Since the incidence rate of malignant melanoma is increasing annually, development of drugs against melanoma cell metastasis has become more urgent. Luteolin, a naturally occurring flavonoid, is abundant in our daily dietary intake and exhibits a wide spectrum of pharmacological properties. However, the potential anti-cancer role of luteolin in melanoma cells has not been fully investigated. In this study, we have explored whether luteolin inhibits the migration and invasion of A375 human melanoma cells and further elucidated the underlying anti-cancer molecular mechanism of luteolin in melanoma cells. A proliferation assay, flow cytometry and an apoptosis assay were applied to detect the effect of luteolin on the growth and apoptosis of A375 cells. Wound healing assay and transwell invasion assay were used to explore the impact of luteolin on the migration and invasion of A375 cells. Real-time quantitative PCR, western blot and immunofluorescence analysis were used to investigate the effects of luteolin on the expressions of MMP-2, MMP-9 and PI3K/AKT1 in A375 cells. A xenograft tumor animal model was used to investigate the anti-cancer effect of luteolin on the growth of the A375 cells in vivo. Our data indicated that luteolin significantly inhibited the proliferation, migration and invasion of A375 cells and induced the apoptosis of A375 cells in a concentration-dependent manner. Moreover, luteolin reduced the expressions of MMP-2 and MMP-9 and increased the expression of TIMP-1 and TIMP-2. Furthermore, luteolin significantly inhibited the tumor growth of A375 cells in a xenograft mouse model. The immunofluorescence and immunoblotting assays indicated that luteolin inhibited the phosphorylation of AKT1 and PI3K. In conclusion, both in vivo and in vitro studies showed that luteolin inhibited the proliferation and induced the apoptosis of A375 human melanoma cells by reducing the expressions of MMP-2 and MMP-9 through the PI3K/AKT pathway. Overall, luteolin can be considered as a promising anti-cancer agent for the treatment of human melanoma.

ε-Viniferin (VNF), a naturally occurring oligostilbene (a resveratrol dimer), is mainly found in grapes and red wines. However, unlike resveratrol, the biological activity of VNF has not been widely studied. This study was conducted to investigate the beneficial effects of VNF on hyperglycemia and hyperlipidemia and further to reveal the underlying mechanism. The ameliorative effects of VNF in high-fat-diet and streptozotocin-induced type 2 diabetic rats were assessed physiologically, biochemically and histologically after oral administration of VNF (30 mg kg⁻¹ and 60 mg kg⁻¹) for 8 weeks. Western blotting and immunohistochemistry experiments were performed to determine the effects of VNF on the AMPK phosphorylation levels in the livers of diabetic rats. Molecular docking and molecular dynamics simulation were further performed to study the molecular-level interaction between VNF and AMPK. Meanwhile, the protective effects of VNF on the liver and kidney were also evaluated. The results showed that the VNF treatment caused a significant decrease in the concentrations of fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), and low density lipoprotein-cholesterol (LDL-C), and improved the glucose tolerance of diabetic rats. In addition, the liver and kidney damage indices such as alanine aminotransferase (ALT), aspartate aminotransaminase (AST), creatinine (CR), and blood urea nitrogen (BUN) were also lowered and improved. Moreover, VNF could increase the AMPK activation and attenuate histopathological changes in the liver of diabetic rats. The molecular docking and molecular dynamics simulation results revealed for the first time that VNF bound to the hinge region between the α- and β-units of AMPK and interacted with the active site of AMPK. In conclusion, VNF can effectively improve hyperglycemia and hyperlipidemia and exhibit protective effects on the liver and kidney functions. The underlying mechanism of VNF in hyperglycemia and hyperlipidemia may be related to the activation of AMPK in vivo. Our findings indicate that VNF is a potentially useful natural agent for the treatment of metabolic diseases, especially type 2 diabetes and hyperlipidemia.

Lung cancer is recognized as the leading cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) being the predominant subtype, accounting for approximately 85% of lung cancer cases. Although great efforts have been made to treat lung cancer, no proven method has been found thus far. Considering β, β-dimethyl-acryl-alkannin (ALCAP2), a natural small-molecule compound isolated from the root of Lithospermum erythrorhizon. We found that lung adenocarcinoma (LUAD) cell proliferation and metastasis can be significantly inhibited after treatment with ALCAP2 in vitro, as it can induce cell apoptosis and arrest the cell cycle. ALCAP2 also significantly suppressed the volume of tumours in mice without inducing obvious toxicity in vivo. Mechanistically, we revealed that ALCAP2-treated cells can suppress the nuclear translocation of β-catenin by upregulating the E3 ligase NEDD4L, facilitating the binding of ubiquitin to β-catenin and eventually affecting the wnt-triggered transcription of genes such as survivin, cyclin D1, and MMP9. As a result, our findings suggest that targeting the oncogene β-catenin with ALCAP2 can inhibit the proliferation and metastasis of LUAD cells, and therefore, ALCAP2 may be a new drug candidate for use in LUAD therapeutics.

Rheumatoid arthritis (RA) is an essential cause of labor loss and disability for people worldwide. Acanthopanax senticosus polysaccharide (ASPS) is one of the most important active components from A. senticosus, which exhibits various pharmacological activities such as antioxidation and immunomodulation. However, no studies have reported the application of ASPS in treating RA. This study aims to investigate the therapeutic effect of ASPS on RA and reveal its underlying mechanism. The potential therapeutic effect of ASPS against RA is initially verified in this study using the collagen‐induced arthritis model. Moreover, the protective benefits of ASPS are transmitted through the fecal microbiota and blocked by simultaneous antibiotic cocktail treatment, indicating that gut microbiota may be correlated with ASPS. The 16S rRNA sequencing using feces samples and untargeted UPLC‐MS metabolomics using serum samples further reveal that ASPS reprograms the arthritic progression triggered dysbiosis, enhances the expression of γ‐glutamylcysteine (GGC) synthetase, and enriches the serum concentration of GGC. Furthermore, metabolites GGC is found to be able to effectively interrupt NLRP3 inflammasome activation via inhibiting ASC nucleation and therefore attenuate inflammatory arthritis. Taken together, this work highlights ASPS's therapeutic potential against RA, which mainly exhibits its effects via modulating gut microbiota and regulating GGC production.