Role of AMPK DOI
Sihai Dave Zhao,

Weilun Fang,

Wei Yu

и другие.

PubMed, Год журнала: 2024, Номер 49(12), С. 1891 - 1901

Опубликована: Дек. 28, 2024

Over 25% of the global population is affected by metabolic dysfunction-associated fatty liver disease (MAFLD), yet its pathogenesis remains unclear. Endoplasmic reticulum stress (ERS) may be involved in onset and progression MAFLD. Adenosine 5'-monophosphate-activated protein kinase α2 (AMPKα2), a key regulator hepatic energy metabolism, influence MAFLD development via ERS modulation. This study aims to investigate role AMPKα2 high-fat diet-induced mouse model regulatory effect on inositol-requiring enzyme 1 alpha (IRE1α)-c-Jun N-terminal (JNK) signaling pathway. Liver-specific knockout mice C57BL/6 background were generated subjected induction. Mice divided into four groups: wild-type control (WT+Chow, basic diet for 12 weeks), (WT+HFD, (AMPKα2 KO+Chow), KO+HFD). Blood glucose, lipid levels, function assessed post-treatment. Liver histology was analyzed using Oil Red O, hematoxylin-eosin, Masson, Sirius staining. Western blotting used evaluate expression AMPKα2, markers, autophagy, apoptosis, ferroptosis-related proteins. Compared with WT+Chow group, WT+HFD group showed significantly elevated blood alanine aminotransferase (ALT), aspartate (AST) levels (all P<0.01); histological analyses revealed steatosis, vacuolization, fibrosis, increased non-alcoholic steatohepatitis activity score (NAS) (P<0.001). Phosphorylated IRE1α autophagy marker microtubule-associated light chain (LC) 3II/LC3I markedly upregulated, while apoptotic proteins (Cleaved-Caspase 3, BAX, Bcl-2) ferroptosis markers (SLC7A11, GPX4) no significant change (P>0.05). In KO+HFD ALT, AST reduced compared group. Histological improvements observed vacuolization accumulation. Expression p-IRE1α, JNK, LC3II/LC3I decreased (P<0.05). Hepatic alleviates induced MAFLD, potentially inhibiting IRE1α-JNK pathway reducing autophagy.

Язык: Английский

The emerging role of E3 ubiquitin ligases and deubiquitinases in metabolic dysfunction-associated steatotic liver disease DOI Creative Commons
Yu Zhang, Jiahui Yang, Jiali Min

и другие.

Journal of Translational Medicine, Год журнала: 2025, Номер 23(1)

Опубликована: Март 25, 2025

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic worldwide, with a prevalence as high 32.4%. MASLD encompasses spectrum of pathologies, ranging from steatosis to metabolic steatohepatitis (MASH), fibrosis, and, in some cases, progression end-stage (cirrhosis and hepatocellular carcinoma). A comprehensive understanding pathogenesis this highly prevalent may facilitate identification novel targets for development improved therapies. E3 ubiquitin ligases deubiquitinases (DUBs) are key regulatory components ubiquitin‒proteasome system (UPS), which plays pivotal role maintaining intracellular protein homeostasis. Emerging evidence implicates that aberrant expression DUBs involved MASLD. Here, we review abnormalities by (1) discussing their targets, mechanisms, functions MASLD; (2) summarizing pharmacological interventions targeting these enzymes preclinical clinical studies; (3) addressing challenges future therapeutic strategies. This synthesizes current highlight strategies based on UPS progressive disease.

Язык: Английский

Процитировано

1

Network pharmacology- and molecular docking-based investigation on the mechanism of action of Si-ni San in the treatment of depression combined with anxiety and experimental verification in adolescent rats DOI Creative Commons
Zhiping Li,

Shimin Liang,

Xulan Cui

и другие.

Frontiers in Psychiatry, Год журнала: 2024, Номер 15

Опубликована: Авг. 23, 2024

Background The incidence rate of adolescent depression and anxiety has been increasing since the outbreak COVID-19, which there are no effective therapeutic drugs available. Si-ni San is commonly used in traditional Chinese medicine for treatment depression-like as well anxiety-like behavior, but its mechanism treating combined with during adolescence not yet clear. Methods Network pharmacology was to explore potential drug molecules related targets, molecular docking dynamics (MD) simulation were evaluate interaction between a model rats following behavioral tests biology verify results from network docking. Results As result, 256 active ingredients 1128 targets screened out. Among them, quercetin, Luteolin, kaempferol, 7-Methoxy-2-methyl isoflavone, formononetin showed be most ingredients; while STAT3, IL6, TNF, AKT1, TP53, IL1B, MAPK3, VEGFA, CASP3, MMP9 targets. AGE-RAGE signaling pathway diabetic complications, IL-17 pathway, HIF-1 PI3K-Akt TNF involved anti-inflammation processes, probable pathways regulated by San. Molecular MD compounds inflammation-associated revealed good binding abilities nobiletin PTGS2 PPARγ. In experiment rats, markedly suppressed early maternal separation (MS) chronic unpredictable mild stress (CUMS)-induced anxiety. qPCR further indicated that oxidative inflammatory response. Conclusion This study demonstrates anxiety- behavior induced MS CUMS can ameliorated improved inflammation hippocampus via targeting Nrf2 helping reveal

Язык: Английский

Процитировано

3

Parishin B blocking TRIB3-AKT1 interaction inhibits breast cancer lung metastasis DOI Creative Commons

Xiongtao Cheng,

Jianguo Sun, Shouhong Chen

и другие.

