The Neuroprotection of Hydrogen Sulfide Against MPTP-Induced Dopaminergic Neuron Degeneration Involves Uncoupling Protein 2 Rather Than ATP-Sensitive Potassium Channels

Lu, Ming; Zhao, Fangfang; Tang, Juanjuan; Su, Cunjin; Fan, Yi; Ding, Jingzhong; Bian, Jin-Song; Hu, Gang

doi:10.1089/ars.2011.4507

Cited by 79 publications

(59 citation statements)

References 38 publications

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“…nervous system (1). We proved that H 2 S exerted a wide range of biological functions, including neuroprotection (8,14), cardioprotection (20,21), antihypertension (13), and osteoblastic protection (37). Most of these functions are attributed to its antioxidant effects.…”

Section: Innovationmentioning

confidence: 84%

“…The mechanisms include suppression of membrane oxidase activity [e.g., NADPH oxidase (37) and glutathione peroxidase (12)], inhibition of reactive oxygen species (ROS) production, and stimulation of synthesis of ROS scavengers [e.g., superoxide dismutase (11) and glutathione (9)]. Recently, we demonstrated that H 2 S protected dopaminergic neurons against degeneration in a mitochondrial uncoupling protein 2-mediated antioxidative mechanism (14), indicating a direct effect of H 2 S on mitochondrial oxidative stress formation. However, the exact action site of H 2 S and its molecular mechanisms is still in need of further exploration.…”

Section: Innovationmentioning

confidence: 99%

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Sulfhydration of p66Shc at Cysteine59 Mediates the Antioxidant Effect of Hydrogen Sulfide

Xie

Shi²,

Xie³

et al. 2014

Antioxidants & Redox Signaling

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113

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Aims: Mitochondrion is considered as the major source of intracellular reactive oxygen species (ROS). H 2 S has been reported to be an antioxidant, but its mechanism remains largely elusive. P66Shc is an upstream activator of mitochondrial redox signaling. The aim of this study was to explore whether the antioxidant effect of H 2 S is mediated by p66Shc. Results: Application of exogenous H 2 S with its donor, NaHS, or overexpression of its generating enzyme, cystathionine b-synthase, induced sulfhydration of p66Shc, but inhibited its phosphorylation caused by H 2 O 2 /D-galactose in SH-SY5Y cells or in the mice cortex. H 2 S also decreased mitochondrial ROS production and protected neuronal cells against stress-induced senescence. PKC bII and PP2A are the two key proteins to regulate p66Shc phosphorylation. Although H 2 S failed to affect the activities of these two proteins, it disrupted their association. Cysteine-59 resides in proximity to serine-36, the phosphorylation site of p66Shc. The C59S mutant attenuated the above-described biological function of H 2 S. Innovation: We revealed a novel mechanism for the antioxidant effect of H 2 S and its role in oxidative stress-related diseases. Conclusion: H 2 S inhibits mitochondrial ROS production via the sulfhydration of Cys-59 residue, which in turn, prevents the phosphorylation of p66Shc. Antioxid. Redox Signal. 21, 2531-2542.

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Section: Innovationmentioning

confidence: 84%

Section: Innovationmentioning

confidence: 99%

Sulfhydration of p66Shc at Cysteine59 Mediates the Antioxidant Effect of Hydrogen Sulfide

Xie

Shi²,

Xie³

et al. 2014

Antioxidants & Redox Signaling

Self Cite

113

View full text Add to dashboard Cite

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“…In particular, recent reports suggest that H 2 S acts as a neuromodulator in brain, in which it is involved in the regulation of the processes of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease [11]. In line with these evidence, a reduction in endogenous H 2 S in the striatum appears to be responsible for the onset of Parkinson's disease and that exogenous H 2 S treatment results in attenuation of DA neuronal degeneration in a mouse model of Parkinson's disease [12][13][14][15]. These findings suggest a neuroprotective effect of H 2 S during the neural injury of Parkinson's disease.…”

