SIN-1 cytotoxicity to PC12 cells is mediated by thiol-sensitive short-lived substances generated through SIN-1 decomposition in culture medium

Konishi, Kanako; Watanabe, Nobuo; Arai, Takao

doi:10.1016/j.niox.2009.02.001

Cited by 23 publications

(44 citation statements)

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“…34,35) In physiological conditions, ONOO Ϫ decomposes rapidly to generate hydroxyl radical, one of the most reactive oxygen species. 36) Mounting evidence suggests an involvement of ONOO Ϫ in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). 37) To determine the mechanism by which pretreatment with geniposide increases cell viabilities induced by SIN-1, we determined the effect of geniposide on the expression of HO-1.…”

Section: Discussionmentioning

confidence: 99%

Geniposide Induces the Expression of Heme Oxygenase-1 via PI3K/Nrf2-Signaling to Enhance the Antioxidant Capacity in Primary Hippocampal Neurons

Yin

Liu

Zheng

et al. 2010

Biological & Pharmaceutical Bulletin

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Oxidative stress in brain is emerging as a potential causal factor in aging and age-related neurodegenerative disorders. A large body of evidence shows that induction of endogenous antioxidative proteins seems to be a reasonable strategy for delaying the progression of cell injury. In this study, geniposide upregulates the expression of heme oxygenase-1 (HO-1) to attenuate the cell apoptosis induced by 3-morpholinosydnonimine hydrochloride (SIN-1) in primary cultured hippocampal neurons. Furthermore, geniposide induces the nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) and activation of phosphatidylinositol 3-kinase (PI3K) in the presence of oxidative stress, and both LY294002 (a specific inhibitor of PI3K) and Zinc protoporphyrin (ZnPP, an inhibitor of HO-1) decrease the cytoprotective action of geniposide in hippocampal neurons. Taken together, the novel cytoprotective mechanism of geniposide to antagonize oxidative stress may be involved in PI3K-and Nrf2-mediated upregulation of the antioxidative enzyme HO-1.

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Section: Discussionmentioning

confidence: 99%

Geniposide Induces the Expression of Heme Oxygenase-1 via PI3K/Nrf2-Signaling to Enhance the Antioxidant Capacity in Primary Hippocampal Neurons

Yin

Liu

Zheng

et al. 2010

Biological & Pharmaceutical Bulletin

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“…30 min). 31,32) Preechinulin, which does not confer cytoprotection against SIN-1-induced toxicity, 8) also failed to confer protection against NO-induced toxicity (Fig. 4A).…”

Section: Discussionmentioning

confidence: 98%

“…− / NO generated in the culture medium. 31) Thus, the system is too complicated for a mechanistic study with neoechinulin A. To gain insight into the cytoprotective mechanism of neoechinulin A, we first assessed whether neoechinulin A treatment for 24 h could also confer resistance to other oxidative and/ or nitrosative stressors.…”

Section: ] Supplementation Of a Known Concentration Of Nad(p) H Or Nmentioning

confidence: 99%

Neoechinulin A Imparts Resistance to Acute Nitrosative Stress in PC12 Cells: A Potential Link of an Elevated Cellular Reserve Capacity for Pyridine Nucleotide Redox Turnover with Cytoprotection

Akashi

Shirai

Okada

et al. 2012

Biological & Pharmaceutical Bulletin

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Treatment of PC12 cells with fungus-derived alkaloid neoechinulin A for more than 12 h renders the cells resistant to subsequent superoxide (O 2 )/nitric oxide (NO) insults derived from 3-morpholinosydnonimine (SIN-1). However, the underlying mechanism(s) remains largely unclear. To elucidate the mechanism(s), we assessed the specificity of the cytoprotection afforded by neoechinulin A treatment using other cytocidal stressors and also clarified the resulting cellular alterations, focusing on the antioxidant and metabolic enzymes systems. Neoechinulin A treatment for more than 12 h endowed PC12 cells with significant resistance to transient NO toxicity, but not persistent NO toxicity, bolus H 2 O 2 toxicity, or oxidative insult from the redox cycling quinone menadione. Cellular antioxidant system profiling revealed no substantial potentiation of the activity of any antioxidant enzyme in lysate from the neoechinulin A-treated cells excluding glutathione (GSH) content, which was significantly decreased (>50%), resulting in a proportional compromise in the thiol-reducing activity of the intact cells. In addition, no differences were observed in the activity for any nicotinamide adenine dinucleotide (phosphate) reduced form (NAD(P)H)-generating enzyme, steady-state NAD(P)H/nicotinamide adenine dinucleotide (phosphate) oxidized form (NAD(P) ) ratios, or the levels of total NAD(P)H. Nevertheless, the neoechinulin A-treated intact cells exhibited increased NAD(P)H redox turnover when driven by extracellular tetrazolium. The structurally inactive analog preechinulin failed to protect cells against NO toxicity or induce these alterations, suggesting their link with the cytoprotective mechanism. These results suggest that neoechinulin A, despite disabling the GSH defense system, confers cytoprotection against nitrosative stresses by elevating the cellular reserve capacity for NAD(P)H generation, which could offset crippling of energy-supplying systems due to nitrosative stress.

