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Ferreira RR, Carvalho RV, Coelho LL, Gonzaga BMDS, Bonecini-Almeida MDG, Garzoni LR, Araujo-Jorge TC. Current Understanding of Human Polymorphism in Selenoprotein Genes: A Review of Its Significance as a Risk Biomarker. Int J Mol Sci 2024; 25:1402. [PMID: 38338681 PMCID: PMC10855570 DOI: 10.3390/ijms25031402] [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: 08/13/2023] [Revised: 11/04/2023] [Accepted: 11/06/2023] [Indexed: 02/12/2024] Open
Abstract
Selenium has been proven to influence several biological functions, showing to be an essential micronutrient. The functional studies demonstrated the benefits of a balanced selenium diet and how its deficiency is associated with diverse diseases, especially cancer and viral diseases. Selenium is an antioxidant, protecting the cells from damage, enhancing the immune system response, preventing cardiovascular diseases, and decreasing inflammation. Selenium can be found in its inorganic and organic forms, and its main form in the cells is the selenocysteine incorporated into selenoproteins. Twenty-five selenoproteins are currently known in the human genome: glutathione peroxidases, iodothyronine deiodinases, thioredoxin reductases, selenophosphate synthetase, and other selenoproteins. These proteins lead to the transport of selenium in the tissues, protect against oxidative damage, contribute to the stress of the endoplasmic reticulum, and control inflammation. Due to these functions, there has been growing interest in the influence of polymorphisms in selenoproteins in the last two decades. Selenoproteins' gene polymorphisms may influence protein structure and selenium concentration in plasma and its absorption and even impact the development and progression of certain diseases. This review aims to elucidate the role of selenoproteins and understand how their gene polymorphisms can influence the balance of physiological conditions. In this polymorphism review, we focused on the PubMed database, with only articles published in English between 2003 and 2023. The keywords used were "selenoprotein" and "polymorphism". Articles that did not approach the theme subject were excluded. Selenium and selenoproteins still have a long way to go in molecular studies, and several works demonstrated the importance of their polymorphisms as a risk biomarker for some diseases, especially cardiovascular and thyroid diseases, diabetes, and cancer.
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Affiliation(s)
- Roberto Rodrigues Ferreira
- Laboratory of Innovations in Therapies, Education and Bioproducts, Oswaldo Cruz Institute (LITEB-IOC/Fiocruz), Oswaldo Cruz Foundation (Fiocruz), Avenida Brasil 4365, Manguinhos, Pav. Cardoso Fontes, Sala 64, Rio de Janeiro 21040-360, Brazil; (R.V.C.); (L.L.C.); (B.M.d.S.G.); (L.R.G.)
| | - Regina Vieira Carvalho
- Laboratory of Innovations in Therapies, Education and Bioproducts, Oswaldo Cruz Institute (LITEB-IOC/Fiocruz), Oswaldo Cruz Foundation (Fiocruz), Avenida Brasil 4365, Manguinhos, Pav. Cardoso Fontes, Sala 64, Rio de Janeiro 21040-360, Brazil; (R.V.C.); (L.L.C.); (B.M.d.S.G.); (L.R.G.)
| | - Laura Lacerda Coelho
- Laboratory of Innovations in Therapies, Education and Bioproducts, Oswaldo Cruz Institute (LITEB-IOC/Fiocruz), Oswaldo Cruz Foundation (Fiocruz), Avenida Brasil 4365, Manguinhos, Pav. Cardoso Fontes, Sala 64, Rio de Janeiro 21040-360, Brazil; (R.V.C.); (L.L.C.); (B.M.d.S.G.); (L.R.G.)
| | - Beatriz Matheus de Souza Gonzaga
- Laboratory of Innovations in Therapies, Education and Bioproducts, Oswaldo Cruz Institute (LITEB-IOC/Fiocruz), Oswaldo Cruz Foundation (Fiocruz), Avenida Brasil 4365, Manguinhos, Pav. Cardoso Fontes, Sala 64, Rio de Janeiro 21040-360, Brazil; (R.V.C.); (L.L.C.); (B.M.d.S.G.); (L.R.G.)
| | - Maria da Gloria Bonecini-Almeida
- Laboratory of Immunology and Immunogenetics, Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Avenida Brasil 4365, Manguinhos, Rio de Janeiro 21040-360, Brazil;
| | - Luciana Ribeiro Garzoni
- Laboratory of Innovations in Therapies, Education and Bioproducts, Oswaldo Cruz Institute (LITEB-IOC/Fiocruz), Oswaldo Cruz Foundation (Fiocruz), Avenida Brasil 4365, Manguinhos, Pav. Cardoso Fontes, Sala 64, Rio de Janeiro 21040-360, Brazil; (R.V.C.); (L.L.C.); (B.M.d.S.G.); (L.R.G.)
