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

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BiliQML: A supervised machine-learning model to quantify biliary forms from digitized whole-slide liver histopathological images. BiliQML:从数字化全切片肝组织病理学图像中量化胆道形态的监督机器学习模型。
IF 4.5 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2024-04-23 DOI: 10.1152/ajpgi.00058.2024
Dominick J. Hellen, M. Fay, David H Lee, Caroline Klindt-Morgan, Ashley L. Bennett, Kimberly J. Pachura, Arash Grakoui, Stacey S. Huppert, Paul A. Dawson, Wilbur A Lam, Saul J. Karpen
{"title":"BiliQML: A supervised machine-learning model to quantify biliary forms from digitized whole-slide liver histopathological images.","authors":"Dominick J. Hellen, M. Fay, David H Lee, Caroline Klindt-Morgan, Ashley L. Bennett, Kimberly J. Pachura, Arash Grakoui, Stacey S. Huppert, Paul A. Dawson, Wilbur A Lam, Saul J. Karpen","doi":"10.1152/ajpgi.00058.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00058.2024","url":null,"abstract":"The progress of research focused on cholangiocytes and the biliary tree during development and following injury is hindered by limited available quantitative methodologies. Current techniques include two-dimensional standard histological cell-counting approaches, which are rapidly performed error-prone and lack architectural context; or three-dimensional analysis of the biliary tree in opacified livers, which introduce technical issues along with minimal quantitation. The present study aims to fill these quantitative gaps with a supervised machine learning model (BiliQML) able to quantify biliary forms in the liver of anti-Keratin 19 antibody-stained whole slide images. Training utilized 5,019 researcher-labeled biliary forms, which following feature selection, and algorithm optimization, generated an F-score of 0.87. Application of BiliQML on seven separate cholangiopathy models; genetic (Afp-CRE;Pkd1l1null/Fl, Alb-CRE;Rbp-jkfl/fl, Albumin-CRE; ROSANICD), surgical (bile duct ligation), toxicological (3,5-diethoxycarbonyl-1,4-dihydrocollidine), and therapeutic (Cyp2c70-/- with ileal bile acid transporter inhibition), allowed for a means to validate the capabilities, and utility of this platform. The results from BiliQML quantification revealed biological and pathological differences across these seven diverse models indicate a highly sensitive, robust, and scalable methodology for the quantification of distinct biliary forms. BiliQML is the first comprehensive machine-learning platform for biliary form analysis, adding much needed morphologic context to standard immunofluorescence - based histology, and provides clinical and basic-science researchers a novel tool for the characterization of cholangiopathies.","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":"140668006","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}
引用次数: 0
Blueberry anthocyanins improve liver fibrosis by regulating NCOA4 ubiquitination through TRIM7 to affect ferroptosis of hepatic stellate cells. 蓝莓花青素通过 TRIM7 调控 NCOA4 泛素化,从而影响肝星状细胞的铁凋亡,从而改善肝纤维化。
IF 4.5 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2024-04-01 Epub Date: 2024-01-30 DOI: 10.1152/ajpgi.00227.2023
Likun Liu, Jinhui Du, Haiqing Fan, Yue Yu, Yilin Luo, Fang Gu, Hui Yu, Xin Liao
{"title":"Blueberry anthocyanins improve liver fibrosis by regulating NCOA4 ubiquitination through TRIM7 to affect ferroptosis of hepatic stellate cells.","authors":"Likun Liu, Jinhui Du, Haiqing Fan, Yue Yu, Yilin Luo, Fang Gu, Hui Yu, Xin Liao","doi":"10.1152/ajpgi.00227.2023","DOIUrl":"10.1152/ajpgi.00227.2023","url":null,"abstract":"<p><p>This study aims to investigate the role and molecular mechanism of anthocyanin in improving liver fibrosis through ferroptosis, providing a basis for drug development and targeted therapy. In this study, a mouse model of liver fibrosis was established using CCl<sub>4</sub>, and the anthocyanin treatment groups were administered 100 mg/kg anthocyanin daily via gavage. Furthermore, real-time fluorescent quantitative PCR (qRT-PCR), Western blotting (WB), and enzyme-linked immunosorbent assay were used to assess liver fibrosis indicators and liver injury markers. Histopathological methods were used to confirm the morphology of liver injury in different treatment groups. The effects of anthocyanins on ferroptosis markers, NCOA4 and FTH1 expression, were