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Recently, covering materials for protecting post-endoscopic ulcers are being developed using hydrogels. Existing hydrogels are not ideal coating materials because it is difficult to control their physical properties. Therefore, we conducted an animal pilot study to investigate the protective effect of a novel ulcer coating material, whose physical properties can be easily controlled and designed. We applied the novel injectable hydrogel to artificial ulcers induced on the gastric mucosa of rats. Rats were assigned to the hydrogel or the control group. To measure the protective effect of hydrogel on ulcers, the perforation rate, ulcer diameter, and ulcer area were evaluated 48 h after gel application. As secondary endpoints, we assessed the residual rate of the hydrogel at the bottom of the ulcer, performed histological analysis, and analyzed adverse events associated with hydrogel. The perforation rate was significantly lower (16% vs. 75%) and the mean diameter of ulcers was significantly smaller (5.4 ± 1.8 mm vs. 7.8 ± 2.8 mm) in the hydrogel group. Histopathological findings revealed the inflammatory cell count was significantly higher in the control group. Our novel hydrogel showed a protective effect on artificial gastric ulcers in a rat model.

Intraperitoneal administration of hydrogen (H 2 )-containing saline inhibited neuronal cell death in ischemic stroke in a number of animal models, but it is unknown whether H 2 is absorbed from the abdominal cavity into the blood and reaches the brain. In this study, we investigated whether intraperitoneal administration of saline containing H 2 inhibits neuronal cell death caused by cerebral ischemia and measured the concentration of H 2 in the carotid artery and inferior vena cava (IVC). Gerbils were subjected to transient unilateral cerebral ischemia twice, and saline or H 2 -rich saline was administered intraperitoneally three or seven times every 12 hours. We evaluated the number of apoptotic cells in the hippocampus and cerebral cortex on day 3 and the number of viable neurons in the hippocampus and cerebral cortex on day 7. In addition, a single dose of saline or H 2 -rich saline was administered intraperitoneally, and blood H 2 levels in the carotid artery and IVC were measured. On day 3 of ischemia/reperfusion, the number of neurons undergoing apoptosis in the cortex was significantly lower in the H 2 -rich saline group than in the saline group, and on day 7, the number of viable neurons in the hippocampus and cerebral cortex was significantly higher in the H 2 -rich saline group. Intraperitoneal administration of H 2 -rich saline resulted in large increases in H 2 concentration in the IVC ranging from 0.00183 mg/L (0.114%) to 0.00725 mg/L (0.453%). In contrast, carotid H 2 concentrations remained in the range of 0.00008 mg/L (0.0049%) to 0.00023 (0.0146%). On average, H 2 concentrations in carotid artery were 0.04 times lower than in IVC. These results indicate that intraperitoneal administration of H 2 -rich saline significantly suppresses neuronal cell death after cerebral ischemia, even though H 2 hardly reaches the brain.

A recent clinical study demonstrated that haemodialysis with a dialysate containing hydrogen (H 2 ) improves blood pressure control in end-stage kidney disease. Herein, we examined whether H 2 has a salutary effect on hypertension in animal models. We subjected 5/6 nephrectomised rats to inhalation of either H 2 (1.3% H 2  + 21% O 2  + 77.7% N 2 ) or control (21% O 2  + 79% N 2 ) gas mixture for 1 h per day. H 2 significantly suppressed increases in blood pressure after 5/6 nephrectomy. The anti-hypertensive effect of H 2 was also confirmed in rats in a stable hypertensive state 3 weeks after nephrectomy. To examine the detailed effects of H 2 on hypertension, we used an implanted telemetry system to continuously monitor blood pressure. H 2 exerted an anti-hypertensive effect not only during daytime rest, but also during night-time activities. Spectral analysis of blood pressure variability revealed that H 2 improved autonomic imbalance, namely by suppressing the overly active sympathetic nervous system and augmenting parasympathetic nervous system activity; these effects co-occurred with the blood pressure-lowering effect. In conclusion, 1-h daily exposure to H 2 exerts an anti-hypertensive effect in an animal model of hypertension.

