Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"Chronic Gastroesophageal Reflux Dysregulates Proteostasis in Esophageal Epithelial Cells","authors":"Kodisundaram Paulrasu ,&nbsp;Ravindran Caspa Gokulan ,&nbsp;Wael El-Rifai ,&nbsp;Zhibin Chen ,&nbsp;Jianwen Que ,&nbsp;Timothy C. Wang ,&nbsp;Olivier G. Boutaud ,&nbsp;Karoline Briegel ,&nbsp;Sergey I. Dikalov ,&nbsp;Monica T. Garcia-Buitrago ,&nbsp;Alexander I. Zaika","doi":"10.1016/j.jcmgh.2024.101434","DOIUrl":"10.1016/j.jcmgh.2024.101434","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Gastroesophageal reflux disease (GERD) is a common digestive disorder that is characterized by esophageal tissue damage produced by exposure of the esophageal lining to the gastric refluxate. GERD can raise the risk of multiple serious complications including esophageal tumors. At the molecular levels, GERD-affected tissues are characterized by strong oxidative stress and the formation of reactive isolevuglandins (isoLGs). These products of lipid peroxidation rapidly interact with cellular proteins forming protein adducts. Here, we investigated the interrelationship between isoLG adduction and aggregation of cellular proteins.</div></div><div><h3>Methods</h3><div>Protein misfolding and aggregation were analyzed using multiple protein misfolding and aggregation assays. Pathologic consequences of protein adduction and aggregation were studied using human and murine esophageal tissues. Surgical model of esophageal reflux injury and L2-IL1β transgenic mice were used to investigate the mechanisms of protein misfolding and aggregation.</div></div><div><h3>Results</h3><div>Our studies demonstrate that gastroesophageal reflux causes protein misfolding and aggregation that is associated with severity of GERD. Dysregulation of proteostasis induces ferroptotic cell death and is mediated by modification of cellular proteins with reactive isoLGs that can be prevented by isoLG scavengers.</div></div><div><h3>Conclusions</h3><div>GERD causes dysregulation of cellular proteostasis, accumulation of isoLG protein adducts, misfolded, and aggregated proteins that promote ferroptotic cell death. Taken together, this study suggests that GERD has similarities to other known pathologic conditions that are characterized by protein misfolding and aggregation.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101434"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788019","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":"Extrinsic Innervation of Myenteric Plexus of Human Large Intestine Via Colonic Nerves","authors":"Adam Humenick,&nbsp;Bao Nan Chen,&nbsp;Michaela E. Johnson,&nbsp;Wai Ping Yew,&nbsp;David A. Wattchow,&nbsp;Tiong Cheng Sia,&nbsp;Dayan Defontgalland,&nbsp;Nick J. Spencer,&nbsp;Phil G. Dinning,&nbsp;Marcello Costa,&nbsp;Simon J.H. Brookes","doi":"10.1016/j.jcmgh.2025.101479","DOIUrl":"10.1016/j.jcmgh.2025.101479","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 5","pages":"Article 101479"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470063","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":"New Molecular Player In Colitis and Colitis-Associated Cancer","authors":"Kim E. Barrett","doi":"10.1016/j.jcmgh.2024.101441","DOIUrl":"10.1016/j.jcmgh.2024.101441","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101441"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886517","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":"Dysregulated Proteostasis-induced Ferroptosis in Gastroesophageal Reflux Disease: Hero or Villain?","authors":"David H. Wang","doi":"10.1016/j.jcmgh.2024.101445","DOIUrl":"10.1016/j.jcmgh.2024.101445","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101445"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907896","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":"In vivo CRISPR Activation Screening, a Powerful Tool to Discover Oncogenic Driver Genes in Hepatocellular Carcinoma","authors":"Shaimaa Gad,&nbsp;Ruisong Ye,&nbsp;Wei Qiu","doi":"10.1016/j.jcmgh.2024.101459","DOIUrl":"10.1016/j.jcmgh.2024.101459","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 5","pages":"Article 101459"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043224","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":"Single-cell