Hepatic‐Accumulated Obeticholic Acid and Atorvastatin Self‐Assembled Nanocrystals Potentiate Ameliorative Effects in Treatment of Metabolic‐Associated Fatty Liver Disease DOI Creative Commons

Huanfen Lu,

Zhenglan Ban,

Kai Xiao

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(10)

Published: Jan. 9, 2024

Abstract Exploration of medicines for efficient and safe management metabolic‐associated fatty liver disease (MAFLD) remains a challenge. Obeticholic acid (OCA), selective farnesoid X receptor agonist, has been reported to ameliorate injury inflammation in various diseases. However, its clinical application is mainly limited by poor solubility, low bioavailability, potential side effects. Herein hepatic‐targeted nanodrugs composed OCA cholesterol‐lowering atorvastatin (AHT) with an ideal active pharmaceutical ingredient (API) content orally combined treatment MAFLD created. Such carrier‐free nanocrystals (OCAHTs) are self‐assembled, not only improving the stability gastroenteric environments but also achieving hepatic accumulation through bile transporter‐mediated enterohepatic recycling process. Orally administrated OCAHT outperforms simple combination AHT ameliorating damage both acetaminophen‐challenged mice high‐fat diet‐induced less systematic toxicity. Importantly, exerts profoundly reverse effects on MAFLD‐associated molecular pathways, including impairing lipid metabolism, reducing inflammation, enhancing antioxidation response. This work provides facile transporter‐based strategy hepatic‐targeting drug delivery presents full‐API nanocrystal which facilitate practical translation nanomedicines against MAFLD.

Language: Английский

Aging and aging-related diseases: from molecular mechanisms to interventions and treatments DOI Creative Commons
Jun Guo, Xiuqing Huang, Lin Dou

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Dec. 16, 2022

Aging is a gradual and irreversible pathophysiological process. It presents with declines in tissue cell functions significant increases the risks of various aging-related diseases, including neurodegenerative cardiovascular metabolic musculoskeletal immune system diseases. Although development modern medicine has promoted human health greatly extended life expectancy, aging society, variety chronic diseases have gradually become most important causes disability death elderly individuals. Current research on focuses elucidating how endogenous exogenous stresses (such as genomic instability, telomere dysfunction, epigenetic alterations, loss proteostasis, compromise autophagy, mitochondrial cellular senescence, stem exhaustion, altered intercellular communication, deregulated nutrient sensing) participate regulation aging. Furthermore, thorough pathogenesis to identify interventions that promote longevity caloric restriction, microbiota transplantation, nutritional intervention) clinical treatment methods for (depletion senescent cells, therapy, antioxidative anti-inflammatory treatments, hormone replacement therapy) could decrease incidence turn healthy longevity.

Language: Английский

Citations

700
Role of Oxidative Stress in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: Implications for Prevention and Therapy DOI
Johanna C. Arroyave-Ospina, Zongmei Wu, Yana Geng

et al.

Antioxidants, Journal Year: 2021, Volume and Issue: 10(2), P. 174 - 174

Published: Jan. 26, 2021

Oxidative stress (OxS) is considered a major factor in the pathophysiology of inflammatory chronic liver diseases, including non-alcoholic disease (NAFLD). Chronic impairment lipid metabolism closely related to alterations oxidant/antioxidant balance, which affect metabolism-related organelles, leading cellular lipotoxicity, peroxidation, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Increased OxS also triggers hepatocytes pathways, inflammation fibrogenesis, contributing progression steatohepatitis (NASH). The antioxidant response, regulated by Nrf2/ARE pathway, key component this process counteracts oxidative stress-induced damage, restoration normal metabolism. Therefore, modulation response emerges as an interesting target prevent NAFLD development progression. This review highlights link between disturbed context NAFLD. In addition, emerging potential therapies based on effects their likely molecular targets are discussed.