| | - Tania C. Araujo-Jorge
- Laboratory of Innovations in Therapies, Education and Bioproducts, Oswaldo Cruz Institute (LITEB-IOC/Fiocruz), Oswaldo Cruz Foundation (Fiocruz), Avenida Brasil 4365, Manguinhos, Pav. Cardoso Fontes, Sala 64, Rio de Janeiro 21040-360, Brazil; (R.V.C.); (L.L.C.); (B.M.d.S.G.); (L.R.G.)
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Cai YX, Wu YQ, Liu J, Pan H, Deng W, Sun W, Xie C, Huang XF. Proteome-wide analysis reveals potential therapeutic targets for Colorectal cancer: a two-sample mendelian randomization study. BMC Cancer 2023; 23:1188. [PMID: 38049731 PMCID: PMC10696874 DOI: 10.1186/s12885-023-11669-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 11/23/2023] [Indexed: 12/06/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a leading cause of cancer-related mortality, highlighting an unmet clinical need for more effective therapies. This study aims to evaluate the causal relationship between 4,489 plasma proteins and CRC to identify potential therapeutic targets for CRC. METHODS We conducted two-sample Mendelian randomization (MR) analysis to examine the causal effects of plasma proteins on CRC. Mediation analysis was performed to assess the indirect effects of plasma proteins on CRC through associated risk factors. In addition, we conducted a phenome-wide association study using the UK Biobank dataset to examine associations between these plasma proteins and other phenotypes. RESULTS Out of 4,489 plasma proteins, MR analysis revealed causal associations with CRC for 23 proteins, including VIMP, MICB, TNFRSF11B, C5orf38 and SLC5A8. Our findings also confirm the associations between reported risk factors and CRC. Mediation analysis identified mediating effects of proteins on CRC outcomes through risk factors. Furthermore, MR analysis identified 154 plasma proteins are causally linked to at least one CRC risk factor. CONCLUSIONS Our study evaluated the causal relationships between plasma proteins and CRC, providing a more complete understanding of potential therapeutic targets for CRC.
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Affiliation(s)
- Yi-Xin Cai
- Zhejiang Provincial Clinical Research Center for Pediatric Disease, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yi-Qing Wu
- Department of Pediatrics, the Second School of Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jie Liu
- Information Technology Center, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Huanle Pan
- Department of Radiation and Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wenhai Deng
- Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Weijian Sun
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Congying Xie
- Department of Radiation and Medical Oncology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Xiu-Feng Huang
- Zhejiang Provincial Clinical Research Center for Pediatric Disease, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
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Dogaru CB, Duță C, Muscurel C, Stoian I. "Alphabet" Selenoproteins: Implications in Pathology. Int J Mol Sci 2023; 24:15344. [PMID: 37895024 PMCID: PMC10607139 DOI: 10.3390/ijms242015344] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/08/2023] [Accepted: 10/16/2023] [Indexed: 10/29/2023] Open
Abstract
Selenoproteins are a group of proteins containing selenium in the form of selenocysteine (Sec, U) as the 21st amino acid coded in the genetic code. Their synthesis depends on dietary selenium uptake and a common set of cofactors. Selenoproteins accomplish diverse roles in the body and cell processes by acting, for example, as antioxidants, modulators of the immune function, and detoxification agents for heavy metals, other xenobiotics, and key compounds in thyroid hormone metabolism. Although the functions of all this protein family are still unknown, several disorders in their structure, activity, or expression have been described by researchers. They concluded that selenium or cofactors deficiency, on the one hand, or the polymorphism in selenoproteins genes and synthesis, on the other hand, are involved in a large variety of pathological conditions, including type 2 diabetes, cardiovascular, muscular, oncological, hepatic, endocrine, immuno-inflammatory, and neurodegenerative diseases. This review focuses on the specific roles of selenoproteins named after letters of the alphabet in medicine, which are less known than the rest, regarding their implications in the pathological processes of several prevalent diseases and disease prevention.
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Affiliation(s)
| | | | - Corina Muscurel
- Department of Biochemistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania (I.S.)