examined through qRT-PCR, WB, and Co-IP. Confocal microscopy was used to validate the colocalization of ferritin and lysosomes. A differential expression model of TRIM7 was constructed to verify its impact on the progression of liver fibrosis. The present study demonstrates the hepatoprotective effects of anthocyanins in liver fibrosis, highlighting their ability to enhance hepatic stellate cell (HSC) ferroptosis and regulate ferritin autophagy. Moreover, TRIM7 is identified as a key mediator of anthocyanin-induced regulation of hepatic stellate cells activation for liver fibrosis treatment through modulation of ferroautophagy. Mechanistic investigations further reveal that TRIM7 exerts its influence on the process of ferroautophagy by controlling NCOA4 ubiquitination. Our study discovered that anthocyanins could improve liver fibrosis by regulating NCOA4 ubiquitination through TRIM7, thereby affecting hepatic stellate cells' ferroptosis levels.<b>NEW & NOTEWORTHY</b> This was the first study to demonstrate that anthocyanins can improve the progression of liver fibrosis by promoting hepatic stellate cell (HSC) ferroptosis. Anthocyanins could affect the content of Fe<sup>2+</sup> by promoting ferroautophagy in HSCs, thereby promoting the level of ferroptosis. This study demonstrates for the first time that anthocyanins can inhibit the expression of TRIM7 and then affect the ubiquitination of NCOA4 to regulate the level of ferritin autophagy and ferroptosis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139641509","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}
引用次数: 0
Lipidomic signatures discriminate subtle hepatic changes in the progression of porcine nonalcoholic steatohepatitis. 脂质体特征可区分猪非酒精性脂肪性肝炎进展过程中肝脏的细微变化。
IF 4.5 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2024-04-01 Epub Date: 2024-02-20 DOI: 10.1152/ajpgi.00264.2023
Luis V Herrera-Marcos, Roberto Martínez-Beamonte, Carmen Arnal, Cristina Barranquero, Juan J Puente-Lanzarote, José M Lou-Bonafonte, Gonzalo Gonzalo-Romeo, Gabriele Mocciaro, Benjamin Jenkins, Joaquín C Surra, María J Rodríguez-Yoldi, Víctor Alastrué-Vera, Jesús Letosa, Agustín García-Gil, Antonio Güemes, Albert Koulman, Jesús Osada
{"title":"Lipidomic signatures discriminate subtle hepatic changes in the progression of porcine nonalcoholic steatohepatitis.","authors":"Luis V Herrera-Marcos, Roberto Martínez-Beamonte, Carmen Arnal, Cristina Barranquero, Juan J Puente-Lanzarote, José M Lou-Bonafonte, Gonzalo Gonzalo-Romeo, Gabriele Mocciaro, Benjamin Jenkins, Joaquín C Surra, María J Rodríguez-Yoldi, Víctor Alastrué-Vera, Jesús Letosa, Agustín García-Gil, Antonio Güemes, Albert Koulman, Jesús Osada","doi":"10.1152/ajpgi.00264.2023","DOIUrl":"10.1152/ajpgi.00264.2023","url":null,"abstract":"<p><p>Recently, the development of nonalcoholic steatohepatitis (NASH) in common strains of pigs has been achieved using a diet high in saturated fat, fructose, cholesterol, and cholate and deficient in choline and methionine. The aim of the present work was to characterize the hepatic and plasma lipidomic changes that accompany the progression of NASH and its reversal by switching pigs back to a chow diet. One month of this extreme steatotic diet was sufficient to induce porcine NASH. The lipidomic platform using liquid chromatography-mass spectrometry analyzed 467 lipid species. Seven hepatic phospholipids [PC(30:0), PC(32:0), PC(33:0), PC(33:1), PC(34:0), PC(34:3) and PC(36:2)] significantly discriminated the time of dietary exposure, and PC(30:0), PC(33:0), PC(33:1) and PC(34:0) showed rapid adaptation in the reversion period. Three transcripts (<i>CS</i>, <i>MAT1A</i>, and <i>SPP1</i>) showed significant changes associated with hepatic triglycerides and PC(33:0). Plasma lipidomics revealed that these species [FA 16:0, FA 18:0, LPC(17:1), PA(40:5), PC(37:1), TG(45:0), TG(47:2) and TG(51:0)] were able to discriminate the time of dietary exposure. Among them, FA 16:0, FA 18:0, LPC(17:1) and PA(40:5) changed the trend in the reversion phase. Plasma LDL-cholesterol and IL12P40 were good parameters to study the progression of NASH, but their capacity was surpassed by hepatic [PC(33:0), PC(33:1), and PC(34:0)] or plasma lipid [FA 16:0, FA 18:0, and LPC(17:1)] species. Taken together, these lipid species can be used as biomarkers of metabolic changes in the progression and regression of NASH in this model. The lipid changes suggest that the development of NASH also affects peripheral lipid metabolism.