Profiling of Intrahepatic Immune Cells Reveals an Expansion of Tissue-resident Cytotoxic CD4+ T Lymphocyte Subset Associated With Pathogenesis of Alcoholic-associated Liver Diseases","authors":"Chao Gao ,&nbsp;Shiguan Wang ,&nbsp;Xiaoyu Xie ,&nbsp;Pierluigi Ramadori ,&nbsp;Xinying Li ,&nbsp;Xiaoyu Liu ,&nbsp;Xue Ding ,&nbsp;Jinyuan Liang ,&nbsp;Bowen Xu ,&nbsp;Yawei Feng ,&nbsp;Xueying Tan ,&nbsp;Haoran Wang ,&nbsp;Yan Zhang ,&nbsp;Haiyan Zhang ,&nbsp;Tingguo Zhang ,&nbsp;Ping Mi ,&nbsp;Shiyang Li ,&nbsp;Cuijuan Zhang ,&nbsp;Detian Yuan ,&nbsp;Mathias Heikenwalder ,&nbsp;Peng Zhang","doi":"10.1016/j.jcmgh.2024.101411","DOIUrl":"10.1016/j.jcmgh.2024.101411","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The immunological mechanisms underpinning the pathogenesis of alcoholic-associated liver disease (ALD) remain incompletely elucidated. This study aims to explore the transcriptomic profiles of hepatic immune cells in ALD compared with healthy individuals and those with metabolic dysfunction-associated steatotic liver disease (MASLD).</div></div><div><h3>Methods</h3><div>We utilized single-cell RNA sequencing to analyze liver samples from healthy subjects and patients with MASLD and ALD, focusing on the immune cell landscapes within the liver. Key alterations in immune cell subsets were further validated using liver biopsy samples from additional patient cohorts.</div></div><div><h3>Results</h3><div>We observed a significant accumulation of CD4⁺ T cells in livers of patients with ALD, surpassing the prevalence of CD8⁺ T cells, in contrast to patients with MASLD and healthy counterparts, whereas natural killer (NK) cells and γδT cells exhibited reduced intrahepatic infiltration. In-depth transcriptional and developmental trajectory analyses unveiled that a distinct CD4⁺ subset characterized by granzyme K (GZMK) expression, displaying a tissue-resident signature and terminal effector state, prominently enriched among CD4⁺ T cells infiltrating the livers of patients with ALD. Subsequent examination of an independent ALD patient cohort corroborated the substantial enrichment of GZMK⁺CD4⁺ T lymphocytes, primarily within liver fibrotic zones, suggesting their potential involvement in disease progression. Additionally, we noted shifts in myeloid populations, with expanded APOE⁺ macrophage and FCGR3B⁺ monocyte subsets in ALD samples relative to MASLD and healthy tissues.</div></div><div><h3>Conclusions</h3><div>In summary, this study unravels the intricate cellular diversity within hepatic immune cell populations, highlighting the pivotal immune pathogenic role of the GZMK⁺CD4⁺ T lymphocyte subset in ALD pathogenesis.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 2","pages":"Article 101411"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11719870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142333076","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":"Normalization of Cystic Fibrosis Immune System Reverses Intestinal Neutrophilic Inflammation and Significantly Improves the Survival of Cystic Fibrosis Mice","authors":"Callie E. Scull ,&nbsp;Yawen Hu ,&nbsp;Scott Jennings,&nbsp;Guoshun Wang","doi":"10.1016/j.jcmgh.2024.101424","DOIUrl":"10.1016/j.jcmgh.2024.101424","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Cystic fibrosis (CF) is an autosomal recessive genetic disorder, affecting multiple organ systems. CF intestinal disease develops early, manifesting as intestinal bacterial overgrowth/dysbiosis, neutrophilic inflammation, and obstruction. As unresolvable infection and inflammation reflect host immune deficiency, we sought to determine if the CF-affected immune system plays any significant role in CF intestinal disease pathogenesis.</div></div><div><h3>Methods</h3><div>CF and sibling wild-type (WT) mice underwent reciprocal bone marrow transplantation. After immune reconstitution, their mortality, intestinal transit, fecal inflammatory markers, and mucosal immune cell composition were assessed. Moreover, reciprocal neutrophil transfusion was conducted to determine if neutrophil function affects intestinal movement. Furthermore, expression of induced nitric oxide synthase (iNOS) and production of nitric oxide (NO) in CF and WT neutrophils were compared. Lastly, specific iNOS inhibitor 1400W was tested to prevent CF intestinal obstruction.