Stroke is the second leading cause of death worldwide,and oxidative stress plays a crucial role.Celastrol exhibits strong antioxidant properties in several diseases;however,whether it can affect oxidation in cerebral ischemic-reperfusion injury(CIRI)remains unclear.This study aimed to determine whether celastrol could reduce oxidative damage during CIRI and to elucidate the underlying mechanisms.Here,we found that celastrol attenuated oxidative injury in CIRI by upregulating nuclear factor E2-related factor 2(Nrf2).Using alkynyl-tagged celastrol and liquid chromatography-tandem mass spectrometry,we showed that celastrol directly bound to neuronally expressed developmentally downregulated 4(Nedd4)and then released Nrf2 from Nedd4 in astrocytes.Nedd4 promoted the degradation of Nrf2 through K48-linked ubiquitination and thus contributed to astrocytic reactive oxygen species production in CIRI,which was significantly blocked by celastrol.Furthermore,by inhibiting oxidative stress and astrocyte activation,celastrol effectively rescued neurons from axon damage and apoptosis.Our study uncovered Nedd4 as a direct target of celastrol,and that celastrol exerts an antioxidative effect on as-trocytes by inhibiting the interaction between Nedd4 and Nrf2 and reducing Nrf2 degradation in CIRI.

Objective:To explore the relationship between executive functioning and community integration after a traumatic brain injury and to identify the main factors influencing community integration.Methods:A cross-sectional study of 30 traumatic brain injury survivors was conducted recording their gender, age, years of education, days in coma, living status and mobility. Their executive functioning was assessed using the Disorders of Executive Function Questionnaire (DEX) and the Wisconsin Card Sorting Test (WCST). Their community integration was evaluated using the Community Integration Questionnaire (CIQ). The independent correlations of demographic characteristics, life status, mobility and executive functioning with CIQ score were quantified.Results:The average total CIQ score was negatively correlated with the average WCST-RP, DEX and WCST-RPE scores, but it was positively correlated with mobility. It was also significantly correlated with life status. DEX scores and WCST-RP scores were significant independent predictors of community integration. The average CIQ family integration score was negatively correlated with days spent in a coma and significantly correlated with living status. The average CIQ social integration score was positively correlated with mobility (and negatively correlated with DEX, WCST-RP and WCST-RPE score. WCST-RP score and mobility were significant independent predictors of CIQ social integration scores. The average CIQ productive activity scores correlated negatively with the DEX, WCST-RP and WCST-RPE scores, and with the DEX and WCST-RP executive function scores. They were significant independent predictors of CIQ productive activity scores.Conclusions:Executive functioning can predict community integration, especially its social integration dimension.