Pub Date : 2025-01-22DOI: 10.1016/j.jcmgh.2024.101450
Jonathan P Katz, Michele A Battle, Alexander M Vaeth
{"title":"The Evolution of CMGH as The Basic Research Journal in Gastroenterology and Hepatology: \"H\" is for \"Home\".","authors":"Jonathan P Katz, Michele A Battle, Alexander M Vaeth","doi":"10.1016/j.jcmgh.2024.101450","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2024.101450","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101450"},"PeriodicalIF":7.1,"publicationDate":"2025-01-22","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-21DOI: 10.1016/j.jcmgh.2024.101459
Shaimaa Gad, Ruisong Ye, Wei Qiu
{"title":"In vivo CRISPR Activation Screening, a Powerful Tool to Discover Oncogenic Driver Genes in Hepatocellular Carcinoma.","authors":"Shaimaa Gad, Ruisong Ye, Wei Qiu","doi":"10.1016/j.jcmgh.2024.101459","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2024.101459","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101459"},"PeriodicalIF":7.1,"publicationDate":"2025-01-21","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}
Pub Date : 2025-01-17DOI: 10.1016/j.jcmgh.2024.101445
David H Wang
{"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":" ","pages":"101445"},"PeriodicalIF":7.1,"publicationDate":"2025-01-17","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-17DOI: 10.1016/j.jcmgh.2024.101455
Shagun Sharma, Thomas Wallach
{"title":"Nothing but NET: A Novel Model of Alcohol Induced Acute-on-Chronic Liver Failure Demonstrates Both Enhanced Mechanistic Insight and a Possible Therapeutic Pathway.","authors":"Shagun Sharma, Thomas Wallach","doi":"10.1016/j.jcmgh.2024.101455","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2024.101455","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101455"},"PeriodicalIF":7.1,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143016738","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}
Pub Date : 2025-01-15DOI: 10.1016/j.jcmgh.2024.101441
Kim E Barrett
{"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":" ","pages":"101441"},"PeriodicalIF":7.1,"publicationDate":"2025-01-15","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-15DOI: 10.1016/j.jcmgh.2024.101437
Aveline Filliol
{"title":"PKMζ: A Brain Kinase Driving Metabolic Reprogramming and Myofibroblastic Differentiation.","authors":"Aveline Filliol","doi":"10.1016/j.jcmgh.2024.101437","DOIUrl":"10.1016/j.jcmgh.2024.101437","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101437"},"PeriodicalIF":7.1,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886518","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}
Pub Date : 2025-01-15DOI: 10.1016/j.jcmgh.2025.101463
Ning Kuo, Pei Li, Juliana Bragazzi Cunha, Lu Chen, Jordan A Shavit, M Bishr Omary
Background & aims: Erythropoietic protoporphyria (EPP) is caused by mutations in ferrochelatase which inserts iron into protoporphyrin-IX (PP-IX) to generate heme. EPP is characterized by PP-IX accumulation, skin photosensitivity, cholestasis, and end-stage liver disease. Despite available drugs that address photosensitivity, treatment of EPP-related liver disease remains an unmet need.
Methods: We administered delta-aminolaevulinic acid (ALA) and deferoxamine (DFO), which results in PP-IX overproduction and accumulation. High-throughput compound screening of ALA+DFO-treated zebrafish identified chlorcyclizine (first generation H1-antihistamine receptor blocker), as a drug that reduces zebrafish liver PP-IX levels. The effect of chlorcyclizine was validated in porphyrin-loaded primary mouse hepatocytes (PMH), transgenic Fechm1Pas EPP mice, and mice fed the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Plasma and tissue PP-IX were measured by fluorescence; livers were analyzed by histology, immunoblotting, and qPCR.
Results: Chlorcyclizine-treated zebrafish larvae, DDC-fed and transgenic EPP mice manifested reduced hepatic PP-IX levels compared to controls. Histamine increased PP-IX accumulation in porphyrin-stressed hepatocytes, while H1/H2-receptor blockade decreased PP-IX levels. In both mouse models, chlorcyclizine lowered PP-IX level in female but not male mice in liver, erythrocytes, and bone marrow; improved liver injury; decreased porphyrin-triggered protein aggregation and oxidation; and increased clearance of stool PP-IX. In PMH, chlorcyclizine induced nuclear translocation of constitutive androstane and farnesoid X receptors, and transactivated bile acid transporter expression. Knockdown of the transporters BSEP and MRP4 led to increased detection of sequestosome-1 (p62 protein) high-molecular-weight species. Chlorcyclizine also reduced hepatic mast cell number and histamine level in EPP mice.
