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.

Role and potential therapeutic value of histone methyltransferases in drug resistance mechanisms in lung cancer.

Lung cancer, ranking second globally in both incidence and high mortality among common malignant tumors, presents a significant challenge with frequent occurrences of drug resistance despite the continuous emergence of novel therapeutic agents. This exacerbates disease progression, tumor recurrence, and ultimately leads to poor prognosis. Beyond acquired resistance due to genetic mutations, mounting evidence suggests a critical role of epigenetic mechanisms in this process. Numerous studies have indicated abnormal expression of Histone Methyltransferases (HMTs) in lung cancer, with the abnormal activation of certain HMTs closely linked to drug resistance. HMTs mediate drug tolerance in lung cancer through pathways involving alterations in cellular metabolism, upregulation of cancer stem cell-related genes, promotion of epithelial-mesenchymal transition, and enhanced migratory capabilities. The use of HMT inhibitors also opens new avenues for lung cancer treatment, and targeting HMTs may contribute to reversing drug resistance. This comprehensive review delves into the pivotal roles and molecular mechanisms of HMTs in drug resistance in lung cancer, offering a fresh perspective on therapeutic strategies. By thoroughly examining treatment approaches, it provides new insights into understanding drug resistance in lung cancer, supporting personalized treatment, fostering drug development, and propelling lung cancer therapy into novel territories.

The need to belong: A parallel process latent growth curve model of late life negative affect and cognitive function.

OBJECTIVE: Late life negative affect (NA) often co-occurs with poor cognitive function (CF); however, very little is known about the mechanism of the relationship between them. We examined the longitudinal relationship between NA and CF over a 12-year period and the effects of several related risk factors in a general sample. METHODS: Five waves of data on Chinese Longitudinal Healthy Longevity Survey (CLHLS) were collected from a total of 1,314 elderly Chinese, aged 60 and over. A parallel process latent growth curve model with two time-invariant covariates and seven time-varying covariates was used to demonstrate the joint trajectories of NA and CF to assess their related factors in the elderly during a 12-year period. RESULTS: Significant association of negative affect and cognitive decline was found at baseline and over time for our sample. Poorer initial cognitive performance predicted a faster increase in negative affect over time. Being female was associated with worse initial performance and a faster rate of deterioration of NA and CF. Regular exercise, married status, social activities, and Mahjong playing were associated with slower rates of negative affect increase and cognitive decline. CONCLUSION: These findings demonstrated that the late life negative affect co-occurs with cognitive decline and negative affect might be a mutative mental reaction to cognitive dysfunction. Gender difference, exercise benefit, and the "need to belong" effect were observed over time, highlighting the importance of exercise and socialization for older females.

Changes in depression among older adults in China: A latent transition analysis.

BACKGROUND: Depression in late life is an important public health problem in developing countries. It is timely to investigate stability and transition patterns of depressive symptom subtypes. METHODS: Longitudinal data were used from the China Health and Retirement Longitudinal Study (CHARLS). A total of 853 women and 930 men aged 60-96 years were recruited. Latent class and latent transition analysis (LCA/LTA) were used to identify meaningful subgroups, transitions between those classes across time, and baseline demographic features that help to predict and design tailored interventions. RESULTS: Three depression subgroups were identified: Class 1 was labeled "Mild Depression"; Class 2 was labeled "Severe Depression" and class 3 was labeled "Lack of Positive Affect". A predominant tendency for stability appeared rather than change, meanwhile individual in Mild Depression and Severe Depression latent status both had a high probability to convert to the Lack of Positive Affect latent status. Social activities played a significant role in buffering the effect of depression, while individuals with chronic diseases, having difficulty with ADLs and smoking might be at-risk groups. LIMITATIONS: The limitations of the present study were inherent limitation in the LTA model and some small proportion of transitions. CONCLUSIONS: This study demonstrated a transition pattern in older adult depression within a person-centered approach. Differential treatment effects were found across baseline depression class, suggesting the benefit for tailored intervention programs to improve depression outcomes among older adults.