<b>NEW & NOTEWORTHY</b> A NASH stage was obtained in crossbred pigs. Hepatic [PC(33:0), PC(33:1) and PC(34:0)] or plasma [FA 16:0, FA 18:0 and LPC(17:1)] species were sensitive parameters to detect subtle changes in development and regression of nonalcoholic steatohepatitis (NASH). These findings may delineate the liquid biopsy to detect subtle changes in progression or in treatments. Furthermore, phospholipid changes according to the insult-inducing NASH may play an important role in accepting or rejecting fatty livers in transplantation.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139904842","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}
引用次数: 0
A simple and effective genotyping workflow for rapid detection of CRISPR genome editing. 用于快速检测 CRISPR 基因组编辑的简单有效的基因分型工作流程。
IF 3.9 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2024-04-01 Epub Date: 2024-02-27 DOI: 10.1152/ajpgi.00013.2024
Lingxiang Wang, Jiale Wang, Dongfeng Feng, Bin Wang, Yasmin Jahan-Mihan, Ying Wang, Yan Bi, DoYoung Lim, Baoan Ji
{"title":"A simple and effective genotyping workflow for rapid detection of CRISPR genome editing.","authors":"Lingxiang Wang, Jiale Wang, Dongfeng Feng, Bin Wang, Yasmin Jahan-Mihan, Ying Wang, Yan Bi, DoYoung Lim, Baoan Ji","doi":"10.1152/ajpgi.00013.2024","DOIUrl":"10.1152/ajpgi.00013.2024","url":null,"abstract":"<p><p>Genetically engineered mouse models play a pivotal role in the modeling of diseases, exploration of gene functions, and the development of novel therapies. In recent years, clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9)-mediated genome editing technology has revolutionized the process of developing such models by enabling precise genome modifications of the multiple interested genes simultaneously. Following genome editing, an efficient genotyping methodology is crucial for subsequent characterization. However, current genotyping methods are laborious, time-consuming, and costly. Here, using targeting the mouse trypsinogen genes as an example, we introduced common applications of CRISPR-Cas9 editing and a streamlined cost-effective genotyping workflow for CRISPR-edited mouse models, in which Sanger sequencing is required only at the initial steps. In the F0 mice, we focused on identifying the presence of positive editing by PCR followed by Sanger sequencing without the need to know the exact sequences, simplifying the initial screening. In the F1 mice, Sanger sequencing and algorithms decoding were used to identify the precise editing. Once the edited sequence was established, a simple and effective genotyping strategy was established to distinguish homozygous and heterozygous status by PCR from tail DNA. The genotyping workflow applies to deletions as small as one nucleotide, multiple-gene knockout, and knockin studies. This simplified, efficient, and cost-effective genotyping shall be instructive to new investigators who are unfamiliar with characterizing CRISPR-Cas9-edited mouse strains.<b>NEW & NOTEWORTHY</b> This study presents a streamlined, cost-effective genotyping workflow for clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) edited mouse models, focusing on trypsinogen genes. It simplifies initial F0 mouse screening using PCR and Sanger sequencing without needing exact sequences. For F1 mice, precise editing is identified through Sanger sequencing and algorithm decoding. The workflow includes a novel PCR strategy for distinguishing homozygous and heterozygous statuses in subsequent generations, effective for small deletions, multiple-gene knockouts, and knockins.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11216750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139970665","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}
引用次数: 0
Role of mechanoregulation in mast cell-mediated immune inflammation of the smooth muscle in the pathophysiology of esophageal motility disorders. 食管运动障碍病理生理学中肥大细胞介导的平滑肌免疫炎症的机械调节作用。
IF 3.9 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2024-04-01 Epub Date: 2024-01-30 DOI: 10.1152/ajpgi.00258.2023
Raj K Goyal, Satish Rattan
