
1133 We observed in IBD patients a ∼6–30‐fold increased expression of MOR mRNA in inflamed small bowel and colon compared with healthy intestine. 16299031
1134 Without any significant detectable MOR protein expression in epithelial, endothelial, and smooth muscle cells, expression of MOR in the human inflamed intestine during IBD is thus mainly restricted to inflammatory mucosal mononuclear and lymphocytic cells. 16299031
1135 Compared with healthy small bowel or colon specimens, we failed to detect any significant increase in the numbers of MOR immunopositive nerve cells bodies in the inflamed tissues of IBD patients.  16299031
1136 No specific staining was constantly observed in epithelial, endothelial, or smooth muscle cells. 16299031
1137 Chlamydia species were detected in 17 of the 33 atherectomy samples (51.5%). 16490835
1138 We observed frequent colonization of atherosclerotic lesions in CHD. 16490835
1139 However, large, randomized, controlled studies (Weekly Intervention With Zithromax Against Atherosclerosis and Related Disorders [WIZARD], Pravastatin or Atorvastatin Evaluation and Infection Therapy [PROVE-IT], Randomised Trial of Roxithromycin in Non– Q-Wave Coronary Syndromes [ROXIS], Azithromycin and Coronary Events Study [ACES]) that were completed recently have failed to show a benefit for specific antibiotics such as roxithromycin or azithromycin in the treatment of CHD.13–17 16490835
1140 The mean number of stools per day over the 3-day treatment phase (days 3–5) for the bisacodyl treatment group (1.8+- 1.5/day, mean +- s.d.) was statistically significantly greater (P = 0.0061) than that for the placebo group (0.95 +- 0.60/day). 16669963
1141 In terms of the designation of stool consistency, this change of )1.4 (95% CI: )2.0 to )0.76) represented a difference between a value signifying between ‘soft’ and ‘well-formed’ in the bisacodyl group and between ‘moderately hard’ and ‘hard’ in the placebo group, suggesting a significant improvement in clinical status for the bisacodyl-treated group. 16669963
1142 Neomycin Improves Constipation-Predominant Irritable Bowel Syndrome in a Fashion That Is Dependent on the Presence of Methane Gas: Subanalysis of a Double-Blind Randomized Controlled Study 16832617
1143 B. infantis 35624 is a probiotic that specifically relieves many of the symptoms of IBS. 16863564
1144 Activation of PPAR-c also has anti-tumourigenic effects which manifest as anti-proliferative activities, pro-differentiation activities, pro-apoptotic activities, inhibition of the formation of aberrant crypts foci and inhibition of the development of colon tumours. 16939423
1145 The key to an integrated understanding of the mechanism of action was the realization that the anti-inflammatory actions of 5-ASA produce effects similar to activation of the gamma-form peroxisome proliferator- activated receptors (PPAR-gamma), e.g. modulation of inflammatory cytokine production, modulation of RelA/p65 dephosphorylation, leading to decreased transcriptional activity of NF-jB, and reduced synthesis of prostaglandins and leukotrienes.8, 14, 15 16939423
1146 At a concentration of 109 CFU/d, the analgesic effect was induced rapidly within 10 d, maintained for the duration of the treatment (10, 14 or 21 d; Fig. 2d) and disappeared 3 d after the last NCFM administration (Fig. 2e). 17159985
1147 In a model of chronic colonic hypersensitivity, elicited by butyrate enemas and mimicking irritable bowel syndrome (Fig. 2a and ref. 12), the hypersensitivity of rats was improved by the NCFM strain: treatment with NCFM increased the colorectal distension threshold by 44% compared to that in untreated rats (P o 0.01; Fig. 2f). 17159985
1148 In this model, NCFM resulted in an antinociceptive effect of the same magnitude as that caused by the subcutaneous administration of 1 mg morphine per kg (body weight) (Fig. 2f). 17159985
1149 NCFM-induced analgesia was significantly inhibited by peritoneal administration of the CB2-selective antagonist AM-630 (3 mg/kg, Tocris; P o 0.001) but not by the opioid receptor antagonist naloxone methiodide (2 mg/kg, Sigma) (Fig. 2h), providing indirect evidence for a physiological role of CB2 in the control of intestinal pain 17159985
1150 The similar efficacy, in treating pain, of orally administered L. acidophilus NCFM and a standard dosage of morphine suggests that specific modulation of intestinal flora may be a promising, safe and relatively inexpensive new treatment for abdominal pain, a prominent symptom of irritable bowel syndrome, which affects 20% of the general population. 17159985
1151 Concerning cannabinoid receptor expression, only the L. acidophilus NCFM strain was able to induce significant CNR2 mRNA expression compared to that observed in resting epithelial cells (P o 0.01, Fig. 1a). 17159985
1152 In an immunohistochemistry analysis using antibodies to opioid receptor m1 (MOR1) and CB2, we detected the expression of both these receptors in HT-29 epithelial cells incubated with the NCFM strain (Fig. 1c). 17159985
1153 In the colonic section of untreated mice and rats, we detected MOR1 and CB2 expression in approximately 0–20% of epithelial cells; in contrast, the administration of NCFM induced the expression of these proteins in 25–60% of epithelial cells (Fig. 1e,f). 17159985
1154 L. acidophilus NCFM and L. salivarius Ls-33 induced a sustained increase of OPRM1 mRNA expression in human HT-29 epithelial cells, starting 1 h after bacterial stimulation (Fig. 1a). 17159985
1155 The inducible effect of NCFM on OPRM1 and CNR2 expression in epithelial cells was equally reproduced when we used bacteria killed by 80 1C heat (Fig. 1b). 17159985
1156 We found no macroscopic or histological alteration in NCFM-treated rodents, demonstrating that NCFM does not induce adverse effects in the intestinal tract. 17159985
1157 Acute psychological stress and central injection of CRF and urocortin 1 exert an inhibitory effect on duodenal and small-intestinal transit and propulsive motility, similar to their effects on gastric functions (6, 54, 65, 66, 75–77). 17200704
1158 All reports, except 2 (61, 63), have identified the vagus nerve as the main pathway mediating the delayed gastric transit and inhibition of gastric motility induced by central injection of either CRF or urocortin 1 in rats and dogs (54,55, 57, 59, 62, 64, 65). 17200704
1159 As established for a number of neuropeptides (such as somatostatin opiates, and calcitonin gene–related peptides) that act in the brain to influence gut motility (99), the CRF ligands and receptors that were initially characterized in the brain (where they function to influence gut motor function) have recently been shown to be widely expressed in peripheral tissues, including the gastrointestinal tract of experimental animals and humans (19, 32, 100–103). 17200704
1160 By contrast, the delayed gastric emptying induced by injection of urocortin 2 into the CSF is not altered by gastric vagotomy and instead requires the integrity of the sympathetic nervous system and peripheral á-adrenergic receptors (57). 17200704
1161 In contrast to the inhibitory effects of CRF and urocortin 1 injected into the CSF on gastric and small-intestinal motor unction, these peptides stimulate colonic transit and defecation and induce diarrhea through increased sacral parasympathetic outflow to the large intestine in female and male rats, mice, and gerbils (6, 7, 56, 61, 80–85). 17200704
1162 In particular, injection of CRF either i.v. or i.p. inhibited gastric emptying, delayed small-intestinal transit, stimulated colonic transit and defecation, and induced diarrhea with a potency similar to that of CRF injected into the CSF (6,61, 106). 17200704
1163 Peptide-inhibitory action is mediated directly by vagal nerves and is independent of activation of the HPA axis (6, 61, 66, 78). 17200704
1164 whereas peripheral injection of CRF or urocortin 1 stimulates colonic motility through activation of CRF1 expressed by colonic myenteric neurons (19) 17200704
1165 Removal of the pituitary gland or adrenal glands had no effect on CRF inhibition of gastric emptying; this indicates that the gastric effect is not secondary to the activation of the HPA axis (61, 62). 17200704
1166 This was shown by the fact that injection of the selective CRF2 agonists, urocortin 2, or, less potently, urocortin 3 either i.p. or i.v. inhibited gastric emptying of a solid or liquid meal but did not influence distal colonic transit in rodents (106, 112). 17200704
1167 Little is known about the interaction of these species with the chelating drugs DMSA or DMPS, although it has been seen that simultaneous administration of selenium with DMSA or DMPS leads to reduced effectiveness of the chelators (Juresa et al., 2005). 17408840
1168 Both ALA and DHLA are known to form chelates with various heavy metals (Packer et al., 1997, 1995). 17408840
1169 DMPS is a water-soluble dithiol. It has been used in the treatment of arsenic, lead, mercury and cadmium poisoning and has also been used to treat Wilson’s disease (an inborn error of copper metabolism leading to bioaccumulation of cop- per). 17408840
1170 DMPS is known to chelate the essential min- erals copper, chromium and zinc (Risher and Amler, 2005). 17408840
1171 DMSA has a half-life of 3.2h (Aposhian et al., 1992b; Frumkin et al., 2001) and is known to chelate the essential minerals copper and zinc (Risher and Amler, 2005). 17408840
1172 DMSA is administered orally and is rapidly but incompletely absorbed. It has been used to chelate lead, arsenic,cadmium,mercury and other metals. 17408840
1173 However, the handful of studies that do exist seem to point to dietary fibre as potentially enhancing the elimination of methylmercury from the body. 17408840
1174 Indeed, in one study NAC supplementation appeared to increase brain mer- cury concentration (Aposhian et al., 2003). 17408840
1175 It has also been suggested that in humans, control of plasma cysteine levels is important in the control of symptoms and the treatment of mercury toxicity (Cutler, 1999). 17408840
1176 It seems apparent from the body of research reviewed by Bridges and Zalups (2005), that endogenous thiols, such as cysteine, homocysteine, GSH and NAC play an important role in the distribution of mercury throughout the body. 17408840
1177 Mice that received NAC in the drinking water (10 mg/ml) starting at 48 hr after methylmercury administration excreted from 47 to 54% of the 203Hg in urine over the subsequent 48 hr, as compared to 4-10% excretion in control animals. 17408840
1178 NAC and GSH merit special mention as some physi- cians recommend them as antidotes to mercury toxicity. At first glance this would seem logical, since GSH is known to be involved in the biliary excretion of methylmercury (Ballatori and Clarkson, 1985) and it is thought that intracellular GSH plays a role in pro- tecting cells (Clarkson, 2002). 17408840
1179 The side-effects of DMSA include GI disorders, skin rashes and flu-like symptoms. 17408840
1180 This raises the question as to whether dietary intake (or vitamin supplementation) of thiol-containing foods affects the transport of mercury into organs, and thus affects toxi- city. 17408840
1181 Though less toxic than older chelation agents such as British Anti-Lewisite (BAL) and d-Penicillamine, they do have some toxic side-effects (particularly DMPS). There is a clear need for the development of more effec- tive, safe chelating agents that are capable of removing mercury from the brain. 17408840
1182 Unlike DMSA and DMPS, ALA is taken up by all areas of the CNS and peripheral nerves (Packer et al., 1997). 17408840
1183 DMPS is not effective at removing mercury from the brain (Aposhian et al., 2003; Buchet and Lauwerys, 1989; George et al., 2004). 17408840
1184 ESR was raised in 61%, 79%, 75%, and 100%, and CRP was elevated in 54%, 70%, 75%, and 100%, respectively, of subjects with quiescent, mild, moderate, and severe disease 17436102
1185 The ESR was increased in 29%, 25%, 73%, and 100%, and CRP was elevated in 14%, 42%, 64%, and 83%, respectively, of subjects with quiescent, mild, moderate, and severe disease 17436102
1186 The correlation in UC was lost in distal disease and proctitis, i.e., it has to extend beyond the sigmoid colon 17436102
1187 LPS acts through both MyD88-dependent and -independent TLR4 signaling pathways to directly inhibit GHR gene expression. 17601656
1188 It thus appears that, although inflammation alone is sufficient to promote the overgrowth of Enterobacteriaceae, both inflammation and the presence of an invading pathogen are necessary for the decrease in the total numbers of intestinal bacteria to reach its maximal magnitude. 18005726
1189 Enterococcus faecalis are facultative anaerobic bacteria that may be benefiting from the potentially increased oxygen availability in the inflamed intestine, in the manner similar to C. rodentium and nonpathogenic E. coli. 18005726
1190 In all of these studies, an increase in the proportion of nonpathogenic g-Proteobacteria (Enterobacteriaceae family) and/or presence of pathogenic g-Proteobacteria was observed in IBD patients relative to healthy controls. 18005726
1191 It also appears that the inflammatory response triggered by the invading pathogen functions to enhance its colonization, thereby further facilitating its virulence. 18005726
1192 Initial results with double knockout LDLr−/−TLR2−/− mice showed that whole body deficiency of TLR2 results in decreased lesion burden after 10 or 14 weeks of consuming a high-fat diet [25]. 18031244
1193 These studies showed that TLR4 and MyD88 deficiency retards disease development, whereas CD14 deficiency has no effect on disease development. 18031244
1194 Thus transplantation of BMDC into ApoE−/− mice from ApoEexpressing mice reverses the ApoE deficiency phenotype of the recipient mouse [20]. 18031244
1195 In additional experiments, we showed that administration of Pam3 (Pam3 CSK4; Invivogen) promoted additional dramatic disease in the hyperlipidaemic LDLr−/− mice and that this was abrogated in LDLr−/−TLR2−/− mice [25]. 18031244
1196 Concentrations of inorganic mercury in blood and of total mercury in urine and saliva differed significantly between individuals with amalgam fillings and amalgam-free volunteers, 18259961
1197 Concentrations of total and inorganic mercury in body fluids do not distinguish between asymptomatic amalgam bearers and those who suffer from a poorly defined syndrome of multiple nonspecific symptoms. 18259961
1198 Flavanols are a sub-class of a larger group of plant com- pounds known as flavonoids. Flavanols (also known as flavan-3-ols, or catechins) are present in a number of com- monly consumed foods and beverages including grapes and grape products, apples, teas, cocoa and cocoa products. 18296356
1199 Antibiotic treatment dramatically changed the ob/ob mice gut microbiota; reduced Lactobacillus spp., Bifidobacterium spp., and Bacteroides-Prevotella spp.; and lowered metabolic endotoxemia. 18305141
1200 Furthermore, dietary fibers, which reduce the impact of high-fat diet on the occurrence of the metabolic diseases (5), normalized the Gram negative–to–Gram positive ratio and plasma endotoxemia (6). 18305141
1201 High-fat feeding decreased the number of bifidobacteria (4,6). 18305141
1202 Interestingly, we also found that ob/ob mice treated for 4 weeks with an endotoxin inhibitor (43) administered via osmotic mini-pumps improved glucose tolerance and lowered adipose tissue fat mass (Supplemental Fig. 2). 18305141
1203 Most importantly, the corresponding LPS receptor CD14 knockout mouse resisted the occurrence of the diseases. 18305141
1204 The modulation of gut bacteria after high-fat diet strongly increased intestinal permeability by reducing the expression of genes coding for tight junction proteins ZO-1 and occludin. 18305141
1205 This group of bacteria has been shown to reduce intestinal LPS levels in mice and to improve the mucosal barrier function (36 –38). 18305141
1206 Although the reasons for its increase in plasma during high-fat feeding were undetermined, its levels were closely correlated but not causatively demonstrated, with changes in intestinal microbiota where the Gram negative–to–Gram positive ratio increased during high-fat feeding (4). 18305141
1207 However, we have recently reported that moderate increase of plasma concentration of the inflammatory reagent, the bacterial lipopolysaccharide (LPS), increased during a fat-enriched diet, and defined metabolic endotoxemia (4). 18305141
1208 In the present study, we further provide evidence that the mechanisms involved in the development of metabolic endotoxemia and the corresponding metabolic disorders in response to high-fat feeding are associated with an increased intestinal permeability. 18305141
1209 The lipid content was dramatically increased in mice treated with antibiotics, suggesting that intestinal flora contributes to energy harvesting or absorption. 18305141
1210 Therefore, we characterized several inflammatory markers and found that the increase in PAI-1, IL-1, and TNF- mRNA concentrations after high-fat feeding was completely abolished by the antibiotic treatment. 18305141
1211 These animals are characterized by different gut microbiota (8,12), higher inflammatory tone, and endotoxemia when compared with wild-type mice (23). 18305141
1212 We demonstrated that LPS was responsible for the onset of metabolic diseases (4), because a continuous subcutaneous low-rate infusion of LPS induced most, if not all, of the features of metabolic diseases. 18305141
1213 We identified here that metabolic endotoxemia was due to changes in intestinal microbiota, because the antibiotic treatment, which dramatically reduced the local intestinal microbiota, restored normal plasma LPS values in high-fat diet–fed mice. 18305141
1214 Individuals with low levels of methane in their breathe contain <102to 5 × 106methanogen cells/g feces.90,92Acetogens predominate in these in- dividuals, and the numbers of acetogens have a negative correlation with that of methanogens. 18378594
1215 About one-third of healthy human adults are strong methane-producers and possess breathe methane lev- els >1ppm above the atmospheric methane level.90,91 MostoftheproducedCH4gasisexcretedasflatusandsome is absorbed in the blood and excreted in breath. Methanogens number 108–1010cells/g feces in these individuals. 18378594
1216 Individuals with low levels of methane in their breathe contain <102to 5 × 106methanogen cells/g feces.90,92Acetogens predominate in these in- dividuals, and the numbers of acetogens have a nega-tive correlation with that of methanogens. 18378594
1217 Neither the cell numbers of sulfate-reducing bacteria nor the concen- trations of sulfate and sulfide in feces are significantly differentbetweenmethane-producingandnonproduc-ing 18378594
1218 Appendectomy is another factor with potentially opposing effects on Crohn’s disease versus ulcerative colitis. It seems to protect against future presentation with ulcerative colitis while either having no effect or predisposing to presentation with Crohn’s disease. 18515412
1219 Crohn’s disease incidence was not correlated with intake of fish protein and was inversely correlated with intake of vegetable protein (r=20.941, p,0.001). 18515412
1220 Elsewhere, citrus fruit consumption protected against development of both Crohn’s disease and ulcerative colitis. 18515412
1221 Finally, vitamin D has increasingly been shown to have an important impact on health, and this may include the predisposition to IBD. 18515412
1222 In contrast, polyunsaturated fatty acids of the v-3 series produce antiinflammatory mediators LTB-5 and prostaglandin E3 which suppress inflammation.85 18515412
1223 In one study of newly diagnosed children where recall bias may be less of an issue than in adults with the help of interviewed parents and with a shorter lifespan to review, it was reported that higher amounts of vegetables, fruits, fish, dietary fibre and long-chain v-3 fatty acids significantly protected from Crohn’s disease. 18515412
1224 Saturated fats increase the activation of nuclear factorkB through Toll-like receptors, and this activation is suppressed by derivatives of v-3 fatty acid 18515412
1225 The intake of vitamin C significantly protected against ulcerative colitis. 18515412
1226 A higher omega-6/omega-3 fatty acids ratio was significantly associated with higher risks for Crohn’s disease. 18515412
1227 Crohn’s disease was associated (by a factor of two- to threefold) with consumption of fish and shellfish, the intake of total fat, monounsaturated fatty acids, polyunsaturated fatty acids, v-3 and v-6 fatty acids, and vitamin E. 18515412
1228 In addition, polyunsaturated fatty acids of the v-6 series produce proinflammatory leucotriene B-4 (LTB-4) which enhances the inflammatory reaction. 18515412
1229 M avium subsp. paratuberculosis causes Johne disease in cattle, a disease that is similar to Crohn’s disease in its distribution, morphology and phenotype. 18515412
1230 Migrant offspring reared in the adoptive country or those who migrate during childhood have the greatest risk of developing IBD. 18515412