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Yang T, Lee SY, Park KC, Park SH, Chung J, Lee S. The Effects of Selenium on Bone Health: From Element to Therapeutics. Molecules 2022; 27:392. [PMID: 35056706 PMCID: PMC8780783 DOI: 10.3390/molecules27020392] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/31/2021] [Accepted: 01/04/2022] [Indexed: 02/06/2023] Open
Abstract
Osteoporosis, characterized by low bone mass and a disruption of bone microarchitecture, is traditionally treated using drugs or lifestyle modifications. Recently, several preclinical and clinical studies have investigated the effects of selenium on bone health, although the results are controversial. Selenium, an important trace element, is required for selenoprotein synthesis and acts crucially for proper growth and skeletal development. However, the intake of an optimum amount of selenium is critical, as both selenium deficiency and toxicity are hazardous for health. In this review, we have systematically analyzed the existing literature in this field to determine whether dietary or serum selenium concentrations are associated with bone health. In addition, the mode of administration of selenium as a supplement for treating bone disease is important. We have also highlighted the importance of using green-synthesized selenium nanoparticles as therapeutics for bone disease. Novel nanobiotechnology will be a bridgehead for clinical applications of trace elements and natural products.
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Affiliation(s)
- Taeyoung Yang
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si 13496, Korea; (T.Y.); (S.-Y.L.)
| | - So-Young Lee
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si 13496, Korea; (T.Y.); (S.-Y.L.)
| | - Kyung-Chae Park
- Health Promotion Center, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si 13488, Korea;
| | - Sin-Hyung Park
- Department of Orthopaedic Surgery, Bucheon Hospital, Soonchunhyang University School of Medicine, Bucheon-si 14584, Korea;
| | - Jaiwoo Chung
- Department of Orthopaedic Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si 13496, Korea;
| | - Soonchul Lee
- Department of Orthopaedic Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si 13496, Korea;
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Schomburg L. Selenium Deficiency Due to Diet, Pregnancy, Severe Illness, or COVID-19-A Preventable Trigger for Autoimmune Disease. Int J Mol Sci 2021; 22:8532. [PMID: 34445238 PMCID: PMC8395178 DOI: 10.3390/ijms22168532] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 07/30/2021] [Accepted: 08/06/2021] [Indexed: 12/11/2022] Open
Abstract
The trace element selenium (Se) is an essential part of the human diet; moreover, increased health risks have been observed with Se deficiency. A sufficiently high Se status is a prerequisite for adequate immune response, and preventable endemic diseases are known from areas with Se deficiency. Biomarkers of Se status decline strongly in pregnancy, severe illness, or COVID-19, reaching critically low concentrations. Notably, these conditions are associated with an increased risk for autoimmune disease (AID). Positive effects on the immune system are observed with Se supplementation in pregnancy, autoimmune thyroid disease, and recovery from severe illness. However, some studies reported null results; the database is small, and randomized trials are sparse. The current need for research on the link between AID and Se deficiency is particularly obvious for rheumatoid arthritis and type 1 diabetes mellitus. Despite these gaps in knowledge, it seems timely to realize that severe Se deficiency may trigger AID in susceptible subjects. Improved dietary choices or supplemental Se are efficient ways to avoid severe Se deficiency, thereby decreasing AID risk and improving disease course. A personalized approach is needed in clinics and during therapy, while population-wide measures should be considered for areas with habitual low Se intake. Finland has been adding Se to its food chain for more than 35 years-a wise and commendable decision, according to today's knowledge. It is unfortunate that the health risks of Se deficiency are often neglected, while possible side effects of Se supplementation are exaggerated, leading to disregard for this safe and promising preventive and adjuvant treatment options. This is especially true in the follow-up situations of pregnancy, severe illness, or COVID-19, where massive Se deficiencies have developed and are associated with AID risk, long-lasting health impairments, and slow recovery.
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Affiliation(s)
- Lutz Schomburg
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Institut für Experimentelle Endokrinologie, Cardiovascular-Metabolic-Renal (CMR)-Research Center, Hessische Straße 3-4, Charitéplatz 1, 10117 Berlin, Germany
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Capelle CM, Zeng N, Danileviciute E, Rodrigues SF, Ollert M, Balling R, He FQ. Identification of VIMP as a gene inhibiting cytokine production in human CD4+ effector T cells. iScience 2021; 24:102289. [PMID: 33851102 PMCID: PMC8024663 DOI: 10.1016/j.isci.2021.102289] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 02/08/2021] [Accepted: 03/05/2021] [Indexed: 12/14/2022] Open
Abstract
Many players regulating the CD4+ T cell-mediated inflammatory response have already been identified. However, the critical nodes that constitute the regulatory and signaling networks underlying CD4 T cell responses are still missing. Using a correlation-network-guided approach, here we identified VIMP (VCP-interacting membrane protein), one of the 25 genes encoding selenoproteins in humans, as a gene regulating the effector functions of human CD4 T cells, especially production of several cytokines including IL2 and CSF2. We identified VIMP as an endogenous inhibitor of cytokine production in CD4 effector T cells via both the E2F5 transcription regulatory pathway and the Ca2+/NFATC2 signaling pathway. Our work not only indicates that VIMP might be a promising therapeutic target for various inflammation-associated diseases but also shows that our network-guided approach can significantly aid in predicting new functions of the genes of interest.
