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Li N, Zhang Z, Shen L, Song G, Tian J, Liu Q, Ni J. Selenium metabolism and selenoproteins function in brain and encephalopathy. SCIENCE CHINA. LIFE SCIENCES 2025; 68:628-656. [PMID: 39546178 DOI: 10.1007/s11427-023-2621-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 06/09/2024] [Indexed: 11/17/2024]
Abstract
Selenium (Se) is an essential trace element of the utmost importance to human health. Its deficiency induces various disorders. Se species can be absorbed by organisms and metabolized to hydrogen selenide for the biosynthesis of selenoproteins, selenonucleic acids, or selenosugars. Se in mammals mainly acts as selenoproteins to exert their biological functions. The brain ranks highest in the specific hierarchy of organs to maintain the level of Se and the expression of selenoproteins under the circumstances of Se deficiency. Dyshomeostasis of Se and dysregulation of selenoproteins result in encephalopathy such as Alzheimer's disease, Parkinson's disease, depression, amyotrophic lateral sclerosis, and multiple sclerosis. This review provides a summary and discussion of Se metabolism, selenoprotein function, and their roles in modulating brain diseases based on the most currently published literature. It focuses on how Se is utilized and transported to the brain, how selenoproteins are biosynthesized and function physiologically in the brain, and how selenoproteins are involved in neurodegenerative diseases. At the end of this review, the perspectives and problems are outlined regarding Se and selenoproteins in the regulation of encephalopathy.
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Affiliation(s)
- Nan Li
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518055, China
- Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Fundamental Research Institutions, Shenzhen, 518055, China
| | - Zhonghao Zhang
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518055, China
| | - Liming Shen
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518055, China
- Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Fundamental Research Institutions, Shenzhen, 518055, China
| | - Guoli Song
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518055, China
| | - Jing Tian
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518055, China.
| | - Qiong Liu
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518055, China.
| | - Jiazuan Ni
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518055, China
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Wei S, Ma F, Feng S, Ha X. Integrating transcriptomics and proteomics to understand the molecular mechanisms underlying the pathogenesis of type 2 diabetes mellitus. Genomics 2024; 116:110964. [PMID: 39571829 DOI: 10.1016/j.ygeno.2024.110964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 11/12/2024] [Accepted: 11/14/2024] [Indexed: 11/25/2024]
Abstract
The liver plays an important role in glucose regulation, and their dysfunction is closely associated with the development of type 2 diabetes mellitus (T2DM), and insulin resistance (IR) in hepatocyte mediate the pathogenesis of diabetes mellitus. In T2DM rats and their correlated control, we investigated various genes expression at transcriptional and translational level by utilizing transcriptomic using RNA sequencing (RNA-seq) and proteomics using isobaric tags for relative and absolute quantification (iTRAQ) to disclose potential candidates for Type 2 diabetes diagnosis and therapy. We found the lecithin retinol acyltransferase (Lrat) gene regulate hepatocyte IR in T2DM. Furthermore, BRL-3A cells, rat liver cells, worked as the IR model in vitro study. Hence, Lrat gene was overexpressed in BRL-3A cells to explore the role of Lrat gene in IR by measuring the cellular glucose consumption, TCHO, and LDL-C levels. Finally, we found that Lrat gene can improve the level of glycolipid metabolism in BRL-3A cells and reduce the degree of IR in BRL-3A cells. Therefore, further exploration of Lrat gene related molecular mechanism is meaningful.
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Affiliation(s)
- Shuyao Wei
- Department of Clinical Laboratory, The 940th Hospital of Joint Logistics Support force of Chinese People's Liberation Army, Lanzhou 730050, China; Department of Clinical Laboratory, Xuzhou Municipal First People's Hospital, Xuzhou 221009, China; Clinical Laboratory Diagnostics, Gansu University of Chinese Medicine, Lanzhou 730000, China; Key Laboratory of Stem Cells and Gene Drugs, Lanzhou 730050, China
| | - Feifei Ma
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China; Key Laboratory of Stem Cells and Gene Drugs, Lanzhou 730050, China
| | - Shanshan Feng
- Clinical Laboratory Diagnostics, Gansu University of Chinese Medicine, Lanzhou 730000, China; Key Laboratory of Stem Cells and Gene Drugs, Lanzhou 730050, China
| | - Xiaoqin Ha
- Department of Clinical Laboratory, The 940th Hospital of Joint Logistics Support force of Chinese People's Liberation Army, Lanzhou 730050, China; Clinical Laboratory Diagnostics, Gansu University of Chinese Medicine, Lanzhou 730000, China; Key Laboratory of Stem Cells and Gene Drugs, Lanzhou 730050, China.
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Baumel-Alterzon S, Katz LS, Lambertini L, Tse I, Heidery F, Garcia-Ocaña A, Scott DK. NRF2 is required for neonatal mouse beta cell growth by maintaining redox balance and promoting mitochondrial biogenesis and function. Diabetologia 2024; 67:547-560. [PMID: 38206362 PMCID: PMC11521447 DOI: 10.1007/s00125-023-06071-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 11/13/2023] [Indexed: 01/12/2024]
Abstract
AIMS/HYPOTHESIS All forms of diabetes result from insufficient functional beta cell mass. Due to the relatively limited expression of several antioxidant enzymes, beta cells are highly vulnerable to pathological levels of reactive oxygen species (ROS), which can lead to the reduction of functional beta cell mass. During early postnatal ages, both human and rodent beta cells go through a burst of proliferation that quickly declines with age. The exact mechanisms that account for neonatal beta cell proliferation are understudied but mitochondrial release of moderated ROS levels has been suggested as one of the main drivers. We previously showed that, apart from its conventional role in protecting beta cells from oxidative stress, the nuclear factor erythroid 2-related factor 2 (NRF2) is also essential for beta cell proliferation. We therefore hypothesised that NRF2, which is activated by ROS, plays an essential role in beta cell proliferation at early postnatal ages. METHODS Beta cell NRF2 levels and beta cell proliferation were measured in pancreatic sections from non-diabetic human cadaveric donors at different postnatal ages, childhood and adulthood. Pancreatic sections from 1-, 7-, 14- and 28-day-old beta cell-specific Nrf2 (also known as Nfe2l2)-knockout mice (βNrf2KO) or control (Nrf2lox/lox) mice were assessed for beta cell NRF2 levels, beta cell proliferation, beta cell oxidative stress, beta cell death, nuclear beta cell pancreatic duodenal homeobox protein 1 (PDX1) levels and beta cell mass. Seven-day-old βNrf2KO and Nrf2lox/lox mice were injected daily with N-acetylcysteine (NAC) or saline (154 mmol/l NaCl) to explore the potential contribution of oxidative stress to the phenotypes seen in βNrf2KO mice at early postnatal ages. RNA-seq was performed on 7-day-old βNrf2KO and Nrf2lox/lox mice to investigate the mechanisms by which NRF2 stimulates beta cell proliferation at early postnatal ages. Mitochondrial biogenesis and function were determined using dispersed islets from 7-day-old βNrf2KO and Nrf2lox/lox mice by measuring MitoTracker intensity, mtDNA/gDNA ratio and ATP/ADP ratio. To study the effect of neonatal beta cell-specific Nrf2 deletion on glucose homeostasis in adulthood, blood glucose, plasma insulin and insulin secretion were determined and a GTT was performed on 3-month-old βNrf2KO and Nrf2lox/lox mice fed on regular diet (RD) or high-fat diet (HFD). RESULTS The expression of the master antioxidant regulator NRF2 was increased at early postnatal ages in both human (1 day to 19 months old, 31%) and mouse (7 days old, 57%) beta cells, and gradually declined with age (8% in adult humans, 3.77% in adult mice). A significant correlation (R2=0.568; p=0.001) was found between beta cell proliferation and NRF2 levels in human beta cells. Seven-day-old βNrf2KO mice showed reduced beta cell proliferation (by 65%), beta cell nuclear PDX1 levels (by 23%) and beta cell mass (by 67%), and increased beta cell oxidative stress (threefold) and beta cell death compared with Nrf2lox/lox control mice. NAC injections increased beta cell proliferation in 7-day-old βNrf2KO mice (3.4-fold) compared with saline-injected βNrf2KO mice. Interestingly, RNA-seq of islets isolated from 7-day-old βNrf2KO mice revealed reduced expression of mitochondrial RNA genes and genes involved in the electron transport chain. Islets isolated from 7-day old βNrf2KO mice presented reduced MitoTracker intensity (by 47%), mtDNA/gDNA ratio (by 75%) and ATP/ADP ratio (by 68%) compared with islets from Nrf2lox/lox littermates. Lastly, HFD-fed 3-month-old βNrf2KO male mice displayed a significant reduction in beta cell mass (by 35%), a mild increase in non-fasting blood glucose (1.2-fold), decreased plasma insulin (by 14%), and reduced glucose tolerance (1.3-fold) compared with HFD-fed Nrf2lox/lox mice. CONCLUSIONS/INTERPRETATION Our study highlights NRF2 as an essential transcription factor for maintaining neonatal redox balance, mitochondrial biogenesis and function and beta cell growth, and for preserving functional beta cell mass in adulthood under metabolic stress. DATA AVAILABILITY Sequencing data are available in the NCBI Gene Expression Omnibus, accession number GSE242718 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE242718 ).
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Affiliation(s)
- Sharon Baumel-Alterzon
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Liora S Katz
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Luca Lambertini
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Isabelle Tse
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Fatema Heidery
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Adolfo Garcia-Ocaña
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes & Metabolism Research Institute at City of Hope, Duarte, CA, USA
| | - Donald K Scott
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Wei B, Zhang X, Qian J, Tang Z, Zhang B. Nrf2: Therapeutic target of islet function protection in diabetes and islet transplantation. Biomed Pharmacother 2023; 167:115463. [PMID: 37703659 DOI: 10.1016/j.biopha.2023.115463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/06/2023] [Accepted: 09/07/2023] [Indexed: 09/15/2023] Open
Abstract
Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been reported as a major intracellular regulator of antioxidant stress, notably in islet β cells with low antioxidant enzyme content. Nrf2 is capable of regulating antioxidant function, while it can also regulate insulin secretion, proliferation, and differentiation of β cells, ER stress, as well as mitochondrial function. Thus, Nrf2 pharmacological activators have been employed in the laboratory for the treatment of diabetic mice. Islet cells are exposed to oxidative environment when islet is being transplanted. Accordingly, less than 50% of islet cells are well transplanted, and their normal function is maintained. The pharmacological activation of Nrf2 has been confirmed to protect islet cells at different stages of transplantation stages during experiments for islet transplantation.
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Affiliation(s)
- Butian Wei
- Department of general Surgery, The Fourth affiliated Hospital, Zhejiang university School of Medicine, Yiwu 322000, China
| | - Xin Zhang
- Department of general Surgery, The Fourth affiliated Hospital, Zhejiang university School of Medicine, Yiwu 322000, China
| | - Jiwei Qian
- Department of general Surgery, The Fourth affiliated Hospital, Zhejiang university School of Medicine, Yiwu 322000, China
| | - Zhe Tang
- Department of general Surgery, The Fourth affiliated Hospital, Zhejiang university School of Medicine, Yiwu 322000, China
| | - Bo Zhang
- Department of general Surgery, The Second affiliated Hospital, Zhejiang university School of Medicine, Hangzhou 310000, China.
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Vatamaniuk MZ, Huang R, Zhao Z, Lei XG. SXRF for Studying the Distribution of Trace Metals in the Pancreas and Liver. Antioxidants (Basel) 2023; 12:antiox12040846. [PMID: 37107221 PMCID: PMC10135242 DOI: 10.3390/antiox12040846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/27/2023] [Accepted: 03/28/2023] [Indexed: 04/05/2023] Open
Abstract
Transition metals such as iron, copper and zinc are required for the normal functioning of biological tissues, whereas others, such as cadmium, are potentially highly toxic. Any disturbances in homeostasis caused by lack of micronutrients in the diet, pollution or genetic heredity result in malfunction and/or diseases. Here, we used synchrotron X-ray fluorescence, SXRF, microscopy and mice with altered functions of major antioxidant enzymes to show that SXRF may become a powerful tool to study biologically relevant metal balance in the pancreas and liver of mice models with disturbed glucose homeostasis.