{"title":"Role of mechanoregulation in mast cell-mediated immune inflammation of the smooth muscle in the pathophysiology of esophageal motility disorders.","authors":"Raj K Goyal, Satish Rattan","doi":"10.1152/ajpgi.00258.2023","DOIUrl":"10.1152/ajpgi.00258.2023","url":null,"abstract":"<p><p>Major esophageal disorders involve obstructive transport of bolus to the stomach, causing symptoms of dysphagia and impaired clearing of the refluxed gastric contents. These may occur due to mechanical constriction of the esophageal lumen or loss of relaxation associated with deglutitive inhibition, as in achalasia-like disorders. Recently, immune inflammation has been identified as an important cause of esophageal strictures and the loss of inhibitory neurotransmission. These disorders are also associated with smooth muscle hypertrophy and hypercontractility, whose cause is unknown. This review investigated immune inflammation in the causation of smooth muscle changes in obstructive esophageal bolus transport. Findings suggest that smooth muscle hypertrophy occurs above the obstruction and is due to mechanical stress on the smooth muscles. The mechanostressed smooth muscles release cytokines and other molecules that may recruit and microlocalize mast cells to smooth muscle bundles, so that their products may have a close bidirectional effect on each other. Acting in a paracrine fashion, the inflammatory cytokines induce genetic and epigenetic changes in the smooth muscles, leading to smooth muscle hypercontractility, hypertrophy, and impaired relaxation. These changes may worsen difficulty in the esophageal transport. Immune processes differ in the first phase of obstructive bolus transport, and the second phase of muscle hypertrophy and hypercontractility. Moreover, changes in the type of mechanical stress may change immune response and effect on smooth muscles. Understanding immune signaling in causes of obstructive bolus transport, type of mechanical stress, and associated smooth muscle changes may help pathophysiology-based prevention and targeted treatment of esophageal motility disorders.<b>NEW & NOTEWORTHY</b> Esophageal disorders such as esophageal stricture or achalasia, and diffuse esophageal spasm are associated with smooth muscle hypertrophy and hypercontractility, above the obstruction, yet the cause of such changes is unknown. This review suggests that smooth muscle obstructive disorders may cause mechanical stress on smooth muscle, which then secretes chemicals that recruit, microlocalize, and activate mast cells to initiate immune inflammation, producing functional and structural changes in smooth muscles. Understanding the immune signaling in these changes may help pathophysiology-based prevention and targeted treatment of esophageal motility disorders.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139641510","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}
引用次数: 0
A ganglionic intestinointestinal reflex activated by acute noxious challenge. 急性毒性挑战激活的神经节肠道反射。
IF 4.5 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2024-04-01 Epub Date: 2024-01-16 DOI: 10.1152/ajpgi.00145.2023
Martin J Stebbing, Anthony D Shafton, Catherine E Davey, Madeleine R Di Natale, John B Furness, Robin M McAllen
{"title":"A ganglionic intestinointestinal reflex activated by acute noxious challenge.","authors":"Martin J Stebbing, Anthony D Shafton, Catherine E Davey, Madeleine R Di Natale, John B Furness, Robin M McAllen","doi":"10.1152/ajpgi.00145.2023","DOIUrl":"10.1152/ajpgi.00145.2023","url":null,"abstract":"<p><p>To investigate noxious stimulation-responsive neural circuits that could influence the gut, we recorded from intestinally directed (efferent) nerve filaments dissected from mesenteric nerves close to the small intestine in anesthetized rats. These exhibited baseline multiunit activity that was almost unaffected by vagotomy (VagX) and reduced only slightly by cutting the splanchnic nerves. The activity was halved by hexamethonium (Hex) treatment. When an adjacent gut segment received an intraluminal stimulus 2,4,6-trinitrobenzenesulfonate (TNBS) in 30% ethanol, mesenteric efferent nerve activity increased for more than 1 h. The increased activity was almost unaffected by bilateral vagotomy or splanchnic nerve section, indicating a lack of central nervous involvement, but it was 60% reduced by hexamethonium. Spike sorting discriminated efferent single and predominantly single-unit spike trains that responded to TNBS, were unaffected by splachnectomy but were silenced by hexamethonium. After noxious stimulation of one segment, the adjacent segment showed no evidence of suppression of gut motility or vasoconstriction. We conclude that luminal application of a noxious stimulus to the small intestine activates an entirely peripheral, intestinointestinal reflex pathway. This pathway involves enteric intestinofugal neurons that excite postganglionic sympathetic neurons via a nicotinic synapse. We suggest that the final sympathetic efferent neurons that respond to a tissue damaging stimulus are distinct from vasoconstrictor, secretomotor, and motility inhibiting neurons.