NAFLD: Mechanisms, Treatments, and Biomarkers

Biomolecules, Год журнала: 2022, Номер 12(6), С. 824 - 824

Опубликована: Июнь 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.

Язык: Английский

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Pathophysiological communication between hepatocytes and non-parenchymal cells in liver injury from NAFLD to liver fibrosis

Advanced Drug Delivery Reviews, Год журнала: 2021, Номер 176, С. 113869 - 113869

Опубликована: Июль 16, 2021

Язык: Английский

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Recent Advances in Understanding of Pathogenesis of Alcohol-Associated Liver Disease

Annual Review of Pathology Mechanisms of Disease, Год журнала: 2022, Номер 18(1), С. 411 - 438

Опубликована: Окт. 21, 2022

Alcohol-associated liver disease (ALD) is one of the major diseases arising from chronic alcohol consumption and most common causes liver-related morbidity mortality. ALD includes asymptomatic steatosis, fibrosis, cirrhosis, alcohol-associated hepatitis its complications. The progression involves complex cell-cell organ-organ interactions. We focus on impact dysregulation homeostatic mechanisms regulation injury repair in liver. In particular, we discuss recent advances understanding disruption balance between programmed cell death prosurvival pathways, such as autophagy membrane trafficking, pathogenesis ALD. also summarize current innate immune responses, sinusoidal endothelial dysfunction hepatic stellate activation, gut-liver adipose-liver cross talk response to ethanol. addition,we describe potential therapeutic targets clinical trials aimed at alleviating hepatocyte injury, reducing inflammatory targeting gut microbiota, for treatment

Язык: Английский

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Exosomes derived from human adipose mesenchymal stem cells ameliorate hepatic fibrosis by inhibiting PI3K/Akt/mTOR pathway and remodeling choline metabolism

Journal of Nanobiotechnology, Год журнала: 2023, Номер 21(1)

Опубликована: Янв. 25, 2023

Liver fibrosis is a chronic liver disease with the presence of progressive wound healing response caused by injury. Currently, there are no approved therapies for fibrosis. Exosomes derived from human adipose mesenchymal stem cells (hADMSCs-Exo) have displayed prominent therapeutic effect on diseases. However, few studies evaluated hADMSCs-Exo in and cirrhosis, its precise mechanisms action remain unclear. Herein, we investigated anti-fibrotic efficacy vitro vivo, identified important metabolic changes detailed mechanism through transcriptomic metabolomic profiling. We found could inhibit proliferation activated hepatic stellate aggravating apoptosis arresting G1 phase, effectively inhibiting expression profibrogenic proteins epithelial-to-mesenchymal transition (EMT) vitro. Moreover, it significantly block collagen deposition EMT process, improve function reduce inflammation cirrhosis mice model. The omics analysis revealed that key anti-hepatic was inhibition PI3K/AKT/mTOR signaling pathway affecting metabolites lipid metabolism, mainly regulating choline metabolism. CHPT1 facilitated formation maintenance vesicular membranes. Thus, our study indicates can attenuate cell activation suppress progression fibrosis, which holds significant potential use as extracellular nanovesicles-based therapeutics treatment possibly other intractable

Язык: Английский

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STING mediates hepatocyte pyroptosis in liver fibrosis by Epigenetically activating the NLRP3 inflammasome

Redox Biology, Год журнала: 2023, Номер 62, С. 102691 - 102691

Опубликована: Март 29, 2023

The activation of stimulator interferon genes (STING) and NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis signaling pathways represent two distinct central mechanisms in liver disease. However, the interconnections between these epigenetic regulation STING-NLRP3 axis hepatocyte during fibrosis remain unknown. STING NLRP3 inflammasome are activated fibrotic livers but suppressed by Sting knockout. knockout ameliorated hepatic pyroptosis, inflammation, fibrosis. In vitro, induces primary murine hepatocytes activating inflammasome. H3K4-specific histone methyltransferase WD repeat-containing 5 (WDR5) DOT1-like H3K79 (DOT1L) identified to regulate expression STING-overexpressing AML12 hepatocytes. WDR5/DOT1L-mediated methylation enhances regulatory transcription factor (IRF3) binding Nlrp3 promoter promotes STING-induced Moreover, hepatocyte-specific deletion downstream Gasdermin D (Gsdmd) attenuate RNA-sequencing metabolomics analysis show that oxidative stress metabolic reprogramming might participate NLRP3-mediated STING-NLRP3-GSDMD inhibition suppresses ROS generation. conclusion, this study describes a novel mechanism which STING-WDR5/DOT1L/IRF3-NLRP3 pathway inflammation

Язык: Английский

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The role of matrix metalloproteinase 9 in fibrosis diseases and its molecular mechanisms

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 171, С. 116116 - 116116

Опубликована: Янв. 5, 2024

Fibrosis is a process of tissue repair that results in the slow creation scar to replace healthy and can affect any or organ. Its primary feature massive deposition extracellular matrix (mainly collagen), eventually leading dysfunction organ failure. The progression fibrotic diseases has put significant strain on global health economy, as result, there an urgent need find some new therapies. Previous studies have identified inflammation, oxidative stress, cytokines, remodeling play crucial role are essential avenues for treating diseases. Among them, metalloproteinases (MMPs) considered main targets treatment since they driver involved ECM degradation, inhibitors (TIMPs) natural endogenous MMPs. Through previous studies, we found MMP-9 target However, it worth noting plays bidirectional regulatory different stages same disease. Previously inhibitors, such pirfenidone nintedanib, suffer from rather pronounced side effects, therefore, investigate drugs. In this review, explore mechanism action signaling pathways tissues organs, hoping provide ideas developing safer more effective biologics.

