Paraquat Induces Apoptosis through Cytochrome C Release and ERK Activation

Seo, Hong Joo; Choi, Sang Joon; Lee, Jung-Hee

doi:10.4062/biomolther.2014.115

Cited by 23 publications

(10 citation statements)

References 42 publications

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“…Exposure of E18 neuroblast cells to low concentrations of PQ resulted in early increases in PKB, ERK1/2, and JNK1/2 phosphorylation . Seo et al found that PQ treatment resulted in the activation of ERK1/2, p38, and JNK MAPKs, but only ERK MAPK was associated with PQ‐induced apoptosis in mouse embryo fibroblast cell . PQ activates p38 and JNK MAPK signaling pathways and promotes the release of proinflammatory cytokines that facilitate cell death .…”

Section: Discussionmentioning

confidence: 99%

Melatonin protects against paraquat‐induced damage during in vitro maturation of bovine oocytes

Pang

Jiang

Wang

et al. 2018

Journal of Pineal Research

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Paraquat (PQ), a broad-spectrum agricultural pesticide, causes cellular toxicity by increasing oxidative stress levels in various biological systems, including the reproductive system. PQ exposure causes embryotoxicity and reduces the developmental abilities of embryos. However, there is little information regarding the toxic effects of PQ on oocyte maturation. In this study, we studied the toxic effects of PQ exposure and the effects of melatonin on PQ-induced damage in bovine oocytes. PQ exposure disrupted nuclear and cytoplasmic maturation, which was manifested as decreased cumulus cell expansion, reduced first polar body extrusion, and abnormal distribution patterns of cortical granules and mitochondria. In addition, PQ treatment severely disrupted the ability of the resulted in vitro-produced embryos to develop to the blastocyst stage. Moreover, PQ exposure significantly increased the intracellular reactive oxygen species (ROS) level and early apoptotic rate, and decreased the glutathione (GSH) level, antioxidative CAT and GPx4 mRNA, and apoptotic-related Bcl-2/Bax mRNA ratio. These results indicated that PQ causes reproductive toxicity in bovine oocytes. Melatonin application resulted in significant protection against the toxic effects of PQ in PQ-exposed oocytes. The mechanisms underlying the role of melatonin included the inhibition of PQ-induced p38 mitogen-activated protein kinase (MAPK) activation, and restoration of abnormal trimethyl-histone H3 lysine 4 (H3K4me3) and trimethyl-histone H3 lysine 9 (H3K9me3) levels. These results reveal that melatonin serves as a powerful agent against experimental PQ-induced toxicity during bovine oocyte maturation and could form a basis for further studies to develop therapeutic strategies against PQ poisoning. K E Y W O R D Sbovine, melatonin, oocyte maturation, oxidative damage, paraquat 2 of 15 | PANG et Al.

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Section: Discussionmentioning

confidence: 99%

Melatonin protects against paraquat‐induced damage during in vitro maturation of bovine oocytes

Pang

Jiang

Wang

et al. 2018

Journal of Pineal Research

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“…Mitochondrial outer membrane permeabilization (MOMP) and mitochondrial swelling are the prominent characteristics of mitochondrial morphology during apoptosis 29 . The apoptotic signal ultimately activates ERK1/2 and Bax to promote MOMP, resulting in the release of cytochrome c and Caspase 3 activation 29 , 30 . Western blot results indicated that SFN persistently activated ERK1/2, upregulated Bax and Caspase 3 in a dose-dependent and time-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Sulforaphane Induced Apoptosis via Promotion of Mitochondrial Fusion and ERK1/2-Mediated 26S Proteasome Degradation of Novel Pro-survival Bim and Upregulation of Bax in Human Non-Small Cell Lung Cancer Cells

