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      The Role of Reactive Oxygen Species in Arsenic Toxicity

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          Abstract

          Arsenic poisoning is a global health problem. Chronic exposure to arsenic has been associated with the development of a wide range of diseases and health problems in humans. Arsenic exposure induces the generation of intracellular reactive oxygen species (ROS), which mediate multiple changes to cell behavior by altering signaling pathways and epigenetic modifications, or cause direct oxidative damage to molecules. Antioxidants with the potential to reduce ROS levels have been shown to ameliorate arsenic-induced lesions. However, emerging evidence suggests that constructive activation of antioxidative pathways and decreased ROS levels contribute to chronic arsenic toxicity in some cases. This review details the pathways involved in arsenic-induced redox imbalance, as well as current studies on prophylaxis and treatment strategies using antioxidants.

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          Links between metabolism and cancer.

          Chi Dang (2012)
          Metabolism generates oxygen radicals, which contribute to oncogenic mutations. Activated oncogenes and loss of tumor suppressors in turn alter metabolism and induce aerobic glycolysis. Aerobic glycolysis or the Warburg effect links the high rate of glucose fermentation to cancer. Together with glutamine, glucose via glycolysis provides the carbon skeletons, NADPH, and ATP to build new cancer cells, which persist in hypoxia that in turn rewires metabolic pathways for cell growth and survival. Excessive caloric intake is associated with an increased risk for cancers, while caloric restriction is protective, perhaps through clearance of mitochondria or mitophagy, thereby reducing oxidative stress. Hence, the links between metabolism and cancer are multifaceted, spanning from the low incidence of cancer in large mammals with low specific metabolic rates to altered cancer cell metabolism resulting from mutated enzymes or cancer genes.
          Article 0 comments Cited 373 times – based on 0 reviews     Review now
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            A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62.

            Alexandria Lau, Xiao-Jun Wang, Fei Zhao … (2010)
            In response to stress, cells can utilize several cellular processes, such as autophagy, which is a bulk-lysosomal degradation pathway, to mitigate damages and increase the chances of cell survival. Deregulation of autophagy causes upregulation of p62 and the formation of p62-containing aggregates, which are associated with neurodegenerative diseases and cancer. The Nrf2-Keap1 pathway functions as a critical regulator of the cell's defense mechanism against oxidative stress by controlling the expression of many cellular protective proteins. Under basal conditions, Nrf2 is ubiquitinated by the Keap1-Cul3-E3 ubiquitin ligase complex and targeted to the 26S proteasome for degradation. Upon induction, the activity of the E3 ubiquitin ligase is inhibited through the modification of cysteine residues in Keap1, resulting in the stabilization and activation of Nrf2. In this current study, we identified the direct interaction between p62 and Keap1 and the residues required for the interaction have been mapped to 349-DPSTGE-354 in p62 and three arginines in the Kelch domain of Keap1. Accumulation of endogenous p62 or ectopic expression of p62 sequesters Keap1 into aggregates, resulting in the inhibition of Keap1-mediated Nrf2 ubiquitination and its subsequent degradation by the proteasome. In contrast, overexpression of mutated p62, which loses its ability to interact with Keap1, had no effect on Nrf2 stability, demonstrating that p62-mediated Nrf2 upregulation is Keap1 dependent. These findings demonstrate that autophagy deficiency activates the Nrf2 pathway in a noncanonical cysteine-independent mechanism.
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              Arsenic: toxicity, oxidative stress and human disease.

              Z Jenisova, D Hudecova, K Jomova … (2011)
              Arsenic (As) is a toxic metalloid element that is present in air, water and soil. Inorganic arsenic tends to be more toxic than organic arsenic. Examples of methylated organic arsenicals include monomethylarsonic acid [MMA(V)] and dimethylarsinic acid [DMA(V)]. Reactive oxygen species (ROS)-mediated oxidative damage is a common denominator in arsenic pathogenesis. In addition, arsenic induces morphological changes in the integrity of mitochondria. Cascade mechanisms of free radical formation derived from the superoxide radical, combined with glutathione-depleting agents, increase the sensitivity of cells to arsenic toxicity. When both humans and animals are exposed to arsenic, they experience an increased formation of ROS/RNS, including peroxyl radicals (ROO•), the superoxide radical, singlet oxygen, hydroxyl radical (OH•) via the Fenton reaction, hydrogen peroxide, the dimethylarsenic radical, the dimethylarsenic peroxyl radical and/or oxidant-induced DNA damage. Arsenic induces the formation of oxidized lipids which in turn generate several bioactive molecules (ROS, peroxides and isoprostanes), of which aldehydes [malondialdehyde (MDA) and 4-hydroxy-nonenal (HNE)] are the major end products. This review discusses aspects of chronic and acute exposures of arsenic in the etiology of cancer, cardiovascular disease (hypertension and atherosclerosis), neurological disorders, gastrointestinal disturbances, liver disease and renal disease, reproductive health effects, dermal changes and other health disorders. The role of antioxidant defence systems against arsenic toxicity is also discussed. Consideration is given to the role of vitamin C (ascorbic acid), vitamin E (α-tocopherol), curcumin, glutathione and antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase in their protective roles against arsenic-induced oxidative stress. Copyright © 2011 John Wiley & Sons, Ltd.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Biomolecules
                Journal ID (iso-abbrev): Biomolecules
                Journal ID (publisher-id): biomolecules
                Title: Biomolecules
                Publisher: MDPI
                ISSN (Electronic): 2218-273X
                Publication date (Electronic): 05 February 2020
                Publication date Collection: February 2020
                Volume: 10
                Issue: 2
                Electronic Location Identifier: 240
                Affiliations
                [1 ]Experimental Teaching Center, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang 110122, China; yxhu@ 123456cmu.edu.cn (Y.H.); gwang@ 123456cmu.edu.cn (G.W.); cwlu@ 123456cmu.edu.cn (C.L.)
                [2 ]Program of Environmental Toxicology, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang 110122, China; L1019Jin@ 123456163.com (J.L.); binlougg@ 123456gmail.com (B.L.); rui1224984970@ 123456163.com (R.W.); hhwang@ 123456cmu.edu.cn (H.W.); jbpi@ 123456cmu.edu.cn (J.P.)
                Author notes
                Author information
                https://orcid.org/0000-0002-2589-3007
                https://orcid.org/0000-0003-2354-9453
                Article
                Publisher ID: biomolecules-10-00240
                DOI: 10.3390/biom10020240
                PMC ID: 7072296
                PubMed ID: 32033297
                SO-VID: b532b963-e992-4323-b4df-da329fde5d2c
                Copyright © © 2020 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 13 January 2020
                Date accepted : 29 January 2020
                Categories
                Subject: Review

                Keywords: antioxidants,arsenic,nrf2,ros,signaling pathway
                Data availability:
                Keywords: antioxidants, arsenic, nrf2, ros, signaling pathway

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