Study on the Nanoaggregate Formation Mechanism and Antipyretic Effect of Maxing Shigan Decoction.

Traditional Chinese medicine (TCM) formula decoctions easily form nanoaggregates due to self-assembly during the decoction process. However, research on nanoaggregates in TCM is still in its infancy with limited systematic studies. Maxing Shigan Decoction (MXSGT), a TCM formula, has been commonly used for the treatment of fever for thousands of years in China. This study used MXSGT as an example to investigate the antipyretic effects of MXSGT nanoaggregates (MXSGT-NAs) in its decoction, shedding light on the compatibility mechanisms of Chinese medicine. MXSGT-NAs were isolated by using high-speed centrifugation and dialysis techniques. The morphology, particle size distribution, and electrical potential of MXSGT-NAs were characterized. High-performance liquid chromatography (HPLC) was used to detect ephedrine and pseudoephedrine in MXSGT-NAs. The self-assembly mechanism of MXSGT-NAs was investigated by deconstructing the prescription. In pharmacodynamic experiments, a rat fever model was established through the subcutaneous injection of dry yeast to investigate the antipyretic effects of MXSGT-NAs. The results showed the presence of regularly shaped spherical nanoaggregates in MXSGT. It contains carbon, oxygen (O), sulfur (S), sodium, aluminum (Al), calcium (Ca), iron, magnesium, bismuth (Bi), etc. MXSGT-NAs exerted substantial antipyretic effects on febrile rats. Furthermore, we found micrometer-sized particles composed of Ca, O, S, potassium, and Bi in Shi gao decoctions. This study is the first to provide evidence for the self-assembling property of Shi gao, elucidate the scientific connotation of dispensing Shi gao in MXSGT, and provide a novel perspective for the study of TCM decoctions.

Discovery of a novel 1H-pyrazole- [3,4-b] pyridine-based lysine demethylase 5B inhibitor with potential anti-prostate cancer activity that perturbs the phosphoinositide 3-kinase/AKT pathway.

Lysine demethylase 5B (KDM5B) is a member of the Jumonji AT-rich interactive domain 1 family. Its main function is to demethylate di/trimethyl histone H3 lysine 4 and it plays a crucial role in the occurrence and development of cancer. In this study, we performed structure-based optimization of KDM5B inhibitors based on our previous work and the most active compound we synthesized was 11ad. Molecular modeling studies and thermal shift assays revealed that 11ad specifically targets KDM5B at the molecular and cellular levels. Crucially, 11ad demonstrated good pharmacokinetic properties and anti-prostate cancer activity in a xenograft model. Furthermore, unexpectedly, the specificity of 11ad for prostate cancer was found to be related to its inhibition of the phosphoinositide 3-kinase/AKT pathway. This is the first report of a KDM5B inhibitor affecting this pathway. Taken together, our findings indicate that 11ad is a novel KDM5B inhibitor that may serve as a lead compound for the development of treatments for prostate cancer.