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There have been major advances in defining the immunological events associated with fibrosis in various chronic liver diseases. We have taken advantage of this data to focus on the mechanisms of action of a unique multi-kinase inhibitor, coined sorafenib, on CCl4-induced murine liver fibrosis, including the effects of this agent in models of both acute and chronic CCl4-mediated pathology. Importantly, sorafenib significantly attenuated chronic liver injury and fibrosis, including reduction in liver inflammation and histopathology as well as decreased expression of liver fibrosis-related genes, including α-smooth muscle actin, collagen, matrix metalloproteinases and the tissue inhibitor of metalloproteinase-1. Furthermore, sorafenib treatment resulted in translocation of cytoplasmic STAT3 to the nucleus in its active form. Based on this observation, we used hepatocyte-specific STAT3 knockout (STAT3(Hep-/-)) mice to demonstrate that hepatic STAT3 was critical for sorafenib-mediated protection against liver fibrosis, and that the upregulation of STAT3 phosphorylation was dependent on Kupffer cell-derived IL-6. In conclusion, these data reflect the clinical potential of the multi-kinase inhibitor sorafenib for the prevention of fibrosis as well as the treatment of established liver fibrosis and illustrate the immunological mechanisms that underlie the protective effects of sorafenib.
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http://dx.doi.org/10.1016/j.jaut.2013.07.008 | DOI Listing |
Am J Pathol
December 2024
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas. Electronic address:
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of chronic liver conditions, ranging from simple steatosis to nonalcoholic steatohepatitis, which may progress to fibrosis/cirrhosis. Here, the GSE163211 data set was analyzed, and Asah1 (encoding acid ceramidase) was identified as a crucial lysosomal gene that positively correlated with NAFLD stages in obese patients. To evaluate the role of Asah1 in the progression of NAFLD, Asah1/Alb mice (hepatocyte-specific deletion of Asah1) and Asah1 floxed (Asah1/wild-type) mice were fed with either a normal diet or a high-fat, high-cholesterol paigen diet (PD) for 20 weeks.
View Article and Find Full Text PDFUpdates Surg
December 2024
Surgery Clinic 3, Regional Institute of Gastroenterology and Hepatology "Prof. Dr. Octavian Fodor", "Iuliu Hațieganul" University of Medicine and Pharmacy, 400394, Cluj-Napoca-Napoca, Romania.
Patients with esophageal cancer and concomitant liver cirrhosis (LC) pose a surgical challenge because of the increased risk of postoperative complications and mortality. Purpose of this study was to review the existing literature and estimate perioperative short-term outcomes of esophagectomy in this patient population. Systematic review and meta-analysis.
View Article and Find Full Text PDFMol Cell Biochem
December 2024
Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Henan Xinxiang, 453003, People's Republic of China.
To investigate the promoting effect of extracellular vesicles derived from myocardial cells (CM-EVs) on the reprogramming of cardiac fibroblasts (CFs) into cardiomyocyte-like cells (iCMs) and their therapeutic effect on myocardial infarction (MI) in rats. Cell experiments: The differential adhesion method was used to obtain Sprague Dawley (SD) suckling rat CFs and cardiomyocytes (CMs), while the ultracentrifugation method was used to obtain CM-EVs. Transmission electron microscopy and nanoparticle tracking technology were used to analyze and determine the morphology and particle size of CM-EVs.
View Article and Find Full Text PDFMol Biol Rep
December 2024
State Key Laboratory of Cell Differentiation and Regulation, College of Life Sciences, Henan Normal University, Xinxiang, 453007, China.
Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are key downstream effectors of the Hippo pathway that regulate organ size, tissue homeostasis, and cancer development. YAP/TAZ play crucial regulatory roles in organ growth, cell proliferation, cell renewal, and regeneration. Mechanistically, YAP/TAZ influence the occurrence and progression of liver regeneration (LR) through various signaling pathways, including Notch, Wnt/β-catenin, TGF-β/Smad.
View Article and Find Full Text PDFJ Assoc Nurses AIDS Care
December 2024
Jennifer C. Price, MD, PhD, is a Professor, Division of Gastroenterology and Hepatology, University of California San Francisco, San Francisco, California, USA. Kyoko Hirose, BA, is a Research Coordinator, Division of Gastroenterology and Hepatology, University of California San Francisco, San Francisco, California, USA. Naga Chalasani, MD, is a Professor, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA. Holly Crandall, RN, BSN, CCRP, is a Project Manager, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA. Sonya Heath, MD, is a Professor, Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA. Rohit Loomba, MD MHSc, is a Professor, Division of Gastroenterology and Hepatology, University of California, San Diego, California, USA. Susanna Naggie, MD, is a Professor, Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA. Richard K. Sterling, MD, MSc, is a Professor, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, Virginia, USA. Mark Sulkowski, MD, is a Professor, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Laura Wilson, ScM, is a Senior Research Associate, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA. Jordan E. Lake, MD, MSc, is an Associate Professor, Division of Infectious Disease, University of Texas Health Sciences Center at Houston, Houston, Texas, USA.
Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in people with HIV (PWH) and increases the risk of hepatic fibrosis and hepatocellular carcinoma. We sent an online survey to providers of the American Academy of HIV Medicine. Of respondents (n = 214, 8% response rate), 65% reported screening for NAFLD in PWH, with 28% routinely screening all patients.
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