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Affiliation(s)
| | - Rong Huang
- Cornell High Energy Synchrotron Source (CHESS), Cornell University, Ithaca, NY 14850, USA
| | - Zeping Zhao
- Animal Science Department, Cornell University, Ithaca, NY 14853, USA
| | - Xin Gen Lei
- Animal Science Department, Cornell University, Ithaca, NY 14853, USA
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Wang H, Vatamaniuk MZ, Zhao Z, Lei XG. Interdependencies of Gene Expression and Function between Two Redox Enzymes and REG Family Proteins in Murine Pancreatic Islets and Human Pancreatic Cells. Antioxidants (Basel) 2023; 12:antiox12040849. [PMID: 37107224 PMCID: PMC10135238 DOI: 10.3390/antiox12040849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/10/2023] [Accepted: 03/30/2023] [Indexed: 04/05/2023] Open
Abstract
Our laboratory previously revealed that regenerating islets-derived protein 2 (REG2) was diminished in pancreatic islets of glutathione peroxidase-1-overexpressing mice (Gpx1-OE). It remained unknown if there is an inverse relationship between the expression and function of all Reg family genes and antioxidant enzymes in the pancreatic islets or human pancreatic cells. This research was to determine how altering the Gpx1 and superoxide dismutase-1 (Sod1) genes alone or together (dKO) affected the expression of all seven murine Reg genes in murine pancreatic islets. In Experiment 1, Gpx1-/-, Gpx1-OE, their wild-type (WT), Sod1-/-, dKO, and their WT (male, 8-wk old, n = 4–6) were fed a Se-adequate diet and their islets were collected to assay the mRNA levels of Reg family genes. In Experiment 2, islets from the six groups of mice were treated with phosphate-buffered saline (PBS), REG2, or REG2 mutant protein (1 µg/mL), and/or GPX mimic (ebselen, 50 µM) and SOD mimic (copper [II] diisopropyl salicylate, CuDIPS, 10 µM) for 48 h before the proliferation assay using bromodeoxyuridine (BrdU). In Experiment 3, human pancreatic cells (PANC1) were treated with REG2 (1 µg/mL) and assayed for REG gene expression, GPX1 and SOD1 activities, viability, and responses to Ca2+. Compared with the WT, knockouts of Gpx1 and/or Sod1 up-regulated (p < 0.05) the mRNA levels of most of the murine Reg genes in islets whereas the Gpx1 overexpression down-regulated (p < 0.05) Reg mRNA levels. REG2, but not the REG2 mutant, inhibited islet proliferation in Gpx1 or Sod1-altered mice. Such inhibition was abolished by co-incubation the Gpx1-/- islets with ebselen and the Sod1-/- islets with CuDIPS. Treating PANC1 cells with murine REG2 protein induced expression of its human orthologue REG1B and three other REG genes, but decreased SOD1 and GPX1 activities and cell viability. In conclusion, our results revealed an interdependence of REG family gene expression and/or function on intracellular GPX1 and SOD1 activities in murine islets and human pancreatic cells.
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Affiliation(s)
- Hong Wang
- Department of Animal Science, Cornell University, Ithaca, NY 14853, USA
- College of Light Industry and Food Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | | | - Zeping Zhao
- Department of Animal Science, Cornell University, Ithaca, NY 14853, USA
| | - Xin Gen Lei
- Department of Animal Science, Cornell University, Ithaca, NY 14853, USA
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Dludla PV, Mabhida SE, Ziqubu K, Nkambule BB, Mazibuko-Mbeje SE, Hanser S, Basson AK, Pheiffer C, Kengne AP. Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress. World J Diabetes 2023; 14:130-146. [PMID: 37035220 PMCID: PMC10075035 DOI: 10.4239/wjd.v14.i3.130] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/26/2022] [Accepted: 02/28/2023] [Indexed: 03/15/2023] Open
Abstract
Insulin resistance and pancreatic β-cell dysfunction are major pathological mechanisms implicated in the development and progression of type 2 diabetes (T2D). Beyond the detrimental effects of insulin resistance, inflammation and oxidative stress have emerged as critical features of T2D that define β-cell dysfunction. Predominant markers of inflammation such as C-reactive protein, tumor necrosis factor alpha, and interleukin-1β are consistently associated with β-cell failure in preclinical models and in people with T2D. Similarly, important markers of oxidative stress, such as increased reactive oxygen species and depleted intracellular antioxidants, are consistent with pancreatic β-cell damage in conditions of T2D. Such effects illustrate a pathological relationship between an abnormal inflammatory response and generation of oxidative stress during the progression of T2D. The current review explores preclinical and clinical research on the patho-logical implications of inflammation and oxidative stress during the development of β-cell dysfunction in T2D. Moreover, important molecular mechanisms and relevant biomarkers involved in this process are discussed to divulge a pathological link between inflammation and oxidative stress during β-cell failure in T2D. Underpinning the clinical relevance of the review, a systematic analysis of evidence from randomized controlled trials is covered, on the potential therapeutic effects of some commonly used antidiabetic agents in modulating inflammatory makers to improve β-cell function.
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Affiliation(s)
- Phiwayinkosi V Dludla
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town 7505, South Africa
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3880, South Africa
| | - Sihle E Mabhida
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town 7505, South Africa
| | - Khanyisani Ziqubu
- Department of Biochemistry, North-West University, Mmabatho 2745, South Africa
| | - Bongani B Nkambule
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
| | | | - Sidney Hanser
- Department of Physiology and Environmental Health, University of Limpopo, Sovenga 0727, South Africa
| | - Albert Kotze Basson
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3880, South Africa
| | - Carmen Pheiffer
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town 7505, South Africa
| | - Andre Pascal Kengne
- Department of Medicine, University of Cape Town, Cape Town 7500, South Africa
- Non-Communicable Diseases Research Unit, South African Medical Research Council, Tygerberg 7505, South Africa
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Evidence and Metabolic Implications for a New Non-Canonical Role of Cu-Zn Superoxide Dismutase. Int J Mol Sci 2023; 24:ijms24043230. [PMID: 36834640 PMCID: PMC9966940 DOI: 10.3390/ijms24043230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/10/2023] Open
Abstract
Copper-zinc superoxide dismutase 1 (SOD1) has long been recognized as a major redox enzyme in scavenging superoxide radicals. However, there is little information on its non-canonical role and metabolic implications. Using a protein complementation assay (PCA) and pull-down assay, we revealed novel protein-protein interactions (PPIs) between SOD1 and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) or epsilon (YWHAE) in this research. Through site-directed mutagenesis of SOD1, we studied the binding conditions of the two PPIs. Forming the SOD1 and YWHAE or YWHAZ protein complex enhanced enzyme activity of purified SOD1 in vitro by 40% (p < 0.05) and protein stability of over-expressed intracellular YWHAE (18%, p < 0.01) and YWHAZ (14%, p < 0.05). Functionally, these PPIs were associated with lipolysis, cell growth, and cell survival in HEK293T or HepG2 cells. In conclusion, our findings reveal two new PPIs between SOD1 and YWHAE or YWHAZ and their structural dependences, responses to redox status, mutual impacts on the enzyme function and protein degradation, and metabolic implications. Overall, our finding revealed a new unorthodox role of SOD1 and will provide novel perspectives and insights for diagnosing and treating diseases related to the protein.
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Turck D, Bohn T, Castenmiller J, de Henauw S, Hirsch‐Ernst K, Knutsen HK, Maciuk A, Mangelsdorf I, McArdle HJ, Peláez C, Pentieva K, Siani A, Thies F, Tsabouri S, Vinceti M, Aggett P, Crous Bou M, Cubadda F, Ciccolallo L, de Sesmaisons Lecarré A, Fabiani L, Titz A, Naska A. Scientific opinion on the tolerable upper intake level for selenium. EFSA J 2023; 21:e07704. [PMID: 36698500 PMCID: PMC9854220 DOI: 10.2903/j.efsa.2023.7704] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the tolerable upper intake level (UL) for selenium. Systematic reviews of the literature were conducted to identify evidence regarding excess selenium intake and clinical effects and potential biomarkers of effect, risk of chronic diseases and impaired neuropsychological development in humans. Alopecia, as an early observable feature and a well-established adverse effect of excess selenium exposure, is selected as the critical endpoint on which to base a UL for selenium. A lowest-observed-adverse-effect-level (LOAEL) of 330 μg/day is identified from a large randomised controlled trial in humans (the Selenium and Vitamin E Cancer Prevention Trial (SELECT)), to which an uncertainty factor of 1.3 is applied. A UL of 255 μg/day is established for adult men and women (including pregnant and lactating women). ULs for children are derived from the UL for adults using allometric scaling (body weight0.75). Based on available intake data, adult consumers are unlikely to exceed the UL, except for regular users of food supplements containing high daily doses of selenium or regular consumers of Brazil nuts. No risk has been reported with the current levels of selenium intake in European countries from food (excluding food supplements) in toddlers and children, and selenium intake arising from the natural content of foods does not raise reasons for concern. Selenium-containing supplements in toddlers and children should be used with caution, based on individual needs.
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Huang YC, Combs GF, Wu TL, Zeng H, Cheng WH. Selenium status and type 2 diabetes risk. Arch Biochem Biophys 2022; 730:109400. [PMID: 36122760 PMCID: PMC9707339 DOI: 10.1016/j.abb.2022.109400] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/12/2022] [Accepted: 09/13/2022] [Indexed: 12/15/2022]
Abstract
Optimal selenium (Se) status is necessary for overall health. That status can be affected by food intake pattern, age, sex, and health status. At nutritional levels of intake, Se functions metabolically as an essential constituent of some two dozen selenoproteins, most, if not all, of which have redox functions. Insufficient dietary intake of Se reduces, to varying degrees, the expression of these selenoproteins. Recent clinical and animal studies have indicated that both insufficient and excessive Se intakes may increase risk of type 2 diabetes mellitus (T2D), perhaps by way of selenoprotein actions. In this review, we discuss the current evidence linking Se status and T2D risk, and the roles of 14 selenoproteins and other proteins involved in selenoprotein biosynthesis. Understanding such results can inform the setting of safe and adequate Se intakes.
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Affiliation(s)
- Ying-Chen Huang
- Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, MS, USA
| | - Gerald F Combs
- Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA
| | - Tung-Lung Wu
- Department of Mathematics and Statistics, Mississippi State University, Mississippi State, MS, USA
| | - Huawei Zeng
- USDA, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND, USA
| | - Wen-Hsing Cheng
- Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, MS, USA.
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Kulkarni A, Muralidharan C, May SC, Tersey SA, Mirmira RG. Inside the β Cell: Molecular Stress Response Pathways in Diabetes Pathogenesis. Endocrinology 2022; 164:bqac184. [PMID: 36317483 PMCID: PMC9667558 DOI: 10.1210/endocr/bqac184] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Indexed: 11/05/2022]
Abstract
The pathogeneses of the 2 major forms of diabetes, type 1 and type 2, differ with respect to their major molecular insults (loss of immune tolerance and onset of tissue insulin resistance, respectively). However, evidence suggests that dysfunction and/or death of insulin-producing β-cells is common to virtually all forms of diabetes. Although the mechanisms underlying β-cell dysfunction remain incompletely characterized, recent years have witnessed major advances in our understanding of the molecular pathways that contribute to the demise of the β-cell. Cellular and environmental factors contribute to β-cell dysfunction/loss through the activation of molecular pathways that exacerbate endoplasmic reticulum stress, the integrated stress response, oxidative stress, and impaired autophagy. Whereas many of these stress responsive pathways are interconnected, their individual contributions to glucose homeostasis and β-cell health have been elucidated through the development and interrogation of animal models. In these studies, genetic models and pharmacological compounds have enabled the identification of genes and proteins specifically involved in β-cell dysfunction during diabetes pathogenesis. Here, we review the critical stress response pathways that are activated in β cells in the context of the animal models.
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Affiliation(s)
- Abhishek Kulkarni
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
| | - Charanya Muralidharan
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
| | - Sarah C May
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
| | - Sarah A Tersey
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
| | - Raghavendra G Mirmira
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
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Zhao J, Zou H, Huo Y, Wei X, Li Y. Emerging roles of selenium on metabolism and type 2 diabetes. Front Nutr 2022; 9:1027629. [PMID: 36438755 PMCID: PMC9686347 DOI: 10.3389/fnut.2022.1027629] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 10/10/2022] [Indexed: 07/22/2023] Open
Abstract
Selenium is recognized as an essential element for human health and enters human body mainly via diet. Selenium is a key constituent in selenoproteins, which exert essential biological functions, including antioxidant and anti-inflammatory effects. Several selenoproteins including glutathione peroxidases, selenoprotein P and selenoprotein S are known to play roles in the regulation of type 2 diabetes. Although there is a close association between certain selenoproteins with glucose metabolism or insulin resistance, the relationship between selenium and type 2 diabetes is complex and remains uncertain. Here we review recent advances in the field with an emphasis on roles of selenium on metabolism and type 2 diabetes. Understanding the association between selenium and type 2 diabetes is important for developing clinical practice guidelines, establishing and implementing effective public health policies, and ultimately combating relative health issues.
