Blocking the Mineralocorticoid Receptor Improves Cognitive Impairment after Anesthesia/Splenectomy in Rats.

Recent mounting studies showed that neuroinflammation caused by surgery or anesthesia is closely related to postoperative cognitive dysfunction (POCD). This study investigated the effect of mineralocorticoid receptor (MR) on neuroinflammation and POCD. To detect the MR effect in an animal model, we randomly divided rats into control, anesthesia, and surgery groups. To determine whether the MR-specific blocker eplerenone (EPL) could improve cognitive dysfunction, we assigned other animals into the control, surgery and EPL treatment, and surgery groups. Cognitive function was detected using the Morris water maze. Serum cytokine levels were measured by ELISA, and the histopathological changes of hippocampal neurons were identified by hematoxylin/eosin and Nissl staining. Our research confirmed that anesthesia and surgical stimulation could lead to IL-1ß, IL-6, and TNF-α activation and hippocampal neuronal degeneration and pathological damage. MR was upregulated in the hippocampus under cognitive impairment condition. Additionally, EPL could alleviate inflammatory activation and neuronal damage by exerting neuroprotective effects. The preclinical model of sevoflurane anesthesia/splenectomy implied that MR expression is upregulated by regulating the neuroinflammation in the brain under POCD condition. Manipulating the MR expression by EPL could improve the inflammation activation and neuronal damage.

The synthesis and anti-tumour properties of novel 4-substituted phthalazinones as Aurora B kinase inhibitors.

A series of novel 4-substituted phthalazinones as Aurora B kinase inhibitors was synthesized and evaluated the anti-proliferative activities against A549, HCT116, MCF-7 and HepG2 cells. 1-(4-(2-((4-Oxo-3,4-dihydrophthalazin-1-yl)amino)ethyl) phenyl)-3-(3-(trifluoromethyl)phenyl)urea (17b) exhibited the most potent anti-proliferative activity against HCT116 cells with IC50 value of 4.35 ± 1.21 µM, as well as the moderate Aurora B inhibitory activity with the IC50 value of 142 nM. Furthermore, 17b inhibited the phosphorylation of Aurora B on Thr232, leading to cell cycle arrest in the G2/M phase by down-regulating the expression of CyclinB1 and Cdc2 proteins, and apoptosis by up-regulating the expression of BAD and Bax proteins in HCT116 cells. In addition, a docking study revealed that 17b could form key hydrogen bonds with Ala173, Glu171 and Glu177 in Aurora B. All the results reveal that 17b is worthy of further development as an Aurora B kinase inhibitor.