Research development of cytokine release syndrome induced by monoclonal antibody and cytokine release assays in vitro / 中国药理学通报

Cytokine-release syndrome (CRS) triggered by mon-oclonal antibodies ( mAbs) is characterized by rapid onset and severe damage, and difficulty in prediction and control. Recent years,it has been a research focus on establishing a reliable ani-mal model in vivo and cytokine release assay( CRA) in vitro to predict CRS for preclinical safety evaluation. In this paper we summarize matters related to CRA applicable objects, considera-tions of method design and method optimization, aiming to pro-vide suggestions for the optimization of CRA prediction platform.

Progress of the study of mechanism on drug induced kidney injury / 药学学报

Drug-induced nephrotoxicity is very common in both new drug development and clinic practice. Various drugs can induce kidney injuries, including tubulointerstitial, glomerular and renal vascular disease. To investigate the mechanism of drug induced nephrotoxicity is important for risk reduction of new drug development, reasonable drug usage, early discovery and effective prevention/treatment of adverse effects in clinics.

Tetrandrine-induced apoptosis in rat primary hepatocytes is initiated from mitochondria: caspases and endonuclease G (Endo G) pathway.

Tetrandrine, a bisbenylisoquinoline alkaloid isolated from the dried root of Stephenia tetrandra (S Moore), possesses a remarkable pharmacological profile. However, the mechanisms of tetrandrine hepatotoxicity remain to be elucidated. In this study, we first proved apoptosis and mitochondrial dysfunction induced by tetrandrine in Sprague-Dawley rat liver in vivo. By further assuming apoptosis as an important mechanism in tetrandrine-induced hepatotoxicity, we focused on mitochondria-initiated apoptosis in primary hepatocytes isolated from Sprague-Dawley male rats. Tetrandrine treatment led to significant release of cytochrome c and downregulation of Bcl-X(L) accompanied by caspase 3 activation, and ultimately, DNA fragmentation. Caspase 3 activation was markedly inhibited by cyclosporin A (CsA) and Ac-DEVD-CHO. Furthermore, Endo G, a caspase-independent apoptotic protein, was detected for its expression and DNase activity. CsA blocked the release both of Endo G and cytochrome c significantly. Additionally, the generation of reactive oxygen species (ROS) increased in a time-dependent manner corresponding with a fall in intracellular GSH content after 10 microM tetrandrine treatment in 4h. Tetrandrine also induced mitochondrial dysfunction indicated by transition of mitochondrial transmembrane potential and decrease of intracellular ATP level. The findings indicated that the caspase-dependent mitochondrial apoptosis pathway was primarily involved in tetrandrine-induced apoptosis in rat primary hepatocytes. In addition, a caspase-independent pathway indicated by Endo G also contributed to apoptosis caused by tetrandrine. Meanwhile, ROS was proved an important inducer in this apoptosis process.