American journal of physiology. Gastrointestinal and liver physiology最新文献

{"title":"Ion transport and epithelial barrier dysfunction in experimental models of ulcerative colitis.","authors":"Geoffrey I Sandle, Vazhaikkurich M Rajendran","doi":"10.1152/ajpgi.00204.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00204.2024","url":null,"abstract":"<p><p>The global prevalence of ulcerative colitis (UC) and Crohn's disease (CD) is increasing, placing greater burdens on national health systems. The pathophysiology of diarrhea, the commonest debilitating symptom in UC and CD patients, has been studied more extensively in UC, where it reflects defective colonic Na⁺ absorption combined with changes in colonic Cl^- and K⁺ transport which greatly reduce colonic water absorption. Dysfunctional ion transport in patients with UC is accompanied by abnormalities in tight junctional protein distribution and function, which cause the inflamed colonic epithelium to become 'leakier'. Progress in understanding how abnormal colonic ion transport in UC might be influenced pharmacologically has been hampered by the low availability of clinical material. To counter this, various animal models of acute colitis have been developed, but differ in the way mucosal inflammation is induced. Identifying models that closely mimic human UC in terms of pathology and ion transport abnormalities remains challenging. However, the introduction of human colonic epithelial organoids (colonoids) has added a new and exciting dimension to research in this area. Here, we review current knowledge about abnormal colonic ion transport and barrier function in experimental and human colitis as well as the use and potential of human colonoids to better understand the pathophysiology of UC, which may ultimately lead to novel approaches to the treatment of diarrhea in this disease.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143784478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of potassium on laryngeal induced swallowing rate in rats.","authors":"Satomi Kawada, Titi Chotirungsan, Charng-Rong Pan, Yuhei Tsutsui, Keiichiro Okamoto, Jin Magara, Takanori Tsujimura, Makoto Inoue","doi":"10.1152/ajpgi.00012.2025","DOIUrl":"https://doi.org/10.1152/ajpgi.00012.2025","url":null,"abstract":"<p><p>The swallowing reflex can be induced by peripheral stimulation of the larynx. Although previous studies have suggested that potassium ions exert facilitatory effects on the initiation of swallowing, little information is available on the mechanism underlying the potassium ion-evoked swallowing reflex. In this study, we evaluated the effects of potassium ions on peripheral afferent responses and the initiation of swallowing in conscious and anesthetized rats. Furthermore, the possible receptors involved were explored. The topical application of potassium chloride (KCl) significantly facilitated the swallowing reflex; these facilitatory effects were more prominent than those of distilled water (DW) or sodium chloride (NaCl). This phenomenon depended not on the concentrations of anions but on those of potassium ions. The potassium ion-induced response in the superior laryngeal nerve was most prominent after treatment with KCl, especially at the early stage. In chronic rats, without differences in licking behavior between DW, NaCl, and KCl, the intervals between swallows were the smallest during KCl-associated licking. Inward rectifier potassium channel (Kir)3.1- and Kir6.2-positive cells were detected in the nodose ganglion and vocal folds. The rate of expression of these molecules in immunoreactive cells was relatively high at 74.1% for Kir3.1 and 75.3% for Kir6.2. Kir3.1- and Kir6.2- blockers significantly decreased the number of KCl-induced swallows. Possible mechanisms underlying potassium ion-induced swallowing are discussed. Our findings suggest that Kir3.1 and Kir6.2 are involved in K ion-induced swallowing in rats.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deletion of H-ferritin in macrophages mitigates the development of steatohepatitis and hepatocellular carcinoma in mice.","authors":"Yasumasa Ikeda, Masafumi Funamoto, Haruka Itami, Mizuho Yamamoto, Hai Du Ly-Nguyen, Masaki Imanishi, Koichiro Tsuchiya","doi":"10.1152/ajpgi.00328.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00328.2024","url":null,"abstract":"<p><strong>Background: </strong>Nonalcoholic fatty liver disease (NAFLD) is an increasing global health concern. Approximately one-quarter of patients have non-alcoholic steatohepatitis (NASH), which leads to the development of hepatocellular carcinoma. Several studies have shown the involvement of iron in NASH, but it remains unclear which cell of iron is at issue.