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Affiliation(s)
- Christophe M. Capelle
- Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29, rue Henri Koch, 4354 Esch-sur-Alzette, Luxembourg
- Faculty of Science, Technology and Medicine, University of Luxembourg, 2, avenue de Université, 4365 Esch-sur-Alzette, Luxembourg
| | - Ni Zeng
- Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29, rue Henri Koch, 4354 Esch-sur-Alzette, Luxembourg
| | - Egle Danileviciute
- Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29, rue Henri Koch, 4354 Esch-sur-Alzette, Luxembourg
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6, avenue du Swing, 4367 Belvaux, Luxembourg
| | - Sabrina Freitas Rodrigues
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6, avenue du Swing, 4367 Belvaux, Luxembourg
| | - Markus Ollert
- Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29, rue Henri Koch, 4354 Esch-sur-Alzette, Luxembourg
- Department of Dermatology and Allergy Center, Odense Research Center for Anaphylaxis (ORCA), University of Southern Denmark, Odense, 5000 C, Denmark
| | - Rudi Balling
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6, avenue du Swing, 4367 Belvaux, Luxembourg
| | - Feng Q. He
- Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29, rue Henri Koch, 4354 Esch-sur-Alzette, Luxembourg
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6, avenue du Swing, 4367 Belvaux, Luxembourg
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
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Donadio JLS, Duarte GBS, Borel P, Cozzolino SMF, Rogero MM. The influence of nutrigenetics on biomarkers of selenium nutritional status. Nutr Rev 2021; 79:1259-1273. [PMID: 33570152 DOI: 10.1093/nutrit/nuaa136] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Selenium (Se) is an essential micronutrient for human biology that executes its functions as the amino acid selenocysteine via selenoproteins, which have important functions in, for example, antioxidation, immunomodulation, thyroid metabolism, and human fertility. Se nutritional status is assessed using the quantification of blood Se biomarkers, which are influenced by several factors, including diet, age, gender, smoking status, alcohol consumption, health condition, and the genetic characteristics of individuals. Nutrigenetic studies have identified single nucleotide polymorphisms in selenoproteins that might clarify the high variability in values reported for biomarkers of Se nutritional status in different populations, and the response of these biomarkers to Se supplementation with either organic or inorganic forms of Se. This review aims to (1) define the basic aspects of Se biology, (2) describe the current most commonly used biomarkers of Se nutritional status, and (3) provide a summary of associations between functional single nucleotide polymorphisms in selenoproteins and biomarkers of Se status in healthy populations.
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Affiliation(s)
- Janaina L S Donadio
- J.L.S. Donadio, G.B.S. Duarte, and S.M.F. Cozzolino are with the Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil. J.L.S. Donadio and M.M. Rogero are with the Food Research Center (FoRC), CEPID-FAPESP Research Innovation and Dissemination Centers, São Paulo Research Foundation, São Paulo, Brazil. P. Borel is with the C2VN, INRAE, INSERM, Aix Marseille University, Marseille, France. M.M. Rogero is with the Department of Nutrition, School of Public Health, University of São Paulo, São Paulo, Brazil
| | - Graziela B S Duarte
- J.L.S. Donadio, G.B.S. Duarte, and S.M.F. Cozzolino are with the Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil. J.L.S. Donadio and M.M. Rogero are with the Food Research Center (FoRC), CEPID-FAPESP Research Innovation and Dissemination Centers, São Paulo Research Foundation, São Paulo, Brazil. P. Borel is with the C2VN, INRAE, INSERM, Aix Marseille University, Marseille, France. M.M. Rogero is with the Department of Nutrition, School of Public Health, University of São Paulo, São Paulo, Brazil
| | - Patrick Borel
