Xincong Kang

Dysregulated lipid metabolism is a core pathogenic driver of type 2 diabetes. Honokiol (HKL), the major bioactive constituent of Magnolia officinalis, possesses anti-diabetic and lipid-regulatory properties. However, the underlying molecular mechanism remains elusive. This study investigates how HKL ameliorates high-glucose/high-fat (HGHF)-induced hepatic lipid accumulation, with a focus on the role of SIRT3-mediated deacetylation of peroxisome proliferator-activated receptor γ (PPARG). The core targets of HKL were identified through network pharmacology and molecular docking. Human hepatic MIHA cells were treated with glucose (Glu, 40 mM) and palmitic acid (0.2~0.3 mM PA) to establish a lipid accumulation model, followed by treatment with HKL (5–10 μM) with or without a confirmed selective SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP). Lipid accumulation was assessed by Oil Red O staining and by measuring triglyceride (TG) and total cholesterol (TC) levels. Protein expression and the SIRT3-PPARG interaction were analyzed by Western blot and co-immunoprecipitation (Co-IP). SIRT3 and PPARG were identified as core targets of HKL, exhibiting strong binding with calculated energies of −6.834 and −6.579 kcal/mol, respectively. In MIHA cells, HGHF (40 mM Glu + 0.2–0.3 mM PA) induced lipid accumulation, including increased lipid droplets, and elevated TG (2.5–3.2-fold) and TC (2.2–2.8-fold) contents in a dose-dependent manner, accompanied by downregulated SIRT3/PPARG expression and heightened global protein acetylation. The non-cytotoxic HGHF-M condition (40 mM Glu + 0.2 mM PA) was selected for further experiments. HKL (5–10 μM) dose-dependently reduced lipid accumulation by ~38–60%, decreased TG and TC levels by up to ~13% and ~30%, and restored SIRT3/PPARG expression. The protective effects of HKL were reversed by inhibition of SIRT3 with 3-TYP. Co-IP confirmed the interaction between SIRT3 and PPARG, and SIRT3 overexpression significantly decreased the acetylation level of PPARG. This study suggests that HKL ameliorates hepatic lipid accumulation via SIRT3-mediated deacetylation of PPARG, providing an experimental basis for considering HKL as a potential therapeutic agent against metabolic disorders.

Purpose: There is an urgent need to develop antidiabetic medications with minimal side effects and low toxicity. Ganoderma lucidum, a food-medicine homologous in China, has been used to treat diabetes. This study was aimed to explore the active ingredients and mechanism of G. lucidum in the treatment of diabetes. Materials and Methods: Relevant compounds and targets of Ganoderma were collected from the TCMSP database, BATMAN-TCM database, relevant literature and PubChem. A diabetes-related target database was constructed using TTD, BATMAN-TCM, and Uniprot. A PPI network and H-C-T-P network were constructed to analyze interactions among these targets. GO and KEGG enrichment analyses were performed using WebGestalt. Molecular docking of the core compounds and key targets was carried out using AutoDock Vina. The predicted key targets were verified via qRT-PCR in PA-induced HepG2 cells, using GLAE (ethanol extract of Ganoderma lucidum) as the treatment. Results: A total of 58 compounds were screened out in G. lucidum, of which 17 had predicted targets. G. lucidum was involved in metabolic processes, such as lipid binding, insulin secretion, and other pathways. Molecular docking results showed that the core component β-sitosterol had strong binding activity with key targets CASP3, PRKACA, and PGR. Based on the results of network pharmacology, the top 10 targets related to glucose and lipid metabolism were selected for validation. The results indicated that in a high-fat environment, glucose and lipid metabolism in HepG2 cells was improved, with decreased mRNA expression of CASP3, PRKACA, CYP19A1, NR3C1, JUN, and increased expression of PGR and RXRA. Conclusion: Glucose and lipid metabolism are important for the anti-diabetic activity of G. lucidum. A strong interaction of β-sitosterol with CASP3, PRKACA, and PGR, which may be related to cell apoptosis, gluconeogenesis and insulin secretion, etc. This study lays the foundational groundwork for future drug development and therapeutic optimization.

Lipid accumulation and oxidative stress, which could be improved by autophagy, are the “hits” of metabolic-associated fatty liver disease (MAFLD). Ganoderma lucidum spore powder (GLSP) has the effect of improving liver function. However, there are few reports about its effects on and mechanisms impacting MAFLD alleviation. This study investigated the effect of GLSP on hepatic lipid accumulation and oxidative stress and explored the role that autophagy played in this effect. The results showed that GLSP effectively reduced lipid accumulation and activated autophagy in the livers of mice with high-fat-diet-induced disease and palmitic acid-induced hepatocytes. GLSP reduced the lipid accumulation by reducing lipogenesis and promoting lipid oxidation in HepG2 cells. It decreased the production of ROS, increased the activity of SOD and CAT, and improved the mitochondrial membrane potential via the Keap1/Nrf2 pathway. The alleviating effects of GLSP on the lipid accumulation and oxidative stress was reversed by 3-methyladenine (3-MA), an autophagy inhibitor. GLSP activated autophagy via the AMPK pathway in HepG2 cells. In conclusion, GLSP could attenuate MAFLD by the improvement of lipid accumulation and oxidative stress via autophagy. This paper is the first to report the improvement of MAFLD through autophagy promotion. It will shed novel light on the discovery of therapeutic strategies targeting autophagy for MAFLD.

ISHS XXVIII International Horticultural Congress on Science and Horticulture for People (IHC2010): A New Look at Medicinal and Aromatic Plants Seminar COMPARATIVE STUDIES ON THE ACTIVE INGREDIENTS CONTENTS IN NATURAL AND CULTIVATED PORIA COCOS