Conclusions: Histamine plays an important role in PP-IX accumulation in zebrafish and two experimental EPP models. Chlorcyclizine and/or other antihistamines, provide a potential therapeutic strategy to treat EPP-associated liver disease via decreasing PP-IX accumulation.
背景与目的:红细胞生成性原卟啉症(EPP)是由铁螯合酶突变引起的,该酶将铁插入原卟啉- ix (PP-IX)中产生血红素。EPP的特征是PP-IX积聚、皮肤光敏、胆汁淤积和终末期肝病。尽管现有的药物可以解决光敏性问题,但epp相关肝病的治疗仍然是一个未满足的需求。方法:给药氨基乙酸(ALA)和去铁胺(DFO)导致PP-IX过量产生和积累。对ALA+ dfo处理的斑马鱼进行高通量化合物筛选,发现氯环嗪(第一代h1 -抗组胺受体阻滞剂)可降低斑马鱼肝脏PP-IX水平。在载卟啉原代小鼠肝细胞(PMH)、转基因Fechm1Pas EPP小鼠和饲喂卟啉源化合物3,5-二氧羰基-1,4-二氢碰撞碱(DDC)的小鼠中验证了氯环嗪的作用。荧光法测定血浆和组织中PP-IX;采用组织学、免疫印迹和qPCR对肝脏进行分析。结果:与对照组相比,氯环嘧啶处理的斑马鱼幼虫、ddc喂养的和转基因EPP小鼠的肝脏PP-IX水平降低。组胺增加了卟啉应激肝细胞中PP-IX的积累,而H1/ h2受体阻断降低了PP-IX的水平。在两种小鼠模型中,氯环利嗪均能降低雌性小鼠肝脏、红细胞和骨髓中的PP-IX水平,而雄性小鼠没有;改善肝损伤;卟啉引发的蛋白聚集和氧化减少;并增加粪便PP-IX的清除率。在PMH中,氯环嗪诱导构成雄甾烷和法内酯X受体的核易位,并激活胆汁酸转运体的表达。转运蛋白BSEP和MRP4的敲低导致高分子量物种sequestosome-1 (p62蛋白)的检测增加。氯环利嗪还能降低EPP小鼠肝肥大细胞数量和组胺水平。结论:组胺在斑马鱼和两种实验性EPP模型中PP-IX积累中起重要作用。氯环嗪和/或其他抗组胺药通过减少PP-IX的积累,为治疗epp相关的肝脏疾病提供了一种潜在的治疗策略。
{"title":"The histamine pathway is a target to treat hepatic experimental erythropoietic protoporphyria.","authors":"Ning Kuo, Pei Li, Juliana Bragazzi Cunha, Lu Chen, Jordan A Shavit, M Bishr Omary","doi":"10.1016/j.jcmgh.2025.101463","DOIUrl":"10.1016/j.jcmgh.2025.101463","url":null,"abstract":"<p><strong>Background & aims: </strong>Erythropoietic protoporphyria (EPP) is caused by mutations in ferrochelatase which inserts iron into protoporphyrin-IX (PP-IX) to generate heme. EPP is characterized by PP-IX accumulation, skin photosensitivity, cholestasis, and end-stage liver disease. Despite available drugs that address photosensitivity, treatment of EPP-related liver disease remains an unmet need.</p><p><strong>Methods: </strong>We administered delta-aminolaevulinic acid (ALA) and deferoxamine (DFO), which results in PP-IX overproduction and accumulation. High-throughput compound screening of ALA+DFO-treated zebrafish identified chlorcyclizine (first generation H1-antihistamine receptor blocker), as a drug that reduces zebrafish liver PP-IX levels. The effect of chlorcyclizine was validated in porphyrin-loaded primary mouse hepatocytes (PMH), transgenic Fech<sup>m1Pas</sup> EPP mice, and mice fed the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Plasma and tissue PP-IX were measured by fluorescence; livers were analyzed by histology, immunoblotting, and qPCR.</p><p><strong>Results: </strong>Chlorcyclizine-treated zebrafish larvae, DDC-fed and transgenic EPP mice manifested reduced hepatic PP-IX levels compared to controls. Histamine increased PP-IX accumulation in porphyrin-stressed hepatocytes, while H1/H2-receptor blockade decreased PP-IX levels. In both mouse models, chlorcyclizine lowered PP-IX level in female but not male mice in liver, erythrocytes, and bone marrow; improved liver injury; decreased porphyrin-triggered protein aggregation and oxidation; and increased clearance of stool PP-IX. In PMH, chlorcyclizine induced nuclear translocation of constitutive androstane and farnesoid X receptors, and transactivated bile acid transporter expression. Knockdown of the transporters BSEP and MRP4 led to increased detection of sequestosome-1 (p62 protein) high-molecular-weight species. Chlorcyclizine also reduced hepatic mast cell number and histamine level in EPP mice.</p><p><strong>Conclusions: </strong>Histamine plays an important role in PP-IX accumulation in zebrafish and two experimental EPP models. Chlorcyclizine and/or other antihistamines, provide a potential therapeutic strategy to treat EPP-associated liver disease via decreasing PP-IX accumulation.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101463"},"PeriodicalIF":7.1,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143016740","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}
Pub Date : 2025-01-13DOI: 10.1016/j.jcmgh.2025.101462
Sushmita Debnath, Dante J Heredia, Nicole M Procacci, Camila Fedi, Emer P Ni Bhraonain, Caroline A Cobine, Thomas W Gould
Background and aims: Gastrointestinal motility persists when peripheral cholinergic signaling is blocked genetically or pharmacologically, and a recent study suggests nitric oxide drives propagating neurogenic contractions.
