Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"Piezo1-specific Deletion in Macrophage Protects the Progression of Chronic Inflammatory Bowel Disease in Mice.","authors":"Yuman Wang, Tianjiao Chu, Chengzhen Meng, Yifei Bian, Jing Li","doi":"10.1016/j.jcmgh.2025.101495","DOIUrl":"10.1016/j.jcmgh.2025.101495","url":null,"abstract":"<p><strong>Background & aims: </strong>Piezo1, a recently identified mechanically activated nonselective cation channel protein, demonstrates sensitivity to various mechanical stimuli, such as matrix stiffness and shear stress. Although accumulating evidence implicates Piezo1 channels in numerous physiologic and pathophysiologic processes, its involvement in dextran sulfate sodium (DSS)-induced acute and chronic inflammatory bowel disease (IBD) remains incompletely understood. This study aimed to investigate the effect of Piezo1 channels in macrophage polarization and its associated functions in IBD.</p><p><strong>Methods: </strong>DSS-induced inflammatory bowel disease model was established in Piezo1^td/Tdt or Piezo1^fl/fl and Piezo1^△LysM male mice. Additionally, bone marrow-derived macrophages from Piezo1^fl/fl and Piezo1^△LysM male mice were isolated to elucidate the downstream targets of Piezo1 and the associated underlying molecular mechanisms.</p><p><strong>Results: </strong>Our findings revealed that Piezo1 deficiency in macrophages could protect mice from DSS-induced chronic IBD, as evidenced by improved colon length and the preservation of colon structure. The mitigation of inflammation during chronic IBD progression was observed with Piezo1 deficiency in macrophages, characterized by reduced macrophage accumulation, M1 macrophage polarization, T helper 1 infiltration, and decreased inflammatory cytokine secretion. Further investigations unveiled that Piezo1-deficient macrophages inhibit the expression and activity of Nod-like receptor protein 3 and nuclear factor kappa B in colon tissues and bone marrow-derived macrophages while regulating the nuclear translocation of p65. Conversely, macrophage Piezo1 activation enhanced inflammatory cytokine secretion by activating Nod-like receptor protein 3/nuclear factor kappa B pathways.</p><p><strong>Conclusions: </strong>Myeloid Piezo1 mediates colonic immune response, and disrupting Piezo1 inhibits the progression of chronic IBD. This study provides hitherto undocumented evidence of the pivotal role of macrophage Piezo1 channels in regulating the progression of chronic IBD. Targeting macrophage Piezo1 may offer a promising therapeutic strategy against chronic IBD.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101495"},"PeriodicalIF":7.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Irritable Bowel Syndrome With Diarrhea in Pediatric Patients Is Associated With Type 2 and Type 9 T Cells in the Intestinal Mucosa.","authors":"Xin Chen, Brener Cunha Carvalho, Anika Sinha, Nanci Pittman, Keith Benkov, Joanne Lai, Maria Curotto de Lafaille, David Dunkin","doi":"10.1016/j.jcmgh.2025.101488","DOIUrl":"10.1016/j.jcmgh.2025.101488","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101488"},"PeriodicalIF":7.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Great Reset: A \"Tuft\" Journey Towards Tumorigenesis.","authors":"Monica E Brown, Ken S Lau","doi":"10.1016/j.jcmgh.2025.101476","DOIUrl":"10.1016/j.jcmgh.2025.101476","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101476"},"PeriodicalIF":7.1,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Of Zebrafish, Mice, and Men: Identifying New Biology and Developing New Treatments for Erythropoietic Protoporphyria.","authors":"Jean P Molleston, Chaowapong Jarasvaraparn","doi":"10.1016/j.jcmgh.2025.101477","DOIUrl":"10.1016/j.jcmgh.2025.101477","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101477"},"PeriodicalIF":7.1,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Human Milk-derived Peptide Drives Rapid Regulation of Macrophage Inflammation Responses in the Neonatal Intestine","authors":"Fuqiang Yuan ,&nbsp;Xu Han ,&nbsp;Masha Huang ,&nbsp;Yinglin Su ,&nbsp;Yiting Zhang ,&nbsp;Mengyuan Hu ,&nbsp;Xiang Yu ,&nbsp;Weilai Jin ,&nbsp;Yun Li ,&nbsp;Le Zhang","doi":"10.1016/j.jcmgh.2024.101420","DOIUrl":"10.1016/j.jcmgh.2024.101420","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The interactions between human milk and the regulation of innate immune homeostasis in newborns, and their impact on intestinal health, are not fully understood. This study aimed to explore the role of peptides in human milk extracellular vesicles (EVs) in this process.