Praeruptorin C alleviates cognitive impairment in type 2 diabetic mice through restoring PI3K/AKT/GSK3ß pathway.

Diabetic encephalopathy is a common consequence of diabetes mellitus that causes cognitive dysfunction and neuropsychiatric disorders. Praeruptorin C (Pra-C) from the traditional Chinese medicinal herb Peucedanum praeruptorum Dunn. is a potential antioxidant and neuroprotective agent. This study was conducted to investigate the molecular mechanisms underlying the effect of Pra-C on diabetic cognitive impairment. A novel object recognition test and the Morris water maze test were performed to assess the behavioral performance of mice. Electrophysiological recordings were made to monitor synaptic plasticity in the hippocampus. A protein-protein interaction network of putative Pra-C targets was constructed, and molecular docking simulations were performed to predict the potential mechanisms of the action of Pra-C. Protein expression levels were detected by western blotting. Pra-C administration significantly lowered body weight and fasting blood glucose levels and alleviated learning and memory deficits in type 2 diabetic mice. Network pharmacology and molecular docking results suggested that Pra-C affects the PI3K/AKT/GSK3ß signaling pathway. Western blot analysis confirmed significant increases in phosphorylated PI3K, AKT, and GSK3ß levels in vivo and in vitro upon Pra-C administration. Pra-C alleviated cognitive impairment in type 2 diabetic mice by activating PI3K/AKT/GSK3ß pathway.

Association between well-characterized gene polymorphisms and the hypnosis response caused by sevoflurane-induced anaesthesia.

WHAT IS KNOWN AND OBJECTIVE: Sevoflurane is the most widely used volatile anaesthetic in clinical practice. It exhibits a hypnotic (unconsciousness) effect and causes a loss of reaction to noxious stimuli (immobility). However, to date, the mechanism of action of sevoflurane is poorly understood. In this study, we explored the effects of genetic variations on sevoflurane-induced hypnosis. METHODS: Sixty-six SNPs in 18 candidate genes were genotyped using MALDI-TOF MassARRAY in a discovery cohort containing 161 patients administered sevoflurane. Significant polymorphisms were assessed in a validation cohort containing 265 patients. RESULTS AND DISCUSSION: Three polymorphisms (GRIN1 rs28681971, rs79901440 and CHRNA7 rs72713539) were significantly associated with the time to loss of consciousness in patients treated with sevoflurane in the discovery cohort; among them, GRIN1 rs28681971 showed a significant association even after false discovery rate (FDR) correction (pFDR  = 0.039). Following the validation analysis, GRIN1 rs28681971 and rs79901440 showed statistical efficacy (pFDR  = 0.027, 0.034). Combined assessments and meta-analysis of the results of the two cohorts indicated that the C carriers of rs28681971 and T carriers of rs79901440 in GRIN1 require a longer time to achieve unconsciousness. WHAT IS NEW AND CONCLUSION: These findings suggest that GRIN1 polymorphisms are associated with sevoflurane-induced unconsciousness. Thus, the genotypes of GRIN1 may serve as novel and meaningful biomarkers for sevoflurane-induced unconsciousness.

Effect of quercetin on CYP3A activity in Chinese healthy participants.

The aims of this study were to investigate the effect of quercetin on CYP3A activity in vivo. An open, randomized, 2-period crossover experiment was performed in 18 healthy male volunteers. Genotyped data were available from a total of 165 participants. The allelic frequency was 52.5%. Every volunteer ingested orally 500 mg quercetin or placebo once a day for 13 consecutive days. On day 14, a single 7.5-mg midazolam tablet was administrated orally. The plasma concentrations of midazolam and 1-OH-midazolam were determined over 24 hours. The results showed that coadministration of quercetin in CYP3A5*1/*1 and CYP3A5*1/*3 individuals significantly decreased the area under the curve (AUC(0-12 h)) of midazolam (160.88 ± 45.58 ng·h/mL vs 188.07 ± 65.75 ng·h/mL, P < .05), significantly decreased the AUC(0-∞) of midazolam (165.46 ± 47.15 ng·h/mL vs 211.84 ± 75.80 ng·h/mL, P < .01), shortened t(1/2) (2.06 ± 0.51 h vs 2.75 ± 0.89 h, P < .01), and decreased t(max) significantly (0.48 ± 0.36 h vs 1.06 ± 0.69 h, P < .01), respectively. In conclusion, quercetin significantly induced CYP3A activity to substrate midazolam, and the induction was partly related to the CYP3A5 genotype, being more prominent in CYP3A5*1/*1 and CYP3A5*1/*3 individuals.