Background The cholinergic anti-inflammatory pathway is a novel physiological mechanism found at various locations in the body where the nicotinic regulation of inflammatory cells through the autonomic nervous system is involved. In this study, we tested the hypothesis that cholinergic nerve stimulation by a 5-HT₄ agonist may modulate the progression of gastric mucosal ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs). Methods Acute gastric ulcers were induced in rats by the oral administration of indomethacin. Results Gastric damage analysis indicated that pretreatment with mosapride, a selective 5-HT₄ agonist, at 0.25, 0.5, and 0.75 mg/kg, inhibited the mucosal damage induced by indomethacin. In gastric emptying analysis, an evacuation effect was observed in the 3.0 mg/kg mosapride pretreatment group, but this effect was not observed in the lower dose (0.5 mg/kg) group. The antiulcerogenic activity of mosapride treatment (at 0.5 mg/kg) was blocked by a 5-HT₄-specific antagonist, GR113808 (1 mg/kg, i.v.). Additionally, we demonstrated that methyllycaconitine (0.29 and 0.87 mg/kg i.p.), a selective inhibitor of α7 nicotinic acetylcholine (ACh) receptors (α7nAChRs), ablated the antiulcerogenic action of mosapride. Conclusions These results suggest that the mucosal protective action of mosapride may be mediated by an action on immune cells through the acceleration of ACh release from parasympathetic nerves via the activation of 5-HT₄ receptors, followed by activation of the nicotinic anti-inflammatory system. It appears that the α7nAChR may be involved in the antiulcerogenic action of mosapride.

Background Chronic intestinal inflammation is frequently accompanied by motility disorders. We previously reported that proinflammatory cytokines, such as tumor necrosis factor α and interleukin (IL)-1β downregulate CPI-17, an endogenous inhibitor of serine/threonine protein phosphatase in smooth-muscle cells, which results in the inhibition of myosin light chain phosphorylation and contractility. However, its clinical relevance has not been clarified. Methods The present study examined the changes in CPI-17 expression in chronic intestinal inflammation using smooth-muscle tissues from IL-10 knockout mice and from patients with ulcerative colitis (UC). Results The IL-10 knockout mice developed spontaneous and chronic colitis accompanied by immune cell infiltration, submucosal fibrosis, and thickening of the muscularis externa. The expression of α-smooth muscle actin protein in the smooth-muscle layer did not change, whereas that of CPI-17 protein was decreased by about 40% compared with healthy wild-type controls. Consistent with this observation, smooth-muscle contractile force and myosin light chain phosphorylation induced by a muscarinic agonist were reduced in the knockout mice. Moreover, we observed that CPI-17 protein expression was decreased in smooth-muscle tissues from patients with UC compared with controls. Conclusions CPI-17 downregulation might contribute to the decreased motor function in chronic inflammatory bowel diseases.

BackgroundThe main symptom of postoperative ileus (POI) is an intestinal motility disorder in which monocytes/macrophages and neutrophils play crucial roles. Prokinetic 5-hydroxytryptamine 4 receptor (5-HT4R) agonists and dopamine receptor antagonists are potential therapeutic agents for directly ameliorating the motility disorder associated with POI.AimTo determine the effects of the 5-HT4R agonists mosapride citrate (MOS) and CJ-033466 on intestinal smooth muscle contractility relative to immune reactions after POI.MethodsIntestinal manipulation (IM) was applied to the rat distal ileum. Both MOS (0.3 and 1 mg/kg, s.c.) and CJ-033466 (1 mg/kg, s.c.) were administered to the animals before and after IM. At 24 h after IM, isolated intestinal smooth muscle contractile activity in vitro, gastrointestinal transit in vivo, inflammatory mediator expression and leucocyte infiltration were measured.ResultsAfter IM, ileal circular muscle contractility in vitro and gastrointestinal transit in vivo were reduced and the number of macrophages and neutrophils increased in the inflamed muscle layer, resulting in the induction of inflammatory mediators such as interleukin 1 β (IL-1β), IL-6, tumour necrosis factor α (TNFα), monocyte chemoattractant protein 1 (MCP-1) and inducible nitric oxide synthase (iNOS). Both MOS and CJ-033466 significantly attenuated not only the intestinal motility dysfunction but also the leucocyte infiltration and inflammatory mediator expression after IM. The autonomic ganglionic blocker hexamethonium (1 mg/kg, i.p.) and the α7-nicotinic acetylcholine receptor (α7nAChR) antagonist methyl lycaconitine citrate (0.087 mg/kg, i.p.) blocked MOS-mediated ameliorative actions. Immunohistochemically, α7nAChR is expressed by monocytes/macrophages but not by neutrophils in the inflamed intestine.ConclusionStimulating the 5-HT4R accelerates acetyl choline (ACh) release from cholinergic myenteric neurons, which subsequently activates α7nAChR on activated monocytes/macrophages to inhibit their inflammatory reactions in the muscle layer. In addition to their gastroprokinetic action, 5-HT4R agonists might serve as novel therapeutic agents for POI characterised by anti-inflammatory potency.