1231 Of the different infectious agents considered as possible causes of Crohn’s disease, Mycobacterium avium subspecies paratuberculosis is the most durable. 18515412
1232 Several studies have shown that supernatants of colonic mucosal biopsies from IBS patients contain elevated concentrations of mast cell mediators including histamine and serine proteases, typically associated with allergic type responses. 18515412
1233 The univariate analysis showed that the increased incidence of Crohn’s disease was strongly correlated (p,0.001) with increased dietary intake of total fat (r=0.919), animal fat (r=0.880), v-6 polyunsaturated fatty acids (r=0.883), animal protein (r=0.908), milk protein (r=0.924) and the ratio of v-6 to v-3 fatty acid intake (r=0.792). 18515412
1234 Thorough investigation of biopsies from PI-IBS patients consistently reveal a chronic but low grade immune activation, with increased numbers of resident immune cells including mast cells and T cells. 18515412
1235 Ulcerative colitis was strongly associated (by a factor of two- to threefold) of a higher consumption of sweets and fats and oils. 18515412
1236 While the cessation of smoking is often associated with the onset of ulcerative colitis or the exacerbation of established disease, smoking represents one of the most consistently observed environmental influences on Crohn’s disease. 18515412
1237 Other non-lanthionine containing bacteriocins are small antimicrobial peptides produced by Lactobacilli. 18623173
1238 Probiotic bacteria, especially strains of Lactobacilli, produce acetic, lactic, and propionic acid that lower the local pH, leading to inhibit growth of a wide range of Gramnegative pathogenic bacteria. 18623173
1239 A single microbial molecule from Bacterial fragillis has also been shown to protect its host from inflammatory disease caused by Helicobacter hepaticus in an animal model of experimental colitis, suggesting that natural antiinflammatory molecules from the bacteria microbiota can actively promote human health, and may potentially be therapies for human inflammatory disorders. 18626975
1240 In an experiment that used methylated and nonmethylated genomic DNA isolated from the probiotic preparation VSL#3, DNAse-treated probiotics, and E. coli genomic DNA, the authors demonstrated that genomic DNA (but not methylated DNA, calf thymus DNA, or DNAse-treated probiotics) ameliorated the severity of colitis in DSS-induced, TNBS-induced, and spontaneous colitis in IL-10 KO mice 18626975
1241 In the same study, intragastric and subcutaneous administration of gamma- irradiated nonviable bacteria and live bacteria had similar beneficial effects 18626975
1242 Individual strains within VSL#3 displayed distinct immunomodulatory effects on DC; the most marked antiinflammatory effects were produced by bifidobacteria strains (B. longum, B. infantis and B. breve), which upregulated IL-10 production by DC. 18626975
1243 Lacticin 3147, a broad-spectrum bacteriocin produced by Lactococcus lactis subsp., inhibits a range of genetically distinct C. difficile isolates from healthy subjects and patients with IBD. 18626975
1244 Parenteral administration of L. salivarius in IL-10 KO mice ameliorates the severity of colitis, a beneficial effect similar to that demonstrated by the same group previously for oral administration. 18626975
1245 Studies using a 16S rRNA technique have shown reductions in bifidobacteria108,109 and lactobacilli in patients with UC.110 18626975
1246 The number of different commensal bacteria is altered in IBD patients with increased bacteroides, adherent or invasive Escherichia coli, and enterococci, and reduced bifidobacterium and lactobacillus species.3,6 18626975
1247 They also showed that the probiotic effect is not diseasespecific, with a similar beneficial effect demonstrated in collagen- induced murine arthritis.112 18626975
1248 VSL#3 probiotic bacteria produced soluble factors that inhibited chymotrypsin-like activity of the proteosome in intestinal epithelial cells, thereby inhibiting the NF-kappaB pathway and inducing expression of cytoprotective heat shock proteins. 18626975
1249 Adhesive E. coli have been implicated in the pathogenesis of UC 18626975
1250 E. coli Nissle 1917 induced IL-8 secretion by intestinal epithelial cell lines in a dose-dependent manner, suggesting that the ability to prevent secretion of IL-8 from epithelial cells is not a feature of all probiotic bacteria 18626975
1251 For example, in healthy rats, L. brevis enhanced barrier function as assessed by permeability to mannitol in excluded colonic loops. 18626975
1252 For example, L. plantarum 299v increased MUC2 and MUC3 mRNA expression when incubated with the epithelial cell line HT-29. 18626975
1253 Lammers et al113 demonstrated that bifidobacterium genomic DNA induced the secretion of IL-10 by peripheral blood mononuclear cells from healthy donors, demonstrating the immunomodulatory effects of bacteria DNA. 18626975
1254 The probiotic E. coli Nissle strain induced expression of human beta-defensin 2 (hBD-2) in Caco-2 intestinal epithelial cells42; this type of effect may contribute to an improved mucosal barrier and provide a means of limiting access of enteric pathogens. 18626975
1255 The probiotic mixture VSL#3 normalized barrier integrity as assessed by short circuit currents, transepithelial potential differences, and mannitol fluxes in excised tissue from mice. 18626975
1256 This concept was demonstrated by Lammers et al62 and Otte and Podolsky58 who showed that probiotic bacteria in the VSL#3 combination did not induce IL-8 secretion by epithelial cells compared with intestinal pathogens such as enteropathogenic E. coli, Salmonella dublin, Shigella dysenteriae, and Listeria monocytogenes, all of which did induce secretion of IL-8. 18626975
1257 VSL#3 and E. coli Nissle strain increased MUC2, MUC3, and MUC5AC gene and protein expression. 18626975
1258 We have also shown that these results can be extrapolated to the in vivo situations. Patients with UC treated with VSL#3 have increased IL-10 and reduced IL-12p40 production by colonic DC; these effects were not seen in placebo-treated patients.76 18626975
1259 In conclusion, it appears that in man, as in the rat, the jejunum is the major area of fat absorption 18668739
1260 The absorption of fat, carbohydrate and protein begins in the duodenum and is completed in the proximal 100 cm. of the jejunum, more proximal for fat than for carbohydrate and more proximal for carbohydrate than for protein. 18668739
1261 There were four main findings in IBS patients: (i) basal levels of plasma ACTH were significantly decreased, while both 24-h basal plasma cortisol levels and stress-induced cortisol levels tended to be increased; (ii) basal cortisol levels prior to a visceral stressor positively correlated with the presence of anxiety symptoms; and (iii) exploratory evaluation of mucosal cytokine expression demonstrates decreased or normal levels of cytokines in the sigmoid colon. 18684212
1262 Artemisinins are derived from extracts of sweet wormwood (Artemisia annua) and are well established for the treatment of malaria, including highly drug-resistant strains. 18752857
1263 Other than antimalarial activity, artemisinin was found to be a good antibacterial, antifungal, antileishmanial, and antitumor agent. 18752857
1264 Our results would suggest that blocking chylomicron formation, by dietary or pharmacological means, could perhaps be of benefit in Crohnʼs Disease by preventing activation of immune cells in the MLN by LPS. 18815435
1265 We observed that cultured CaCo-2 cells basolaterally secrete cell-associated LPS during OAinduced chylomicron formation, which was not observed when the cells were incubated with short-chain butyric acid (BA), which does not induce chylomicron formation or when OA was added together with the inhibitor of chylomicron formation, Pluronic L-81 (Pl-81). 18815435
1266 However, LPS has been detected even in the blood of healthy animals(20) and in the plasma of healthy human subjects at low concentrations (between 1 and 200 pg/ml)(19,21,22), suggesting that small amounts of LPS are constantly passing through the intestines. 18815435
1267 In the present study, we also show for the first time that dietary LCT stimulate TNFa expression in the MLN (Fig. 4), an important center of intestinal immunity (60). 18815435
1268 Our data also show for the first time that chylomicron formation correlates with increased deposition of LPS in the MLN (Fig. 3). 18815435
1269 This novel observation could be of relevance to inflammatory bowel disease, since long-chain dietary fat is considered to be harmful to a significant subpopulation of patients suffering from Crohnʼs Disease (63). 18815435
1270 This possibility is further supported by the fact that intestinal epithelial cells express LPS binding protein (59), which mediates the association of LPS with chylomicron particles in the circulation (15). 18815435
1271 Thus, our data that suggest that LPS is secreted from cell-associated pools in a chylomicrondependent manner could be partially explained by loading of cell-associated LPS onto nascent chylomicrons. 18815435
1272 Using in vivo studies, we observed that dietary triolein (TO) significantly promoted LPS absorption into blood and mesenteric lymph nodes (MLN) compared with tributyrin (TB) and caused significant increases of TNFa mRNA. 18815435
1273 Fourth, our data show that OA does not cause tight junction disruption in cultured intestinal-epithelial cells. 18815435
1274 Indeed, using the lactulose/mannitol test, elevated intestinal permeability has been documented in 12–50% of IBS patients, depending on the infective nature of IBS, inclusion of patients with adverse reaction to food or various IBS criteria 18824556
1275 It has been recently demonstrated that patients with IBS had a marked increase in colonic mucosal area occupied by mast cells with increased release of histamine and tryptase compared to healthy subjects. 18824556
1276 The current study showed that paracellular permeability of colonic biopsies of patients with IBS is increased irrespective of IBS subtype 18824556
1277 in contrast to the small intestine, this increase (observed in colonic biopsies and also induced by soluble factors from biopsies) is independent of IBS subtype. 18824556
1278 Taken together, these data suggest that histamine could be involved in the increased viscerosensitivity in IBS, but not in the increased paracellular permeability. 18824556
1279 In humans and animal models, cardiovascular disease is increased by bacterial infection of the supporting tissue of the teeth, a condition known as periodontal disease. 18948273
1280 Hypercholesterolemic LDLr2/2 mice with a total deficiency of TLR2 have only minimal lesions (25). 18980945
1281 Liu et al. (26) recently confirmed the same influence of a TLR2-deficiency in apoE2/2 mice and Madan (27) observed a similar level of disease protection in apoE1/2 mice. 18980945
1282 Fifty two of 197 (26%) patients randomised to peppermint oil had persistent symptoms compared with 127 of 195 (65%) receiving placebo (relative risk 0.43, 0.32 to 0.59; fig 4), with statistically significant heterogeneity detected between studies (I2=31.1%, P=0.23). The number needed to treat with peppermint oil to prevent one patient having persistent symptoms was 2.5 (2.0 to 3.0). 19008265
1283 In total, 350 of 905 (39%) patients assigned to antispasmodics had persistent symptoms after treatment compared with 485 of 873 (56%) allocated to placebo (relative risk 0.68, 95% confidence interval 0.57 to 0.81), with statistically significant heterogeneity detected between studies (I2=62.6%, P<0.001; fig 3). The number needed to treat to prevent symptoms persisting in one patient was 5 (95% confidence interval 4 to 9). 19008265
1284 This effect was limited to ispaghula (0.78, 0.63 to 0.96). 19008265
1285 When only the seven studies scoring 4 or more on the Jadad scale were considered in the analysis the treatment effect for fibre was no longer statistically significant (relative risk of persistent symptoms 0.90, 0.75 to 1.08). 19008265
1286 When only these studies were considered in the analysis the treatment effect for ispaghula was no longer statistically significant 19008265
1287 In murine models, antibiotic administration suppressed expression of the commensalinduced antimicrobial protein RegIII and allowed pathogen overgrowth. 19026645
1288 Additionally, supplementation of mice with TLR ligands reinduced RegIII and corrected innate immune defects.150 19026645
1289 Notably, these experiments illustrate that dysbiosis can be a direct result of innate immune dysfunction. 19026645
1290 L. acidophilus NCFM attached to DCs and induced a concentrationdependent production of IL-10, and low IL-12p70. 19047644
1291 L. acidophilus NCFM stimulated DCs produced more IL-4. 19047644
1292 In addition, Macrophage expression of PPAR a reduces atherosclerosis in LDL receptor-deficient mice (Babaev et al., 2007). 19049899
1293 PPAR g-specific agonists such as rosiglitazone and GW7845 strongly inhibit the development of atherosclerosis in LDL receptor-deficient mice (Li et al., 2000). 19049899
1294 The present study demonstrates that C. pneumoniae down-regulates the expression of PPAR a and PPAR g at mRNA and protein levels in a dosedependent manner in THP-1-derived macrophages when cocultured with LDL. 19049899
1295 Chlamydial lipopolysaccharide (LPS) has been shown to enhance native LDL uptake, whereas Chlamydial heat-shock protein 60 (chsp60), an inflammatory antigen that was recently localized within atheroma macrophages, induce LDL oxidation and foam cell formation (Kalayoglu and Byrne, 1998; Kalayoglu et al., 1999). 19049899
1296 Earlier studies have shown that C. pneumoniae induces human and murine macrophage foam cell formation partly by stimulating low density lipoprotein (LDL) oxidation and entry, implicating this organism as a causative agent in atherosclerosis (Kalayoglu and Byrne, 1998; Kalayoglu et al., 1999). 19049899
1297 PPAR a and PPAR g activators induce the expression of ATP binding cassette transporter A1(ABCA1), an important cholesterol efflux regulatory protein, promoting cholesterol efflux from macrophages, thereby reducing intracellular cholesterol accumulation (Chawla et al., 2001; Castrillo and Tontonoz, 2004). 19049899
1298 This study demonstrates that higher doses of C. pneumoniae infection (5 106 and 1 106 IFU) obviously increase the accumulation of lipid droplets containing CE (morphology) and the ratio of CE to TC (biochemistry) in THP-1 macrophages when co-cultured with LDL, indicating that C. pneumoniae infection increases the accumulation of LDL-derived lipids, resulting in macrophage-derived foam cell formation. 19049899
1299 In contrast, LDL-treated THP-1 macrophages without C. pneumoniae infection cannot transform into foam cells from morphological and biochemical criteria. 19049899
1300 Bacteriological analysis of fecal samples collected at the end of a 2·wk feeding period showed that ingestion of 3 x 5 g fructooligosaccharides/d significantly increased the proportion of bifidobacteria from 6 to 22%, whereas bacteroides, clostridia and fusobacteria were decreased from 25 to 4%, 1 to 0.2% and 4 to 0.4%, respectively (Fig. 8). 19079930
1301 19079930
1302 Consistent with its anti-inflammatory role, a 1,25(OH)2VD3 analogue has been successfully used as a therapy for psoriasis135,136. 19172691
1303 Furthermore, 1,25(OH)2VD3 also inhibits TH17-cell responses, probably owing in part to its capacity to inhibit IL-6 and IL-23 production34,35, and induces the reciprocal differentiation and/or expansion of forkhead box protein 3 (FOXP3)+ regulatory T (TReg) cells35–37. 19172691
1304 In addition to its inhibitory effects on T cells, 1,25(OH)2VD3 decreases B-cell proliferation, plasma-cell differentiation and IgG secretion8,20 (FIG. 2). 19172691
1305 Overall, the net result of 1,25(OH)2VD3 action on T cells is to block the induction of T-helper-1 (TH1)-cell cytokines, particularly IFNγ, while promoting TH2-cell responses, an effect mediated both indirectly by decreasing IFNγ production and directly by enhancing IL-4 production7. 19172691
1306 The activity of 1,25(OH)2 VD3 on effector T-cell differentiation is further enhanced by its effect on antigen-presenting DCs, in which it suppresses the synthesis of IL-12, a cytokine that promotes TH1-cell responses32,33 19172691
1307 These inhibitory effects of 1,25 (OH)2VD3 are most pronounced in the memory T-cell compartment30, which is concomitant with the higher expression of VDR in effector and memory T cells compared with naive T cells31. 19172691
1308 Although 1,25(OH)2VD3 could be a potentially useful immunomodulatory agent for clinical use, it can cause some serious adverse effects, in particular the induction of hypercalcaemia and bone resorption7. 19172691
1309 As 1,25(OH)2VD3 in combination with glucocorticoids induces IL-10-producing TR1 cells133, it is possible that 1,25 (OH)2VD3 might exert its therapeutic effect, at least in part, through the generation of TR1 cells. 19172691
1310 Consistent with this idea, levels of serum 1,25(OH)2VD3 are often decreased in patients with type I diabetes123 and SLE8,124, and 1,25(OH)2VD3 levels are inversely correlated with disease activity in patients with rheumatoid arthritis125. 19172691
1311 However, although children with rickets (typically caused by insufficient dietary supply of vitamin D) have a higher incidence of diabetes than VD3-sufficient children7, they are also more susceptible to infection7,128, which suggests that VD3 might also be important for protective immune responses. 19172691
1312 Moreover, VD3 deficiency accelerates intestinal inflammation in IL-10-deficient mice, which develop inflammatory bowel disease126 19172691
1313 This effect could be partially mediated by the capacity of 1,25(OH)2VD3 to increase the bactericidal capacity of macrophages5,23. 19172691
1314 LR ingestion increased excitability (threshold for evoking action potentials) and number of action potentials per depolarizing pulse, decreased calcium-dependent potassium channel (IKCa) opening and decreased the slow afterhyperpolarization (sAHP) in sensory AH neurons, similar to the IKCa antagonists Tram-34 and clotrimazole. 19210574
1315 Antioxidants have been shown to normalize intestinal permeability in alcoholic patients 19251117
1316 Indeed, studies in animal models of ALD have revealed that treatment with antibiotics to sterilize the gut and thus eliminate this source of endotoxin can prevent alcohol-induced liver injury (Adachi et al., 1995). 19251117
1317 LGG also decreases systemic inflammation markers caused by LPS in rats 19251117
1318 LGG has also been shown to reduce intestinal oxidative stress 19251117
1319 Moreover, Lactobacillus GG supplementation significantly decreased severity of liver injury in a rat model of alcoholic steatohepatitis (Nanji et al., 1994). 19251117
1320 Our data now support our proposed hypothesis that LGG inhibition of NF-kB activation by alcohol results in decreased iNOS expression and reduced oxidative stress resulting in the reduced markers of oxidative stress. 19251117
1321 Patients who received probiotic therapy with bifidobacteria and lactobacillus spp. restored numbers of these species to levels seen in controls and demonstrated significant improvement in liver function.  19251117
1322 Probiotics including LGG have been shown to have several beneficial effects on intestinal function including stimulating intestinal development and mucosal immunity, ameliorating diarrhea, prolonging remission in ulcerative colitis and pouchitis, and maintaining and improving intestinal barrier function  19251117
1323 The authors showed that chronic alcoholics have an abnormal profile of gut microbiota with significantly lower numbers of bifidobacteria and lactobacilli.  19251117
1324 We also showed that oats supplementation prevented both increased intestinal permeability and steatohepatitis in chronically alcohol fed rats  19251117
1325 For example, ALD patients and animal models of chronic alcoholism have abnormally high plasma endotoxin levels  19251117
1326 The cause of alcohol-induced endotoxemia is not well established but several studies suggest that alcohol-induced increased intestinal permeability to gut derived endotoxin is the possible mechanism  19251117
1327 Thus we propose that oxidative stress is the key element driving alcohol-induced intestinal hyperpermeability and anti-oxidants may be effective therapeutic agents to prevent ASH. 19251117
1328 We have also shown that alcohol increases intestinal epithelial cell permeability in vitro through an oxidant stress mediated mechanism 19251117
1329 However, in both WT and A2BAR -/- mice, L-NAME (NO-synthase inhibitor) and ODQ (soluble guanylate cyclase inhibitor) caused significant inhibition of relaxation (P0.01), indicating the NOcGMP dependence of relaxation (Fig. 3B). 19357134
1330 The addition of A2BAR antagonists SPT (P0.05) and MRS-1754 (P0.05) resulted in significant inhibition of relaxation in WT, but not in A2BAR -/- mice. 19357134