Language: Английский

Citations

355
NAFLD: Mechanisms, Treatments, and Biomarkers DOI Creative Commons
Fatiha Nassir

Biomolecules, Journal Year: 2022, Volume and Issue: 12(6), P. 824 - 824

Published: June 13, 2022

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated (MAFLD), is one of the most common causes diseases worldwide. NAFLD growing in parallel with obesity epidemic. No pharmacological treatment available to treat NAFLD, specifically. The reason might be that a multi-factorial an incomplete understanding mechanisms involved, absence accurate and inexpensive imaging tools, lack adequate non-invasive biomarkers. consists accumulation excess lipids liver, causing lipotoxicity progress steatohepatitis (NASH), fibrosis, hepatocellular carcinoma. for pathogenesis current interventions management disease, role sirtuins as potential targets are discussed here. In addition, diagnostic non-coding RNAs emerging biomarkers summarized. availability biomarkers, diagnosis tools crucial detection early signs progression NAFLD. This will expedite clinical trials validation therapeutic treatments.

Language: Английский

Citations

252
Pathogenesis and treatment of non-alcoholic steatohepatitis and its fibrosis DOI Creative Commons
Kuei‐Chuan Lee, Pei-Shan Wu, Han‐Chieh Lin

et al.

Clinical and Molecular Hepatology, Journal Year: 2022, Volume and Issue: 29(1), P. 77 - 98

Published: Oct. 13, 2022

The initial presentation of non-alcoholic steatohepatitis (NASH) is hepatic steatosis. dysfunction lipid metabolism within hepatocytes caused by genetic factors, diet, and insulin resistance causes accumulation. Lipotoxicity, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress would further contribute to hepatocyte injury death, leading inflammation immune in the liver. During healing process, accumulation an excessive amount fibrosis might occur while healing. development NASH liver fibrosis, gut-liver axis, adipose-liver renin-angiotensin system (RAS) may be dysregulated impaired. Translocation bacteria or its end-products entering could activate hepatocytes, Kupffer cells, stellate exacerbating steatosis, inflammation, fibrosis. Bile acids regulate glucose through Farnesoid X receptors intestine. Increased adipose tissue-derived non-esterified fatty aggravate leptin also plays a role fibrogenesis, decreased adiponectin resistance. Moreover, dysregulation peroxisome proliferator-activated liver, adipose, muscle tissues impair metabolism. In addition, RAS acid metabolism, treatment includes lifestyle modification, pharmacological therapy, non-pharmacological therapy. Currently, weight reduction modification surgery most effective However, vitamin E, pioglitazone, obeticholic have been suggested. this review, we will introduce some new clinical trials experimental therapies for related

Language: Английский

Citations

113
Therapeutic targets, novel drugs, and delivery systems for diabetes associated NAFLD and liver fibrosis DOI
Virender Kumar, Xiaofei Xin, Jingyi Ma

et al.

Advanced Drug Delivery Reviews, Journal Year: 2021, Volume and Issue: 176, P. 113888 - 113888

Published: July 24, 2021

Language: Английский

Citations

109
Engineered human hepatocyte organoids enable CRISPR-based target discovery and drug screening for steatosis DOI Creative Commons
Delilah Hendriks, Jos F. Brouwers,

Karien M. Hamer

et al.

Nature Biotechnology, Journal Year: 2023, Volume and Issue: 41(11), P. 1567 - 1581

Published: Feb. 23, 2023

Abstract The lack of registered drugs for nonalcoholic fatty liver disease (NAFLD) is partly due to the paucity human-relevant models target discovery and compound screening. Here we use human fetal hepatocyte organoids model first stage NAFLD, steatosis, representing three different triggers: free acid loading, interindividual genetic variability (PNPLA3 I148M) monogenic lipid disorders ( APOB MTTP mutations). Screening drug candidates revealed compounds effective at resolving steatosis. Mechanistic evaluation uncovered repression de novo lipogenesis as convergent molecular pathway. We present FatTracer, a CRISPR screening platform identify steatosis modulators putative targets using −/− organoids. From screen targeting 35 genes implicated in metabolism and/or NAFLD risk, FADS2 (fatty desaturase 2) emerged an important determinant hepatic Enhancement expression increases polyunsaturated abundancy which, turn, reduces lipogenesis. These organoid facilitate study etiology targets.