</p><p><strong>Aim: </strong>To explore the role of iron in macrophages in NASH development.</p><p><strong>Methods: </strong>Conditional macrophage-specific H-ferritin knockout (LysM-Cre <i>Fth</i>KO) mice were divided into four groups: wild-type (WT) and LysM-Cre <i>Fth</i>KO mice fed a normal diet, and WT and LysM-Cre <i>Fth</i>KO mice with NASH model induced by diet and chemical.</p><p><strong>Results: </strong>Histological analysis revealed that the NAS score and hepatic fibrosis were alleviated in the livers of LysM-Cre <i>Fth</i>KO mice with NASH compared with WT mice with NASH. The expression and signaling of inflammatory cytokines and fibrosis-related genes were increased in the livers of WT mice with NASH, but not elevated in the livers of LysM-Cre <i>Fth</i>KO mice with NASH. Similarly, macrophage infiltration and oxidative stress were augmented in the livers of WT mice with NASH but were inhibited in the livers of LysM-Cre <i>Fth</i>KO mice with NASH. Additionally, hepatocellular carcinoma development was observed in 90% of WT mice and 62% of LysM-Cre <i>Fth</i>KO mice 30 weeks after NASH induction, with tumor number and size being lower in LysM-Cre <i>Fth</i>KO mice.</p><p><strong>Conclusions: </strong>Deletion of macrophage FTH alleviated NASH development by reducing inflammation, fibrosis, and oxidative stress. The findings of this study highlight macrophage iron levels as a potential therapeutic target in NASH.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic balance of human livers during long-term normothermic machine perfusion.","authors":"Bianca Lascaris, Linda C Woltjes, Silke Bodewes, Robert J Porte, Vincent E de Meijer, Maarten W Nijsten","doi":"10.1152/ajpgi.00404.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00404.2024","url":null,"abstract":"<p><p><b>Background & Aims:</b> Normothermic machine perfusion (NMP) is used to preserve and assess the viability of (extended criteria) high-risk donor livers. Long-term NMP (LT-NMP; ≥24h) is emerging as a method to improve or repair livers initially deemed unsuitable for transplantation. This study investigated metabolism during LT-NMP, focusing on hepatic energy consumption and nitrogen and electrolyte balances to better understand long-term perfusion requirements. <b>Methods:</b> In this study, we measured oxygen consumption (V̇ CO2) and carbon dioxide production (V̇ O₂) to determine the energy expenditure of 14 human livers during LT NMP for 7 days. Additionally, hepatic balances of glucose and lactate, as well as of nitrogen and electrolytes were determined. <b>Results:</b> Initial high metabolic rates during the first day of LT-NMP decreased and stabilized at nearly 50% on day 3, suggesting a quiescent state until day 7. Most energy was derived from glucose (75-88%). Continuous amino acid supplementation was essential to maintain an anabolic state, whereas livers without supplementation became catabolic. While net electrolyte balances were close to zero, significant uptake and release of electrolytes occurred throughout LT-NMP. <b>Conclusions:</b> During LT-NMP, livers reached a metabolically quiescent state after 3 days with decreased energy consumption. Tailoring perfusate composition and supplementation protocols to the specific needs of the liver could enhance organ preservation and potentially expand the pool of viable donor livers after LT-NMP.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mass cytometric analysis of circulating monocyte subsets in a murine model of diabetic gastroparesis.","authors":"Shefaa AlAsfoor, Erik Jessen, Suraj R Pullapantula, Jennifer R Voisin, Linda C Hsi, Kevin D Pavelko, Samera Farwana, Jack A Patraw, Xin-Yi Chai, Sihan Ji, Michael A Strausbauch, Gianluca Cipriani, Lai Wei, David R Linden, Ruixue Hou, Richard Myers, Yogesh Bhattarai, Jill Wykosky, Alan J Burns, Surendra Dasari, Gianrico Farrugia, Madhusudan Grover","doi":"10.1152/ajpgi.00229.2024","DOIUrl":"10.1152/ajpgi.00229.2024","url":null,"abstract":"<p><p>Circulating monocytes (Mo) are precursors to a subset of gastric resident muscularis macrophages. Changes in muscularis macrophages (MMs) result in delayed gastric emptying (DGE) in diabetic gastroparesis. However, the dynamics of Mo in the development of DGE in an animal model are unknown. Using cytometry by time-of-flight and computational approaches, we show a high heterogeneity within the Mo population. In DGE mice, via unbiased