Elucidating the mechanism of action of Isobavachalcone induced autophagy and apoptosis in non-small cell lung cancer by network pharmacology and experimental validation methods.

BACKGROUND: Lung cancer is the leading cause of cancer deaths, and non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer-related mortality. In recent years, there have been numerous treatments for non-small cell lung cancer, but the cure and survival rates are still extremely low. Isobavachalcone (IBC) belongs to the chalcone component of the traditional Chinese medicine Psoralea corylifolia L., and is a unique Protein kinase B (AKT) pathway inhibitor with significant anticancer effects. Previous studies have shown that IBC possess a variety of biological properties, including anti-cancer, anti-inflammatory, and antioxidant properties. This study focused on the use of network pharmacology analysis, molecular docking technology and experimental validation to elucidate the potential mechanisms of IBC for the treatment of NSCLC. METHODS: Screening key genes and pathways of IBC action in NSCLC using network pharmacology. The IBC target genes were from The Encyclopedia of Traditional Chinese Medicine (ETCM) and BATMAN-TCM databases, the NSCLC target genes were from GeneCards, Online Mendelian Inheritance in Man (OMIM) and The Therapeutic Target database (TTD) databases, both of which were taken as intersecting genes for protein-protein interaction network analysis and enrichment analysis, and the binding energies of the compounds to the core targets were further verified by molecular docking. Cell lines in vitro experiments were then performed to further unravel the mechanism of IBC for NSCLC. RESULTS: A total of 279 potential targets were retrieved by searching the intersection of IBC and NSCLC targets. Protein-protein interaction (PPI) network analysis indicated that 6 targets, including AKT1, RXRA, NCOA1, RXRB, RARA, PPARG were hub genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that IBC treatment of NSCLC mainly involves steroid binding, transcription factor activity, Pathways in cancer, cAMP signaling pathway, Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway. Among them, the AMPK signaling pathway, which contained the largest number of enriched genes, may play a greater role in the treatment of NSCLC. Then, the results of in vitro experiment indicated that IBC could inhibit proliferation of NSCLC cells and induce cell autophagy and apoptosis. The results also showed that IBC could increase the protein expression of AMPK and decrease the protein expression of AKT and mammalian target of rapamycin (mTOR), suggesting that IBC can treat NSCLC by inducing cellular autophagy and apoptosis as well as modulating AMPK and AKT signaling pathways. CONCLUSIONS: In summary, this study provided a new insight into the protective mechanism of IBC against NSCLC through network pharmacology and experimental validation.

Targeting autophagy to discover the Piper wallichii petroleum ether fraction exhibiting antiaging and anti-Alzheimer's disease effects in Caenorhabditis elegans.

BACKGROUND: With population aging, the incidence of aging-related Alzheimer's disease (AD) is increasing, accompanied by decreased autophagy activity. At present, Caenorhabditis elegans (C. elegans) is widely employed to evaluate autophagy and in research on aging and aging-related diseases in vivo. To discover autophagy activators from natural medicines and investigate their therapeutic potential in antiaging and anti-AD effects, multiple C. elegans models related to autophagy, aging, and AD were used. METHOD: In this study, we employed the DA2123 and BC12921 strains to discover potential autophagy inducers using a self-established natural medicine library. The antiaging effect was evaluated by determining the lifespan, motor ability, pumping rate, lipofuscin accumulation of worms, and resistance ability of worms under various stresses. In addition, the anti-AD effect was examined by detecting the paralysis rate, food-sensing behavior, and amyloid-ß and Tau pathology in C. elegans. Moreover, RNAi technology was used to knock down the genes related to autophagy induction. RESULTS: We discovered that Piper wallichii extract (PE) and the petroleum ether fraction (PPF) activated autophagy in C. elegans, as evidenced by increased GFP-tagged LGG-1 foci and decreased GFP-p62 expression. In addition, PPF extended the lifespan and enhanced the healthspan of worms by increasing body bends and pumping rates, decreasing lipofuscin accumulation, and increasing resistance to oxidative, heat, and pathogenic stress. Moreover, PPF exhibited an anti-AD effect by decreasing the paralysis rate, improving the pumping rate and slowing rate, and alleviating Aß and Tau pathology in AD worms. However, the feeding of RNAi bacteria targeting unc-51, bec-1, lgg-1, and vps-34 abolished the antiaging and anti-AD effects of PPF. CONCLUSION: Piper wallichii may be a promising drug for antiaging and anti-AD. More future studies are also needed to identify autophagy inducers in Piper wallichii and clarify their molecular mechanisms.