- J.L.S. Donadio, G.B.S. Duarte, and S.M.F. Cozzolino are with the Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil. J.L.S. Donadio and M.M. Rogero are with the Food Research Center (FoRC), CEPID-FAPESP Research Innovation and Dissemination Centers, São Paulo Research Foundation, São Paulo, Brazil. P. Borel is with the C2VN, INRAE, INSERM, Aix Marseille University, Marseille, France. M.M. Rogero is with the Department of Nutrition, School of Public Health, University of São Paulo, São Paulo, Brazil
| | - Silvia M F Cozzolino
- J.L.S. Donadio, G.B.S. Duarte, and S.M.F. Cozzolino are with the Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil. J.L.S. Donadio and M.M. Rogero are with the Food Research Center (FoRC), CEPID-FAPESP Research Innovation and Dissemination Centers, São Paulo Research Foundation, São Paulo, Brazil. P. Borel is with the C2VN, INRAE, INSERM, Aix Marseille University, Marseille, France. M.M. Rogero is with the Department of Nutrition, School of Public Health, University of São Paulo, São Paulo, Brazil
| | - Marcelo M Rogero
- J.L.S. Donadio, G.B.S. Duarte, and S.M.F. Cozzolino are with the Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil. J.L.S. Donadio and M.M. Rogero are with the Food Research Center (FoRC), CEPID-FAPESP Research Innovation and Dissemination Centers, São Paulo Research Foundation, São Paulo, Brazil. P. Borel is with the C2VN, INRAE, INSERM, Aix Marseille University, Marseille, France. M.M. Rogero is with the Department of Nutrition, School of Public Health, University of São Paulo, São Paulo, Brazil
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Leonardi A, Evke S, Lee M, Melendez JA, Begley TJ. Epitranscriptomic systems regulate the translation of reactive oxygen species detoxifying and disease linked selenoproteins. Free Radic Biol Med 2019; 143:573-593. [PMID: 31476365 PMCID: PMC7650020 DOI: 10.1016/j.freeradbiomed.2019.08.030] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 08/28/2019] [Accepted: 08/29/2019] [Indexed: 02/07/2023]
Abstract
Here we highlight the role of epitranscriptomic systems in post-transcriptional regulation, with a specific focus on RNA modifying writers required for the incorporation of the 21st amino acid selenocysteine during translation, and the pathologies linked to epitranscriptomic and selenoprotein defects. Epitranscriptomic marks in the form of enzyme-catalyzed modifications to RNA have been shown to be important signals regulating translation, with defects linked to altered development, intellectual impairment, and cancer. Modifications to rRNA, mRNA and tRNA can affect their structure and function, while the levels of these dynamic tRNA-specific epitranscriptomic marks are stress-regulated to control translation. The tRNA for selenocysteine contains five distinct epitranscriptomic marks and the ALKBH8 writer for the wobble uridine (U) has been shown to be vital for the translation of the glutathione peroxidase (GPX) and thioredoxin reductase (TRXR) family of selenoproteins. The reactive oxygen species (ROS) detoxifying selenocysteine containing proteins are a prime examples of how specialized translation can be regulated by specific tRNA modifications working in conjunction with distinct codon usage patterns, RNA binding proteins and specific 3' untranslated region (UTR) signals. We highlight the important role of selenoproteins in detoxifying ROS and provide details on how epitranscriptomic marks and selenoproteins can play key roles in and maintaining mitochondrial function and preventing disease.
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Affiliation(s)
- Andrea Leonardi
- Colleges of Nanoscale Science and Engineering, University at Albany, State University of New York, Albany, NY, USA
| | - Sara Evke
- Colleges of Nanoscale Science and Engineering, State University of New York Polytechnic Institute, Albany, NY, USA
| | - May Lee
- Colleges of Nanoscale Science and Engineering, State University of New York Polytechnic Institute, Albany, NY, USA
| | - J Andres Melendez
- Colleges of Nanoscale Science and Engineering, State University of New York Polytechnic Institute, Albany, NY, USA.
| | - Thomas J Begley
- Department of Biological Sciences, University at Albany, State University of New York, Albany, NY, USA; RNA Institute, University at Albany, State University of New York, Albany, NY, USA.
