Vine tea (Ampelopsis grossedentata) ameliorates chronic alcohol-induced hepatic steatosis, oxidative stress, and inflammation via YTHDF2/PGC-1α/SIRT3 axis.

For over a millennium, the leaves of Ampelopsis grossedentata (Hand.-Mazz.) W. T. Wang, commonly known as vine tea, have been revered as a popular tea and traditional herbal remedy, possessing antioxidant, anti-inflammatory, hepatoprotective, and antiviral properties. In recent years, the incidence of alcohol-related liver injury has been on the rise, imposing a significant public health burden worldwide. Previous studies have indicated that extracts of vine tea (AGE) can ameliorate alcoholic liver disease (ALD), yet the pharmacological mechanisms underlying this effect remain poorly understood. In this study, we first employed UPLC-Q-TOF-MS to analyze the chemical constituents of AGE. Subsequently, an ALD model was established in mice fed with Lieber-DeCarli diet, and the hepatoprotective benefits of AGE were assessed by measuring biochemical indicators and hepatic pathological changes. Moreover, a suite of bioinformatics tools, including transcriptomics, weighted gene co-expression network analysis, and single-cell data mining, were utilized to reveal that the YTHDF2/PGC-1α/SIRT3 signaling axis may be the potential mechanism by which AGE exerts its anti-ALD effects. Additionally, Western blotting and immunofluorescence staining techniques were employed to further substantiate the aforementioned mechanism. Our findings demonstrate that administration of vine tea significantly alleviated chronic ethanol-induced hepatic lipid accumulation, oxidative stress, and inflammation. Notably, knockdown of YTHDF2 partially protected the liver from ethanol-induced injury. Mechanistically, bioinformatics analysis and in vitro and in vivo experiments identified YTHDF2 as a key pharmacological target of AGE in treating ALD, acting through the downstream PGC-1α/SIRT3 pathway. In summary, in this study, we provide the first evidence that AGE mitigates ethanol-induced liver injury by inhibiting YTHDF2 and enhancing the expression of PGC-1α and SIRT3. Vine tea, as a tea food with unique medicinal value, shows significant potential and value in the treatment of ALD.

Luo Q ，Qiu J ，Chen M ，Yang N ，Li X ，Huang S ，Ma Q ，Li Z ，Lou D ，Du Y ，Chen L ，Shen Q ，Chen F ，Li C ，Qiu P ... -  《-》

GTPBP8 mitigates nonalcoholic steatohepatitis (NASH) by depressing hepatic oxidative stress and mitochondrial dysfunction via PGC-1α signaling.

Nonalcoholic steatohepatitis (NASH) is emerging as a major cause of liver transplantation and hepatocellular carcinoma (HCC). Regrettably, its pathological mechanisms are still not fully comprehended. GTP-binding protein 8 (GTPBP8), belonging to the GTP-binding protein superfamily, assumes a crucial role in RNA metabolism, cell proliferation, differentiation, and signal transduction. Its aberrant expression is associated with oxidative stress and mitochondrial dysfunctions. Nevertheless, its specific functions and mechanisms of action, particularly in NASH, remain elusive. In our current study, we initially discovered that human hepatocytes L02 displayed evident mitochondrial respiratory anomaly, mitochondrial damage, and dysfunction upon treatment with palmitic acids and oleic acids (PO), accompanied by significantly reduced GTPBP8 expression levels through RNA-Seq, RT-qPCR, western blotting, and immunofluorescence assays. We then demonstrated that GTPBP8 overexpression mediated by adenovirus vector (Ad-GTPBP8) markedly attenuate lipid accumulation, inflammatory response, and mitochondrial impair and dysfunction in hepatocytes stimulated by PO. Conversely, adenovirus vector-mediated GTPBP8 knockdown (Ad-shGTPBP8) significantly accelerated lipid deposition, inflammation and mitochondrial damage in PO-treated hepatocytes in vitro. Furthermore, we constructed an in vivo NASH murine model by giving a 16-week high fat high cholesterol diet (HFHC) diet to hepatocyte specific GTPBP8-knockout (GTPBP8HKO) mice. We firstly found that HFHC feeding led to metabolic disorder in mice, including high body weight, blood glucose and insulin levels, and liver dysfunctions, which were accelerated in these NASH mice with GTPBP8 deficiency in hepatocytes. Consistently, GTPBP8HKO remarkably exacerbated the progression of NASH phenotypes induced by HFHC, as proved by the anabatic lipid accumulation, inflammation, fibrosis and reactive oxygen species (ROS) production in liver tissues, which could be largely attributed to the severe mitochondrial damage and dysfunction. Mechanistically, we further identified that GTPBP8 interacted with peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in hepatocytes. Importantly, the hepaprotective effects of GTPBP8 against mitochondrial dysfunction, oxidative stress and inflammation was largely dependent on PGC-1α expression. Collectively, GTPBP8 may exert a protective role in the progression of NASH, and targeting the GTPBP8/PGC-1α axis may represent a potential strategy for NASH treatment by improving mitochondrial functions.

Meng D ，Chang M ，Dai X ，Kuang Q ，Wang G ... -  《-》

Ferulic acid from Angelica sinensis (Oliv.) Diels ameliorates lipid metabolism in alcoholic liver disease via AMPK/ACC and PI3K/AKT pathways.

Lu J ，Wang C 《-》

Ribes diacanthum Pall modulates bile acid homeostasis and oxidative stress in cholestatic mice by activating the SIRT1/FXR and Keap1/Nrf2 signaling pathways.

