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

{"title":"Mechanisms driving fasting-induced protection from genotoxic injury in the small intestine.","authors":"Kali Deans-Fielder, Timothy Wu, Thanh Nguyen, Sarah To, Yang-Zhe Huang, Steven J Bark, Jason C Mills, Noah F Shroyer","doi":"10.1152/ajpgi.00126.2023","DOIUrl":"10.1152/ajpgi.00126.2023","url":null,"abstract":"<p><p>Genotoxic agents such as doxorubicin (DXR) can cause damage to the intestines that can be ameliorated by fasting. How fasting is protective and the optimal timing of fasting and refeeding remain unclear. Here, our analysis of fasting/refeeding-induced global intestinal transcriptional changes revealed metabolic shifts and implicated the cellular energetic hub mechanistic target of rapamycin complex 1 (mTORC1) in protecting from DXR-induced DNA damage. Our analysis of specific transcripts and proteins in intestinal tissue and tissue extracts showed that fasting followed by refeeding at the time of DXR administration reduced damage and caused a spike in mTORC1 activity. However, continued fasting after DXR prevented the mTORC1 spike and damage reduction. Surprisingly, the mTORC1 inhibitor, rapamycin, did not block fasting/refeeding-induced reduction in DNA damage, suggesting that increased mTORC1 is dispensable for protection against the initial DNA damage response. In <i>Ddit4^-/-</i> mice [DDIT4 (DNA-damage-inducible transcript 4) functions to regulate mTORC1 activity], fasting reduced DNA damage and increased intestinal crypt viability vs. ad libitum-fed <i>Ddit4^-/-</i> mice. Fasted/refed <i>Ddit4^-/-</i> mice maintained body weight, with increased crypt proliferation by 5 days post-DXR, whereas ad libitum-fed <i>Ddit4^-/-</i> mice continued to lose weight and displayed limited crypt proliferation. Genes encoding epithelial stem cell and DNA repair proteins were elevated in DXR-injured, fasted vs. ad libitum <i>Ddit4^-/-</i> intestines. Thus, fasting strongly reduced intestinal damage when normal dynamic regulation of mTORC1 was lost. Overall, the results confirm that fasting protects the intestines against DXR and suggests that fasting works by pleiotropic - including both mTORC1-dependent and independent - mechanisms across the temporally dynamic injury response.<b>NEW & NOTEWORTHY</b> New findings are <i>1</i>) DNA damage reduction following a 24-h fast depends on the timing of postfast refeeding in relation to chemotherapy initiation; <i>2</i>) fasting/refeeding-induced upregulation of mTORC1 activity is not required for early (6 h) protection against DXR-induced DNA damage; and <i>3</i>) fasting increases expression of intestinal stem cell and DNA damage repair genes, even when mTORC1 is dysregulated, highlighting fasting's crucial role in regulating mTORC1-dependent and independent mechanisms in the dynamic recovery process.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11376978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139721288","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":"Panaxynol improves crypt and mucosal architecture, suppresses colitis-enriched microbes, and alters the immune response to mitigate colitis.","authors":"Brooke M Bullard, Sierra J McDonald, Thomas D Cardaci, Brandon N VanderVeen, Ahmed D Mohammed, Jason L Kubinak, Joseph F Pierre, Ioulia Chatzistamou, Daping Fan, Lorne J Hofseth, E Angela Murphy","doi":"10.1152/ajpgi.00004.2024","DOIUrl":"10.1152/ajpgi.00004.2024","url":null,"abstract":"<p><p>Ulcerative colitis (UC) is an idiopathic inflammatory disease of the large intestine, which impacts millions worldwide. Current interventions aimed at treating UC symptoms can have off-target effects, invoking the need for alternatives that may provide similar benefits with less unintended consequences. This study builds on our initial data, which showed that panaxynol-a novel, potent, bioavailable compound found in American ginseng-can suppress disease severity in murine colitis. Here we explore the underlying mechanisms by which panaxynol improves both chronic and acute murine colitis. Fourteen-week-old C57BL/6 female mice were either given three rounds of dextran sulfate sodium (DSS) in drinking water to induce chronic colitis or one round to induce acute colitis. Vehicle or panaxynol (2.5 mg/kg) was administered via oral gavage three times per week for the study duration. Consistent with our previous findings, panaxynol significantly (<i>P</i> < 0.05) improved the disease activity index and endoscopic scores in both models. Using the acute model to examine potential mechanisms, we show that panaxynol significantly (<i>P</i> < 0.05) reduced DSS-induced crypt distortion, goblet cell loss, and mucus loss in the colon. 