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Selenoprotein S inhibits inflammation-induced vascular smooth muscle cell calcification. J Biol Inorg Chem 2018; 23:739-751. [PMID: 29721770 DOI: 10.1007/s00775-018-1563-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 04/24/2018] [Indexed: 12/12/2022]
Abstract
Vascular calcification is a prominent feature of many diseases including atherosclerotic cardiovascular disease (CVD), leading to high morbidity and mortality rates. A significant association of selenoprotein S (SelS) gene polymorphism with atherosclerotic CVD has been reported in epidemiologic studies, but the underlying mechanism is far from clear. To investigate the role of SelS in inflammation-induced vascular calcification, osteoblastic differentiation and calcification of vascular smooth muscle cells (VSMCs) induced by lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-α were compared between the cells with and without SelS knockdown. LPS or TNF-α induced osteoblastic differentiation and calcification of VSMCs, as showed by the increases of runt-related transcription factor 2 (Runx2) protein levels, Runx2 and type I collagen mRNA levels, alkaline phosphatase activity, and calcium deposition content. These changes were aggravated when SelS was knocked down by small interfering RNA. Moreover, LPS activated both classical and alternative pathways of nuclear factor-κB (NF-κB) signaling in calcifying VSMCs, which were further enhanced under SelS knockdown condition. SelS knockdown also exacerbated LPS-induced increases of proinflammatory cytokines TNF-α and interleukin-6 expression, as well as increases of endoplasmic reticulum (ER) stress markers glucose-regulated protein 78 and inositol-requiring enzyme 1α expression in calcifying VSMCs. In conclusion, the present study suggested that SelS might inhibit inflammation-induced VSMC calcification probably by suppressing activation of NF-κB signaling pathways and ER stress. Our findings provide new understanding of the role of SelS in vascular calcification, which will be potentially beneficial to the prevention of atherosclerotic CVD.
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Addinsall AB, Wright CR, Shaw CS, McRae NL, Forgan LG, Weng CH, Conlan XA, Francis PS, Smith ZM, Andrikopoulos S, Stupka N. Deficiency of selenoprotein S, an endoplasmic reticulum resident oxidoreductase, impairs the contractile function of fast-twitch hindlimb muscles. Am J Physiol Regul Integr Comp Physiol 2018; 315:R380-R396. [PMID: 29668323 DOI: 10.1152/ajpregu.00244.2017] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Selenoprotein S (Seps1) is an endoplasmic reticulum (ER) resident antioxidant implicated in ER stress and inflammation. In human vastus lateralis and mouse hindlimb muscles, Seps1 localization and expression were fiber-type specific. In male Seps1+/- heterozygous mice, spontaneous physical activity was reduced compared with wild-type littermates ( d = 1.10, P = 0.029). A similar trend was also observed in Seps1-/- knockout mice ( d = 1.12, P = 0.051). Whole body metabolism, body composition, extensor digitorum longus (EDL), and soleus mass and myofiber diameter were unaffected by genotype. However, in isolated fast EDL muscles from Seps1-/- knockout mice, the force frequency curve (FFC; 1-120 Hz) was shifted downward versus EDL muscles from wild-type littermates ( d = 0.55, P = 0.002), suggestive of reduced strength. During 4 min of intermittent, submaximal (60 Hz) stimulation, the genetic deletion or reduction of Seps1 decreased EDL force production ( d = 0.52, P < 0.001). Furthermore, at the start of the intermittent stimulation protocol, when compared with the 60-Hz stimulation of the FFC, EDL muscles from Seps1-/- knockout or Seps1+/- heterozygous mice produced 10% less force than those from wild-type littermates ( d = 0.31, P < 0.001 and d = 0.39, P = 0.015). This functional impairment was associated with reduced mRNA transcript abundance of thioredoxin-1 ( Trx1), thioredoxin interacting protein ( Txnip), and the ER stress markers Chop and Grp94, whereas, in slow soleus muscles, Seps1 deletion did not compromise contractile function and Trx1 ( d = 1.38, P = 0.012) and Txnip ( d = 1.27, P = 0.025) gene expression was increased. Seps1 is a novel regulator of contractile function and cellular stress responses in fast-twitch muscles.
