European journal of pharmacology最新文献

Lung cancer is one of the most commonly diagnosed cancers worldwide, with non-small cell lung cancer (NSCLC) accounting for 80-85% of cases. To clarify the mechanisms underlying its onset and development, and to identify small molecule compounds that target related pathways effectively inhibiting tumor development and transformation. Small molecular compounds with a β-carboline nucleus exhibit a range of biological activities, with significant anti-tumor effects. A series of small molecule β-carboline compounds were synthesized and the dominant structure 1- (3-chlorophenyl) - 9H -pyridino - [3,4-b] indole - 3 -carboxylic acid methyl ester (10830733) was initially screened out. However, the effect of 10830733 on NSCLC is unclear. In this study, we investigated the anti-NSCLC activity of 10830733 and explored its potential mechanisms of action. First, we found that 10830733 decreased proliferation and invasion and promoted apoptosis, as well as S and G2 phase cell cycle arrest in NSCLC cells. Furthermore, network pharmacological analysis and Western blot confirmed that 10830733 inhibits the PI3K/Akt/GSK 3β pathway, and that the PI3K inhibitor LY294002 enhances the effects of 10830733 on proliferation, invasion, apoptosis, S and G2 phase arrest, and the expression of PI3K/Akt/GSK 3β related proteins. In conclusion, our data demonstrate that 10830733 reduces proliferation and invasion, promotes S and G2 phase arrest and apoptotic cell death in NSCLC cells by suppressing the PI3K/Akt/GSK 3β signaling pathway, suggesting that 10830733 could be a promising new candidate for NSCLC therapy.

In an era of rapid scientific advancement, gene therapy has emerged as a groundbreaking approach with the potential to revolutionize the treatment of a myriad of diseases and medical conditions. The trend of current clinical trials suggests that there is growing interest and investment in exploring gene therapy as a viable treatment option. In 2023, a significant milestone was achieved with the approval of seven gene therapies by the Food and Drug Administration (FDA). Projections indicate that between 10 and 20 gene therapies could receive annual FDA approval by 2025. In this review, we conducted a comprehensive analysis of registered clinical trials on Clinicaltrials.gov to determine the progression status of gene therapies. Upon extraction of the data, we conducted a comprehensive analysis of the 2809 included studies. This involved a systematic approach, commencing with an overview, followed by a detailed examination of gene therapy strategies employed in various malignant and non-malignant disorders. Additionally, the study will cover the types of vectors utilized in current trials. Lastly, a meticulous review of 105 phase III-IV clinical trials was conducted to identify potential therapies demonstrating promise. We trust that the comprehensive overview provided will serve as a solid foundation for forthcoming research and study designs, ultimately contributing to the progression of gene therapy and its practical application within healthcare settings. Also, we anticipate that such inquiries will bolster the formulation of practical policies and guidelines for pharmaceutical companies engaged in gene therapy research and development.

The present study aimed to investigate the therapeutic potential of Osmundacetone (Osu), a natural plant product, for the treatment of rheumatoid arthritis (RA). The study revealed that Osu effectively reduced arthritis-induced swelling and bone destruction, as well as alleviating inflammation-related factors and oxidative stress in animal models. We focused the mechanism exploration on its regulatory mechanism on osteoclastogenesis in the next investigation. In vitro experiments demonstrated a dose-dependent inhibition of osteoclastic differentiation by Osu, as evidenced by tartrate resistant acid phosphatase (TRAP) staining and a reduction in osteoclastic differentiation markers observed through Western blotting analysis. And three different approaches Osu inhibiting osteoclastogenesis were found in our researches: (1) The binding of Receptor Activator of Nuclear Factor Kappa B (RANK) and Osu was revealed by the in-silico analysis. (2) According to 2,7-Dichlorodihydrofluorescein diacetate (DCFH-DA) staining, Osu attenuated the level of reactive oxygen species (ROS), and western blotting studies revealed this effect was modulated by the regulation of Kelch-like ECH-associated protein 1 / Nuclear Factor erythroid 2-Related Factor 2 (Keap1/Nrf2) pathway. (3) Interestingly, we found that Osu increased the lipid peroxidation via downregulating the expression of glutathione peroxidase 4 (GPX4) at the same time as reducing the ROS, leading to the reduction of the fluidity of the membrane and the fusion of osteoclasts which could be reversed by using the ferroptosis inhibitor- Ferrostatin-1 (Fer-1). Overall, a natural compound to the existing therapeutics for rheumatoid arthritis was confirmed and a new strategy for inhibiting osteoclastogenesis was added.