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13
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Yan X, Zhao Z, Weaver J, Sun T, Yun JW, Roneker CA, Hu F, Doliba NM, McCormick CCW, Vatamaniuk MZ, Lei XG. Role and mechanism of REG2 depletion in insulin secretion augmented by glutathione peroxidase-1 overproduction. Redox Biol 2022; 56:102457. [PMID: 36063729 PMCID: PMC9463454 DOI: 10.1016/j.redox.2022.102457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 08/15/2022] [Accepted: 08/24/2022] [Indexed: 11/23/2022] Open
Abstract
We previously reported a depletion of murine regenerating islet-derived protein 2 (REG2) in pancreatic islets of glutathione peroxidase-1 (Gpx1) overexpressing (OE) mice. The present study was to explore if and how the REG2 depletion contributed to an augmented glucose stimulated insulin secretion (GSIS) in OE islets. After we verified a consistent depletion (90%, p < 0.05) of REG2 mRNA, transcript, and protein in OE islets compared with wild-type (WT) controls, we treated cultured and perifused OE islets (70 islets/sample) with REG2 (1 μg/ml or ml · min) and observed 30-40% (p < 0.05) inhibitions of GSIS by REG2. Subsequently, we obtained evidences of co-immunoprecipitation, cell surface ligand binding, and co-immunofluorescence for a ligand-receptor binding between REG2 and transmembrane, L-type voltage-dependent Ca2+ channel (CaV1.2) in beta TC3 cells. Mutating the C-type lectin binding domain of REG2 or deglycosylating CaV1.2 removed the inhibition of REG2 on GSIS and(or) the putative binding between the two proteins. Treating cultured OE and perifused WT islets with REG2 (1 μg/ml or ml · min) decreased (p < 0.05) Ca2+ influx triggered by glucose or KCl. An intraperitoneal (ip) injection of REG2 (2 μg/g) to OE mice (6-month old, n = 10) decreased their plasma insulin concentration (46%, p < 0.05) and elevated their plasma glucose concentration (25%, p < 0.05) over a 60 min period after glucose challenge (ip, 1 g/kg). In conclusion, our study identifies REG2 as a novel regulator of Ca2+ influx and insulin secretion, and reveals a new cascade of GPX1/REG2/CaV1.2 to explain how REG2 depletion in OE islets could decrease its binding to CaV1.2, resulting in uninhibited Ca2+ influx and augmented GSIS. These findings create new links to bridge redox biology, tissue regeneration, and insulin secretion.
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Affiliation(s)
- Xi Yan
- Department of Animal Science, Cornell University, Ithaca, NY, 14853, USA
| | - Zeping Zhao
- Department of Animal Science, Cornell University, Ithaca, NY, 14853, USA
| | - Jeremy Weaver
- Department of Animal Science, Cornell University, Ithaca, NY, 14853, USA
| | - Tao Sun
- Department of Animal Science, Cornell University, Ithaca, NY, 14853, USA
| | - Jun-Won Yun
- Department of Animal Science, Cornell University, Ithaca, NY, 14853, USA; Laboratory of Veterinary Toxicology, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Carol A Roneker
- Department of Animal Science, Cornell University, Ithaca, NY, 14853, USA
| | - Fenghua Hu
- Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, 14853, USA
| | - Nicolai M Doliba
- Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | | | - Marko Z Vatamaniuk
- Department of Animal Science, Cornell University, Ithaca, NY, 14853, USA.
| | - Xin Gen Lei
- Department of Animal Science, Cornell University, Ithaca, NY, 14853, USA.
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14
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Handy DE, Loscalzo J. The role of glutathione peroxidase-1 in health and disease. Free Radic Biol Med 2022; 188:146-161. [PMID: 35691509 PMCID: PMC9586416 DOI: 10.1016/0003-2697(88)90167-4.handy 10.1016/j.freeradbiomed.2022.06.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/01/2022] [Accepted: 06/03/2022] [Indexed: 11/05/2024]
Abstract
Glutathione peroxidase 1 (GPx1) is an important cellular antioxidant enzyme that is found in the cytoplasm and mitochondria of mammalian cells. Like most selenoenzymes, it has a single redox-sensitive selenocysteine amino acid that is important for the enzymatic reduction of hydrogen peroxide and soluble lipid hydroperoxides. Glutathione provides the source of reducing equivalents for its function. As an antioxidant enzyme, GPx1 modulates the balance between necessary and harmful levels of reactive oxygen species. In this review, we discuss how selenium availability and modifiers of selenocysteine incorporation alter GPx1 expression to promote disease states. We review the role of GPx1 in cardiovascular and metabolic health, provide examples of how GPx1 modulates stroke and provides neuroprotection, and consider how GPx1 may contribute to cancer risk. Overall, GPx1 is protective against the development and progression of many chronic diseases; however, there are some situations in which increased expression of GPx1 may promote cellular dysfunction and disease owing to its removal of essential reactive oxygen species.
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Affiliation(s)
- Diane E Handy
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
| | - Joseph Loscalzo
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
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15
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Handy DE, Loscalzo J. The role of glutathione peroxidase-1 in health and disease. Free Radic Biol Med 2022; 188:146-161. [PMID: 35691509 PMCID: PMC9586416 DOI: 10.1016/j.freeradbiomed.2022.06.004] [Citation(s) in RCA: 96] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/01/2022] [Accepted: 06/03/2022] [Indexed: 02/06/2023]
Abstract
Glutathione peroxidase 1 (GPx1) is an important cellular antioxidant enzyme that is found in the cytoplasm and mitochondria of mammalian cells. Like most selenoenzymes, it has a single redox-sensitive selenocysteine amino acid that is important for the enzymatic reduction of hydrogen peroxide and soluble lipid hydroperoxides. Glutathione provides the source of reducing equivalents for its function. As an antioxidant enzyme, GPx1 modulates the balance between necessary and harmful levels of reactive oxygen species. In this review, we discuss how selenium availability and modifiers of selenocysteine incorporation alter GPx1 expression to promote disease states. We review the role of GPx1 in cardiovascular and metabolic health, provide examples of how GPx1 modulates stroke and provides neuroprotection, and consider how GPx1 may contribute to cancer risk. Overall, GPx1 is protective against the development and progression of many chronic diseases; however, there are some situations in which increased expression of GPx1 may promote cellular dysfunction and disease owing to its removal of essential reactive oxygen species.
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Affiliation(s)
- Diane E Handy
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
| | - Joseph Loscalzo
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
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16
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Moon JS, Riopel M, Seo JB, Herrero-Aguayo V, Isaac R, Lee YS. HIF-2α Preserves Mitochondrial Activity and Glucose Sensing in Compensating β-Cells in Obesity. Diabetes 2022; 71:1508-1524. [PMID: 35472707 PMCID: PMC9233300 DOI: 10.2337/db21-0736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 04/08/2022] [Indexed: 11/13/2022]
Abstract
In obesity, increased mitochondrial metabolism with the accumulation of oxidative stress leads to mitochondrial damage and β-cell dysfunction. In particular, β-cells express antioxidant enzymes at relatively low levels and are highly vulnerable to oxidative stress. Early in the development of obesity, β-cells exhibit increased glucose-stimulated insulin secretion in order to compensate for insulin resistance. This increase in β-cell function under the condition of enhanced metabolic stress suggests that β-cells possess a defense mechanism against increased oxidative damage, which may become insufficient or decline at the onset of type 2 diabetes. Here, we show that metabolic stress induces β-cell hypoxia inducible factor 2α (HIF-2α), which stimulates antioxidant gene expression (e.g., Sod2 and Cat) and protects against mitochondrial reactive oxygen species (ROS) and subsequent mitochondrial damage. Knockdown of HIF-2α in Min6 cells exaggerated chronic high glucose-induced mitochondrial damage and β-cell dysfunction by increasing mitochondrial ROS levels. Moreover, inducible β-cell HIF-2α knockout mice developed more severe β-cell dysfunction and glucose intolerance on a high-fat diet, along with increased ROS levels and decreased islet mitochondrial mass. Our results provide a previously unknown mechanism through which β-cells defend against increased metabolic stress to promote β-cell compensation in obesity.
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Affiliation(s)
- Jae-Su Moon
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Matthew Riopel
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Jong Bae Seo
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Vicente Herrero-Aguayo
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
- Maimonides Institute of Biomedical Research of Cordoba, Cordoba, Spain
| | - Roi Isaac
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Yun Sok Lee
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
- Corresponding author: Yun Sok Lee,
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17
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Gorini F, Vassalle C. Selenium and Selenoproteins at the Intersection of Type 2 Diabetes and Thyroid Pathophysiology. Antioxidants (Basel) 2022; 11:antiox11061188. [PMID: 35740085 PMCID: PMC9227825 DOI: 10.3390/antiox11061188] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/07/2022] [Accepted: 06/15/2022] [Indexed: 02/04/2023] Open
Abstract
Type 2 diabetes (T2D) is considered one of the largest global public-health concerns, affecting approximately more than 400 million individuals worldwide. The pathogenesis of T2D is very complex and, among the modifiable risk factors, selenium (Se) has recently emerged as a determinant of T2D pathogenesis and progression. Selenium is considered an essential element with antioxidant properties, and is incorporated into the selenoproteins involved in the antioxidant response. Furthermore, deiodinases, the enzymes responsible for homeostasis and for controlling the activity of thyroid hormones (THs), contain Se. Given the crucial action of oxidative stress in the onset of insulin resistance (IR) and T2D, and the close connection between THs and glucose metabolism, Se may be involved in these fundamental relationships; it may cover a dual role, both as a protective factor and as a risk factor of T2D, depending on its basal plasma concentration and the individual’s diet intake. In this review we discuss the current evidence (from experimental, observational and randomized clinical studies) on how Se is associated with the occurrence of T2D and its influence on the relationship between thyroid pathophysiology, IR and T2D.
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Affiliation(s)
- Francesca Gorini
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy
- Correspondence:
| | - Cristina Vassalle
- Fondazione CNR-Regione Toscana Gabriele Monasterio, 56124 Pisa, Italy;
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18
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Baumel-Alterzon S, Scott DK. Regulation of Pdx1 by oxidative stress and Nrf2 in pancreatic beta-cells. Front Endocrinol (Lausanne) 2022; 13:1011187. [PMID: 36187092 PMCID: PMC9521308 DOI: 10.3389/fendo.2022.1011187] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 08/26/2022] [Indexed: 01/05/2023] Open
Abstract
The beta-cell identity gene, pancreatic duodenal homeobox 1 (Pdx1), plays critical roles in many aspects of the life of beta-cells including differentiation, maturation, function, survival and proliferation. High levels of reactive oxygen species (ROS) are extremely toxic to cells and especially to beta-cells due to their relatively low expression of antioxidant enzymes. One of the major mechanisms for beta-cell dysfunction in type-2 diabetes results from oxidative stress-dependent inhibition of PDX1 levels and function. ROS inhibits Pdx1 by reducing Pdx1 mRNA and protein levels, inhibiting PDX1 nuclear localization, and suppressing PDX1 coactivator complexes. The nuclear factor erythroid 2-related factor (Nrf2) antioxidant pathway controls the redox balance and allows the maintenance of high Pdx1 levels. Therefore, pharmacological activation of the Nrf2 pathway may alleviate diabetes by preserving Pdx1 levels.
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Affiliation(s)
- Sharon Baumel-Alterzon
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- *Correspondence: Sharon Baumel-Alterzon,
| | - Donald K. Scott
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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19
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Revisiting the contribution of mitochondrial biology to the pathophysiology of skeletal muscle insulin resistance. Biochem J 2021; 478:3809-3826. [PMID: 34751699 DOI: 10.1042/bcj20210145] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 10/14/2021] [Accepted: 10/15/2021] [Indexed: 12/18/2022]
Abstract
While the etiology of type 2 diabetes is multifaceted, the induction of insulin resistance in skeletal muscle is a key phenomenon, and impairments in insulin signaling in this tissue directly contribute to hyperglycemia. Despite the lack of clarity regarding the specific mechanisms whereby insulin signaling is impaired, the key role of a high lipid environment within skeletal muscle has been recognized for decades. Many of the proposed mechanisms leading to the attenuation of insulin signaling - namely the accumulation of reactive lipids and the pathological production of reactive oxygen species (ROS), appear to rely on this high lipid environment. Mitochondrial biology is a central component to these processes, as these organelles are almost exclusively responsible for the oxidation and metabolism of lipids within skeletal muscle and are a primary source of ROS production. Classic studies have suggested that reductions in skeletal muscle mitochondrial content and/or function contribute to lipid-induced insulin resistance; however, in recent years the role of mitochondria in the pathophysiology of insulin resistance has been gradually re-evaluated to consider the biological effects of alterations in mitochondrial content. In this respect, while reductions in mitochondrial content are not required for the induction of insulin resistance, mechanisms that increase mitochondrial content are thought to enhance mitochondrial substrate sensitivity and submaximal adenosine diphosphate (ADP) kinetics. Thus, this review will describe the central role of a high lipid environment in the pathophysiology of insulin resistance, and present both classic and contemporary views of how mitochondrial biology contributes to insulin resistance in skeletal muscle.
