Nuclear and Mitochondrial Compartmentation of Oxidative Stress and Redox Signaling

Hansen, Jason M.; Go, Young‐Mi; Jones, Dean P.

doi:10.1146/annurev.pharmtox.46.120604.141122

Cited by 378 publications

(390 citation statements)

References 95 publications

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“…Trx is well-known for its anti-apoptotic effects by the inhibition of the ASK1 pathway [14,20,43–45], and reduced apoptosis could be one of the contributing factors for cancer onset/progression [46]. Our current and previous studies also show that Trx1 overexpression in mice inhibits the ASK1 pathway, which could facilitate cancer growth in old animals.…”

Section: Discussionsupporting

confidence: 65%

Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice

Flores

Roman

Cunningham

et al. 2018

Pathobiology of Aging & Age-related Diseases

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We examined the effects of continuous overexpression of thioredoxin (Trx) 1 on aging in Trx1 transgenic mice [Tg(TXN)+/0]. This study was conducted to test whether increased thioredoxin expression over the lifespan in mice would alter aging and age-related pathology because our previous study demonstrated that Tg(act-TXN)+/0 mice had no significant maximum life extension, possibly due to the use of actin as a promoter, which may have resulted in loss of Trx1 overexpression during aging. To test this hypothesis, we generated new Trx1 transgenic mice using a fragment of the human genome containing the TXN gene with an endogenous promoter to ensure continuous overexpression of Trx1 throughout the lifespan. Universal overexpression of Trx1 was observed, and Trx1 overexpression was maintained during aging (up to 22–24 months old) in the Tg(TXN)+/0 mice. The levels of Trx1 are significantly higher (approximately 4 to 31 fold) in all of the tissues examined in the Tg(TXN)+/0 mice compared to the wild-type (WT) littermates. The overexpression of Trx1 did not cause any changes in the levels of Trx2, glutaredoxin, glutathione, or other major antioxidant enzymes. The survival study demonstrated that male Tg(TXN)+/0 mice slightly extended the earlier part of the lifespan compared to WT littermates, but no significant life extension was observed over the lifespan. The cross-sectional pathological analysis (22–25 months old) showed that Tg(TXN)+/0 mice had a significantly higher severity of lymphoma and more tumor burden than WT mice, which was associated with the suppression of the apoptosis signal-regulating kinase 1 (ASK1) pathway. Our findings suggest that the increased levels of Trx1 over the lifespan in Tg(TXN)+/0 mice showed some beneficial effects (slight extension of lifespan) in the earlier part of life but had no significant effects on median or maximum lifespans, and increased Trx1 levels enhanced tumor development in old mice.

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Section: Discussionsupporting

confidence: 65%

Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice

Flores

Roman

Cunningham

et al. 2018

Pathobiology of Aging & Age-related Diseases

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“…This imbalance may originate from an overproduction of ROS or from a reduction in antioxidant defenses or both [57]. An inverse relationship between lipid peroxidation and GSH and its dependent enzymes, along with the activities of catalase and superoxide dismutase is well known [31,32]. A reduction in GSH may impair H 2 O 2 clearance and promote hydroxyl radical formation, thus increasing the free radical load, which triggers oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…NADPH also acts as a peroxynitrite reductant, thereby providing enzymatic defense against peroxynitrite [58]. Glutathione peroxidase (GPx) and glutathione reductase (GR) protect the neurons from oxidative stress by catalyzing the reduction of H 2 O 2 at the expense of glutathione [31,32]. Glutathine-S-transferase (GST) play a role in neuroprotection by catalyzing the formation of the GSH-HNE conjugate, which is then removed from neurons by the action of the multidrug resistant protein-1 [59] In AD brain, both GST and MRP-1 are oxidatively modified and likely dysfunctional [59].…”

Section: Discussionmentioning

confidence: 99%

“…Glutathione is widely recognized as an endogenous nonenzymatic antioxidant, an oxyradical scavenger, thereby useful in protecting against oxidative damage by free radicals and inhibiting lipid peroxidation and DNA damage [29][30][31][32][33]. Glutathione has been implicated in a wide range of metabolic processes, including cell division, DNA repair, regulation of enzyme activity, activation of transcription factors, modulation of anion and cation homeostasis and protection against oxidative damage [34].…”

Section: Introductionmentioning

confidence: 99%

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In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: Relevance to Alzheimer’s disease and other oxidative stress-related neurodegenerative disorders

Ansari

Joshi

Huang

et al. 2006

Free Radical Biology and Medicine

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Tricyclodecan-9-yl-xanthogenate (D609) has in vivo and in vitro antioxidant properties. D609 mimics glutathione (GSH), has a free thiol group, which upon oxidation forms a disulfide. The resulting dixanthate is a substrate for glutathione reductase, regenerating D609. Recent studies have also shown that D609 protects brain in vivo and neuronal cultures in vitro against the potential Alzheimer's disease (AD) causative factor, Aβ (1-42)-induced oxidative stress and cytotoxicity. Mitochondria are important organelles with both pro-and anti-apoptotic factor proteins. The present study was undertaken to test the hypothesis that i.p. injection of D609 would provide neuroprotection against free radical-induced, mitochondria-mediated apoptosis in vitro. Brain mitochondria were isolated from gerbils 1 h post injection intraperitonially (i.p.) with D609 and subsequently treated in vitro with the oxidants Fe 2+ /H 2 O 2 (hydroxyl free radicals), 2,2-azobis-(2-amidinopropane) dihydrochloride (AAPH, alkoxyl and peroxyl free radicals) and AD-relevant amyloid β-peptide 1-42 [Aβ (1-42)]. Brain mitochondria isolated from the gerbils previously injected i.p. with D609 and subjected to these oxidative stress inducers, in vitro, showed significant reduction in levels of protein carbonyls, protein-bound hydroxynonenal (HNE) [a lipid peroxidation product], 3-nitrotyrosine (3-NT), and cytochrome-c release compared to oxidant-treated brain mitochondria isolated from salineinjected gerbils. D609 treatment significantly maintains the GSH/GSSG ratio in oxidant-treated mitochondria. Increased activity of glutathione-S-transferase (GST), glutathione peroxidase (GPx) and glutathione reductase (GR) in brain isolated from D609-injected gerbils is consistent with the notion that D609 acts like GSH. These anti-apoptotic findings are discussed with reference to the potential use of this brain-accessible glutathione mimetic in the treatment of oxidative stress-related neurodegenerative disorders, including AD.

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“…Porém, quando em concentração excedente ao normal, essas espécies podem causar duas categorias de efeitos potencialmente importantes: a) danos celulares, ao atacar membranas, proteínas, polissacarídeos e ácidos nucleicos, com consequente alteração funcional e prejuízo das funções vitais em diversos tecidos -adiposo, vascular e cerebral, e órgãos, como músculo e fígado, 8 ocasionando eventualmente algumas doenças, 3,9-11 e b) ativação de caminhos de sinalização específicos. 4,12,13 Estudos epidemiológicos têm mostrado que dietas ricas em frutas e verduras estão associadas a uma menor incidência de doenças crô-nicas e degenerativas, [14][15][16][17][18] embora prova definitiva de que suplementos antioxidantes possam prevenir doenças crônicas não tenha sido obtida ou consistentemente suportada pelos testes de intervenção encontrados na literatura. Há muita controvérsia nessa área de pesquisa, indicando a necessidade de obtenção de evidências inequívocas a respeito da eficácia, segurança e dosagem apropriada de antioxidantes em relação a doenças crônicas.…”

Section: Introductionunclassified