Yang¹,

Zhou²,

Wu³

et al. 2017

J. Cancer

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Previous studies in our laboratory showed that sulforaphane (SFN) induced apoptosis by sustained activation of extracellular regulated protein kinases 1/2 (ERK1/2). However, the underlying mechanisms associated with SFN-induced apoptosis and downstream cascades which are modulated by ERK1/2 were not elucidated. Herein we demonstrated for the first time that alteration of mitochondrial dynamics contributed to SFN-induced apoptosis in human non-small cell lung cancer (NSCLC) cells. Reports showed that protein Bim not only induced apoptosis but also promoted proliferation under certain circumstances. We found that Bim was related to cell growth in NSCLC cells. Pro-survival Bim downregulation was shown to induce apoptosis in response to SFN. Further, Using the ERK1/2 inhibitor, PD98059, we found that SFN upregulated Bax and downregulated Bim through the ERK1/2-dependent signaling pathway. Furthermore, SFN activated ERK1/2 to increase 26S proteasome activity to degrade Bim, while the proteasome inhibitor MG132 reversed this effect. Therefore, SFN phosphorylated ERK1/2 and activated the proteasome system leading to the degradation of Bim, which contributed to apoptosis in NSCLC cells. These findings provided a novel insight into SFN-related therapeutics in cancer treatment.

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“…In the intrinsic pathway, the pro-apoptotic signaling cascade is proceeded by the release of mitochondrial cytochrome C. ERK 1/2 belong to the family of mitogen-activated protein kinases (MAPKs) which are involved in different cell processes and cell death ( 44 ). Phosphorylation and, thus, activation of ERK 1/2 by extracellular stimuli (such as DAMPs) results in the release of cytochrome C ( 45 ). Indeed, our data indicate that the exposure of HS to cardiomyocytes results in an increased expression of phosphorylation of ERK 1/2 and cytochrome C release (Figures 2 A,B).…”

Section: Discussionmentioning

confidence: 99%

Heparan Sulfate Induces Necroptosis in Murine Cardiomyocytes: A Medical-In silico Approach Combining In vitro Experiments and Machine Learning

et al. 2018

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Life-threatening cardiomyopathy is a severe, but common, complication associated with severe trauma or sepsis. Several signaling pathways involved in apoptosis and necroptosis are linked to trauma- or sepsis-associated cardiomyopathy. However, the underling causative factors are still debatable. Heparan sulfate (HS) fragments belong to the class of danger/damage-associated molecular patterns liberated from endothelial-bound proteoglycans by heparanase during tissue injury associated with trauma or sepsis. We hypothesized that HS induces apoptosis or necroptosis in murine cardiomyocytes. By using a novel Medical-In silico approach that combines conventional cell culture experiments with machine learning algorithms, we aimed to reduce a significant part of the expensive and time-consuming cell culture experiments and data generation by using computational intelligence (refinement and replacement). Cardiomyocytes exposed to HS showed an activation of the intrinsic apoptosis signal pathway via cytochrome C and the activation of caspase 3 (both p < 0.001). Notably, the exposure of HS resulted in the induction of necroptosis by tumor necrosis factor α and receptor interaction protein 3 (p < 0.05; p < 0.01) and, hence, an increased level of necrotic cardiomyocytes. In conclusion, using this novel Medical-In silico approach, our data suggest (i) that HS induces necroptosis in cardiomyocytes by phosphorylation (activation) of receptor-interacting protein 3, (ii) that HS is a therapeutic target in trauma- or sepsis-associated cardiomyopathy, and (iii) indicate that this proof-of-concept is a first step toward simulating the extent of activated components in the pro-apoptotic pathway induced by HS with only a small data set gained from the in vitro experiments by using machine learning algorithms.

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Paraquat Induces Apoptosis through Cytochrome C Release and ERK Activation

Cited by 23 publications

References 42 publications

Melatonin protects against paraquat‐induced damage during in vitro maturation of bovine oocytes

Melatonin protects against paraquat‐induced damage during in vitro maturation of bovine oocytes

Sulforaphane Induced Apoptosis via Promotion of Mitochondrial Fusion and ERK1/2-Mediated 26S Proteasome Degradation of Novel Pro-survival Bim and Upregulation of Bax in Human Non-Small Cell Lung Cancer Cells

Heparan Sulfate Induces Necroptosis in Murine Cardiomyocytes: A Medical-In silico Approach Combining In vitro Experiments and Machine Learning

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