Objective·To evaluate the changes in cognitive function in overweight and obese adolescents,and explore the association between cognitive function and fibroblast growth factor 21(FGF21).Methods·A total of 175 adolescents from a senior high school in Shanghai were divided into normal weight group(n=50),overweight group(n=50)and obese group(n=75)based on their body mass index(BMI).General information,anthropometric data and laboratory testing indicators of the adolescents were collected and compared.The cognitive function of the three groups of adolescents was assessed by using the accuracy(ACC)and reaction time of Flanker task and n-back task.Enzyme-linked immunosorbent assay(ELISA)was used to detect the serum FGF21 level of the three groups of adolescents.Partial correlation analysis and multiple linear regression model were used to evaluate the correlation between cognitive task performance and anthropometric data and laboratory testing indicators.Results·Compared with the normal weight group,systolic blood pressure,diastolic blood pressure,and the levels of fasting plasma glucose,glycosylated hemoglobin and triacylglycerol in the obese group were higher(all P<0.05).Under congruent or incongruent stimulus conditions in the Flanker task,there was no significant difference in ACC between any two groups;compared with the normal weight and overweight groups,the reaction time of the adolescents in the obese group was prolonged(all P<0.05).In the n-back task,there were no significant differences in ACC between any two groups,while the obese group had longer reaction time in the 1-back and 2-back tasks compared to the normal weight and overweight groups(all P<0.05).Compared with the normal weight group,serum FGF21 levels of the adolescents in the obese group were higher(P=0.000).Partial correlation analysis showed that the reaction time of the adolescents in Flanker and n-back tasks was correlated with their BMI,body fat mass,waist circumference,waist-to-hip ratio and FGF21 level(all P<0.05).Multiple linear regression analysis further confirmed that BMI was associated with prolonged reaction time in cognitive-related behavioral tasks in the adolescents(all P<0.05),and FGF21 level was associated with ACC in the 2-back task(P=0.000)and reaction time in the incongruent stimulus condition(P=0.048).Conclusion·Overweight and obese adolescents have cognitive impairments,and BMI and serum FGF21 levels are associated with changes in their cognitive function.

Background and aims:Kehuang(KH)capsule is an herbal medical product approved for the treatment of liver diseases,including liver injury,in China.However,the mechanism is still unclear.This study aimed to elucidate the protective effects of KH capsule against carbon tetrachloride(CCl4)-induced acute liver injury(ALI)in a murine model.Methods:Mice were randomly divided into control,model(CCl4),CCl4+KH_Low and CCl4+KH_High group.Liver enzyme levels and histological changes were assessed to evaluate liver injury.Oxidative stress markers and inflammatory cell infiltration in liver tissues were measured.Additionally,network pharmacology was employed to explore the potential mechanisms of KH capsule.Results:KH capsule significantly reduced serum alanine aminotransferase(ALT)and aspartate amino-transferase(AST)levels,as well as the necrotic area in liver tissue.KH capsule also decreased the infil-tration of macrophages and neutrophils,thereby inhibiting the expression of interleukin-6(IL-6),tumor necrosis factor-alpha(TNF-α),and interleukin-1 beta(IL-1β).Furthermore,KH capsule decreased liver malondialdehyde(MDA)levels and increased superoxide dismutase(SOD)activity.The number of ter-minal deoxynucleotidyl transferase(TdT)-mediated dUTP nick-end labeling(TUNEL)-positive cells in liver tissue was also reduced.The expression of nuclear factor erythroid 2 related factor 2(Nrf2)and heme oxygenase-1(HO-1)proteins was significantly elevated,while the protein expression of cyto-chrome P450 2E1(CYP2E1)was significantly reduced.Mass spectrometry identified genistein,galangin,wogonin,skullcapflavone Ⅱ,and hispidulin as potential active ingredients of KH capsule.Network pharmacology analysis revealed enrichment in the mitogen-activated protein kinase(MAPK)and phosphatidylinositol 3-kinase(PI3K)-protein kinase B(AKT)signaling pathways.Western blot analysis confirmed that KH capsule suppressed AKT,extracellular signal-regulated kinase(ERK),and p38 signaling.Conclusions:These findings suggest that KH capsule could exert protective effects against CCl4-induced ALI,with the inhibition of MAPK and PI3K-AKT signaling pathways playing a crucial role in its mecha-nism of action.

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.

The recent discovery of activator compounds binding to an allosteric site on the NAD