Oxidative Stress in Methylmercury-Induced Cell Toxicity

Santos, Alessandra Antunes dos; Ferrer, Bertha Beatriz Socarrás; Gonçalves, Filipe Marques; Tsatsakis, Aristidis; Renieri, Elisavet; Skalny, Anatoly V.; Farina, Marcelo; Rocha, João Batista Teixeira da; Aschner, Michael

doi:10.3390/toxics6030047

Cited by 79 publications

(32 citation statements)

References 141 publications

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“…Several reports have suggested that calcium dyshomeostasis 44,45 , oxidative stress 46,47 , and disruption of the cytoskeleton 48 are important mechanisms accounting for MeHg-induced neurotoxicity. How do these mechanistic signals regulate JNK-activated autophagy induction?…”

Section: Discussionmentioning

confidence: 99%

MeHg-induced autophagy via JNK/Vps34 complex pathway promotes autophagosome accumulation and neuronal cell death

et al. 2019

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Methylmercury (MeHg), an environmental toxin, may specifically cause neurological disorders. Recent studies have reported that autophagy can be induced by metals and be involved in metal cytotoxicity. However, the role of autophagy in MeHg-induced neurotoxicity remains unknown. Here, we demonstrate that MeHg induces mTOR-independent autophagy through JNK/Vps34 complex pathway, which further promotes autophagosome accumulation and neuronal cell death. In addition to cell death, MeHg increased LC3-II expression in a concentration- and time-dependent manner in neuronal cells; furthermore, western blot analysis of LC3-II expression under baf A1-treated condition indicates that MeHg activates autophagy induction. However, we found lysosomal degradative function was impaired by MeHg. Under this condition, MeHg-activated autophagy induction would elicit autophagosome accumulation and cell death. Consistent with this inference, the autophagy inhibitor decreased the MeHg-induced autophagosome accumulation and neuronal cells death, whereas the autophagy inducers further augmented MeHg cytotoxicity. Then, the mechanism of autophagy induction is investigated. We show that MeHg-induced autophagy is mTOR-independent. Vacuolar protein sorting 34 (Vps34) complex is critical for mTOR-independent autophagy. MeHg induced the interaction between Beclin1 and Vps34 to form Vps34 complex. Importantly, knockdown of Vps34 inhibited autophagy induction by MeHg. Furthermore, we found that JNK, but not p38 or ERK, promoted the formation of Vps34 complex and autophagy induction. Finally, inhibition of JNK or downregulation of Vps34 decreased autophagosome accumulation and alleviated MeHg-induced neuronal cell death. The present study implies that inhibiting JNK/Vps34 complex autophagy induction pathway may be a novel therapeutic approach for the treatment of MeHg-induced neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

MeHg-induced autophagy via JNK/Vps34 complex pathway promotes autophagosome accumulation and neuronal cell death

et al. 2019

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“…Environmental triggers, such as exposure to cigarette smoke, UV radiation, heavy metal ions, ozone, allergens, drugs or toxins, pollutants, pesticides, or insecticides, may all contribute to the increase of ROS production in cells (Antunes dos Santos et al, 2018;Mahajan et al, 2018;Oke et al, 2019).…”

Section: Exogenous Rosmentioning

confidence: 99%

Lifestyle, Oxidative Stress, and Antioxidants: Back and Forth in the Pathophysiology of Chronic Diseases

et al. 2020

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Oxidative stress plays an essential role in the pathogenesis of chronic diseases such as cardiovascular diseases, diabetes, neurodegenerative diseases, and cancer. Long term exposure to increased levels of pro-oxidant factors can cause structural defects at a mitochondrial DNA level, as well as functional alteration of several enzymes and cellular structures leading to aberrations in gene expression. The modern lifestyle associated with processed food, exposure to a wide range of chemicals and lack of exercise plays an important role in oxidative stress induction. However, the use of medicinal plants with antioxidant properties has been exploited for their ability to treat or prevent several human pathologies in which oxidative stress seems to be one of the causes. In this review we discuss the diseases in which oxidative stress is one of the triggers and the plant-derived antioxidant compounds with their mechanisms of antioxidant defenses that can help in the prevention of these diseases. Finally, both the beneficial and detrimental effects of antioxidant molecules that are used to reduce oxidative stress in several human conditions are discussed.

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“…Subsequently, NRF2 translocates into the nucleus and binds to the antioxidant response element (ARE) located within the promoter region of specific target genes, inducing the expression of a large number of cytoprotective proteins with antioxidant and detoxifying roles [2][3][4][5]. The importance of NRF2 function has been demonstrated by several studies using NRF2-deficient mice showing an increased susceptibility to redox disturbances and xenobiotic stress [6][7][8]. It has also been shown that tissue oxidative damage after ischemia and reperfusion is efficiently counteracted by NRF2 induction [9].…”

Section: Introductionmentioning

confidence: 99%

Potential Applications of NRF2 Modulators in Cancer Therapy

et al. 2020

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The nuclear factor erythroid 2-related factor 2 (NRF2)–Kelch-like ECH-associated protein 1 (KEAP1) regulatory pathway plays an essential role in protecting cells and tissues from oxidative, electrophilic, and xenobiotic stress. By controlling the transactivation of over 500 cytoprotective genes, the NRF2 transcription factor has been implicated in the physiopathology of several human diseases, including cancer. In this respect, accumulating evidence indicates that NRF2 can act as a double-edged sword, being able to mediate tumor suppressive or pro-oncogenic functions, depending on the specific biological context of its activation. Thus, a better understanding of the mechanisms that control NRF2 functions and the most appropriate context of its activation is a prerequisite for the development of effective therapeutic strategies based on NRF2 modulation. In line of principle, the controlled activation of NRF2 might reduce the risk of cancer initiation and development in normal cells by scavenging reactive-oxygen species (ROS) and by preventing genomic instability through decreased DNA damage. In contrast however, already transformed cells with constitutive or prolonged activation of NRF2 signaling might represent a major clinical hurdle and exhibit an aggressive phenotype characterized by therapy resistance and unfavorable prognosis, requiring the use of NRF2 inhibitors. In this review, we will focus on the dual roles of the NRF2-KEAP1 pathway in cancer promotion and inhibition, describing the mechanisms of its activation and potential therapeutic strategies based on the use of context-specific modulation of NRF2.

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Oxidative Stress in Methylmercury-Induced Cell Toxicity

Cited by 79 publications

References 141 publications

MeHg-induced autophagy via JNK/Vps34 complex pathway promotes autophagosome accumulation and neuronal cell death

MeHg-induced autophagy via JNK/Vps34 complex pathway promotes autophagosome accumulation and neuronal cell death

Lifestyle, Oxidative Stress, and Antioxidants: Back and Forth in the Pathophysiology of Chronic Diseases

Potential Applications of NRF2 Modulators in Cancer Therapy

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