CT2-3 induces cell cycle arrest and apoptosis in rheumatoid arthritis fibroblast-like synoviocytes through regulating PI3K/AKT pathway.

Rheumatoid arthritis (RA) is a kind of chronic autoimmune disease. The existing therapies encountered several challenges. Therefore, continued novel anti-RA drug discovery remains necessary for RA therapy. Recently, our group reported a novel compound named CT2-3, which could be realized as a hybrid of the natural product magnolol and phthalimide and exhibited anti-lung cancer activity. However, the effect of CT2-3 on RA is unclear. Here, we aim to explore the effect and potential mechanism of CT2-3 on the abnormal functions of RA-fibroblast-like synoviocytes (RA-FLSs). In this study, we identified the important role of the dysregulated cell cycle and apoptosis of RA-FLSs in RA progression. Interestingly, we found that CT2-3 inhibited the proliferation and DNA replication of primary RA-FLSs and immortalized RA-FLSs namely MH7A. In addition, CT2-3 downregulated the mRNA and protein expression of cyclin-dependent kinase 2 (CDK2), cyclin A2, and cyclin B1, resulting in cell cycle arrest of primary RA-FLSs and MH7A cells. Also, CT2-3 downregulated the level of B-cell lymphoma-2 (Bcl-2), and increased the level of Bcl-2 associated X (Bax), contributing to apoptosis of primary RA-FLSs and MH7A cells. Furthermore, differential analyses of RNA-sequencing, Western blot, and network pharmacological analysis confirmed that CT2-3 inhibited phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway of primary RA-FLSs and MH7A cells. In conclusion, CT2-3 induces cell cycle arrest and apoptosis in RA-FLSs through modulating PI3K/AKT pathway, which may serve as a potential lead compound for further novel small molecule anti-RA drug development.

Schisandrin A ameliorates airway inflammation in model of asthma by attenuating Th2 response.

Asthma is a persistent respiratory ailment that displays periodicity and is linked to the equilibrium of T cells. Several compounds obtained from Chinese herbal medicines display beneficial impacts on T cell regulation and the attenuation of inflammatory mediator synthesis. Schisandrin A, an active lignan derived from the Schisandra fruit, exhibits anti-inflammatory characteristics. In the present study, the network analysis conducted revealed that the nuclear factor-kappaB (NF-κB) signaling pathway is likely a prominent contributor to the anti-asthmatic effects of schisandrin A. In addition, it has been established that the inhibition of cyclooxygenase 2 (COX-2/PTGS2) is likely a significant factor in this process. The results of in vitro experiments have substantiated that schisandrin A can effectively lower the expression of COX-2 and inducible nitric oxide synthase (iNOS) in 16 HBE cells and RAW264.7 cells in a manner that is dependent on the dosage administered. It was able to effectively reduce the activation of the NF-κB signaling pathway while simultaneously improving the injury to the epithelial barrier function. Furthermore, an investigation utilizing immune infiltration as a metric revealed an inequity in Th1/Th2 cells and a surge in Th2 cytokines in asthma patients. In the OVA-induced asthma mice model, it was observed that schisandrin A treatment effectively suppressed inflammatory cell infiltration, reduced the Th2 cell ratio, inhibited mucus secretion, and prevented airway remodeling. To summarize, the administration of schisandrin A has been found to effectively alleviate the symptoms of asthma by impeding the production of inflammation, which includes reducing the Th2 cell ratio and improving the integrity of the epithelial barrier function. These findings offer valuable insights into the potential therapeutic applications of schisandrin A for the treatment of asthma.