1331 A2BAR -/- mice exhibit increased stool retention and delayed colonic emptying 19357134
1332 A2BAR stimulation results in increased intracellular cAMP levels in intestinal epithelial cells (14) and was recently found to activate cGMP and NO in the penile epithelia (15). 19357134
1333 Among the adenosine receptors, A2BAR has the highest expression in the colon (10), where it is expressed both in the epithelial cells (10, 11) as well as in the enteric neurons (12). 19357134
1334 The ATL-801-fed mice exhibited delayed colonic emptying, which was evident from decreased stool frequency in A2BAR -/- mice, measured as number of pellets extrudedper hour (P0.01) compared to control mice (Fig. 5A). 19357134
1335 These data suggest that a component of NO-dependent relaxation in the murine distal colon involves A2BAR activation. 19357134
1336 These data suggest that A2BAR activation by NECA promotes relaxation, which involves NO release from inhibitory neurons. 19357134
1337 These results support our findings that NO production in enteric neurons involves signaling through A2BAR. 19357134
1338 Constipated IBS patients showed similar numbers of EC cells to healthy controls but elevated 5-HT content such that the 5-HT content per EC cell was nearly double normal. The 5-HIAA/5-HT ratio was significantly depressed at 0.14 compared with 1.2 for health controls in keeping with the impaired release [39]. 19361459
1339 Decreased postprandial plasma serotonin levels have been reported to occur in C-IBS, [39,40] and increased plasma levels have been reported to occur in D-IBS. [37,38,40]. 19361459
1340 Incontrast, PI-IBS patients showed increased EC cell numbers, normal 5-HT content, but also a significant reduction in 5-HIAA/5-HT ratio to 0.21 [39]. This implies an impairment of 5-HT reuptake and metabolism. 19361459
1341 It could be possible that individuals with IBS have a genetic predisposition for decreased SERT expression. 19361459
1342 Pumosetrag (MKC-733, DDP-733), an gastro prokinetic agent and locally acting 5-HT3 partial agonist, for the potential treatment of IBS with constipation and nocturnal gastro esophageal reflux disease (GERD) is under phase IIb trail [115]. Prucalopride, a selective 5-HT4receptor agonist, safely and effectively increases bowel movement frequency in adults with chronic con- stipation, according to a clinical trial [116]. 19361459
1343 The mucosal 5-HT content at the duodenum, jejunum and ileum in C-IBS patients were all lower than normal group, with a significant difference at the jejunum. 19361459
1344 There is a 44 bp insertion/deletion in the 5′ flanking promoter region (5-HTTLPR), which create a short (S) and a long (L) allele. It has been shown that the presence of the short allele is associated with lower transcriptional activityand, as a consequence, lowers level of SERT expression and reuptake of serotonin [89]. The long variant was associated with higher rate of 5-HT uptake, and higher level of 5-HT binding in platelets [90]. 19361459
1345 These findings were supported in a larger independent study of 29 C-IBS patients and 55 D-IBS patients compared with 35 healthy controls. IBS patients with diarrhea had significantly elevated postprandial platelet-depleted plasma concentrations while the constipated patients had reduced values[40]. C-IBS patients had increased platelet 5-HT compared with D-IBS patients, again supporting the idea that SERT might be defective in D-IBS[40]. The higher levels of platelet 5-HT in constipated IBS patients was also observed in Dunlop's study when compared with PI-IBS [39]. 19361459
1346 It can stimulate cholinergic neurons to release acetylcholine, which results in smooth muscle contraction, or it can stimulate inhibitory nitrergic neurons to release nitric oxide, which results in smooth muscle relaxation [9,12,13] (Fig. 2). 19361459
1347 Mucosal stimulation such as stroking activates 5-HT intrinsic afferent neurons in the sub mucosal plexus; this effect is increased by the serotonin selective reuptake inhibitor (SSRI), fluoxetine, which inhibits mucosal 5-HT uptake [25]. 19361459
1348 Recently, Moskwa et al. showed fasting blood serotonin concentration increased in both D-IBS and C-IBS patients and urine 5-hydroxyindole acetic acid excretion is decreased in IBS-subjects [75]. 19361459
1349 SERT deficient mice display increased anxiety related behavior based on increased serotonergic neurotrans- mission resulting in desensitized and down regulated 5-HT1A[68] and -HT2A or 19361459
1350 When patients were divided into those who were symptomatic following ingestion of the meal, 31 who were symptomatic had significantly greater increase in postprandial plasma 5-HT compared to those without symptoms and controls [38]. 19361459
1351 Recently, Kerkhoven et al. done meta analysis to investigated the association between polymorphism of serotonin transporter gene and IBS subtypes. They concluded that this polymorphism is not associated with the IBS [102]. 19361459
1352 Although one study points to a link between antibiotic treatment in general and FGID[26], prolonged gastrointestinal symptoms is not reported as a side effect of metronidazole. Although we can not fully exclude this possibility, we think the Giardia infection is a far more plausible cause of the later FGID than its treatment. 19383162
1353 In our study population we find a pattern of IBS-subtypes with a high frequency of diarrhoeal symptoms and little constipation. This agrees well with previous descriptions of PI-IBS as a distinctive subgroup of IBS patients [18]. 19383162
1354 It is known that Giardia may cause prolonged symptoms for several weeks after successful treatment due to secondary lactose intolerance [20]. 19383162
1355 Modulation of serotonin (5-HT) receptor activity is clearly beneficial in D-IBS, with the re-emerging success of alosetron, a 5-HT3 receptor antagonist, after initial problems.81 19566823
1356 Infection with either the nematode Trichinella spiralis or trinitrobenzene sulphonic acid (TNBS) treatment induces transmural damage and visceral hypersensitivity.53–57 19566823
1357 Similarly, chemical agents such as zymozan and acetic acid can induce long-term hypersensitivity of colonic afferents without an associated acute inflammatory response.50,51 19566823
1358 These studies have demonstrated that the PBMC of patients with PI-IBS or D-IBS secrete greater amounts of the proinflammatory cytokines tumour necrosis factor (TNF)-a, interleukin (IL)-6 and IL-1b than do C-IBS; in addition, D-IBS patients are more prone to overproduce TNF-a.12,31 19566823
1359 We found that our developed 1-D immunoblot assay readily enables to reveal antibodies against 28 L. acidophilus antigenic proteins in patients‘ and controls‘ sera. 19573144
1360 Since the excretion rate of lactulose does not increase over time, the data are consistent with low permeability of intestinal and colonic mucosa to lactulose. 19614866
1361 This radioisotope is not approved for use in the United States. 19614866
1362 Although it cannot be excluded that fatty acids might have contributed to this effect (see Discussion), the data in Fig. 3 suggest that chylomicron-dependent absorption of LPS should be considered as a novel contributor to inflammatory responses. 19614866
1363 Differential absorption and excretion of molecular probes provide evidence of altered permeability of the intestine in gastrointestinal diseases including celiac disease, Crohn’s disease and irritable bowel syndrome (IBS). 19614866
1364 Greater paracellular permeability could facilitate passage of luminal antigens, leading to local mucosal immune responses and resulting in inflammation (1) or stimulation of bowel dysfunction or visceral pain. 19614866
1365 In another study, there was no statistically significant difference between PI-IBS and controls using the pre-specified cut-off for increased permeability [lactulose:mannitol ratio (LMR) >0.025], although the proportion of controls with LMR <0.02 was higher than the proportion of IBS patients (6). 19614866
1366 In fact, in order to collect urine samples that reflect small intestinal permeability, it may prove necessary to obtain urine samples every 30 minutes over the first 2 hours, or to conduct simultaneous imaging in order to identify the urine samples that correspond to the time when none of the isotope (and sugars) reach the colon. 19614866
1367 In one study (21), 51Cr-EDTA in a 24- hour urine collection was proposed as an ideal marker for increased colonic permeability in ulcerative colitis. 19614866
1368 We observed that the later urine collections had higher LMRs, and this may initially suggest that the permeability of the colon is greater than that of the small intestine. 19614866
1369 As shown in Fig. 6, there was no significant difference in transepithelial dextran transport between the various treatment groups. 19614866
1370 Ideally, probes used to measure colonic permeability should be stable in the colonic environment. Mannitol and lactulose are fermented by colonic bacteria; studies have explored the fraction of different sugars remaining after in vitro degradation by rat colonic contents. 19614866
1371 In view of the potential pitfall in its interpretation, we question whether LMR at 8–24 hours should be used to measure colonic mucosal permeability. 19614866
1372 Moreover, T84 cells, a colonic epithelial cell line that did not release apoB into the basolateral medium (not shown), did not secrete 125I-LPS after addition of OA (Fig. 5B). 19614866
1373 Studies of permeability function in colonic mucosal biopsies using Ussing chambers (22–25) do not provide in vivo assessment of permeability. 19614866
1374 The amounts of lactulose and mannitol in the normal diet are negligible to trace. 19614866
1375 Relative to the placebo group, single and combination probiotics reduced fever incidence by 53.0% (P = .0085) and 72.7% (P = .0009), coughing incidence by 41.4% (P = .027) and 62.1% (P = .005), and rhinorrhea incidence by 28.2% (P = .68) and 58.8% (P = .03), respectively. 19651563
1376 Mahony et al.9also reported that IBS symptoms (abdominal pain, bloating and bowel movement difficulty) are improved by administration of probiotics. 19903265
1377 Our findings prove the three hypotheses that we set out to test: that IBS patients in this study had higher counts of Lactobacillus and Veillonella than controls, higher levels of acetic acid, propionic acid and total organic acids than controls, and that levels of acetic acid and propionic acid were associated with GI symptoms, impaired QOL and negative emotion. 19903265
1378 19903265
1379 Accordingly, micromolar concentrations of NaHS, in the range of 30–60 lmol/L, are able to severely decrease HT-29 cellular oxygen consumption. 20020161
1380 Also, H2S is known to severely inhibit cytochrome oxidase activity; an effect characterized by a binding constant similar to the one measured with cyanide (i.e., 0.2 lmol/L) using purified cytochrome c oxidase (Petersen 1977; Hill et al. 1984). 20020161
1381 Also, the intraluminal compounds responsible for sulfide binding need further works for identification and charac- terization since they are likely to represent one major parameter in determining the free sulfide luminal concen- tration. 20020161
1382 H2S has been reported to be able to inhibit butyrate oxidation in isolated human colonocytes (Roediger et al. 1993a). 20020161
1383 In addition to the potential production of H2S, inorganic anions like sulfate affect the route of carbohydrate fermentation. They act as electron sinks that divert hydrogen from other intestinal bacteria metabolism. The main consequences are an increased acetate production and a decreased butyrate and lactate formation (Macfarlane and Macfarlane 2003b). 20020161
1384 In isolated segments of mouse colon, sodium H2S causes an inhibition of spontaneous motor complexes (Gallego et al. 2008). This agent was also able to inhibit the spon- taneous motility in strips from human and rat colons. 20020161
1385 Pre-treatment of the human colonic epithelial cells HT-29 with 1 mmol/L NaHS for 2 h induced neither cell necrosis nor apoptosis, but induced a marked decrease of the cell proliferative capacity (Leschelle et al. 2005). 20020161
1386 Another enzyme, namely rhodanese, which is expressed in the submucosa and crypts of the colon has been proposed to be involved in the process of sulfide detoxication in the large intestine (Picton et al. 2002). 20020161
1387 At physiological pH (i.e., pH 7.4), approxi- mately one-third of H2S remains undissociated (Wang 2002), whereas remaining two-third is hydrosulfide anion (HS-) at equilibrium with H2S. 20020161
1388 Because of its lipid solubility, H2S penetrates biological membranes (Reiffenstein et al. 1992). 20020161
1389 Consequently, if col- onocytes are facing a continuous production of luminal sulfide by the microbiota which is lower than their oxida- tive capacity, they will detoxify sulfide and will use it as a mineral energy substrate. 20020161
1390 Dietary sulfate and faster intestinal transit increase fecal sulfate reduction rate and sulfide concentration. 20020161
1391 From experimental work performed with rat liver, it appears that the mem- brane-bound mitochondrial enzyme sulfide quinone reductase (SQR) is the mitochondrial enzymatic activity involved in the first step of sulfide detoxication (Hilde- brand and Grieshaber 2008) allowing conversion of H2S to persulfide. 20020161
1392 From these results, the authors concluded that dysregulation of TST activity in the colonic mucosa could represent a factor involved in colorectal cancer. 20020161
1393 However, conversion of sulfide to thiosulfate appears to represent the main process for sulfide detoxication in colonic epithelial cells. In fact, analysis of cecal venous blood obtained after intracecal instillation of radioactive H2S in rats reveals that virtually all absorbed H2S is oxidized to thiosulfate (Levitt et al. 1999). 20020161
1394 Human colonic mucins are known to be more highly sulfated than small intestine mucins (Liau and Horowitz 1976) and the thickness of both the firm and loosely adherent layers is higher in the large than in the small intestine (Allen and Flemstro ¨m 2005) raising the view that large intestine mucus can represent a significant precursor for H2S pro- duction. 20020161
1395 In human volunteers, the ingestion of sulfate supplement was found to increase the fecal sul- fide production rate (Lewis and Cochrane 2007). 20020161
1396 In the colonic mucosa, Wilson et al. (2008) have proposed that sulfide oxidase, as the first and rate- limiting step, catalyses the conversion of H2S to thiosul- fate; thiosulfate being then converted to thiocyanate by the rhodanese activity. 20020161
1397 In the experimental model of dextran sul- fate sodium-evoked colitis in mice, Taniguchi et al. (2009) found that rhodanese expression and activity was decreased in the colonic tissues in parallel with the development of colitis. 20020161
1398 In this study, it was found that high consumption of meat, protein as well as high sulfur or sulfate intakes was associated with an increased likelihood of relapse for patients. 20020161
1399 It also raises the view that the balance between the sulfide production by the intestinal microbiota and the colonocyte oxidative capacity would determine the nature of sulfide i.e., a friend or a foe. 20020161
1400 It is also possible that the capacity of colonic epithelial cells for H2S detoxification is altered in ulcera- tive colitis patients, but a role of such a defect remains a working hypothesis that needs to be urgently tested. 20020161
1401 Kanazawa et al. (1996) found increased fecal excretion of sulfide in the sigmoid cancer group although the possible causal relationship between the two parameters would require new investigations. 20020161
1402 Moreover, longer colonic transit time affect the catabolism of carbo- hydrates and proteins leading to carbohydrate depletion and synthesis of putrefactive metabolites (Macfarlane and Macfarlane 2003a). 20020161
1403 Much interestingly, the demonstration that mice invalidated for the mitochondrial dioxygenase ETHE1 dies between the fifth and the sixth week after birth due to sulfide toxicity clearly demonstrates that this enzymatic activity is of paramount importance for sulfide detoxification (Tiranti et al. 2009). 20020161
1404 Some bacteria, including anaerobic ones, are then able to derive energy from the carbon chains of peptides and amino acids. Those bacterial sulfur-containing amino-acid- degrading activities produce sulfide (Smith and Marcfarlane 1997; Awano et al. 2005). 20020161
1405 The use of the same millimolar concentrations of sulfide leads to immediate poisoning of the mitochondrial respiration. 20020161
1406 In this latter study, and as expected, the authors found that bound sulfide has little effect on butyrate oxidation by colonocytes. 20020161
1407 It is worth noting that the presence of bacteria utilizing H2S as electron donor (lithotrophic bacteria) has never been reported. 20020161
1408 Dietary LCT appeared to increase OVA absorption compared with MCT, which does not stimulate chylomicron production, and the effect of LCT was sensitive to the inhibitor of chylomicron secretion, Pluronic L-81. 20041190
1409 This has typically been ascribed to mitogenic properties of free fatty acids [11], but we have previously demonstrated that dietary LCT also promote chylomicrondependent absorption and transport of bacterial lipopolysaccharides (LPS) through the MLN [12]. This potent immune activator could perhaps contribute to postprandial T-cell activation. 20041190
1410 Clinical evaluation of 82 of these people 14–29 months after the outbreak showed continuing abdominal symptoms, particularly diarrhoea-predominant IBS [8]. 20056486
1411 That 40% of people infected in the Bergen outbreak report fatigue and IBS-like symptoms two years after successful treatment is remarkable 20056486
1412 Giardiasis, malabsorption, lactose intolerance, celiac disease, ulcerative colitis, nodular lymphoid hyperplasia, and malign proliferation are among the associated diseases. 20101521
1413 In general, serum IgA level of less than 7 mg/dL (0.07 g/L) is considered as selective IgA deficiency since this concentration is the lowest detectable limit established by most of the laboratories. 20101521
1414 Caffeine causes most of its biological effects via antagonizing all types of adenosine receptors (ARs). 20164566
1415 Caffeine increases production of stomach acid; high usage over time can lead to peptic ulcers, erosive esophagitis, and gastroesophageal reflux disease. 20164566
1416 The combination of glucose or water and the HFHC meal induced oxidative and inflammatory stress and an increase in TLR expression and plasma endotoxin concentrations. 20200256
1417 Four controlled studies in humans showed that B lactis DN-173-010 shortened the colonic transit time and two trials also showed reduction of bloating in patients IBS or functional disorders. 20207630
1418 Absence of Microbiota (Germ-Free Conditions) Accelerates the Atherosclerosis in ApoE-Deficient Mice Fed Standard Low Cholesterol Diet 20379054
1419 Differences in atherosclerotic plaques between GF and CV ApoE-/- mice are not so apparent when mice are fed a high cholesterol diet. 20379054
1420 In contrast to the absence of atherosclerotic plaques in conventionally reared ApoE-deficient mice, germ-free ApoE-/- mice consuming the same low cholesterol standard diet developed atherosclerotic plaques in the aorta. 20379054
1421 By contrast, Myd88−/− macrophages display enhanced cholesterol efflux to BSA-containing media (Fig. 6A); thus, whether MyD88 also suppresses ‘diffusional’ cholesterol efflux through a distinct mechanism is a question worthy of future study. 20519121
1422 Conversely, LPS inhibits RCT (McGillicuddy et al., 2009), and innate immunity is conventionally considered pro-atherogenic 20519121
1423 Whereas apoA-I upregulates ABCA1 in macrophages through intracellular signals (Wang et al., 2003), LPS impairs cholesterol efflux through downregulation of ABCA1 (Baranova et al., 2002; Khovidhunkit et al., 2003; McGillicuddy et al., 2009). 20519121
1424 In summary, we report that apoA-I utilizes MyD88 as a signal in RCT. 20519121
1425 Most importantly, in vivo RCT, induced by endogenous apolipoproteins, was also MyD88-dependent 20519121
1426 Our finding that apoA-I activates NF-κB was somewhat unexpected given that apoA-I has conventionally been considered anti-inflammatory (Berbee et al., 2005). 20519121
1427 PB abolished LPS-induced TNFα, but did not affect TNFα induction by apoA-I; moreover, protease treatment of apoA-I abolished its ability to induce TNFα, but did not affect LPS or Pam3CSK4 (Fig. S2F). 20519121
1428 Unlike C57BL/6 mice injected with BSA or saline, neutrophils were recruited to the peritoneum of apoA-I-injected mice (Fig. S3), indicating acute inflammation. 20519121
1429 We propose that MyD88 may promote apoA-I-induced cholesterol efflux at least in part through inducing TNFα, thus allowing for its autocrine feedback upon the macrophage (Fig. 6F). 20519121