<b>NEW & NOTEWORTHY</b> An intraluminal noxious chemical stimulus applied to one segment of small intestine increased mesenteric efferent nerve activity to an adjacent segment. This was identified as a peripheral ganglionic reflex that did not require vagal or spinal connections. Hexamethonium blocked most, but not all, ongoing and reflex mesenteric efferent activity. The prevertebral sympathetic efferent neurons that are activated likely affect inflammatory and immune functions of other gut segments.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139471806","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}
引用次数: 0
Alterations in gene expression and microbiome composition upon calcium-sensing receptor deletion in the mouse esophagus. 小鼠食道钙传感受体缺失后基因表达和微生物组组成的改变
IF 3.9 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2024-04-01 Epub Date: 2024-01-09 DOI: 10.1152/ajpgi.00066.2023
Solange M Abdulnour-Nakhoul, Jay K Kolls, Erik K Flemington, Nathan A Ungerleider, Hani N Nakhoul, Kejing Song, Nazih L Nakhoul
{"title":"Alterations in gene expression and microbiome composition upon calcium-sensing receptor deletion in the mouse esophagus.","authors":"Solange M Abdulnour-Nakhoul, Jay K Kolls, Erik K Flemington, Nathan A Ungerleider, Hani N Nakhoul, Kejing Song, Nazih L Nakhoul","doi":"10.1152/ajpgi.00066.2023","DOIUrl":"10.1152/ajpgi.00066.2023","url":null,"abstract":"<p><p>The calcium-sensing receptor (CaSR), a G protein-coupled receptor, regulates Ca<sup>2+</sup> concentration in plasma by regulating parathyroid hormone secretion. In other tissues, it is reported to play roles in cellular differentiation and migration and in secretion and absorption. We reported previously that CaSR can be conditionally deleted in the mouse esophagus. This conditional knockout (KO) (<i><sup>Eso</sup>CaSR<sup>-/-</sup></i>) model showed a significant reduction in the levels of adherens and tight junction proteins and had a marked buildup of bacteria on the luminal esophageal surface. To further examine the role of CaSR, we used RNA sequencing to determine gene expression profiles in esophageal epithelia of control and <i><sup>Eso</sup>CaSR<sup>-/-</sup></i>mice RNA Seq data indicated upregulation of gene sets involved in DNA replication and cell cycle in <i><sup>Eso</sup>CaSR<sup>-/-</sup></i>. This is accompanied by the downregulation of gene sets involved in the innate immune response and protein homeostasis including peptide elongation and protein trafficking. Ingenuity pathway analysis (IPA) demonstrated that these genes are mapped to important biological networks including calcium and Ras homologus A (RhoA) signaling pathways. To further explore the bacterial buildup in <i><sup>Eso</sup>CaSR<sup>-/-</sup></i> esophageal tissue, 16S sequencing of the mucosal-associated bacterial microbiome was performed. Three bacterial species, <i>g_Rodentibacter</i>, s<i>_Rodentibacter_unclassified</i>, and <i>s_Lactobacillus_hilgardi</i> were significantly increased in <i><sup>Eso</sup>CaSR<sup>-/-</sup></i>. Furthermore, metagenomic analysis of 16S sequences indicated that pathways related to oxidative phosphorylation and metabolism were downregulated in <i><sup>Eso</sup>CaSR<sup>-/-</sup></i> tissues. These data demonstrate that CaSR impacts major pathways of cell proliferation, differentiation, cell cycle, and innate immune response in esophageal epithelium. The disruption of these pathways causes inflammation and significant modifications of the microbiome.<b>NEW & NOTEWORTHY</b> Calcium-sensing receptor (CaSR) plays a significant role in maintaining the barrier function of esophageal epithelium. Using RNA sequencing, we show that conditional deletion of CaSR from mouse esophagus causes upregulation of genes involved in DNA replication and cell cycle and downregulation of genes involved in the innate immune response, protein translation, and cellular protein synthesis. Pathway analysis shows disruption of signaling pathways of calcium and actin cytoskeleton. These changes caused inflammation and esophageal dysbiosis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139401465","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}
