Dihydrotanshinone I Attenuates Diet‐Induced Nonalcoholic Fatty Liver Disease via Up‐Regulation of IRG1 DOI Open Access
Xiang Yang, Ge Kuang,

Xia Gong

et al.

Phytotherapy Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is the most common chronic disease, but effective therapeutic drugs are still lacking. Dihydrotanshinone I (DHTS), a natural product isolated from Salvia miltiorrhiza , has been shown to have ameliorative effects on NAFLD. The aim of this study was investigate hepatoprotective effect DHTS NAFLD and its mechanism. A model treatment established using Western diet observe NAFLD, which were detected by immunohistochemical, immunofluorescence, other experiments. mechanism further explored constructing immune responsive gene 1 (IRG1) knockout mice, RNA sequence, molecular docking. results revealed that significantly improved diet‐induced metabolic disorders in notably alleviating inflammation, oxidative stress, fibrosis. Further analysis intervention associated with activation IRG1. Subsequent experiments confirmed IRG1 deletion reversed above protective Mechanistically, enhanced antioxidant nuclear factor–erythroid 2‐related factor 2 (Nrf2) pathway through IRG1/itaconate blocked stress response liver. In addition, also inhibited NACHT‐, leucine‐rich repeat (LRR)–, pyrin domain (PYD)–containing protein 3 (NLRP3) inflammasome via IRG1/itaconate, blocking inflammatory amplification suggests may be potential drug for exerts regulatory mainly pathway.

Language: Английский

Silent information regulator sirtuin 1 ameliorates acute liver failure via the p53/glutathione peroxidase 4/gasdermin D axis DOI

Xing-Nian Zhou,

Quan Zhang, Hong Peng

et al.

World Journal of Gastroenterology, Journal Year: 2024, Volume and Issue: 30(11), P. 1588 - 1608

Published: March 21, 2024

BACKGROUND Acute liver failure (ALF) has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis. The silent information regulator sirtuin 1 (SIRT1)-mediated deacetylation affects multiple biological processes, including cellular senescence, apoptosis, sugar lipid metabolism, oxidative stress, inflammation. AIM To investigate the association between pyroptosis upstream regulatory mechanisms. METHODS This study included 30 patients ALF healthy individuals who underwent serum alanine aminotransferase (ALT) aspartate (AST) testing. C57BL/6 mice were also intraperitoneally pretreated SIRT1, p53, or glutathione peroxidase 4 (GPX4) inducers inhibitors injected lipopolysaccharide (LPS)/D-galactosamine (D-GalN) to induce ALF. Gasdermin D (GSDMD)-/- used as an experimental group. Histological changes in tissue monitored by hematoxylin eosin staining. ALT, AST, glutathione, reactive oxygen species, iron levels measured using commercial kits. Ferroptosis- pyroptosis-related protein mRNA expression was detected western blot quantitative real-time polymerase chain reaction. GSDMD assessed immunofluorescence analysis. RESULTS Serum AST ALT elevated solute carrier family 7a member 11 (SLC7A11), GPX4 decreased acetylated p5, GSDMD, acyl-CoA synthetase long-chain (ACSL4) human tissue. In p53 inhibitor-treated GSDMD-/- groups, interleukin (IL)-1β, tumour necrosis factor alpha, IL-6, IL-2 C-C motif ligand 2 hepatic impairment mitigated. knockout, reduced, increased, ferroptotic events (depletion of SLC7A11, elevation ACSL4, accumulation) detected. vitro , knockdown overexpression reduced levels, cytostatic rate, expression, restoring SLC7A11 depletion. Moreover, SIRT1 agonist alleviated acute injury deposition compared results model group, accompanied increased GPX4. Inactivation exacerbated pyroptotic cell aggravated LPS/D-GalN-induced vivo models. CONCLUSION activation attenuates inhibiting p53/GPX4/GSDMD signaling pathway

Language: Английский

Citations

10
Oxidative stress in alcoholic liver disease, focusing on proteins, nucleic acids, and lipids: A review DOI

Weiwen Lai,

Jiahua Zhang,

Jiawei Sun

et al.

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 278, P. 134809 - 134809

Published: Aug. 16, 2024

Language: Английский

Citations

10
Bazi Bushen capsule improves the deterioration of the intestinal barrier function by inhibiting NLRP3 inflammasome-mediated pyroptosis through microbiota-gut-brain axis DOI Creative Commons
Shixiong Zhang, Mengnan Li, Liping Chang

et al.