Frontiers in Pharmacology, Год журнала: 2025, Номер 15

Опубликована: Янв. 15, 2025

TRIB3 has been reported to mediate breast cancer (BC) proliferation and metastasis by interacting with AKT1, blocking the interaction between AKT1 can inhibit progression of BC. Besides, inhibiting turn "cold tumor" hot also proved be an effective therapeutic strategy for Thus, this study aim find drugs that bind BC progression, further elucidate its mechanism. The possible inhibitors were screened high-throughput molecular docking, CETSA, CO-IP assay. Then, effect inhibitor anti was assessed CCK-8 assay, flow cytometry, plate colony formation transwell assay; RNA-seq empolyed potential mechanism Parishin B (PB) anti-BC. Finally, on lung in vivo evaluated. PB as a TRIB3, CETSA assay indicated could target block TRIB3-AKT1 interaction. In addition, exhibited good anti-BC activity without drug toxicity normal cells experiments vitro, analysis suggested invasion related cell cycle. It vivo. demonstrated regulating cycle, providing agent treatment

Язык: Английский

Процитировано

0

Discovery of a novel quinoxaline derivative modulator via a dual P53/TLR2 targeting strategy for the alleviation of radiation damage DOI

Zhaolun He,

Yaowen Cui,

Tingting Chen

и другие.

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер 290, С. 117505 - 117505

Опубликована: Март 13, 2025

Язык: Английский

Процитировано

0

MYCBP2-mediated HNF4α ubiquitination reprogrammed lipid metabolism in MASH-associated hepatocellular carcinoma DOI
Hao Zhang,

Xiangxu Kong,

Haoran Qu

и другие.

Oncogene, Год журнала: 2025, Номер unknown

Опубликована: Апрель 3, 2025

Язык: Английский

Процитировано

0

TRIM25‐Mediated INSIG1 Ubiquitination Promotes MASH Progression Through Reprogramming Lipid Metabolism DOI Creative Commons
Hao Zhang,

Xiangxu Kong,

Wei Wang

и другие.

Advanced Science, Год журнала: 2025, Номер unknown

Опубликована: Апрель 15, 2025

Abstract The global incidence of Metabolic dysfunction‐associated steatohepatitis (MASH) is increasing, highlighting the urgent need for new treatment strategies. This study aimed to investigate involvement tripartite motif‐containing 25 (TRIM25) in MASH progression and explore therapeutic potential TRIM25 inhibitor, C 27 H 26 N 2 O 4 S. Functional studies reveal that promoted lipid accumulation inflammation by ubiquitinating degrading insulin‐induced gene 1 (INSIG1), thereby enhancing nuclear translocation sterol regulatory element‐binding protein (SREBP2) upregulating biosynthesis genes. In vivo experiments using knockout mice demonstrated deletion ameliorated progression, reduced fibrosis, decreased inflammatory cell infiltration. It identifies S as a specific inhibitor TRIM25. effectively INSIG1 ubiquitination attenuated hepatocytes. To enhance hepatic delivery S, it utilizes exosomes derived from stellate cells (HSC‐EVs). Biodistribution analysis confirmed HSC‐EVs preferentially accumulated liver. mouse model, HSC‐EV‐encapsulated (C S@HSC‐EV) significantly alleviated severity fibrosis. highlights critical role presents S@HSC‐EV promising approach treatment.

Язык: Английский

Процитировано

0

Balancing metabolism and regeneration in liver diseases through HNF4α targeting DOI
Céline Van Dender, Jolien Vandewalle, Claude Libert

и другие.

Trends in Endocrinology and Metabolism, Год журнала: 2025, Номер unknown

Опубликована: Май 1, 2025

Язык: Английский

Процитировано

0

Mechanical mechanics-reclaiming a new battlefield for chronic liver disease DOI Creative Commons

Y Zhang,

Tianle Ma,

XingXing Lu

и другие.

Journal of Advanced Research, Год журнала: 2025, Номер unknown

Опубликована: Май 1, 2025

Язык: Английский

Процитировано

0

Hepatoprotective drug screening identifies daclatasvir a promising therapeutic candidate for MASLD by targeting PLIN2 DOI Creative Commons

Rui Shu,

Song Tian, Weiyi Qu

и другие.

Journal of Lipid Research, Год журнала: 2025, Номер unknown, С. 100835 - 100835

Опубликована: Май 1, 2025

Metabolic dysfunction-associated steatohepatitis (MASH) has become global health challenges with limited therapeutic strategy. Here, the present study aims to identify promising drug candidates for MASH and clarify their pharmacological mechanism. By an extensive screening of FDA-approved hepatoprotective medicines using a PA/OA-stimulated hepatocytes model, we identified daclatasvir showing potent anti-MASH capacity against hepatic steatosis deposition inflammatory response. The benefits was further validated in mouse models, induced by high-fat high-cholesterol (HFHC) diet 16 weeks or methionine-choline-deficient (MCD) 4 weeks, as supported markedly improved histopathological characteristics, serum biochemical level, transcriptomic analyses. Using molecular docking assay followed isothermal titration calorimetry confirmation, that functions new perilipin-2 (PLIN2) inhibitor interrupting its stability. In specific, PLIN2 subjected MARCH6-mediated protein degradation K11-type ubiquitination. Daclatasvir can directly bind enhance interaction MARCH6, leading strengthened ubiquitinational subsequent decline lipid droplet disintegration lipotoxicity. specific mutation at binding amino acid sites largely abolished benefit daclatasvir. conclusion, findings our first time anti-HCV novel degradant protection.

Язык: Английский

Процитировано

0

Post-translational modifications in the pathophysiological process of metabolic dysfunction‑associated steatotic liver disease DOI Creative Commons

Yiyang Min,

Yiqiao Zhang,

Yu Ji

и другие.

Cell & Bioscience, Год журнала: 2025, Номер 15(1)

Опубликована: Июнь 5, 2025

Язык: Английский

Процитировано

0