[Mechanism of Gynostemma pentaphyllum in treatment of metabolism associated fatty liver disease based on network pharmacology and molecular docking].

The present study explored the mechanism of action of Gynostemma pentaphyllum in the treatment of metabolism associa-ted fatty liver disease(MAFLD) by network pharmacology and molecular docking. The main active components and action targets of G. pentaphyllum were collected from TCMSP. Disease-related targets were obtained from GeneCards, OMIM and TTD, and the common targets of the three databases were screened out, which were converted to the genes with standard names by UniProt. The drug-disease common target genes were obtained through Venn tool and uploaded to STRING for the construction of the protein-protein interaction(PPI) network. Cytoscape was used to construct and analyze the drug-active component-common target-disease network. The gene ontology(GO) analysis and Kyoto encyclopedia of genes and genomes(KEGG) pathway enrichment analysis were performed on the common targets by DAVID. Pymol was adopted to perform molecular docking of active components and the common targets and predict their binding ability. Twenty-four active components(such as gypenosides, quercetin and sitosterol) of G. pentaphyllum were screened out. Ninety-two targets were obtained and 54 common targets were identified. Key targets included TNF, IL6, PTGS2, TP53, CCL2 and VEGFA. GO analysis on biological processes, molecular functions and cellular components and KEGG pathway analysis were performed, and the results indicated that NF-κB, PI3 K-Akt, TNF and HIF-1 signaling pathways were mainly involved. Molecular docking results showed that gypenosides and quercetin had a strong binding ability to TNF, IL6 and PTGS2. The findings of this study revealed that the therapeutic efficacy of G. pentaphyllum on MAFLD might be achieved by resisting inflammation and oxidative stress and improving insulin resistance, providing ideas and a theoretical basis for the development and application of G. pentaphyllum in the treatment of MAFLD.

Causal relationships between the gut microbiota, inflammatory cytokines, and alcoholic liver disease: a Mendelian randomization analysis.

Objective: Previous studies have suggested a potential association between gut microbiota and the development of alcohol-related liver disease (ALD). However, the causal relationship between gut microbiota and ALD, as well as the role of inflammatory cytokines as mediators, remains unclear. This study aims to explore the causal relationship between gut microbiota and ALD using Mendelian randomization (MR) methods, and to analyze the mediating role of inflammatory cytokines. Methods: Gut microbiota, 91 inflammatory cytokines, and ALD were identified from summary data of large-scale genome-wide association studies (GWAS). MR was employed to investigate the causal relationship between gut microbiota, cytokines, and ALD, with the inverse variance-weighted method (IVW) as the primary statistical approach. Additionally, we examined whether inflammatory cytokines act as mediating factors in the pathway from gut microbiota to ALD. Results: The IVW results confirmed two positive and one negative causal effect between genetic liability in the gut microbiota and ALD. Escherichia coli (P= 0.003) was identified as a protective factor for ALD, while Roseburia hominis (P=0.023) and Family Porphyromonadaceae (P=0.038) were identified as risk factors for ALD. Furthermore, there were five positive and two negative causal effects between inflammatory cytokines and ALD, with CUB domain-containing protein 1 (P= 0.035), Macrophage colony-stimulating factor 1 (P=0.047), Cystatin D (P = 0.035), Fractalkine (P=0.000000038), Monocyte chemoattractant protein-1 (P=0.004) positively associated with ALD onset. CD40L receptor (P= 0.044) and Leukemia inhibitory factor (P = 0.024) exhibited protective effects against ALD. Mediation MR analysis indicated that CUB domain-containing protein 1 (mediation proportion=1.6%, P=0.035), Cystatin D (mediation proportion=1.5%, P=0.012), and Monocyte chemoattractant protein-1 (mediation proportion=3.3%, P=0.005) mediated the causal effect of Roseburia hominis on ALD. Conclusion: In conclusion, our study supports a causal relationship among gut microbiota, inflammatory cytokines and ALD, with inflammatory cytokines potentially acting as mediating factors in the pathway from gut microbiota to ALD.

Programmed cell death and lipid metabolism of macrophages in NAFLD.

