Glutathione Efflux and Cell Death

Franco, Rodrigo; Cidlowski, John A.

doi:10.1089/ars.2012.4553

Cited by 200 publications

(142 citation statements)

References 255 publications

(141 reference statements)

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“…However, this denitrosylation system is dependent on cellular levels of reduced glutathione, which initially acts as a NO sink. Under physiological conditions, glutathione reductases reduce GSSG to GSH [93]. Under pathological conditions, ROS and RNS may cause GSH depletion by its oxidation to GSSG [94,95].…”

Section: Depletion Of Glutathione and Subsequent Loss Of Denitrosylationmentioning

confidence: 99%

Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome

Morris¹,

Berk

Klein

et al. 2016

Mol Neurobiol

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Nitric oxide plays an indispensable role in modulating cellular signaling and redox pathways. This role is mainly effected by the readily reversible nitrosylation of selective protein cysteine thiols. The reversibility and sophistication of this signaling system is enabled and regulated by a number of enzymes which form part of the thioredoxin, glutathione, and pyridoxine antioxidant systems. Increases in nitric oxide levels initially lead to a defensive increase in the number of nitrosylated proteins in an effort to preserve their function. However, in an environment of chronic oxidative and nitrosative stress (O&NS), nitrosylation of crucial cysteine groups within key enzymes of the thioredoxin, glutathione, and pyridoxine systems leads to their inactivation thereby disabling denitrosylation and transnitrosylation and subsequently a state described as "hypernitrosylation." This state leads to the development of pathology in multiple domains such as the inhibition of enzymes of the electron transport chain, decreased mitochondrial function, and altered conformation of proteins and amino acids leading to loss of immune tolerance and development of autoimmunity. Hypernitrosylation also leads to altered function or inactivation of proteins involved in the regulation of apoptosis, autophagy, proteomic degradation, transcription factor activity, immune-inflammatory pathways, energy production, and neural function and survival. Hypernitrosylation, as a consequence of chronically elevated O&NS and activated immune-inflammatory pathways, can explain many characteristic abnormalities observed in neuroprogressive disease including major depression and chronic fatigue syndrome/myalgic encephalomyelitis. In those disorders, increased bacterial translocation may drive hypernitrosylation and autoimmune responses against nitrosylated proteins.

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Section: Depletion Of Glutathione and Subsequent Loss Of Denitrosylationmentioning

confidence: 99%

Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome

Morris¹,

Berk

Klein

et al. 2016

Mol Neurobiol

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“…It has been shown that the decrease of GSH content is a common feature in apoptotic cell death (38). Previous studies reported that plumbagin regulates the cellular redox state by modulation of GSH (36,39).…”

Section: Gsh Depletion By Plumbagin Increases the Production Of Rosmentioning

confidence: 99%

Plumbagin enhances TRAIL-induced apoptosis of human leukemic Kasumi-1 cells through upregulation of TRAIL death receptor expression, activation of caspase-8 and inhibition of cFLIP

Kong

Luo

et al. 2017

Oncology Reports

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Abstract. Although the patients with t(8;21) acute myeloid leukemia (AML) have a favorable prognosis compared with other non-acute promyelocytic leukemia AML patients, only ~50% patients with this relatively favorable subtype can survive for 5 years and refractory/relapse is common in clinical practice. So it is necessary to find novel agents to treat this type of AML. In this study, the effects and the mechanisms of plumbagin and recombinant soluble tumor necrosis factor-α-related apoptosis-inducing ligand (rsTRAIL) on leukemic Kasumi-1 cells were primarily investigated. Plumbagin and/or rsTRAIL could significantly inhibit the growth of Kasumi-1 cells and induce apoptosis in vitro and in vivo. Plumbagin enhanced TRAIL-induced apoptosis of Kasumi-1 cells in association with mitochondria damage, caspase activation, upregulation of death receptors (DRs) and decreased cFLIP expression. The effects of plumbagin on the expression of DR5, Bax and cFLIP could be partially abolished by the reactive oxygen species (ROS) scavenger NAC. Glutathione (GSH) depletion by plumbagin increased the production of ROS. In vivo, there was no obvious toxic pathologic change in the heart, liver and kidney tissues in any of the groups. Comparing with the control mice, a significantly increased number of apoptotic cells were observed in the combined treated mice by flow cytometry. Plumbagin also increased the expression of DR4 and DR5 in cells of xenograft tumors. Collectively, our results suggest that both plumbagin and rsTRAIL could be used as a single agent or synergistical agents to induce apoptosis of leukemic Kasumi-1 cells in vitro and in vivo.

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“…Under certain circumstances, such as in the onset of apoptosis, glutathione could efflux from the cells (Oda et al, 1999), which lowers the reducing capability of the cells and can consequently result in oxidative stress without interference of ROS generation. Therefore, GSH depletion is often taken as a marker of oxidative stress (Franco and Cidlowski, 2012). Oxidative stress causes profound alterations of various biological structures, including cellular membranes, lipids, proteins and nucleic acids, and it is involved in numerous malignancies.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the protective role of quercetin and lecithin on Ifosfamide neurotoxicity in rats

Nashwah¹,

Lobna²,

Sabry³

2016

Int. J. Adv. Res. Biol. Sci.

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Objective: The present study aimed to contribute the ability of quercetin and /or lecithin to attenuate ifosfamide neurotoxicity. Seventy female albino rats were randomly divided into seven groups. Ifosfamide (IFO; 80mg/kg b.wt.) was administrated for five consecutive days intraperitoneally (i.p.), while quercetin (50mg/kg b.wt.) and lecithin (100mg/kg b.wt) were given orally either singly or in-combination with IFO for six consecutive days. Results: Ifosfamide induce neural toxicity as indicated by decreased GSH/GSSG ratio and elevated NO level in different brain areas. As well as altering neurotransmitters levels accompanied by inhibition of choline esterase activity in serum. Also, it stimulates an apoptotic signaling program by up-regulation of caspase-3 and assimilation of Bcl-2 gene expression in all tested brain areas. Pretreatment with quercetin and lecithin singly or incombination could attenuate ifosfamide neurotoxicity by variable degrees of improvement. This improvement seems to be a parameter selective among different brain areas. Conclusion: The present study concludes that pretreatment with combined therapy showed more pronounced effect compared to singular one. Therefore, we suggested that the synergistic effect of quercetin and lecithin in the combined treatment results in marked neuroprotective effect in part through their antioxidant properties and intervening in apoptotic pathways.

show abstract

Glutathione Efflux and Cell Death

Cited by 200 publications

References 255 publications

Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome

Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome

Plumbagin enhances TRAIL-induced apoptosis of human leukemic Kasumi-1 cells through upregulation of TRAIL death receptor expression, activation of caspase-8 and inhibition of cFLIP

Evaluation of the protective role of quercetin and lecithin on Ifosfamide neurotoxicity in rats

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