1430 We propose that MyD88 promotes apoA-I-induced cholesterol efflux at least in part through promoting ABCA1 upregulation (Fig. 6D). 20519121
1431 Whether the Liver X Receptors regulate apoA-I-induced cholesterol efflux, in part, through effects on TNFα induction is an interesting question worthy of future study. 20519121
1432 The response is not triggered, however, by HDL. 20519121
1433 Bacteroides isolates degraded pure celluloses, but not microcrystalline filter paper, while Ruminococcus sp. and Enterococcus sp. efficiently hydrolysed all types of substrates (Robert & Berna- lier-Donadille, 2003). 20662929
1434 However, no microcrystalline cellulose-de- grading Ruminococcus sp. could be cultivated from CH4? subjects, suggesting that some members of this phylogenetic subgroup could be non-cellulose-degraders such as Rumino- coccus bromii, another member of the cluster IV subgroup capable of degrading resistant starch, but not cellulose. 20662929
1435 Roseburia sp. expressed CMCase activity when grown on CWS, but were unable to grow on pure cellulose. 20662929
1436 Bacteroides sp. produced only small amounts of hydrogen in cellulose-grown cultures, while Enterococcus, Ruminococ- cus and Roseburia sp. produced large amounts of this gas from cellulose and/or CWS fermentation. 20662929
1437 In CH41 subjects, a high population level of methanogens was determined to correlate significantly (P=0.008) with a high population level of human cellulose- degrading ruminococci. 20662929
1438 In contrast, CWS-degrading populations were detected in all subjects, regardless of the methane excretion status. 20662929
1439 Metabolite production and ratios varied depending on the strain considered. Bacteroides sp. produced mainly acetate, propionate and succinate during cellulose metabo- lism, while Enterococcus and Ruminococcus isolates synthe- sized mostly acetate and succinate and Roseburia sp. formed butyrate (data not shown). 20662929
1440 Roseburia sp. are an important group of butyrate- producing bacteria that predominate in the gut of all healthy human individuals (Aminov et al., 2006; Duncan et al., 2006), while Enterococcus sp. are also indigenous, but sub- dominant bacterial species. 20662929
1441 Roseburia sp. expressed CMCase activity when grown on CWS, but were unable to grow on pure cellulose. Roseburia sp. were also shown to express high xylanase activity (Chassard et al., 2007), suggesting that this bacterial species was selected on CWS medium because of its ability to use other complex polysaccharides present in CWS. Roseburia sp. could thus potentially interact with cellulose- degrading microorganisms to ensure efficient degradation of complex substrates such as spinach in the human gut. 20662929
1442 The dominant cellulose degraders isolated from non-methane-excreting subjects belong mainly to Bacteroi- detes, while they are predominantly composed of Firmicutes in methane-excreting individuals. 20662929
1443 The dominant microcrystalline cellulose-degrading species isolated from CH41 subjects belong to new Ruminococcus sp. and some Enterococcus sp. closely related to Enterococcus faecalis (Robert & Bernalier- Donadille, 2003). 20662929
1444 These microcrystalline cellulose-degrad- ing species wereshown to produce high amounts of H2from cellulose fermentation. 20662929
1445 This hypothesis stems from our previous results (Robert & Bernalier-Donadille, 2003), de- monstrating that microcrystalline cellulose-degrading bacteria could only be detected in methane-excreting subjects. 20662929
1446 We demonstrated previously that the presence or absence of microcrystalline cellulose-degrading bacteria was related to the methane status of volunteers (Robert & Bernalier-Donadille, 2003). 20662929
1447 The absence of cultivable microcrystalline cellulose-de- grading organisms in faecal samples from CH4?individuals does not reflect the total absence of cellulose-degrading bacteria in this non-methane-producing ecosystem as both cellulase and xylanase activities could be detected in this faecal microbial community (Robert & Bernalier-Donadille, 2003). 20662929
1448 The population of human microcrystal- line cellulose-degrading ruminococci was detected in the majorityof subjects regardless of themethane excretion status (Fig. 1), and this population level ranged from log6.1 to log9.2g faecesdepending onthe subjectconsidered. 20662929
1449 The present results show that: 1) bowel inflammation is associated with an enhanced adenosine deaminase expression; and 2) the anti-inflammatory actions of adenosine deaminase inhibitors against chronic established colitis depend on the sparing of endogenous adenosine, leading to enhanced A2A and A3 receptor activation. 20668053
1450 Immunosensitization is one of the key mechanisms of Salmonella cytotoxicity; accumulation of Salmonella choleraesuis in tumours induces neutrophil infiltration and antitumour immune responses64. 20944664
1451 Many successful experiments have shown that the natural toxicity of bacteria is sufficient to regress tumours (TABLE 1). 20944664
1452 More recently, Salmonella has been tested for its anticancer properties4,46 and, similar to Clostridium, Salmonella is naturally cytotoxic and has been shown to regress tumours when administered alone (TABLE 1). 20944664
1453 Accordingly, we determined the pH of luminal content and stool. Compared with WT animals, the pH levels of the luminal contents and stools of IAP-KO mice were marginally higher but the difference was not statistically significant (data not shown). 20947883
1454 Furthermore, exogenous administration of oral IAP promotes restoration of the normal gut microbiota following antibiotic exposure and also appears to inhibit the colonisation and infection of the gut pathogen Salmonella. 20947883
1455 However, to our surprise we observed no growth of aerobic Gram-negative bacteria in the stools of KO mice, as determined by culturing the stool samples in MacConkey agar plates (figure 1B). AlthoughMacConkey media preferentially allow the growth of Gram-negative bacteria, there are some Gram-negative bacteria that do not grow in this medium. 20947883
1456 IAP has the ability to detoxify lipopolysaccharides (LPS) from Gram-negative bacteria and exogenous IAP has been shown to attenuate LPS-mediated toxicity.12 13 20947883
1457 In addition, oral IAP treatment may be of benefit in human IBD.30 20947883
1458 Our data (figure 5A) showing enhanced recovery of the gut microbiota in WTanimals treated with an antibiotic in the presence of cIAP suggests that IAP could be an effective therapeutic agent to prevent or treat AAD and CDAD. 20947883
1459 Tuin et al29 recently reported that IAP attenuates the colonic inflammation in DSS-induced IBD in rats. 20947883
1460 However, under controlled laboratory environmental conditions, we and others have found no gross phenotypic differences except for KO mice being obese when fed a high-fat diet. 20947883
1461 Accordingly, mice deficient in functional TLR signalling have reduced adiposity and improved glucosemetabolism[20–23], largely because of modulation of inflammation in peripheral organs. 21050286
1462 Both in rodents and humans, lactobacilli have been shown to reduce blood cholesterol levels [83, 84], possibly as a result of the fact that some bacteria express the bacterial enzyme bile salt hydrolase, which can affect cholesterol re-absorption in the intestine. 21050286
1463 By contrast, preliminary data from our laboratory demonstrated that GF ApoE-⁄- male mice were protected from atherosclerosis compared with conventional ApoE-⁄- mice after 12 weeks of high-fat feeding (Fa°k et al. in preparation). 21050286
1464 Conversely, inhibition of chylomicron formation blocked LPS absorption in vivo [36]. 21050286
1465 In high-fat dietfed mice, manipulation of the gut microbiota by administration of the prebiotic oligofructose reduces plasma LPS levels, concentrations of circulating inflammatory cytokines and hepatic inflammation, which correlate with reduced intestinal permeability and improved tight-junction integrity [41]. 21050286
1466 Of interest, TLR4 inhibits activation of LXRs, presumably through an MyD88- independent pathway [63] (Fig. 2). 21050286
1467 Several TLRs are expressed on macrophages and vascular cells in human atheromas [56], and it is interesting that the TLR4 polymorphisms Asp299Gly and Thr399Ile, which lead to impaired TLR4 signalling, are associated with reduction in the incidence of atherosclerosis [57]. 21050286
1468 Similarly, ablation of Tlr2 or Tlr4 inmice reduces atherosclerotic plaque formation[58, 59]. 21050286
1469 Smoak et al. recently demonstrated that TLR2 and TLR4 are essential for RCT as apolipoprotein A-I, but not highdensity lipoprotein, utilizes MyD88-dependent signalling [64]. 21050286
1470 A recent study showed that LPS secretion fromthe human epithelial colorectal cell line CaCo-2 is increasedwhen cells are stimulated with fatty acids, which promote chylomicron formation [36]. 21050286
1471 Epidemiological studies have shown a link between periodontitis, Chlamydia pneumoniae and Helicobacter pylori infections and atherosclerosis [66], indicating that infectious agents might be involved in cardiovascular disease initiation or progression. 21050286
1472 Impaired dental health is associated with an elevated risk of myocardial infarction [73], and the results of several studies have suggested an oral source for plaque-associated bacteria [74–77]. 21050286
1473 Indeed, C. pneumoniae can induce formation of foam cells in the blood vessel wall, and bacterial DNA can be identified in more than 50% of all plaques [67, 68]. 21050286
1474 It is interesting that circulating LPS correlates with insulin levels, and patients with type 2 diabetes have increased amounts of circulating LPS[31]. 21050286
1475 It is interesting that circulating LPS correlates with insulin levels, and patients with type 2 diabetes have increasedamounts of circulating LPS[31]. 21050286
1476 It is noteworthy that RCT induced by endogenous apolipoprotein was also shown to be MyD88 dependent in vivo. 21050286
1477 The increased LPS levels correlated with increased adipose macrophage infiltration and insulin resistance [32]. 21050286
1478 These data support the model of chylomicron facilitated transport to explain how LPS is transported from the gut lumen into the circulation and how the transport correlates with food intake and composition. 21050286
1479 The results have been inconsistent and no consensus regarding the effect of antibiotics in preventing or reducing atherosclerosis has been reached, and studies using anti-chlamydial antibiotics have not demonstrated any major benefits in patients with arterial disease [70–72]. 21050286
1480 Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. 21475195
1481 Dietary supplementation of mice with choline, TMAO or betaine promoted up-regulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. 21475195
1482 Three metabolites of the dietary lipid phosphatidylcholine, namely choline, trimethylamine N-oxide (TMAO), and betaine, were identified and then shown to predict risk for CVD in an independent large clinical cohort. 21475195
1483 Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary choline-enhanced atherosclerosis. 21475195
1484 It is also interesting to find that the mice protected by 50,000 Tregs, which were tube-fed with either one of the probiotics, had decreased levels of IL-12, IFNc, and CXCL9 in serum compared to the unfed controls. 21495121
1485 Most strikingly, we found the expression of cxcl5 and its receptor il8rb (CXCR2) to be extremely low in both of the probiotic- fed groups compared to the unfed controls (Fig. 4). 21495121
1486 Furthermore, the peripheral mu-specific agonist [D-Arg2,Lys4]dermorphin-(1,4)-amide (DALDA)18 reduces inflammation in two experimental models of murine colitis: 2,4,6-trinitrobenzene sulfonic acid (TNBS) and adoptive transfer of CD45RBhiCD4 T cells.19 21801866
1487 With the use of a chemical model of acute injury and wound healing that is independent of T and B cells,21 we observed that the mu opioid agonist DALDA protects against dextran sodium sulfate (DSS)-induced intestinal injury and promotes healing through activation of Stat3 and induction of cytoprotective factors regulated in part by Stat3. 21801866
1488 Conversely, experimental colitis is exacerbated in mu opioid receptor (MOR) knockout mice,19 and MOR expression is up-regulated in mucosal samples from human patients with IBD compared with controls.20 21801866
1489 In summary, this report establishes mu-specific opioids as promoters of colonocyte migration/restitution and proliferation in the intestine involving the activation of Stat3-dependent pathways. 21801866
1490 Inverse associations were also seen with amino acids and proteins versus carbohydrates (Spearman r = –0.73, P < 0.0001) and with fat versus carbo- hydrates (Spearman r = –0.61, P = 0.0001). 21885731
1491 The nutrients from fat versus plant products and fiber showed inverse associations with microbial taxa (Spearman r = –0.68, P < 0.0001). 21885731
1492 The Prevotella enterotype, in contrast, was associated with low values for these groups but high values for carbohydrates and simple sugars, indicat- ing association with a carbohydrate-based diet more typical of agrarian societies. 21885731
1493 At an FDR of 25%, nutrients from the long- term FFQ but not the short-term Recall question- naire were associated with enterotype composition, indicating that long-term diet strongly correlates with enterotype (the relatively high FDR was used to avoid excessively strict filtering and to visualize the full pattern). 21885731
1494 Figure 1 21885731
1495 The Bacteroides enterotype was highly associated with animal protein,a variety of amino acids, and saturated fats (Fig. 2C), 21885731
1496 Thus, over the 10 days of the dietary intervention, we did not see stable switching between the two enterotype groups characterized by the dietary extremes, despite feeding of a low-fat/high-fiber diet to half the subjects. 21885731
1497 In quantitative terms, SCFAs are the principal end- products generated by the colonic microbiota, whereas the formation of reduced substances (electron sink products) such as hydrogen gas, lactate, succinate, butyrate, and ethanol is used to effect redox balance.13,14An equation describing overall carbohydrate fermentation in the large gut has been outlined by Cummings.15 21992950
1498 In quantitative terms, SCFAs are the principal end- products generated by the colonic microbiota, whereas the formation of reduced substances (electron sink products) such as hydrogen gas, lactate, succinate, butyrate, and ethanol is used to effect redox balance.13,14An equation describing overall carbohydrate fermentation in the large gut has been outlined by Cummings.15 59C6H12O6 + 38H2O -> 60acetate + 22propionate + 18butyrate + 96CO2 + 256H+ 21992950
1499 We established a murine model system to study this question, and showed that mice nasally pre-colonized with S. epidermidis became more resistant to colonization with MRSA. 21998712
1500 BCFA, phenols and indoles are not produced by human enzymes and are therefore unique colonic bacterial meta- bolites. As a consequence, excretion of those metabolites is often considered as a marker to estimate the degree of protein fermentation in the colon [22]. 22121108
1501 Contrary to SCFA, branched chain fatty acids (BCFA) exclusively originate from fermentation of branched amino acids. 22121108
1502 Evenepoel et al. compared the digestibility of raw and cooked egg protein and showed that the amount of protein entering the colon and the amount of fermentation metabolites retrieved in urine depends on the digestibility of the proteins [13]. 22121108
1503 Fecal sulfide concentration correlated significantly with dietary protein intake (po0.001) [27]. 22121108
1504 Fermentation of dietary and mucinous sulfate and sulfur amino acids, such as methionine, cystine, cysteine and taurine, by sulfate-reducing bacteria results in the production of hydrogen sulfide (H2S) [23, 24]. H2S is an extremely toxic agent (LD50 for rodents comparable to cyanide [25]) and luminal H2S concentrations in the large intestine range between 1.0 and 2.4mM [26]. 22121108
1505 In the proximal colon, pH is more acid due to the production of short chain fatty acids (SCFA) from carbohydrate fermentation. Upon progression to more distal parts of the colon, carbohydrates get depleted, pH increases and protein fermentation becomes more efficient. 22121108
1506 Increased Firmicutes abundance has previously been recorded in IBS subjects.10e12 15 In our current study, this was combined with a decrease in the abundance of Bacteroidetes. 22180058
1507 However, butyrate promoted visceral hypersensitivity in a rat model41 and the butyrate-producing associated Clostridium cluster XIVa group42 and some specific butyrate-producing species such as Eubacterium hallii and Eubacterium desmolans43 were associated with IBS in this study. 22180058
1508 Of the 73 OTUs of the phylum Firmicutes that were differentially expressed across the groups, 70 were Clostridia/Clostridiales. 22180058
1509 The possibility that flagellin-producing species might be relevant to the pathophysiology of IBS is supported by the documentation of a low level of mucosal inflammation within the GI tract, as well as a systemic pro-inflammatory cytokine phenotype, in all subtypes of IBS.32 22180058
1510 This increase in the ratio of Firmicutes to Bacteroidetes was associated with over half of the IBS samples studied. 22180058
1511 While this observation deserves further study and requires confirmation, it does tempt one to speculate that microbiota analysis may permit differentiation of IBS patients into two groups: those in whom psychological comorbidity is highly prevalent and those in whom a more ‘organic’ pathophysiology, such as microbe-host immune interaction, may be more operative. 22180058
1512 However, recent studies in our laboratory (Riboulet-Bisson, O’Toole et al, submitted) show very modest effects on the intestinal microbiota of mice and pigs administered large doses of bacteriocinproducing probiotic lactobacilli, and the effects in humans are also modest.52 53 22180058
1513 In particular, it has been reported that δ-opioid receptors act as natural inhibitors of stress and anxiety [199]. DOR agonists have been shown to produce antidepressant and anxiolytic effects in rodent models. 22204322
1514 Nonetheless, acute and chronic opioid administration is known to have inhibitory effects on humoral and cellular immune responses including antibody production, natural killer cell activity, cytokine expression, and phagocytic activity [235, 236, 238–240]. 22204322
1515 Opioid agonists and antagonists have corresponding stimulatory and inhibitory effects on feeding. 22204322
1516 Studies showed that stimulation of μ-opioid receptors preferentially increases the intake of a high fat diet. 22204322
1517 In a prospective, randomized trial of 90 patients, Lauritano and coworkers demonstrated the efficacy of rifaximin for SIBO eradication by showing normaliza- tion of abnormal glucose breath test findings in IBS subjects.88 22298980
1518 A recent meta-analysis revealed that the rate of IBS development after a single episode of acute gastroenteritis may be as high as 10%, and up to 57% of patients continue to have altered bowel function 6 years after recovery from the acute episode.36,37 22298980
1519 Evidence indicates the presence of excessively high numbers of coliforms in the small bowels of IBS patients; data demonstrate a high prevalence of SIBO in IBS, based on abnormal breath testing (although a valid definition of SIBO based on culture is debatable); eradication of SIBO results in significant relief of IBS symptoms; and recur- rence of SIBO corresponds with the return of IBS symp- toms.20,22,44 22298980
1520 For the first time, these data suggest a significant attributable causative factor in IBS that can be examined prospec- tively. In a new animal model of postinfectious IBS, it was shown that acute gastroenteritis due to a common pathogen implicated in postinfectious IBS in humans (Campylobacter jejuni) led to the development of altered stool consistency 3 months after clearance of the initial infection.38 22298980
1521 Cafestol, a coffee-specific diterpene, induces peripheral antinociception mediated by endogenous opioid peptides 22332877
1522 Furthermore, patients with NAFLD had a markedly higher protein intake, which seemed to have resulted from a higher intake of animal derived proteins (e.g., red meat). 22427130
1523 In patients with NAFLD, blood alcohol levels were higher than in controls despite that neither group had consumed alcohol before the measurements were performed. 22427130
1524 Indeed, it has been shown that under anaerobic conditions, bacterial metabolism of pyruvate being produced during the breakdown of carbohydrates, generates acetaldehyde, can then be further reduced to form ethanol [40, 41]. 22427130
