American journal of physiology. Gastrointestinal and liver physiology最新文献

{"title":"A novel gene therapy for ARPKD based on CFTR.","authors":"Cristian Ciobanu, Patricia Outeda, William B Guggino, Liudmila Cebotaru","doi":"10.1152/ajpgi.00109.2025","DOIUrl":"10.1152/ajpgi.00109.2025","url":null,"abstract":"<p><p>Autosomal recessive polycystic kidney disease (ARPKD) is associated with cysts derived from abnormal bile ducts. We focused on targeting the cysts and show that a gene therapy for ARPKD that targets the abnormal bile ducts is feasible. We injected 1-mo-old, <i>Pkhd1</i>^{del3-4/del3-4} mice intraperitoneally with 2 × 10¹² particles/kg of adeno-associated virus (AAV1) containing either a GFP vector or a truncated cystic fibrosis transmembrane conductance regulator (CFTR) vector, Δ27-264-CFTR, or left them untreated. Two months after treatment, the cyst area and size in the liver were lower in the CFTR vector-treated mice than in mice receiving the GFP vector. We detected vector genomes and mRNA expression only in mice receiving the corresponding CFTR or GFP vector. We observed abundant GFP immunofluorescence in the cholangiocytes of the cysts and also saw expression of GFP and CFTR proteins above background levels in the corresponding treated mice. CFTR immunofluorescence was predominantly apically located in the ARPKD cholangiocytes, but after CFTR vector installation, it increased in the basolateral membrane. We stained mouse livers with <i>Maackia amurensis</i> lectin (MAL) or <i>Sambucus nigra</i> lectin (SNA), specific for α2,3- and α2,6-N-linked sialic acid, respectively, to detect the presence of sialic acid moieties contributing to AAV1 binding. Although immunofluorescent SNA was detected in the wild-type bile ducts, MAL 1 was not. MAL immunofluorescence was present in remarkably high levels on the apical surfaces of the cysts in cholangiocytes, offering a good target for AAV gene therapy. A gene therapy using an AAV1-based vector containing a truncated CFTR could be therapeutic in ARPKD.<b>NEW & NOTEWORTHY</b> Autosomal recessive polycystic kidney disease (ARPKD) causes severe disease in babies in the womb. Those who survive the neonatal period face chronic kidney and liver disease throughout their life. The overall goal of our study here is to develop a gene therapy to treat ARPKD.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G434-G442"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Budding baboon blues: the prenatal diet lands a lasting gut punch.","authors":"Anna Grigorian, Mengyun Wu, Jerrold R Turner","doi":"10.1152/ajpgi.00252.2025","DOIUrl":"10.1152/ajpgi.00252.2025","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G510-G512"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144939552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging advances in intestinal models for in vitro preclinical research.","authors":"Precious Adedayo Adesina, Masato Ooka, Charlotte TeKrony, Menghang Xia","doi":"10.1152/ajpgi.00087.2025","DOIUrl":"10.1152/ajpgi.00087.2025","url":null,"abstract":"<p><p>Traditional in vitro intestinal model systems frequently fail to accurately replicate human intestinal physiology for absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessments. These limitations, coupled with the growing demand for faster drug discovery and high-throughput screening capabilities, have refined more physiologically relevant models. Recent advancements have led to the development of cell-based intestinal systems that better reflect in vivo conditions, ranging from monolayer and coculture models to complex three-dimensional (3-D) cell culture systems, microfluidic devices, and bioengineered models. This review provides a comprehensive overview of current progress, ongoing challenges, and future directions in developing and applying human in vitro intestinal models for chemical testing.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G403-G416"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum for Lastuvkova et al., 2025, volume 328, p. G558-G577.","authors":"","doi":"10.1152/ajpgi.00262.2024_COR","DOIUrl":"https://doi.org/10.1152/ajpgi.00262.2024_COR","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"329 3","pages":"G433"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144939521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic insights into intestinal stem cell disruption during infection.","authors":"Naomi Chege, Constance A M Finney","doi":"10.1152/ajpgi.00352.2024","DOIUrl":"10.1152/ajpgi.00352.2024","url":null,"abstract":"<p><p>The intestinal epithelium is in continual flux. It must balance maintaining a healthy microbiota with detecting and destroying intestinal pathogens. Intestinal stem cells (ISCs), which sit in the crypts below the intestinal villi, control this process. Depending on the molecular signals they receive, ISCs rapidly differentiate into the different intestinal epithelial cell subsets, making the intestine a remarkably adaptable organ. However, pathogens can hijack ISC functions to their advantage and establish infections. In this review, we explore the mechanisms used by pathogens to exploit ISCs.