[Abst ract] Objective To explore the relationship between expression of S100B in hippocampus of depression model rats induced by chronic stress and its depression like behavior,and the antidepressant effect of fluoxetine.Methods 40 rats were put into control group,fluoxetine group,CUS group and CUS plus fluoxetine group,using random number table.Rats in each groups received corresponding treatment.Chronic unpredictable stresses (CUS) were performed on rats for 42 days.Fluoxetine (5 mg/(kg · d)) were delivered to rats by intragastric administration from day 22 to day 42.Then,S100B protein were marked and observed by immunohistochemical method.Open-field test,sucrose consumption and body weight were used to evaluate behavioral changes.Results Scores in behavioral test were reduced significantly by 42 days of stress (main effects of stress,P＜0.05).Effects of stress on behavioral scores were reversed by 21 days fluoxetine treatment (interactions,P＜0.05).CUS resulted in elevated expression of S100B in CA1,CA3 and DG sub-regions in experimental rats (OD values,CUS,0.331 ±0.01,0.353 ± 0.01,0.381 ± 0.007 ; control,0.238 ± 0.007,0.237 ± 0.010,0.228 ± 0.006.Simple effects of stress,P=0.000; P=0.000; P=0.000).Fluoxetine treatment reversed the elevated expression of S100B in CA1,CA3 and DG sub-regions in model rats (OD values:CUS plus fluoxetine,0.233 ± 0.015,0.240 ± 0.005,0.254± 0.015; fluoxetine,0.241±0.007,0.233±0.013,0.227±0.017; Interactions between fluoxetine and CUS,P=0.000; P=0.000; P=0.000).Conclusion Sub-regional over expression of S 100B in hippocampus is associated with depression like behavior of rats.Reversed S100B expression in these sub-regions is an indicator of effective antidepressant treatment but not a mechanism for it.

Qi She Pill (QSP) is a traditional Chinese medicine (TCM) prescription that has been used in treating cervical spondylosis radiculopathy for many years. In this study, a simple and sensitive method using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) on a reverse-phase C18 column was developed for the simultaneous determination of the 19 major components in QSP. We found that the optimum mobile phase for gradient elution was 0.1% formic acid and methanol. The correlation coefficients of all calibration curves were greater than 0.99. Recoveries measured at three concentration levels varied from 95.43% to 102.35%. Relative standard deviations of intra- and inter-day precisions were less than 4.45%. After successfully validating our method, we then applied it to the quantification of 19 components in QSP products to show that this method provides a new standard in quality assessment of TCM prescriptions containing multiple bioactive components.

SIRT6 belongs to the conserved NAD⁺-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD⁺. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC₅₀ of 2.33 μmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.