Physical fatigue (peripheral fatigue), which affects a considerable portion of the world population, is a decline in the ability of muscle fibers to contract effectively due to alterations in the regulatory processes of muscle action potentials. However, it lacks an efficacious therapeutic intervention. The present study explored bioactive compounds and the mechanism of action of Citrus reticulata peel (CR-P) in treating physical fatigue by utilizing network pharmacology (NP), molecular docking, and simulation-based molecular dynamics (MD). The bioactive ingredients of CR-P and prospective targets of CR-P and physical fatigue were obtained from various databases. A PPI network was generated by the STRING database, while the key overlapping targets were analyzed for enrichment by adopting KEGG and GO. The binding affinities of bioactive ingredients to the hub targets were determined by molecular docking. The results were further validated by MD simulation. Five bioactive compounds were screened, and 56 key overlapping targets were identified for CR-P and physical fatigue, whereas the hub targets with a greater degree in the PPI network were AKT1, TP53, STAT3, MTOR, KRAS, HRAS, JAK2, IL6, EGFR, and ESR1. The findings of the enrichment analysis indicated significant enrichment of the targets in three key signaling pathways, namely PI3K-AKT, MAPK, and JAK-STAT. The molecular docking and MD simulation results revealed that the bioactive compounds of CR-P exhibit a stronger affinity for interacting with the hub targets. The present work suggests that bioactive compounds of CR-P, specifically Hesperetin and Sitosterol, may ameliorate physical fatigue via the PI3K-AKT signaling pathway by targeting AKT1, KRAS, and MTOR proteins.

Type 2 diabetic osteoporosis (T2DOP) is a common complication in diabetic patients that seriously affects their health and quality of life. The pathogenesis of T2DOP is complex, and there are no targeted governance means in modern medicine. Citri Reticulatae Pericarpium (CRP) is a traditional Chinese medicine that has a long history and has been used in the treatment of osteoporosis diseases. However, the molecular mechanism for the CRP treatment of T2DOP is not clear. Therefore, this study aimed to explore the underlying mechanisms of CRP for the treatment of T2DOP by using network pharmacology and molecular modeling techniques. By retrieving multiple databases, we obtained 5 bioactive compounds and 63 common targets of bioactive compounds with T2DOP, and identified AKT 1, TP 53, JUN, BCL 2, MAPK 1, NFKB 1, and ESR 1 as the core targets of their PPI network. Enrichment analysis revealed that these targets were mainly enriched in the estrogen signaling pathway, TNF signaling pathway, and AGE-RAGE signaling pathway in diabetics, which were mainly related to oxidative stress and hormonal regulation. Molecular docking and molecular dynamics simulations have shown the excellent binding effect of the bioactive compounds of CRP and the core targets. These findings reveal that CRP may ameliorate T2DOP through multiple multicomponent and multitarget pathways.

Obesity is a serious public health issue worldwide. Growing evidence demonstrates the efficacy of the ketogenic diet (KD) for weight loss, but there may be some adverse side effects such as dyslipidemia and hepatic steatosis. Aerobic exercise is a widely recognized approach for improving these metabolic markers. Here we explored the combined impacts of KD and moderate aerobic exercise for an 8-week intervention on body weight and fat loss, serum biomarkers, and hepatic lipid metabolism in a mouse model of high-fat diet-induced obesity. Both KD and KD combined with exercise significantly reduced body weight and fat mass. No significant adverse effects of KD were observed in serum biomarkers or hepatic lipid storage, except for an increase in circulating triglyceride level. However, aerobic exercise lowered serum triglyceride levels, and further ameliorated serum parameters, and hepatic steatosis in KD-fed mice. Moreover, gene and protein expression analysis indicated that KD combined with exercise was associated with increased expression of lipolysis-related genes and protein levels, and reduced expression of lipogenic genes relative to KD without exercise. Overall, our findings for mice indicate that further work on humans might reveal that KD combined with moderate aerobic exercise could be a promising therapeutic strategy for obesity.

Bayberry is known to be a rich source of natural flavonoids and has been reported to have various health-promoting abilities. However, its function on regulating skeletal muscle fiber type remains unclear. This study examined whether bayberry extract affects skeletal muscle fiber type by promoting fast myofiber formation, as well as the potential molecular mechanism. After eight weeks, the “Biqi” bayberry extract (BBE) groups mice displayed markedly enhanced grip strength and improved metabolic rate compared to the control group mice. BBE also significantly increased myofibers size, LDH activity, MyHC-IIb (fast-twitch mRNA) expression, and the percentage of fast-twitch myofibers, while decreasing SDH activity, MyHC-I (slow-twitch mRNA) expression, and slow-twitch myofibers percentage in the skeletal muscle of the mice. The effect of BBE on regulating skeletal muscle fiber type remodeling is likely attributed to its activation of the Akt-FoxO1 pathway. Our findings indicated that BBE can effectively regulate the expression and proportion of fast-twitch fibers, making it a potential therapy for improving glucose homeostasis of skeletal muscle.