BACKGROUND: The main symptom of postoperative ileus (POI) is an intestinal motility disorder in which monocytes/macrophages and neutrophils play crucial roles. Prokinetic 5-hydroxytryptamine 4 receptor (5-HT4R) agonists and dopamine receptor antagonists are potential therapeutic agents for directly ameliorating the motility disorder associated with POI. AIM: To determine the effects of the 5-HT4R agonists mosapride citrate (MOS) and CJ-033466 on intestinal smooth muscle contractility relative to immune reactions after POI. METHODS: Intestinal manipulation (IM) was applied to the rat distal ileum. Both MOS (0.3 and 1 mg/kg, s.c.) and CJ-033466 (1 mg/kg, s.c.) were administered to the animals before and after IM. At 24 h after IM, isolated intestinal smooth muscle contractile activity in vitro, gastrointestinal transit in vivo, inflammatory mediator expression and leucocyte infiltration were measured. RESULTS: After IM, ileal circular muscle contractility in vitro and gastrointestinal transit in vivo were reduced and the number of macrophages and neutrophils increased in the inflamed muscle layer, resulting in the induction of inflammatory mediators such as interleukin 1 beta (IL-1 beta ), IL-6, tumour necrosis factor alpha (TNF alpha ), monocyte chemoattractant protein 1 (MCP-1) and inducible nitric oxide synthase (iNOS). Both MOS and CJ-033466 significantly attenuated not only the intestinal motility dysfunction but also the leucocyte infiltration and inflammatory mediator expression after IM. The autonomic ganglionic blocker hexamethonium (1 mg/kg, i.p.) and the alpha 7-nicotinic acetylcholine receptor ( alpha 7nAChR) antagonist methyl lycaconitine citrate (0.087 mg/kg, i.p.) blocked MOS-mediated ameliorative actions. Immunohistochemically, alpha 7nAChR is expressed by monocytes/macrophages but not by neutrophils in the inflamed intestine. CONCLUSION: Stimulating the 5-HT4R accelerates acetyl choline (ACh) release from cholinergic myenteric neurons, which subsequently activates alpha 7nAChR on activated monocytes/macrophages to inhibit their inflammatory reactions in the muscle layer. In addition to their gastroprokinetic action, 5-HT4R agonists might serve as novel therapeutic agents for POI characterised by anti-inflammatory potency.

Resident macrophages are distributed in the network of interstitial cells of Cajal (ICC) and the myenteric nerve within the myenteric plexus. We evaluated changes in chemoattractant protein mRNA expression in macrophages and neutrophils, the ICC, nerve and macrophages in the myenteric plexus of model rats with TNBS-induced colitis. Chemoattractant proteins, MCP-1, GRO, MIP-2 and CINC-2alpha were upregulated in the colonic muscle layer after inflammation. Leukocyte infiltration and MPO activity were increased in the muscle layer. Electron microscopy indicated an irregular contour of the myenteric ganglia into which numerous macrophages had penetrated. Macrophages were also distributed near the ICC in the inflamed myenteric plexus. Immunohistochemistry showed that the ICC network and myenteric nerve system had disappeared from the inflamed region, whereas the number of resident macrophages was increased. TTX-insensitive, possibly ICC-mediated, rhythmic contractions of circular smooth muscle strips and enteric neuron-mediated TTX-sensitive peristalsis in the whole proximal colon tissue were significantly inhibited in the inflamed colon, indicating that the ICC-myenteric nerve system was dysfunctional in the inflamed muscle layer. Their accumulation around the myenteric nerve plexus and the ICC network suggests that macrophages play an important role in inducing intestinal dysmotility in gut inflammation.

The cholinergic anti-inflammatory pathway is a novel physiological mechanism found at various locations in the body where the nicotinic regulation of inflammatory cells through the autonomic nervous system is involved. In this study, we tested the hypothesis that cholinergic nerve stimulation by a 5-HT.sub.4 agonist may modulate the progression of gastric mucosal ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs). Acute gastric ulcers were induced in rats by the oral administration of indomethacin. Gastric damage analysis indicated that pretreatment with mosapride, a selective 5-HT.sub.4 agonist, at 0.25, 0.5, and 0.75 mg/kg, inhibited the mucosal damage induced by indomethacin. In gastric emptying analysis, an evacuation effect was observed in the 3.0 mg/kg mosapride pretreatment group, but this effect was not observed in the lower dose (0.5 mg/kg) group. The antiulcerogenic activity of mosapride treatment (at 0.5 mg/kg) was blocked by a 5-HT.sub.4-specific antagonist, GR113808 (1 mg/kg, i.v.). Additionally, we demonstrated that methyllycaconitine (0.29 and 0.87 mg/kg i.p.), a selective inhibitor of [alpha]7 nicotinic acetylcholine (ACh) receptors ([alpha]7nAChRs), ablated the antiulcerogenic action of mosapride. These results suggest that the mucosal protective action of mosapride may be mediated by an action on immune cells through the acceleration of ACh release from parasympathetic nerves via the activation of 5-HT.sub.4 receptors, followed by activation of the nicotinic anti-inflammatory system. It appears that the [alpha]7nAChR may be involved in the antiulcerogenic action of mosapride.