Frontiers in Microbiology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 8, 2024

Purpose The senescence-accelerated prone mouse 8 (SAMP8) is a widely used model for accelerating aging, especially in central aging. Mounting evidence indicates that the microbiota-gut-brain axis may be involved pathogenesis and progression of aging-related diseases. This study aims to investigate whether Bazi Bushen capsule (BZBS) attenuates deterioration intestinal function aging animal model. Methods In our study, SAMP8 mice were randomly divided into group, BZ-low group (0.5 g/kg/d BZBS), BZ-high (1 BZBS) RAPA (2 mg/kg/d rapamycin). Age-matched SAMR1 as control group. Next, cognitive was detected through Nissl staining two-photon microscopy. gut microbiota composition fecal samples analyzed by 16S rRNA gene sequencing. Ileum tissue morphology observed hematoxylin eosin staining, barrier immunofluorescence. expression senescence-associated secretory phenotype (SASP) factors, including P53, TNF-α, NF-κB, IL-4, IL-6, IL-10 measured real-time quantitative PCR. Macrophage infiltration proliferation differentiation cells assessed immunohistochemistry. We also inflammasome pyroptosis levels ileum western blotting. Results BZBS improved neuronal density mice. restored villus structure function, which damaged reduced SASP factors macrophages tissues, indicating lower level inflammation. enhanced cells, are essential maintaining homeostasis. modulated composition, inhibited activation inflammasomes intestine. Conclusion could restore dysbiosis prevent inhibiting NLRP3 inflammasome-mediated pyroptosis. These results suggested attenuated mice, at least partially, targeting axis.

Language: Английский

Citations

9
Single-cell transcriptomic analysis reveals characteristic feature of macrophage reprogramming in liver Mallory-Denk bodies pathogenesis DOI Creative Commons

Zixuan Fang,

Bei Zhong,

Yi Shi

et al.

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 16, 2025

Chronic liver diseases are highly linked with mitochondrial dysfunction and macrophage infiltration. Mallory-Denk bodies (MDBs) protein aggregates associated hepatic inflammation, MDBs pathogenesis could be induced in mice by feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Here, we investigate the heterogeneity role of during on DDC-induced mouse model single-nucleus RNA sequencing (snRNA-seq). We defined macrophages into four distinct subsets including monocyte-derived (MDMs) subset three Kupffer cells (KCs) (Gpnmbhigh KCs, Peam1high Gpnmblow Pecam1low KCs). Particularly, identified a novel Gpnmbhigh KCs as lipid-associated (LAM) high expression Trem2, CD63, CD9. Interestingly, LAM showed potential immunosuppressive characteristic expressing anti-inflammatory genes IL-7R formation. Using contact transwell co-culture systems, released mtDNA from hepatocytes was found to induce activation inflammasome macrophages. Furthermore, revealed damaged DNA activate NOD-like receptor family pyrin domain containing-3 (NLRP3) subsequently form apoptosis-associated speck-like containing caspase recruit (ASC) specks Collectively, our results firstly injured pathogenesis, providing crucial understanding chronic disease.

Language: Английский

Citations

1
Dihydrotanshinone I Attenuates Diet‐Induced Nonalcoholic Fatty Liver Disease via Up‐Regulation of IRG1 DOI Open Access
Xiang Yang, Ge Kuang,

Xia Gong

et al.

Phytotherapy Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is the most common chronic disease, but effective therapeutic drugs are still lacking. Dihydrotanshinone I (DHTS), a natural product isolated from Salvia miltiorrhiza , has been shown to have ameliorative effects on NAFLD. The aim of this study was investigate hepatoprotective effect DHTS NAFLD and its mechanism. A model treatment established using Western diet observe NAFLD, which were detected by immunohistochemical, immunofluorescence, other experiments. mechanism further explored constructing immune responsive gene 1 (IRG1) knockout mice, RNA sequence, molecular docking. results revealed that significantly improved diet‐induced metabolic disorders in notably alleviating inflammation, oxidative stress, fibrosis. Further analysis intervention associated with activation IRG1. Subsequent experiments confirmed IRG1 deletion reversed above protective Mechanistically, enhanced antioxidant nuclear factor–erythroid 2‐related factor 2 (Nrf2) pathway through IRG1/itaconate blocked stress response liver. In addition, also inhibited NACHT‐, leucine‐rich repeat (LRR)–, pyrin domain (PYD)–containing protein 3 (NLRP3) inflammasome via IRG1/itaconate, blocking inflammatory amplification suggests may be potential drug for exerts regulatory mainly pathway.

Language: Английский

Citations

1