Antioxidant and anti-inflammatory agents in chronic liver diseases: Molecular mechanisms and therapy

World Journal of Hepatology, Journal Year: 2023, Volume and Issue: 15(2), P. 180 - 200

Published: Feb. 24, 2023

Chronic liver disease (CLD) is a continuous process that causes reduction of function lasting more than six months. CLD includes alcoholic (ALD), non-alcoholic fatty (NAFLD), chronic viral infection, and autoimmune hepatitis, which can lead to fibrosis, cirrhosis, cancer. Liver inflammation oxidative stress are commonly associated with the development progression CLD. Molecular signaling pathways such as AMP-activated protein kinase (AMPK), C-Jun N-terminal kinase, peroxisome proliferator-activated receptors (PPARs) implicated in pathogenesis Therefore, antioxidant anti-inflammatory agents from natural products new potent therapies for ALD, NAFLD, hepatocellular carcinoma (HCC). In this review, we summarize some powerful be potential applied all stages CLD, ALD/NAFLD HCC. The selected β-sitosterol, curcumin, genistein, silymarin regulate activation several important molecules, including AMPK, Farnesoid X receptor, nuclear factor erythroid 2-related factor-2, PPARs, phosphatidylinositol-3-kinase, lysyl oxidase-like proteins. addition, clinical trials undergoing evaluate their efficacy safety.

Language: Английский

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Treating NASH by targeting peroxisome proliferator-activated receptors

Journal of Hepatology, Journal Year: 2023, Volume and Issue: 79(5), P. 1302 - 1316

Published: July 17, 2023

Language: Английский

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Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease?

Metabolism, Journal Year: 2024, Volume and Issue: 157, P. 155937 - 155937

Published: May 21, 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD) closely associates with obesity and type 2 diabetes. Lifestyle intervention bariatric surgery aiming at substantial weight loss are cornerstones of MASLD treatment by improving histological outcomes reducing risks comorbidities. Originally developed as antihyperglycemic drugs, incretin (co-)agonists SGLT2 inhibitors also reduce steatosis cardiorenovascular events. Certain agonists effectively improve features MASLD, but not fibrosis. Of note, beneficial effects on may necessarily require loss. Despite moderate gain, one PPARγ agonist improved adipose tissue certain benefit fibrosis in post-hoc analyses. Likewise, the first THRβ-agonist was recently provisionally approved because significant improvements We here discuss liver-related metabolic induced different treatments their association Therefore, we compare results from clinical trials drugs acting via (incretin (co)agonists, inhibitors) those exerting no (pioglitazone; resmetirom). Furthermore, other development directly targeting hepatic lipid metabolism (lipogenesis inhibitors, FGF21 analogs) addressed. Although THRβ-agonism outcomes, concepts should consider all cardiometabolic risk factors for effective reduction morbidity mortality affected people.

Language: Английский

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A 5:2 intermittent fasting regimen ameliorates NASH and fibrosis and blunts HCC development via hepatic PPARα and PCK1

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(6), P. 1371 - 1393.e7

Published: May 7, 2024

The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen prevents NASH development as well ameliorates established fibrosis without affecting total calorie intake. Furthermore, the blunted NASH-HCC when applied therapeutically. timing, length, number cycles type diet were critical parameters determining benefits fasting. Combined proteome, transcriptome, metabolome analyses peroxisome-proliferator-activated receptor alpha (PPARα) glucocorticoid-signaling-induced PCK1 act co-operatively hepatic executors response. In line with this, PPARα targets reduced human NASH. Notably, only initiated during active phase mice robustly induced glucocorticoid signaling free-fatty-acid-induced signaling. However, hepatocyte-specific deletion partially abrogated contrast, combined knockdown Ppara Pck1 vivo abolished beneficial outcomes against inflammation fibrosis. Moreover, overexpression alone or together lowered triglycerides steatosis. Our data support notion is a promising intervention subsequent liver cancer.