</div></div><div><h3>Methods</h3><div>A comprehensive screening of peptides within human milk EVs was performed, leading to the identification of a beta-casein-derived peptide (CASB_135-150). The effects of CASB_135-150 on intestinal injury were evaluated in a rat necrotizing enterocolitis (NEC) model. Immunofluorescence analysis was used to determine its distribution, and its impact on NF-κB signaling and inflammation was studied in bone marrow-derived macrophages (BMDMs) and intestinal macrophages. Protein-protein interaction (PPI) analysis, single-cell RNA-seq (scRNA-seq), and co-immunoprecipitation (co-IP) experiments were conducted to explore the mechanism underlying CASB_135-150 function.</div></div><div><h3>Results</h3><div>CASB_135-150 significantly mitigated intestinal injury in the rat NEC model. Immunofluorescence analysis revealed that CASB_135-150 could target intestinal macrophages and rapidly inhibited NF-κB signaling and reduced inflammation. ScRNA-seq analyses indicated a strong association between FHL2 and NEC development, and co-IP confirmed the interaction between CASB_135-150 and FHL2. CASB_135-150 disrupted the FHL2/TRAF6 complex, reducing TRAF6 protein levels. Mutation of key amino acids in CASB_135-150 disrupted its interaction with FHL2 and abolished its ability to inhibit NF-κB signaling, which also prevented its protective effect in vivo. RNA-seq of intestinal tissue further highlighted the impact of CASB_135-150 on the NF-κB signaling pathway.</div></div><div><h3>Conclusions</h3><div>Our study identifies CASB_135-150, a novel peptide in human milk EVs, that rapidly regulates macrophage inflammatory responses and protects against NEC-induced intestinal injury. These findings provide new insights into the role of human milk in modulating the infant immune system and intestinal health.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 2","pages":"Article 101420"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11652890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142481784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prostaglandin E2 and Akt Promote Stemness in Apc Mutant Dclk1+ Cells to Give Rise to Colitis-associated Cancer","authors":"Hayley J. Good ,&nbsp;Frederikke Larsen ,&nbsp;Alice E. Shin ,&nbsp;Liyue Zhang ,&nbsp;Mathieu Derouet ,&nbsp;David Meriwether ,&nbsp;Daniel Worthley ,&nbsp;Srinivasa T. Reddy ,&nbsp;Timothy C. Wang ,&nbsp;Samuel Asfaha","doi":"10.1016/j.jcmgh.2025.101469","DOIUrl":"10.1016/j.jcmgh.2025.101469","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Loss of the tumor suppressor gene Apc in Lgr5+ intestinal stem cells results in aberrant Wnt signaling and colonic tumorigenesis. In the setting of injury, however, we and others have also shown that non-stem cells can give rise to colonic tumors. The mechanism by which inflammation leads to cellular plasticity and cancer, however, remains largely unknown.</div></div><div><h3>Methods</h3><div>RNA expression analysis of Wnt, COX, and Akt signaling was assessed in patients with quiescent or active ulcerative colitis (UC) and patients with UC-associated neoplasia using available datasets. The role of COX signaling in colonic tumorigenesis was examined using epithelial and doublecortin-like kinase 1 (Dclk1)+ cell-specific conditional COX-1 knockout mice and pharmacologic treatment with different nonsteroidal anti-inflammatory drugs.</div></div><div><h3>Results</h3><div>In this study, we show that prostaglandins and phospho-Akt are key inflammatory mediators that promote stemness in Apc mutant Dclk1+ cells that give rise to colorectal cancer. Moreover, prostaglandin E₂ (PGE₂) and Akt are increased in colitis in both mice and humans, leading to inflammation-associated dysplasia upon activation of Wnt signaling. Importantly, inhibition of epithelial-derived COX-1 by aspirin or conditional knockout in Dclk1+ cells reduced PGE₂ levels and prevented the development of inflammation-associated colorectal cancer.</div></div><div><h3>Conclusions</h3><div>Our data shows that epithelial and Dclk1+ cell-derived COX-1 plays an important role in inflammation-associated tumorigenesis. Importantly, low-dose aspirin was effective in chemo-prevention through inhibition of COX-1 that reduced colitis-associated cancer.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 6","pages":"Article 101469"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143069837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interferon Signaling Alters Epithelial Function in Eosinophilic Esophagitis","authors":"Yash Choksi","doi":"10.1016/j.jcmgh.2025.101464","DOIUrl":"10.1016/j.jcmgh.2025.101464","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 5","pages":"Article 101464"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Evolution of CMGH as The Basic Research Journal in Gastroenterology and Hepatology: “H” is for “Home”","authors":"Jonathan P. Katz,&nbsp;Michele A. Battle,&nbsp;Alexander M. Vaeth","doi":"10.1016/j.jcmgh.2024.101450","DOIUrl":"10.1016/j.jcmgh.2024.101450","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101450"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myosin