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Affiliation(s)
- Alex B Addinsall
- Centre for Molecular and Medical Research, School of Medicine, Deakin University, Waurn Ponds, Victoria , Australia
| | - Craig R Wright
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Waurn Ponds, Victoria , Australia
| | - Chris S Shaw
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Waurn Ponds, Victoria , Australia
| | - Natasha L McRae
- Centre for Molecular and Medical Research, School of Medicine, Deakin University, Waurn Ponds, Victoria , Australia
| | - Leonard G Forgan
- Centre for Molecular and Medical Research, School of Medicine, Deakin University, Waurn Ponds, Victoria , Australia
| | - Chia-Heng Weng
- Department of Medicine-Austin Health, The University of Melbourne , Heidelberg, Victoria , Australia
| | - Xavier A Conlan
- Centre for Chemistry and Biotechnology, School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, Waurn Ponds, Victoria , Australia
| | - Paul S Francis
- Centre for Chemistry and Biotechnology, School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, Waurn Ponds, Victoria , Australia
| | - Zoe M Smith
- Centre for Chemistry and Biotechnology, School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, Waurn Ponds, Victoria , Australia
| | - Sofianos Andrikopoulos
- Department of Medicine-Austin Health, The University of Melbourne , Heidelberg, Victoria , Australia
| | - Nicole Stupka
- Centre for Molecular and Medical Research, School of Medicine, Deakin University, Waurn Ponds, Victoria , Australia
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Emerging roles of endoplasmic reticulum-resident selenoproteins in the regulation of cellular stress responses and the implications for metabolic disease. Biochem J 2018; 475:1037-1057. [PMID: 29559580 DOI: 10.1042/bcj20170920] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 02/12/2018] [Accepted: 02/13/2018] [Indexed: 12/25/2022]
Abstract
Chronic metabolic stress leads to cellular dysfunction, characterized by excessive reactive oxygen species, endoplasmic reticulum (ER) stress and inflammation, which has been implicated in the pathogenesis of obesity, type 2 diabetes and cardiovascular disease. The ER is gaining recognition as a key organelle in integrating cellular stress responses. ER homeostasis is tightly regulated by a complex antioxidant system, which includes the seven ER-resident selenoproteins - 15 kDa selenoprotein, type 2 iodothyronine deiodinase and selenoproteins S, N, K, M and T. Here, the findings from biochemical, cell-based and mouse studies investigating the function of ER-resident selenoproteins are reviewed. Human experimental and genetic studies are drawn upon to highlight the relevance of these selenoproteins to the pathogenesis of metabolic disease. ER-resident selenoproteins have discrete roles in the regulation of oxidative, ER and inflammatory stress responses, as well as intracellular calcium homeostasis. To date, only two of these ER-resident selenoproteins, selenoproteins S and N have been implicated in human disease. Nonetheless, the potential of all seven ER-resident selenoproteins to ameliorate metabolic dysfunction warrants further investigation.
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Liu Q, Yang J, Cai J, Luan Y, Sattar H, Liu M, Xu S, Zhang Z. Analysis of the Interactions Between Thioredoxin and 20 Selenoproteins in Chicken. Biol Trace Elem Res 2017; 179:304-317. [PMID: 28251482 DOI: 10.1007/s12011-017-0961-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 02/06/2017] [Indexed: 12/14/2022]
Abstract
Thioredoxin (Trx) is a small molecular protein with complicated functions in a number of processes, including inflammation, apoptosis, embryogenesis, cardiovascular disease, and redox regulation. Some selenoproteins, such as glutathione peroxidase (Gpx), iodothyronine deiodinase (Dio), and thioredoxin reductase (TR), are involved in redox regulation. However, whether there are interactions between Trx and selenoproteins is still not known. In the present paper, we used a Modeller, Hex 8.0.0, and the KFC2 Server to predict the interactions between Trx and selenoproteins. We used the Modeller to predict the target protein in objective format and assess the accuracy of the results. Molecular interaction studies with Trx and selenoproteins were performed using the molecular docking tools in Hex 8.0.0. Next, we used the KFC2 Server to further test the protein binding sites. In addition to the selenoprotein physiological functions, we also explored potential relationships between Trx and selenoproteins beyond all the results we got. The results demonstrate that Trx has the potential to interact with 19 selenoproteins, including iodothyronine deiodinase 1 (Dio1), iodothyronine deiodinase 3 (Dio3), glutathione peroxidase 1 (Gpx1), glutathione peroxidase 2 (Gpx2), glutathione peroxidase 3 (Gpx3), glutathione peroxidase 4 (Gpx4), selenoprotein H (SelH), selenoprotein I (SelI), selenoprotein M (SelM), selenoprotein N (SelN), selenoprotein T (SelT), selenoprotein U (SelU), selenoprotein W (SelW), selenoprotein 15 (Sep15), methionine sulfoxide reductase B (Sepx1), selenophosphate synthetase 1 (SPS1), TR1, TR2, and TR3, among which TR1, TR2, TR3, SPS1, Sep15, SelN, SelM, SelI, Gpx2, Gpx3, Gpx4, and Dio3 exhibited intense correlations with Trx. However, additional experiments are needed to verify them.
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Affiliation(s)
- Qi Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Jie Yang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Jingzeng Cai
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Yilin Luan
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Hamid Sattar
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Man Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Shiwen Xu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Ziwei Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China.
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Abstract
Cancer survival is largely impacted by the dissemination of cancer cells from the original tumor site to secondary tissues or organs through metastasis. Targets for antimetastatic therapies have recently become a focus of research, but progress will require a better understanding of the molecular mechanisms driving metastasis. Selenoproteins play important roles in many of the cellular activities underlying metastasis including cell adhesion, matrix degradation and migration, invasion into the blood and extravasation into secondary tissues, and subsequent proliferation into metastatic tumors along with the angiogenesis required for growth. In this review the roles identified for different selenoproteins in these steps and how they may promote or inhibit metastatic cancers is discussed. These roles include selenoenzyme modulation of redox tone and detoxification of reactive oxygen species, calcium homeostasis and unfolded protein responses regulated by endoplasmic reticulum selenoproteins, and the multiple physiological responses influenced by other selenoproteins.