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G371-G389"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hysteresis of the lower esophageal sphincter: relevance to the pathogenesis of esophageal achalasia and its phenotypes.","authors":"Anand S Jain, William Breaux, Joshua K Robertson, Se-Eun Kim, Billynda McAdoo, Steven Keilin, Felix Fernandez, Shanthi Srinivasan, Ravinder K Mittal","doi":"10.1152/ajpgi.00089.2025","DOIUrl":"10.1152/ajpgi.00089.2025","url":null,"abstract":"<p><p>Hysteresis is a change in strain for a given repeated stress; it is a material property of the viscoelastic tissues. We aimed to determine hysteresis of the esophagogastric junction (EGJ) in patients with esophageal achalasia and differences in EGJ hysteresis in different achalasia phenotypes. In a cross-sectional study design, we measured the change in EGJ distensibility index (DI) with repeated distensions (a marker of hysteresis) and the effects of atropine on the DI using functional lumen imaging probe in 40 patients with esophageal achalasia (types 1, 2, and 3). The DI increased significantly with second distension (hysteresis) as compared with first distension, but not with subsequent ones. Atropine, which ablates active smooth muscle contraction, had no effect on the DI value. Patients with type 1 esophageal achalasia and those with severe dilatation (stage III and IV disease) had a higher DI and lower hysteresis, as compared with esophageal achalasia subtypes 2 and 3. A low DI following atropine suggests that the passive elements (viscoelastic properties) of EGJ are an important cause of low DI in esophageal achalasia. Hysteresis of the EGJ, a material property of the viscoelastic tissue, is different in different achalasia subtypes.<b>NEW & NOTEWORTHY</b> Hysteresis, a key biomechanical property of the esophagogastric junction (EGJ), may play a crucial role in achalasia pathogenesis. Using functional lumen imaging probe (FLIP) topography, we demonstrate that EGJ distensibility increases with repeated distensions, with subtype-dependent variability. Our findings suggest that hysteresis is associated with achalasia progression and treatment outcomes, offering novel insights into esophageal biomechanics. These results may guide refinements in FLIP-based diagnostics and inform future therapeutic approaches targeting determinants of hysteresis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G500-G509"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12413816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholangiocytes' primary cilia regulate DNA damage response and repair.","authors":"Estanislao Peixoto, Kishor Pant, Seth Richard, Juan Pablo Popoca, Juan E Abrahante, Wioletta Czaja, Sergio A Gradilone","doi":"10.1152/ajpgi.00055.2025","DOIUrl":"10.1152/ajpgi.00055.2025","url":null,"abstract":"<p><p>Primary cilia have been considered tumor-suppressing organelles in cholangiocarcinoma (CCA), though the mechanisms behind their protective role are not fully understood. This study investigates how the loss of primary cilia affects DNA damage response (DDR) and DNA repair processes. Human cholangiocyte cell lines were used to examine the colocalization of DNA repair proteins at the cilia and assess the impact of experimental deciliation on DNA repair pathways. Deciliation was induced using shRNA knockdown or CRISPR knockout of IFT20, IFT88, or KIF3A, followed by exposure to the genotoxic agents cisplatin, methyl methanesulfonate (MMS), or irradiation. Cell survival, cell cycle progression, and apoptosis rates were evaluated, and DNA damage was assessed using comet assays and phosphorylated H2AX (γH2AX) quantification. An in vivo liver-specific IFT88 knockout model, generated using Albumin-Cre/Lox recombination, was used to study the loss of primary cilia in the liver. Results showed that RAD51 localized predominantly at the base of the cilium, whereas Ataxia Telangiectasia and Rad3-related protein (ATR), PARP1, CHK1, and CHK2 were also detected within the ciliary shaft. Deciliated cells displayed dysregulation in critical DNA repair pathways. These cells also showed reduced survival and increased S-phase arrest after genotoxic challenges as compared with ciliated cells. Enhanced DNA damage was observed via increased γH2AX signals and comet assay results. An increase in γH2AX expression was also observed in our in vivo model, indicating elevated DNA damage. In addition, key DDR proteins such as Ataxia Telangiectasia Mutated protein (ATM), p53, and p21, were downregulated in deciliated cells after irradiation. This study underscores the crucial role of primary cilia in regulating DNA repair and suggests that targeting cilia-related mechanisms could present a novel therapeutic approach for CCA.<b>NEW & NOTEWORTHY</b> Our study reveals a novel link between primary cilia and DNA repair in cholangiocytes. We show that DNA damage response (DDR) and repair proteins localize to cilia, and deciliation impairs survival and induces S-phase arrest under genotoxic stress. Deciliated cells exhibit increased DNA damage after cisplatin, irradiation, or methyl methanesulfonate (MMS) challenge. Following irradiation, Ataxia Telangiectasia Mutated protein (ATM), p53, and p21 are downregulated in deciliated cells. Similarly, IFT88 knockout mice show heightened DNA damage, highlighting the role of primary cilia in genome stability.