Language: Английский

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Metabolic Dysfunction–Associated Steatotic Liver Disease: From Pathogenesis to Current Therapeutic Options

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(11), P. 5640 - 5640

Published: May 22, 2024

The epidemiological burden of liver steatosis associated with metabolic diseases is continuously growing worldwide and in all age classes. This condition generates possible progression damage (i.e., inflammation, fibrosis, cirrhosis, hepatocellular carcinoma) but also independently increases the risk cardio-metabolic cancer. In recent years, terminological evolution from “nonalcoholic fatty disease” (NAFLD) to “metabolic dysfunction-associated (MAFLD) and, finally, steatotic (MASLD) has been paralleled by increased knowledge mechanisms linking local hepatic) systemic pathogenic pathways. As a consequence, need for an appropriate classification individual phenotypes oriented investigation innovative therapeutic tools. Besides well-known role lifestyle change, number pharmacological approaches have explored, ranging antidiabetic drugs agonists acting on gut–liver axis at level (mainly farnesoid X receptor (FXR) agonists, PPAR thyroid hormone agonists), anti-fibrotic anti-inflammatory agents. intrinsically complex pathophysiological history MASLD makes selection single effective treatment major challenge, so far. this evolving scenario, cooperation between different stakeholders (including subjects risk, health professionals, pharmaceutical industries) could significantly improve management disease implementation primary secondary prevention measures. high healthcare search new, effective, safe pressing need, together accurate characterization phenotypes. Recent promising advances indicate that we may soon enter era precise personalized therapy MASLD/MASH.

Language: Английский

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Drug Advances in NAFLD: Individual and Combination Treatment Strategies of Natural Products and Small-Synthetic-Molecule Drugs

Biomolecules, Journal Year: 2025, Volume and Issue: 15(1), P. 140 - 140

Published: Jan. 17, 2025

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic and is closely associated with metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), syndrome. However, effective treatment strategies for NAFLD are still lacking. In recent years, progress been made in understanding pathogenesis of NAFLD, identifying multiple therapeutic targets providing new directions drug development. This review summarizes advances focusing on mechanisms action natural products, small-synthetic-molecule drugs, combination therapy strategies. aims to provide insights treating NAFLD.

Language: Английский

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Current Therapeutic Landscape for Metabolic Dysfunction-Associated Steatohepatitis

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1778 - 1778

Published: Feb. 19, 2025

In recent years, “metabolic dysfunction-associated steatotic liver disease” (MASLD) has been proposed to better connect disease metabolic dysfunction, which is the most common chronic worldwide. MASLD affects more than 30% of individuals globally, and it diagnosed by combination hepatic steatosis obesity, type 2 diabetes, or two risk factors. begins with buildup extra fat, often greater 5%, within liver, causing hepatocytes become stressed. This can proceed a severe form, steatohepatitis (MASH), in 20–30% people, where inflammation causes tissue fibrosis, limits blood flow over time. As fibrosis worsens, MASH may lead cirrhosis, failure, even cancer. While pathophysiology not fully known, current “multiple-hits” concept proposes that dietary lifestyle factors, genetic epigenetic factors contribute elevated oxidative stress inflammation, fibrosis. review article provides an overview pathogenesis evaluates existing therapies as well pharmacological drugs are currently being studied clinical trials for MASH.

Language: Английский

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Current Research on the Pathogenesis of NAFLD/NASH and the Gut–Liver Axis: Gut Microbiota, Dysbiosis, and Leaky-Gut Syndrome

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(19), P. 11689 - 11689

Published: Oct. 2, 2022

Global lifestyle changes have led to an increased incidence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), requiring further in-depth research understand the mechanisms develop new therapeutic strategies. In particular, high-fat high-fructose diets been shown increase intestinal permeability, which can expose endotoxins. Indeed, accumulating evidence points a link between these diseases axis, including dysbiosis gut microbiome leaky-gut syndrome. Here, we review contributing links small intestine in pathogenesis NAFLD/NASH, focusing on roles microbiota their metabolites influence enzymes essential for proper metabolism function. Advances next-generation sequencing technology facilitated analyses metagenome, providing insights into functions physiological pathological mechanisms. This summarizes recent linking diseases, offering directions elucidate detailed novel targets treatment prevention.