引用次数: 0
GSK3β/NF-κB -dependent transcriptional regulation of homeostatic hepatocyte Tnf production. GSK3β/NF-κB依赖性转录调控肝细胞Tnf的同源性产生。
IF 3.9 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2024-04-01 Epub Date: 2024-01-09 DOI: 10.1152/ajpgi.00229.2023
Maya R Grayck, William C McCarthy, Mack Solar, Emma Golden, Natarajan Balasubramaniyan, Lijun Zheng, Laura G Sherlock, Clyde J Wright
{"title":"GSK3β/NF-κB -dependent transcriptional regulation of homeostatic hepatocyte <i>Tnf</i> production.","authors":"Maya R Grayck, William C McCarthy, Mack Solar, Emma Golden, Natarajan Balasubramaniyan, Lijun Zheng, Laura G Sherlock, Clyde J Wright","doi":"10.1152/ajpgi.00229.2023","DOIUrl":"10.1152/ajpgi.00229.2023","url":null,"abstract":"<p><p>Maintenance of hepatocyte homeostasis plays an important role in mediating the pathogenesis of many diseases. A growing body of literature has established a critical role played by tumor necrosis factor-α (TNFα) in maintaining hepatocyte homeostasis; however, the transcriptional mechanisms underlying constitutive <i>Tnf</i> expression are unknown. Whole liver fractions and primary hepatocytes from adult control C57BL/6 mice and the murine hepatocyte cell line AML12 were assessed for constitutive <i>Tnf</i> expression. Impacts of glycogen synthase kinase-3 β (GSK3β) and nuclear factor κB (NF-κB) inhibition on constitutive <i>Tnf</i> expression were assessed in AML12 cells. Finally, AML12 cell proliferation following GSK3β and NF-κB inhibition was evaluated. Constitutive <i>Tnf</i> gene expression is present in whole liver, primary hepatocytes, and cultured AML12 hepatocytes. Cytokine-induced <i>Tnf</i> gene expression is regulated by NF-κB activation. Pharmacological inhibition of GSK3β resulted in a time- and dose-dependent inhibition of <i>Tnf</i> gene expression. GSK3β inhibition decreased nuclear levels of the NF-κB subunits p65 and p50. We determined that NF-κB transcription factor subunit p65 binds to consensus sequence elements present in the murine TNFα promoter and inhibition of GSK3β decreases binding and subsequent <i>Tnf</i> expression. Finally, AML12 cell growth was significantly reduced following GSK3β and NF-κB inhibition. These results demonstrate that GSK3β and NF-κB are essential for mediating <i>Tnf</i> expression and constitutive hepatocyte cell growth. These findings add to a growing body of literature on TNFα mediated hepatocyte homeostasis and identify novel molecular mechanisms involved in mediating response to various disease states in the liver.<b>NEW & NOTEWORTHY</b> Maintenance of hepatocyte homeostasis plays an important role in controlling the pathogenesis of many diseases. Our findings add to a growing body of literature on tumor necrosis factor-α (TNFα)-mediated hepatocyte homeostasis and identify novel molecular mechanisms involved in regulating this response.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11211040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139401470","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}
引用次数: 0
Inhibition of visceral adipose tissue-derived pathogenic signals by activation of adenosine A2AR improves hepatic and cardiac dysfunction of NASH mice. 通过激活腺苷 A2AR 抑制内脏脂肪组织衍生的致病信号,改善 NASH 小鼠的肝脏和心脏功能障碍。
IF 3.9 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2024-04-01 Epub Date: 2024-01-22 DOI: 10.1152/ajpgi.00104.2023
Chia-Chang Huang, Hsiao-Yun Yeh, Roger Lin, Tsai-Ling Liao, Hsiao-Chin Shen, Ying-Ying Yang, Han-Chieh Lin