clustering, we identified two reduced Mo clusters that exhibit migratory phenotype (Ly6C^hiCCR2^hi-intCD62L^hiLy6G^hiCD45R^hiMERTK^hiintLGALS3^intCD14^intCX3CR1^lowSiglec-H^int-low) resembling classical Mo (CMo-like). All markers enriched in these clusters are known to regulate cell differentiation, proliferation, adhesion, and migration. Trajectory inference analysis predicted these Mo as precursors to subsequent Mo lineages. In gastric muscle tissue, we demonstrated an increase in the gene expression levels of chemokine receptor C-C chemokine receptor type 2 (<i>Ccr2</i>) and its C-C motif ligand 2 (<i>Ccl2</i>), suggesting increased trafficking of classical-Mo. These findings establish a link between two CMo-like clusters and the development of the DGE phenotype and contribute to a better understanding of the heterogenicity of the Mo population.<b>NEW & NOTEWORTHY</b> Using 32 immune cell surface markers, we identified 23 monocyte clusters in murine blood. Diabetic gastroparesis was associated with a significant decrease in two circulating classical monocyte-like clusters and an upregulation of the <i>Ccr2-Ccl2</i> axis in the gastric muscularis propria, suggesting increased tissue monocyte migration. This study offers new targets by pointing to a possible role for two classical monocyte subsets connected to the <i>Ccr2</i>-<i>Ccl2</i> axis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G323-G341"},"PeriodicalIF":3.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of corticotropin-release hormone on duodenal permeability and immune activation in healthy volunteers in a double-blind placebo-controlled study.","authors":"Jolien Schol, I-Hsuan Huang, Lukas Balsiger, Joran Tóth, Karen Van den Houte, Annelies Verheyden, Karlien Raymenants, Bert Broeders, Tim Vanuytsel, Jan Tack","doi":"10.1152/ajpgi.00130.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00130.2024","url":null,"abstract":"<p><p><b>Introduction:</b> In functional dyspepsia, increased gut permeability, low-grade inflammation and altered sensorimotor function have been reported. Both stress and corticotropin-release hormone(CRH) have been shown to increase small bowel permeability in a mast-cell dependent fashion. Moreover, eosinophil-derived CRH has been implicated in mast-cell activation. The aim of this study was to evaluate whether CRH administration alters duodenal permeability and immune activation in healthy volunteers(HVs). <b>Methods:</b> An intravenous bolus of 100μg CRH or placebo was administered in HVs in a crossover, double-blind, randomized fashion. Two hours later, a gastroscopy was performed to measure permeability in Ussing chambers and to count mast-cells and eosinophils on duodenal biopsies. Supernatant was assessed for eosinophil-derived neurotoxin(EDN), tryptase and chymase. In addition, CRH was administrated ex-vivo to baseline biopsies pretreated with or without lodoxamide. Results are described as mean±SD. p-values<0.05 were considered significant. <b>Results:</b> Twenty HVs completed the study. Mast-cell or eosinophil counts were not significantly altered after CRH versus placebo(respectively p=0.31 and p=0.069). Tryptase but not chymase, significantly decreased after CRH (resp. p=0.037 and p=0.44) with a trend for a decrease in EDN(p=0.053). Permeability was unaltered comparing both conditions. Ex-vivo, transepithelial electrical resistance significantly decreased after CRH exposure compared to baseline(p=0.010), which was not prevented by pre-treatment with lodoxamide. <b>Conclusion:</b> In-vivo CRH administration reduced tryptase levels in supernatant of duodenal biopsies without affecting permeability, whereas ex-vivo duodenal permeability increased regardless of mast51 cell stabilization. These results suggest the involvement of mast-cells in regulating gut permeability in HVs in response to CRH, possibly influenced by in-vivo compensatory mechanisms.