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20
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Li T, Zhang J, Wang PJ, Zhang ZW, Huang JQ. Selenoproteins Protect Against Avian Liver Necrosis by Metabolizing Peroxides and Regulating Receptor Interacting Serine Threonine Kinase 1/Receptor Interacting Serine Threonine Kinase 3/Mixed Lineage Kinase Domain-Like and Mitogen-Activated Protein Kinase Signaling. Front Physiol 2021; 12:696256. [PMID: 34456747 PMCID: PMC8397447 DOI: 10.3389/fphys.2021.696256] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 07/12/2021] [Indexed: 12/17/2022] Open
Abstract
Liver necroptosis of chicks is induced by selenium (Se)/vitamin E (VE) deficiencies and may be associated with oxidative cell damage. To reveal the underlying mechanisms of liver necrosis, a pool of the corn-soy basal diet (10 μg Se/kg; no VE added), a basal diet plus all-rac-α-tocopheryl acetate (50 mg/kg), Se (sodium selenite at 0.3 mg/kg), or both of these nutrients were provided to day-old broiler chicks (n = 40/group) for 6 weeks. High incidences of liver necrosis (30%) of chicks were induced by -SE-VE, starting at day 16. The Se concentration in liver and glutathione peroxidase (GPX) activity were decreased (P < 0.05) by dietary Se deficiency. Meanwhile, Se deficiency elevated malondialdehyde content and decreased superoxide dismutase (SOD) activity in the liver at weeks 2 and 4. Chicks fed with the two Se-deficient diets showed lower (P < 0.05) hepatic mRNA expression of Gpx1, Gpx3, Gpx4, Selenof, Selenoh, Selenok, Selenom, Selenon, Selenoo, Selenop, Selenot, Selenou, Selenow, and Dio1 than those fed with the two Se-supplemented diets. Dietary Se deficiency had elevated (P < 0.05) the expression of SELENOP, but decreased the downregulation (P < 0.05) of GPX1, GPX4, SELENON, and SELENOW in the liver of chicks at two time points. Meanwhile, dietary Se deficiency upregulated (P < 0.05) the abundance of hepatic proteins of p38 mitogen-activated protein kinase, phospho-p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, phospho-c-Jun N-terminal kinase, extracellular signal-regulated kinase, phospho-mitogen-activated protein kinase, receptor-interacting serine-threonine kinase 1 (RIPK1), receptor-interacting serine-threonine kinase 3 (RIPK3), and mixed lineage kinase domain-like (MLKL) at two time points. In conclusion, our data confirmed the differential regulation of dietary Se deficiency on several key selenoproteins, the RIPK1/RIPK3/MLKL, and mitogen-activated protein kinase signaling pathway in chicks and identified new molecular clues for understanding the etiology of nutritional liver necrosis.
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Affiliation(s)
- Tong Li
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing, China
| | - Jing Zhang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing, China
- Administrative Engineering College, Xu Zhou University of Technology, Xuzhou, China
| | - Peng-Jie Wang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing, China
- Key Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, China Agricultural University, Beijing, China
| | - Zi-Wei Zhang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing, China
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Jia-Qiang Huang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing, China
- Key Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, China Agricultural University, Beijing, China
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21
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Finger JW, Kelley MD, Zhang Y, Hamilton MT, Elsey RM, Mendonca MT, Kavazis AN. Antioxidant Enzymes in Destructible and Non-Destructible Tissues in American Alligators (Alligator mississippiensis). SOUTH AMERICAN JOURNAL OF HERPETOLOGY 2021. [DOI: 10.2994/sajh-d-19-00118.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- John W. Finger
- Department of Biological Sciences, Auburn University, Auburn, AL 36849, USA
| | - Meghan D. Kelley
- Department of Biological Sciences, Auburn University, Auburn, AL 36849, USA
| | - Yufeng Zhang
- School of Health Studies, University of Memphis, Memphis, TN 38152, USA
| | - Matthew T. Hamilton
- Department of Forestry and Natural Resources, Purdue University, West Lafayette, IN 47907, USA
| | - Ruth M. Elsey
- Louisiana Department of Wildlife and Fisheries, Rockefeller Wildlife Refuge, Grand Chenier, LA 70643, USA
| | - Mary T. Mendonca
- Department of Biological Sciences, Auburn University, Auburn, AL 36849, USA
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22
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Prokai D, Pudasaini A, Kanchwala M, Moehlman AT, Waits AE, Chapman KM, Chaudhary J, Acevedo J, Keller P, Chao X, Carr BR, Hamra FK. Spermatogonial Gene Networks Selectively Couple to Glutathione and Pentose Phosphate Metabolism but Not Cysteine Biosynthesis. iScience 2021; 24:101880. [PMID: 33458605 PMCID: PMC7797946 DOI: 10.1016/j.isci.2020.101880] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 11/02/2020] [Accepted: 11/25/2020] [Indexed: 01/15/2023] Open
Abstract
In adult males, spermatogonia maintain lifelong spermatozoa production for oocyte fertilization. To understand spermatogonial metabolism we compared gene profiles in rat spermatogonia to publicly available mouse, monkey, and human spermatogonial gene profiles. Interestingly, rat spermatogonia expressed metabolic control factors Foxa1, Foxa2, and Foxa3. Germline Foxa2 was enriched in Gfra1Hi and Gfra1Low undifferentiated A-single spermatogonia. Foxa2-bound loci in spermatogonial chromatin were overrepresented by conserved stemness genes (Dusp6, Gfra1, Etv5, Rest, Nanos2, Foxp1) that intersect bioinformatically with conserved glutathione/pentose phosphate metabolism genes (Tkt, Gss, Gc l c , Gc l m, Gpx1, Gpx4, Fth), marking elevated spermatogonial GSH:GSSG. Cystine-uptake and intracellular conversion to cysteine typically couple glutathione biosynthesis to pentose phosphate metabolism. Rat spermatogonia, curiously, displayed poor germline stem cell viability in cystine-containing media, and, like primate spermatogonia, exhibited reduced transsulfuration pathway markers. Exogenous cysteine, cysteine-like mercaptans, somatic testis cells, and ferroptosis inhibitors counteracted the cysteine-starvation-induced spermatogonial death and stimulated spermatogonial growth factor activity in vitro.
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Affiliation(s)
- David Prokai
- Division of Reproductive Endocrinology and Infertility, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Ashutosh Pudasaini
- Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- GenomeDesigns Laboratory, LLC, 314 Stonebridge Drive, Richardson, TX 75080, USA
| | - Mohammed Kanchwala
- McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Andrew T. Moehlman
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Alexandrea E. Waits
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Karen M. Chapman
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jaideep Chaudhary
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jesus Acevedo
- Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Cecil H. & Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Patrick Keller
- Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Cecil H. & Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xing Chao
- McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Bruce R. Carr
- Division of Reproductive Endocrinology and Infertility, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - F. Kent Hamra
- Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Cecil H. & Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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23
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Stancill JS, Corbett JA. The Role of Thioredoxin/Peroxiredoxin in the β-Cell Defense Against Oxidative Damage. Front Endocrinol (Lausanne) 2021; 12:718235. [PMID: 34557160 PMCID: PMC8453158 DOI: 10.3389/fendo.2021.718235] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/19/2021] [Indexed: 02/02/2023] Open
Abstract
Oxidative stress is hypothesized to play a role in pancreatic β-cell damage, potentially contributing to β-cell dysfunction and death in both type 1 and type 2 diabetes. Oxidative stress arises when naturally occurring reactive oxygen species (ROS) are produced at levels that overwhelm the antioxidant capacity of the cell. ROS, including superoxide and hydrogen peroxide, are primarily produced by electron leak during mitochondrial oxidative metabolism. Additionally, peroxynitrite, an oxidant generated by the reaction of superoxide and nitric oxide, may also cause β-cell damage during autoimmune destruction of these cells. β-cells are thought to be susceptible to oxidative damage based on reports that they express low levels of antioxidant enzymes compared to other tissues. Furthermore, markers of oxidative damage are observed in islets from diabetic rodent models and human patients. However, recent studies have demonstrated high expression of various isoforms of peroxiredoxins, thioredoxin, and thioredoxin reductase in β-cells and have provided experimental evidence supporting a role for these enzymes in promoting β-cell function and survival in response to a variety of oxidative stressors. This mini-review will focus on the mechanism by which thioredoxins and peroxiredoxins detoxify ROS and on the protective roles of these enzymes in β-cells. Additionally, we speculate about the role of this antioxidant system in promoting insulin secretion.
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24
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Zheng X, Ren B, Li X, Yan H, Xie Q, Liu H, Zhou J, Tian J, Huang K. Selenoprotein F knockout leads to glucose and lipid metabolism disorders in mice. J Biol Inorg Chem 2020; 25:1009-1022. [DOI: 10.1007/s00775-020-01821-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 08/30/2020] [Indexed: 02/07/2023]
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25
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Zhang K, Han Y, Zhao Q, Zhan T, Li Y, Sun W, Li S, Sun D, Si X, Yu X, Qin Y, Tang C, Zhang J. Targeted Metabolomics Analysis Reveals that Dietary Supranutritional Selenium Regulates Sugar and Acylcarnitine Metabolism Homeostasis in Pig Liver. J Nutr 2020; 150:704-711. [PMID: 32060554 DOI: 10.1093/jn/nxz317] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 07/22/2019] [Accepted: 12/03/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The association between high selenium (Se) intake and metabolic disorders such as type 2 diabetes has raised great concern, but the underlying mechanism remains unclear. OBJECTIVE Through targeted metabolomics analysis, we examined the liver sugar and acylcarnitine metabolism responses to supranutritional selenomethionine (SeMet) supplementation in pigs. METHODS Thirty-six castrated male pigs (Duroc-Landrace-Yorkshire, 62.0 ± 3.3 kg) were fed SeMet adequate (Se-A, 0.25 mg Se/kg) or SeMet supranutritional (Se-S, 2.5 mg Se/kg) diets for 60 d. The Se concentration, biochemical, gene expression, enzyme activity, and energy-targeted metabolite profiles were analyzed. RESULTS The Se-S group had greater fasting serum concentrations of glucose (1.9-fold), insulin (1.4-fold), and free fatty acids (FFAs,1.3-fold) relative to the Se-A group (P < 0.05). The liver total Se concentration was 4.2-fold that of the Se-A group in the Se-S group (P < 0.05), but expression of most selenoprotein genes and selenoenzyme activity did not differ between the 2 groups. Seven of 27 targeted sugar metabolites and 4 of 21 acylcarnitine metabolites significantly changed in response to high SeMet (P < 0.05). High SeMet supplementation significantly upregulated phosphoenolpyruvate carboxy kinase (PEPCK) activity by 64.4% and decreased hexokinase and succinate dehydrogenase (SDH) activity by 46.5-56.7% (P < 0.05). The relative contents of glucose, dihydroxyacetone phosphate, α-ketoglutarate, fumarate, malate, erythrose-4-phosphate, and sedoheptulose-7-phosphate in the Se-S group were 21.1-360% greater than those in the Se-A group (P < 0.05). The expression of fatty acid synthase (FASN) and the relative contents of carnitine, hexanoyl-carnitine, decanoyl-carnitine, and tetradecanoyl-carnitine in the Se-S group were 35-97% higher than those in the Se-A group (P < 0.05). CONCLUSIONS Dietary high SeMet-induced hyperglycemia and hyperinsulinemia were associated with suppression of sugar metabolism and elevation of lipid synthesis in pig livers. Our research provides novel insights into high SeMet intake-induced type 2 diabetes.
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Affiliation(s)
- Kai Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China.,Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Yunsheng Han
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China.,Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Qingyu Zhao
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China.,Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Tengfei Zhan
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China.,Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Ying Li
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China.,Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Wenjuan Sun
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China.,Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Shuang Li
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China.,Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Dandan Sun
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China.,Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Xueyang Si
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China.,Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Xiaonan Yu
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China.,Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Yuchang Qin
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Chaohua Tang
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China.,Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Junmin Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China.,Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing 100193, China
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Perrone MA, Gualtieri P, Gratteri S, Ali W, Sergi D, Muscoli S, Cammarano A, Bernardini S, Di Renzo L, Romeo F. Effects of postprandial hydroxytyrosol and derivates on oxidation of LDL, cardiometabolic state and gene expression: a nutrigenomic approach for cardiovascular prevention. J Cardiovasc Med (Hagerstown) 2019; 20:419-426. [PMID: 31593559 DOI: 10.2459/jcm.0000000000000816] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND AND AIM Cardiovascular diseases (CVDs) are the most frequent causes of death in the world. Inflammation and oxidative damage contribute significantly to the development of atherosclerosis and CVDs. European Food Safety Authority scientific opinion has acknowledged that hydroxytyrosol (3,4-dihydroxyphenylethanol) and derivatives, contained in extra virgin olive oil (EVOO), typically used in Mediterranean diet may play a crucial role in the reduction of the inflammatory pathway and in the prevention of CVDs. The aim of the study was to determine the effect in healthy volunteers of 25 g of phenols-rich EVOO (p-EVOO). METHODS The clinical study was a randomized, controlled trial to determine the acute effect in the postprandial time of 25 g of p-EVOO. We evaluated nutritional status using anthropometric parameters, body composition, serum metabolites, oxidative stress biomarkers and gene expression of eight genes related to oxidative stress and human inflammasome pathways, lasting 2 h after p-EVOO administration. Twenty-two participants resulted as eligible for the study. RESULTS A significant reduction of oxidized LDL, malondialdehyde, triglycerides and visceral adiposity index was highlighted (P < 0.05). Significant upregulation of catalase, superoxide dismutase 1 and upstream transcription factor 1 were observed (P < 0.05). CONCLUSION The current study shows that intake of 25 g of p-EVOO has been able to be modulated, in the postprandial time, the antioxidant profile and the expression of inflammation and oxidative stress-related genes, as superoxide dismutase 1, upstream transcription factor 1 and catalase. We also observed a significant reduction of oxidized LDL, malondialdehyde, triglycerides and visceral adiposity index. We have demonstrated that a daily intake of phenols and antioxidants can reduce the inflammatory pathway and oxidative stress and therefore the risk of atherosclerosis and CVDs. More studies on a larger population are necessary before definitive conclusions can be drawn.Trial registration ClinicalTrials.gov NCT01890070.
