Contribution of mitochondrial GSH transport to matrix GSH status and colonic epithelial cell apoptosis

Circu, Magdalena L.; Rodríguez, Cynthia; Maloney, Ronald E.; Moyer, Mary Pat; Aw, Tak Yee

doi:10.1016/j.freeradbiomed.2007.09.011

Cited by 66 publications

(80 citation statements)

References 48 publications

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“…This association was confirmed by the fact that pre-treatment with NAC, a potent GSH precursor, abolishes apoptosis and cytotoxicity generated by AA. Therefore, as previously shown in Caco-2 cells [13,14] an in other cell types [29,30], the loss of cellular GSH redox status seems to be an important player in apoptotic signalling.…”

Section: Discussionsupporting

confidence: 62%

“…Hence, increased ROS have been shown to activate signalling cascades involving the MAPK-JNKs that play a key role in the regulation of many cellular processes, including apoptosis [10]. Interestingly, studies in intestinal cells [13,14] have demonstrated that loss of cellular glutathione redox balance is 4 an important player in apoptotic signalling and cell death. Therefore, depletion of GSH levels favouring cellular oxidative stress and apoptosis may be suggested as a potential mechanism for AA toxicity.…”

Section: Introductionmentioning

confidence: 99%

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Procyanidin B2 and a cocoa polyphenolic extract inhibit acrylamide-induced apoptosis in human Caco-2 cells by preventing oxidative stress and activation of JNK pathway

Rodríguez-Ramiro¹,

Ramos²,

Bravo³

et al. 2011

The Journal of Nutritional Biochemistry

128

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Humans are exposed to dietary acrylamide (AA) during their lifetime, it is therefore necessary to investigate the mechanisms associated with AA induced toxic effects.Accumulating evidence indicates that oxidative stress may contribute to AA cytotoxicity but the link between oxidative stress and AA cytotoxicity in the gastrointestinal tract, the primary organ in contact with dietary AA, has not been described. In this study, we evaluate the alterations of the redox balance induced by AA in Caco-2 intestinal cells as well as the potential protective role of natural antioxidants such as a well-standardized cocoa polyphenolic extract (CPE) and its main polyphenol components epicatechin (EC) and procyanidin B2 (PB2). We found that AA-induced oxidative stress in Caco-2 cells is evidenced by glutathione (GSH) depletion and reactive oxygen species (ROS) overproduction. AA also activated the extracellular-regulated kinases (ERKs) and the c-jun N-amino terminal kinases (JNKs) leading to an increase in caspase-3 activity and cell death. Studies with appropriate inhibitors confirmed the implication of oxidative stress and JNKs activation in AA-induced apoptosis. Additionally, AA cytotoxicity was counteracted by CPE or PB2 by inhibiting GSH consumption and ROS generation, increasing the levels of gamma-glutamyl cysteine synthase (γ-GCS) and glutathione-S-transferase (GST) and blocking the apoptotic pathways activated by AA. Therefore, AA-induced cytotoxicity and apoptosis are closely related to oxidative stress in Caco-2 cells. Interestingly, natural dietary antioxidant such as PB2 and CPE were able to suppress AA toxicity by improving the redox status of Caco-2 cells and by blocking the apoptotic pathway activated by AA.3

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Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Procyanidin B2 and a cocoa polyphenolic extract inhibit acrylamide-induced apoptosis in human Caco-2 cells by preventing oxidative stress and activation of JNK pathway

Rodríguez-Ramiro¹,

Ramos²,

Bravo³

et al. 2011

The Journal of Nutritional Biochemistry

128

View full text Add to dashboard Cite

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“…31,32 Recently, inhibition of mitochondrial GSH transport has been reported to exacerbate oxidant-induced cytochrome c (Cyt c) release, caspase 9 activation, and apoptosis. 33 Intracellular GSH depletion is an early hallmark in the progression of cell death in response to different apoptotic stimuli 3,4 (Figure 2). GSH depletion during apoptosis induced by cytotoxic agents, which by themselves induce oxidative stress such as xenobiotics, chemotherapeutics, and metals, has been reported to be mediated by GSH oxidation to GSSG by reactive species (RS) of both oxygen (ROS) and nitrogen (RNS), or by its conjugation to highly reactive compounds 34,35 ( Figure 3).…”

