Mito-TEMPO, a mitochondria-targeted antioxidant, prevents N-nitrosodiethylamine-induced hepatocarcinogenesis in mice

Shetty, Shricharith; Kumar, Rajesh; Bharati, Sanjay

doi:10.1016/j.freeradbiomed.2019.03.037

Cited by 46 publications

(21 citation statements)

References 66 publications

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“…Many antioxidants exhibit anti-carcinogenic activity in experimental models. Antioxidants may be used for the prevention of arsenic-induced carcinogenesis, NDMA-induced hepatocellular carcinogenesis, and NDEA-induced esophageal carcinogenesis ( Hei & Filipic, 2004 ; Shetty, Kumar, & Bharati, 2019 ; Shi, Godschalk, & van Schooten, 2017 ). Tocopherols, a form of vitamin E, have been suggested to have antioxidant properties, including ability to physically trap nitrogen species leading to protection in an AOM/DSS model of colon carcinogenesis ( Bansal et al, 2005b ; Ju et al, 2009 ; Lambert et al, 2009 ; Lee, Ju, et al, 2009 ).…”

Section: Mechanisms Of Pro-tumorigenic Activity By Carcinogensmentioning

confidence: 99%

Carcinogenesis: Failure of resolution of inflammation?

Fishbein

Hammock

Serhan

et al. 2021

Pharmacology & Therapeutics

129

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Inflammation in the tumor microenvironment is a hallmark of cancer and is recognized as a key characteristic of carcinogens. However, the failure of resolution of inflammation in cancer is only recently being understood. Products of arachidonic acid and related fatty acid metabolism called eicosanoids, including prostaglandins, leukotrienes, lipoxins, and epoxyeicosanoids, critically regulate inflammation, as well as its resolution. The resolution of inflammation is now appreciated to be an active biochemical process regulated by endogenous specialized pro-resolving lipid autacoid mediators which combat infections and stimulate tissue repair/regeneration. Environmental and chemical human carcinogens, including aflatoxins, asbestos, nitrosamines, alcohol, and tobacco, induce tumor-promoting inflammation and can disrupt the resolution of inflammation contributing to a devastating global cancer burden. While mechanisms of carcinogenesis have focused on genotoxic activity to induce mutations, nongenotoxic mechanisms such as inflammation and oxidative stress promote genotoxicity, proliferation, and mutations. Moreover, carcinogens initiate oxidative stress to synergize with inflammation and DNA damage to fuel a vicious feedback loop of cell death, tissue damage, and carcinogenesis. In contrast, stimulation of resolution of inflammation may prevent carcinogenesis by clearance of cellular debris via macrophage phagocytosis and inhibition of an eicosanoid/cytokine storm of pro-inflammatory mediators. Controlling the host inflammatory response and its resolution in carcinogen-induced cancers will be critical to reducing carcinogen-induced morbidity and mortality. Here we review the recent evidence that stimulation of resolution of inflammation, including pro-resolution lipid mediators and soluble epoxide hydrolase inhibitors, may be a new chemopreventive approach to prevent carcinogen-induced cancer that should be evaluated in humans.

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Section: Mechanisms Of Pro-tumorigenic Activity By Carcinogensmentioning

confidence: 99%

Carcinogenesis: Failure of resolution of inflammation?

Fishbein

Hammock

Serhan

et al. 2021

Pharmacology & Therapeutics

129

View full text Add to dashboard Cite

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“…Therefore, we evaluated the potential role of mitochondria in heme-mediated EC death. Staining with the mROS indicator MitoSOX [ 34 ] revealed that heme-mediated up-regulation of mROS is blocked by A1AT, as similarly observed for the mitochondria-specific superoxide scavenger mito-TEMPO [ 35 ] ( Fig. 4 A).…”