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Affiliation(s)
- Marco A Perrone
- Division of Cardiology.,Division of Clinical Biochemistry and Clinical Molecular Biology.,University Sports Centre
| | - Paola Gualtieri
- Division of Clinical Nutrition and Nutrigenomics, University of Rome Tor Vergata, Rome
| | - Santo Gratteri
- Department of Surgery and Medical Science, Magna Græcia University, Catanzaro, Germaneto, Italy
| | - Wahid Ali
- Department of Pathology, King George S. Medical University, Lucknow, Uttar Pradesh, India
| | | | | | - Andrea Cammarano
- Division of Clinical Nutrition and Nutrigenomics, University of Rome Tor Vergata, Rome
| | - Sergio Bernardini
- Division of Clinical Biochemistry and Clinical Molecular Biology.,University Sports Centre
| | - Laura Di Renzo
- Division of Clinical Nutrition and Nutrigenomics, University of Rome Tor Vergata, Rome
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SOD1 deficiency alters gastrointestinal microbiota and metabolites in mice. Exp Gerontol 2019; 130:110795. [PMID: 31805337 DOI: 10.1016/j.exger.2019.110795] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Abstract
Redox imbalance induces oxidative damage and causes age-related pathologies. Mice lacking the antioxidant enzyme SOD1 (Sod1-/-) exhibit various aging-like phenotypes throughout the body and are used as aging model mice. Recent reports suggested that age-related changes in the intestinal environment are involved in various diseases. We investigated cecal microbiota profiles and gastrointestinal metabolites in wild-type (Sod1+/+) and Sod1-/- mice. Firmicutes and Bacteroidetes were dominant in Sod1+/+ mice, and most of the detected bacterial species belong to these two phyla. Meanwhile, the Sod1-/- mice had an altered Firmicutes and Bacteroidetes ratio compared to Sod1+/+ mice. Among the identified genera, Paraprevotella, Prevotella, Ruminococcus, and Bacteroides were significantly increased, but Lactobacillus was significantly decreased in Sod1-/- mice compared to Sod1+/+ mice. The correlation analyses between cecal microbiota and liver metabolites showed that Bacteroides and Prevotella spp. were grouped into the same cluster, and Paraprevotella and Ruminococcus spp. were also grouped as another cluster. These four genera showed a positive and a negative correlation with increased and decreased liver metabolites in Sod1-/- mice, respectively. In contrast, Lactobacillus spp. showed a negative correlation with increased liver metabolites and a positive correlation with decreased liver metabolites in Sod1-/- mice. These results suggest that the redox imbalance induced by Sod1 loss alters gastrointestinal microflora and metabolites.
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Abdellatif AM, Jensen Smith H, Harms RZ, Sarvetnick NE. Human Islet Response to Selected Type 1 Diabetes-Associated Bacteria: A Transcriptome-Based Study. Front Immunol 2019; 10:2623. [PMID: 31781116 PMCID: PMC6857727 DOI: 10.3389/fimmu.2019.02623] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 10/22/2019] [Indexed: 12/12/2022] Open
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease that results from destruction of pancreatic β-cells. T1D subjects were recently shown to harbor distinct intestinal microbiome profiles. Based on these findings, the role of gut bacteria in T1D is being intensively investigated. The mechanism connecting intestinal microbial homeostasis with the development of T1D is unknown. Specific gut bacteria such as Bacteroides dorei (BD) and Ruminococcus gnavus (RG) show markedly increased abundance prior to the development of autoimmunity. One hypothesis is that these bacteria might traverse the damaged gut barrier, and their constituents elicit a response from human islets that causes metabolic abnormalities and inflammation. We have tested this hypothesis by exposing human islets to BD and RG in vitro, after which RNA-Seq analysis was performed. The bacteria altered expression of many islet genes. The commonly upregulated genes by these bacteria were cytokines, chemokines and enzymes, suggesting a significant effect of gut bacteria on islet antimicrobial and biosynthetic pathways. Additionally, each bacteria displayed a unique set of differentially expressed genes (DEGs). Ingenuity pathway analysis of DEGs revealed that top activated pathways and diseases included TREM1 signaling and inflammatory response, illustrating the ability of bacteria to induce islet inflammation. The increased levels of selected factors were confirmed using immunoblotting and ELISA methods. Our data demonstrate that islets produce a complex anti-bacterial response. The response includes both symbiotic and pathogenic aspects. Both oxidative damage and leukocyte recruitment factors were prominent, which could induce beta cell damage and subsequent autoimmunity.
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Affiliation(s)
- Ahmed M. Abdellatif
- Department of Surgery-Transplant, University of Nebraska Medical Center, Omaha, NE, United States
- Mary and Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, United States
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Heather Jensen Smith
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE, United States
| | - Robert Z. Harms
- Department of Surgery-Transplant, University of Nebraska Medical Center, Omaha, NE, United States
- Mary and Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, United States
| | - Nora E. Sarvetnick
- Department of Surgery-Transplant, University of Nebraska Medical Center, Omaha, NE, United States
- Mary and Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, United States
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29
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Ježek P, Jabůrek M, Plecitá-Hlavatá L. Contribution of Oxidative Stress and Impaired Biogenesis of Pancreatic β-Cells to Type 2 Diabetes. Antioxid Redox Signal 2019; 31:722-751. [PMID: 30450940 PMCID: PMC6708273 DOI: 10.1089/ars.2018.7656] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 11/05/2018] [Indexed: 12/14/2022]
Abstract
Significance: Type 2 diabetes development involves multiple changes in β-cells, related to the oxidative stress and impaired redox signaling, beginning frequently by sustained overfeeding due to the resulting lipotoxicity and glucotoxicity. Uncovering relationships among the dysregulated metabolism, impaired β-cell "well-being," biogenesis, or cross talk with peripheral insulin resistance is required for elucidation of type 2 diabetes etiology. Recent Advances: It has been recognized that the oxidative stress, lipotoxicity, and glucotoxicity cannot be separated from numerous other cell pathology events, such as the attempted compensation of β-cell for the increased insulin demand and dynamics of β-cell biogenesis and its "reversal" at dedifferentiation, that is, from the concomitantly decreasing islet β-cell mass (also due to transdifferentiation) and low-grade islet or systemic inflammation. Critical Issues: At prediabetes, the compensation responses of β-cells, attempting to delay the pathology progression-when exaggerated-set a new state, in which a self-checking redox signaling related to the expression of Ins gene expression is impaired. The resulting altered redox signaling, diminished insulin secretion responses to various secretagogues including glucose, may lead to excretion of cytokines or chemokines by β-cells or excretion of endosomes. They could substantiate putative stress signals to the periphery. Subsequent changes and lasting glucolipotoxicity promote islet inflammatory responses and further pathology spiral. Future Directions: Should bring an understanding of the β-cell self-checking and related redox signaling, including the putative stress signal to periphery. Strategies to cure or prevent type 2 diabetes could be based on the substitution of the "wrong" signal by the "correct" self-checking signal.
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Affiliation(s)
- Petr Ježek
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Martin Jabůrek
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Lydie Plecitá-Hlavatá
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
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30
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Newsholme P, Keane KN, Carlessi R, Cruzat V. Oxidative stress pathways in pancreatic β-cells and insulin-sensitive cells and tissues: importance to cell metabolism, function, and dysfunction. Am J Physiol Cell Physiol 2019; 317:C420-C433. [PMID: 31216193 DOI: 10.1152/ajpcell.00141.2019] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
It is now accepted that nutrient abundance in the blood, especially glucose, leads to the generation of reactive oxygen species (ROS), ultimately leading to increased oxidative stress in a variety of tissues. In the absence of an appropriate compensatory response from antioxidant mechanisms, the cell, or indeed the tissue, becomes overwhelmed by oxidative stress, leading to the activation of intracellular stress-associated pathways. Activation of the same or similar pathways also appears to play a role in mediating insulin resistance, impaired insulin secretion, and late diabetic complications. The ability of antioxidants to protect against the oxidative stress induced by hyperglycemia and elevated free fatty acid (FFA) levels in vitro suggests a causative role of oxidative stress in mediating the latter clinical conditions. In this review, we describe common biochemical processes associated with oxidative stress driven by hyperglycemia and/or elevated FFA and the resulting clinical outcomes: β-cell dysfunction and peripheral tissue insulin resistance.
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Affiliation(s)
- Philip Newsholme
- School of Pharmacy and Biomedical Sciences, and Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
| | - Kevin N Keane
- School of Pharmacy and Biomedical Sciences, and Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
| | - Rodrigo Carlessi
- School of Pharmacy and Biomedical Sciences, and Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
| | - Vinicius Cruzat
- Faculty of Health, Torrens University Australia, Melbourne, Victoria, Australia
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31
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Yun JW, Zhao Z, Yan X, Vatamaniuk MZ, Lei XG. Glutathione peroxidase-1 inhibits transcription of regenerating islet-derived protein-2 in pancreatic islets. Free Radic Biol Med 2019; 134:385-393. [PMID: 30703484 PMCID: PMC6588445 DOI: 10.1016/j.freeradbiomed.2019.01.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 01/06/2019] [Accepted: 01/20/2019] [Indexed: 12/22/2022]
Abstract
Our group previously demonstrated that overexpression of selenium-dependent glutathione peroxidase-1 (GPX1) in mice (OE) led to escalated glucose-stimulated insulin secretion and hyperinsulinemia. Because we found a strong correlation of this phenotype with a diminished expression of regenerating islet-derived protein 2 (REG2) in the OE pancreatic islets, the present study was to reveal underlying mechanisms for that down-regulation of REG2 by GPX1 as a major scavenger of reactive oxygen species. We first treated the OE and wild-type (WT) mice and their islets with ROS-generating diquat, streptozotocin, and H2O2 and ROS-scavenging ebselen and N-acetylcysteine (NAC). Their effects on pancreatic and islet REG2 protein and(or) secretion were opposite (P < 0.05). Thereafter, we identified 13 transcriptional factors with putative binding sites in the Reg2 proximate promoter, and found that only activator protein-1 (AP-1) and albumin D box-binding protein (DBP) mRNA and protein levels were affected (elevated) (P < 0.05) by the GPX1 overproduction in the OE pancreatic islets compared with the WT islets. Contrary to that of Reg2 expression, their mRNA abundances in the cultured islets were elevated (P < 0.05) by ebselen and NAC, but decreased (P < 0.05) by H2O2. Both AP-1 and DBP could bind to the Reg2 promoter at the location of -168 to 0 base pair (bp) in the OE islets. Deleting the AP-1 (-143/-137 and -60/-57 bp) and(or) DBP (-35/-29 bp) binding domains in the Reg2 promoter attenuated and(or) abolished the inhibition of Reg2 promoter activation by ebselen as the GPX1 mimic in βTC-3 cells. In conclusion, the down-regulation of Reg2 expression in the GPX1-overproducing pancreatic islets was mediated by a transcriptional inhibition of the gene through two ROS responsive transcription factors AP-1 and DBP. Our findings reveal GPX1 as a novel regulator of Reg2 expression, and linking these two previously-unrelated proteins will have broad biomedical implications.
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Affiliation(s)
- Jun-Won Yun
- Department of Animal Science, Cornell University, Ithaca, NY 14853, USA; Department of Biotechnology, The Catholic University of Korea, Bucheon 14662, Republic of Korea
| | - Zeping Zhao
- Department of Animal Science, Cornell University, Ithaca, NY 14853, USA
| | - Xi Yan
- Department of Animal Science, Cornell University, Ithaca, NY 14853, USA
| | | | - Xin Gen Lei
- Department of Animal Science, Cornell University, Ithaca, NY 14853, USA.
