Nitroxide Tempol down-regulates kinase activities associated with NADPH oxidase function in phagocytic cells and potentially decreases their fungicidal response

Santos, Gérsika Bitencourt; Ribeiro, Ana Carolina Guimarães; Lima, Samuel Nuno Pereira; Trostchansky, Andrés; Cerdeira, Cláudio Daniel; Brigagão, Maı́sa Ribeiro Pereira Lima

doi:10.1016/j.cbi.2017.11.016

Cited by 6 publications

(2 citation statements)

References 44 publications

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“…Tempol blocked the release of cytokines from cultured human umbilical vein endothelial cells challenged with macrophage chemotactic protein-1 or interleukin-6 [21]; reduced the pleural exudation and the polymorphonuclear cell migration in a rat carrageenan-induced model of pleurisy [22] and reduced the inflammation in a rodent model of periodontitis [23]. Recently, Santos, Ribeiro and collaborators (2018) also reported that Tempol inhibited neutrophil kinase activities in phagocytic cells [24]. According to Gomez-Pinilla and collaborators (2010), the reduction in the expression of inflammatory markers observed after Tempol treatment makes this antioxidant a good candidate to be tested as a non-steroidal anti-inflammatory drug [25].…”

Section: Discussionmentioning

confidence: 99%

Tempol treatment shows phenotype improvement in mdx mice

Hermes¹,

Mâncio²,

Macedo³

et al. 2019

PLoS ONE

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Considering potential Tempol effects on mdx muscle fibers, in this study we evaluated its effects on relevant dystrophic phenotypic characteristics, such as muscle degeneration, inflammatory process and angiogenesis, which as yet have not been investigated. Mdx mice were randomly assigned into three groups: mdxS , the control group receiving intraperitoneal (i.p.) injections of saline solution (100μL); mdxP , positive control group receiving prednisolone (1mg/kg) by oral gavage; and mdx T, treated group receiving i.p. injections of tempol (100 mg/kg). C57BL/10 mice were also used as controls. Tempol treatment promoted gain in muscle strength and reduced myonecrosis and inflammatory response in the dystrophic diaphragm (DIA) and biceps brachii (BB) muscles. No evidence of Tempol's beneficial performance on angiogenesis in DIA and BB mdx muscles was found. The findings presented here show that Tempol treatment improves dystrophic phenotype, supporting its use as a potential therapeutic strategy in DMD.

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Section: Discussionmentioning

confidence: 99%

Tempol treatment shows phenotype improvement in mdx mice

Hermes¹,

Mâncio²,

Macedo³

et al. 2019

PLoS ONE

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“…However, since we have not quantified renal clearance for this study, other possibilities for the brief antifungal effect need to be considered. It has previously been shown that tempol affects phagocyte activities in vitro , such as release of DNA traps and kinase activity important for ROS generation (Hosseinzadeh et al, 2012; Santos et al, 2018). As these effects directly hamper phagocyte antifungal activity, tempol treatment could lead to ineffective fungal clearance at later time points.…”

Section: Discussionmentioning

confidence: 99%

Stable Redox-Cycling Nitroxide Tempol Has Antifungal and Immune-Modulatory Properties

et al. 2019

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Invasive mycoses remain underdiagnosed and difficult to treat. Hospitalized individuals with compromised immunity increase in number and constitute the main risk group for severe fungal infections. Current antifungal therapy is hampered by slow and insensitive diagnostics and frequent toxic side effects of standard antifungal drugs. Identification of new antifungal compounds with high efficacy and low toxicity is therefore urgently required. We investigated the antifungal activity of tempol, a cell-permeable nitroxide. To narrow down possible mode of action we used RNA-seq technology and metabolomics to probe for pathways specifically disrupted in the human fungal pathogen Candida albicans due to tempol administration. We found genes upregulated which are involved in iron homeostasis, mitochondrial stress, steroid synthesis, and amino acid metabolism. In an ex vivo whole blood infection, tempol treatment reduced C. albicans colony forming units and at the same time increased the release of pro-inflammatory cytokines, such as interleukin 8 (IL-8, monocyte chemoattractant protein-1, and macrophage migration inhibitory factor). In a systemic mouse model, tempol was partially protective with a significant reduction of fungal burden in the kidneys of infected animals during infection onset. The results obtained propose tempol as a promising new antifungal compound and open new opportunities for the future development of novel therapies.

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Synthesis and Characterization of Two Chiral Pyrrolyl α-Nitronyl Nitroxide Radicals and Determination of their Cytotoxicity and Radioprotective Properties in C6 Cells and Mice under Ionizing Radiation

et al. 2019

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In this study, two chiral nitronyl nitroxyl radicals, L1 and D1, were synthesized and evaluated for their potential radioprotective properties invitro and invivo. We synthesized the new stable nitronyl nitroxide radicals, L1 and D1, according to Ullman’s method, and their chemical structures were characterized using UV-vis absorption, electron spin resonance (ESR), and circular dichroism (CD) spectra. The cytotoxicity of L1 and D1 on C6 glioma cells (C6 cells) was examined using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. To study the anti-radiation effects of L1 and D1 on C6 cells, we determined the optical density (OD) values of irradiated C6 cells using the MTT assay. The effects of L1 and D1 on the survival rate of mice after radiation exposure was evaluated. To demonstrate the influence of L1 and D1 pre-treatment on the antioxidant enzyme system, we studied the activities of superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and glutathione peroxidase (GSH) in mouse plasma after exposure to 6.5 Gy gamma radiation. The results showed that L1 and D1 did not have any obvious cytotoxicity at concentrations below 125μgmL−1. Moreover, L1 and D1 had the same cytotoxic effects on C6 cells. L1 and D1 significantly enhanced C6 cell survival after 8, 10, and 12 Gy radiation exposure, and there was no significant difference in the OD values between L1 and D1. The effects of these drugs on mouse survival rates were dose-dependent. Pre-treatment with different concentrations of L1, D1, or WR2721 significantly increased the activity of SOD, CAT, and GSH and significantly decreased the activity of MDA compared with radiation exposure only. In addition, the activities of SOD, CAT, and GSH in the L1 group were higher than those in the D1 group, whereas the activity of MDA was lower. Therefore, L1 and D1 have potential as safe and efficient therapeutic drugs against radiation damage.

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Nitroxide Tempol down-regulates kinase activities associated with NADPH oxidase function in phagocytic cells and potentially decreases their fungicidal response

Cited by 6 publications

References 44 publications

Tempol treatment shows phenotype improvement in mdx mice

Tempol treatment shows phenotype improvement in mdx mice

Stable Redox-Cycling Nitroxide Tempol Has Antifungal and Immune-Modulatory Properties

Synthesis and Characterization of Two Chiral Pyrrolyl α-Nitronyl Nitroxide Radicals and Determination of their Cytotoxicity and Radioprotective Properties in C6 Cells and Mice under Ionizing Radiation

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