AIM:Irritable bowel syndrome(IBS)is a functional bowel disorder characterized by visceral hypersensitivity and altered bowel motility.There is increasing evidence suggesting the role of inflammation in the pathogenesi...AIM:Irritable bowel syndrome(IBS)is a functional bowel disorder characterized by visceral hypersensitivity and altered bowel motility.There is increasing evidence suggesting the role of inflammation in the pathogenesis of IBS,which addresses the possibility that formerly established rat model of colitis could be used as an IBS model after the inflammation subsided. METHODS:Colitis was induced by intracolonic instillation of 4% acetic acid in male Sprague-Dawley rats.The extent of inflammation was assessed by histological examination and myeloperoxidase(MPO)activity assay.After subsidence of colitis,the rats were subjected to rectal distension and restraint stress,then the abdominal withdrawal reflex and the number of stress-induced fecal output were measured, respectively. RESULTS:At 2 days post-induction of colitis,the colon showed characteristic inflammatory changes in histology and 8-fold increase in MPO activity.At 7 days post-induction of colitis,the histological features and MPO activity returned to normal.The rats at 7 days post-induction of colitis showed hypersensitive response to rectal distension without an accompaning change in rectal compliance,and defecated more stools than control animals when under stress.CONCLUSION: These results concur largely with the characteristic features of IBS, visceral hypersensitivity and altered defecation pattern in the absence of detectable disease, suggesting that this animal model is a methodologically convenient and useful model for studying a subset of IBS.展开更多
AIM: Irritable bowel syndrome (IBS) is characterized by abdominal pain and changes in stool habits. Visceral hypersensitivity is a key factor in the pathophysiology of IBS. The aim of this study was to examine the eff...AIM: Irritable bowel syndrome (IBS) is characterized by abdominal pain and changes in stool habits. Visceral hypersensitivity is a key factor in the pathophysiology of IBS. The aim of this study was to examine the effect of rectal balloon-distention stimulus by blood oxygenation leveldependent functional magnetic resonance imaging (BOLDfMRI) in visceral pain center and to compare the distribution,extent, and intensity of activated areas between IBS patients and normal controls.
METHODS: Twenty-six patients with IBS and eleven normal controls were tested for rectal sensation, and the subjective pain intensity at 90 ml and 120 ml rectal balloon-distention was reported by using Visual Analogue Scale. Then, BOLDfMRI was performed at 30 ml, 60 ml, 90 ml, and 120 ml rectal balloon-distention in all subjects.
RESULTS: Rectal distention stimulation increased the activity of anterior cingulate cortex (35/37), insular cortex (37/37),prefrontal cortex (37/37), and thalamus (35/37) in most cases.At 120 ml of rectal balloon-distention, the activation area and percentage change in MR signal intensity of the regions of interest (ROI) at IC, PFC, and THAL were significantly greater in patients with IBS than that in controls. Score of pain sensation at 90 ml and 120 ml rectal balloon-distention was significantly higher in patients with IBS than that in controls.
CONCLUSION: Using fMRI, some patients with IBS can be detected having visceral hypersensitivity in response to painful rectal balloon-distention. fMRI is an objective brain imaging technique to measure the change in regional cerebral activation more precisely. In this study, IC and PFC of the IBS patients were the major loci of the CNS processing of visceral perception.展开更多
AIM: To examine the effects of tegaserod, a serotonin(5-HT) 4 receptor partial agonist, on abdominal withdrawalreflex (AWR) to rectal distention (RD) and c-Fos expressionin limbic system.METHODS: Neonatal Sprague-Dawl...AIM: To examine the effects of tegaserod, a serotonin(5-HT) 4 receptor partial agonist, on abdominal withdrawalreflex (AWR) to rectal distention (RD) and c-Fos expressionin limbic system.METHODS: Neonatal Sprague-Dawley rats randomlyreceived colonic irritation by acetic acid from postnatal day8 to d 21 as a visceral hypersensitive model (group H) or byintrarectal saline as a control group (group C). When theybecame adults, rectal distention (RD) was performed by aballoon (6F; Fogarty arterial embolectomy catheter; length,20 mm; diameter, 2 mm) which was rapidly inflated withincreasing volumes of saline (0.4, 0.8 and 1.2 mL) for 20 sat five-minute intervals. Five subgroups of group H (H-saline,H-vehicle, H-Teg0.1, H-Teg0.3 and H-Tegl.0) were injectedrandomly with saline, vehicle (1-methyl-2-thpyrrolidone) ortegaserod at doses of 0.1, 0.3 and 1.0 mg/kg ip, respectively.Two subgroups of group C (C-Saline and C-Tegl.0) wereinjected with saline or tegaserod (1.0 mg/kg) ip. RD wasperformed 10 rain after injection, AWR was recorded andc-Fos expression in limbic system was analyzed quantitativelyby immunohistochemistry.RESULTS: Compared to saline, tegaserod significantlyinhibited AWR in group H (0.4 mL: from 2.0 to 0.5; 0.8 mL:from 3.5 to 1.5; 1.2 mL: from 4.0 to 3.0, P<0.01), but hadno significant effect on group C. Tegaserod dose-dependentlyattenuated the number of c-Fos positive neurons in limbicstructures, anterior cingulate cortex (ACC) showed thegreatest attenuation. In group H, tegaserod (1.0 mg/kg)resulted in a significant overall decrease to 57% of H-saline(283+41 vs 162+16, P<0.01), in ACC to 42% of H-saline(72+10 vs31+8, P<0.01). In group C, tegaserod (1.0 mg/kg)resulted in an overall decrease to 77% of C-saline (214+13vs 164+22, P<0.01), in ACC to 65% of C-saline (48+8 vs31+7, P<0.01).CONCLUSION: Tegaserod inhibits the response to rectaldistention in rats with visceral hypersensitivity and dose-dependently attenuates c-Fos expression in limbic system,especially in anterior cingulate cortex.展开更多
Objective:The present study aims to evaluate the in vivo efficacy of YINDARA-4 in improving the symptoms of irritable bowel syndrome(IBS)in a rat model and investigate the impact of YINDARA-4 on potential targets of I...Objective:The present study aims to evaluate the in vivo efficacy of YINDARA-4 in improving the symptoms of irritable bowel syndrome(IBS)in a rat model and investigate the impact of YINDARA-4 on potential targets of IBS management,such as the serotonin level in intestinal tissues and the structure and composition of the gut microbiota.Methods:We developed an IBS rat model by combining stress from maternal separation,acetic acid administration,and restraint.We administered YINDARA-4 water extract to the IBS rat model for 10 consecutive days.The fecal water content,visceral sensitivity,gut microbiota,and serotonin levels in the colonic tissue were then analyzed and compared between the control group,IBS model group,and YINDARA-4–treated groups.Results:Treatment with YINDARA-4 reversed visceral hypersensitivity in a dose-dependent manner in the experimental rat model of IBS.The relief of visceral hypersensitivity upon treatment with YINDARA-4 involved regulation of the gut microbiota structure and composition,and normalization of elevated serotonin levels in the colon.The decrease in colonic serotonin levels with YINDARA-4 treatment might be associated with a reduction in the abundance of Helicobacter and enrichment of Butyricimonas.Conclusions:Treatment with YINDARA-4 was beneficial against visceral hypersensitivity in a rat model of IBS.The improved symptoms exhibited in IBS rats were associated with favorably altered gut microbiota and normalization of serotonin levels in the colon.展开更多
Proteases, enzymes catalyzing the hydrolysis of peptide bonds, are present at high concentrations in the gastrointestinal tract. Besides their well-known role in the digestive process, they also function as signaling ...Proteases, enzymes catalyzing the hydrolysis of peptide bonds, are present at high concentrations in the gastrointestinal tract. Besides their well-known role in the digestive process, they also function as signaling molecules through the activation of protease-activated receptors(PARs). Based on their chemical mechanism for catalysis, proteases can be classified into several classes: serine, cysteine, aspartic, metallo- and threonine proteases represent the mammalian protease families. In particular, the class of serine proteases will play a significant role in this review. In the last decades, proteases have been suggested to play a key role in the pathogenesis of visceral hypersensitivity, which is a major factor contributing to abdominal pain in patients with inflammatory bowel diseases and/or irritable bowel syndrome. So far, only a few preclinical animal studies have investigated the effect of protease inhibitors specifically on visceral sensitivity while their effect on inflammation is described in more detail. In our accompanying review we describe their effect on gastrointestinal permeability. On account of their promising results in the field of visceral hypersensitivity, further research is warranted. The aim of this review is to give an overview on the concept of visceral hypersensitivity as well as on the physiological and pathophysiological functions of proteases herein.展开更多
