Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"Cover","authors":"","doi":"10.1016/S2352-345X(24)00187-5","DOIUrl":"10.1016/S2352-345X(24)00187-5","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 1","pages":"Article 101432"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143135559","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":"Activation of AMP-activated Protein Kinase by Metformin Inhibits Dedifferentiation of Platelet-derived Growth Factor-BB-induced Vascular Smooth Muscle Cells to Improve Arterial Remodeling in Cirrhotic Portal Hypertension","authors":"Guangbo Wu , Qiang Fan , Min Chen , Guqing Luo, Zhenghao Wu, Jinbo Zhao, Jiayun Lin, Chihao Zhang, Hongjie Li, Xiaoliang Qi, Haizhong Huo, Lei Zheng, Meng Luo","doi":"10.1016/j.jcmgh.2025.101487","DOIUrl":"10.1016/j.jcmgh.2025.101487","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Portal hypertension (PHT) is the potentially deadly complication of liver cirrhosis. Intrahepatic vascular resistance and the splanchnic hyperdynamic circulation are 2 principal driving factors contributing to the maintenance and exacerbation of PHT. However, in the advanced stages of cirrhosis, the fibrotic process in the liver becomes irreversible, leading to persistent and intractable increases in intrahepatic vascular resistance. Arterial remodeling emerges as a crucial mechanism driving the hyperdynamic splanchnic circulation. Therefore, ameliorating the hyperdynamic splanchnic circulation has become an indispensable component of PHT therapeutic strategies.</div></div><div><h3>Methods</h3><div>Liver cirrhosis with PHT was induced in the rats by common bile duct ligation (BDL). Based on the transcriptomic sequencing of the mesenteric arteries, we investigated the effects and mechanisms of metformin on the arterial remodeling at different stages of cirrhosis. We further validated potential molecular mechanisms through <em>in vitro</em> experiments using the A7r5 smooth muscle cell line and primary vascular smooth muscle cells (VSMCs).</div></div><div><h3>Results</h3><div>Our findings revealed the beneficial effects of metformin on liver cirrhosis and PHT in rats following BDL for 4 and 6 weeks. Metformin was observed to ameliorate PHT and splanchnic hyperdynamic circulation in BDL rats, even in the advanced stages of liver cirrhosis. This effect was evidenced by reduced portal pressure and cardiac output, decreased superior mesenteric artery (SMA) flow, accompanied by improvements in systemic vascular resistance and SMA resistance. Moreover, chronic inflammation in BDL rats was alleviated by metformin, which might inhibit the driving factors of angiogenesis and arterial remodeling. Notably, SMA dilation and arterial remodeling in BDL rats were potent alleviated following metformin treatment. Metformin ameliorated arterial remodeling in BDL rats by inhibiting the dedifferentiation of contractile VSMCs, resulting in the upregulation of contractile protein expressions such as alpha-smooth muscle actin (α-SMA) and smooth muscle 22α (SM22α). Platelet-derived growth factor-BB (PDGF-BB)/platelet-derived growth factor receptor beta (PDGFR-β) signaling exerted crucial roles in regulating the VSMCs cell phenotype. Activation of AMP-activated protein kinase (AMPK) by metformin blocked the downstream pathway of PDGF-BB/PDGFRβ. Furthermore, <em>in vitro</em> cell experiments, VSMCs were respectively treated with AMPK activator metformin or AMPK inhibitor Compound C. We revealed the molecular mechanism that metformin inhibited the phenotypic switching of A7r5 cells induced by PDGF-BB and primary VSMCs from BDL rats, which was mediated by activating AMPK to enhance the expression of contractile protein α-SMA. These findings suggest that AMPK can ameliorate the progression of arterial remodeling during PHT via suppressi","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 6","pages":"Article 101487"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538136","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":"Studies of Slc30a10 Deficiency in Mice Reveal That Intestinal Iron Transporters Dmt1 and Ferroportin Transport Manganese","authors":"Milankumar Prajapati ,&nbsp;Jared Z. Zhang ,&nbsp;Grace S. Chong ,&nbsp;Lauren Chiu ,&nbsp;Courtney J. Mercadante ,&nbsp;Heather L. Kowalski ,&nbsp;Olga Antipova ,&nbsp;Barry Lai ,&nbsp;Martina Ralle ,&nbsp;Brian P. Jackson ,&nbsp;Tracy Punshon ,&nbsp;Shuling Guo ,&nbsp;Mariam Aghajan ,&nbsp;Thomas B. Bartnikas","doi":"10.1016/j.jcmgh.2025.101489","DOIUrl":"10.1016/j.jcmgh.2025.101489","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>SLC11A2 (DMT1) and SLC40A1 (ferroportin) are essential for dietary iron absorption, but their role in manganese transport is debated. SLC30A10 deficiency causes severe manganese excess due to loss of gastrointestinal manganese excretion. Patients are treated with chelators but also respond to oral iron, suggesting that iron can outcompete manganese for absorption in this disease. Here, we determine if divalent metal transport 1 (Dmt1) and ferroportin can transport manganese using Slc30a10-deficient mice as a model.</div></div><div><h3>Methods</h3><div>Manganese absorption and levels and other disease parameters were assessed in <em>Slc30a10</em>^<em>-/-</em> mice with and without intestinal Dmt1 and ferroportin deficiency using gastric gavage, surgical bile collections, multiple metal assays, and other techniques. The contribution of intestinal Slc30a10 deficiency to ferroportin-dependent manganese absorption was explored by determining if intestinal Slc30a10 deficiency increases manganese absorption in a mouse model of hereditary hemochromatosis, a disease of iron excess due to ferroportin upregulation.</div></div><div><h3>Results</h3><div>Manganese absorption was increased in Slc30a10-deficient mice despite manganese excess. Intestinal Dmt1 and ferroportin deficiency attenuated manganese absorption and excess in Slc30a10-deficient mice. Intestinal Slc30a10 deficiency increased manganese absorption and levels in the hemochromatosis mouse model.</div></div><div><h3>Conclusions</h3><div>Aberrant absorption contributes prominently to SLC30A10 deficiency, a disease previously attributed to impaired excretion, and is dependent upon intestinal Dmt1 and ferroportin and exacerbated by loss of intestinal Slc30a10. This work expands our understanding of overlaps between manganese and iron transport and the mechanisms by which the body regulates absorption of 2 nutrients that can share transport pathways. We propose that a reconsideration of the role of Dmt1 and ferroportin in manganese homeostasis is warranted.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 7","pages":"Article 101489"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538200","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 Protective Role of DDIT4 in Helicobacter pylori-induced Gastric Metaplasia Through Metabolic Regulation of Ferroptosis","authors":"Huan Wang ,&nbsp;Xinbo Xu ,&nbsp;Yaobin Ouyang ,&nbsp;Xiao Fei ,&nbsp;Cong He ,&nbsp;Xianhe Yang ,&nbsp;Yuping Ren ,&nbsp;Yanan Zhou ,&nbsp;Sihai Chen ,&nbsp;Yi Hu ,&nbsp;Jianping Liu ,&nbsp;Zhongming Ge ,&nbsp;William Ka Kei Wu ,&nbsp;Nonghua Lu ,&nbsp;Chuan Xie ,&nbsp;Xidong Wu ,&nbsp;Yin Zhu ,&nbsp;Nianshuang Li","doi":"10.1016/j.jcmgh.2024.101448","DOIUrl":"10.1016/j.jcmgh.2024.101448","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div><em>Helicobacter pylori</em> (<em>H pylori</em>) infection is a significant factor leading to gastric atrophy, metaplasia and cancer development. Here, we investigated the role of the stress response gene DDIT4 in the pathogenesis of <em>H pylori</em> infection.</div></div><div><h3>Methods</h3><div>Cell lines, transgenic mice, and human tissue samples were implemented. Proteomics were performed on <em>Ddit4</em>^<em>+/+</em> and <em>Ddit4</em>^<em>-/-</em> mice infected with <em>H pylori</em> strain PMSS1. C57BL/6 mice were administered with tamoxifen to induce gastric metaplasia. Stomach tissues were analyzed for histopathologic features, reactive oxygen species, Fe²⁺, lipid peroxidation, expression of DDIT4, and ferroptosis-related proteins.