Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"Extracellular inosine induces anergy in B cells to alleviate autoimmune hepatitis.","authors":"Nana Cui, Qiwei Qian, Yujie Zhou, Heng Zhang, Huayang Zhang, Binghong Wang, Yikang Li, Qixia Wang, Min Lian, Zhengrui You, Xiong Ma","doi":"10.1016/j.jcmgh.2025.101539","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101539","url":null,"abstract":"<p><strong>Background and aims: </strong>Dysregulation of naïve BCR signaling and the generation of antibody-secreting B cells (ASCs) have been implicated in the development of autoimmune diseases. Anergic B cells (B_NDs) are naïve B cells with a low-density of surface IgM-BCR, thus demonstrating attenuated autoantigen responsiveness. However, potential regulatory mechanisms of B cell anergy and their roles in autoimmune hepatitis (AIH) remain unestablished.</p><p><strong>Methods: </strong>The frequency of circulating B cell subsets and comparative phenotypic analyses were conducted using flow cytometry. Primary human CD19⁺ B cells were differentiated in vitro with inosine or specific inhibitors, followed by qPCR, western blotting, and flow cytometry analyses. The effects of inosine were evaluated in a concanavalin A-induced AIH mouse model, and a specific equilibrative nucleoside transporter 1 (ENT1) inhibitor was utilized both in vitro and in vivo.</p><p><strong>Results: </strong>An elevated frequency of ASCs but a diminish of B_NDs were observed in AIH. B_NDs showed attenuated activated status compared to C_NBs. B_NDs uniquely exhibited high-level expression of CD73, the rate-limiting enzyme in purinergic metabolism. Inosine, as the end-product of the extracellular purinergic pathway, significantly enhanced B_NDs expansion and inhibited ASCs differentiation in vitro. Mechanically, extracellular inosine was taken up via ENT1, promoting surface IgM internalization by inhibiting the PARP14-STAT6 signaling pathway. Pharmacological inhibition of ENT1 with dipyridamole reversed therapeutic effects of inosine both in vitro and in vivo.</p><p><strong>Conclusions: </strong>Our findings revealed that inosine was a crucial metabolite that induced immune tolerance of B cells, thus proposing a potential intervention strategy for AIH.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101539"},"PeriodicalIF":7.1,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133214","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":"A Dual Role of HGF-ERK Signaling in IL6/HGF-induced Hepatocyte Proliferation.","authors":"Jingwei Zhang, Shitong Wang, Jiani Yu, Bing Li, Shun Wang, Na Suo, Ren Guo, Xin Xie","doi":"10.1016/j.jcmgh.2025.101538","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101538","url":null,"abstract":"<p><strong>Background & aims: </strong>Primary hepatocytes are difficult to expand in vitro. HGF and EGF have long been used to maintain primary hepatocytes in vitro but with limited growth promotion effect. Previously, we have reported that the combination of IL6 with HGF and EGF (or the combination of IL6 with either of these growth factors) could support almost infinite growth of hepatocytes. However, the downstream pathways of these growth factors in hepatocyte proliferation remain elusive.</p><p><strong>Methods: </strong>Transcriptome analysis was carried out to analyze the activation of pathways under various culture condition. Pathway inhibitors were used in cell culture and a hepatectomy mouse model to study the function of different pathways in hepatocyte growth and liver regeneration.</p><p><strong>Results: </strong>We discover in surprise, that under growth condition, TGFβ pathway which is typically linked to growth inhibition is activated. TGFβ activation is mainly induced by HGF via MAPK-ERK signaling, blocking TGFβ pathway significantly enhances H6 (HGF and IL6)-induced hepatocyte expansion in vitro. However, blocking the MAPK-ERK signaling almost completely blocks H6-induced cell growth, indicating a dual effect of the ERK pathway. Further study demonstrates that the HGF-ERK pathway could also upregulate the protein level of YAP and the downstream genes associated with the Hippo-YAP signaling pathway, exerting a positive effect in hepatocyte proliferation. In mouse partial hepatectomy model, blockade of the activated TGFβ signaling also significantly promotes liver regeneration in vivo.