Section: Figure 1 Apoptotic Signaling Pathways (See Text For Furthermentioning

confidence: 99%

Apoptosis and glutathione: beyond an antioxidant

2009

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Apoptosis is a conserved homeostatic process critical for organ and tissue morphogenesis, development, and senescence. This form of programmed cell death also participates in the etiology of several human diseases including cancer, neurodegenerative, and autoimmune disorders. Although the signaling pathways leading to the progression of apoptosis have been extensively characterized, recent studies highlight the regulatory role of changes in the intracellular milieu (permissive apoptotic environment) in the efficient activation of the cell death machinery. In particular, glutathione (GSH) depletion is a common feature of apoptotic cell death triggered by a wide variety of stimuli including activation of death receptors, stress, environmental agents, and cytotoxic drugs. Although initial studies suggested that GSH depletion was only a byproduct of oxidative stress generated during cell death, recent discoveries suggest that GSH depletion and post-translational modifications of proteins through glutathionylation are critical regulators of apoptosis. Here, we reformulate these emerging paradigms into our current understanding of cell death mechanisms. Apoptosis or programmed cell death is a ubiquitous homeostatic process involved in numerous biological systems. Under physiological conditions it is critical not only in the turnover of cells in tissues but also during normal development and senescence. Moreover, its deregulation has been widely observed to occur as either a cause or consequence of distinct pathologies including cancer, autoimmune, and neurodegenerative diseases. Apoptosis is a highly organized program induced by a myriad of stimuli that are characterized by the progressive activation of precise pathways leading to specific biochemical and morphological alterations in individual cells without involving an inflammatory response. Early stages of apoptosis are characterized by initiator caspase activation, cell shrinkage, loss of plasma membrane lipid asymmetry, and chromatin condensation. The execution phase of apoptosis is characterized by activation of executioner caspases and endonucleases, apoptotic body formation, and cell fragmentation 1 (Figure 1). Interestingly, recent studies have shown that changes in the intracellular milieu of the cells, such as alterations in the redox environment, are important regulators of the progression to apoptosis. 2 These discoveries have lead to the concept of a permissive apoptotic environment necessary for the activation of the proper signaling pathways regulating apoptosis. Glutathione (GSH) depletion is an early hallmark in the progression of cell death in response to a variety of apoptotic stimuli in numerous cell types 3,4 (Figure 2), although the exact role of GSH depletion in apoptosis is still controversial. We review recent data that show new insights into the understanding of the causes and consequences that alterations in the redox environment of the cell have on apoptosis.The Role of GSH in the Regulation of Apoptosis GSH synthesis, depletion, and apopt...

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“…As occurs under various pathological states (Lash, 2006), the decreased GSH levels evoke the overproduction of reactive oxygen species (ROS) which activates signalling cascades involving members of the mitogen-activated protein kinase (MAPK) family, such as Jun kinases (JNKs), that play a key role in the regulation of many cellular processes including apoptosis (Li et al 2006;Valko et al 2007). Studies in intestinal cells have demonstrated that loss of cellular glutathione redox balance is an important player in apoptotic signalling and cell death (Circu et al 2008;Wang et al 2000). In line with this, we have recently shown that AA-induced cytotoxicity and apoptosis are closely related to oxidative stress in Caco-2 cells (Rodríguez-Ramiro et al 2011), a human cell line originating from the gastrointestinal tract that retains many of the morphological and enzymatic features typical of normal human colonocytes.…”

Section: Introductionmentioning

confidence: 99%

Olive oil hydroxytyrosol reduces toxicity evoked by acrylamide in human Caco-2 cells by preventing oxidative stress

et al. 2011

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Humans are exposed to dietary acrylamide (AA) during their lifetime, it is therefore necessary to investigate the mechanisms associated with AA-induced toxic effects. Accumulating evidence indicates that oxidative stress contributes to AA cytotoxicity, thus, dietary antioxidants might have a protective role in colonic cells against AA toxicity. We have recently reported that hydroxytyrosol (HTy), a natural antioxidant abundant in olive oil, is able to enhance the cellular antioxidant defence capacity, thereby protecting cells from oxidative stress. In this study, we evaluate the protective role of HTy on alterations of the redox balance induced by AA in Caco-2 intestinal cells. AA cytotoxicity was counteracted by HTy by powerfully reducing ROS generation, recovering the excited enzyme antioxidant defences and decreasing phospho-Jun Kinase concentration and caspase-3 activity induced by AA. Therefore, AA-induced cytotoxicity and apoptosis are closely related to oxidative stress in Caco-2 cells and the olive oil natural dietary antioxidant HTy was able to contain AA toxicity by improving the redox status of Caco-2 cells and by partly restraining the apoptotic pathway activated by AA. Manuscript significanceThe results of the present study show that acrylamide-induced cytotoxicity and apoptosis are closely related to oxidative stress in Caco-2 cells and the olive oil natural dietary antioxidant HTy is able to decrease acrylamide toxicity by improving the cellular redox status and by partially restraining the apoptotic pathway activated by the toxin. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 Abstract Humans are exposed to dietary acrylamide (AA) during their lifetime, it is therefore necessary to investigate the mechanisms associated with AA-induced toxic effects. List of at least 4 recommended reviewers for the manuscriptAccumulating evidence indicates that oxidative stress contributes to AA cytotoxicity, thus, dietary antioxidants might have a protective role in colonic cells against AA toxicity. We have recently reported that hydroxytyrosol (HTy), a natural antioxidant abundant in olive oil, is able to enhance the cellular antioxidant defence capacity, thereby protecting cells from oxidative stress.In this study, we evaluate the protective role of HTy on alterations of the redox balance induced by AA in Caco-2 intestinal cells. AA cytotoxicity was counteracted by HTy by powerfully reducing ROS generation, recovering the excited enzyme antioxidant defences and decreasing phospho-Jun Kinase concentration and caspase-3 activity induced by AA. Therefore, AA-...

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Contribution of mitochondrial GSH transport to matrix GSH status and colonic epithelial cell apoptosis

Cited by 66 publications

References 48 publications

Procyanidin B2 and a cocoa polyphenolic extract inhibit acrylamide-induced apoptosis in human Caco-2 cells by preventing oxidative stress and activation of JNK pathway

Procyanidin B2 and a cocoa polyphenolic extract inhibit acrylamide-induced apoptosis in human Caco-2 cells by preventing oxidative stress and activation of JNK pathway

Apoptosis and glutathione: beyond an antioxidant

Olive oil hydroxytyrosol reduces toxicity evoked by acrylamide in human Caco-2 cells by preventing oxidative stress

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