</div></div><div><h3>Results</h3><div>DDIT4 expression was upregulated at 6 hours but significantly decreased at 24 hours in response to <em>H pylori</em> infection in gastric epithelial cells. Gastric DDIT4 were downregulated in INS-GAS mice at 4 months post <em>H pylori</em> infection. Notably, <em>H pylori</em> infection led to more severe gastric metaplasia lesion in <em>Ddit4</em>-knockout mice. The proteomic profiling revealed an increase in ferroptosis in the gastric tissues of infected <em>Ddit4</em>-deficient mice, compared with infected wild-type mice. Mechanistically, knockout of DDIT4 promoted <em>H pylori</em>-induced ferroptosis through the accumulation of lipid peroxides and ROS levels, and alterations in proteins such as GPX4, ALOX15, and HMOX1. Overexpression of DDIT4 counteracted <em>H pylori</em>-induced stem cell marker CD44V9 through modulation of ferroptosis. Similarly, in another mouse model of gastric metaplasia treated with tamoxifen, as well as in human GIM tissues, we observed the loss of DDIT4 and induction of ferroptosis.</div></div><div><h3>Conclusions</h3><div>Our results indicate that DDIT4 serves as a protective factor against <em>H pylori</em>-induced gastric metaplasia by metabolic resistance to ferroptosis.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 5","pages":"Article 101448"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411715","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":"Periplakin Attenuates Liver Fibrosis via Reprogramming CD44Low Cells into CD44High Liver Progenitor Cells","authors":"Lichao Zhang ,&nbsp;Zhiyong Xiong ,&nbsp;Zebin Chen ,&nbsp;Meiyining Xu ,&nbsp;Siyu Zhao ,&nbsp;Xianzhi Liu ,&nbsp;Kefeng Jiang ,&nbsp;Yunyi Hu ,&nbsp;Shurui Liu ,&nbsp;Xi Sun ,&nbsp;Zhongdao Wu ,&nbsp;Jia Shen ,&nbsp;Lifu F. Wang","doi":"10.1016/j.jcmgh.2025.101498","DOIUrl":"10.1016/j.jcmgh.2025.101498","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Liver progenitor cells (LPCs) contribute significantly to the restoration of injured liver parenchyma and promote liver regeneration, thereby ameliorating liver fibrosis. However, the mechanism of the derivation of LPCs remains poorly understood.</div></div><div><h3>Methods</h3><div>We first examined the expression of periplakin (PPL) in patients and mouse models with liver fibrosis. Adenovirus overexpressing PPL was injected into the tail vein of mouse models to detect the regulatory effect of PPL on liver fibrosis. Single-cell sequencing explored how PPL influences liver fibrosis progression. Additionally, PPL⁺CD44^Low cells and PPL⁺CD44^High LPCs were transplanted into 3,5-diethoxycarbonyl-1,4-dihydrocollidine–induced mouse models to assess their therapeutic efficacy in treating liver fibrosis.</div></div><div><h3>Results</h3><div>The expression of PPL is upregulated in fibrotic livers in human and mouse models of liver fibrosis. Functionally, we found that PPL overexpression significantly attenuated liver fibrosis. Mechanistically, PPL was specifically expressed in LPCs and promoted LPC expansion. Moreover, we observed that PPL⁺ cells could be categorized into PPL⁺CD44^Low and PPL⁺CD44^High subsets, and PPL⁺CD44^Low cells were found to redifferentiate into PPL⁺CD44^High LPCs during liver fibrosis. Furthermore, transplantation of PPL⁺CD44^High LPCs notably suppressed liver fibrosis.</div></div><div><h3>Conclusions</h3><div>These findings demonstrate that PPL⁺CD44^Low cells can be reprogrammed into PPL⁺CD44^High LPCs, which ameliorate liver fibrosis, suggesting a potential application of PPL for the treatment of liver fibrosis.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 7","pages":"Article 101498"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665522","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":"Cellular Crosstalk Promotes Hepatic Progenitor Cell Proliferation and Stellate Cell Activation in 3D Co-culture","authors":"Maya W. Haaker ,&nbsp;Jung-Chin Chang ,&nbsp;Brian K. Chung ,&nbsp;Tobias S. Pieper ,&nbsp;Falko Noé ,&nbsp;Tongtong Wang ,&nbsp;Niels Geijsen ,&nbsp;Martin Houweling ,&nbsp;Christian Wolfrum ,&nbsp;Arie B. Vaandrager ,&nbsp;Espen Melum ,&nbsp;Bart Spee ,&nbsp;J. Bernd Helms","doi":"10.1016/j.jcmgh.2025.101472","DOIUrl":"10.1016/j.jcmgh.2025.101472","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Following liver damage, ductular reaction often coincides with liver fibrosis. Proliferation of hepatic progenitor cells is observed in ductular reaction, whereas activated hepatic stellate cells (HSCs) are the main drivers of liver fibrosis. These observations may suggest a functional interaction between these 2 cell types. Here, we report on an <em>in vitro</em> co-culture system to examine these interactions and validate their co-expression in human liver explants.