</p><p><strong>Conclusions: </strong>We report a dual role of HGF-ERK signaling in hepatocyte culture. By blocking the growth-inhibiting TGFβ pathway, we could further promote H6-induced hepatocyte proliferation.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101538"},"PeriodicalIF":7.1,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133173","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 molecular motor Myosin 5B and its folding chaperone UNC45A are decreased in colorectal cancer.","authors":"Sarah A Dooley, Rachel Stubler, Priti Parsanna Maity, Jorge Múnera, Antonis Kourtidis, Melinda A Engevik, Amy C Engevik","doi":"10.1016/j.jcmgh.2025.101537","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101537","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer ranks among the most common and deadliest cancers worldwide. Previous studies have found that the molecular motor Mysoin 5b (MYO5B) is decreased at the level of mRNA in colorectal cancer, but the mechanism behind this reduction remains unknown. In normal cells, MYO5B function is contingent on proper folding by the chaperone protein UNC45A. However, little is known about the role of UNC45A in colorectal cancer.</p><p><strong>Methods: </strong>We examined RNA, methylation and protein levels of MYO5B and UNC45A and identified microRNAs targeting UNC45A in normal colon, colon adenocarcinoma (COAD) samples, cancer cell lines and human colonic organoids. Cells were treated with the DNA-demethylating agent 5-aza-2'-deoxycytidine to examine the role of methylation in regulating MYO5B levels. Additionally, the UNC45A targeting miR-296-3p was inhibited in cells and UNC45A levels were examined.</p><p><strong>Results: </strong>Consistent with previous reports, we found that MYO5B mRNA was reduced in COAD compared to controls. We observed that the MYO5B gene was hyper-methylated in COAD and treatment of cancer cells with a demethylating compound increased MYO5B expression; suggesting that methylation silences MYO5B in COAD. The MYO5B folding chaperone UNC45A was not changed at the mRNA level but was decreased at the protein level. We identified several UNC45A targeting miRNAs which were elevated in COAD patients. We confirmed that these miRNAs were elevated in colon cancer cell lines compared to normal colonic organoids and found that inhibition of one of these miRNAs increased UNC45A protein.</p><p><strong>Conclusions: </strong>These findings suggest that decreased levels of MYO5B in COAD may result from gene methylation and improper folding by UNC45A.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101537"},"PeriodicalIF":7.1,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133321","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":"Targeting Tumor Stroma in CMS4 Colorectal Cancer: Phospholamban Takes Center Stage.","authors":"Christopher Shawn Williams","doi":"10.1016/j.jcmgh.2025.101529","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101529","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101529"},"PeriodicalIF":7.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133265","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":"HMG Box-Containing Protein 1 (HBP1) Protects Against Pancreatic Injury in Acute Pancreatitis but Promotes Neoplastic Progression.","authors":"Seung-Won Lee, Taelor Ekstrom, Elise C Manalo, Shangyuan Ye, Mark Berry, Dmytro Grygoryev, Malwina Szczepaniak, Jinho Lee, Carlos Origel Marmolejo, Syber Haverlack, Juyoung Lee, Vidhi M Shah, Dove Keith, John L Muschler, Koei Chin, Rosalie C Sears, Stuart P Weisberg, Terry Morgan, Jungsun Kim","doi":"10.1016/j.jcmgh.2025.101536","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101536","url":null,"abstract":"<p><strong>Background & aims: </strong>Pancreatitis is an inflammatory disease of the exocrine pancreas and a known risk factor for pancreatic ductal adenocarcinoma (PDAC). Previously, we identified HMG-box transcription factor 1 (HBP1) as a potential master transcription factor (TF) in the early progression of PDAC, with its expression associated with poor patient survival, underscoring its significance in pancreatic disease. However, the functional role of HBP1 in the onset and progression of acute pancreatitis (AP) remains unknown.