Nobiletin Alleviates Astrocyte Activation and Oxidative Stress Induced by Hypoxia In Vitro

Abstract

Increasing evidence indicates that nobiletin (NOB) is a promising neuroprotective agent. Astrocyte activation plays a key role in neurodegenerative disorders. Thus, this study aims to investigate the effects of NOB on astrocyte activation and the potential mechanisms. In this study, astrocytes were exposed to hypoxia injury for 24 h to induce activation in vitro. Glial fibrillary acidic protein (GFAP) was chosen as a marker of astrocyte activation. To evaluate the effects of NOB on the migration of activated astrocytes, we used a scratch wound healing assay and Transwell migration assay. In addition, the levels of reactive oxygen species (ROS), malondialdehyde (MDA), mitochondrial membrane potential, Nrf2 and HO-1 were measured to investigate the mechanisms of NOB in the activation of astrocytes. We found that NOB alleviated astrocyte activation and decreased GFAP expression during hypoxia. Simultaneously, NOB alleviated the migration of astrocytes induced by hypoxia. With NOB treatment, hypoxia-induced oxidative stress was partially reversed, including reducing the production of ROS and MDA. Furthermore, NOB significantly improved the mitochondrial dysfunction in activated astrocytes. Finally, NOB promoted Nrf2 nuclear translocation and HO-1 expression in response to continuous oxidative damage. Our study indicates, for the first time, that NOB alleviates the activation of astrocytes induced by hypoxia in vitro, in part by ameliorating oxidative stress and mitochondrial dysfunction. This provides new insights into the neuroprotective effects of NOB.

Nobiletin alleviates cisplatin-induced ototoxicity via activating autophagy and inhibiting NRF2/GPX4-mediated ferroptosis

“…Excessive ROS could lead to the disruption or depletion of antioxidant defense system and damage the function of antioxidant enzymes, such as SOD, simultaneously creating lipid peroxides, such as 4-HNE 31 . Nobiletin was previously reported to mitigate oxidative stresses in response to diverse stimuli 32 , 33 . In our study, the results of DCFH-DA staining showed that nobiletin considerably decreased the production of intracellular ROS triggered by cisplatin.…”

“…Previous studies have demonstrated that NRF2 contributes to the regulation of antioxidant enzymes and plays cytoprotective roles to resist oxidative stresses 43 , while the transcriptional activation of NRF2 safeguarded auditory cells against cisplatin-elicited ototoxicity 44 , 45 . Numerous studies have shown that nobiletin activated NRF2 signaling pathway to resist oxidative stress triggered by hypoxia and nonalcoholic fatty liver diseases 32 , 33 . Furthermore, nobiletin has been demonstrated to directly augment the expression of NRF2 and HMOX1, even under physiological conditions in the absence of oxidative stress or mitochondrial dysfunction 46 .…”

Astrocytes as a Therapeutic Target in Alzheimer’s Disease–Comprehensive Review and Recent Developments

“…These effects involve increasing levels of superoxide dismutase (SOD), catalase and GSH peroxidase [ 189 ]. Nobiletin, a polymethoxylated flavone derived from citrus peels, and resveratrol, a polyphenol present in grapes, promote HO-1 upregulation, an antioxidant which is associated with decline in ROS, reduction in astrocytic GFAP, and improved mitochondrial function [ 190 , 191 , 192 ]. Another study found that curcumin, a phenolic compound present in the Curcuma longa plant, might counteract some effects of oxidative stress such as mitochondrial dysfunction and astrogliosis [ 193 ].…”

Nobiletin Ameliorates Aging of Chicken Ovarian Prehierarchical Follicles by Suppressing Oxidative Stress and Promoting Autophagy

“…Nob was able to regulate oxidative stress and mitochondrial dysfunction to reduce liver inflammation and cell death [ 23 ]. Furthermore, Nob could alleviate hypoxia-induced oxidative stress, reduce ROS and malonaldehyde (MDA) production, and significantly improve mitochondrial dysfunction [ 24 ]. Increasing studies have shown that the protective effect of Nob on cells is achieved through the regulation of autophagy and the alleviation of inflammatory response.…”