Targeting Metabolism: Innovative Therapies for MASLD Unveiled

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 4077 - 4077

Published: April 25, 2025

The recent introduction of the term metabolic-dysfunction-associated steatotic liver disease (MASLD) has highlighted critical role metabolism in disease’s pathophysiology. This innovative nomenclature signifies a shift from previous designation non-alcoholic fatty (NAFLD), emphasizing condition’s progressive nature. Simultaneously, MASLD become one most prevalent diseases worldwide, highlighting urgent need for research to elucidate its etiology and develop effective treatment strategies. review examines delineates revised definition MASLD, exploring epidemiology pathological changes occurring at various stages disease. Additionally, it identifies metabolically relevant targets within provides summary latest targeted drugs under development, including those clinical some preclinical stages. finishes with look ahead future therapy goal summarizing providing fresh ideas insights.

Language: Английский

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Lipid sensing nuclear receptors involved in the pathogenesis of fatty liver disease

FEBS Letters, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 13, 2024

Non-alcoholic fatty liver disease (NAFLD) begins with lipid accumulation and progresses toward inflammation fibrosis. Nuclear receptors (NRs), like the Peroxisome Proliferator-Activated Receptors alpha gamma (PPARα PPARy), Farnesoid X Receptor (FXR), Liver receptor (LXR), regulate genes by heterodimerizing Retinoid (RXR). These are emerging targets for pharmaceutical intervention metabolic diseases.

Language: Английский

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Exploring the Role of Bempedoic Acid in Metabolic Dysfunction Associated Steatotic Liver Disease: Actual Evidence and Future Perspectives

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 6938 - 6938

Published: June 25, 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD) involves excessive lipid accumulation in hepatocytes, impacting global healthcare due to its high prevalence and risk of progression severe conditions. Its pathogenesis genetic, metabolic, inflammatory factors, with cardiovascular events as the leading cause mortality. This review examines role lipid-lowering therapies MASLD, a particular focus on bempedoic acid, recently approved cholesterol-lowering agent for hypercholesterolemia cardiovascular-risk patients. It explores potential by modulating metabolism pathways based most recent studies available. Bempedoic acid inhibits ATP-citrate lyase, reducing cholesterol fatty synthesis while activating AMP-activated protein kinase suppress gluconeogenesis lipogenesis. Animal indicate efficacy hepatic steatosis, inflammation, fibrosis. holds promise therapeutic offering dual benefits inflammation. Further clinical trials are required confirm safety MASLD patients, potentially addressing multifaceted nature this disease.

Language: Английский

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Free Cholesterol‐Induced Liver Injury in Non‐Alcoholic Fatty Liver Disease: Mechanisms and a Therapeutic Intervention Using Dihydrotanshinone I

Advanced Science, Journal Year: 2024, Volume and Issue: 12(2)

Published: Nov. 19, 2024

Abstract Build‐up of free cholesterol (FC) substantially contributes to the development and severity non‐alcoholic fatty liver disease (NAFLD). Here, we investigate specific mechanism by which FC induces injury in NAFLD propose a novel therapeutic approach using dihydrotanshinone I (DhT). Rather than ester (CE), observed elevated levels total cholesterol, FC, alanine transaminase (ALT) patients high‐cholesterol diet‐induced mice compared those healthy controls. The level demonstrated positive correlation with ALT both mice. Mechanistic studies revealed that reactive oxygen species level, impaired function lysosomes, disrupted lipophagy process, consequently inducing cell apoptosis. We then found DhT protected on an HCD diet, independent gut microbiota. functioned as potent ligand for peroxisome proliferator‐activated receptor α (PPARα), stimulating its transcriptional enhancing catalase expression lower (ROS) level. Notably, protective effect was nullified hepatic PPARα knockdown. Thus, these findings are first report detrimental role NAFLD, could lead new treatment strategies leveraging potential pathway.

Language: Английский

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Design of a multi-target focused library for antidiabetic targets using a comprehensive set of chemical transformation rules

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Nov. 2, 2023

Virtual small molecule libraries are valuable resources for identifying bioactive compounds in virtual screening campaigns and improving the quality of terms physicochemical properties, complexity, structural diversity. In this context, computational-aided design focused against antidiabetic targets can provide novel alternatives treating type II diabetes mellitus (T2DM). work, we integrated information generated to date on with activity, advances computational methods, knowledge chemical transformations available literature multi-target compound T2DM. We evaluated novelty diversity newly library by comparing it approved clinical use, natural products, tested vivo experimental models. The designed freely a starting point drug design, synthesis, biological evaluation or further filtering. Also, compendium 280 transformation rules identified medicinal chemistry context is made linear notation SMIRKS use other enumeration hit optimization approaches.