16S Sequencing revealed panaxynol altered microbial composition to suppress colitis-enriched genera (i.e., <i>Enterococcus, Eubacterium,</i> and <i>Ruminococcus</i>). In addition, panaxynol significantly (<i>P</i> < 0.05) suppressed macrophages and induced regulatory T-cells in the colonic lamina propria. The beneficial effects of panaxynol on mucosal and crypt architecture, combined with its microbial and immune-mediated effects, provide insight into the mechanisms by which panaxynol suppresses murine colitis. Overall, this data is promising for the use of panaxynol to improve colitis in the clinic.<b>NEW & NOTEWORTHY</b> In the current study, we report that panaxynol ameliorates chemically induced murine colitis by improving colonic crypt and mucosal architecture, suppressing colitis-enriched microbes, reducing macrophages, and promoting the differentiation of regulatory T-cells in the colonic lamina propria. This study suggests that this novel natural compound may serve as a safe and effective treatment option for colitis patients.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11376977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140100890","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":"<i>Bacteroides thetaiotaomicron</i> and <i>Faecalibacterium prausnitzii</i> served as key components of fecal microbiota transplantation to alleviate colitis.","authors":"Binqiang Xu, Yang Fu, Nuoming Yin, Wenfei Qin, Zehua Huang, Wei Xiao, Huizhen Huang, Qixiang Mei, Junjie Fan, Yue Zeng, Chunlan Huang","doi":"10.1152/ajpgi.00303.2023","DOIUrl":"10.1152/ajpgi.00303.2023","url":null,"abstract":"<p><p>Fecal microbiota transplantation (FMT) is a promising therapy for inflammatory bowel disease (IBD) via rectifying gut microbiota. The aim of this study was to identify a mechanism of how specific bacteria-associated immune response contributes to alleviated colitis. Forty donors were divided into high (<i>donor H</i>) and low (<i>donor L</i>) groups according to the diversity and the abundance of <i>Bacteroides</i> and <i>Faecalibacterium</i> by 16S rRNA sequencing. FMT was performed on dextran sulfate sodium (DSS)-induced colitis in mice. Mice with colitis showed significant improvement in intestinal injury and immune imbalance after FMT with <i>group donor H</i> (<i>P</i> < 0.05). <i>Bacteroides thetaiotaomicron</i> and <i>Faecalibacterium prausnitzii</i> were identified as targeted strains in donor feces by real-time PCR and droplet digital PCR. Mice with colitis were treated with mono- or dual-bacterial gavage therapy. Dual-bacterial therapy significantly ameliorated intestinal injury compared with mono-bacterial therapy (<i>P</i> < 0.05). Dual-bacterial therapy increased the M2/M1 macrophage polarization and improved the Th17/Treg imbalance and elevated IL-10 production by Tregs compared with the DSS group (<i>P</i> < 0.05). Metabolomics showed increased abundance of lecithin in the glycerophospholipid metabolism pathway. In conclusion, <i>B. thetaiotaomicron and F. prausnitzii</i>, as the key bacteria in donor feces, alleviate colitis in mice. The mechanism may involve increasing lecithin and regulating IL-10 production of intestinal Tregs.<b>NEW & NOTEWORTHY</b> We demonstrate that donors with high abundance of <i>Bacteroides</i> and <i>Faecalibacterium</i> ameliorate dextran sulfate sodium (DSS)-induced colitis in mice by fecal microbiota transplantation (FMT). The combination therapy of <i>Bacteroides thetaiotaomicron</i> and <i>Faecalibacterium prausnitzii</i> is superior to mono-bacterial therapy in ameliorating colitis in mice, of which mechanism may involve promoting lecithin and inducing IL-10 production of intestinal Tregs.