1525 Indeed, results of several studies suggest that a diet rich in carbohydrates, and herein particularly fructose, may be associated with the development of NAFLD and increase the odds to develop the later stages of the disease (e.g., NASH) [6, 12–14]. 22427130
1526 Interestingly, despite not displaying any signs of SIBO or altered intestinal motility, results of the measurements of the lactulose/ mannitol excretion and plasma endotoxin levels suggest that patients with NAFLD had an increased intestinal permeability/permeation of bacterial endotoxin. 22427130
1527 Taken together, the results of the present study lend further support to the hypothesis that (1) alteration of the intestinal barrier function, (2) an increased formation of endogenous ethanol, and (3) alterations of the dietary pattern towards a carbohydrate and protein-rich diet may be involved in the development of NAFLD. 22427130
1528 Taken together, these data suggest that not only an increased sugar and herein particularly fructose intake but also the intake of animal-derived protein are associated with the development of NAFLD in humans. 22427130
1529 By contrast, the morning chronotype was associated especially with a greater intake of calcium and vitamin B6, as well as eating more vegetables and pulses. 22652369
1530 Of proteins, amino acid TRP is the most promising candidate as a sleep-promoting nutrient at least with pharmacological doses 22652369
1531 Several lines of evidence indicate that overexpression of astroglial ADK and adenosine deficiency are pathological hallmarks of the epileptic brain. 22700220
1532 A negative correlation between Bifidobacterium spp. and plasma LPS levels has been observed, and an increase in bifidobacteria induced by prebiotic intake reduces endotoxaemia(10). 22717075
1533 Another important mechanism is the dephosphorylation of LPS by the enzyme alkaline phosphatase, which induces a 100-fold reduction in lipid A toxicity(86,87) 22717075
1534 Bifidobacteria can reduce the levels of endotoxins by improving gut barrier function(50 – 53). 22717075
1535 Another consequence of the consumption of high-fat diets is the increased production of bile observed in both obese and lean animals(49). 22717075
1536 Dietary fat can indirectly affect intestinal permeability through the activation of mast cells in the intestinal mucosa(45). Mast cells are directly related to the regulation of transcellular and paracellular intestinal permeability through the secretion of mediators, such as TNF-a, IL-1b, IL-4 and IL-13 as well as tryptase via protease activation receptor-2(46), which in turn favour LPS translocation. 22717075
1537 Excessive fat intake may favour an increase in circulatory LPS, leading to metabolic endotoxaemia (10,22,32 – 35). 22717075
1538 Healthy men presented postprandial increases in LPS levels after consumption of high-fat meals (33 and 50 g) when compared to those who fasted(19,22). 22717075
1539 In contrast, increasing the proportion of Gram-negative bacteria can decrease the integrity of the intestinal mucosa and lead to higher levels of plasma LPS(11). 22717075
1540 It has been demonstrated that during fat absorption, the intestinal epithelium becomes temporarily injured and is repaired approximately 50 min later(43). After injury, the gut barrier can become compromised, increasing intestinal permeability, especially through the paracellular space, to molecules of higher molecular weight, such as LPS. 22717075
1541 It has been observed that the consumption of butter in a meal resulted in lower postprandial lipaemia and chylomicron accumulation in the circulation in young men than that in men who consumed olive and sunflower oils(99). 22717075
1542 LPS is one of the main components of the external cell wall of Gram-negative bacteria. 22717075
1543 LPS is thought to be a major inducer of the inflammatory response, suggesting a possible association between intestinal LPS and these metabolic diseases(10 – 13). 22717075
1544 Sprague–Dawley rats fed high-fat diets presented higher alkaline phosphatase activity in the duodenum and jejunum. 22717075
1545 The oral administration of oil or water to mice confirmed the role of fat intake in LPS movement into the circulatory system; increases in plasma LPS levels were observed only after the ingestion of oil. 22717075
1546 The palm oil group presented the highest level of IL-6 in plasma; and the highest expression of IL-1b, TLR4 and CD14 was in white adipose tissue(102). 22717075
1547 IBS patients treated with the probiotic Bifidobacterium infantis 35624 show improvement of symptoms, but also a normalisation of cytokine ratios.22 22767422
1548 Our results demonstrate that healthy human immune cells actively secrete β-endorphin which acts to dampen viscero-sensory mechanosensation. 22767422
1549 The cytokine profile of C-IBS patients more closely resembled that of HS with the exception of IL-1β which was increased above HS levels but not to the same extent as observed in D-IBS patients, and decreased concentrations of CCL5 and interestingly IL-2RA, the opposite of that in D-IBS (Supplementary figure 3). 22767422
1550 The number of β-endorphin positive colonic mucosal lamina propria cells was reduced in C-IBS patients compared with HS, but was not changed in D-IBS patients (figure 2D). 22767422
1551 Critically, we found that TNF-α, IL-1β and IL-6 individually sensitised colonic afferents to mechanical stimuli, via activation of their respective receptors expressed on colonic afferents, while their increased levels correlated directly with self reported symptoms of pain in D-IBS patients. 22767422
1552 D-IBS supernatants differed significantly from C-IBS supernatants, with substantial increases in the cytokines IL-1β, IL-10, TNF-α, IL-6, CCL3, CCL4, CCL5, IL-2RA and IL-12 (figure 3A). 22767422
1553 Furthermore, our results indicate immune derived mediators such as TNF-α are increased specifically in D-IBS patients where they correlate with symptoms of pain intensity and pain frequency and sensitise colonic afferents to mechanical stimuli. 22767422
1554 Importantly, the high levels of TNF-α correlated significantly with self reported symptoms of pain frequency (figure 3B) and pain intensity (figure 3C) in D-IBS patients, but not in C-IBS patients. 22767422
1555 Interestingly, the studies investigating mast cell function indicate that while mediator levels are increased in IBS patients, there is no difference between D-IBS and C-IBS. This may suggest mast cell derived mediators are equally important in signalling pain in both patient subtypes but are not involved in mediating motility related events. 22767422
1556 Our results confirm previous findings that the PBMCs of D-IBS patients have increased concentrations of both Th1 and Th2 cytokines.20 21 22767422
1557 Several studies have shown that supernatants of colonic mucosal biopsies from IBS patients contain elevated concentrations of mast cell mediators including histamine and serine proteases, typically associated with allergic type responses.12 29–31 22767422
1558 Thorough investigation of biopsies from PI-IBS patients consistently reveal a chronic but low grade immune activation, with increased numbers of resident immune cells including mast cells and T cells.7–10 22767422
1559 However, the enthusiasm generated by these results is tempered by the lack of benefit shown by treatment of Campylobacter infected PI-IBS patients with the steroid Prednisolone, or in unselected IBS patients with the mast cell stabiliser Ketotifen, despite much promise from preclinical studies.11 12 29–31 52 53 22767422
1560 Interestingly, such changes in β-endorphin immunoreactivity were not observed in biopsies from D-IBS patients, suggesting the inhibitory effects are still present in supernatants from these patients. 22767422
1561 These results further demonstrate that the gut microbiota contributes to the development of NAFLD independently of obesity 23197411
1562 Consequently, this increase would increase absorption and decrease secretion of water and electrolytes, strengthening the ileal brake and inhibiting intestinal motility, which leads to constipation. 23292145
1563 In the duodenum of IBS patients, the number of CCK cells was also low (29). 23292145
1564 In the large intestine of sporadic IBS patients, PYY cell density was found to be low in both IBS-constipation and IBS-diarrhea patients (Fig. 1) (27). 23292145
1565 In the large intestine of the same patients, serotonin cell density was reduced and the mucosal 5-HT concentration was also reported to be low (28). 23292145
1566 The find- ings of genetic in transmission pathways of serotonin and CCK (41-44) support the assumption that the change in colonic PYY cells is secondary to changes in serotonin and CCK. 23292145
1567 The levels of circulating PYY in these patients were elevated (108). This elevation may be an adapta- tion to compensate for the rapid gastric transit, and an attempt to slow it. 23292145
1568 Although PYY cell density is not affected by aging (16), it is abnormal in several gastrointestinal diseases and disorders (17). 23292145
1569 Basal and postpran- dial plasma levels of PYY are elevated in patients with celiac disease (76,77). 23292145
1570 Further studies on humans have shown that PYY immunoreactive cells occur in the ileum, colon, and rectum, with the highest density in the rectum (7). 23292145
1571 Furthermore, PYY immunoreactivity has been localized ultrastructurally in large intestinal H(L)-cells, whose secretory product was previously unknown (7). 23292145
1572 In clinical trials, nausea and fullness are the most common side-effects of PYY (115). 23292145
1573 In humans, PYY has been found local- ized in endocrine cells in the colon (6). 23292145
1574 PYY cells have been reported to be increased compared to controls in the ascending colon of patients with CST (71). 23292145
1575 PYY plays an important role in regulating gastro- intestinal motility and absorption of water and electrolytes (23-25). 23292145
1576 PYY release can also be mediated via a neural reflex involving the vagus nerve, as well as by other gut neuroendocrine peptides such as vasoactive intestinal peptide (VIP), cholecystokinin (CCK), gastrin, and glucagon-like peptide-1 (GLP-1) (18). 23292145
1577 Serotonin also stimulates the secretion of chloride and water from the small intestine by acting through 5-HT3 and 5-HT4 receptors (36-40). 23292145
1578 The concentration of PYY in colonic tissue extracts from patients with CST has been reported to be high (73), but basal and peak plasma PYY levels have been reported to be unaffected (74). 23292145
1579 The elevated levels of circulating PYY in patients with celiac disease appear to be involved in this hormonal process, and are probably a response to diarrhea and steatorrhea, an attempt to slow down the intes- tinal transit time and increase intestinal absorption. 23292145
1580 The increase in the number of colonic PYY cells and PYY synthesis seems to be primary and may be one of the etiologic factors for CST. 23292145
1581 The low density of serotonin cells is likely to reduce motility and secretion of chloride and water in the colons of patients with IBS. As compensation for this, PYY is reduced. 23292145
1582 The release of PYY from intestinal endocrine cells is stim- ulated by intraluminal nutrients, lipids, short-chain fatty acids, glucose, amino-acids, and bile salts. 23292145
1583 Thus, a low CCK could contribute to the low density of large intestinal PYY cells in IBS patients. 23292145
1584 Histopathological exam- ination fails to identify any abnormality in the colon of these patients (64,65). 23292145
1585 In another study from our laboratory, however, the number of colonic PYY cells was unaffected (72). 23292145
1586 This condition is characterized by chronic severe constipation, which is not alleviated by bulking agents, prokinetic drugs or other laxative treatments. 23292145
1587 Male adult mice exposed to a mixture of antibiotics (neomycin 5 mg/ml and bacitracin 5 mg/ml) together with the antifungal agent, pimaricin, for 7 days showed reduced anxiety-like and increased exploratory behavior in the step-down and L/D tests [52]. 23384445
1588 methane gas slows transit remains unknown; however, research in pulmonary circulation suggests that methane has an effect on smooth muscle through a serotonergic mechanism [16]. Studies have also shown that after glucose administration, there was a significantly lower serum serotonin concentration in methane producing IBS subjects compared to hydrogen producing IBS patients. 23470880
1589 By assessing hydrogen and methane levels it was surprisingly determined that 15% of patients (473 in total) were considered to have intragastric fermentation even after overnight fasting (regardless of abdominal symptoms). 23470880
1590 ABT-702 (Fig. 3) was shown to have an EC50 of 1.7 nM and was equally effective on long and short isoforms of ADK from different organs and species (Jarvis et al., 2000). It was shown to be orally active and efficacious in reducing acute somatic nociception (ED50: 65 mmol/kg p.o.) in the mouse hot-plate assay. 23592612
1591 Activation of the A1R, which is coupled to pertussis toxin-sensitive Gi proteins, leads to inhibition of adenylyl cyclase activity (van Calker et al., 1979; Cooper et al., 1980) and to increased activity of phospholipase C (PLC) (Rogel et al., 2005; Tawfik et al., 2005). 23592612
1592 Activation of the A3R leads to inhibition of adenylyl cyclase (Zhou et al., 1992), stimulation of PLC (Abbracchio et al., 1995), and mobilization of calcium (Englert et al., 2002; Fossetta et al., 2003; Shneyvays et al., 2004, 2005). 23592612
1593 Adenosine is known to regulate thermoregulation through A1R- and A2AR-dependent mechanisms (Jonzon et al., 1986; Zarrindast and Heidari, 1993; Fredholm et al., 2011b) and cooler pups were more likely to be culled by their mothers than normothermic littermates. 23592612
1594 All mutations caused disruptions in the methionine cycle resulting in hypermethioninemia, inhibition of transmethylation, and severe liver pathology reminiscent to changes found in Adk2/2 mice (Bjursell et al., 2011). 23592612
1595 As discussed above, the homoeostasis of adenosine receptor signaling is also of critical significance for the chronic inflammatory reactions in IBD (Hasko et al., 2008). 23592612
1596 Behaviorally, Adk-tg mice were resistant to amphetamine induced hyperlocomotion (Yee et al., 2007; Shen et al., 2012) and displayed severe learning deficits in the Morris water maze task and in Pavlovian conditioning (Yee et al., 2007). 23592612
1597 Consequently, disruption of adenosine homeostasis by overexpression of ADK altered sleep physiology, with Adk-tg mice being awake more than 58 minutes more per day than wild-type mice and spending significantly less time in rapid eye movement (REM) sleep (Palchykova et al., 2010). 23592612
1598 Intriguingly, it was shown that cyclosporine A and FK506 (tacrolimus) decreased ADK activity in T-lymphocytes 23592612
1599 It was found that AMP concentrations below 5 mM activated the enzyme, whereas concentrations above 5 mM inhibited the enzyme (Hawkins and Bagnara, 1987). 23592612
1600 Parasitic ADK therefore plays important roles in adenosine salvage, a feature that can be exploited therapeutically. 23592612
1601 Surprisingly, ADK from several tissues is inhibited by its own substrate adenosine (Miller et al., 1979a; Fisher and Newsholme, 1984). 23592612
1602 Transcription factor binding assays, hypoxia inducible factor 1-a (HIF-1a) loss- and gain-of-function studies, as well as abrogation of Adk transcriptional repression by ambient hypoxia in conditional HIF-1a mutant mice, demonstrated a definitive role of HIF-1a in the transcriptional repression of the Adk gene (Morote-Garcia et al., 2008). 23592612
1603 Whether mammalian ADK is regulated by a similar chaperone-based mechanism remains to be demonstrated. 23592612
1604 23592612
1605 Because of the prominent liver pathology and early death of most mutants, further insight into the role of ADK in other organ systems could not be derived. 23592612
1606 Epileptic seizures developed in all six children with an age of onset between 10 and 35 months (Bjursell et al., 2011). 23592612
1607 Given the important role of ADK for metabolic clearance of SAH-derived adenosine, ADK is expected to be a regulator of transmethylation reactions. 23592612
1608 Homozygous mutants were characterized by early postnatal mortality. 23592612
1609 Hypoxia is known to lead to a rapid rise in adenosine— likely a homeostatic protective response of a tissue (Berne, 1963; Berne et al., 1974; Decking et al., 1997; Frenguelli et al., 2003). 23592612
1610 In contrast, activation of the A2AR leads to an increase in adenylyl cyclase activity. 23592612
1611 Mutant pups developed intermittent periods of apnea up to two times per hour and up to 20 seconds in duration, which contributed to lethal outcome during the first days after birth (Boison et al., 2002b). 23592612
1612 Physiologically, overexpression of ADK in the brain of Adk-tg mice resulted in frequent electrographic seizures at a rate of about four seizures per hour (Fedele et al., 2005; Li et al., 2007a, 2008b). 23592612
1613 The authors concluded that insulin activates Adk gene transcription via activation of the MAPK cascade and subsequent phosphorylation of Elk-1 and increased expression of c-fos and c-jun (Pawelczyk et al., 2003). 23592612
1614 Thus, under steady-state conditions of adenosine production, the extracellular adenosine concentration is determined by the rate of intracellular adenosine clearance (Greene, 2011). 23592612
1615 On the contrary, infusion of SCFAs at higher concentration (100 mM) into the lumen of an isolated rat colon decreased the contractile activity in the proximal, middle, and distal regions of the colon, but not in the cecum (except for butyric acid). 24033744
1616 Lactulose fermentation produces a tonic contraction of the human colon,4 whereas starch fermentation increases the number of high amplitude propagated contractions (HAPCs).5 24033744
1617 Mucosal application of low concentrations of SCFAs (propionate and butyrate up to 0.1 mM) on segments of the rat colon in vitro evoked a phasic contraction which was dose depen- dent.19 24033744
1618 In healthy volunteers, we found that infusions of an acidic saline solution or of a Short Chain Fatty Acid (SCFA) mixture do not modify the colonic motor activity. 24033744
1619 This mechanism suggests that LPS could contribute to obesity by triggering hyperplasia. 24049740
1620 We here demonstrate in vivo that metabolic endotoxemia directly increases the proliferation of adipocyte precursors i.e. hyperplasia and the macrophage number within the fat pad itself, througha CD14-dependent mechanism. 24049740
1621 No increase in the cell number was observed in the CD14KO grafted fat pad in response to LPS further demonstrating that CD14 was required in the fat pad itself. 24049740
1622 However, in IBS patients a single dose of asimadoline significantly decreased pain perception across a range of colonic distension pressures, 4 while in a phase IIb study of 596 patients asimadoline’s efficacy against IBS symptoms was greatest in D-IBS patients, with at least moderate pain at baseline.5 24285775
1623 These findings add another layer of complexity to KOR signalling, whereby KOR expression is upregulated during inflammation and CVH. 24285775
1624 Artemisinins have been reported to possess robust inhibitory effects against viruses (e.g. Human cytomegalovirus), protozoa (e.g. Toxoplasma gondii), helminths (e.g. Schistosoma species and Fasciola hepatica) and fungi (e.g. Cryptococcus neoformans). 24316259
1625 In an initial cohort study, we found that Na+ storage in muscle and in skin increased with age, was more pronounced in men than women, and was directly associated with blood pressure levels [16▪▪]. 24401786
1626 These pathways are mutually exclusive in humans, such that only indi- viduals with methane excretion demonstrate methanogenesis in feces, whereas nonmethanogenic individuals show high levels of sulfate reduction in the feces ( 16 ). 24466443
1627 Compared to the HCs, Faecalibacterium prausnitzii was sharply decreased in both the fecal and biopsy specimens of the active CD patients (0.3% versus 14.0%, P<0.0001 for fecal samples; 0.8% versus 11.4%, P<0.0001 for biopsy specimens) and the active UC patients (4.3% versus 14.0%, P0.001 for fecal samples; 2.8% versus 11.4%, P<0.0001 for biopsy specimens). 24478468
1628 Bifidobacterium was significantly increased in the biopsy specimens of active UC patients compared to those in the HCs (4.6% versus 2.1%, P0.001), and the proportion of Bifidobacterium was significantly higher in the biopsy specimens than in the fecal samples in active CD patients (2.7% versus 2.0%, P0.012). 24478468
1629 The Lactobacillus group was significantly increased in the biopsy specimens of active CD patients compared to those in the HCs (3.4% versus 2.3%, P 0.036). 24478468
1630 In addition, intravenous administration of NAC to patients with acute sever sepsis is reported to aggravate sepsis-induced organ failure, suggesting that the effects of NAC are not always anti-inflammatory [21]. 24504121
