School Of Basic And Applied Sciences

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Author: search.filters.author.Mantha, Anil K.Subject: search.filters.subject.Nrf2

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    Organophosphate-pesticides induced survival mechanisms and APE1-mediated Nrf2 regulation in non-small-cell lung cancer cells
    (John Wiley and Sons Inc, 2020-10-20T00:00:00) Thakur, Shweta; Sarkar, Bibekananda; Dhiman, Monisha; Mantha, Anil K.
    Epidemiological and molecular studies have indicated that environmental exposure to organophosphate pesticides (OPPs) is associated with increased cancer risk; however, the underlying molecular mechanisms still need to be explained. Increasing cancer incidence is linked�to OPPs-induced oxidative stress (OS). Our study evaluates monocrotophos (MCP) and chlorpyrifos (CP)-induced OS responses and apurinic/apyrimidinic endonuclease 1 (APE1) role in human non-small-cell lung cancer (NSCLC) cells. Our prior study has implicated OPPs-induced base excision repair (BER)-pathway dysregulation and APE1-mediated regulation of transcription factor (TF) c-jun in A549 cells. We further investigated the effects of MCP and CP on apoptosis, proliferation, and APE1's redox-regulation of nuclear factor-like 2 (Nrf2). Data demonstrates that MCP and CP at subtoxic concentrations induced reactive oxygen species generation and oxidative DNA base damage 8-oxo-dG lesions in NCI-H1299 cells. CP moderately upregulated�the apoptosis-inducing factor (AIF) in A549 cells, however, it did not trigger other pro-apoptotic factors viz. caspase-9 and caspase-3, suggesting early caspase-independent apoptosis. However, dose-dependent AIF-downregulation was observed for MCP treatment. Furthermore, CP and MCP treatments upregulated proliferating cell nuclear antigen levels. Immunofluorescent confocal imaging showed the colocalization of APE1 with Nrf2 in 10 �M CP- and MCP-treated NCI-H1299 cells. Immunoprecipitation confirmed that APE1 and Nrf2 physically interacted, indicating the role of APE1-mediated Nrf2 activation following OPPs treatment. This study suggests that low concentration MCP and CP exposure generates OS along with DNA damage, and modulates apoptosis, and APE1-mediated Nrf2 activation, which might be considered as the possible mechanism promoting lung cancer cell survival, suggesting that APE1 may have the potential to become a therapeutic target for the treatment of NSCLC. � 2020 Wiley Periodicals LLC
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    Organophosphate-pesticides induced survival mechanisms and APE1-mediated Nrf2 regulation in non-small-cell lung cancer cells
    (John Wiley and Sons Inc, 2020-10-20T00:00:00) Thakur, Shweta; Sarkar, Bibekananda; Dhiman, Monisha; Mantha, Anil K.
    Epidemiological and molecular studies have indicated that environmental exposure to organophosphate pesticides (OPPs) is associated with increased cancer risk; however, the underlying molecular mechanisms still need to be explained. Increasing cancer incidence is linked�to OPPs-induced oxidative stress (OS). Our study evaluates monocrotophos (MCP) and chlorpyrifos (CP)-induced OS responses and apurinic/apyrimidinic endonuclease 1 (APE1) role in human non-small-cell lung cancer (NSCLC) cells. Our prior study has implicated OPPs-induced base excision repair (BER)-pathway dysregulation and APE1-mediated regulation of transcription factor (TF) c-jun in A549 cells. We further investigated the effects of MCP and CP on apoptosis, proliferation, and APE1's redox-regulation of nuclear factor-like 2 (Nrf2). Data demonstrates that MCP and CP at subtoxic concentrations induced reactive oxygen species generation and oxidative DNA base damage 8-oxo-dG lesions in NCI-H1299 cells. CP moderately upregulated�the apoptosis-inducing factor (AIF) in A549 cells, however, it did not trigger other pro-apoptotic factors viz. caspase-9 and caspase-3, suggesting early caspase-independent apoptosis. However, dose-dependent AIF-downregulation was observed for MCP treatment. Furthermore, CP and MCP treatments upregulated proliferating cell nuclear antigen levels. Immunofluorescent confocal imaging showed the colocalization of APE1 with Nrf2 in 10 �M CP- and MCP-treated NCI-H1299 cells. Immunoprecipitation confirmed that APE1 and Nrf2 physically interacted, indicating the role of APE1-mediated Nrf2 activation following OPPs treatment. This study suggests that low concentration MCP and CP exposure generates OS along with DNA damage, and modulates apoptosis, and APE1-mediated Nrf2 activation, which might be considered as the possible mechanism promoting lung cancer cell survival, suggesting that APE1 may have the potential to become a therapeutic target for the treatment of NSCLC. � 2020 Wiley Periodicals LLC
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    Curcumin revitalizes Amyloid beta (25–35)-induced and organophosphate pesticides pestered neurotoxicity in SH-SY5Y and IMR-32 cells via activation of APE1 and Nrf2
    (Springer, 2017) Sarkar, Bibekananda; Dhiman, Monisha; Mittal, Sunil; Mantha, Anil K.
    Amyloid beta (Aβ) peptide deposition is the primary cause of neurodegeneration in Alzheimer’s disease (AD) pathogenesis. Several reports point towards the role of pesticides in the AD pathogenesis, especially organophosphate pesticides (OPPs). Monocrotophos (MCP) and Chlorpyrifos (CP) are the most widely used OPPs. In this study, the role of MCP and CP in augmenting the Aβ-induced oxidative stress associated with the neurodegeneration in AD has been assessed in human neuroblastoma IMR-32 and SH-SY5Y cell lines. From the cell survival assay, it was observed that MCP and CP reduced cell survival both dose- and time-dependently. Nitro blue tetrazolium (NBT) based assay for determination of intracellular reactive oxygen species (ROS) demonstrated that Aβ(25–35), MCP or CP produce significant oxidative stress alone or synergistically in IMR-32 and SH-SY5Y cells, while pretreatment of curcumin reduced ROS levels significantly in all treatment combinations. In this study, we also demonstrate that treatment of Aβ(25–35) and MCP upregulated inducible nitric oxide synthase (iNOS/NOS2) whereas, no change was observed in neuronal nitric oxide synthase (nNOS/NOS1), but down-regulation of the nuclear factor erythroid 2-related factor 2 (Nrf2) level was observed. While curcumin pretreatment resulted in upregulation of iNOS and Nrf2 proteins. Also, the expression of key DNA repair enzymes APE1, DNA polymerase beta (Pol β), and PARP1 were found to be downregulated upon treatment with MCP, Aβ(25–35) and their combinations at 24 h and 48 h time points. In this study, pretreatment of curcumin to the SH-SY5Y cells enhanced the expression of DNA repair enzymes APE1, pol β, and PARP1 enzymes to counter the oxidative DNA base damage via base excision repair (BER) pathway, and also activated the antioxidant element (ARE) via Nrf2 upregulation. Furthermore, the immunofluorescent confocal imaging studies in SH-SY5Y and IMR-32 cells treated with Aβ(25–35) and MCP-mediated oxidative stress and their combinations at different time periods suggesting for cross-talk between the two proteins APE1 and Nrf2. The APE1’s association with Nrf2 might be associated with the redox function of APE1 that might be directly regulating the ARE-mediated neuronal survival mechanisms.