Non-alcoholic fatty liver disease (NAFLD) has now become the leading chronic liver disease worldwide with lifestyle changes. This may lead to NAFLD becoming the leading cause of end-stage liver disease in the future. To date, there are still no effective therapeutic drugs for NAFLD. An in-depth exploration of the pathogenesis of NAFLD can help to provide a basis for new therapeutic agents or strategies. As the most important immune cells of the liver, macrophages play an important role in the occurrence and development of liver inflammation and are expected to become effective targets for NAFLD treatment. Programmed cell death (PCD) of macrophages plays a regulatory role in phenotypic transformation, and there is also a certain connection between different types of PCD. However, how PCD regulates macrophage polarization has still not been systematically elucidated. Based on the role of lipid metabolic reprogramming in macrophage polarization, PCD may alter the phenotype by regulating lipid metabolism. We reviewed the effects of macrophages on inflammation in NAFLD and changes in their lipid metabolism, as well as the relationship between different types of PCD and lipid metabolism in macrophages. Furthermore, interactions between different types of PCD and potential therapeutic agents targeting of macrophages PCD are also explored.

Corrigendum: Programmed cell death and lipid metabolism of macrophages in NAFLD.

[This corrects the article DOI: 10.3389/fimmu.2023.1118449.].

The promising role of probiotics/prebiotics/synbiotics in energy metabolism biomarkers in patients with NAFLD: A systematic review and meta-analysis.

Background: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease with a high prevalence worldwide, seriously harming human health, and its pathogenesis remains unclear. In recent years, increasing evidence has indicated that intestinal microbiota plays an important role in the occurrence and development of NAFLD. The regulation method of probiotics/prebiotics/synbiotics can alter the intestinal microbiota and has been suggested as an option in the treatment of NAFLD. Methods: Five databases of PubMed, Embase, the Cochrane Library, clinicaltrails.gov, and China National Knowledge Infrastructure were searched initially, and then the eligible studies were screened. Finally, the data of included studieswere extracted, combined and analyzed. Results: A total of 29 randomized controlled trials involving 2,110 patients were included in this study. The results showed that using probiotics/prebiotics/synbiotics in the intervention group could reduce the levels of glucose (SMD = -0.23, 95% CI [-0.45, -0.01], P = 0.04), HOMA-IR (SMD = -0.47, 95% CI [-0.63, -0.31], P < 0.00001) and insulin (SMD = -0.46, 95% CI [-0.76, -0.16], P = 0.002) in sugar metabolism; in terms of lipid metabolism, the levels of TC (SMD = -0.62, 95%CI [-0.87, -0.36], P < 0.00001), and LDL-C (SMD = -0.57, 95%CI [-0.85, -0.28], P < 0.00001) were decreased; and the level of ALB was decreased in protein metabolism (SMD = -0.34, 95%CI [-0.61, -0.06], P = 0.02). Conclusions: Based on the current evidence, probiotics/prebiotics/synbiotics may improve energy metabolism biomarkers in the NAFLD population, but these effects still need to be confirmed by further research. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/#aboutpage.

α­lipoic acid protects against carbon tetrachloride­induced liver cirrhosis through the suppression of the TGF­ß/Smad3 pathway and autophagy.

α­lipoic acid (ALA) is a naturally occurring antioxidant with protective effects against various hepatic injuries. The aim of the present study was to investigate the mechanisms by which ALA protects the liver from carbon tetrachloride (CCl4)­induced liver cirrhosis. The widely used liver cirrhosis rat model was established via an intraperitoneal injection of 2 mg/kg 50% CCl4, three times/week for 8 weeks. Simultaneously, 50 or 100 mg/kg ALA was orally administrated to the rats every day for 8 weeks. The activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was detected in the serum. The pathological liver injuries were analyzed using hematoxylin and eosin and Masson's trichrome staining. The principal factors involved in the transforming growth factor­ß (TGF­ß)/mothers against decapentaplegic homolog 9 (Smad3) and protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways and in autophagy were examined using reverse transcription­quantitative polymerase chain reaction or western blot analysis. The results demonstrated that the administration of ALA alleviated CCl4­induced liver injury, as demonstrated by decreased ALT and AST activity, improved pathological injuries and reduced collagen deposition. The CCl4­induced increase in TGF­ß and phosphorylated­Smad3 expression levels was additionally inhibited by treatment with ALA. Furthermore, the administration of ALA reversed the CCl4­induced upregulation of light chain 3II and Beclin­1, and downregulation of p62. The CCl4­induced suppression of the AKT/mTOR pathway was additionally restored following treatment with ALA. In combination, the results of the present study demonstrated that ALA was able to protect CCl4­induced liver cirrhosis, an effect that may be associated with inactivation of the TGF­ß/Smad3 pathway and suppression of autophagy.