{"title":"Inhibition of visceral adipose tissue-derived pathogenic signals by activation of adenosine A<sub>2A</sub>R improves hepatic and cardiac dysfunction of NASH mice.","authors":"Chia-Chang Huang, Hsiao-Yun Yeh, Roger Lin, Tsai-Ling Liao, Hsiao-Chin Shen, Ying-Ying Yang, Han-Chieh Lin","doi":"10.1152/ajpgi.00104.2023","DOIUrl":"10.1152/ajpgi.00104.2023","url":null,"abstract":"<p><p>A<sub>2A</sub>R-disrupted mice is characterized by severe systemic and visceral adipose tissue (VAT) inflammation. Increasing adenosine cyclase (AC), cAMP, and protein kinase A (PKA) formation through A<sub>2A</sub>R activation suppress systemic/VAT inflammation in obese mice. This study explores the effects of 4 wk A<sub>2A</sub>R agonist PSB0777 treatment on the VAT-driven pathogenic signals in hepatic and cardiac dysfunction of nonalcoholic steatohepatitis (NASH) obese mice. Among NASH mice with cardiac dysfunction, simultaneous decrease in the A<sub>2A</sub>R, AC, cAMP, and PKA levels were observed in VAT, liver, and heart. PSB0777 treatment significantly restores AC, cAMP, PKA, and hormone-sensitive lipase (HSL) levels, decreased <i>SREBP-1/FASN</i>, MCP-1, and CD68 levels, reduces infiltrated CD11b<sup>+ </sup>F4/80<sup>+</sup> cells and adipogenesis in VAT of NASH + PSB0777 mice. The changes in VAT were accompanied by the suppression of hepatic and cardiac lipogenic/inflammatory/injury/apoptotic/fibrotic markers, the normalization of cardiac contractile [sarco/endoplasmic reticulum Ca<sup>2+ </sup>ATPase (SERCA2)] marker, and cardiac dysfunction. The in vitro approach revealed that conditioned media (CM) of VAT of NASH mice (CMnash) trigger palmitic acid (PA)-like lipotoxic (lipogenic/inflammatory/apoptotic/fibrotic) effects in AML-12 and H9c2 cell systems. Significantly, A<sub>2A</sub>R agonist pretreatment-related normalization of A<sub>2A</sub>R-AC-cAMP-PKA levels was associated with the attenuation of CMnash-related upregulation of lipotoxic markers and the normalization of lipolytic (AML-12 cells) or contractile (H9C2 cells) marker/contraction. The in vivo and in vitro experiments revealed that A<sub>2A</sub>R agonists are potential agent to inhibit the effects of VAT inflammation-driven pathogenic signals on the hepatic and cardiac lipogenesis, inflammation, injury, apoptosis, fibrosis, hypocontractility, and subsequently improve hepatic and cardiac dysfunction in NASH mice.<b>NEW & NOTEWORTHY</b> Protective role of adenosine A<sub>2A</sub>R receptor (A<sub>2A</sub>R) and AC-cAMP-PKA signaling against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) possibly via its actions on adipocytes is well known in the past decade. Thus, this study evaluates pharmacological activities of A<sub>2A</sub>R agonist PSB0777, which has already demonstrated to treat NASH. In this study, the inhibition of visceral adipose tissue-derived pathogenic signals by activation of adenosine A<sub>2A</sub>R with A<sub>2A</sub>R agonist PSB0777 improves the hepatic and cardiac dysfunction of high-fat diet (HFD)-induced NASH mice.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139519625","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}
引用次数: 0
Gastrointestinal dysmotility in rodent models of Parkinson's disease. 帕金森病啮齿动物模型中的胃肠道运动障碍。
IF 3.9 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2024-04-01 Epub Date: 2024-01-23 DOI: 10.1152/ajpgi.00225.2023
Carolina Pellegrini, R Alberto Travagli
{"title":"Gastrointestinal dysmotility in rodent models of Parkinson's disease.","authors":"Carolina Pellegrini, R Alberto Travagli","doi":"10.1152/ajpgi.00225.2023","DOIUrl":"10.1152/ajpgi.00225.2023","url":null,"abstract":"<p><p>Multiple studies describe prodromal, nonmotor dysfunctions that affect the quality of life of patients who subsequently develop Parkinson's disease (PD). These prodromal dysfunctions comprise a wide array of autonomic issues, including severe gastrointestinal (GI) motility disorders such as dysphagia, delayed gastric emptying, and chronic constipation. Indeed, strong evidence from studies in humans and animal models suggests that the GI tract and its neural, mainly vagal, connection to the central nervous system (CNS) could have a major role in the etiology of PD. In fact, misfolded α-synuclein aggregates that form Lewy bodies and neurites, i.e., the histological hallmarks of PD, are detected in the enteric nervous system (ENS) before clinical diagnosis of PD. The aim of the present review is to provide novel insights into the pathogenesis of GI dysmotility in PD, focusing our attention on functional, neurochemical, and molecular alterations in animal models.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139541196","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}
引用次数: 0
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