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11376976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140157385","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":"NHE3 inhibitor tenapanor maintains intestinal barrier function, decreases visceral hypersensitivity, and attenuates TRPV1 signaling in colonic sensory neurons.","authors":"Andrew J King, Lin Chang, Qian Li, Liansheng Liu, Yaohui Zhu, Pankaj J Pasricha, Ji Wang, Matthew Siegel, Jeremy S Caldwell, Susan Edelstein, David P Rosenbaum, Kenji Kozuka","doi":"10.1152/ajpgi.00233.2023","DOIUrl":"10.1152/ajpgi.00233.2023","url":null,"abstract":"<p><p>The pathogenesis of irritable bowel syndrome (IBS) is multifactorial, characterized in part by increased intestinal permeability, and visceral hypersensitivity. Increased permeability is associated with IBS severity and abdominal pain. Tenapanor is FDA-approved for the treatment of IBS with constipation (IBS-C) and has demonstrated improvements in bowel motility and a reduction in IBS-related pain; however, the mechanism by which tenapanor mediates these functions remains unclear. Here, the effects of tenapanor on colonic pain signaling and intestinal permeability were assessed through behavioral, electrophysiological, and cell culture experiments. Intestinal motility studies in rats and humans demonstrated that tenapanor increased luminal sodium and water retention and gastrointestinal transit versus placebo. A significantly reduced visceral motor reflex (VMR) to colonic distension was observed with tenapanor treatment versus vehicle in two rat models of visceral hypersensitivity (neonatal acetic acid sensitization and partial restraint stress; both <i>P</i> < 0.05), returning VMR responses to that of nonsensitized controls. Whole cell voltage patch-clamp recordings of retrogradely labeled colonic dorsal root ganglia (DRG) neurons from sensitized rats found that tenapanor significantly reduced DRG neuron hyperexcitability to capsaicin versus vehicle (<i>P</i> < 0.05), an effect not mediated by epithelial cell secretions. Tenapanor also attenuated increases in intestinal permeability in human colon monolayer cultures caused by incubation with proinflammatory cytokines (<i>P</i> < 0.001) or fecal supernatants from patients with IBS-C (<i>P</i> < 0.005). These results support a model in which tenapanor reduces IBS-related pain by strengthening the intestinal barrier, thereby decreasing permeability to macromolecules and antigens and reducing DRG-mediated pain signaling.<b>NEW & NOTEWORTHY</b> A series of nonclinical experiments support the theory that tenapanor inhibits IBS-C-related pain by strengthening the intestinal barrier. Tenapanor treatment reduced visceral motor responses to nonsensitized levels in two rat models of hypersensitivity and reduced responses to capsaicin in sensitized colonic nociceptive dorsal root ganglia neurons. Intestinal permeability experiments in human colon monolayer cultures found that tenapanor attenuates increases in permeability induced by either inflammatory cytokines or fecal supernatants from patients with IBS-C.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11376972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139519016","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":"Effects of corticotropin-releasing hormone on gastric electrical activity and sensorimotor function in healthy volunteers: a double-blinded crossover study.","authors":"I-Hsuan Huang, Jolien Schol, Stefan Calder, Armen A Gharibans, Karen Van den Houte, Annelies Verheyden, Bert Broeders, Florencia Carbone, Greg O'Grady, Jan Tack","doi":"10.1152/ajpgi.00298.2023","DOIUrl":"10.1152/ajpgi.00298.2023","url":null,"abstract":"<p><p>Biopsychosocial factors are associated with disorders of gut-brain interaction (DGBI) and exacerbate gastrointestinal symptoms. The mechanisms underlying pathophysiological alterations of stress remain unclear. Corticotropin-releasing hormone (CRH) is a central regulator of the hormonal stress response and has diverse impact on different organ systems. The aim of the present study was to investigate the effects of peripheral CRH infusion on meal-related gastrointestinal symptoms, gastric electrical activity, and gastric sensorimotor function in healthy volunteers (HVs). In a randomized, double-blinded, placebo-controlled, crossover study, we evaluated the effects of CRH on gastric motility and sensitivity. HVs were randomized to receive either peripheral-administered CRH (100 µg bolus + 1 µg/kg/h) or placebo (saline), followed by at least a 7-day washout period and assignment to the opposite treatment. Tests encompassed saliva samples, gastric-emptying (GE) testing, body surface gastric mapping (BSGM, Gastric Alimetry; Alimetry) to assess gastric myoelectrical activity with real-time symptom profiling, and a gastric barostat study to assess gastric sensitivity to distention and accommodation. Twenty HVs [13 women, mean age 29.2 ± 5.3 yr, body mass index (BMI) 23.3 ± 3.8 kg/m²] completed GE tests, of which 18 also underwent BSGM measurements during the GE tests. The GE half-time decreased significantly after CRH exposure (65.2 ± 17.4 vs. 78.8 ± 24.5 min, <i>P</i> = 0.02) with significantly increased gastric amplitude [49.7 (34.7-55.6) vs. 31.7 (25.7-51.0) µV, <i>P</i> < 0.01], saliva cortisol levels, and postprandial symptom severity. Eleven HVs also underwent gastric barostat studies on a separate day. However, the thresholds for discomfort during isobaric distensions, gastric compliance, and accommodation did not differ between CRH and placebo.