Methods: To determine the neuronal substrates that underlie these contractions, we measured contractile-associated movements together with calcium responses of cholinergic or nitrergic myenteric neurons in un-paralyzed ex vivo preparations of whole mouse colon. We chose to look at these two subpopulations because they encompass nearly all myenteric neurons.
Results: Many but not all cholinergic neurons of the middle colon exhibited contractile-associated calcium responses with distinct features. By contrast, a large population of nitrergic neurons of the middle colon shut their activity off just before contraction onset, whereas another population of nitrergic neurons initiated a response just after contraction onset. When contractions were evoked by a variety of stimuli to the proximal and distal colon, the same neuronal subtypes exhibited the same activity patterns during the contraction. However, stimulation of proximal colon produced a transient, stimulation-locked response before the ensuing contraction in a subpopulation of cholinergic neurons and in nearly all nitrergic neurons, suggesting that distinct neuronal activity patterns underlie specific stimuli. Finally, although blockade of nitric oxide failed to arrest the generation or propagation of neurogenic contractions, chemogenetic elimination of nitrergic activity impaired their propagation to middle and distal colon.
Conclusions: Genetic approaches were used to study the activity patterns of enteric neurons underlying spontaneous and evoked neurogenic contractions in un-paralyzed colon. These approaches can be combined with a variety of other approaches to identify the neuronal subtypes and subclasses that coordinate colonic motility.
{"title":"Enteric neuronal substrates underlying spontaneous and evoked neurogenic contractions in mouse colon.","authors":"Sushmita Debnath, Dante J Heredia, Nicole M Procacci, Camila Fedi, Emer P Ni Bhraonain, Caroline A Cobine, Thomas W Gould","doi":"10.1016/j.jcmgh.2025.101462","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101462","url":null,"abstract":"<p><strong>Background and aims: </strong>Gastrointestinal motility persists when peripheral cholinergic signaling is blocked genetically or pharmacologically, and a recent study suggests nitric oxide drives propagating neurogenic contractions.</p><p><strong>Methods: </strong>To determine the neuronal substrates that underlie these contractions, we measured contractile-associated movements together with calcium responses of cholinergic or nitrergic myenteric neurons in un-paralyzed ex vivo preparations of whole mouse colon. We chose to look at these two subpopulations because they encompass nearly all myenteric neurons.</p><p><strong>Results: </strong>Many but not all cholinergic neurons of the middle colon exhibited contractile-associated calcium responses with distinct features. By contrast, a large population of nitrergic neurons of the middle colon shut their activity off just before contraction onset, whereas another population of nitrergic neurons initiated a response just after contraction onset. When contractions were evoked by a variety of stimuli to the proximal and distal colon, the same neuronal subtypes exhibited the same activity patterns during the contraction. However, stimulation of proximal colon produced a transient, stimulation-locked response before the ensuing contraction in a subpopulation of cholinergic neurons and in nearly all nitrergic neurons, suggesting that distinct neuronal activity patterns underlie specific stimuli. Finally, although blockade of nitric oxide failed to arrest the generation or propagation of neurogenic contractions, chemogenetic elimination of nitrergic activity impaired their propagation to middle and distal colon.</p><p><strong>Conclusions: </strong>Genetic approaches were used to study the activity patterns of enteric neurons underlying spontaneous and evoked neurogenic contractions in un-paralyzed colon. These approaches can be combined with a variety of other approaches to identify the neuronal subtypes and subclasses that coordinate colonic motility.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101462"},"PeriodicalIF":7.1,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143016736","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}
Background & aims: The incidence of graft fibrosis is elevated following 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.