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progressive impairment in gastric and duodenal slow waves and autonomic function during progression of type 2 diabetes in rats.","authors":"Gaojue Wu, Fei Li, Yan Li, Shiying Li, Md Jahangir Alam, Jiande D Z Chen","doi":"10.1152/ajpgi.00278.2024","DOIUrl":"10.1152/ajpgi.00278.2024","url":null,"abstract":"<p><p>The abnormalities of gastrointestinal (GI) slow waves play key roles in the pathophysiology of diabetic gastroparesis, which is highly prevalent in type 2 diabetes (T2D). Although relatively well-investigated in diabetic enteric neuropathy, abnormalities and progressive impairments of gastric slow waves (GSWs) and duodenal slow waves (DSWs) are underinvestigated during the progression of T2D. The aim of this study was to explore alterations in GSW and DSW during the development of diabetes induced by high-fat diet (HFD) followed by a low dose of streptozotocin (STZ). Weekly recordings of slow waves from healthy, prediabetic to diabetes stages exhibited a progressively decreased percentage of normal slow waves (%NSW) starting after HFD feeding (prediabetic stage) in the fasting state and starting after STZ injection (diabetic stage) in the postprandial state. The postprandial increase in the power of slow waves observed in normal control rats was absent starting from 2 wk after HFD and persisted after STZ. The mechanism might be attributed to both progressively increased blood glucose (BG) and impaired autonomic function in view of the following results: <i>1</i>) the %NSW was negatively correlated with the fasting BG; <i>2</i>) during the oral glucose tolerance test, %NSW of DSW and BG exhibited a positive correlation in rats with hemoglobin A1C (HbA1C) < 5.0%, but a negative correlation in rats with HbA1C ≥ 5.0%; and <i>3</i>) in comparison with baseline (healthy stage) of the same cohort, plasma pancreatic polypeptide (reflecting vagal activity) was progressively decreased, whereas plasma norepinephrine (reflecting sympathetic activity) was progressively increased.<b>NEW & NOTEWORTHY</b> This study recorded the progressive impairment in the regularity of gastric and duodenal slow waves in a rat model mimicking the progression to type 2 diabetes including the stage of health, prediabetic stage, and diabetes. The progressive impairment in gastric/duodenal slow waves might be attributed to the progressive increase in blood glucose and impairment in autonomic function.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G386-G398"},"PeriodicalIF":3.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Duodenogastric reflux in health and disease: insights from a computational fluid dynamics model of the stomach.","authors":"Sharun Kuhar, Jung-Hee Seo, Pankaj Jay Pasricha, Michael Camilleri, Rajat Mittal","doi":"10.1152/ajpgi.00241.2024","DOIUrl":"10.1152/ajpgi.00241.2024","url":null,"abstract":"<p><p>The stomach is responsible for physically and chemically processing the ingested meal before controlled emptying into the duodenum through the pyloric sphincter. An incompetent pylorus allows reflux from the duodenum back into the stomach, and if the amount of reflux is large enough, it could alter the low-pH environment of the stomach and erode the mucosal lining of the lumen. In some cases, the regurgitated contents can also reach the esophagus, leading to additional complications. In this work, \"StomachSim\", an in silico model of the fluid dynamics of the stomach, is used to study the mechanism of duodenogastric reflux. The effects of variations in food properties and motility disorders on reflux are investigated. The simulations show that the primary driver of reflux is the relaxation of the antrum after a stomach contraction terminates near the pylorus. The region of the stomach walls exposed to the regurgitated contents depends significantly on the density of the stomach contents. For stomach contents of higher viscosity, the increased pressure required to maintain gastric emptying reduces the amount of duodenogastric reflux. Concomitant stomach motility disorders that weaken the relaxation of the walls also affect the amount of reflux. The study illustrates the utility of in silico models in analyzing the factors at play in gastrointestinal diseases.<b>NEW & NOTEWORTHY</b> An in silico model of the stomach is presented to study the phenomenon of duodenogastric reflux. We use the model to investigate the role of pyloric incompetence, food properties, and gastroparesis on reflux. This first-ever in silico study of duodenogastric reflux provides new insights into the mechanisms and factors implicated in this reflux and the sequelae of conditions that result from the exposure of the stomach lumen to bile.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G411-G425"},"PeriodicalIF":3.