Language: Английский

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Utility of Ultrasound-Guided Attenuation Parameter for Grading Steatosis With Reference to MRI-PDFF in a Large Cohort

Clinical Gastroenterology and Hepatology, Journal Year: 2021, Volume and Issue: 20(11), P. 2533 - 2541.e7

Published: Nov. 10, 2021

Background & AimsUltrasound-guided attenuation parameter (UGAP) is recently developed for noninvasive evaluation of steatosis. However, reports on its usefulness in clinical practice are limited. This prospective multicenter study analyzed the diagnostic accuracy grading steatosis with reference to magnetic resonance imaging–based proton density fat fraction (MRI-PDFF), a method high accuracy, large cohort.MethodsAltogether, 1010 patients chronic liver disease who underwent MRI-PDFF and UGAP were recruited prospectively enrolled from 6 Japanese centers. Linearity was evaluated using intraclass correlation coefficients between values. Bias, defined as mean difference values, assessed by Bland-Altman analysis. cutoffs pairwise MRI-PDFF-based grade determined area under receiver-operating characteristic curve (AUROC) analyses.ResultsUGAP values shown be normally distributed. because PDFF not distributed, they log-transformed (MRI-logPDFF). significantly correlated MRI-logPDFF (intraclass coefficient = 0.768). Additionally, analysis showed good agreement bias 0.0002% narrow range (95% confidence interval [CI], –0.015 0.015). The AUROCs distinguishing ≥1 (MRI-PDFF ≥5.2%), ≥2 ≥11.3%), 3 ≥17.1%) 0.910 CI, 0.891–0.928), 0.912 0.894–0.929), 0.894 0.873–0.916), respectively.ConclusionsUGAP has excellent MRI-PDFF. linearity negligible bias, suggesting that technical performance characteristics can widely used trials patient care. (UMIN Clinical Trials Registry, Number: UMIN000041196). Ultrasound-guided cohort. Altogether, analyses. respectively.

Language: Английский

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Longitudinal association of magnetic resonance elastography‐associated liver stiffness with complications and mortality

Alimentary Pharmacology & Therapeutics, Journal Year: 2021, Volume and Issue: 55(3), P. 292 - 301

Published: Dec. 19, 2021

Magnetic resonance elastography (MRE) has the highest diagnostic accuracy for liver fibrosis; however, association between MRE-associated stiffness and development of hepatic extrahepatic complications as well mortality remains unclear.In this study, we investigated longitudinal mortality.This retrospective study included 2373 consecutive patients with chronic disease. All received standard care was assessed every 1-6 months.Newly diagnosed hepatocellular carcinoma (HCC), decompensation, major adverse cardiovascular events (MACE), cancer death were observed in 99, 117, 73, 77 170 respectively. In multivariable analysis, adjusted hazard ratios (aHR) (95% confidence interval [CI]) HCC, MACE, 1.28 (1.2-1.4), 1.34 (1.3-1.4), 0.96 (0.9-1.1), 1.00 (0.9-1.1) 1.17 (1.1-1.2), respectively, each 1-kPa increase stiffness. Similarly, aHR CI) 4.20 (2.2-8.2), 67.5 (9.2-492), 0.83 (0.4-1.7), 0.90 (0.5-1.7) 2.90 (1.6-5.4), cirrhosis (>4.7 kPa) compared to those minimal fibrosis (<3 kPa).Increased associated increased risk decompensation a dose-dependent fashion but not MACE or cancer, implicating significant role MRE liver-related mortality; further studies are warranted explore its cancer.

Language: Английский

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