Methods: We tested the hypothesis by analyzing multi-omics data from human protocol liver biopsy samples 2 years after liver transplant, performing rat LT with different CIT and conducting in vitro studies in HSC cell lines with MYL9 knockdown and overexpression.
Results: 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 following MYL9 knockdown. Conversely, overexpression of the 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 TLR4 signaling was inhibited in rats.
Conclusions: Our findings demonstrates the prolonged CIT upregulates the expression of MYL9 in liver graft after LT. MYL9 activates HSCs and promotes fibrosis through a TLR4/MYD88/NF-κB signaling dependent manner.
{"title":"Myosin light chain 9 mediates graft fibrosis after pediatric liver transplantation through TLR4/MYD88/NF-κB signaling.","authors":"Zhixin Zhang, Chong Dong, Shengqiao Zhao, Zhuyuan Si, Weiping Zheng, Kai Wang, Chao Sun, Zhuolun Song, Wei Gao","doi":"10.1016/j.jcmgh.2024.101453","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2024.101453","url":null,"abstract":"<p><strong>Background & aims: </strong>The incidence of graft fibrosis is elevated following 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.</p><p><strong>Methods: </strong>We tested the hypothesis by analyzing multi-omics data from human protocol liver biopsy samples 2 years after liver transplant, performing rat LT with different CIT and conducting in vitro studies in HSC cell lines with MYL9 knockdown and overexpression.</p><p><strong>Results: </strong>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 following MYL9 knockdown. Conversely, overexpression of the 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 TLR4 signaling was inhibited in rats.</p><p><strong>Conclusions: </strong>Our findings demonstrates the prolonged CIT upregulates the expression of MYL9 in liver graft after LT. MYL9 activates HSCs and promotes fibrosis through a TLR4/MYD88/NF-κB signaling dependent manner.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101453"},"PeriodicalIF":7.1,"publicationDate":"2025-01-06","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-03DOI: 10.1016/j.jcmgh.2024.101447
Marianne R Spalinger, Golshid Sanati, Pritha Chatterjee, Rong Hai, Jiang Li, Alina N Santos, Tara M Nordgren, Michel L Tremblay, Lars Eckmann, Elaine Hanson, Michael Scharl, Xiwei Wu, Brigid S Boland, Declan F McCole
Background & aims: 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, PTPN2, which also confers elevated risk to develop inflammatory bowel disease, affects susceptibility to SARS-CoV-2 viral uptake.
Methods: Using samples from PTPN2 genotyped patients with inflammatory bowel disease, PTPN2-deficient mice, and human intestinal and lung epithelial cell lines, we investigated how PTPN2 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.
Results: We report that the autoimmune PTPN2 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.
Conclusion: 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.
{"title":"Tofacitinib Mitigates the Increased SARS-CoV-2 Infection Susceptibility Caused by an IBD Risk Variant in the PTPN2 Gene.","authors":"Marianne R Spalinger, Golshid Sanati, Pritha Chatterjee, Rong Hai, Jiang Li, Alina N Santos, Tara M Nordgren, Michel L Tremblay, Lars Eckmann, Elaine Hanson, Michael Scharl, Xiwei Wu, Brigid S Boland, Declan F McCole","doi":"10.1016/j.jcmgh.2024.101447","DOIUrl":"10.1016/j.jcmgh.2024.101447","url":null,"abstract":"<p><strong>Background & aims: </strong>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, PTPN2, which also confers elevated risk to develop inflammatory bowel disease, affects susceptibility to SARS-CoV-2 viral uptake.</p><p><strong>Methods: </strong>Using samples from PTPN2 genotyped patients with inflammatory bowel disease, PTPN2-deficient mice, and human intestinal and lung epithelial cell lines, we investigated how PTPN2 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.</p><p><strong>Results: </strong>We report that the autoimmune PTPN2 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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101447"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}