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combination of dietary fiber and exercise training improves fat loss in mice but does not ameliorate MASLD more than exercise alone.","authors":"Artemiy Kovynev, Mikołaj M Charchuta, Amina Begtašević, Quinten R Ducarmon, Patrick C N Rensen, Milena Schönke","doi":"10.1152/ajpgi.00317.2024","DOIUrl":"10.1152/ajpgi.00317.2024","url":null,"abstract":"<p><p>Lifestyle interventions, such as diet and exercise, are currently the main therapies against metabolic dysfunction-associated steatotic liver disease (MASLD). However, not much is known about the combined impact of fiber and exercise on the modulation of gut-liver axis and MASLD amelioration. Here, we studied the impact of the combination of exercise training and a fiber-rich diet on the amelioration of MASLD. Male APOE*3-Leiden.CETP mice were fed a high-fat high-cholesterol diet with or without the addition of fiber (10% inulin) and exercise trained on a treadmill, or remained sedentary. Exercise training and fiber supplementation reduced fat mass gain and lowered plasma glucose levels. Only the combination treatment, however, induced fat loss and decreased plasma triglyceride and cholesterol levels compared with sedentary control mice. Exercise training with and without the addition of fiber had a similar ameliorating effect on the MASLD score. Only exercise without fiber decreased the hepatic expression of inflammatory markers. Fiber diet was mainly responsible for remodeling the gut microbial composition, with an increase in the relative abundance of the short-chain fatty acid (SCFA)-producing genera <i>Anaerostipes</i> and <i>Muribaculaceae</i>, whereas, surprisingly, exercise training alone and with fiber resulted in the highest increase of SCFA production. Overall, the combination of exercise training and dietary fiber decreases fat mass and improves glucose and lipid homeostasis but does not have an additional synergistic positive effect on liver health compared with exercise training alone.<b>NEW & NOTEWORTHY</b> The combination of dietary fiber intake and exercise training has a synergetic beneficial effect on the metabolic health, resulting in fat loss, lowered blood glucose, and lowered plasma lipid levels in mice with steatotic liver disease. However, fiber supplementation, despite a positive remodulation of the gut-liver axis, does not have an additional positive effect on liver health compared with exercise training alone.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G399-G410"},"PeriodicalIF":3.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of hedgehog signaling ameliorates severity of chronic pancreatitis in experimental mouse models.","authors":"Srikanth Iyer, Mohammad Tarique, Preeti Sahay, Sagnik Giri, Ejas P Bava, JiaShiung Guan, Tejeshwar Jain, Utpreksha Vaish, Xiuwen Jin, Sabrina Moon, David K Crossman, Vikas Dudeja","doi":"10.1152/ajpgi.00212.2024","DOIUrl":"10.1152/ajpgi.00212.2024","url":null,"abstract":"<p><p>Chronic pancreatitis (CP) is a fibro-inflammatory disease of the pancreas with no specific cure. Research highlighting the pathogenesis and especially the therapeutic aspect remains limited. Aberrant activation of developmental pathways in adults has been implicated in several diseases. Hedgehog pathway is a notable embryonic signaling pathway, known to promote fibrosis of various organs when overactivated. The aim of this study is to explore the role of the hedgehog pathway in the progression of CP and evaluate its inhibition as a novel therapeutic strategy against CP. CP was induced in mice by repeated injections of l-arginine or caerulein in two separate models. Mice were administered with the FDA-approved pharmacological hedgehog pathway inhibitor, vismodegib during or after establishing the disease condition to inhibit hedgehog signaling. Various parameters of CP were analyzed to determine the effect of hedgehog pathway inhibition on the severity and progression of the disease. Our study shows that hedgehog signaling was overactivated during CP and its inhibition was effective in improving the histopathological parameters associated with CP. Vismodegib administration not only halted the progression of CP but was also able to resolve already-established fibrosis. In addition, inhibition of hedgehog signaling resulted in the reversal of pancreatic stellate cell activation ex vivo. Findings from our study justify conducting clinical trials using vismodegib against CP and, thus, could lead to the development of a novel therapeutic strategy for the treatment of CP.<b>NEW & NOTEWORTHY</b> Hedgehog signaling is activated in human and experimental models of CP. Inhibition of hedgehog signaling using an FDA-approved inhibitor, vismodegib, leads to the resolution of fibrosis and improves CP. This study has immense and immediate translational benefits.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G342-G363"},"PeriodicalIF":3.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}