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Chen XD, Zhao ZP, Zhou JC, Lei XG. Evolution, regulation, and function of porcine selenogenome. Free Radic Biol Med 2018; 127:116-123. [PMID: 29698745 PMCID: PMC6420226 DOI: 10.1016/j.freeradbiomed.2018.04.560] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 04/09/2018] [Accepted: 04/18/2018] [Indexed: 12/31/2022]
Abstract
Much less research on regulation and function of selenoproteins has been conducted in domestic pigs than in rodents or humans, although pigs are an excellent model of human nutrition and medicine and pork is a widely consumed meat in the world. Phylogenetically, the 25 identified porcine selenoproteins fell into two primitive groups, and might be further divided into three parallel branches. Despite a high similarity to that of humans and rodents, the porcine selenoproteome exhibited the closest evolutionary relationship with that of sheep and cattle among eight domestic species. Expression (mRNA, protein, and/or enzyme activity) of 2/3 of the 25 porcine selenoproteins in various tissues of pigs was affected by dietary Se intakes, and 14 of them showed responses to a high fat diet. When dietary Se deficiency mainly down-regulated the expression of selected selenoproteins, dietary Se excess exerted rather diverse effects on their expression. Overdosing pigs with dietary Se induced hyperinsulinemia, along with lipid accumulation and protein increase, in the liver and muscle by affecting key genes and(or) proteins involved in the metabolisms of glucose, lipid, and protein. In conclusion, expression of porcine selenoproteins was highly responsive to dietary Se and fat intakes, and was involved in body glucose, lipid, and protein metabolism as those of rodents and humans.
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Affiliation(s)
- Xiao-Dong Chen
- College of Life Science and Technology, Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, PR China
| | - Ze-Ping Zhao
- Department of Animal Science, Cornell University, Ithaca, NY 14853, USA
| | - Ji-Chang Zhou
- School of Public Health School (Shenzhen), Sun Yat-Sen University, Shenzhen 518100, China; Molecular Biology Laboratory, Shenzhen Center for Chronic Disease Control, Shenzhen 518020, China
| | - Xin Gen Lei
- Department of Animal Science, Cornell University, Ithaca, NY 14853, USA; Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100083, China.
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Zhang L, Zeng H, Cheng WH. Beneficial and paradoxical roles of selenium at nutritional levels of intake in healthspan and longevity. Free Radic Biol Med 2018; 127:3-13. [PMID: 29782991 DOI: 10.1016/j.freeradbiomed.2018.05.067] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 05/15/2018] [Accepted: 05/17/2018] [Indexed: 11/15/2022]
Abstract
Accumulation of genome and macromolecule damage is a hallmark of aging, age-associated degeneration, and genome instability syndromes. Although processes of aging are irreversible, they can be modulated by genome maintenance pathways and environmental factors such as diet. Selenium (Se) confers its physiological functions mainly through selenoproteins, but Se compounds and other proteins that incorporate Se nonspecifically also impact optimal health. Bruce Ames proposed that the aging process could be mitigated by a subset of low-hierarchy selenoproteins whose levels are preferentially reduced in response to Se deficiency. Consistent with this notion, results from two selenotranscriptomic studies collectively implicate three low-hierarchy selenoproteins in age or senescence. Experimental evidence generally supports beneficial roles of selenoproteins in the protection against damage accumulation and redox imbalance, but some selenoproteins have also been reported to unexpectedly display harmful functions under sporadic conditions. While longevity and healthspan are usually thought to be projected in parallel, emerging evidence suggests a trade-off between longevity promotion and healthspan deterioration with damage accumulation. We propose that longevity promotion under conditions of Se deficiency may be attributed to 1) stress-response hormesis, an advantageous event of resistance to toxic chemicals at low doses; 2) reduced expression of selenoproteins with paradoxical functions to a lesser extent. In particular, selenoprotein H is an evolutionally conserved nuclear selenoprotein postulated to confer Se functions in redox regulation, genome maintenance, and senescence. This review highlights the need to pinpoint roles of specific selenoproteins and Se compounds in healthspan and lifespan for a better understanding of Se contribution at nutritional levels of intake to healthy aging.
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Affiliation(s)
- Li Zhang
- Department of Food Science, Nutrition and Health Promotion, Mississippi State University, MS 39762, USA
| | - Huawei Zeng
- USDA, Agricultural Research Service, Grand Forks Human Nutrition Center, Grand Forks, ND 58202, USA
| | - Wen-Hsing Cheng
- Department of Food Science, Nutrition and Health Promotion, Mississippi State University, MS 39762, USA.
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Huang JQ, Zhou JC, Wu YY, Ren FZ, Lei XG. Role of glutathione peroxidase 1 in glucose and lipid metabolism-related diseases. Free Radic Biol Med 2018; 127:108-115. [PMID: 29800654 PMCID: PMC6168395 DOI: 10.1016/j.freeradbiomed.2018.05.077] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 05/20/2018] [Accepted: 05/21/2018] [Indexed: 01/14/2023]
Abstract
Glutathione peroxidase 1 (GPX1) is a selenium-dependent enzyme that reduces intracellular hydrogen peroxide and lipid peroxides. While past research explored regulations of gene expression and biochemical function of this selenoperoxidase, GPX1 has recently been implicated in the onset and development of chronic diseases. Clinical data have shown associations of human GPX1 gene variants with elevated risks of diabetes. Knockout and overexpression of Gpx1 in mice may induce types 1 and 2 diabetes-like phenotypes, respectively. This review assembles the latest advances in this new field of selenium biology, and attempts to postulate signal and molecular mechanisms mediating the role of GPX1 in glucose and lipid metabolism-related diseases. Potential therapies by harnessing the beneficial effects of this ubiquitous redox-modulating enzyme are briefly discussed.
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Affiliation(s)
- Jia-Qiang Huang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100083, China; Key Laboratory of Functional Dairy, Co-constructed by Ministry of Education and Beijing Government, China Agricultural University, China
| | - Ji-Chang Zhou
- School of Public Health (Shenzhen), Sun Yat-Sen University, Shenzhen 518100, China; Molecular Biology Laboratory, Shenzhen Center for Chronic Disease Control, Shenzhen 518020, China
| | - Yuan-Yuan Wu
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100083, China
| | - Fa-Zheng Ren
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100083, China; Key Laboratory of Functional Dairy, Co-constructed by Ministry of Education and Beijing Government, China Agricultural University, China
| | - Xin Gen Lei
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100083, China; Department of Animal Science, Cornell University, Ithaca, NY 14853, USA.
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35
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Wang X, Gao H, Wu W, Xie E, Yu Y, He X, Li J, Zheng W, Wang X, Cao X, Meng Z, Chen L, Min J, Wang F. The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α-mediated regulation of Glut2. Protein Cell 2018; 10:436-449. [PMID: 30324491 PMCID: PMC6538592 DOI: 10.1007/s13238-018-0580-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 09/10/2018] [Indexed: 12/17/2022] Open
Abstract
Zinc levels are high in pancreatic β-cells, and zinc is involved in the synthesis, processing and secretion of insulin in these cells. However, precisely how cellular zinc homeostasis is regulated in pancreatic β-cells is poorly understood. By screening the expression of 14 Slc39a metal importer family member genes, we found that the zinc transporter Slc39a5 is significantly down-regulated in pancreatic β-cells in diabetic db/db mice, obese ob/ob mice and high-fat diet-fed mice. Moreover, β-cell-specific Slc39a5 knockout mice have impaired insulin secretion. In addition, Slc39a5-deficient pancreatic islets have reduced glucose tolerance accompanied by reduced expression of Pgc-1α and its downstream target gene Glut2. The down-regulation of Glut2 in Slc39a5-deficient islets was rescued using agonists of Sirt1, Pgc-1α and Ppar-γ. At the mechanistic level, we found that Slc39a5-mediated zinc influx induces Glut2 expression via Sirt1-mediated Pgc-1α activation. These findings suggest that Slc39a5 may serve as a possible therapeutic target for diabetes-related conditions.
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Affiliation(s)
- Xinhui Wang
- School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Hong Gao
- School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Wenhui Wu
- School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Enjun Xie
- School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Yingying Yu
- School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Xuyan He
- School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Jin Li
- School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Wanru Zheng
- School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Xudong Wang
- School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Xizhi Cao
- School of Pharmaceutical Sciences, State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Zhuoxian Meng
- Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Ligong Chen
- School of Pharmaceutical Sciences, State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
| | - Junxia Min
- School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.
| | - Fudi Wang
- School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.
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36
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Fatty Acid-Stimulated Insulin Secretion vs. Lipotoxicity. Molecules 2018; 23:molecules23061483. [PMID: 29921789 PMCID: PMC6100479 DOI: 10.3390/molecules23061483] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 06/13/2018] [Accepted: 06/15/2018] [Indexed: 12/29/2022] Open
Abstract
Fatty acid (FA)-stimulated insulin secretion (FASIS) is reviewed here in contrast to type 2 diabetes etiology, resulting from FA overload, oxidative stress, intermediate hyperinsulinemia, and inflammation, all converging into insulin resistance. Focusing on pancreatic islet β-cells, we compare the physiological FA roles with the pathological ones. Considering FAs not as mere amplifiers of glucose-stimulated insulin secretion (GSIS), but as parallel insulin granule exocytosis inductors, partly independent of the KATP channel closure, we describe the FA initiating roles in the prediabetic state that is induced by retardations in the glycerol-3-phosphate (glucose)-promoted glycerol/FA cycle and by the impaired GPR40/FFA1 (free FA1) receptor pathway, specifically in its amplification by the redox-activated mitochondrial phospholipase, iPLA2γ. Also, excessive dietary FAs stimulate intestine enterocyte incretin secretion, further elevating GSIS, even at low glucose levels, thus contributing to diabetic hyperinsulinemia. With overnutrition and obesity, the FA overload causes impaired GSIS by metabolic dysbalance, paralleled by oxidative and metabolic stress, endoplasmic reticulum stress and numerous pro-apoptotic signaling, all leading to decreased β-cell survival. Lipotoxicity is exerted by saturated FAs, whereas ω-3 polyunsaturated FAs frequently exert antilipotoxic effects. FA-facilitated inflammation upon the recruitment of excess M1 macrophages into islets (over resolving M2 type), amplified by cytokine and chemokine secretion by β-cells, leads to an inevitable failure of pancreatic β-cells.
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Goutzourelas N, Orfanou M, Charizanis I, Leon G, Spandidos DA, Kouretas D. GSH levels affect weight loss in individuals with metabolic syndrome and obesity following dietary therapy. Exp Ther Med 2018; 16:635-642. [PMID: 30116319 PMCID: PMC6090313 DOI: 10.3892/etm.2018.6204] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 05/10/2018] [Indexed: 12/19/2022] Open
Abstract
This study examined the effects of redox status markers on metabolic syndrome (MetS) and obesity before and after dietary intervention and exercise for weight loss. A total of 103 adults suffering from MetS and obesity participated in this study and followed a personalized diet plan for 6 months. Body weight, body fat (BF) percentage (BF%), respiratory quotient (RQ) and the redox status markers, reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS) and protein carbonyls (CARB), were measured twice in each individual, before and after intervention. Dietary intervention resulted in weight loss, a reduction in BF% and a decrease in RQ. The GSH levels were significantly decreased following intervention, while the levels of TBARS and CARB were not affected. Based on the initial GSH levels, the patients were divided into 2 groups as follows: The high GSH group (GSH, >3.5 µmol/g Hb) and the low GSH group (GSH <3.5 µmol/g Hb). Greater weight and BF loss were observed in patients with high GSH levels. It was observed that patients with MetS and obesity with high GSH values responded better to the dietary therapy, exhibiting more significant changes in weight and BF%. This finding underscores the importance of identifying redox status markers, particularly GSH, in obese patients with MetS. Knowing the levels of GSH may aid in developing a better design of an individualized dietary plan for individuals who wish to lose weight.
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Affiliation(s)
- Nikolaos Goutzourelas
- Department of Biochemistry and Biotechnology, University of Thessaly, 41500 Larissa, Greece.,Eatwalk IKE, 15124 Athens, Greece
| | | | | | | | - Demetrios A Spandidos
- Laboratory of Clinical Virology, University of Crete, Medical School, 71409 Heraklion, Greece
| | - Demetrios Kouretas
- Department of Biochemistry and Biotechnology, University of Thessaly, 41500 Larissa, Greece
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38
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Gan F, Hu Z, Huang Y, Xue H, Huang D, Qian G, Hu J, Chen X, Wang T, Huang K. Overexpression of pig selenoprotein S blocks OTA-induced promotion of PCV2 replication by inhibiting oxidative stress and p38 phosphorylation in PK15 cells. Oncotarget 2018; 7:20469-85. [PMID: 26943035 PMCID: PMC4991468 DOI: 10.18632/oncotarget.7814] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 02/20/2016] [Indexed: 12/12/2022] Open
Abstract
Porcine circovirus type 2 (PCV2) is the primary cause of porcine circovirus disease, and ochratoxin A (OTA)-induced oxidative stress promotes PCV2 replication. In humans, selenoprotein S (SelS) has antioxidant ability, but it is unclear whether SelS affects viral infection. Here, we stably transfected PK15 cells with pig pCDNA3.1-SelS to overexpress SelS. Selenium (Se) at 2 or 4 μM and SelS overexpression blocked the OTA-induced increases of PCV2 DNA copy number and infected cell numbers. SelS overexpression also increased glutathione (GSH), NF-E2-related factor 2 (Nrf2) mRNA, and γ-glutamyl-cysteine synthetase mRNA levels; decreased reactive oxygen species (ROS) levels; and inhibited p38 phosphorylation in PCV2-infected PK15 cells, regardless of OTA treatment. Buthionine sulfoximine reversed all of the above SelS-induced changes. siRNA-mediated SelS knockdown decreased Nrf2 mRNA and GSH levels, increased ROS levels, and promoted PCV2 replication in OTA-treated PK15 cells. These data indicate that pig SelS blocks OTA-induced promotion of PCV2 replication by inhibiting the oxidative stress and p38 phosphorylation in PK15 cells.
