The influence of NQO2 on the dysfunctional autophagy and oxidative stress induced in the hippocampus of rats and in SH‐SY5Y cells by fluoride

Abstract

Introduction For investigating the mechanism of brain injury caused by chronic fluorosis, this study was designed to determine whether NRH:quinone oxidoreductase 2 (NQO2) can influence autophagic disruption and oxidative stress induced in the central nervous system exposed to a high level of fluoride. Methods Sprague–Dawley rats drank tap water containing different concentrations of fluoride for 3 or 6 months. SH‐SY5Y cells were either transfected with NQO2 RNA interference or treated with NQO2 inhibitor or activator and at the same time exposed to fluoride. The enrichment of gene signaling pathways related to autophagy was evaluated by Gene Set Enrichment Analysis; expressions of NQO2 and autophagy‐related protein 5 (ATG5), LC3‐II and p62, and mammalian target of rapamycin (mTOR) were quantified by Western‐blotting or fluorescent staining; and the levels of malondialdehyde (MDA) and superoxide dismutase (SOD) assayed biochemically and reactive oxygen species (ROS) detected by flow cytometry. Results In the hippocampal CA3 region of rats exposed to high fluoride, the morphological characteristics of neurons were altered; the numbers of autophagosomes in the cytoplasm and the levels of NQO2 increased; the level of p‐mTOR was decreased, and the levels of ATG5, LC3‐II and p62 were elevated; and genes related to autophagy enriched. In vitro, in addition to similar changes in NQO2, p‐mTOR, ATG5, LC3 II, and p62, exposure of SH‐SY5Y cells to fluoride enhanced MDA and ROS contents and reduced SOD activity. Inhibition of NQO2 with RNAi or an inhibitor attenuated the disturbance of the autophagic flux and enhanced oxidative stress in these cells exposed to high fluoride. Conclusion Our findings indicate that NQO2 may be involved in regulating autophagy and oxidative stress and thereby exerts an impact on brain injury caused by chronic fluorosis.

Depletion of muscularis macrophages ameliorates inflammation-driven dysmotility in murine colitis model

“…It also was identified as one of the most prominent factors involved in neurodegeneration 50 , 51 , whereas Atf4 was reported as an unequivocally prodeath neuronal transcriptional factor, strongly implicated in Parkinson’s disease 52 , 53 , similarly to Egr1 54 , 55 . ROS-activation driven overexpression of Nqo2 has been identified in preclinical model and neuropsychiatric disorders 56 , 57 . Hdac4 was reported to play a pivotal role in the pathogenesis of ischemic stroke and post-stroke recovery by affecting neuronal death, angiogenesis, and neurogenesis 58 .…”

Depletion of Muscularis Macrophages Ameliorates Inflammation- driven Dysmotility in Murine Colitis Model

“…It also was identi ed as one of the most prominent factors involved in neurodegeneration [43,44], whereas Atf4 was reported as an unequivocally prodeath neuronal transcriptional factor, strongly implicated in Parkinson's disease [45,46], similarly to Egr1 [47,48]. ROSactivation driven overexpression of Nqo2 has been identi ed in preclinical model and neuropsychiatric disorders [49,50]. Hdac4 was reported to play a pivotal role in the pathogenesis of ischemic stroke and post-stroke recovery by affecting neuronal death, angiogenesis, and neurogenesis [51].…”

Polymorphisms and Pharmacogenomics of NQO2: The Past and the Future

“…The toxifying function of NQO2, anticipated in the introduction, was first described in the case of menadione [39], then for a series of substrates and other unrelated compounds [11,13,40,41]. For example, it was reported that NQO2 mediates the generation of ROS by acetaminophen, and thus its toxicological side-effects [42], leading to a new concept that NQO2, despite its reductase capacity, might have been under special circumstances an enzyme that indirectly leads to the enhancement of ROS production.…”