Язык: Английский

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The m6A reader IGF2BP2 regulates glycolytic metabolism and mediates histone lactylation to enhance hepatic stellate cell activation and liver fibrosis

Cell Death and Disease, Год журнала: 2024, Номер 15(3)

Опубликована: Март 5, 2024

Abstract Evidence for the involvement of N 6 -Methyladenosine (m A) modification in etiology and progression liver fibrosis has emerged holds promise as a therapeutic target. Insulin-like growth factor 2 (IGF2) mRNA-binding protein (IGF2BP2) is newly identified m A-binding that functions to enhance mRNA stability translation. However, its role an remains elusive. Here, we observed IGF2BP2 highly expressed activated hepatic stellate cells (HSCs), inhibition protects against HSCs activation fibrogenesis. Mechanistically, protein, regulates expression Aldolase A ( ALDOA ), key target glycolytic metabolic pathway, which turn activation. Furthermore, active metabolism generates large amounts lactate substrate histone lactylation. Importantly, lactylation transforms phenotype HSCs. In conclusion, our findings reveal essential by regulating highlight potential targeting fibrosis.

Язык: Английский

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Microenvironmental regulation of cancer cell metabolism: implications for experimental design and translational studies

Disease Models & Mechanisms, Год журнала: 2018, Номер 11(8)

Опубликована: Авг. 1, 2018

ABSTRACT Cancers have an altered metabolism, and there is interest in understanding precisely how oncogenic transformation alters cellular metabolism these metabolic alterations can translate into therapeutic opportunities. Researchers are developing increasingly powerful experimental techniques to study allowed for the analysis of cancer cell both tumors ex vivo models. These analyses show that, while factors intrinsic cells such as mutations, alter cell-extrinsic microenvironmental also substantially contribute phenotype cells. findings highlight that within tumor, nutrient availability, physical properties extracellular matrix, interactions with stromal cells, influence might ultimately dictate response metabolically targeted therapies. In effort better understand target this Review focuses on evidence regulate tumor implications choosing appropriate model systems approaches.

Язык: Английский

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Mutual interaction between endoplasmic reticulum and mitochondria in nonalcoholic fatty liver disease

Lipids in Health and Disease, Год журнала: 2020, Номер 19(1)

Опубликована: Апрель 13, 2020

Nonalcoholic fatty liver disease (NAFLD) is a common metabolic syndrome. Imbalances between lipid output and input are the direct causes of NAFLD, hepatic steatosis pathological premise basis for NAFLD progression. Mutual interaction endoplasmic reticulum stress (ERS) oxidative play important roles in pathogenesis. Notably, mitochondria-associated membranes (MAMs) act as structural bridges functional clustering molecules, particularly Ca2+, lipids, reactive oxygen species (ROS) exchange. Previous studies have examined crucial ERS ROS shown that MAM integrity determines normal ER- mitochondria communication. Upon disruption integrity, miscommunication directly or indirectly imbalances Ca2+ homeostasis increases stress. Here, we emphasize involvement MAMs glucose metabolism, chronic inflammation insulin resistance summarize MAM-targeting drugs compounds, most which achieve their therapeutic ameliorative effects on by improving integrity. Therefore, targeting may be viable strategy treatment. This review provides new ideas key points basic research drug development centred reticulum.

Язык: Английский

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The anti-inflammatory effects of Akkermansia muciniphila and its derivates in HFD/CCL4-induced murine model of liver injury

Scientific Reports, Год журнала: 2022, Номер 12(1)

Опубликована: Фев. 14, 2022

Abstract Inflammation plays a critical role in the promotion of hepatocyte damage and liver fibrosis. In recent years protective Akkermansia muciniphila , next-generation beneficial microbe, has been suggested for metabolic inflammatory disorders. this study, we aimed to evaluate effects live pasteurized A. its extra cellular vesicles (EVs) on markers involved fibrosis mouse model high-fat diet (HFD)/carbon tetrachloride (CCl 4 )-induced injury. Firstly, responses hepatic stellate cells (HSCs) EVs were examined quiescent LPS-activated LX-2 cells. Next, anti-inflammatory different forms HFD/CCl -induced The gene expression various was evaluated liver, colon, white adipose tissues. cytokine secretion tissues also measured by ELISA. results showed that administration leads amelioration HSCs activation. Based data obtained from histopathological analysis, an improvement gut health observed through enhancing epithelium mucosal layer thickness strengthening intestinal integrity all treatments. Moreover, had inhibitory inflammation hepatocytes damage. addition, tissue production levels revealed more pronounced Furthermore, better modulation related TLRs, PPARs, immune response liver. conclusion, present oral derivatives four weeks could enhance adipose, subsequently prevent injury HFD/CCL mice.

Язык: Английский

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