Section: Resultsmentioning

confidence: 61%

Alpha1-antitrypsin counteracts heme-induced endothelial cell inflammatory activation, autophagy dysfunction and death

et al. 2021

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Free heme toxicity in the vascular endothelium is critical for the pathogenesis of hemolytic disorders including sickle cell disease. In the current study, it is demonstrated that human alpha1-antitrypsin (A1AT), a serine protease inhibitor with high binding-affinity for heme, rescues endothelial cell (EC) injury caused by free heme. A1AT provided endothelial protection against free heme toxicity via a pathway that differs from human serum albumin and hemopexin, two prototypical heme-binding proteins. A1AT inhibited heme-mediated pro-inflammatory activation and death of ECs, but did not affect the increase in intracellular heme levels and up-regulation of the heme-inducible enzyme heme oxygenase-1. Moreover, A1AT reduced heme-mediated generation of mitochondrial reactive oxygen species. Extracellular free heme led to an increased up-take of A1AT by ECs, which was detected in lysosomes and was found to reduce heme-dependent alkalization of these organelles. Finally, A1AT was able to restore heme-dependent dysfunctional autophagy in ECs. Taken together, our findings show that A1AT rescues ECs from free heme-mediated pro-inflammatory activation, cell death and dysfunctional autophagy. Hence, A1AT therapy may be useful in the treatment of hemolytic disorders such as sickle cell disease.

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“…It has been reported that mito‐T is a potent mitochondria‐targeted antioxidant, which could act in ischemic tissues linked with hypoxia‐induced oxidative stress (Ding, Liu, Bi, & Zhang, 2017; Du et al, 2019; Du, Farhood, & Jaeschke, 2017; Li et al, 2018; Liu, Wang, Ding, & Wang, 2018; Nautiyal, Shaltout, Chappell, & Diz, 2019; Shetty, Kumar, & Bharati, 2019; Yang et al, 2018; Zhan et al, 2018). In the present study, mito‐T, a mitochondria‐targeted superoxide dismutase mimetic, dramatically reduced AMA‐induced mitochondrial oxidative stress, and thus effectively protected MSCs.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that mito-T is a potent mitochondriatargeted antioxidant, which could act in ischemic tissues linked with hypoxia-induced oxidative stress (Ding, Liu, Bi, & Zhang, 2017;Du et al, 2019;Du, Farhood, & Jaeschke, 2017;Li et al, 2018;Liu, Wang, Ding, & Wang, 2018;Nautiyal, Shaltout, Chappell, & Diz, 2019;Shetty, Kumar, & Bharati, 2019;Yang et al, 2018;Zhan et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Mitochondria‐targeted antioxidant mito‐TEMPO alleviate oxidative stress induced by antimycin A in human mesenchymal stem cells

Nouri

Gueguen

Saeedi

et al. 2020

Journal Cellular Physiology

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The cell therapy of damaged tissue, which is linked to hypoxia condition might fail, in large part due to the emergence of oxidative stress (OS) and/or mitochondrial dysfunctions. Thus, the invigoration of stem cells against oxidative stress could be a reliable strategy to improve the cell therapy outcome. Of various antioxidants, mito‐Tempo (mito‐T) is one of the potent antioxidants that could target and neutralize the mitochondrial oxidative stress. In this study, for the induction of hypoxia and oxidative stress in mitochondria of the mesenchymal stem cells (MSCs) isolated from human adipose tissue, antimycin A (AMA) was used and then several parameters were analyzed, including cell viability and cell cycle arrest of MSCs exposed to AMA, mito‐T, antioxidant potential, redox homeostasis, and signaling pathways in MSCs under oxidative stress. Based on our findings, the treated MSCs were found to impose a high resistance to the OS‐induced apoptosis, which correlated with the nuclear factor erythroid 2‐related factor 2 (Nrf2) pathway required to manage OS. Upon exposure of the MSCs to high oxidative stress conditions using AMA, the cells failed to scavenge. The use of mito‐T was found to alleviate the damage induced by oxidative stress through both direct functions of the free radical scavenging and the interplay in terms of cell signaling pathways including the upregulation of the Nrf2 pathway. These findings may pave the way in the stem cell therapy for the hypoxia‐mediated tissue damage.

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Mito-TEMPO, a mitochondria-targeted antioxidant, prevents N-nitrosodiethylamine-induced hepatocarcinogenesis in mice

Cited by 46 publications

References 66 publications

Carcinogenesis: Failure of resolution of inflammation?

Carcinogenesis: Failure of resolution of inflammation?

Alpha1-antitrypsin counteracts heme-induced endothelial cell inflammatory activation, autophagy dysfunction and death

Mitochondria‐targeted antioxidant mito‐TEMPO alleviate oxidative stress induced by antimycin A in human mesenchymal stem cells

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