1631 Amongst the Firmicutes, the reduced presence of Faecalibacterium prausnitzii has been well documented in patients with CD as opposed to controls[23,26-30]. 24574795
1632 Helicobacter pylori which has convincingly been found to be negatively correlated with IBD 24574795
1633 The critical role of TLR4 as a first line of defence against potential bacterial pathogens is now beyond doubt. 24574795
1634 The most well defined change that has been noted in patients with IBD is the reduced abundance of the phyla Firmicutes[23-25]. 24574795
1635 A large number of researchers have successfully shown a higher prevalence of MAP in Crohn’s patients compared to controls but, it seems for each of these there has been an equivalent study yielding no association[85-97]. 24574795
1636 A specific pathogenetic group of Escherichia coli (E. coli), adherent-invasive E. coli (AIEC) have recently been extensively implicated in human IBD and are currently one of the most exciting players in the pathogen story 24574795
1637 Another study using faecal samples from newly diagnosed CD patients also found a significant association with C. concisus, 35 of 54 CD patients testing positive and only 11 of 33 healthy controls 24574795
1638 dysbiosis or a definitive change of the normal gut microbiome with a breakdown of host- microbial mutualism is probably the defining event in the development of IBD. 24574795
1639 Further analysis suggests that the Bacteroides enterotype is associated with a “western” protein rich diet as opposed to the Prevotella enterotype which was associated with a carbohydrate rich diet[21] 24574795
1640 Impairment of TLR4 function permits bacterial invasion and persistence, and leads to the characteristic inflammation of IBD. 24574795
1641 In addition, there was a definite decrease in diversity of Firmicutes, with fewer of its constituent species detected in patients with IBD[23,32,33]. 24574795
1642 In human subjects, enterohepatic Helicobacter species prevalence was significantly higher in colonic biopsy samples from patients with UC group compared to control subjects[118]. 24574795
1643 It must be said that the avenue of research in this field was first opened up in 2001 when the first association of the nucleotide-binding oligomerization domain-containing protein 2 (NOD-2) gene mutation and susceptibility to Crohn’s disease was documented[16,17]. 24574795
1644 Most of the known pathogenic bacteria in humans belong to the phylum Proteobacteria, which have been increasingly found to have a key role in IBD[38]. 24574795
1645 This has been countered in a paediatric cohort of patients with CD where there were increased levels of Faecalibacterium prausnitzii suggesting a more dynamic role for this bacterium with a putative protective effect at the point of onset of IBD[31]. 24574795
1646 TLR4 is found to be up regulated in both UC and CD, whereas the levels of TLR2 and TLR5 remain unchanged[56,59]. 24574795
1647 Unlike the other IBD suspects, Campylobacter does not have a suitable animal disease model; instead interest stems from the recognition of Campylobacter jejuni (C. jejuni) as the leading cause of gastroenteritis worldwide[129]. 24574795
1648 An exhaustive analysis of normal global gut bacterial communities suggests the possible existence of distinct enterotypes (Bacteroides, Prevotella or Ruminococcus) which are predominantly driven by dietary intake but independent of age or BMI 24574795
1649 However, a large study found a lack of epidemiological support for environmental exposure[ 84]. 24574795
1650 The most recent study found that although Campylobacter appear to be surprisingly common, with positive PCR in 33/44 IBD patients and 32/42 controls, there was no association with IBD[119]. 24574795
1651 More than a decade after its discovery, NOD2 variants remain the strongest determinants of susceptibility to Crohn’s disease, in genetic association studies and in clinical studies exploring patient risk stratification (discussed later).23,41,59,60 24614343
1652 In this report, we demonstrate in nonobese humans that an OF period (i) increased LBP/sCD14 ratio in the fasting state and (ii) increased the postprandial accumulation of LPS. 24687809
1653 LBP is also considered as a factor related to atherosclerosis [29]. 24687809
1654 Moreover, highplasma concentration of LBP has been observed in humans with mild to morbid obesity [13, 14] and was recently associated with obesity and related abnormalities contrary to sCD14 [19]. 24687809
1655 Recently, LBP was reported as a biological marker in the acute appendicitis 24687809
1656 In contrast, CB2 expression was decreased. 24853043
1657 L-NCFM alone, but not with B-LBi07, induced colonic MOR mRNA and protein expression, as well as downstream signalling, as measured by enterocyte STAT3- phosphorylation 24853043
1658 There have been several other studies which have shown the high number of Blastocystis positive individuals in the IBS group compared to the control group with rates of 71%, 76% and 49% with less than 20% in the control groups [74-76]. 24883113
1659 Using animal models, it was demonstrated that artemisinin abrogates dextran sulfate sodium (DDS)-induced intestinal inflammation. 24886881
1660 Artemisinin was found to prevent or reduce the severity of colonic inflammation by inducing CYP3A expression by activation of PXR. 24886881
1661 The prevalences of irritable bowel syndrome (39.4%) by Rome III criteria and chronic fatigue (30.8%) in the exposed group 6 years after giardiasis were significantly elevated compared with controls, with adjusted relative risks (RRs) of 3.4 (95% confidence interval [CI], 2.9–3.9) and 2.9 (95% CI, 2.3–3.4), respectively. 25115874
1662 As stated above, in the β -arrestin-2 knockout mice, acutely administered morphine reduces constipation (33), indicating that persistent opiate receptor signaling in the colon via β -arrestin-2 (leading to decreased propulsive motility and colonic secretion) could be an important contributor to the development of opioid-induced constipation. 25207608
1663 Opioid receptor agonists can inhibit colon water and electrolyte secretion and this eff ect can contribute to opioid-induced constipation 25207608
1664 Studies on the human colon have shown that morphine acts at MOR and DOR to inhibit inhibitory neuromuscular transmission ( 19 ). Th is will lead to an increase in smooth muscle tone and a decrease in propulsive motility 25207608
1665 In addition, suppression of inhibitory neuromuscular transmission is likely responsible for the cramps caused by opioid drugs. 25207608
1666 Opiate drugs have powerful eff ects on gastrointestinal function, and chronic opiate use for pain relief can cause opioid-induced bowel dysfunction (chronic constipation) and, in extreme cases, narcotic bowel syndrome ( 1 ). 25207608
1667 Consequently, opioids decrease the formation of cyclic AMP,36 which otherwise would have activated several target molecules to regulate cellular functions. The overall effect is the reduced release of neurotransmitters and decreased neuronal activity. 25278772
1668 Opioid antagonists will – at least in theory – normalize sphincter coordination 25278772
1669 Opioid antagonists will alleviate the opioid-induced increased resting tone in the circular muscle layer 25278772
1670 This will likely reduce typical OIBD symptoms, including constipation, gut spasm, and abdominal cramps. 25278772
1671 Although anal sphincter dysfunction in OIBD has not been systematically evaluated, one-third of patients in a recent study of opioid-treated patients reported the sensation of anal blockage.13 25278772
1672 Because opioids inhibit neurotransmitter release, administration will directly disrupt this balance, resulting in abnormal coordination of motility.39 25278772
1673 Opioid-induced sphincter of Oddi dysfunction is a well-known adverse effect of opioid administration, characterized by spasm of the sphincter of Oddi and consequently increased intrabiliary duct pressure 25278772
1674 Opioids may induce esophageal muscular dysfunction which leads to decreased lower esophageal sphincter pressure, and thereby increased incidence of gastroesophageal reflux. 25278772
1675 Thus, each of the sphincters play an important role for normal transit, and any sphincter dyscoordination will lead to bowel dysfunction 25278772
1676 Currently recommended first line therapy for eradication, metronidazole 400 mg three times daily or sulfamethozazole/trimethoprim 160/80mg were administered to 11 symptomatic patients for 14 days. 25349629
1677 Among the plant compounds, Kiwifruit extracts as well as different polyphenols have been found to exert anti-inflammatory effects in models of IBD and in human disease [180-182]. 25407511
1678 CB1R, but not CB2R, exerts a protective role in colonic permeability as shown in CB1R knockout mice that respond to stress with enhanced permeability compared to normal littermates [53] 25407511
1679 Consequently, LX1031, an oral inhibitor of tryptophan hydroxylase, the key enzyme for mucosal serotonin synthesis has been successful for treatment of patients with non-constipating IBS [202]. 25407511
1680 For example, the probiotic E.coli Nissle 1917 (EcN) was shown to prevent barrier disruption caused by infection of T84 and Caco-2 cells with an enteropathogenic E. coli strain [112]. 25407511
1681 For example, VSL#3 seems to be effective not only in pouchitis, but also in mild to moderate UC not responding to conventional therapy [187]. 25407511
1682 Importantly, one study has shown that L. plantarum can regulate human epithelial TJ proteins in vivo and to confer protective effects against chemically induced disruption of the epithelial barrier in an in vitro model [122]. 25407511
1683 In particular, bloating and distension, for with other therapeutic approaches are limited, may improve by probiotic treatment [210,211]. 25407511
1684 In type 2 diabetes, the microbiota looses its capacity to generate SCFA from prebiotics [217], which might be a genuine defect or an adaptation to low fiber intake, which has been revealed by several epidemiologic studies [221,222]. 25407511
1685 It is released during cell activation or cell death and has antiproliferative, antimicrobial, and immunomodulating functions [169,170]. 25407511
1686 Lactobacillus strains seem to have protective effects on the intestinal barrier using different in vitro settings or mouse models of disease, namely L. salivarius strains UCC118 and CCUG38008, L. rhamnosus GG, Lactobacillus casei strain DN-114 001, and L. casei strain Shirota [123-127]. 25407511
1687 Mammals produce larger amounts of secretory immunoglobulin A (sIgA) in the mucosa reflecting its central role in immunity and protection against pathogens. 25407511
1688 Most interestingly, some of the probiotic trials demonstrated that the effects are correlated with an improvement of the intestinal permeability [212]. 25407511
1689 Splanchnic hypo-perfusion can be confirmed in healthy men already after cycling for 60 minutes at 70% of maximum workload capacity. 25407511
1690 Table 8 Factors proposed to support the gut barrier 25407511
1691 The first reports on beneficial effects of probiotics in IBD was on E.coli Nissle 1917 supporting maintenance of remission in patients with UC [183,184]. 25407511
1692 The mechanisms of probiotic effects in IBD is unclear at present, but might involve direct anti-inflammatory effects, e.g. by modulating TLR signaling , or indirect effects such as improvement of the intestinal barrier [190,191]. 25407511
1693 The opposing effects of cannabinoids (either improving or worsening intestinal permeability) might be related to the recent observation that endocannabinoids such as anandamide worsen permeability while phytocannabinoids like cannabidiol and tetrahydrocannabidiol, which might act as (partial) CB1R antagonists, promote protection or recovery from intestinal permeability [52]. 25407511
1694 Therefore, butyrate deficiency can be taken as an indirect indicator of impaired intestinal barrier function. 25407511
1695 A broad range of pathologies can lead to intestinal inflammation such as neoplasia, IBD, IBS, infections, autoimmune diseases, allergies, intestinal hypoperfusion, and selected drugs like non-steroidal anti-inflammatory drugs. 25407511
1696 Already 20 years ago it was found that increased intestinal permeability precedes clinical manifestations of CD, but is insufficient to cause disease suggesting other factors being involved [137,177]. 25407511
1697 Alternatively to the measurement of endotoxin, which yields best results if measured in portal vein plasma, measurement of circulating EndoCAb allowing the quantification of immunoglobulins (IgG, IgM and IgA) against the inner core of endotoxin have been proposed for the acute phase of intestinal barrier damage. 25407511
1698 Apart from calprotectin, other markers of intestinal immunity such as secretory IgA [172] and defensins have been proposed as markers of intestinal permeability. 25407511
1699 Consistently, energy-rich high-fat diets enhanced intestinal permeability resulting in metabolic endotoxinemia. 25407511
1700 Despite well-known technical limitations of the assay, resulting from the low levels detectable in peripheral blood, several studies have successfully used LPS assays to show endotoxemia, mostly in patients with sepsis [149]. 25407511
1701 Fecal calprotectin is nowadays used in clinical practice to evaluate disease activity in the follow-up of patients treated for active IBD and can be easily performed [171]. 25407511
1702 Generally, defects or increased permeability of the mucosal barrier will cause intestinal inflammation in response to the enormous number of bacteria present in the bowel. 25407511
1703 Low circulating levels of D-lactate are found in healthy individuals, but in case of intestinal barrier function loss, these levels will rise as a consequence of increased translocation across the intestinal mucosa. 25407511
1704 More recently, citrulline was established as a valuable marker for chemotherapy-induced mucosal barrier injury in pediatric patients [159]. Most interestingly, sensitivity and specificity seem to be better for the citrulline assay compared with sugar permeability tests [160]. 25407511
1705 Most importantly, there is evidence now that increased intestinal permeability is related to low-grade inflammation, visceral hypersensitivity and pain in IBS [192]. 25407511
1706 Permeability assays are usually useful only for assessing small intestinal permeability, since lactulose is degraded by bacteria in the large intestine. To evaluate whole intestinal permeability, nondegradable probes such as sucralose or erythritol, which remain unaffected by bacteria in the colon, are added to classical DST, resulting in the so-called triple sugar test. 25407511
1707 The altered microbiota in obesity and metabolic diseases contributes to an enhanced harvest of energy from nutrients. 25407511
1708 The result of such alterations is enhanced infiltration of tissues with bacteria and bacterial products and subsequent tissue inflammation and fat accumulation, which can be observed first in the liver and later on in other tissues such as muscle or heart muscle [150,219,228]. 25407511
1709 Using TLR-4 mutant mice we showed that the onset of fructose-induced NAFLD is associated with intestinal bacterial overgrowth and increased intestinal permeability, subsequently leading to an endotoxin-dependent activation of hepatic Kupffer cells [104]. 25407511
1710 Western style diet rich in fat and sugars alters the intestinal barrier in a way resulting in enhanced permeability and elevated endotoxin levels in the portal vein [104,150,227]. 25407511
1711 A plausible explanation for this finding could be impaired local 5-HT uptake in patients with IBS-D and impaired 5-HT release in patients with con- stipation regardless of whether their clinical diagnosis is IBS-C or functional constipation. 25446728
1712 In IBS, the first report of 5-HT abnormalities originates from 1998 when Bearcroft et al.108 showed increased postprandial platelet-depleted plasma levels of 5-HT in a small number of patients with diarrhoea-predominant IBS (IBS-D). 25446728
1713 When analysing the 5-HIAA:5-HT ratio in mucosal biopsy samples as a measurement of 5-HT turnover, it seems that this value is reduced in IBS-D109 and increased in IBS-C.110,112,113 25446728
1714 ? Implied too? 25446728
1715 As the majority of 5-HT in human peripheral blood originates from the gut, platelet-depleted plasma is supposed to reflect the gastrointestinal release.107 25446728
1716 Between 12% and 50% of patients with IBS have been reported to have altered intestinal permeability in research studies136 using various methods to reflect gut permeability at different parts of the gastrointestinal tract,137–139 and both postinfectious IBS as well as non- selected groups of patients with IBS have been investi- gated. 25446728
1717 Chemical stimulants are probably of regional importance as exemplified by the ability of short-chain fatty acids (products of colonic microbiota in humans) to stimulate 5-HT release.99 25446728
1718 Different proteases seems to be of importance in different clinical situa- tions: serine proteases have been found to be elevated in IBS-D,152 and cysteine proteases in patients with IBS-C.151 25446728
1719 Faecal supernatants from patients with IBS are able to increase colonic paracellular permeability in mice, possibly mediated by the protease content that has been shown to be increased in IBS.151,152 25446728
1720 In fact, meta-analyses demonstrated a sixfold to sevenfold increased risk of developing IBS after a gastro- enteritis episode, which makes gastrointestinal infections the best-characterized and probably strongest known risk factor for development of IBS.46,47 25446728
1721 In the previously mentioned study investigating patients with postinfectious IBS, a microbial profile of 27 genus-like groups provided an Index of Microbial Dysbiosis (IMD) that could separate patients with IBS from controls.73 25446728
1722 On the contrary, patients with constipation-predominant IBS (IBS-C) were shown to have a low concentration of platelet- depleted plasma 5-HT after meal intake, which was also reported in patients with functional constipation, without any notable difference compared with IBS-C.111 25446728
1723 Perhaps more controversial is the suggestion that small intestinal bacterial overgrowth explains IBS symptoms in a sizeable proportion of patients with IBS; however, studies with positive and negative find- ings exist.49–52 25446728
1724 Recent studies indicate that intraperitoneal pretreatment with Ucn2 acting through CRF2 receptors inhibits peripheral CRF-or Ucn1 induced stimulation of colonic motor function while pre-treatment with astressin2-B or genetic deletion of CRF2 in mice exacerbated the restraint stress or intraperitoneal CRF and Ucn1 induced stimulatory colonic responses.54,137 25611064
1725 Additio- nally, recent evidence showed the expression of CRF1 receptors and variants on human enterochromaffin-like cells, the BON subclone 1 cells. In these cells, CRF induces a CRF1 receptor mediated stimulation of 5-HT release and up regulated the ex- pression of 5-HT synthesizing enzyme, tryptophan hydro- xylase.36 25611064
1726 Consistent with the brain localization of CRF/CRF1 signaling pathway, convergent preclinical reports point to the role of central CRF1 receptors in stress-related stimulation of colonic secretory motor function.61 First, CRF and Ucn1 injected into the cere- brospinal fluid induces the occurrence of colonic spike burst activ- ity, acceleration of colonic transit, decreased in colonic fluid ab- sorption, stimulation of defecation, and induction of diarrhea in freely moving rats, mice and gerbils, mimicking the effects of ex-posure to acute stressors whereas Ucn2 and Ucn3 under the same conditions have no effect.72-80 25611064
1727 Effector mechanisms within the colon involved parasympathetic chol- inergic mediated activation of colonic serotonin (5-HT) interact- ing with 5-HT3 and 5-HT4 receptors. This is supported by the increase in 5-HT content in the feces of the rat proximal colon in response to icv CRF107 and pharmacological approach using 5-HT3 antagonists (granistron, ramosteron, ondansetron and azasetron), the 5-HT4 antagonist, SB-204070 and the muscar- inic antagonist, atropine that all blocked icv CRF-induced colon- ic motor stimulation and decreases in colonic fluid loss.76,78,88,107 25611064
1728 Gué et al139 provided the first evidence that CRF injected icv induced visceral hyperalgesia to colorectal distention (CRD) in rats, mimicking the response induced by partial restraint stress. 25611064
1729 The actions of peripheral CRF on the colon reported in ex- perimental studies have been largely reproduced in healthy sub- jects or IBS patients along with preliminary evidence of the bene- ficial effect of peripheral injections of peptide CRF antagonist (Tables 1 and 2). With regards to the intestinal motility, one clin- ical report showed that systemic administration of CRF increases the motility index in the descending colon in both healthy and IBS groups with a significant higher response in the IBS groups.177 25611064