Section: Introductionmentioning

confidence: 83%

Involvement of microRNA-135a-5p in the Protective Effects of Hydrogen Sulfide Against Parkinson's Disease

Liu

Liao

Quan

et al. 2016

Cell Physiol Biochem

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Background/Aims: Development of effective therapeutic drugs for Parkinson's disease is in great need. During the progression of Parkinson's disease, Rho-associated protein kinase 2 (ROCK2) is activated to promote neurodegeneration. Hydrogen sulfide (H₂S) has a neuroprotective effect during the neural injury of Parkinson's disease. However, the mechanisms that underlie the effects of ROCK2 and H₂S remain ill-defined. In the current study, we addressed these questions. Methods: We used a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse subacute model of Parkinson's disease to study the effects of H₂S on astrocytic activation in the mouse striatum, on the levels of tyrosine-hydroxylase (TH)-positive neuron loss, on the apomorphine-induced rotational behavior of the mice, and on the changes in ROCK2 and miR-135a-5p expression. Plasmid transfection was applied to modify miR-135a-5p levels in a neuronal cell line HCN-1A. Bioinformatics analysis was performed to predict the relationship between ROCK2 and miR-135a-5p in neuronal cells, and then was confirmed by luciferase reporter assay. Results: H₂S alleviated MPTP-induced astrocytic activation in the mouse striatum, alleviated the increases in TH-positive neuron loss, and improved the apomorphine-induced rotational behavior of the mice. H₂S significantly attenuated the increases in ROCK2 and the decreases in miR-135a-5p by MPTP. MiR-135a-5p targeted the 3'-UTR of ROCK2 mRNA to inhibit its translation in neuronal cells. Conclusion: MiR-135a-5p-regulated ROCK2 may play a role in the protective effects of hydrogen sulfide against Parkinson's disease.

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“…Despite the fact that H 2 S is recognized to be neuroprotective [12,13] and serves as a protective mediator for various tissues [14][15][16], the similar function of bound sulfur is not well known. Therefore, further study is required to resolve the individual mechanisms by which H 2 S and bound sulfur may perform physiological roles.…”

Section: Introductionmentioning

confidence: 99%

Polysulfide exerts a protective effect against cytotoxicity caused by t‐buthylhydroperoxide through Nrf2 signaling in neuroblastoma cells

et al. 2013

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a b s t r a c tPolysulfide is a bound sulfur species derived from endogenous H 2 S. When mouse neuroblastoma, Neuro2A cells were exposed to tert-butyl hydroperoxide after treatment with polysulfide, a significant decline in cell toxicity was observed. Rapid uptake of polysulfides induced translocation of Nrf2 into the nucleus, resulting in acceleration of GSH synthesis and HO-1 expression. We demonstrated that polysulfide reversibly modified Keap1 to form oxidized dimers and induced the translocation of Nrf2. Moreover, polysulfide treatment accelerated Akt phosphorylation, which is a known pathway of Nrf2 phosphorylation. Thus, polysulfide may mediate the activation of Nrf2 signaling, thereby exerting protective effects against oxidative damage in Neuro2A cells.

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The Neuroprotection of Hydrogen Sulfide Against MPTP-Induced Dopaminergic Neuron Degeneration Involves Uncoupling Protein 2 Rather Than ATP-Sensitive Potassium Channels

Abstract: H(2)S protects DA neurons against degeneration in a UCP2 rather than Kir6.2/K-ATP channel-dependent mechanism, which will give us an insight into the potential of H(2)S in terms of opening up new therapeutic avenues for PD.

Cited by 79 publications

References 38 publications

Sulfhydration of p66Shc at Cysteine59 Mediates the Antioxidant Effect of Hydrogen Sulfide

Sulfhydration of p66Shc at Cysteine59 Mediates the Antioxidant Effect of Hydrogen Sulfide

Involvement of microRNA-135a-5p in the Protective Effects of Hydrogen Sulfide Against Parkinson's Disease

Polysulfide exerts a protective effect against cytotoxicity caused by t‐buthylhydroperoxide through Nrf2 signaling in neuroblastoma cells

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