AIM To evaluate the role of P2Y1 R in visceral hypersensitivity in rats with experimental irritable bowel syndrome.METHODS A rat model of irritable bowel syndrome was generated by intra-colonic administration of aceti...AIM To evaluate the role of P2Y1 R in visceral hypersensitivity in rats with experimental irritable bowel syndrome.METHODS A rat model of irritable bowel syndrome was generated by intra-colonic administration of acetic acid(AA) and assessed by histology and myeloperoxidase(m PO) activity assay. Then P2Y1 R expression in the colonic tissue was detected by Western blot. In order to explore the regulatory role of P2Y1 R in visceral hypersensitivity, an agonist(m RS2365) and an antagonist(m RS2179) of P2Y1 R were intra-colonically administered and effects were tested through a colorectal distension test. The abdominal withdrawal reflex and abdominal electromyography were tested during the course. RESULTS model assessment tests showed an obvious inflammatoryreaction that appeared on the 2^(nd) d after the AA injection, and the inflammatory reaction gradually recovered and almost disappeared on the 7^(th) d. The model finished on day 8 and showed a clear feature of IBS that had no organic lesion. The average expression of P2Y1 R was significantly higher in the AA group than in the na?ve group(0.319 ± 0.02 vs 0.094 ± 0.016, P < 0.001). m RS2365 could effectively raise the colonic hypersensitivity status at intervention doses of 10(AUC value from 0.30 ± 0.089 to 1.973 ± 0.127 mv?s, P < 0.01) and 100 μmol/L(AUC value from 0.290 ± 0.079 to 1.983 ± 0.195 mv?s, P < 0.01); m RS2179 could effectively reduce the hypersensitivity status at intervention dose of 100 μmol/L(from a mean baseline AUC value of 1.587 ± 0.099 mv?s to 0.140 ± 0.089 mv?s, P < 0.0001). Differences between the m RS2179 group(1.88 ± 1.45) and either the m RS2365 group(3.96 ± 0.19) or the combined treatment(m RS2179 and m RS2365) group(3.28 ± 0.11) were significant(P < 0.01).CONCLUSION P2Y1 R plays a regulatory role in visceral hypersensitivity in rats with experimental IBS. Specific antagonists of P2Y1 R may have potential therapeutic value in treating abdominal pain in IBS.展开更多
基金the Research Institute of Veterinary Science,College of Veterinary Medieine,Seoul National University
文摘AIM:Irritable bowel syndrome(IBS)is a functional bowel disorder characterized by visceral hypersensitivity and altered bowel motility.There is increasing evidence suggesting the role of inflammation in the pathogenesis of IBS,which addresses the possibility that formerly established rat model of colitis could be used as an IBS model after the inflammation subsided. METHODS:Colitis was induced by intracolonic instillation of 4% acetic acid in male Sprague-Dawley rats.The extent of inflammation was assessed by histological examination and myeloperoxidase(MPO)activity assay.After subsidence of colitis,the rats were subjected to rectal distension and restraint stress,then the abdominal withdrawal reflex and the number of stress-induced fecal output were measured, respectively. RESULTS:At 2 days post-induction of colitis,the colon showed characteristic inflammatory changes in histology and 8-fold increase in MPO activity.At 7 days post-induction of colitis,the histological features and MPO activity returned to normal.The rats at 7 days post-induction of colitis showed hypersensitive response to rectal distension without an accompaning change in rectal compliance,and defecated more stools than control animals when under stress.CONCLUSION: These results concur largely with the characteristic features of IBS, visceral hypersensitivity and altered defecation pattern in the absence of detectable disease, suggesting that this animal model is a methodologically convenient and useful model for studying a subset of IBS.
文摘AIM: Irritable bowel syndrome (IBS) is characterized by abdominal pain and changes in stool habits. Visceral hypersensitivity is a key factor in the pathophysiology of IBS. The aim of this study was to examine the effect of rectal balloon-distention stimulus by blood oxygenation leveldependent functional magnetic resonance imaging (BOLDfMRI) in visceral pain center and to compare the distribution,extent, and intensity of activated areas between IBS patients and normal controls.