</div></div><div><h3>Methods</h3><div>In a 3D organoid co-culture system, we combined freshly isolated quiescent mouse HSCs and fluorescently labeled progenitor cells (undifferentiated intrahepatic cholangiocyte organoids), permitting real-time observation of cell morphology and behavior. After 7 days, cells were sorted based on the fluorescent label and analyzed for changes in gene expression.</div></div><div><h3>Results</h3><div>In the 3D co-culture system, the proliferation of progenitor cells is enhanced, and HSCs are activated, recapitulating the cellular events observed in the patient liver. Both effects in 3D co-culture require close contact between the 2 different cell types. HSC activation during 3D co-culture differs from quiescent (3D mono-cultured) HSCs and activated HSCs on plastic (2D mono-culture). Upregulation of a cluster of genes containing <em>Aldh1a2</em>, <em>Cthrc1</em>, and several genes related to frizzled binding/Wnt signaling were exclusively observed in 3D co-cultured HSCs. The localized co-expression of specific genes was confirmed by spatial transcriptomics in human liver explants.</div></div><div><h3>Conclusion</h3><div>An <em>in vitro</em> 3D co-culture system provides evidence for direct interactions between HSCs and progenitor cells, which are sufficient to drive responses that are similar to those seen during ductular reaction and fibrosis. This model paves the way for further research into the cellular basis of liver pathology.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 5","pages":"Article 101472"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076594","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":"Splicing, Signaling, and Survival: The Role of RBM39 in Cholangiocarcinoma Progression","authors":"Meng Xu,&nbsp;Diego F. Calvisi,&nbsp;Xin Chen","doi":"10.1016/j.jcmgh.2024.101419","DOIUrl":"10.1016/j.jcmgh.2024.101419","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 1","pages":"Article 101419"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142570578","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":"Cover","authors":"","doi":"10.1016/S2352-345X(25)00008-6","DOIUrl":"10.1016/S2352-345X(25)00008-6","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101467"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403268","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":"Sphingosine Kinase 1 – A Therapeutic Opportunity for Alleviating Liver Fibrosis?","authors":"Jia Ming Nickolas Teo,&nbsp;Guang Sheng Ling","doi":"10.1016/j.jcmgh.2024.101430","DOIUrl":"10.1016/j.jcmgh.2024.101430","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 2","pages":"Article 101430"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793096","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":"Early Onset Colorectal Cancer: Molecular Underpinnings Accelerating Occurrence","authors":"Atehkeng Zinkeng ,&nbsp;F. Lloyd Taylor ,&nbsp;Samuel H. Cheong ,&nbsp;Heyu Song ,&nbsp;Juanita L. Merchant","doi":"10.1016/j.jcmgh.2024.101425","DOIUrl":"10.1016/j.jcmgh.2024.101425","url":null,"abstract":"<div><div>The onset of colorectal cancer (CRC) in patients younger than 50 continues to rapidly increase. This study highlights the epidemiologic changes, risk factors, clinical characteristics, and molecular profiles prevalent in early onset CRC patients, and identifies key areas for future research. It has been noted that only a small fraction of early onset CRC cases is attributed to known hereditary mutations and fit the canonical pathway of late-onset colorectal cancer development. To highlight this, we review the genetic and epigenetic modifications specific to early onset CRC. We also discuss the synergetic effect of single-nucleotide polymorphisms and environmental factors on the early onset of CRC. Additionally, we discuss the potential of noninvasive biomarker assays to enhance early detection, screening, diagnosis, and prognostic outcome predictions.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 2","pages":"Article 101425"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607582","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}