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Affiliation(s)
- Fang Gan
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China.,Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Zhihua Hu
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China.,Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Yu Huang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China.,Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Hongxia Xue
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China.,Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Da Huang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China.,Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Gang Qian
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China.,Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Junfa Hu
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China.,Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Xingxiang Chen
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China.,Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Tian Wang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Kehe Huang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China.,Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
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39
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Kietzmann T, Petry A, Shvetsova A, Gerhold JM, Görlach A. The epigenetic landscape related to reactive oxygen species formation in the cardiovascular system. Br J Pharmacol 2017; 174:1533-1554. [PMID: 28332701 PMCID: PMC5446579 DOI: 10.1111/bph.13792] [Citation(s) in RCA: 172] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 03/06/2017] [Accepted: 03/08/2017] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular diseases are among the leading causes of death worldwide. Reactive oxygen species (ROS) can act as damaging molecules but also represent central hubs in cellular signalling networks. Increasing evidence indicates that ROS play an important role in the pathogenesis of cardiovascular diseases, although the underlying mechanisms and consequences of pathophysiologically elevated ROS in the cardiovascular system are still not completely resolved. More recently, alterations of the epigenetic landscape, which can affect DNA methylation, post-translational histone modifications, ATP-dependent alterations to chromatin and non-coding RNA transcripts, have been considered to be of increasing importance in the pathogenesis of cardiovascular diseases. While it has long been accepted that epigenetic changes are imprinted during development or even inherited and are not changed after reaching the lineage-specific expression profile, it becomes more and more clear that epigenetic modifications are highly dynamic. Thus, they might provide an important link between the actions of ROS and cardiovascular diseases. This review will provide an overview of the role of ROS in modulating the epigenetic landscape in the context of the cardiovascular system. LINKED ARTICLES This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.
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Affiliation(s)
- Thomas Kietzmann
- Faculty of Biochemistry and Molecular Medicine, Biocenter OuluUniversity of OuluOuluFinland
| | - Andreas Petry
- Experimental and Molecular Pediatric CardiologyGerman Heart Center Munich at the TU MunichMunichGermany
- DZHK (German Centre for Cardiovascular Research)Partner Site Munich Heart AllianceMunichGermany
| | - Antonina Shvetsova
- Faculty of Biochemistry and Molecular Medicine, Biocenter OuluUniversity of OuluOuluFinland
| | - Joachim M Gerhold
- Institute of Molecular and Cell BiologyUniversity of TartuTartuEstonia
| | - Agnes Görlach
- Experimental and Molecular Pediatric CardiologyGerman Heart Center Munich at the TU MunichMunichGermany
- DZHK (German Centre for Cardiovascular Research)Partner Site Munich Heart AllianceMunichGermany
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40
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M. Fetherolf M, Boyd SD, Winkler DD, Winge DR. Oxygen-dependent activation of Cu,Zn-superoxide dismutase-1. Metallomics 2017; 9:1047-1059. [DOI: 10.1039/c6mt00298f] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Copper zinc superoxide dismutase (Sod1) is a critical enzyme in limiting reactive oxygen species in both the cytosol and the mitochondrial intermembrane space.
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Affiliation(s)
| | - Stefanie D. Boyd
- Department of Biological Sciences
- University of Texas at Dallas
- Richardson
- USA
| | - Duane D. Winkler
- Department of Biological Sciences
- University of Texas at Dallas
- Richardson
- USA
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41
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Graciano MF, Leonelli M, Curi R, R.Carpinelli A. Omega-3 fatty acids control productions of superoxide and nitrogen oxide and insulin content in INS-1E cells. J Physiol Biochem 2016; 72:699-710. [DOI: 10.1007/s13105-016-0509-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 07/19/2016] [Indexed: 11/25/2022]
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42
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Sakiyama H, Fujiwara N, Yoneoka Y, Yoshihara D, Eguchi H, Suzuki K. Cu,Zn-SOD deficiency induces the accumulation of hepatic collagen. Free Radic Res 2016; 50:666-77. [PMID: 26981929 DOI: 10.3109/10715762.2016.1164856] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic diseases, and results in the development of fibrosis. Oxidative stress is thought to be one of the underlying causes of NAFLD. Copper/zinc superoxide dismutase (SOD1) is a primary antioxidative enzyme that scavenges superoxide anion radicals. Although SOD1 knockout (KO) mice have been reported to develop fatty livers, it is not known whether this lack of SOD1 leads to the development of fibrosis. Since the accumulation of collagen typically precedes liver fibrosis, we assessed the balance between the synthesis and degradation of collagen in liver tissue from SOD1 KO mice. We found a higher accumulation of collagen in the livers of SOD1 KO mice compared to wild type mice. The level of expression of HSP47, a chaperone of collagen, and a tissue inhibitor (TIMP1) of matrix metalloproteinases (a collagen degradating enzyme) was also increased in SOD1 KO mice livers. These results indicate that collagen synthesis is increased but that its degradation is inhibited in SOD1 KO mice livers. Moreover, SOD1 KO mice liver sections were extensively modified by advanced glycation end products (AGEs), which suggest that collagen in SOD1 KO mice liver might be also modified with AGEs and then would be more resistant to the action of collagen degrading enzymes. These findings clearly show that oxidative stress plays an important role in the progression of liver fibrosis.
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Affiliation(s)
- Haruhiko Sakiyama
- a Department of Biochemistry, Hyogo College of Medicine , Nishinomiya , Hyogo , Japan
| | - Noriko Fujiwara
- a Department of Biochemistry, Hyogo College of Medicine , Nishinomiya , Hyogo , Japan
| | - Yuka Yoneoka
- a Department of Biochemistry, Hyogo College of Medicine , Nishinomiya , Hyogo , Japan
| | - Daisaku Yoshihara
- a Department of Biochemistry, Hyogo College of Medicine , Nishinomiya , Hyogo , Japan
| | - Hironobu Eguchi
- a Department of Biochemistry, Hyogo College of Medicine , Nishinomiya , Hyogo , Japan
| | - Keiichiro Suzuki
- a Department of Biochemistry, Hyogo College of Medicine , Nishinomiya , Hyogo , Japan
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43
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Kuo T, Kim-Muller JY, McGraw TE, Accili D. Altered Plasma Profile of Antioxidant Proteins as an Early Correlate of Pancreatic β Cell Dysfunction. J Biol Chem 2016; 291:9648-56. [PMID: 26917725 DOI: 10.1074/jbc.m115.702183] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Indexed: 12/22/2022] Open
Abstract
Insulin resistance and β cell dysfunction contribute to the pathogenesis of type 2 diabetes. Unlike insulin resistance, β cell dysfunction remains difficult to predict and monitor, because of the inaccessibility of the endocrine pancreas, the integrated relationship with insulin sensitivity, and the paracrine effects of incretins. The goal of our study was to survey the plasma response to a metabolic challenge in order to identify factors predictive of β cell dysfunction. To this end, we combined (i) the power of unbiased iTRAQ (isobaric tag for relative and absolute quantification) mass spectrometry with (ii) direct sampling of the portal vein following an intravenous glucose/arginine challenge (IVGATT) in (iii) mice with a genetic β cell defect. By so doing, we excluded the effects of peripheral insulin sensitivity as well as those of incretins on β cells, and focused on the first phase of insulin secretion to capture the early pathophysiology of β cell dysfunction. We compared plasma protein profiles with ex vivo islet secretome and transcriptome analyses. We detected changes to 418 plasma proteins in vivo, and detected changes to 262 proteins ex vivo The impairment of insulin secretion was associated with greater overall changes in the plasma response to IVGATT, possibly reflecting metabolic instability. Reduced levels of proteins regulating redox state and neuronal stress markers, as well as increased levels of coagulation factors, antedated the loss of insulin secretion in diabetic mice. These results suggest that a reduced complement of antioxidants in response to a mixed secretagogue challenge is an early correlate of future β cell failure.
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Affiliation(s)
- Taiyi Kuo
- From the Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York 10032 and
| | - Ja Young Kim-Muller
- From the Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York 10032 and
| | - Timothy E McGraw
- the Department of Biochemistry, Weill Cornell Medical College, New York, New York 10065
| | - Domenico Accili
- From the Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York 10032 and
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44
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Lei XG, Zhu JH, Cheng WH, Bao Y, Ho YS, Reddi AR, Holmgren A, Arnér ESJ. Paradoxical Roles of Antioxidant Enzymes: Basic Mechanisms and Health Implications. Physiol Rev 2016; 96:307-64. [PMID: 26681794 DOI: 10.1152/physrev.00010.2014] [Citation(s) in RCA: 274] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from aerobic metabolism, as a result of accidental electron leakage as well as regulated enzymatic processes. Because ROS/RNS can induce oxidative injury and act in redox signaling, enzymes metabolizing them will inherently promote either health or disease, depending on the physiological context. It is thus misleading to consider conventionally called antioxidant enzymes to be largely, if not exclusively, health protective. Because such a notion is nonetheless common, we herein attempt to rationalize why this simplistic view should be avoided. First we give an updated summary of physiological phenotypes triggered in mouse models of overexpression or knockout of major antioxidant enzymes. Subsequently, we focus on a series of striking cases that demonstrate "paradoxical" outcomes, i.e., increased fitness upon deletion of antioxidant enzymes or disease triggered by their overexpression. We elaborate mechanisms by which these phenotypes are mediated via chemical, biological, and metabolic interactions of the antioxidant enzymes with their substrates, downstream events, and cellular context. Furthermore, we propose that novel treatments of antioxidant enzyme-related human diseases may be enabled by deliberate targeting of dual roles of the pertaining enzymes. We also discuss the potential of "antioxidant" nutrients and phytochemicals, via regulating the expression or function of antioxidant enzymes, in preventing, treating, or aggravating chronic diseases. We conclude that "paradoxical" roles of antioxidant enzymes in physiology, health, and disease derive from sophisticated molecular mechanisms of redox biology and metabolic homeostasis. Simply viewing antioxidant enzymes as always being beneficial is not only conceptually misleading but also clinically hazardous if such notions underpin medical treatment protocols based on modulation of redox pathways.
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Affiliation(s)
- Xin Gen Lei
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing,China; Department of Animal Science, Cornell University, Ithaca, New York; Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi; Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom; Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan; Georgia Institute of Technology, School of Chemistry and Biochemistry, Parker Petit Institute for Bioengineering and Biosciences, Atlanta, Georgia; and Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Jian-Hong Zhu
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing,China; Department of Animal Science, Cornell University, Ithaca, New York; Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi; Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom; Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan; Georgia Institute of Technology, School of Chemistry and Biochemistry, Parker Petit Institute for Bioengineering and Biosciences, Atlanta, Georgia; and Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Wen-Hsing Cheng
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing,China; Department of Animal Science, Cornell University, Ithaca, New York; Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi; Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom; Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan; Georgia Institute of Technology, School of Chemistry and Biochemistry, Parker Petit Institute for Bioengineering and Biosciences, Atlanta, Georgia; and Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Yongping Bao
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing,China; Department of Animal Science, Cornell University, Ithaca, New York; Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi; Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom; Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan; Georgia Institute of Technology, School of Chemistry and Biochemistry, Parker Petit Institute for Bioengineering and Biosciences, Atlanta, Georgia; and Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Ye-Shih Ho
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing,China; Department of Animal Science, Cornell University, Ithaca, New York; Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi; Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom; Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan; Georgia Institute of Technology, School of Chemistry and Biochemistry, Parker Petit Institute for Bioengineering and Biosciences, Atlanta, Georgia; and Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Amit R Reddi
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing,China; Department of Animal Science, Cornell University, Ithaca, New York; Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi; Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom; Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan; Georgia Institute of Technology, School of Chemistry and Biochemistry, Parker Petit Institute for Bioengineering and Biosciences, Atlanta, Georgia; and Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Arne Holmgren
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing,China; Department of Animal Science, Cornell University, Ithaca, New York; Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi; Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom; Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan; Georgia Institute of Technology, School of Chemistry and Biochemistry, Parker Petit Institute for Bioengineering and Biosciences, Atlanta, Georgia; and Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Elias S J Arnér
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing,China; Department of Animal Science, Cornell University, Ithaca, New York; Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi; Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom; Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan; Georgia Institute of Technology, School of Chemistry and Biochemistry, Parker Petit Institute for Bioengineering and Biosciences, Atlanta, Georgia; and Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Hamasaki H, Kawashima Y, Yanai H. Serum Zn/Cu Ratio Is Associated with Renal Function, Glycemic Control, and Metabolic Parameters in Japanese Patients with and without Type 2 Diabetes: A Cross-sectional Study. Front Endocrinol (Lausanne) 2016; 7:147. [PMID: 27895622 PMCID: PMC5108809 DOI: 10.3389/fendo.2016.00147] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 11/01/2016] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Zinc (Zn) and copper (Cu) may play a pivotal role in the pathogenesis of diabetes and diabetic complications by mediating oxidative stress. Both Zn deficiency and excess of Cu are associated with an increased risk of type 2 diabetes and cardiovascular disease. We aimed to investigate the relationships between serum Zn/Cu ratio and glycemic status, renal function, and metabolic parameters in patients with and without type 2 diabetes. METHODS We conducted a cross-sectional study on 355 subjects (149 type 2 diabetic and 206 non-diabetic) in whom serum Zn and Cu levels were measured at the same time. Associations between serum Zn/Cu ratio and clinical data were evaluated using multiple regression analysis. We also evaluated associations between serum Zn/Cu ratio and the prevalence of type 2 diabetes and glycemic control by multivariate logistic regression analysis. RESULTS Serum Zn/Cu ratio was positively associated with estimated glomerular filtration rate after adjustment for body mass index (BMI) (β = 0.137, p = 0.014). Plasma B-type natriuretic peptide levels were negatively associated with serum Zn/Cu ratio after adjustment for age, sex, and BMI (β = -0.258, p = 0.032). In patients with type 2 diabetes, serum Zn/Cu ratio was negatively associated with plasma HbA1c levels after adjustment for age, sex, and BMI (β = -0.239, p = 0.003). In addition, multivariate logistic regression analysis revealed that the highest quartile of serum Zn/Cu ratio was associated with a reduced risk of poor (HbA1c ≥ 7%) glycemic control (odds ratio = 0.382; 95% confidence interval, 0.165-0.884; p = 0.025) in patients with type 2 diabetes. CONCLUSION Serum Zn/Cu ratio was favorably associated with renal function in all subjects and glycemic control in patients with type 2 diabetes. The Zn/Cu ratio, in addition to the individual serum levels of trace elements, is important for metabolism in humans.