</p><p><strong>Methods: </strong>We examined HBP1 expression in human pancreatitis samples and a cerulein-induced AP mouse model. Pancreatic-specific conditional HBP1 knockout mice, with or without an oncogenic Kras mutation, were generated and compared to their littermate controls. Spatial transcriptomics and multiplexed protein assays, histological analysis, and immunostaining were utilized to characterize pathological changes. Findings from mouse models were validated using inducible HBP1-overexpressing human pancreatic ductal epithelial cells.</p><p><strong>Results: </strong>HBP1 was upregulated in pancreatic exocrine cells in human chronic pancreatitis and mouse acute pancreatitis, with its expression in human chronic pancreatitis correlating with cancer presence. Pancreatic HBP1 ablation disrupted acinar homeostasis by impairing autophagic flux and exacerbating inflammation following injury. In the presence of oncogenic KRAS, HBP1 ablation delayed the formation of pancreatic intraepithelial neoplasia (PanIN), the precursor to PDAC, and slowed its progression to higher-grade lesions.</p><p><strong>Conclusions: </strong>HBP1 upregulation in pancreatitis mitigates pancreatic inflammatory injury; however, in the presence of oncogenic KRAS, it facilitates PanIN progression. Thus, HBP1 serves as a critical regulator in both pancreatitis and early pancreatic neoplasia, representing a potential therapeutic target for intervening pancreatitis and PanIN progression.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101536"},"PeriodicalIF":7.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129376","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":"Human induced pluripotent stem cell derived gut organoids recapitulate regional specific genetic programs and a role for cAMP in lineage specification.","authors":"Elizabeth Y Flores, Aditya Mithal, Pushpinder Bawa, Feiya Wang, Andrew D'Amico, Aoife K O'Connell, Hans P Gertje, Anna E Tseng, Nicholas A Crossland, Yuriy Alekseyev, Gustavo Mostoslavsky","doi":"10.1016/j.jcmgh.2025.101534","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101534","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101534"},"PeriodicalIF":7.1,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144095876","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":"Goblet cell loss linked to NOD2 and secondary resection in Crohn's disease is induced by dysbiosis and epithelial MyD88.","authors":"Serre-Yu Wong, Maria Manuela Estevinho, Thomas Heaney, Allison A Marshall, Elisabeth Giselbrecht, Scott G Daniel, Chaoting Zhou, Adriana Rosas-Villegas, Kyung Ku Jang, Hairu Yang, Huaibin Mabel Ko, John D Paulson, Yi Ding, Kyle Bittinger, Judy H Cho, James D Lewis, Deepshika Ramanan, Ken Cadwell","doi":"10.1016/j.jcmgh.2025.101533","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101533","url":null,"abstract":"<p><strong>Background & aims: </strong>The role of goblet cells in small intestinal inflammation in Crohn's disease is unknown. Polymorphisms of NOD2 confer risk for Crohn's disease (CD) and associate with small intestinal disease location. We previously showed in mice that Nod2 deficiency leads to overexpansion of Phocaeicola vulgatus in the gut and downstream goblet cell defects, which preceded small intestinal inflammation. In this study, we ask whether goblet cell defects occur in CD patients with NOD2 polymorphisms and investigate in mice how P. vulgatus signals through the intestinal epithelium.</p><p><strong>Methods: </strong>We performed a retrospective study of patients with CD to assess clinical outcomes and goblet cell histology by NOD2 status. We evaluated the contribution of microbiota and MyD88 signaling in the intestinal epithelium to goblet cell defects in the setting of Nod2 deficiency using genetic mouse models and germ-free mice.</p><p><strong>Results: </strong>In patients with CD who have undergone ileocolic resection, NOD2 risk alleles confer a risk for re-operation (OR 8.12, P = .047) and for increased pERK and goblet cell defects in uninflamed ileal tissue. We show that patients with CD with ileal involvement harbor P. vulgatus regardless of NOD2 risk allele status. We show that intestinal epithelial MyD88 and TLR4 are required for goblet cell defects in Nod2^-/- mice harboring P. vulgatus. Finally, we show that P. vulgatus requires complex microbiota to exert its effects in Nod2-deficient mice.