Tanshinone I Induces Mitochondrial Protection through an Nrf2-Dependent Mechanism in Paraquat-TreatedHuman Neuroblastoma SH-SY5Y Cells

Abstract

Tanshinone I (T-I; 1,6-Dimethylnaphtho[1,2-g][1]benzofuran-10,11-dione; CHO), which may be found in Salvia miltiorrhiza Bunge (Danshen), is a potent anti-inflammatory, antioxidant, and anti-cancer agent. At least in part, T-I exerts antioxidant activity by activating signaling pathways associated with the maintenance of the redox state in mammalian cells. In this context, the upregulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) has received attention regarding the role of this transcription factor in modulating the expression of antioxidant enzymes and the metabolism of glutathione (GSH). Even though there is a growing body of evidence suggesting that T-I mediates protection against several pro-oxidant challenges in both in vitro and in vivo experimental models, it remains to be examined whether and how T-I would modulate mitochondrial function during redox disturbances. Therefore, we aimed to reveal whether T-I would exhibit protective effects on mitochondria of SH-SY5Y cells treated with paraquat (PQ), a well-known mitochondrial toxic agent. We found that T-I pretreatment significantly protected mitochondria against PQ-induced redox impairment through an Nrf2-dependent mechanism involving upregulation of antioxidant enzymes, such as Mn-superoxide dismutase (Mn-SOD), glutathione peroxidase (GPx), and both catalytic and modifier subunits of γ-glutamate-cysteine ligase (γ-GCL). T-I prevented complex I and mitochondrial membrane potential (MMP) impairments elicited by PQ. Thus, T-I may be viewed as a new mitochondrial protective agent whose complete mechanism of action needs to be investigated, but it seems to involve mitochondriotropic aspects related to the chemistry of this molecule.

Glutathione homeostasis is significantly altered by quercetin via the Keap1/Nrf2 and MAPK signaling pathways in rats

“…Nrf2 expression plays an important role in modulating the expression of some GSH-related enzymes, especially GCL and GR. ( 50 , 51 ) Nrf2 down-expression blocked the GCL expression induced by isorhamnetin. ( 52 ) Down-expression of Nrf2 also decreased GR activity and mRNA expression, and reduced GSH content in fish gill with amino acid phenylalanine deficiency.…”

The Natural Flavone Acacetin Confers Cardiomyocyte Protection Against Hypoxia/Reoxygenation Injury via AMPK-Mediated Activation of Nrf2 Signaling Pathway

“…Activation of Nrf2 results in the induction of many cytoprotective proteins including HO-1, SOD1, and SOD2, etc. ( Higdon et al, 2012 ; de Oliveira et al, 2017 ). This notion is supported by the present study, in which acacetin activates Nrf2, induces the expression of HO-1, SOD1, and SOD2 and exerts protection of cardiomyocytes against hypoxia/reoxygenation insult.…”

Tanshinone I alleviates motor and cognitive impairments via suppressing oxidative stress in the neonatal rats after hypoxic-ischemic brain damage

“…Although HIBD is a complex multifactorial disease, a growing body of evidence has shown that oxidative damage to vital cellular structures plays a critical role in the pathogenesis of brain damage in both the immature and mature nervous system [ 6 , 41 , 42 ]. Several studies have indicated that TsI is able to exert antioxidative and antiapoptotic effects in cellular and mouse model of Parkinson’s disease (PD) [ 18 , 19 , 43 ]. In full agreement with these findings, we here found that treatment with TsI markedly reversed the decrease of antioxidants and the increase of pro-oxidants induced by HIBD in neonatal rats (Figs.…”

“…5 and 6 ). The exact underlying cellular and molecular mechanisms remain to be determined, but may be at least in part due to the up-regulating effects of TsI on nuclear factor erythroid-2-related factor 2 (Nrf2), since previous studies have supported that the antioxidation of TsI is involved in Nrf2 signaling pathway both in vitro and in mouse model of PD [ 43 , 44 ]. Thus, future experiments examining Nrf2 signaling pathway in neonatal HIBD animals with or without TsI treatment will help determine whether the therapeutic effects of TsI in neonatal HIBD rats can be attributed to its up-regulation of Nrf2.…”