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Affiliation(s)
- Hidetaka Hamasaki
- Department of Internal Medicine, National Center for Global Health and Medicine, Kohnodai Hospital, Chiba, Japan
- *Correspondence: Hidetaka Hamasaki,
| | - Yu Kawashima
- Department of Radiology, Chiba University Hospital, Chiba, Japan
| | - Hidekatsu Yanai
- Department of Internal Medicine, National Center for Global Health and Medicine, Kohnodai Hospital, Chiba, Japan
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Glutathionyl systems and metabolic dysfunction in obesity. Nutr Rev 2015; 73:858-68. [DOI: 10.1093/nutrit/nuv042] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 04/18/2015] [Indexed: 12/18/2022] Open
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Mikhed Y, Görlach A, Knaus UG, Daiber A. Redox regulation of genome stability by effects on gene expression, epigenetic pathways and DNA damage/repair. Redox Biol 2015; 5:275-289. [PMID: 26079210 PMCID: PMC4475862 DOI: 10.1016/j.redox.2015.05.008] [Citation(s) in RCA: 116] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 05/28/2015] [Accepted: 05/29/2015] [Indexed: 02/07/2023] Open
Abstract
Reactive oxygen and nitrogen species (e.g. H2O2, nitric oxide) confer redox regulation of essential cellular signaling pathways such as cell differentiation, proliferation, migration and apoptosis. In addition, classical regulation of gene expression or activity, including gene transcription to RNA followed by translation to the protein level, by transcription factors (e.g. NF-κB, HIF-1α) and mRNA binding proteins (e.g. GAPDH, HuR) is subject to redox regulation. This review will give an update of recent discoveries in this field, and specifically highlight the impact of reactive oxygen and nitrogen species on DNA repair systems that contribute to genomic stability. Emphasis will be placed on the emerging role of redox mechanisms regulating epigenetic pathways (e.g. miRNA, DNA methylation and histone modifications). By providing clinical correlations we discuss how oxidative stress can impact on gene regulation/activity and vise versa, how epigenetic processes, other gene regulatory mechanisms and DNA repair can influence the cellular redox state and contribute or prevent development or progression of disease.
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Affiliation(s)
- Yuliya Mikhed
- 2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Agnes Görlach
- German Heart Center Munich at the Technical University Munich, DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Ulla G Knaus
- Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland
| | - Andreas Daiber
- 2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
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Huang JQ, Ren FZ, Jiang YY, Xiao C, Lei XG. Selenoproteins protect against avian nutritional muscular dystrophy by metabolizing peroxides and regulating redox/apoptotic signaling. Free Radic Biol Med 2015; 83:129-38. [PMID: 25668720 DOI: 10.1016/j.freeradbiomed.2015.01.033] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Revised: 01/09/2015] [Accepted: 01/30/2015] [Indexed: 01/01/2023]
Abstract
Nutritional muscular dystrophy (NMD) of chicks is induced by dietary selenium (Se)/vitamin E (Vit. E) deficiencies and may be associated with oxidative cell damage. To reveal the underlying mechanisms related to the presumed oxidative cell damage, we fed four groups of 1-day-old broiler chicks (n = 40/group) with a basal diet (BD; 10 μg Se/kg; no Vit. E added, -Se -Vit. E) or the BD plus all-rac-α-tocopheryl acetate at 50mg/kg (-Se +Vit. E), Se (as sodium selenite) at 0.3mg/kg (+Se -Vit. E), or both of these nutrients (+Se +Vit. E) for 6 weeks. High incidences of NMD (93%) and mortality (36%) of the chicks were induced by the BD, starting at week 3. Dietary Se deficiency alone also induced muscle fiber rupture and coagulation necrosis in the pectoral muscle of chicks at week 3 and thereafter, with increased (P < 0.05) malondialdehyde, decreased (P < 0.05) total antioxidant capacity, and diminished (P < 0.05) glutathione peroxidase activities in the muscle. To link these oxidative damages of the muscle cells to the Se-deficiency-induced NMD, we first determined gene expression of the potential 26 selenoproteins in the muscle of the chicks at week 2 before the onset of symptoms. Compared with the +Se chicks, the -Se chicks had lower (P < 0.05) muscle mRNA levels of Gpx1, Gpx3, Gpx4, Sepp1, Selo, Selk, Selu, Selh, Selm, Sepw1, and Sep15. The -Se chicks also had decreased (P < 0.05) production of 6 selenoproteins (long-form selenoprotein P (SelP-L), GPx1, GPx4, Sep15, SelW, and SelN), but increased levels (P < 0.05) of the short-form selenoprotein P in muscle at weeks 2 and 4. Dietary Se deficiency elevated (P < 0.05) muscle p53, cleaved caspase 3, cleaved caspase 9, cyclooxygenase 2 (COX2), focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3K), phospho-Akt, nuclear factor-κB (NF-κB), p38 mitogen-activated protein kinase (p38 MAPK), phospho-p38 MAPK, phospho-JNK, and phospho-ERK and decreased (P < 0.05) muscle procaspase 3, procaspase 9, and NF-κB inhibitor α. In conclusion, the downregulation of SelP-L, GPx1, GPx4, Sep15, SelW, and SelN by dietary Se deficiency might account for induced oxidative stress and the subsequent peroxidative damage of chick muscle cells via the activation of the p53/caspase 9/caspase 3, COX2/FAK/PI3K/Akt/NF-κB, and p38 MAPK/JNK/ERK signaling pathways. Metabolism of peroxides and redox regulation are likely to be the mechanisms whereby these selenoproteins prevented the onset of NMD in chicks.
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Affiliation(s)
- Jia-Qiang Huang
- The Innovation Centre of Food Nutrition and Human Health (Beijing), Beijing Laboratory of Food Quality and Safety, and Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Fa-Zheng Ren
- The Innovation Centre of Food Nutrition and Human Health (Beijing), Beijing Laboratory of Food Quality and Safety, and Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; Beijing Higher Institution Engineering Research Center for Animal Products, Beijing 100083, China.
| | - Yun-Yun Jiang
- The Innovation Centre of Food Nutrition and Human Health (Beijing), Beijing Laboratory of Food Quality and Safety, and Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; Beijing Higher Institution Engineering Research Center for Animal Products, Beijing 100083, China
| | - Chen Xiao
- The Innovation Centre of Food Nutrition and Human Health (Beijing), Beijing Laboratory of Food Quality and Safety, and Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; Beijing Higher Institution Engineering Research Center for Animal Products, Beijing 100083, China
| | - Xin Gen Lei
- The Innovation Centre of Food Nutrition and Human Health (Beijing), Beijing Laboratory of Food Quality and Safety, and Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; Department of Animal Science, Cornell University, Ithaca, NY 14853, USA.
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Pacifici F, Arriga R, Sorice GP, Capuani B, Scioli MG, Pastore D, Donadel G, Bellia A, Caratelli S, Coppola A, Ferrelli F, Federici M, Sconocchia G, Tesauro M, Sbraccia P, Della-Morte D, Giaccari A, Orlandi A, Lauro D. Peroxiredoxin 6, a novel player in the pathogenesis of diabetes. Diabetes 2014; 63:3210-20. [PMID: 24947358 DOI: 10.2337/db14-0144] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Enhanced oxidative stress contributes to the pathogenesis of diabetes and its complications. Peroxiredoxin 6 (PRDX6) is a key regulator of cellular redox balance, with the peculiar ability to neutralize peroxides, peroxynitrite, and phospholipid hydroperoxides. In the current study, we aimed to define the role of PRDX6 in the pathophysiology of type 2 diabetes (T2D) using PRDX6 knockout (-/-) mice. Glucose and insulin responses were evaluated respectively by intraperitoneal glucose and insulin tolerance tests. Peripheral insulin sensitivity was analyzed by euglycemic-hyperinsulinemic clamp, and molecular tools were used to investigate insulin signaling. Moreover, inflammatory and lipid parameters were evaluated. We demonstrated that PRDX6(-/-) mice developed a phenotype similar to early-stage T2D caused by both reduced glucose-dependent insulin secretion and increased insulin resistance. Impaired insulin signaling was present in PRDX6(-/-) mice, leading to reduction of muscle glucose uptake. Morphological and ultrastructural changes were observed in islets of Langerhans and livers of mutant animals, as well as altered plasma lipid profiles and inflammatory parameters. In conclusion, we demonstrated that PRDX6 is a key mediator of overt hyperglycemia in T2D glucose metabolism, opening new perspectives for targeted therapeutic strategies in diabetes care.
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Affiliation(s)
- Francesca Pacifici
- Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Roberto Arriga
- Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Gian Pio Sorice
- Division of Endocrinology and Metabolic Diseases, Università Cattolica del Sacro Cuore, Rome, Italy Diabetic Care Clinics, Associazione dei Cavalieri Italiani Sovrano Militare Ordine di Malta, Rome, Italy
| | - Barbara Capuani
- Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Maria Giovanna Scioli
- Anatomic Pathology, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Donatella Pastore
- Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Giulia Donadel
- Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Alfonso Bellia
- Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Sara Caratelli
- Department of System Medicine, University of Rome Tor Vergata, Rome, Italy Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Andrea Coppola
- Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Francesca Ferrelli
- Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Massimo Federici
- Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Giuseppe Sconocchia
- Department of System Medicine, University of Rome Tor Vergata, Rome, Italy Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Manfredi Tesauro
- Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Paolo Sbraccia
- Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - David Della-Morte
- Department of System Medicine, University of Rome Tor Vergata, Rome, Italy Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana, Rome, Italy
| | - Andrea Giaccari
- Division of Endocrinology and Metabolic Diseases, Università Cattolica del Sacro Cuore, Rome, Italy Fondazione Don Carlo Gnocchi, Milan, Italy
| | - Augusto Orlandi
- Anatomic Pathology, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Davide Lauro
- Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
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Watanabe K, Shibuya S, Ozawa Y, Nojiri H, Izuo N, Yokote K, Shimizu T. Superoxide dismutase 1 loss disturbs intracellular redox signaling, resulting in global age-related pathological changes. BIOMED RESEARCH INTERNATIONAL 2014; 2014:140165. [PMID: 25276767 PMCID: PMC4170698 DOI: 10.1155/2014/140165] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Revised: 07/29/2014] [Accepted: 08/06/2014] [Indexed: 01/14/2023]
Abstract
Aging is characterized by increased oxidative stress, chronic inflammation, and organ dysfunction, which occur in a progressive and irreversible manner. Superoxide dismutase (SOD) serves as a major antioxidant and neutralizes superoxide radicals throughout the body. In vivo studies have demonstrated that copper/zinc superoxide dismutase-deficient (Sod1(-/-)) mice show various aging-like pathologies, accompanied by augmentation of oxidative damage in organs. We found that antioxidant treatment significantly attenuated the age-related tissue changes and oxidative damage-associated p53 upregulation in Sod1(-/-) mice. This review will focus on various age-related pathologies caused by the loss of Sod1 and will discuss the molecular mechanisms underlying the pathogenesis in Sod1(-/-) mice.
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Affiliation(s)
- Kenji Watanabe
- Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
- Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Shuichi Shibuya
- Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Yusuke Ozawa
- Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Hidetoshi Nojiri
- Department of Orthopaedics, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Naotaka Izuo
- Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Koutaro Yokote
- Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Takahiko Shimizu
- Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
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