</div></div><div><h3>Results</h3><div>Immune restoration in CF mice reversed the intestinal neutrophilic inflammation, improved the intestinal dysmotility, and rescued the mice from mortality. Transfusion of WT neutrophils into CF mice ameliorated the retarded bowel movement. CF neutrophils expressed significantly more iNOS and produced significantly more NO. Pharmaceutical blocking of iNOS significantly improved intestinal transit and survival of CF mice.</div></div><div><h3>Conclusions</h3><div>CF immune defect plays a critical role in CF intestinal disease development. Activation of iNOS in inflammatory cells produces excessive NO, slows the bowel movement, and facilitates intestinal paralysis and obstruction in CF. Thus, normalization of the CF immune system may offer a novel therapy to treat CF intestinal disease.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 2","pages":"Article 101424"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11720009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607586","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":"Augmenter of Liver Regeneration Crotonylation Assists in Mitochondria-ER Contact to Alleviate Hepatic Steatosis","authors":"Xiao-lin Wang ,&nbsp;Jia-hao He ,&nbsp;Ping Xie,&nbsp;Yuan Wu,&nbsp;Ling-yue Dong,&nbsp;Wei An","doi":"10.1016/j.jcmgh.2024.101436","DOIUrl":"10.1016/j.jcmgh.2024.101436","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Crotonylation (Kcr), a newly identified post-translation modification (PTM), has been confirmed to be involved in diverse biological processes and human diseases as well. Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a serious threat to people’s health. Augmenter of liver regeneration (ALR) is an important liver regulatory protein, and the insufficiency of ALR expression is reported to accelerate liver steatosis progression to liver fibrosis or even hepatic carcinoma (HCC). However, the connection between dysregulated ALR crotonylation and MASLD pathogenesis remains largely unknown.</div></div><div><h3>Methods</h3><div>Steatotic liver samples from human and Western diet (WD)-fed mice were employed for detecting Kcr levels. Mitochondrial function and mitochondria-ER interaction (MAM) relevant to ALR-Kcr modification was evaluated for hepatocyte lipid metabolism both in <em>in vivo</em> and <em>in vitro</em> experiments.</div></div><div><h3>Results</h3><div>Global protein crotonylation (Kcr) as well as ALR-Kcr was significantly decreased in liver samples of patients with MASLD and WD mice. Histone deacetylase1/2 (HDAC1/2) and lysine acetyltransferase 8 (KAT8) were identified responsible for regulation of ALR-Kcr, which takes place at lysine 78 (K78). The decrease of ALR crotonylation might be related to the imbalance between HDAC1/2 and KAT8 expression, inhibited its interaction with MFN2, expanding MAM distance and impairing mitochondrial lipid metabolism, and consequently deteriorating hepatic steatosis.</div></div><div><h3>Conclusions</h3><div>The insufficient ALR crotonylation might be a crucial mechanism contributing to the pathogenesis of MASLD. Keeping ALR crotonylation level would be beneficial for the prevention and treatment of MASLD.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101436"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796457","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":"The Effect of FOXA3 Overexpression on Hepatocyte Differentiation and Liver Regeneration in a Fah cKO Mouse Model","authors":"Shao Li ,&nbsp;Chupeng Ou ,&nbsp;Jiajun Zhang ,&nbsp;Min Zeng ,&nbsp;Kangyan Liang ,&nbsp;Qing Peng ,&nbsp;Yi Gao","doi":"10.1016/j.jcmgh.2024.101438","DOIUrl":"10.1016/j.jcmgh.2024.101438","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Stimulated by injury or disease, hepatocytes can regenerate and repair liver tissues through proliferation and differentiation. Partial hepatectomy and liver transplantation are effective treatments for liver diseases. This study investigated the effect of FOXA3 on cell differentiation in HepaRG cell lines under 2- and 3-dimensional culture conditions.