</p><p><strong>Conclusions: </strong>Goblet cell defects may be a harbinger of small intestinal inflammation in CD patients, particularly in the postoperative setting. Our findings in mice show that small intestinal goblet cell loss associated with Nod2 mutation is induced by microbiome dysbiosis and epithelial MyD88, in part due to TLR4 signaling.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101533"},"PeriodicalIF":7.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086929","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":"Intestinal Iron Transporters Facilitate Manganese Absorption Under Non-physiological Conditions.","authors":"James F Collins","doi":"10.1016/j.jcmgh.2025.101519","DOIUrl":"10.1016/j.jcmgh.2025.101519","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101519"},"PeriodicalIF":7.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056237","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":"Lactate facilitates pancreatic repair following acute pancreatitis by promoting reparative macrophage polarization.","authors":"Jing Jiang, Ruiyan Wang, Pengli Song, Qi Peng, Xuerui Jin, Bin Li, Jianbo Ni, Jie Shen, Jingpiao Bao, Zengkai Wu, Xiaolu Ge, Xingpeng Wang, Guoyong Hu","doi":"10.1016/j.jcmgh.2025.101535","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101535","url":null,"abstract":"<p><strong>Background & aims: </strong>During acute pancreatitis (AP), glycolysis is enhanced. The upregulation of glycolysis increases the level of metabolite lactate. Lactate has been shown to facilitate tissue repair across various pathological conditions. However, its role in the recovery following AP remains unclear. This study aims to explore the role of lactate in the regenerative processes following AP and to elucidate its underlying molecular mechanisms.</p><p><strong>Methods: </strong>The caerulein-induced recovery AP model was established using wild type and 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (Pfkfb3) heterozygous mice. Pancreatic repair was evaluated histologically, while lactate levels and inflammatory markers were measured serologically. Macrophages were isolated from pancreatic tissue using fluorescence-activated cell sorting for mRNA sequencing to identify phenotypes. In ex vivo, macrophages were indirectly co-cultured with inflammatory acinar, and the effect of lactate on macrophage phenotype were investigated through immunoprecipitation, fluorescence analysis, and western blotting.</p><p><strong>Results: </strong>We first found that exogenous lactate administration promoted pancreatic repair, while Pfkfb3 deficiency lowered lactate levels and ultimately delayed pancreatic repair. Mechanistically, lactate altered macrophage phenotype during recovery after AP, by reducing the proportion of pro-inflammatory macrophages and increasing the percentage of reparative macrophages. In the indirectly co-cultured macrophage, lactate increased lactylation levels and enhanced repair gene expression. Treatment with AZD3965, a chemical inhibitor of lactate transportation, blocked the effects on lactylation and gene expression. Besides, lactate repressed the JAK2-STAT1 pathway via GPR132 receptor, thereby suppressing the expression of pro-inflammatory genes.</p><p><strong>Conclusions: </strong>Lactate facilitates pancreatic repair by promoting reparative macrophage polarization, achieved through promoting lactylation and inhibiting JAK2-STAT1 signaling. This phenotypic shift alleviates inflammation and facilitates tissue recovery, highlighting a potential therapeutic approach for AP.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101535"},"PeriodicalIF":7.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013798","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":"Intercepting Modes of Cellular Communication.","authors":"Kristin E Claflin, Matthew J Potthoff","doi":"10.1016/j.jcmgh.2025.101531","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101531","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101531"},"PeriodicalIF":7.1,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058891","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}