Light Chain 9 Mediates Graft Fibrosis After Pediatric Liver Transplantation Through TLR4/MYD88/NF-κB Signaling","authors":"Zhixin Zhang ,&nbsp;Chong Dong ,&nbsp;Shengqiao Zhao ,&nbsp;Zhuyuan Si ,&nbsp;Weiping Zheng ,&nbsp;Kai Wang ,&nbsp;Chao Sun ,&nbsp;Zhuolun Song ,&nbsp;Wei Gao","doi":"10.1016/j.jcmgh.2024.101453","DOIUrl":"10.1016/j.jcmgh.2024.101453","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The incidence of graft fibrosis is elevated after pediatric liver transplantation (pLT) and is influenced by cold ischemic time (CIT). Myosin light chain 9 (MYL9), a member of the myosin family, could act on hepatic stellate cells (HSCs) and induce a transition to active phase. We hypothesized that cold ischemic injury could stimulate MYL9 expression and lead to graft fibrosis.</div></div><div><h3>Methods</h3><div>We tested the hypothesis by analyzing multi-omics data from human protocol liver biopsy samples 2 years after LT, performing rat LT with different CIT and conducting in vitro studies in HSC cell lines with MYL9 knockdown and overexpression.</div></div><div><h3>Results</h3><div>Clinically, CIT is an independent risk factor for graft fibrosis after pLT. Omics analysis identified MYL9 as a prominent contributor in graft fibrosis. MYL9 is strongly correlated with liver fibrosis grade and the progression of fibrosis. The study of rat LT model demonstrated MYL9 expression increases with the prolongation of CIT, and its role is specific to transplant setting. Mechanistically, in vitro experiments with HSCs exposed to hypoxia/reoxygenation revealed a substantial decrease in HSCs activation after MYL9 knockdown. Conversely, overexpression of MYL9 significantly enhanced the activation of HSCs. Subsequent transcriptome sequencing of HSCs with MYL9 knockdown unveiled that MYL9 primarily functions through the TLR4/MYD88/NF-κB signaling pathway. Liver graft fibrosis was ameliorated when toll like receptor 4 signaling was inhibited in rats.</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate that prolonged CIT up-regulates the expression of MYL9 in liver graft after LT. MYL9 activates HSCs and promotes fibrosis through a TLR4/MYD88/NF-κB signaling dependent manner.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 5","pages":"Article 101453"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142959422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tofacitinib Mitigates the Increased SARS-CoV-2 Infection Susceptibility Caused by an IBD Risk Variant in the PTPN2 Gene","authors":"Marianne R. Spalinger ,&nbsp;Golshid Sanati ,&nbsp;Pritha Chatterjee ,&nbsp;Rong Hai ,&nbsp;Jiang Li ,&nbsp;Alina N. Santos ,&nbsp;Tara M. Nordgren ,&nbsp;Michel L. Tremblay ,&nbsp;Lars Eckmann ,&nbsp;Elaine Hanson ,&nbsp;Michael Scharl ,&nbsp;Xiwei Wu ,&nbsp;Brigid S. Boland ,&nbsp;Declan F. McCole","doi":"10.1016/j.jcmgh.2024.101447","DOIUrl":"10.1016/j.jcmgh.2024.101447","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Coronavirus disease (COVID-19), caused by severe acquired respiratory syndrome-Coronavirus-2 (SARS-CoV-2), triggered a global pandemic with severe medical and socioeconomic consequences. Although fatality rates are higher among the elderly and those with underlying comorbidities, host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases. The aim of our study was to investigate whether the autoimmunity risk gene, <em>PTPN2,</em> which also confers elevated risk to develop inflammatory bowel disease, affects susceptibility to SARS-CoV-2 viral uptake.</div></div><div><h3>Methods</h3><div>Using samples from <em>PTPN2</em> genotyped patients with inflammatory bowel disease, <em>PTPN2-</em>deficient mice, and human intestinal and lung epithelial cell lines, we investigated how <em>PTPN2</em> affects expression of the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2), and uptake of virus-like particles expressing the SARS-CoV2 spike protein and live SARS-CoV-2 virus.</div></div><div><h3>Results</h3><div>We report that the autoimmune <em>PTPN2</em> loss-of-function risk variant rs1893217 promotes expression of the SARS-CoV-2 receptor, ACE2, and increases cellular entry of SARS-CoV-2 spike protein and live virus. Elevated ACE2 expression and viral entry were mediated by increased Janus kinase-signal transducers and activators of transcription signaling and were reversed by the Janus kinase inhibitor, tofacitinib.</div></div><div><h3>Conclusion</h3><div>Collectively, our findings uncover a novel risk biomarker for increased expression of the SARS-CoV-2 receptor and viral entry, and identify a clinically approved therapeutic agent to mitigate this risk.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 5","pages":"Article 101447"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}