</div></div><div><h3>Methods</h3><div>Experiments were performed using a HepaRG cell line that stably overexpressed FOXA3 (RF3) and hepatocyte-specific functions. Moreover, a Fah conditional knockout mouse model (Fah cKO mice) was constructed using the CRISPR-Cas9 method and treated with RF3 spheroids for transplantation. Various molecular biology and immunostaining experiments were performed to assess liver function, hepatocyte structure, and expression levels of cell cycle–related proteins.</div></div><div><h3>Results</h3><div>HepaRG cells that overexpressed FOXA3 had hepatocyte-specific functions. RF3 spheroids expressed liver markers following gene and protein expression analysis. After RF3 spheroid transplantation, Fah cKO mice exhibited increased survival, reduced weight loss, normalization of liver function and hepatocyte structure, and enhanced expression of hepatocyte differentiation factors. However, the expression of cell cycle–related proteins, including p53 and p21, was decreased in vivo. Injection of an HNF4α antagonist revealed that inhibition of HNF4α effectively suppressed the regenerative capacity of the liver after RF3 spheroid transplantation, resulting in an increase in the number of p53- and p21-positive cells and a decrease in the expression levels of liver function–related genes.</div></div><div><h3>Conclusions</h3><div>FOXA3 plays an important role in hepatocyte function. RF3 spheroid transplantation had a therapeutic effect in the Fah cKO mouse model, improving liver function and promoting liver regeneration.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101438"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815193","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":"Elevated Bile Acids Induce Circadian Rhythm Sleep Disorders in Chronic Liver Diseases","authors":"Lan Zhou ,&nbsp;Min Yan ,&nbsp;Qin Luo ,&nbsp;Wen Qiu ,&nbsp;Yu-Ru Guo ,&nbsp;Xiao-Qing Guo ,&nbsp;Hong-Bin Yu ,&nbsp;Jing-Ru Huo ,&nbsp;Yan-Lin Feng ,&nbsp;De-Ping Wang ,&nbsp;Teng Sun ,&nbsp;Kai-Fang Wang ,&nbsp;Jian-Yun Shi ,&nbsp;Xuan Shang ,&nbsp;Mei-Na Wu ,&nbsp;Lin Wang ,&nbsp;Ji-Min Cao","doi":"10.1016/j.jcmgh.2024.101439","DOIUrl":"10.1016/j.jcmgh.2024.101439","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Sleep disorders (SDs) are common in chronic liver diseases (CLDs). Some SDs arise from impaired internal clock and are, hence, circadian rhythm SDs (CRSDs). Bile acids (BAs), whose levels are increased in many CLDs, reciprocally interact with circadian rhythm. This study explores the mechanisms underlying CRSDs in CLDs and novel therapies.</div></div><div><h3>Methods</h3><div>We monitored the sleep of patients with CLD using actigraphic watch and established male mouse cholemia models by feeding with BA or bile duct ligation. Sleep-wake cycle and circadian rhythm were analyzed by electroencephalogram-electromyography and locomotor wheel-running experiments.</div></div><div><h3>Results</h3><div>Patients with CLD showed CRSD-like phenotypes including increased night activity and early awakening, which were strongly correlated with increased BA levels (ie, cholemia). CRSDs, including shortened circadian period, were recapitulated in 2 cholemic mouse models. Mechanistically, elevated BAs in the suprachiasmatic nucleus (SCN) activated BA receptor Takeda G protein-coupled receptor 5 (Tgr5), which, in turn, increased the level and phosphorylation of Period2 (Per2), a master rhythm regulator, through extracellular signal-regulated kinase (Erk) and casein kinase 1ε (CK1ε). Per2 phosphorylation inhibited its nuclear import, which would release its transcriptional inhibition and expedite the circadian cycle. Cholemia also blunted the light entrainment response and light-induced phase change of SCN mediated by the neurons expressing gastrin releasing peptide through Tgr5-Per2 axis. BA sequestrant or CK1 inhibitor reversed the CRSDs in cholemic mice by restoring Per2 distribution.</div></div><div><h3>Conclusions</h3><div>Cholemia is a major risk factor for CRSDs in CLDs and, hence, a promising target in future clinical study.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101439"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142820349","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}