<b>NEW & NOTEWORTHY</b> In healthy volunteers, peripheral corticotropin-releasing hormone (CRH) infusion accelerates gastric-emptying rate and increases postprandial gastric response, accompanied by a rise in symptoms, but does not alter gastric sensitivity or meal-induced accommodation. These findings underscore a significant link between stress and dyspeptic symptoms, with CRH playing a pivotal role in mediating these effects.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139904843","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":"Improving morphological and functional properties of enteric neuronal networks in vitro using a novel upside-down culture approach.","authors":"Steven Schulte, Dominique Decker, Bharat Nowduri, Manuela Gries, Anne Christmann, Antoine Meyszner, Holger Rabe, Monika Saumer, Karl-Herbert Schäfer","doi":"10.1152/ajpgi.00170.2023","DOIUrl":"10.1152/ajpgi.00170.2023","url":null,"abstract":"<p><p>The enteric nervous system (ENS) comprises millions of neurons and glia embedded in the wall of the gastrointestinal tract. It not only controls important functions of the gut but also interacts with the immune system, gut microbiota, and the gut-brain axis, thereby playing a key role in the health and disease of the whole organism. Any disturbance of this intricate system is mirrored in an alteration of electrical functionality, making electrophysiological methods important tools for investigating ENS-related disorders. Microelectrode arrays (MEAs) provide an appropriate noninvasive approach to recording signals from multiple neurons or whole networks simultaneously. However, studying isolated cells of the ENS can be challenging, considering the limited time that these cells can be kept vital in vitro. Therefore, we developed an alternative approach cultivating cells on glass samples with spacers (fabricated by photolithography methods). The spacers allow the cells to grow upside down in a spatially confined environment while enabling acute consecutive recordings of multiple ENS cultures on the same MEA. Upside-down culture also shows beneficial effects on the growth and behavior of enteric neural cultures. The number of dead cells was significantly decreased, and neural networks showed a higher resemblance to the myenteric plexus ex vivo while producing more stable signals than cultures grown in the conventional way. Overall, our results indicate that the upside-down approach not only allows to investigate the impact of neurological diseases in vitro but could also offer insights into the growth and development of the ENS under conditions much closer to the in vivo environment.<b>NEW & NOTEWORTHY</b> In this study, we devised a novel approach for culturing and electrophysiological recording of the enteric nervous system using custom-made glass substrates with spacers. This allows to turn cultures of isolated myenteric plexus upside down, enhancing the use of the microelectrode array technique by allowing recording of multiple cultures consecutively using only one chip. In addition, upside-down culture led to significant improvements in the culture conditions, resulting in a more in vivo-like growth.