Cholestatic liver injury (CLI) is a pathophysiological syndrome characterized by the accumulation of bile acids (BAs), which leads to significant hepatic dysfunction. This condition is frequently associated with disturbances in BAs homeostasis and the induction of oxidative stress. Ribes diacanthum Pall (RDP), a conventional folk medicinal plant, has been employed in Mongolia, the Inner Mongolia region of China, and other areas for the remediation of hepatic disorders. However, the specific mechanism and chemical composition by which RDP exerts its effects remain unknown. The aim of this research was to assess the protective impact of RDP on CLI and probe into the underlying mechanism and pinpoint the active constituents of RDP. For this study, a CLI mouse model induced via bile duct ligation (BDL) was used to investigate the hepatoprotective effect of RDP. Mice were administered low, medium, or high doses of RDP for 6 consecutive days, beginning 3 days prior to BDL induction. Subsequently, serum biochemical parameters, hepatic histopathology, and cholestatic markers were analyzed. An HPLC-QTOF-MS/MS analysis was also conducted to identify the prototype constituents in RDP. Furthermore, component-directed network pharmacology was utilized to identify the active constituents, central targets, and signaling cascades of RDP. Eventually, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were adopted to confirm the associated antioxidant enzymes, BAs transporters, and metabolic enzymes. Molecular docking was applied to forecast the binding affinity between the components and core targets. RDP effectively ameliorated the pathological liver damage and cholestasis in BDL-induced CLI mice. Moreover, 43 components within RDP were identified through HPLC-QTOF-MS/MS analysis. Altogether 106 potential targets were detected, and the high-affinity targets, namely Keap1 and SIRT1, were located through the PPI network. The results of GO and KEGG analysis indicated that the reaction to oxidative stress and BAs homeostasis are significantly associated with the RDP treatment of CLI. In the in vivo experimental study, the findings revealed that RDP alleviated the BDL-induced oxidative damage. Simultaneously, RDP augmented the expressions of BAs efflux transporters and the metabolic enzymes in liver tissues, thus promoting BAs excretion and metabolism in cholestatic rodents. Mechanically, RDP attenuated hepatic oxidative stress and the accumulation of BAs, protecting the liver from BDL-induced cholestasis via the Keap1/Nrf2 and SIRT1/FXR signaling axis. The molecular docking result indicated that bolusanthol C and 3,6,3',4'-tetrahydroxyflavone possess a superior binding affinity to the two core targets (Keap1, SIRT1). These results suggest that RDP ameliorate CLI by regulating BAs homeostasis and alleviating oxidative stress through the SIRT1/FXR and Keap1/Nrf2 signaling pathways, presenting a novel therapeutic strategy for cholestasis. Additionally, bolusanthol C and 3,6,3',4'-tetrahydroxyflavone may function as key pharmacological agents in RDP, responsible for its protective effects against CLI.

Bayoude A ，Zhang J ，Shen Y ，Tilyek A ，Chai C ... -  《-》

Dihydromyricetin regulates the miR-155-5p/SIRT1/VDAC1 pathway to promote liver regeneration and improve alcohol-induced liver injury.

Alcohol-related liver disease (ALD) has become an increasingly serious global health issue. In recent years, growing evidence has highlighted the restoration of liver regenerative capacity as an effective therapeutic strategy for improving ALD. Previous studies have demonstrated the protective effect of dihydromyricetin (DMY) in alcohol-induced liver injury, but its pharmacological role in ALD-related liver regeneration impairment remains poorly understood. This study aims to explore the therapeutic potential and molecular mechanisms of DMY in the context of liver regeneration impairment in ALD. The classic Lieber-DeCarli alcohol liquid diet was used to establish an ALD model in vivo. DMY (75 and 150 mg/kg/day) and silybin (200 mg/kg) were administered for 7 weeks to assess the hepatoprotective effects of DMY. First, biochemical markers and liver histopathology were used to evaluate liver inflammation and steatosis in ALD mice. Second, we explored the potential molecular mechanisms by which DMY improves ALD through serum untargeted metabolomics, hepatic transcriptomics, and single-cell sequencing data. Furthermore, in vivo and in vitro experiments, combined with Western blotting, dual-luciferase reporter assays, and immunofluorescence, were conducted to elucidate the protective mechanisms underlying DMY's effects on ALD. In vivo studies showed that DMY significantly ameliorated ALT/AST abnormalities, liver inflammation, and steatosis in ALD mice. Multi-omics and bioinformatics analyses revealed that DMY may exert its anti-ALD effects by regulating the miR-155-5p/SIRT1/VDAC1 pathway, thereby mitigating cellular senescence. Notably, knockdown of miR-155 provided partial protection against ethanol-induced liver damage. Additionally, clinical ALD samples and in vivo and in vitro experiments further confirmed that excessive alcohol exposure induces the production of miR-155-5p in liver Kupffer cells. miR-155-5p targets and inhibits SIRT1, promoting the expression of mitochondrial VDAC1, leading to mitochondrial DNA leakage, thereby accelerating hepatocyte senescence and inflammation. However, DMY improved the disruption of the miR-155-5p/SIRT1/VDAC1 pathway and hepatocyte senescence, thereby restoring liver regenerative function and exerting anti-ALD effects. In this study, we provide the first evidence that DMY improves liver inflammation and cellular senescence by regulating the miR-155-5p/SIRT1/VDAC1 positive feedback loop, promoting liver regeneration to improve ALD. In summary, our work provides important research evidence and theoretical support for DMY as a promising candidate drug for the prevention and treatment of ALD.

Ma Q ，Huang S ，Li MY ，Luo QH ，Chen FM ，Hong CL ，Yan HH ，Qiu J ，Zhao KL ，Du Y ，Zhao JK ，Zhou LQ ，Lou DY ，Efferth T ，Li CY ，Qiu P ... -  《-》