METHODS: Twenty-six patients with IBS and eleven normal controls were tested for rectal sensation, and the subjective pain intensity at 90 ml and 120 ml rectal balloon-distention was reported by using Visual Analogue Scale. Then, BOLDfMRI was performed at 30 ml, 60 ml, 90 ml, and 120 ml rectal balloon-distention in all subjects.
RESULTS: Rectal distention stimulation increased the activity of anterior cingulate cortex (35/37), insular cortex (37/37),prefrontal cortex (37/37), and thalamus (35/37) in most cases.At 120 ml of rectal balloon-distention, the activation area and percentage change in MR signal intensity of the regions of interest (ROI) at IC, PFC, and THAL were significantly greater in patients with IBS than that in controls. Score of pain sensation at 90 ml and 120 ml rectal balloon-distention was significantly higher in patients with IBS than that in controls.
CONCLUSION: Using fMRI, some patients with IBS can be detected having visceral hypersensitivity in response to painful rectal balloon-distention. fMRI is an objective brain imaging technique to measure the change in regional cerebral activation more precisely. In this study, IC and PFC of the IBS patients were the major loci of the CNS processing of visceral perception.
文摘AIM: To examine the effects of tegaserod, a serotonin(5-HT) 4 receptor partial agonist, on abdominal withdrawalreflex (AWR) to rectal distention (RD) and c-Fos expressionin limbic system.METHODS: Neonatal Sprague-Dawley rats randomlyreceived colonic irritation by acetic acid from postnatal day8 to d 21 as a visceral hypersensitive model (group H) or byintrarectal saline as a control group (group C). When theybecame adults, rectal distention (RD) was performed by aballoon (6F; Fogarty arterial embolectomy catheter; length,20 mm; diameter, 2 mm) which was rapidly inflated withincreasing volumes of saline (0.4, 0.8 and 1.2 mL) for 20 sat five-minute intervals. Five subgroups of group H (H-saline,H-vehicle, H-Teg0.1, H-Teg0.3 and H-Tegl.0) were injectedrandomly with saline, vehicle (1-methyl-2-thpyrrolidone) ortegaserod at doses of 0.1, 0.3 and 1.0 mg/kg ip, respectively.Two subgroups of group C (C-Saline and C-Tegl.0) wereinjected with saline or tegaserod (1.0 mg/kg) ip. RD wasperformed 10 rain after injection, AWR was recorded andc-Fos expression in limbic system was analyzed quantitativelyby immunohistochemistry.RESULTS: Compared to saline, tegaserod significantlyinhibited AWR in group H (0.4 mL: from 2.0 to 0.5; 0.8 mL:from 3.5 to 1.5; 1.2 mL: from 4.0 to 3.0, P<0.01), but hadno significant effect on group C. Tegaserod dose-dependentlyattenuated the number of c-Fos positive neurons in limbicstructures, anterior cingulate cortex (ACC) showed thegreatest attenuation. In group H, tegaserod (1.0 mg/kg)resulted in a significant overall decrease to 57% of H-saline(283+41 vs 162+16, P<0.01), in ACC to 42% of H-saline(72+10 vs31+8, P<0.01). In group C, tegaserod (1.0 mg/kg)resulted in an overall decrease to 77% of C-saline (214+13vs 164+22, P<0.01), in ACC to 65% of C-saline (48+8 vs31+7, P<0.01).CONCLUSION: Tegaserod inhibits the response to rectaldistention in rats with visceral hypersensitivity and dose-dependently attenuates c-Fos expression in limbic system,especially in anterior cingulate cortex.