Language: Английский

Citations

107
The intersection between alcohol-related liver disease and nonalcoholic fatty liver disease DOI
Luis Antonio Díaz, Juan Pablo Arab, Alexandre Louvet

et al.

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2023, Volume and Issue: 20(12), P. 764 - 783

Published: Aug. 15, 2023

Language: Английский

Citations

96
Theabrownin inhibits obesity and non-alcoholic fatty liver disease in mice via serotonin-related signaling pathways and gut-liver axis DOI Creative Commons
Hangyu Li, Siyu Huang, Dan-Dan Zhou

et al.

Journal of Advanced Research, Journal Year: 2023, Volume and Issue: 52, P. 59 - 72

Published: Jan. 11, 2023

Non-alcoholic fatty liver disease (NAFLD) with obesity seriously threats public health. Our previous studies showed that dark tea had more potential on regulating lipid metabolism than other teas, and theabrownin (TB) was considered to be a main contributor the bioactivity of tea.This in vivo study aims reveal effects molecular mechanisms TB NAFLD obesity, role gut-liver axis is explored.The histopathological examinations, biochemical tests, nuclear magnetic resonance were applied evaluate obesity. The untargeted metabolomics used find key molecule for further exploration mechanisms. 16S rRNA gene sequencing assess changes gut microbiota. antibiotic cocktail fecal microbiota transplant clarify microbiota.TB markedly reduced body weight gain (67.01%), fat rate (62.81%), hepatic TG level (51.35%) preventive experiment. Especially, decreased (32.16%), (42.56%), (42.86%) therapeutic action could improvement acid oxidation, lipolysis, oxidative stress via regulation serotonin-related signaling pathways. Also, increased abundance microbiota, such as Akkermansia, Bacteroides Parabacteroides. Antibiotics-induced bacterial dysbiosis disrupted pathways liver, whereas beneficial target proteins regained restoration microbiota.We has by serotonin related through Furthermore, co-contribute alleviating promising medicine

Language: Английский

Citations

56
Obesity and its comorbidities, current treatment options and future perspectives: Challenging bariatric surgery? DOI Creative Commons

Simon Kloock,

Christian G. Ziegler,

Ulrich Dischinger

et al.

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 251, P. 108549 - 108549

Published: Oct. 23, 2023

Obesity and its comorbidities, including type 2 diabetes mellitus, cardiovascular disease, heart failure non-alcoholic liver disease are a major health economic burden with steadily increasing numbers worldwide. The need for effective pharmacological treatment options is strong, but, until recently, only few drugs have proven sufficient efficacy safety. This article provides comprehensive overview of obesity special focus on organ-specific pathomechanisms. Bariatric surgery as the so far most-effective therapeutic strategy, current future strategies will be discussed. An knowledge about gut-brain axis especially identification physiology incretins unfolds high number potential drug candidates impressive weight-reducing potential. Future multi-modal concepts in may surpass effectivity bariatric not regard to weight loss, but also associated comorbidities.

Language: Английский

Citations

51
Updated mechanisms of MASLD pathogenesis DOI Creative Commons
Yuxuan Li,

Peipei Yang,

Jialu Ye

et al.

Lipids in Health and Disease, Journal Year: 2024, Volume and Issue: 23(1)

Published: April 22, 2024

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) has garnered considerable attention globally. Changing lifestyles, over-nutrition, and physical inactivity have promoted its development. MASLD is typically accompanied by obesity strongly linked to metabolic syndromes. Given that prevalence on the rise, there an urgent need elucidate pathogenesis. Hepatic lipid accumulation generally triggers lipotoxicity induces or progress steatohepatitis (MASH) mediating endoplasmic reticulum stress, oxidative organelle dysfunction, ferroptosis. Recently, significant been directed towards exploring role of gut microbial dysbiosis in development MASLD, offering a novel therapeutic target for MASLD. Considering are no recognized pharmacological therapies due diversity mechanisms involved difficulty associated with undertaking clinical trials, potential targets remain elusive. Thus, this article aimed summarize evaluate prominent roles lipotoxicity, ferroptosis, microbes underlying their effects. Furthermore, existing advances challenges treatment were outlined.

Language: Английский

Citations

45