Language: Английский

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Pentadecanoic Acid (C15:0), an Essential Fatty Acid, Shares Clinically Relevant Cell-Based Activities with Leading Longevity-Enhancing Compounds

Published: Oct. 9, 2023

Pentadecanoic acid (C15:0) is an essential odd-chain saturated fatty with broad activities relevant to protecting cardiometabolic, immune, and liver health. C15:0 activates AMPK inhibits mTOR, both of which are core components the human longevity pathway. To assess potential for enhance processes associated healthspan, we used cell-based molecular phenotyping assays compare three longevity-enhancing candidates: acarbose, metformin, rapamycin. (n=36 in 10 12 cell systems) rapamycin (n=32 had most clinically relevant, dose-dependent activities. At their optimal doses, (17 µM) (9 shared 24 across systems, including anti-inflammatory (e.g., lowered MCP-1, TNFɑ, IL-10, IL-17A/F), antifibrotic, anticancer activities, further supported by previously published vitro vivo studies. Paired prior demonstrated abilities target pathways, hallmarks aging, aging rate biomarkers, type 2 diabetes, heart disease, cancer, nonalcoholic our results support as nutrient equivalent to, or surpassing, leading candidate compounds.

Language: Английский

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A novel method to derive a human safety limit for PFOA by gene expression profiling and modelling

Frontiers in Toxicology, Journal Year: 2024, Volume and Issue: 6

Published: March 21, 2024

Perfluorooctanoic acid (PFOA) is a persistent environmental contaminant that can accumulate in the human body due to its long half-life. This substance has been associated with liver, pancreatic, testicular and breast cancers, liver steatosis endocrine disruption. PFOA member of large group substances also known as “forever chemicals” vast majority this lack toxicological data would enable their effective risk assessment terms health hazards. study aimed derive health-based guidance value for intake (ng/kg BW/day) from vitro transcriptomics data. To end, we developed an silico workflow comprising five components: (i) sourcing hepatic concentration-response data; (ii) deriving molecular points departure using BMDExpress3 performing pathway analysis gene set enrichment (GSEA) identify most sensitive pathways exposure; (iii) estimating freely-dissolved concentrations mass balance model; (iv) vivo doses by reverse dosimetry PBK model part quantitative extrapolation (QIVIVE) algorithm; (v) calculating tolerable daily (TDI) PFOA. Fourteen percent interrogated genes exhibited relationships. GSEA revealed “fatty metabolism” was exposure. In free were calculated be 2.9% nominal applied concentrations, these input into QIVIVE workflow. Exposure virtual population 3,000 individuals estimated, which TDI 0.15 ng/kg BW/day benchmark dose modelling software, PROAST. comparable previously published values 1.16, 0.69, 0.86 European Food Safety Authority. conclusion, demonstrates combined utility “omics”-derived point setting anticipation acceptance measurements chemical assessment.

Language: Английский

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Molecular insights into experimental models and therapeutics for cholestasis

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 174, P. 116594 - 116594

Published: April 13, 2024

Cholestatic liver disease (CLD) is a range of conditions caused by the accumulation bile acids (BAs) or disruptions in flow, which can harm and ducts. To investigate its pathogenesis treatment, it essential to establish assess experimental models cholestasis, have significant clinical value. However, owing complex single modelling method merely reflect one few pathological mechanisms, each has adaptability limitations. We summarize existing including animal models, gene-knockout cell organoid models. also describe main types cholestatic simulated clinically. This review provides an overview targeted therapy used for treating cholestasis based on current research status In addition, we discuss respective advantages disadvantages different help that resemble conditions. sum, this not only outlines with but projects prospects thereby bridging basic practical therapeutic applications.

Language: Английский

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PPARs as Key Transcription Regulators at the Crossroads of Metabolism and Inflammation

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(8), P. 4467 - 4467

Published: April 18, 2024

The metabolic and immune systems are complex networks of organs, cells, proteins that involved in the extraction energy from food; this is to run cellular processes defend body against infections while protecting its own tissues, respectively [...].

Language: Английский

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Development of a Robust Read-Across Model for the Prediction of Biological Potency of Novel Peroxisome Proliferator-Activated Receptor Delta Agonists

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(10), P. 5216 - 5216

Published: May 10, 2024

A robust predictive model was developed using 136 novel peroxisome proliferator-activated receptor delta (PPARδ) agonists, a distinct subtype of lipid-activated transcription factors the nuclear superfamily that regulate target genes by binding to characteristic sequences DNA bases. The employs various structural descriptors and docking calculations provides predictions biological activity PPARδ following criteria Organization for Economic Co-operation Development (OECD) development validation quantitative structure–activity relationship (QSAR) models. Specifically focused on small molecules, facilitates identification highly potent selective agonists offers read-across concept providing chemical neighbours compound under study. process conducted Isalos Analytics Software (v. 0.1.17) which an intuitive environment machine-learning applications. final released as user-friendly web tool can be accessed through Enalos Cloud platform’s graphical user interface (GUI).

Language: Английский

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