基金funded by the foundation of the Key Laboratory of Ethnomedicine(Minzu University of China),the Ministry of Education(KLEM-ZZ201903,KLEM-ZZ2020GD01)the Natural Science Foundation of Ningxia(2021AAC03358)funded by the National Natural Science Foundation of China(81901682)
文摘Objective:The present study aims to evaluate the in vivo efficacy of YINDARA-4 in improving the symptoms of irritable bowel syndrome(IBS)in a rat model and investigate the impact of YINDARA-4 on potential targets of IBS management,such as the serotonin level in intestinal tissues and the structure and composition of the gut microbiota.Methods:We developed an IBS rat model by combining stress from maternal separation,acetic acid administration,and restraint.We administered YINDARA-4 water extract to the IBS rat model for 10 consecutive days.The fecal water content,visceral sensitivity,gut microbiota,and serotonin levels in the colonic tissue were then analyzed and compared between the control group,IBS model group,and YINDARA-4–treated groups.Results:Treatment with YINDARA-4 reversed visceral hypersensitivity in a dose-dependent manner in the experimental rat model of IBS.The relief of visceral hypersensitivity upon treatment with YINDARA-4 involved regulation of the gut microbiota structure and composition,and normalization of elevated serotonin levels in the colon.The decrease in colonic serotonin levels with YINDARA-4 treatment might be associated with a reduction in the abundance of Helicobacter and enrichment of Butyricimonas.Conclusions:Treatment with YINDARA-4 was beneficial against visceral hypersensitivity in a rat model of IBS.The improved symptoms exhibited in IBS rats were associated with favorably altered gut microbiota and normalization of serotonin levels in the colon.
基金Supported by University Research Fund Doctoral Projects(BOF-DOCPRO),No.DOCPRO4 2014/ID 2964Research Foundation Flanders(FWO),No.G034113N
文摘Proteases, enzymes catalyzing the hydrolysis of peptide bonds, are present at high concentrations in the gastrointestinal tract. Besides their well-known role in the digestive process, they also function as signaling molecules through the activation of protease-activated receptors(PARs). Based on their chemical mechanism for catalysis, proteases can be classified into several classes: serine, cysteine, aspartic, metallo- and threonine proteases represent the mammalian protease families. In particular, the class of serine proteases will play a significant role in this review. In the last decades, proteases have been suggested to play a key role in the pathogenesis of visceral hypersensitivity, which is a major factor contributing to abdominal pain in patients with inflammatory bowel diseases and/or irritable bowel syndrome. So far, only a few preclinical animal studies have investigated the effect of protease inhibitors specifically on visceral sensitivity while their effect on inflammation is described in more detail. In our accompanying review we describe their effect on gastrointestinal permeability. On account of their promising results in the field of visceral hypersensitivity, further research is warranted. The aim of this review is to give an overview on the concept of visceral hypersensitivity as well as on the physiological and pathophysiological functions of proteases herein.
基金Supported by MIMS(Shanghai)Ltd.of China,No.IDF-2013-07
文摘AIM To evaluate the role of P2Y1 R in visceral hypersensitivity in rats with experimental irritable bowel syndrome.METHODS A rat model of irritable bowel syndrome was generated by intra-colonic administration of acetic acid(AA) and assessed by histology and myeloperoxidase(m PO) activity assay. Then P2Y1 R expression in the colonic tissue was detected by Western blot. In order to explore the regulatory role of P2Y1 R in visceral hypersensitivity, an agonist(m RS2365) and an antagonist(m RS2179) of P2Y1 R were intra-colonically administered and effects were tested through a colorectal distension test. The abdominal withdrawal reflex and abdominal electromyography were tested during the course. RESULTS model assessment tests showed an obvious inflammatoryreaction that appeared on the 2^(nd) d after the AA injection, and the inflammatory reaction gradually recovered and almost disappeared on the 7^(th) d. The model finished on day 8 and showed a clear feature of IBS that had no organic lesion. The average expression of P2Y1 R was significantly higher in the AA group than in the na?ve group(0.319 ± 0.02 vs 0.094 ± 0.016, P < 0.001). m RS2365 could effectively raise the colonic hypersensitivity status at intervention doses of 10(AUC value from 0.30 ± 0.089 to 1.973 ± 0.127 mv?s, P < 0.01) and 100 μmol/L(AUC value from 0.290 ± 0.079 to 1.983 ± 0.195 mv?s, P < 0.01); m RS2179 could effectively reduce the hypersensitivity status at intervention dose of 100 μmol/L(from a mean baseline AUC value of 1.587 ± 0.099 mv?s to 0.140 ± 0.089 mv?s, P < 0.0001). Differences between the m RS2179 group(1.88 ± 1.45) and either the m RS2365 group(3.96 ± 0.19) or the combined treatment(m RS2179 and m RS2365) group(3.28 ± 0.11) were significant(P < 0.01).CONCLUSION P2Y1 R plays a regulatory role in visceral hypersensitivity in rats with experimental IBS. Specific antagonists of P2Y1 R may have potential therapeutic value in treating abdominal pain in IBS.