1730 Importantly, brain CRF1 receptors are not involved in the basal and postprandial regulation of colonic motor function under non-stress conditions.92 25611064
1731 A role for endogenous H2S in smooth muscle inhibitory tone has been recently proposed, as both CBS and CSE inhibitors were able to depolarize resting membrane potential (RMP) and to increase spontaneous motility in the rat colon [11]. 25641403
1732 Moreover, PAG depolarizes the tissue in WT animals when NO synthesis is blocked (l-NNA) or in nNOS KO mice, suggesting that endogenous H2S might be exerting an inhibitory effect on NO production [4,22]. 25641403
1733 The blockade of the enzymes responsible for H2S synthesis gives information about the putative role of constitutively produced H2S. Our study shows that a combination of PAG 2 mM (a CSE inhibitor) and AOAA 1 mM (a CBS inhibitor) causes depolarization of RMP and a transient tone increase in the human colon. 25641403
1734 H2S is synthesized mainly by the two pyridoxal phosphate dependent enzymes cystathionine ?-synthase (CBS; EC and cystathionine ?-lyase (CSE; EC which use l-cysteine as substrate [3,4]. 25641403
1735 Studies performed with the H2S donor NaHS have demonstrated that H2S has pro-secretory effects in several species including the human and rat colon [9,12]. 25641403
1736 These findings suggest a constitutive production of H2S in the human colon, as previously reported in the rat [11] and mouse colon [30], which con- tributes to the maintenance of the smooth muscle inhibitory tone. 25641403
1737 How- ever, the amount of H2S that reaches the subepithelial space is very low due to the capability of faecal components to bind the sulphide as well as to colonic epithelial cells metabolic barrier [7]. 25641403
1738 Recently, Binder et al. [74••] showed that immunization of LDLR KO mice with Streptococcus pneumoniae dramatically reduced lesion development in parallel with elevation of oxLDL-specific IgM antibodies that cross-react with pneumococcal epitopes. 25683179
1739 Moreover, Yan and colleagues in the same study showed that the population of Lactobacilli was depleted in alcohol-treated mice.[20] 25809237
1740 They observed a bacterial overgrowth in the proximal small intestine, dysbiosis and suppression of Reg3b and Reg3g anti-microbial molecules. 25809237
1741 This last evidence could explain the beneficial effect of probiotics in the prevention of increased gut permeability, endotoxinemia and liver injury reported in alcohol-fed mice.[24] 25809237
1742 Among patients with alcoholic liver disease, the mouth-to-caecum transit time was prolonged by 21.5% in comparison with controls not abusing alcohol 25809237
1743 It is well known that alcohol leads to mucosal damage, quantitative and qualitative alterations of gut flora (i.e. small intestinal bacterial overgrowth and dysbiosis), and increased gut permeability, resulting in the translocation of endotoxins and other bacterial products into portal blood flow. 25809237
1744 There was no correlation between severity of drinking and Helicobater pylori infection 25809237
1745 Ruminococcus champanellensis is a recently described (Chassard et al., 2012) anaerobic, mesophilic, Gram- positive bacterium found in the human colon, whose genome has been sequenced. It is the only human colonic bacterium so far reported to efficiently degrade pure cel- lulose (Avicel and filter paper). 25845888
1746 Lastly, a rather elegant study found that, of 26 children with mitochondrial disorders, gastric emptying was delayed in 69% and intestinal transit time was prolonged in 46% (114). 25956238
1747 Clostridia spp. are producers of the short-chain fatty- acid propionic acid (39, 40) following the fermentation of dietary carbohydrates and some proteins. 25956238
1748 Despite the behavioral definition, many children with ASD have co-morbid medical conditions including gastrointestinal (GI) symptoms (3), seizures and epilepsy (4), attention deficits (5), anxiety (6), allergies (7) and mitochondrial disease (8, 9). 25956238
1749 Furthermore, elevated propionic acid levels are present in the stool from individuals with ASD (180). 25956238
1750 In fact, while the prevalence of GI disorders in the general ASD popula- tions was found to be 20%, the prevalence of GI disorders in individuals reported to have ASD with mitochondrial disease was 74%. 25956238
1751 Interestingly, mitochondrial dysfunction has been demon- strated in animal models induced by exogenous toxicants such as the propionic acid adult rodent model (39, 40) 25956238
1752 Mitochondrial neurogastrointestinal encephalopathy syndrome is characterized by progressive GI dysmotility leading to pseudo-obstruction and severe GI symptomatology. This disorder is caused by a mutation in the TYMP gene, a gene for thymidine phosphorylase, which results in nucleotide pool imbalances and mitochondrial deoxyr- ibonucleic acid (mtDNA) depletion. 25956238
1753 Valproic acid is also known to cause hepatotoxicity (116) and pancreatitis (117) as well as being linked to mitochondrial disease and dysfunction (118), and exposure in utero increases the risk of develop- ing ASD (119). 25956238
1754 Mitochondrial neurogastrointestinal encephalopathy syndromeis characterized by progressive GI dysmotility leading to pseudo-obstruction and severe GI symptomatology. This disorder is caused by a mutation in the TYMP gene, a gene for thymidine phosphorylase, which results in nucleotide pool imbalances and mitochondrial deoxyr- ibonucleic acid (mtDNA) depletion. 25956238
1755 Compared to SPF mice, GF have decreased intestinal cholesterol absorption and increased fecal cholesterol excretion, which is associated with reduced expression of NPC1L1 and increased expression of ATP-binding cassette transporter G5 and G8 (ABCG5 and ABCG8). 26015368
1756 Germ-free (GF) mice have reduced stool output. 26015368
1757 Our results together suggest that inhibiting microbiota may lower blood cholesterol, particularly when it is combined with a cholesterol-lowering drug such as ezetimibe. 26015368
1758 We have previously observed that knockout of Niemann-Pick C1-Like 1 (NPC1L1), a cholesterol transporter essential for intestinal cholesterol absorption, reduces the output of dry stool in mice. 26015368
1759 It was shown that trimethylamine-N-oxide (TMAO), a metabolite formed from substrates derived from the gut microbiota, promotes atherosclerosis7, and knockdown of the host enzyme flavin monooxygenase 3 (FMO3) that generates TMAO from bacterial substrates promotes macrophage reverse cholesterol transport in mice51. 26015368
1760 Sallam et al. used a bone marrow transplant approach to demonstrate that deletion of Lbp in hematopoietic cells was protective against atherosclerosis in Ldlr−/− recipient mice. 26164157
1761 It is also an effective scavenger of oxyradicals due to its N-terminal Dmt residue as antioxidant moiety.13 26352668
1762 This population-based cohort study revealed that IBS increases the risk of developing epilepsy. 26356716
1763 Involvement of endogenous opioid peptides in the peripheral antinociceptive effect induced by the coffee specific diterpene kahweol 26398397
1764 Although bacteria in the small intestine are potentially competing with the host for nutrients, host-derived bile acids and antimicrobial peptides limit bacterial growth to low densities in proximal regions. 26499895
1765 In ileostomy samples from humans, the small intestine was found to exhibit lower bacterial diversity than the colon and was highly enriched in certain Clostridium spp. and certain members of the phylum Proteobacteria20. 26499895
1766 In a meta-analysis of 11 randomized controlled studies, the comparative efficacy of tegaserod was reported to be 0.85 (95% CI, 0.80−0.90), suggesting that it is capable of ameliorating symptoms 26576134
1767 In a study of patients with opioid-induced bowel dysfunction, alvimopan, a peripherally acting μ-opioid receptor antagonist (PAMORA), significantly improved stool frequency during the 8 hours and the time required for the first evacuation compared to placebo.56 26576134
1768 Methylnaltrexone, approved by the FDA in 2008, is a selective inhibitor of opioid receptors located in the intestinal muscle cells, and normalizes bowel function without affecting the analgesic effects of opioids.58 26576134
1769 Positive effects of neomycin and rifaximin treatment on patients with IBS-C have been reported.50,51 26576134
1770 Likewise, we observed threshold effects for nasal taxa such as Propionibacterium granulosum and S. epidermidis; however, P. granulosum was negatively correlated with the presence of S. aureus, but S. epidermidis was positively correlated (P. granulosum node n = 4/34, 11.8%; S. epidermidis node n = 13/14, 92.9%) (Fig. 3A). 26601194
1771 Specifically, the rate of S. aureus nasal colonization among individuals at or above the Dolosigranulum threshold was 16.0% (n = 4/25), as compared with 56.0% among the simulated population (n = 56/100). 26601194
1772 The S. aureus absolute abundance model indicated that having low Corynebacterium abundance predicts high S. aureus absolute abundance, 26601194
1773 Host genetics played no significant role in nasal microbiota composition. 26601194
1774 Similarly, in experimental murine colitis, artesunate alleviated colitis developed by DSS or TNBS, but not that induced by oxazolone; it ameliorated weight loss, disease activity, and colonic injury. 27366027
1775 Irritable bowel syndrome was more frequent in PWE compared with that in healthy controls. 27552483
1776 This study substantiates and further extends the relationship between TLR4 activation by LPS and breast cancer using both in vitro and in vivo models. 28296189
1777 A diet containing butyrate boosted the number and function of regulatory T cells, whereas acetate- and butyrate-yielding diets enhanced gut integrity and decreased serum concentration of diabetogenic cytokines such as IL-21. 28346408
1778 A recent study demonstrated that the adenosine receptor agonist 50-N-ethylcarboxamidoadenosine (NECA) stimulates 5-HT release, while the antagonist MRS-1754 inhibits its secretion from EC cells [41]. 29099770
1779 Clostridium difficile toxins upregulate the expression of the A2B receptor in the human colon cell line HCT-8, and the receptor antagonist ATL-692 decreases toxin-induced secretion [40]. 29099770
1780 Furthermore, bacterial toxins trigger the chloride secretion response through the A2B receptor. 29099770
1781 In addition, adenosine A2B receptor-deficient mice display reduced stool water content, suggesting a role of the receptors in chloride secretion [37]. 29099770
1782 The A2B receptor antagonist MRS-1754 prevents the stimulation of secretion by conditioned medium containing ATP released from cells infected with enteropathogenic Escherichia coli [39]. 29099770
1783 Table 1 DOI: 10.1006/jfca.1993.1016
1784 "Sulfuring" of foods and beverages with sulfur dioxide (E220), sulfite or disulfite (E221-E227) is a widely practiced … DOI: 10.1006/jfca.1993.1016
1785 The sulfate in beer may explain, at least in part, its well-known laxative effect. DOI: 10.1006/jfca.1993.1016
1786 Although the capacity to respond to LPS results in activation of a potentially lethal inflammatory mediator response, its evolutionarily conserved role is to support the ability to withstand an acute infectious challenge. DOI: https://doi.org/10.1086/432000
1787 Finally, circulating LPS evokes a neutralizing antibody response [83]. DOI: https://doi.org/10.1086/432000
1788 For example, bactericidal/permeability-increasing protein is a neutrophil product homologous in its C-terminus with LBP; bactericidal/ permeability-increasing protein can competitively bind and neutralize LPS, blocking cellular activation and facilitating LPS clearance [79, 80]. DOI: https://doi.org/10.1086/432000
1789 Other plasma proteins, notably high-density lipoprotein [81] and very-low-density lipoprotein [82], can also bind and inactivate circulating endotoxin. DOI: https://doi.org/10.1086/432000
1790 Absorption of gut endotoxin can cause endotoxemia during acute physiological stresses, such as vigorous exercise [62, 63] or the resumption of feeding following periods of deprivation [64]. DOI: https://doi.org/10.1086/432000
1791 Aggregates of LPS bind to plasma proteins (e.g., albumin, LPS-binding protein [LBP], and soluble CD14) that serve to convert highermolecular- weight endotoxin complexes to monomeric particles that can interact with host cells [59]. DOI: https://doi.org/10.1086/432000
1792 Endotoxin can be detected in the blood of the majority of patients with sepsis, independent of the nature of the infecting organism [54], and in most patients undergoing aortic surgery [55]. DOI: https://doi.org/10.1086/432000
1793 Gram-negative infections result in systemic endotoxemia. DOI: https://doi.org/10.1086/432000
1794 In fact, elevated levels of endotoxin are present in the majority of patients on the day of their admission to an intensive care unit, and endotoxemia is associated with nonspecific illness severity, as measured by the APACHE score, as well as with the presence of infection (both gram-negative and gram-positive) and clinical manifestations of sepsis [56]. DOI: https://doi.org/10.1086/432000
1795 It ubiquity during times of acute physiological stress is reminiscent of the patterns of release of such classic stress hormones as cortisol or epinephrine. DOI: https://doi.org/10.1086/432000
1796 LPS is an intrinsic component of the cell wall of gramnegative bacteria, which, in turn, are ubiquitous symbionts in the gastrointestinal tracts of most animals. DOI: https://doi.org/10.1086/432000
1797 Originally identified by the German microbiologist Richard Pfeiffer in the late 19th century, LPS is the prototypical and best-studied trigger of the host inflammatory response that underlies the pathogenesis of sepsis [53]. DOI: https://doi.org/10.1086/432000
1798 Systemic endotoxemia has been documented after multiple trauma [65] but also after ankle fracture [66] or colonoscopy [67], suggesting that LPS is readily absorbed from the gut. DOI: https://doi.org/10.1086/432000
1799 The structure of the LPS molecule varies from one strain of bacteria to the next, but a constant feature of all species is the presence of a toxic lipid A moiety, covalently joined to a polysaccharide core, with or without variable oligosaccharide side chains (figure 1). DOI: https://doi.org/10.1086/432000
1800 Thus, although endotoxin is not produced by human cells, it is released from stores that are present in all humans in response to a variety of acute stresses. DOI: https://doi.org/10.1086/432000
1801 Animal studies have demonstrated the efficacy of methylnaltrexone in completely preventing morphine- induced emesis. A trial in postoperative patients was unable to reproduce this effect (unpublished data), perhaps due to the multifactorial nature of postoperative nausea and vomiting. DOI: 10.1002/1098-2299(200006)50:2<133::AID-DDR1>3.0.CO;2-8
1802 Recently, we also observed in another in vitro preparation that when methylnaltrexone alone was applied to the gastric area, brainstem neurons were activated, suggesting an inhibitory modulation by gut endogenous opioids [Yuan and Foss, 1999]. DOI: 10.1002/1098-2299(200006)50:2<133::AID-DDR1>3.0.CO;2-8
1803 Utilizing methylnaltrexone to examine the suppression of cough by morphine, and nociception as an indicator of the central activity of the compound, we demonstrated the ability of methylnaltrexone to block opioid-induced cough suppression without affecting pain relief in guinea pigs [Foss et al., 1996]. Utilizing methylnaltrexone to examine the suppression of cough by morphine, and nociception as an indicator of the central activity of the compound, we demonstrated the ability of methylnaltrexone to block opioid-induced cough suppression without affecting pain relief in guinea pigs [Foss et al., 1996]. This result can be compared to human studies in which i.v. methylnaltrexone 0.3 mg/kg did not reverse morphine-induced respiratory depression [Amin et al., 1994]. DOI: 10.1002/1098-2299(200006)50:2<133::AID-DDR1>3.0.CO;2-8
1804 A relative or absolute excess of endogenous opioids or an altered opioid receptor affinity may contribute to or cause hypomotility in idiopathic constipation. DOI: 10.1002/1098-2299(200006)50:2<133::AID-DDR1>3.0.CO;2-8
1805 Nausea and vomiting are common postoperative side effects of opioids. DOI: 10.1002/1098-2299(200006)50:2<133::AID-DDR1>3.0.CO;2-8
1806 Oral–cecal transit time increased after morphine administration in all 12 subjects, and methylnaltrexone prevented the morphine-induced delay in every subject (Fig. 4). DOI: 10.1002/1098-2299(200006)50:2<133::AID-DDR1>3.0.CO;2-8
1807 Using the cold-pressor test [Yuan et al., 1998b], the study in volunteers also demonstrated that methylnaltrexone does not reverse morphine-induced analgesia [Yuan et al., 1996]. DOI: 10.1002/1098-2299(200006)50:2<133::AID-DDR1>3.0.CO;2-8
1808 When methylnaltrexone alone was applied to the tissue bath, the force produced by muscle contraction was enhanced in a dose-related manner up to 27% compared to control levels, suggesting an inhibitory modu-lation by endogenous opioids. DOI: 10.1002/1098-2299(200006)50:2<133::AID-DDR1>3.0.CO;2-8
1809 In this double-blind, randomized, placebo-controlled study in healthy volunteers [Yuan et al., 2000a], we observed that gut transit time increased after i.v. morphine administration in our subjects, and that a lower dose of enteric-coated methylnaltrexone (3.2 mg/kg) completely prevented morphine-induced changes in oral-cecal transit time. DOI: 10.1002/1098-2299(200006)50:2<133::AID-DDR1>3.0.CO;2-8
1810 Methylnaltrexone prevented 97% of morphine-induced changes in oral-cecal transit time (P < 0.01 compared to morphine alone). DOI: 10.1002/1098-2299(200006)50:2<133::AID-DDR1>3.0.CO;2-8
1811 Corresponding to these higher acid levels, the pH is also typically lowest in the transverse colon (5.4 to 5.9) and gradually increases through the distal colon to 6.6 to 6.9 (Nordgaard and Mortensen 1995). DOI: 10.1111/j.1541-4337.2002.tb00009.x
1812 Evidence suggests that increasing the numbers of bi- fidobacteria in the colon and reducing in- testinal pH has a direct impact on carcino- genesis in the large intestine (Goldin and Gorbach 1980; Hill 1988; Koo and Rao 1991). DOI: 10.1111/j.1541-4337.2002.tb00009.x
1813 Historical observational and epidemiological studies from around the world have long support- ed that increased consumption of fruits and vegetables and high fiber intake pro- vide a protective relationship between di- etary fiber intake and colon cancer inci- dence (Trock and others 1990; Steinmetz and Porter 1991; Howe and others 1992; Byers 1995, 2000). DOI: 10.1111/j.1541-4337.2002.tb00009.x
1814 However, early results from a European investigation, the European Prospective Investigation of Cancer (EPIC), involving more than half a million people in 10 European countries, indicates that dietary fiber provides strong protective ef- fects against colon and rectal cancers (Bingham and others 2001). DOI: 10.1111/j.1541-4337.2002.tb00009.x
1815 Later studies, not only with FOS but also with inulin, have shown that they stimu- late colonic Bifidobacteria and Lactobacil- li and provide regularity and laxation properties (for example, Gibson and Rob- erfroid 1995; Kleessen and others 1997; Kruse and others 1999); DOI: 10.1111/j.1541-4337.2002.tb00009.x
1816 Of these anaerobic microorganisms, the clostridia, eubacteria, and anaerobic cocci are the most gas producing, while the bifidobacteria are the only group of the common gut microbiota that do not pro- duce any gases (Hartemink and Rombouts 1997). DOI: 10.1111/j.1541-4337.2002.tb00009.x
1817 Poorly fermented fibers, such as cellu- lose, exert an indirect stool bulking effect that causes shorter fecal transit times, a greater fecal mass, and laxation effects. DOI: 10.1111/j.1541-4337.2002.tb00009.x
1818 The extent of fermentation typically ranges from completely fermented (many water- soluble fibers) to little fermentation, for ex- ample, cellulose particles. DOI: 10.1111/j.1541-4337.2002.tb00009.x
1819 The most notable exceptions are cellulose derivatives, such as carboxyme- thyl cellulose (CMC), which is soluble but almost nonfermentable by the human co- lon flora. DOI: 10.1111/j.1541-4337.2002.tb00009.x
1820 But recent reports by Fuchs and others (1999), Bonithon-Kopp and others (2000), and 2 recent interven- tion trials (Alberts and others 2000, Schatzkin and others 2000) show no pro- tective effect of fiber on recurrence of ade- nomatous polyps or, worse, possibly a negative effect as a result of certain fiber supplements. DOI: 10.1111/j.1541-4337.2002.tb00009.x
1821 The concentrations of these acids are highest where concentrations of microbiota are also highest, namely in the cecum and transverse colon. DOI: 10.1111/j.1541-4337.2002.tb00009.x
