Activation of Nrf2-mediated oxidative stress response in macrophages by hypochlorous acid

Pi, Jingbo; Zhang, Qiang; Woods, Courtney G.; Wong, Victoria A.; Collins, Sheila; Andersen, Melvin E.

doi:10.1016/j.taap.2007.09.016

Cited by 69 publications

(56 citation statements)

References 50 publications

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“…In addition, the induction of HO-1 functions to limit the cytotoxic effect of HOCl by generating CO, biliverdin, and bilirubin. murine macrophage cell line (37). Interestingly, the induction of Nrf2 protein by HOCl is not associated with an increase in Nrf2 mRNA, suggesting that HOCl stimulates Nrf2 protein expression via a posttranscriptional mechanism that may involve protein stabilization (21,54).…”

Section: Discussionmentioning

confidence: 92%

Hypochlorous acid-induced heme oxygenase-1 gene expression promotes human endothelial cell survival

Wei

Liu

Peyton

et al. 2009

American Journal of Physiology-Cell Physiology

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Section: Discussionmentioning

confidence: 92%

Hypochlorous acid-induced heme oxygenase-1 gene expression promotes human endothelial cell survival

Wei

Liu

Peyton

et al. 2009

American Journal of Physiology-Cell Physiology

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“…This may help explain the remarkable co-carcinogenic effects of arsenic and UV irradiation observed in mouse models of dermal carcinogenesis but the absence of activity for arsenic alone [3,4]. Our previous study indicated that exogenous GSH might markedly suppress hypochlorous acid-induced Nrf2 activation in mouse macrophages [50], suggesting the enhanced GSH levels in As-TM cells might be a critical factor for the weakened Nrf2 activation. In addition, increased activities of Nrf2 downstream phase II enzymes in As-TM cells might detoxify both arsenic and tBHQ, and thus results in decreased Nrf2 activation.…”

Section: Discussionmentioning

confidence: 96%

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Diwan

Sun

et al. 2008

Free Radical Biology and Medicine

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147

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Arsenic is a well-known human skin carcinogen but the underlying mechanisms of carcinogenesis are unclear. Transcription factor Nrf2-mediated antioxidant response represents a critical cellular defense mechanism, and emerging data suggest that constitutive activation of Nrf2 contributes to malignant phenotype. In the present study when an immortalized, non-tumorigenic human keratinocyte cell line (HaCaT) was continuously exposed to environmentally relevant level of inorganic arsenite (100 nM) for 28 weeks, malignant transformation occurred as evidenced by the formation of highly aggressive squamous cell carcinoma after inoculation into nude mice. To investigate the mechanisms involved, a broad array of biomarkers for transformation were assessed in these arsenic-transformed cells (termed As-TM). In addition to increased secretion of matrix metalloproteinase-9 (MMP-9), a set of markers for squamous differentiation and skin keratinization, including keratin-1, keratin-10, involucrin, and loricrin, were significantly elevated in As-TM cells. Furthermore, As-TM cells showed increased intracellular glutathione, elevated expression of Nrf2 and its target genes, as well as generalized apoptotic resistance. In contrast to increased basal Nrf2 activity in As-TM cells, a diminished Nrf2-mediated antioxidant response induced by acute exposure to high dose of arsenite or tert-butyl hydroxyquinone occurred. The findings that multiple biomarkers for malignant transformation observed in As-TM cells, including MMP-9 and cytokeratins, are potentially regulated by Nrf2 suggest constitutive Nrf2 activation may be involved in arsenic carcinogenesis of skin. The weakened Nrf2 activation in response to oxidative stressors observed in As-TM cells, coupled with acquired apoptotic resistance, would potentially have increased the likelihood of transmittable oxidative DNA damage and fixation of mutational/DNA damage events.

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“…Our data demonstrate that 10 lM PDTC increased extracellular H 2 O 2 by two fold and the intracellular concentration may have been much higher. It is important to note that catalase was added before the PDTC and both are cellpermeable [33,34]. Thus, catalase was present intracellularly at essentially the same time as PDTC.…”

Section: Discussionmentioning

confidence: 99%

Pyrrolidine dithiocarbamate (PDTC) blocks apoptosis and promotes ionizing radiation-induced necrosis of freshly-isolated normal mouse spleen cells

et al. 2010

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Ionizing radiation (IR) is a pro-oxidant that kills cells by both apoptotic and necrotic mechanisms. Pyrrolidine dithiocarbamate (PDTC) is a thiol-containing compound that may act either as a pro- or anti-oxidant depending on the experimental conditions. This study was designed to determine whether PDTC would reduce or enhance IR-induced cell death of freshly-isolated normal mouse B6/129 spleen cells (NMSC). We determined the effect of increasing doses of IR, PDTC alone and PDTC followed by IR on the viability of NMSC. Annexin V and propidium iodide (Annexin V/PI) staining demonstrated a dose and time-dependent relationship in which PDTC enhanced the percentage of IR-induced apoptotic/necrotic NMSC. Trypan blue dye inclusion confirmed that a loss of membrane integrity was occurring 1 h after incubation with PDTC plus IR. Reduction in the glutathione (GSH)/glutathione disulfide (GSSG) ratio and GSH demonstrated that both IR (8.5 Gy) and PDTC acted as pro-oxidants, but their mechanisms of action differed: In contrast to IR, which promoted p53 activation and caspase 3/7-mediated apoptosis, PDTC inhibited IR-induced p53 and caspase 3/7 activity. However, PDTC increased H(2)O(2) formation and necrosis, resulting in an overall increase in IR-induced cell death. Catalase prevented the PDTC-induced increase in IR cytotoxicity implicating the generation of H(2)O(2) as a major factor in this mechanism. These results demonstrate that in NMSC PDTC acts as pro-oxidant and enhances IR-induced cell cytotoxicity by increasing H(2)O(2)formation and thiol oxidation. As such, they strongly suggest that the use of PDTC as an adjunct to reduce radiation toxicity should be avoided.

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Activation of Nrf2-mediated oxidative stress response in macrophages by hypochlorous acid

Cited by 69 publications

References 50 publications

Hypochlorous acid-induced heme oxygenase-1 gene expression promotes human endothelial cell survival

Hypochlorous acid-induced heme oxygenase-1 gene expression promotes human endothelial cell survival

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Pyrrolidine dithiocarbamate (PDTC) blocks apoptosis and promotes ionizing radiation-induced necrosis of freshly-isolated normal mouse spleen cells

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