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11376983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139401475","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":"Protease-activated receptor 2 drives migration in a colon cancer cell line but not in noncancerous human epithelial cells.","authors":"Larissa Lucena Périco, Andrew J Vegso, Cristiane H Baggio, Wallace K MacNaughton","doi":"10.1152/ajpgi.00284.2023","DOIUrl":"10.1152/ajpgi.00284.2023","url":null,"abstract":"<p><p>The inflamed mucosa contains a complex assortment of proteases that may participate in wound healing or the development of inflammation-associated colon cancer. We sought to determine the role of protease-activated receptor 2 (PAR2) in epithelial wound healing in both untransformed and transformed colonic epithelial cells. Monolayers of primary epithelial cells derived from organoids cultivated from patient colonic biopsies and of the T84 colon cancer cell line were grown to confluence, wounded in the presence of a selective PAR2-activating peptide, and healing was visualized by live cell microscopy. Inhibitors of various signaling molecules were used to assess the relevant pathways responsible for wound healing. Activation of PAR2 induced an enhanced wound-healing response in T84 cells but not primary cells. The PAR2-enhanced wound-healing response was associated with the development of lamellipodia in cells at the wound edge, consistent with sheet migration. The response to PAR2 activation in T84 cells was completely dependent on Src kinase activity and partially dependent on Rac1 activity. The Src-associated signaling molecules, focal adhesion kinase, and epidermal growth factor receptor, which typically mediate wound-healing responses, were not involved in the PAR2 response. Experiments repeated in the presence of the inflammatory cytokines TNF and IFNγ revealed a synergistically enhanced PAR2 wound-healing response in T84s but not primary cells. The epithelial response to proteases may be different between primary and cancer cells and is accentuated in the presence of inflammatory cytokines. Our findings have implications for understanding epithelial restitution in the context of inflammatory bowel disease (IBD) and inflammation-associated colon cancer.<b>NEW & NOTEWORTHY</b> Protease-activated receptor 2 enhances wound healing in the T84 colon cancer cell line, but not in primary cells derived from patient biopsies, an effect that is synergistically enhanced in the presence of the inflammatory cytokines TNF and IFNγ.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140027184","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":"Albumin promoter-driven FlpO expression induces efficient genetic recombination in mouse liver.","authors":"Xiaohui Zhu, Yan Yang, Dongfeng Feng, Oliver Wang, Jiaxiang Chen, Jiale Wang, Bin Wang, Yang Liu, Brandy H Edenfield, Ashley N Haddock, Ying Wang, Tushar Patel, Yan Bi, Baoan Ji","doi":"10.1152/ajpgi.00263.2023","DOIUrl":"10.1152/ajpgi.00263.2023","url":null,"abstract":"<p><p>Tissue-specific gene manipulations are widely used in genetically engineered mouse models. A single recombinase system, such as the one using Alb-Cre, has been commonly used for liver-specific genetic manipulations. However, most diseases are complex, involving multiple genetic changes and various cell types. A dual recombinase system is required for conditionally modifying different genes sequentially in the same cell or inducing genetic changes in different cell types within the same organism. A FlpO cDNA was inserted between the last exon and 3'-UTR of the mouse albumin gene in a bacterial artificial chromosome (BAC-Alb-FlpO). The founders were crossed with various reporter mice to examine the efficiency of recombination. Liver cancer tumorigenesis was investigated by crossing the FlpO mice with FSF-Kras^G12D mice and p53^frt mice (KPF mice). BAC-Alb-FlpO mice exhibited highly efficient recombination capability in both hepatocytes and intrahepatic cholangiocytes. No recombination was observed in the duodenum and pancreatic cells. BAC-Alb-FlpO-mediated liver-specific expression of mutant Kras^G12D and conditional deletion of <i>p53</i> gene caused the development of liver cancer. Remarkably, liver cancer in these KPF mice manifested a distinctive mixed hepatocellular carcinoma and cholangiocarcinoma phenotype. A highly efficient and liver-specific BAC-Alb-FlpO mouse model was developed. In combination with other Cre lines, different genes can be manipulated sequentially in the same cell, or distinct genetic changes can be induced in different cell types of the same organism.<b>NEW & NOTEWORTHY</b> A liver-specific Alb-FlpO mouse line was generated. By coupling it with other existing CreERT or Cre lines, the dual recombinase approach can enable sequential gene modifications within the same cell or across various cell types in an organism for liver research through temporal and spatial gene manipulations.