Protective effects of imperatorin against cerebral ischemia/reperfusion-induced oxidative stress through Nrf2 signaling pathway in rats

OBJECTIVE To investigates the effects of imperatorin on the oxidative stress in the cerebral cortex and hippocampus after focal cerebral ischemia/reperfusion injury.METHODS Transient focal cerebral ischemia/reperfusion model in male Sprague-Dawley rats was induced by 2 h middle cerebral artery occlusion followed by 24 h reperfusion.Imperatorin(1.25 and 2.5 mg·kg-1)or vehicle were administered intraperitoneally at 1,5 and 9 h after the onset of ischemia.At 24 h after reperfusion,the biomarkers of oxidative stress such as the levels of reactive oxygen species(ROS),lipid peroxidation products malondialdehyde(MDA),nitric oxide(NO)and total antioxidant capacity(T-AOC),the activities of inducible nitric oxide synthase(iN OS),superoxide dismutase(SOD)and catalase(CAT)in the cerebral cortex and hippocampus were observed.We also assessed the nuclear factor erythroid 2-related factor 2(Nrf2),heme oxygenase-1(HO-1),and the NAD(P)H-quinone oxidoreductase 1(NQO-1)protein expression by Western blot.RESULTS As compared to vehicle-treated animals,imperatorin treatment significantly reduced the ROS,MDA,NO levels and i NOS activity,increased T-AOC and the activities of SOD and CAT.Furthermore,imperatorin treatment also significantly induced the nuclear translocation of Nrf2,enhanced the protein expression of HO-1 and NQO-1 in the cerebral cortex and hippocampus.CONCLUSION Our findings indicate that imperatorin can protect the brain against the excessive oxidative stress induced by cerebral ischemia/reperfusion through activation of Nrf2 signaling pathway.

Complex structure of human Hsp90~N and a novel small inhibitor FS5

Heat shock proteins(Hsps)are a family of abundantly expressed ATP-dependent chaperone proteins.Hsp90 is an eminent member of Hsp family.Thus far,two primary functions have been described for Hsp90:first,as a regulator of conformational change of some protein kinases and nuclear hormone receptors,and the other as an indispensable factor in cellular stress response.Hsp90 has an essential number of interaction proteins since it participates in almost every biological process and its importance is self-evident.Hsp90 has an inextricable relationship in the pathogenesis of cancer,especially in the proliferation and irradiation of cancer cells,thus being a notable cancer target.Since the discovery of geldanamycin,the first inhibitor of Hsp90,from the bacterial species Streptomyces hygroscopicus,even more attention has been focused toward Hsp90.Many structure-based inhibitors of Hsp90 have been designed to develop an innovative method to defeat cancer.However,already designed inhibitors have various deficiencies,such as hepatotoxicity,poor aqueous solubility,instability,and non-ideal oral bioavailability.Based on the aforementioned reasons and to achieve an optimal performance and fewer side effects,we designed a novel inhibitor of Hsp90,called FS5,and resolved the crystal structure of the Hsp90^N-FS5 complex(1.65 A°,PDB code 5XRB).Furthermore,we compared the complexes Hsp90^N,Hsp90^N-GDM,and Hsp90^N-ATP and suggest that the inhibitor FS5 may compete with ATP for binding to Hsp90,which can be regarded as a potential strategy for the development of novel cancer drugs in the future.

Association of food intake with a risk of metabolic dysfunction-associated fatty liver disease:a cross-sectional study

Background:Metabolic dysfunction-associated fatty liver disease(MAFLD)is a common liver disease,the risk of which can be increased by poor diet.The objective of this study was to evaluate the associations between food items and MAFLD,and to propose reasonable dietary recommendations for the prevention of MAFLD.Methods:Physical examination data were collected from April 2015 through August 2017 at Nanping First Hospital(n=3,563).Dietary intakes were assessed using a semi-quantitative food frequency questionnaire.The association between food intake and the risk of MAFLD was assessed by using the inverse probability weighted propensity score.Results:Beverages(soft drinks and sugar-sweetened beverages)and instant noodles were positively associated with MAFLD risk,adjusting for smoking,drinking,tea intake,and weekly hours of physical activity[adjusted odds ratio(ORadjusted):1.568;P=0.044;ORadjusted:4.363;P=0.001].Milk,tubers,and vegetables were negatively associated with MAFLD risk(ORadjusted:0.912;P=0.002;ORadjusted:0.633;P=0.007;ORadjusted:0.962;P=0.028).In subgroup analysis,the results showed that women[odds ratio(OR):0.341,95%confidence interval(CI):0.172–0.676]had a significantly lower risk of MAFLD through consuming more tubers than men(OR:0.732,95%CI:0.564–0.951).Conclusions:These findings suggest that reducing consumption of beverages(soft drinks and sugar-sweetened beverages)and instant noodles,and consuming more milk,vegetables,and tubers may reduce the risk of MAFLD.