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      Drosophila SLC22 Orthologs Related to OATs, OCTs, and OCTNs Regulate Development and Responsiveness to Oxidative Stress

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          Abstract

          The SLC22 family of transporters is widely expressed, evolutionarily conserved, and plays a major role in regulating homeostasis by transporting small organic molecules such as metabolites, signaling molecules, and antioxidants. Analysis of transporters in fruit flies provides a simple yet orthologous platform to study the endogenous function of drug transporters in vivo. Evolutionary analysis of Drosophila melanogaster putative SLC22 orthologs reveals that, while many of the 25 SLC22 fruit fly orthologs do not fall within previously established SLC22 subclades, at least four members appear orthologous to mammalian SLC22 members (SLC22A16:CG6356, SLC22A15:CG7458, CG7442 and SLC22A18:CG3168). We functionally evaluated the role of SLC22 transporters in Drosophila melanogaster by knocking down 14 of these genes. Three putative SLC22 ortholog knockdowns— CG3168, CG6356, and CG7442/SLC22A—did not undergo eclosion and were lethal at the pupa stage, indicating the developmental importance of these genes. Additionally, knocking down four SLC22 members increased resistance to oxidative stress via paraquat testing ( CG4630: p < 0.05, CG6006: p < 0.05, CG6126: p < 0.01 and CG16727: p < 0.05). Consistent with recent evidence that SLC22 is central to a Remote Sensing and Signaling Network (RSSN) involved in signaling and metabolism, these phenotypes support a key role for SLC22 in handling reactive oxygen species.

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          Most cited references 58

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          Using FlyAtlas to identify better Drosophila melanogaster models of human disease.

          FlyAtlas, a new online resource, provides the most comprehensive view yet of expression in multiple tissues of Drosophila melanogaster. Meta-analysis of the data shows that a significant fraction of the genome is expressed with great tissue specificity in the adult, demonstrating the need for the functional genomic community to embrace a wide range of functional phenotypes. Well-known developmental genes are often reused in surprising tissues in the adult, suggesting new functions. The homologs of many human genetic disease loci show selective expression in the Drosophila tissues analogous to the affected human tissues, providing a useful filter for potential candidate genes. Additionally, the contributions of each tissue to the whole-fly array signal can be calculated, demonstrating the limitations of whole-organism approaches to functional genomics and allowing modeling of a simple tissue fractionation procedure that should improve detection of weak or tissue-specific signals.
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            Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis.

            During primate evolution, a major factor in lengthening life-span and decreasing age-specific cancer rates may have been improved protective mechanisms against oxygen radicals. We propose that one of these protective systems is plasma uric acid, the level of which increased markedly during primate evolution as a consequence of a series of mutations. Uric acid is a powerful antioxidant and is a scavenger of singlet oxygen and radicals. We show that, at physiological concentrations, urate reduces the oxo-heme oxidant formed by peroxide reaction with hemoglobin, protects erythrocyte ghosts against lipid peroxidation, and protects erythrocytes from peroxidative damage leading to lysis. Urate is about as effective an antioxidant as ascorbate in these experiments. Urate is much more easily oxidized than deoxynucleosides by singlet oxygen and is destroyed by hydroxyl radicals at a comparable rate. The plasma urate levels in humans (about 300 microM) is considerably higher than the ascorbate level, making it one of the major antioxidants in humans. Previous work on urate reported in the literature supports our experiments and interpretations, although the findings were not discussed in a physiological context.
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              Oxidative stress and metabolic syndrome.

              Metabolic syndrome is a collection of cardiometabolic risk factors that includes obesity, insulin resistance, hypertension and dyslipidemia. Although there has been significant debate regarding the criteria and concept of the syndrome, this clustering of risk factors is unequivocally linked to an increased risk of developing type 2 diabetes and cardiovascular disease. Metabolic syndrome is often characterized by oxidative stress, a condition in which an imbalance results between the production and inactivation of reactive oxygen species. Reactive oxygen species can best be described as double-edged swords; while they play an essential role in multiple physiological systems, under conditions of oxidative stress, they contribute to cellular dysfunction. Oxidative stress is thought to play a major role in the pathogenesis of a variety of human diseases, including atherosclerosis, diabetes, hypertension, aging, Alzheimer's disease, kidney disease and cancer. The purpose of this review is to discuss the role of oxidative stress in metabolic syndrome and its major clinical manifestations (namely coronary artery disease, hypertension and diabetes). It will also highlight the effects of lifestyle modification in ameliorating oxidative stress in metabolic syndrome. Discussion will be limited to human data.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                15 March 2020
                March 2020
                : 21
                : 6
                Affiliations
                [1 ]Department of Biology, University of California San Diego, San Diego, CA 92093, USA; dengelha@ 123456ucsd.edu
                [2 ]Department of Pediatrics, University of California San Diego, San Diego, CA 92093, USA; pazad@ 123456ucsd.edu (P.A.); saa023@ 123456ucsd.edu (S.A.); ghaddad@ 123456ucsd.edu (G.G.H.)
                [3 ]Department of Bioengineering, University of California San Diego, San Diego, CA 92093, USA; j6granad@ 123456ucsd.edu
                [4 ]Department of Medicine, University of California San Diego, San Diego, CA 92093, USA
                Author notes
                [* ]Correspondence: snigam@ 123456ucsd.edu
                Article
                ijms-21-02002
                10.3390/ijms21062002
                7139749
                32183456
                © 2020 by the authors.

                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/).

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