1822 WHC of dietary fiber was orig- inally thought to be an important element for maintaining water content of stool. However, water content of stool is relative- ly constant at about 25%, and the WHC of dietary fiber likely does not have a direct influence on stool bulk. DOI: 10.1111/j.1541-4337.2002.tb00009.x
1823 Conclusion: Bisacodyl and SPS not only improve stool variables but also quality of life in patients with chronic functional constipation. DOI: 10.4236/ojgas.2017.71005  
1824 The study showed that in patients with chronic constipation there is a significant increase in concentration of endotoxin in the blood as compared with the comparison group: 3,72±1,4 EU/ml versus 0,41±of 0.2 (p<0.01), and its maximum value, 5,58±2.1 (p<0.01) was observed in the decompensated form of chronic colostasis. http://en.pmarchive.ru/level-of-endotoxin-as-a-criterion-of-severity-of-chronic-constipation-and-efficiency-of-its-treatment/
1825 It also should be noted that there is evidence suggesting that caffeine inhibits the development of acute gastric mucosal injury associated with the use of NSAIDs (Koyama et al., 1999). https://doi.org/10.1016/j.neubiorev.2016.09.001
1826 Bindseil and Hau (1991) correlated lower progesterone levels in female mice subclinically infected with the trematode, Eshinostoma caproni, with increased post-implantations losses in early pregnancy. https://doi.org/10.1016/S0960-5428(06)80052-5
1827 For example, activation of mu opioids is consistent with the decreased activity and lowered dominance and altered aggressiveness reported in male CD1 mice infected with Trichinella spiralis (Rau, 1984; Edwards, 1988). https://doi.org/10.1016/S0960-5428(06)80052-5
1828 Isserof et al. (1986, 1989) have indicated that the elevated [3-endorphin levels in S. mansoni infected mice are associated with decreased levels of gonadal steroids and lower reproductive potential. https://doi.org/10.1016/S0960-5428(06)80052-5
1829 It is also during this period that the greatest activations of ~ and K opioid systems, both of which have been shown to have immunosuppressive actions in mice (Taub et al., 1991), occurs. https://doi.org/10.1016/S0960-5428(06)80052-5
1830 There is also evidence for opioid-mediated changes in behaviour from mice infected with subclinical levels of the enteric intracellular protozoan parasite, Eimeria vermiformis, (Colwell and Kavaliers, 1992a; Kavaliers and Colwell, in preparation). https://doi.org/10.1016/S0960-5428(06)80052-5
1831 Appetite depression (anorexia) is a common feature in many parasitised animals (Gibbs, 1987; Elasser, 1988). https://doi.org/10.1016/S0960-5428(06)80052-5
1832 It should be noted that schistosome infection may also induce a differential augmentation and/or modification of the host's endogenous opioid activity, leading to alterations in immune and behavioral functions. Consistent with this are elevated levels of [3-endorphin demonstrated in schistosome infected mice (Isseroff et al., 1986, 1989). https://doi.org/10.1016/S0960-5428(06)80052-5
1833 This suggestion of increased opioid activity in schistosome infected individuals is supported by the findings that S.mansoni releases [Beta-endorphin and other POMCderived immunosuppresive peptides, as well as enkephalins under physiological conditions (Duvaux-Miret et al., 1992; Leung and Stefano, unpublished). https://doi.org/10.1016/S0960-5428(06)80052-5
1834 Together, these observations suggest that schistosome infection leads to an augmentation of endogenous opioid activity. https://doi.org/10.1139/z88-390
1835 In a later study 10 diarrhoea-predominant IBS Blastocystis-positive patients were given 14 days of triple antimicrobial therapy, namely diloxanide furoate 500mg and secnidazole 400 mg three times daily, and trimethoprim-sulfamethoxazole 160/80 mg twice daily, with 60% of the patients eradicating the organism. https://doi.org/10.14264/uql.2016.167
1836 Low serum immunoglobulin A (IgA) levels were found to be associated with carriage of Blastocystis but not symptoms (p<0.001). https://doi.org/10.14264/uql.2016.167
1837 Other previously described host factors, such as cytokine polymorphisms in IBS patients that increase IL-8 production and decrease IL-10, may select subjects for immune activation and symptom development. https://doi.org/10.14264/uql.2016.167
1838 The lower serum IgA level present in Blastocystis carriers was hypothesised to result in changes in the FM that enable Blastocystis to flourish with increased epithelial cell contact. https://doi.org/10.14264/uql.2016.167
1839 Currently recommended first line therapy for eradication, metronidazole 400 mg three times daily or sulfamethozazole/trimethoprim 160/80mg were administered to 11 symptomatic patients for 14 days. No patient was negative for Blastocystis carriage after therapy with either drug. https://doi.org/10.14264/uql.2016.167
1840 Injection of LPS into substantia nigra can cause a constipation in rats,which may be related to the enhanced TH-IR and reduced ChAT-IR in DMV leading to gastrointestinal dysmotility in LPS treated rats. https://doi.org/10.3969/j.issn.1006-7795.2013.04.017
1841 Enteroglucagon is released when fats and glucose are present in the small intestine; which decrease the motility to allow sufficient time for these nutrients to be absorbed. https://en.wikipedia.org/wiki/Enteroglucagon
1842 Enteroglucagon is a peptide hormone derived from preproglucagon. It is a gastrointestinal hormone, secreted from mucosal cellsprimarily of the colon and terminal ileum. It has 37 amino acids. https://en.wikipedia.org/wiki/Enteroglucagon
1843 In-vivo treatment with carbenoxolone (25 mg/kg) prevented 1) ATP-induced currents in enteric glia, 2)the decrease in neuronal density, and 3) colonic inflammation in chronic morphine treated mice. https://scholarscompass.vcu.edu/etd/4658/
1844 In chronic morphine treated mice (75 mg morphine pellet/5 days), ATP-induced currents were significantly enhanced in enteric glia isolated from the mouse colon myenteric plexus. https://scholarscompass.vcu.edu/etd/4658/
1845 The increase in ATP-induced currents, IL-1β expression and ATP release were also observed in isolated glia treated with lipopolysaccharide (LPS) consistent with bacterial translocation as a potential mediator of chronic morphine-induced inflammation. https://scholarscompass.vcu.edu/etd/4658/
1846 The amplitude and frequency of GMCs in IBS-C, STC, idiopathic constipation, and PFD patients are less than half of those in normal subjects; in severe cases of constipation, GMCs are totally absent or scarce [203,268–272]. https://www.ncbi.nlm.nih.gov/books/NBK53473/
1847 The frequency and amplitude of GMCs (Giant migrating contractions) increase significantly in IBS-D patients https://www.ncbi.nlm.nih.gov/books/NBK53473/
1848 Alternatively, the multiple marker test involves ingestion of one capsule daily for 3 days. Plain abdominal radiographs are obtained on days 4 and 7. Retention of more than 20% of the mak- ers on day 7 is indicative of slow transit constipation [ 31 , 32 ]. ISBN 978-1-4939-0332-0
1849 Female predominance has been supported in many studies [ 3 , 4 , 6 , 16 – 19 ], particularly in the irritable bowel syndrome (IBS) population [ 20 ]. ISBN 978-1-4939-0332-0
1850 In a large population- based study of Australian adults, constipation was more frequently reported by subjects of greatest socioeconomic disadvantage in both males (prevalence rate ratio 1.83, 95% CI 1.16–2.51) and females (prevalence rate ratio 1.68, 95% CI 1.31–2.04) compared to those in the highest socioeconomic tier [ 26 ]. ISBN 978-1-4939-0332-0
1851 Increased colonic motor activity is seen postprandially and is referred to by the somewhat misleading term, “gastrocolic refl ex” ISBN 978-1-4939-0332-0
1852 The self-reported prevalence of constipation in African Americans versus Caucasians in the United States is 17.3% versus 12.8%, respectively [ 6 ]. There is no clear explanation for these racial variations [ 4 ]. ISBN 978-1-4939-0332-0
1853 Further, the stress-induced release of catecholamines had been one of the primary mechanisms that had been proposed in PNI-related research to account for the ability of stress to suppress immune responsiveness, and hence increase susceptibility to an infectious challenge (Ader and Cohen 1993; Webster Marketon and Glaser 2008). ISBN: 978-1-4419-5576-0
1854 As has been recognized for many decades, the induction and sustained release of the catecholamines, especially norepinephrine, occurs during many forms of stress extending from psychological to surgical (Fink 2000) ISBN: 978-1-4419-5576-0
1855 The possibility that central stimulant effects of methylxanthines result from competitive antagonism of the depressant effects of endogenous adenosine is appealing for many reasons. ISBN:2742000372
1856 Numerous studies have shown that chronic administration of caffeine or theophylline by intraperitoneal injection (20-100 mg/kg/day), in food (50-600 mg/kg of food), in drinking water (1 g/l), or by implantation (37.5 mg/week), for periods ranging from 1 to 6 weeks, increases the number of adenosine receptors in rat or mouse brain ISBN:2742000372
1857 The stimulant effects of caffeine on the motor activity of mice and rats were demonstrated in the 1930s and 1940 ISBN:2742000372
1858 Use of methylnaltrexone and related compounds for treatment of constipation caused by endogenous opioids Patent: US20040162308
1859 Constipation and Irritable Bowel Syndrome are treated by a delayed and sustained release composition of an opioid antagonist which commences release of the opioid antagonist in the mid to distal small intestine or ascending colon and provides sustained release along any remaining part of the small intestine and along the colon. Preferred opioid antagonists are naloxone and naltrexone. Patent: US6734188
1860 Breakdown of cell wall cellulose is modified by several factors other than its chemical purity. In studies on ruminants the presence of lignin, cutin and silica all impair fermentation,157 while in man the relative resistance of cellulose, and other cell wall polysaccharides, of wheat bran to digestion5 10 12 can be explained partly by its high lignin content relative to other human foods. Bran is about 3% lignin, while most fruit and vegetables contain only one-tenth of this amount.'8 PMC1432575
1861 By contrast, pure cellulose seems to impair absorption of minerals from the gut, when doses of between 10 and 21 g/day are given to healthy volunteers with controlled diets. Faecal excretion of calcium, magnesium, iron, zinc and phosphate are increased and serum calcium, inorganic phosphate and iron concentrations fall.3>32 PMC1432575
1862 In some animal studies cellulose may prevent colon cancer.38 PMC1432575
1863 In studies on ruminants14 purified celluloses are degraded much more slowly than those present in the cell wall and show a 10-15 hour lag before the onset of fermentation, a feature not seen in forage celluloses. PMC1432575
1864 The capacity of colonic microorganisms to digest cellulose in vitro was also tested and in these studies the purified cellulose was virtually indigestible, while that from cabbage was extensively degraded. PMC1432575
1865 Fermentation of cellulose, which requires a complex interaction of micro-organisms,41 eventually produces short chain fatty acids: their importance has been reviewed elsewhere.42 PMC1432575
1866 In 1943 Hummel et a122 noted that digestibility of cellulose was proportional to laxation rate (frequency of defacation), less cellulose being digested in subjects who had more frequent bowel actions. PMC1432575
1867 More recently Southgate and Durnin23 observed that elderly men digested cellulose to a much greater extent than did young men and commented that transit of a marker dye through the gut was slower in the old. PMC1432575
1868 The time that cellulose spends in the gut fermentation chamber, whether that be the rumen, or the large intestine, is therefore important in determining the extent of its breakdown. PMC1432575
1869 This hypothesis has been tested experimentally by Stephen,24 who gave six healthy subjects a controlled diet containing ordinary foods and measured cellulose digestion and mean transit time. She then speeded up transit by giving the volunteers Senakot and found that when transit time fell from 64 hours (control) to 35 hours (+ Senna), cellulose breakdown fell from 72% (control) to 48% (+ Senna). PMC1432575
1870 This is certainly so in rumen studies'4 21 and evidence is also accumulating for this in man. In 1943 Hummel et a122 noted that digestibility of cellulose was proportional to laxation rate (frequency of defacation), less cellulose being digested in subjects who had more frequent bowel actions. PMC1432575
1871 When Heller et al19 fed wheat bran to healthy volunteers at two different particle sizes, the cellulose in the coarse bran was only 6% digested, compared with 23% in the same bran finely ground. PMC1432575
1872 in her study reached a plateau of about 75%. Is there a physiological role for cellulose in the gut? In contrast with other cell-wall polysaccharides, purified cellulose, when given in reasonable quantities does not lower serum cholesterol concentration in man,2527 and only minimally increases faecal bile acid excretion.27 28 Bile acids do not bind to cellulose in vitro.29 PMC1432575
1873 In smooth muscles of the digestive tract activation of A1, receptors by ATP induces inhibition. while activation of A2 receptors evokes excitation. PMC1572235
1874 After 24 hours of culture, we observed a 60% decrease in TNF-a mRNA production in biopsies from CD and UC patients cultured with DALDA 1 or 10 mM compared with non-treated biopsies (fig 6). PMC1856226
1875 Given the increased expression of MOR and the ex vivo beneficial effect of DALDA in active IBD, natural and/or synthetic opioid agonists could help to prevent overt pathological intestinal inflammation PMC1856226
1876 Impaired release of b-endorphin by the gastrointestinal tract and/or by peripheral blood leucocytes have been associated with IBD,37 38 suggesting that chronic inflammation may lead to an exhausted release of b-endorphin or alternatively that MOR activation is somehow critical in IBD development PMC1856226
1877 Recent studies with m opioid receptor (MOR) deficient mice support a physiological anti-inflammatory effect of MOR at the colon interface PMC1856226
1878 Importantly, a mean 6–7-fold increase in MOR expression was observed in inflamed CD ileal and colonic tissues compared with healthy intestine (respectively, 6.5 (2.9) v 0.99 (0.35) (p,0.05) and 7.03 (0.05) v 0.88 (0.39) (p,0.05)). PMC1856226
1879 Incubation with TNF-a significantly upregulated MOR mRNA expression by approximately fivefold compared with untreated Jurkat or THP-1 cells (fig 5A). PMC1856226
1880 Similarly, a 30-fold increase in expression of MOR mRNA levels was observed in inflamed compared with non-inflamed colon of UC patients (30.3 (19.2) v 1.4 (0.4), respectively; p,0.01) (fig 1). PMC1856226
1881 These results suggest that NFkB is involved in the steady state and TNF-a induced MOR expression in monocytes and T cells. PMC1856226
1882 In addition increasing dietary fibre has been shown to worsen symptoms in many patients by causing increased bloating without an improvement in bowel function.6 PMC188368
1883 Adenosine agonists have been shown to be effective in murine models of arthritis [8]. PMC2468887
1884 Murine studies suggest a pivotal role for the A2a and A3 receptors [8] with the administration of adenosine receptor antagonists, caffeine and theophylline, being shown to effectively block the effects of MTX [9]. PMC2468887
1885 Similarly, adenosine receptor 2a (ADORA2a) agonists (e.g. CGS-21680) have anti-inflammatory actions similar to MTX [10]. PMC2468887
1886 Studies suggest that its anti-inflammatory effects are mediated via adenosine release, a potent anti-inflammatory nucleoside [5–7]. PMC2468887
1887 Gastrointestinal: nausea, vomiting or diarrhoea precluding MTX continuation PMC2468887
1888 Our analysis demonstrates an association between five SNPs in the ADORA2a gene and AEs (specifically GI) on MTX. PMC2468887
1889 These inhibit adenosine deaminase and adenosine monophosphate (AMP) deaminase, leading to increased levels of endogenous adenosine [3, 6]. PMC2468887
1890 No association was observed between ADORA2a polymorphisms and MTX inefficacy. PMC2468887
1891 The kappa opioid receptor antagonist reversed the ileal brake so that % recovery increased from 31.9 _+ 6.1% to 69.6 + 7.2% (p< 0.005). Slowing of intestinal transit by fat depends on an opioid pathway acting on kappa receptors. PMC2989736
1892 Of note, a severe IBS-C case with a highly penetrating SCN5A loss-of-function mutation could be successfully treated with mexiletine, a drug known to restore NaV1.5 channel function. PMC4752571
1893 A good example of this phenomenon recently came from a study at the Mayo Clinic in collaboration with our group [13]: sequencing of the SCN5A gene in 584 IBS patients and 1380 asymptomatic controls identified functionally deleterious mutations in 2.2 % of IBS cases but none among controls. PMC4752571
1894 Hence, the association with TNFS15 indicates that inflammatory response may be an important mechanism also in IBS. PMC4752571
1895 Table 1 PMC4752571
1896 The G allele (risk allele for Crohn’s) of rs426839 in TNFSF15 was significantly associated with increased risk of IBS (p = 2.2e-05; OR 1.37) and even more in IBS-C (p = 8.7e-07; OR 1.79). PMC4752571
1897 As a result, the excitatory opioid receptor antagonist treatment enhances the analgesic potency and decreases the undesirable side effects associated with chronic activation by endogenous bimodally-acting opioid peptides, including enkephalins, dynorphins and endorphins, which are markedly upregulated in chronic pain patients (Crain and Shen, 1995). US6194382
1900 [Abstract] 22552247
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1904 CNR1 rs806378 CT/TT was associated with a modest delay in colonic transit at 24 h compared with CC (P = 0.13 for differential treatment effects on postminus pretreatment changes in colonic transit by genotype) 22288893
1905 [Abstract] 24559811
1906 In addition, 62.5 percent of patients in the homeopathic treatment arm (compared to 25.0 percent of those in the usual care arm), achieved a clinically relevant change in irritable bowel symptom severity score, which indicates a promising effect for homeopathic treatment 24931748
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2162 For example, germ-free (GF) mice are resistant to diet-induced obesity [2]. The metabolic mechanisms underlying this resistance include decreased absorption of glucose and generation of short-chain fatty acids from the gut lumen, and the associated reduction in hepatic lipogenesis, increase in fatty acid oxidation and decrease in deposition of triglycerides in adipocytes 21050286
2163 Thirty days after the end of treatment, a 71.3% decrease of the total IBS score was detected in patients with IBS and SIBO compared to 10.6% in those without SIBO (p 0.017). 29508268
2164 [Abstract] 29508268
2165 Although the adverse effects of excess alcohol intake on the liver are established, our results suggest that heavy alcohol consumption (>280 g / week), at least within the extent of intake of the general Japanese population, did not confer a significantly increased risk of FL. 19550408
2166 Excess alcohol intake induces hepatic steatosis through the modification of several signal transduction pathways, including adenosine monophosphate-activated protein kinase and regulatory element binding protein 1 (40,41) . 19550408
2167 Heavy alcohol intake also induces disturbances of the cytokine network, including tumor necrosis factor-alpha and adiponectin (40,42) , which in turn promote systemic inflammatory responses and insulin resistance. 19550408
2168 Indeed, a moderate amount of alcohol ingestion is shown to reduce insulin resistance in animal models (19,24) and in humans (21,22) . 19550408
2169 An Italian study of 257 subjects also showed that the risk of FL was higher by 2.8-fold in heavy (>420 g / week) drinkers compared with non-drinkers among non-obese subjects (12). 19550408
2170 Our results confirmed that VAT is a significant obesity indicator for predicting FL, compared with other obesity indicators, including BMI and waist girth. 19550408
2171 The prevalence of FL was significantly and independently decreased by light and moderate alcohol consumption in men of an asymptomatic Japanese population. 19550408
2172 Conversely, TLR4 polymorphisms (Asp299Gly) that confer decreased responsiveness to LPS [61], [62] increase susceptibility to infection [63], [64]. 22253759
2173 These polymorphisms are strongly associated with a decreased susceptibility to atherosclerosis [65], consistent with the possibility that the decrease in chronic inflammation due to hyporesponsive alleles suppresses atherogenesis. 22253759
2174 Interestingly, these same polymorphisms are associated with increased insulin levels, decreased insulin sensitivity and family history of diabetes [66]. 22253759