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11376971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140100889","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":"A mathematical model of ENaC and Slc26a6 regulation by CFTR in salivary gland ducts.","authors":"Shan Su, Amanda Wahl, John Rugis, Vinod Suresh, David I Yule, James Sneyd","doi":"10.1152/ajpgi.00168.2023","DOIUrl":"10.1152/ajpgi.00168.2023","url":null,"abstract":"<p><p>Cystic fibrosis (CF) is a genetic disease caused by the mutations of cystic fibrosis transmembrane conductance regulator (<i>CFTR</i>), the cystic fibrosis transmembrane conductance regulator gene. Cftr is a critical ion channel expressed in the apical membrane of mouse salivary gland striated duct cells. Although Cftr is primarily a Cl^- channel, its knockout leads to higher salivary Cl^- and Na⁺ concentrations and lower pH. Mouse experiments show that the activation of Cftr upregulates epithelial Na⁺ channel (ENaC) protein expression level and Slc26a6 (a 1Cl^-:2[Formula: see text] exchanger of the solute carrier family) activity. Experimentally, it is difficult to predict how much the coregulation effects of CFTR contribute to the abnormal Na⁺, Cl^-, and [Formula: see text] concentrations and pH in CF saliva. To address this question, we construct a wild-type mouse salivary gland model and simulate CFTR knockout by altering the expression levels of CFTR, ENaC, and Slc26a6. By reproducing the in vivo and ex vivo final saliva measurements from wild-type and CFTR knockout animals, we obtain computational evidence that ENaC and Slc26a6 activities are downregulated in CFTR knockout in salivary glands.<b>NEW & NOTEWORTHY</b> This paper describes a salivary gland mathematical model simulating the ion exchange between saliva and the salivary gland duct epithelium. The novelty lies in the implementation of CFTR regulating ENaC and Slc26a6 in a CFTR knockout gland. By reproducing the experimental saliva measurements in wild-type and CFTR knockout glands, the model shows that CFTR regulates ENaC and Slc26a6 anion exchanger in salivary glands. The method could be used to understand the various cystic fibrosis phenotypes.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139728805","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":"Buprenorphine Affects the Initiation and Severity of Interleukin Induced Acute Pancreatitis in Mice.","authors":"Sarah Jahangir, Biswajit Khatua, Nabil Smichi, Prasad Rajalingamgari, Anoop Narayana Pillai, Megan J Summers, Bryce McFayden, Sergiy Kostenko, Naomi M. Gades, Vijay P Singh","doi":"10.1152/ajpgi.00083.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00083.2024","url":null,"abstract":"Acute pancreatitis (AP) is a common disease with no targeted therapy and has varied outcomes ranging from spontaneous resolution to being lethal. While typically painful, AP can also be painless. Various agents, including opioids are used for pain control in AP; the risks, and benefits of which are often debated. Since experimental AP in mice is used to study the efficacy of potential therapies, we studied the effect of a commonly used opioid buprenorphine on the initiation and progression of AP. For this we administered extended-release buprenorphine subcutaneously prior to inducing the previously established severe AP model that uses Interleukins 12 and 18 (IL12,18) in genetically obese (ob/ob) mice and compared this to mice with AP but without the drug. Mice were monitored over 3 days and parameters of AP induction and progression were compared. Buprenorphine significantly reduced the serum amylase, lipase, pancreatic necrosis, and AP associated fat necrosis which is ubiquitous in obese mice and humans. Buprenorphine delayed the AP associated reduction of carotid artery pulse distention, and development of hypothermia, hastened renal injury, and muted the early increase in respiratory rate vs. IL12,18 alone. The site of buprenorphine injection appeared erythematous, inflamed, and microscopically showed thinning, loss of epidermal layers which had increased apoptosis. In summary, subcutaneous extended-release buprenorphine interfered with the induction of AP by reducing serum amylase, lipase, pancreatic and fat necrosis, the worsening of AP by delaying hypotension, hypothermia, while hastening renal injury, respiratory depression, and causing cutaneous injury at the site of injection.","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140668425","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}