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G469-G483"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stress during pregnancy alters hepatic renin-angiotensin system and redox homeostasis in a sex- and age-specific manner.","authors":"Gabriel Fernandes Teixeira, Juliana Mentzinger, Juliana Arruda de Souza Monnerat, Bianca Bittencourt Lucchetti, Mariana Silva Cytrangulo, Luiza Rocha, Lívia Alves de Oliveira, Matheus Alves Bittencourt, Renata Frauches Medeiros, Antonio Claudio Lucas da Nóbrega, Helena Naly Miguens Rocha, Natália Galito Rocha","doi":"10.1152/ajpgi.00142.2025","DOIUrl":"10.1152/ajpgi.00142.2025","url":null,"abstract":"<p><p>The hypothesis of the development and origin of health and disease (DOHaD) highlights the relationship between exposure to harmful stimuli during pregnancy and the increased cardiometabolic risk in the offspring's adulthood. It is believed that the renin-angiotensin system (RAS) plays a central role in stress-induced hepatic programming. To determine the effects of prenatal stress, sex, and age on hepatic RAS of the offspring, pregnant Wistar rats were divided into control and stress groups. The unpredictable stress protocol was performed in the last week of pregnancy. The offspring were divided according to sex, age, and intervention. At 90 and 120 days, the offspring's blood and liver were collected to measure hepatic enzyme activity, isoprostane levels, and protein expression of the RAS and redox balance. At 90 days old, stress similarly reduced NOX4 in both sexes, whereas NOX2, NOX2/NOX4 ratio, and isoprostane were increased only in female offspring. Stress responses of NOX2 were still higher in females when compared with males. At 120 days, prenatal stress increased the activity of aspartate transaminase (AST) and alanine transaminase (ALT) in females, whereas it decreased AST in males. Furthermore, stress enhances the expression of angiotensin II type 1 receptor, ACE, and Mas receptor in males, whereas reducing NOX2/NOX4 ratio. Still, stress reduced ACE2 expression and continued to increase NOX2/NOX4 ratio in females at 120 days. Prenatal stress induces hepatic programming in offspring in a sex- and age-specific way, altering the RAS and NOX4 pathways at 120-day-old males while inducing early redox changes in females at 90 days and remaining at 120 days.<b>NEW & NOTEWORTHY</b> Prenatal stress may contribute to sex- and age-specific programming of the liver in adult offspring. Our results showed that stress during pregnancy alters the hepatic renin-angiotensin system only at 120-days old and specially in male offspring. Furthermore, the prenatal stress leads to redox imbalances in females at 90 days and remaining at 120 days old independently of the renin-angiotensin system.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G420-G432"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"This is not your off-the-shelf IPA.","authors":"Ji Yeon Kim, Sean P Colgan","doi":"10.1152/ajpgi.00239.2025","DOIUrl":"10.1152/ajpgi.00239.2025","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G417-G419"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Armillariella tabescens</i> polysaccharides alleviate ER stress in 5-FU-induced intestinal epithelial injury and mucositis via ARRB1 modulation.","authors":"Zhongxuan Gui, Yingquan Ye, Mengru Yuan, Ting Wang, Xinru Wan, Ping Li, Haili Jiang, Mei Zhang","doi":"10.1152/ajpgi.00348.2024","DOIUrl":"10.1152/ajpgi.00348.2024","url":null,"abstract":"<p><p><i>Armillariella tabescens</i> polysaccharides (ATPS) were investigated for their protective effects against 5-fluorouracil (5-FU)-induced intestinal mucositis in intestinal epithelial cell 6 (IEC-6) cells and a murine model, with a focus on the role of β-arrestin1 (ARRB1) in endoplasmic reticulum stress (ERS) suppression. The study evaluated cell viability, apoptosis, inflammatory cytokine secretion (interleukin-1β, interleukin-6, tumor necrosis factor-α), and lactate dehydrogenase (LDH) release in IEC-6 cells, whereas diarrhea severity, body weight loss, intestinal histopathology, and tight junction protein expression were assessed in C57BL/6 mice. Western blot, immunohistochemistry, and transmission electron microscopy were used to investigate the underlying mechanisms of ATPS-mediated ERS inhibition. ATPS significantly improved cell survival and proliferation, reduced inflammatory cytokines and apoptosis, alleviated diarrhea severity, mitigated weight loss, and preserved intestinal barrier integrity by upregulating tight junction protein. Mechanistically, ATPS suppressed ERS activation by reducing glucose-regulated protein 78 (GRP78), phosphorylated protein kinase R-like endoplasmic reticulum kinase (p-PERK), phosphorylated eukaryotic translation initiation factor 2α subunit (p-eIF2α), and C/EBP homologous protein (CHOP) expression, effects that were significantly attenuated in ARRB1-knockdown IEC-6 cells and <i>Arrb1^-</i>^/<i>^-</i> mice, indicating that ARRB1 is essential for ATPS-mediated ERS suppression and intestinal protection. These findings suggest that ATPS protects against 5-FU-induced intestinal mucositis by modulating ARRB1 and inhibiting ERS, highlighting its potential as a novel therapeutic strategy for chemotherapy-induced intestinal injury.<b>NEW & NOTEWORTHY</b> This study provides new insights into the therapeutic potential of ATPS in alleviating 5-FU-induced intestinal mucositis by modulating ARRB1 and suppressing ERS. The protective effects of ATPS were validated in both IEC-6 cells and a murine model, demonstrating its ability to enhance intestinal barrier integrity, inhibit apoptosis, and reduce inflammation. These findings suggest that ARRB1-mediated ERS suppression is a critical mechanism underlying ATPS-induced intestinal protection, presenting a novel strategy for mitigating chemotherapy-induced gastrointestinal toxicity.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G443-G456"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}