Dataset Information

Celastrol targeting Nedd4 reduces Nrf2-mediated oxidative stress in astrocytes after ischemic stroke.

ABSTRACT: 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 astrocytes by inhibiting the interaction between Nedd4 and Nrf2 and reducing Nrf2 degradation in CIRI.

SUBMITTER: Hong Z

PROVIDER: S-EPMC9999302 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Celastrol targeting Nedd4 reduces Nrf2-mediated oxidative stress in astrocytes after ischemic stroke.

Hong Zexuan Z Cao Jun J Liu Dandan D Liu Maozhu M Chen Mengyuan M Zeng Fanning F Qin Zaisheng Z Wang Jigang J Tao Tao T

Journal of pharmaceutical analysis 20230107 2

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 fac ...[more]

PMID: 36908855

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Project description:As many proteins prioritize functionality over constancy of structure, a proteome is the shortest stave in the Liebig's barrel of cell sustainability. In this regard, both prokaryotes and eukaryotes possess abundant machinery supporting the quality of the proteome in healthy and stressful conditions. This machinery, namely chaperones, assists in folding, refolding, and the utilization of client proteins. The functions of chaperones are especially important for brain cells, which are highly sophisticated in terms of structural and functional organization. Molecular chaperones are known to exert beneficial effects in many brain diseases including one of the most threatening and widespread brain pathologies, ischemic stroke. However, whether and how they exert the antioxidant defense in stroke remains unclear. Herein, we discuss the chaperones shown to fight oxidative stress and the mechanisms of their antioxidant action. In ischemic stroke, during intense production of free radicals, molecular chaperones preserve the proteome by interacting with oxidized proteins, regulating imbalanced mitochondrial function, and directly fighting oxidative stress. For instance, cells recruit Hsp60 and Hsp70 to provide proper folding of newly synthesized proteins-these factors are required for early ischemic response and to refold damaged polypeptides. Additionally, Hsp70 upregulates some dedicated antioxidant pathways such as FOXO3 signaling. Small HSPs decrease oxidative stress via attenuation of mitochondrial function through their involvement in the regulation of Nrf- (Hsp22), Akt and Hippo (Hsp27) signaling pathways as well as mitophagy (Hsp27, Hsp22). A similar function has also been proposed for the Sigma-1 receptor, contributing to the regulation of mitochondrial function. Some chaperones can prevent excessive formation of reactive oxygen species whereas Hsp90 is suggested to be responsible for pro-oxidant effects in ischemic stroke. Finally, heat-resistant obscure proteins (Hero) are able to shield client proteins, thus preventing their possible over oxidation.

Dataset Information

Celastrol targeting Nedd4 reduces Nrf2-mediated oxidative stress in astrocytes after ischemic stroke.

Publications

Celastrol targeting Nedd4 reduces Nrf2-mediated oxidative stress in astrocytes after ischemic stroke.

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