This study explores the potential therapeutic benefits of using a three-component DGR (composed of specific compounds) to target the NLRP3 inflammasome in the context of non-alcoholic fatty liver disease (NAFLD). To assess the impact of a three-component DGR on NAFLD, specifically examining its effects on liver lipid accumulation, inflammation, and the diversity of intestinal microbial communities. NAFLD was induced in 8-week-old Sprague Dawley rats by feeding them a high-fat emulsion diet every morning for 8 consecutive weeks. Oral administration of DGR or its constituent equivalents in the afternoon. The pharmacological effects of DGR were evaluated using H&E, ORO and ELISA methods to determine the changes in serum and liver tissue indexes of rat-models. Immunohistochemical staining and Western blot were used to assess the interaction between DGR, NLRP3 and IL-1β. The induction of NAFLD resulted in elevated hepatic triglycerides (TG), total cholesterol (TC), and free fatty acids (FFA). However, these alterations were ameliorated upon administration of DGR. It is noteworthy that DGR exhibited superior efficacy in comparison to its constituent compounds, manifesting augmented antioxidant activity, diminished hepatic damage, and the attenuation of pro-inflammatory factors. Both DGR and its individual monomeric constituents exhibited the capacity to attenuate the activation of the NLRP3 inflammasome in the liver, leading to an amelioration of the pathological characteristics associated with NAFLD. An analysis of the intestinal flora unveiled an elevated abundance of p_Firmicutes (1.1-fold), p_Cyanobacteria (5.76-fold), and p_Verrucomicrobia (5.2-fold), accompanied by a heightened p_Firmicutes to p_Bacteroidetes ratio (5.49-fold). In the non-alcoholic fatty liver disease (NAFLD) rat model, the concurrent administration of three-component DGR effectively regulated lipid deposition, suppressed liver inflammation, and restored balance in the intestinal flora, thereby improving NAFLD pathology. These findings propose a promising therapeutic strategy for NAFLD, centered on inhibiting the NLRP3 inflammasome through the use of the three-component DGR.

Background: Ganoderma lucidum spore powder (GLSP) has abundant pharmacological activities. However, the difference in the hepatoprotective function of sporoderm-broken and sporoderm-unbroken Ganoderma spore powder has not been studied. This study is the first to investigate the effects of both sporoderm-damaged and sporoderm-intact GLSP on the improvement of acute alcoholic liver injury in mice and gut microbiota of mice. Methods: Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and interleukin 1β (IL-1β), interleukin 18 (IL-18), and tumor necrosis factor-α (TNF-α) levels in liver tissues from mice in each group were detected by enzyme-linked immunosorbent assay (ELISA) kits, and histological analysis of liver tissue sections was performed to evaluate the liver-protecting effects of both sporoderm-broken and sporoderm-unbroken GLSP. Additionally, 16S rDNA sequencing of feces from the bowels of mice was performed to compare the regulatory effects of both sporoderm-broken and sporoderm-unbroken GLSP on the gut microbiota of mice. Results: Compared with those in the 50% ethanol model group (MG), sporoderm-broken GLSP significantly reduced serum AST and ALT levels (p < 0.0001) and the release of the inflammatory factors, including IL-1β, IL-18, and TNF-α (p < 0.0001), and effectively improved the pathological state of liver cells; sporoderm-unbroken GLSP significantly reduced the ALT content (p = 0.0002) and the release of the inflammatory factors, including IL-1β (p < 0.0001), IL-18 (p = 0.0018), and TNF-α (p = 0.0005), and reduced the serum AST content, but the reduction was not significant; compared with the gut microbiota of the MG, sporoderm-broken GLSP reduced the levels of Verrucomicrobia and Escherichia_Shigella, increased the relative abundance of beneficial bacteria such as Bacteroidetes, and decreased the abundance levels of harmful bacteria, such as Proteobacteria and Candidatus_Saccharibacteria; sporoderm-unbroken GLSP could reduce the abundance levels of harmful bacteria, such as Verrucomicrobia and Candidatus_Saccharibacteria; and GLSP treatment alleviates the downregulation of the levels of translation, ribosome structure and biogenesis, and lipid transport and metabolism in liver-injured mice; Conclusions: GLSP can alleviate the imbalance of gut microbiota and improve liver injury, and the effect of sporoderm-broken GLSP is better.

Beauvericin (BEA), a naturally occurring cyclic peptide with good pharmacological activity, has been widely explored in anticancer research. Although BEA is toxic, studies have demonstrated its antioxidant activity. However, to date, the antioxidant mechanisms of BEA remain unclear. Herein, we conducted a comprehensive and detailed study of the antioxidant mechanism of BEA using an untargeted metabolomics approach, subsequently validating the results. BEA concentrations of 0.5 and 1 μM significantly inhibited H₂O₂-induced oxidative stress (OS), decreased reactive oxygen species levels in PC-12 cells, and restored the mitochondrial membrane potential. Untargeted metabolomics indicated that BEA was primarily involved in lipid-related metabolism, suggesting its role in resisting OS in PC-12 cells by participating in lipid metabolism. BEA combated OS damage by increasing phosphatidylcholine, phosphatidylethanolamine, and sphingolipid levels. In the current study, BEA upregulated proteins related to the PI3K/AKT/mTOR pathway, thereby promoting cell survival. These findings support the antioxidant activity of BEA at low concentrations, warranting further research into its pharmacological effects.