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Function: insertAPISummary
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Background: Hepatic fibrosis is the result of chronic liver injury that can progress to cirrhosis and lead to liver failure. Nevertheless, there are no anti-fibrotic drugs licensed for human use. Here, we investigated the anti-fibrotic activity of GNS561, a new lysosomotropic molecule with high liver tropism.
Methods: The anti-fibrotic effect of GNS561 was determined using LX-2 hepatic stellate cells (HSCs) and primary human HSCs by studying cell viability, activity of caspases 3/7, autophagic flux, cathepsin maturation and activity, HSC activation and transforming growth factor-β1 (TGF-β1) maturation and signaling. The contribution of GNS561 lysosomotropism to its anti-fibrotic activity was assessed by increasing lysosomal pH. The potency of GNS561 on fibrosis was evaluated in a rat model of diethylnitrosamine-induced liver fibrosis.
Results: GNS561 significantly decreased cell viability and promoted apoptosis. Disrupting the lysosomal pH gradient impaired its pharmacological effects, suggesting that GNS561 lysosomotropism mediated cell death. GNS561 impaired cathepsin activity, leading to defective TGF-β1 maturation and autophagic processes. Moreover, GNS561 decreased HSC activation and extracellular matrix deposition by downregulating TGF-β1/Smad and mitogen-activated proteine kinase signaling and inducing fibrolysis. Finally, oral administration of GNS561 (15 mg/kg per day) was well tolerated and attenuated diethylnitrosamine-induced liver fibrosis in this rat model (decrease of collagen deposition and of pro-fibrotic markers and increase of fibrolysis).
Conclusion: GNS561 is a new potent lysosomotropic compound that could represent a valid medicinal option for hepatic fibrosis treatment through both its anti-fibrotic and its pro-fibrolytic effects. In addition, this study provides a rationale for targeting lysosomes as a promising therapeutic strategy in liver fibrosis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366401 | PMC |
http://dx.doi.org/10.1177/2040622320942042 | DOI Listing |
Liver Int
January 2025
Department of Medicine, University of Verona, Verona, Italy.
Background: Studies have reported an association between metabolic dysfunction-associated steatotic liver disease (MASLD) and an increased risk of developing atrial fibrillation (AF). However, the magnitude of the risk and whether this risk varies with the severity of MASLD remains uncertain.
Methods: In this systematic review and meta-analysis, we searched three large electronic databases using predefined keywords to identify cohort studies (published up to 30 September 2024) in which MASLD was diagnosed by liver biopsy, imaging methods, International Classification of Diseases (ICD) codes, or blood-based scores.
Liver Int
January 2025
Liver Center, Digestive Diseases Section, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Background & Aims: Approximately 40% of patients with Primary Biliary Cholangitis (PBC) show incomplete response to ursodeoxycholic acid, thus needing second-line treatment to prevent disease progression. As no head-to-head comparison study is available, we used a network meta-analysis (NMA) to compare efficacy and safety of available second-line therapies.
Methods: We performed a systematic literature review including randomised, placebo-controlled trials of patients with PBC and incomplete response, or intolerance, to ursodeoxycholic acid, and compared relative risks (RRs) for primary (biochemical response at 52-week) and secondary outcomes [incidence of new-onset pruritus and serious adverse events (SAEs)].
Liver Int
January 2025
Depatrtment of Medicine, Karsh Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Background: The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), parallels the rise in sedentary lifestyles. MASLD is the most common form of steatotic liver disease (SLD), which represents the umbrella beneath which the vast majority of chronic liver diseases fall, including alcohol-related liver disease and their overlap. These conditions are the leading contributors to chronic liver disease, significantly impacting global morbidity and mortality.
View Article and Find Full Text PDFLiver Int
January 2025
Division of Gastroenterology-Hepatology, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Introduction: Racial/ethnic disparities have been previously reported in renal and hepatic disease care; however, acute kidney injury (AKI) in the setting of cirrhosis (hepatorenal syndrome [HRS]-AKI) despite its complexity requiring a multidisciplinary approach, remains understudied.
Methods: To identify unique associations of clinical and sociodemographic factors with mortality and length of stay (LOS) among patients hospitalised with HRS-AKI, hierarchical regression analysis was conducted, along with a mediation analysis to estimate how race-related differences in in-hospital mortality were influenced by payer type, area household income, and clinical severity.
Results: Black patients demonstrated a significantly higher odds of in-hospital mortality, compared to their white counterparts, adjusting for (1) sex and age, (2) sex, age, payer type, and area household income and (3) sex, age, and clinical severity [OR 1.
Front Med (Lausanne)
December 2024
Department of Hospital Internal Medicine, Mayo Clinic, Jacksonville, FL, United States.
Introduction: Hepatic artery pseudoaneurysm (HAP) is a rare and potentially life-threatening condition associated with high mortality. This study aims to review the etiology, clinical manifestations, management, and outcomes of patients diagnosed and treated for HAP at the Mayo Clinic.
Methodology: This study was a retrospective chart review of medical records for patients diagnosed and treated for hepatic artery pseudoaneurysm (HAP) at the Mayo Clinic (Florida, Minnesota, and Arizona) between September 1, 1998, and June 30, 2022.
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