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“…Whilst some studies show that SOD has a protective effect against SIN-1 due to reaction with O { : 2 and that catalase has no effect (Ishii et al, 1999), other reports have shown that SOD has no protective effect (Lepore et al, 1999) or even exacerbates toxicity (Gergel et al, 1995), and further work has demonstrated that catalase is able to protect against SIN-1 toxicity (Volk et al, 1995). These disparities were recently investigated and Konishi et al (2009) were able to show that cytotoxicity to neuronal PC12 cells is mediated by thiol-sensitive shortlived substances generated through SIN-1 decomposition in media and not just as a result of peroxynitrite toxicity. Furthermore, the type of media in which SIN-1 decomposed had a significant impact upon the toxicity of the secondary species formed (Konishi et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Peroxynitrite stress is exacerbated by flavohaemoglobin-derived oxidative stress in Salmonella Typhimurium and is relieved by nitric oxide

2010

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2 ) and peroxynitrite play key roles in determining the outcome of bacterial infections. In order to survive within the host and allow proliferation within immune cells such as macrophages, Salmonella isolates have a number of inducible proteins that are able to detoxify these highly reactive species, notably the anoxically functioning NO reductase NorVW, and the aerobically functioning flavohaemoglobin, Hmp, which catalyses the reaction between oxygen and NO to produce relatively inert nitrate. However, in the absence of NO but in the presence of reducing substrates and oxygen, O { :2 is generated from Hmp-mediated electron transfer to bound oxygen and may form a variety of further oxidative species. Hence, Hmp expression is under tight negative regulation by the transcription factor NsrR, abolition of which causes an increase in the production of Hmp. In a previous study, this increase in Hmp levels conferred resistance to the nitrosating agent S-nitrosoglutathione but, perhaps surprisingly, the organism became more sensitive to killing by macrophages. Here, we report that an nsrR mutant that constitutively overexpresses Hmp is also hypersensitive to peroxynitrite in vitro. This sensitivity is alleviated by deletion of the hmp gene or pre-incubation of growing bacteria with NO-releasing agents. We hypothesize that Hmp-expressing cells, in the absence of NO, generate reactive oxygen species, the toxicity of which is exacerbated by peroxynitrite in vitro and in macrophages. RT-PCR confirmed that peroxynitrite causes oxidative stress and upregulation of katG and ahpC, whilst hmp and norV expression are affected very little. The katG gene upregulated by peroxynitrite encodes a catalase peroxidase enzyme with wellestablished roles in detoxifying peroxides. Here, we report that KatG is also able to enhance the breakdown of peroxynitrite, suggesting that the protective role of this enzyme may be wider than previously thought. These data suggest that spatial and temporal fluctuations in the levels of NO and reactive oxygen species will have important consequences for bacterial survival in the macrophage. INTRODUCTIONIn parallel with the development of biological nitric oxide (NO) chemistry, peroxynitrite has become a focus for intense research. Peroxynitrite is formed in cells and tissues from the reaction of NO and superoxide (O { :2 ) at near diffusion-controlled rates (Huie & Padmaja, 1993)2 is a product of the immune system but also a by-product of incomplete oxygen respiration and, under normal physiological conditions, is removed by the potent activities of superoxide dismutases (SODs) (Beckman & Koppenol, 1996;Fridovich, 1995;Miao & St Clair, 2009) The peroxynitrite anion (ONOO 2 ) and its conjugate acid (ONOOH) are powerful nitrating and oxidizing agents, resulting in protein and lipid nitration and extensive damage to critical macromolecules. Previous studies have shown that peroxynitrite, generated within a macrophage from NO synthase-derived NO and O { : 2 generated in the respiratory burst, is able to reac...

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SIN-1 cytotoxicity to PC12 cells is mediated by thiol-sensitive short-lived substances generated through SIN-1 decomposition in culture medium

Cited by 23 publications

References 58 publications

Geniposide Induces the Expression of Heme Oxygenase-1 via PI3K/Nrf2-Signaling to Enhance the Antioxidant Capacity in Primary Hippocampal Neurons

Geniposide Induces the Expression of Heme Oxygenase-1 via PI3K/Nrf2-Signaling to Enhance the Antioxidant Capacity in Primary Hippocampal Neurons

Neoechinulin A Imparts Resistance to Acute Nitrosative Stress in PC12 Cells: A Potential Link of an Elevated Cellular Reserve Capacity for Pyridine Nucleotide Redox Turnover with Cytoprotection

Peroxynitrite stress is exacerbated by flavohaemoglobin-derived oxidative stress in Salmonella Typhimurium and is relieved by nitric oxide

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