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Affiliation(s)
- Michael P Marciel
- John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States
| | - Peter R Hoffmann
- John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States.
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Yu SS, Du JL. Selenoprotein S: a therapeutic target for diabetes and macroangiopathy? Cardiovasc Diabetol 2017; 16:101. [PMID: 28797256 PMCID: PMC5553675 DOI: 10.1186/s12933-017-0585-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 08/01/2017] [Indexed: 12/14/2022] Open
Abstract
Inflammatory response, oxidative stress, and endoplasmic reticulum (ER) stress are important pathophysiological bases of the occurrence and development of diabetes mellitus (DM) and macroangiopathy complications. Selenoprotein S (SELENOS) is involved in the regulation of these mechanisms; therefore, its association with DM and macroangiopathy has gradually received attention from scholars worldwide. SELENOS has different biological functions in different tissues and organs: it exerts antioxidant protection and has anti-ER stress effects in the pancreas and blood vessels, while it promotes the occurrence and development of insulin resistance in the liver, adipose tissue, and skeletal muscle. In addition, studies have confirmed that some SELENOS gene polymorphisms can influence the inflammatory response and are closely associated with the risk for developing DM and macroangiopathy. Therefore, comprehensive understanding of the association between SELENOS and inflammation, oxidative stress, and ER stress may better elucidate and supplement the pathogenic mechanisms of DM and macroangiopathy complications. Furthermore, in-depth investigation of the association of SELENOS function in different tissues and organs with DM and macroangiopathy may facilitate the development of new strategies for the prevention and treatment of DM and macrovascular complications. Here, we summarize the consensus and controversy regarding functions of SELENOS on currently available evidence.
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Affiliation(s)
- Shan-Shan Yu
- Department of Endocrinology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, Liaoning, China
| | - Jian-Ling Du
- Department of Endocrinology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, Liaoning, China.
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Zhao H, Tang J, Xu J, Cao L, Jia G, Long D, Liu G, Chen X, Wang K. Selenoprotein Genes Exhibit Differential Expression Patterns Between Hepatoma HepG2 and Normal Hepatocytes LO2 Cell Lines. Biol Trace Elem Res 2015; 167:236-41. [PMID: 25846212 DOI: 10.1007/s12011-015-0323-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 03/24/2015] [Indexed: 11/27/2022]
Abstract
The purpose of this study was to compare messenger RNA (mRNA) expression of selenoprotein genes between hepatoma HepG2 and normal hepatocytes LO2 cell lines. Liver HepG2 and LO2 cells were cultured in 12-well plates under the same condition until cells grew to complete confluence, and then cells were harvested for total RNA and protein extraction. The qPCRs were performed to compare gene expression of 14 selenoprotein genes and 5 cancer signaling-related genes. Enzyme activities were also assayed. The results showed that human hepatoma HepG2 cells grew faster than normal hepatocytes LO2 cells. Among the genes investigated, 10 selenoprotein genes (Gpx1, Gpx3, Gpx4, Selx, Sepp, Sepw1, Sepn1, Selt, Seli, Selh) and 3 cancer signaling-related genes (Bcl-2A, caspase-3, and P38) were upregulated (P < 0.05), while Selo and Bcl-2B were downregulated (P < 0.05) in hepatoma HepG2 cells compared to LO2 cells. Significant correlations were found between selenoprotein genes and the cancer signaling-related genes Caspase3, P53, Bc1-2A, and Bc1-2B. Our results revealed that selenoprotein genes were aberrantly expressed in hepatoma HepG2 cells compared to normal liver LO2 cells, which indicated that those selenoprotein genes may play important roles in the occurrence and development of liver carcinogenesis.
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Affiliation(s)
- Hua Zhao
- Animal Nutrition Institute, Sichuan Agricultural University, No 211 Huimin Road, Wenjiang, Chengdu, Sichuan, 611130, China,
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Abstract
SIGNIFICANCE Selenoproteins employ selenium to supplement the chemistry available through the common 20 amino acids. These powerful enzymes are affiliated with redox biology, often in connection with the detection, management, and signaling of oxidative stress. Among them, membrane-bound selenoproteins play prominent roles in signaling pathways, Ca(2+) regulation, membrane complexes integrity, and biosynthesis of lipophilic molecules. RECENT ADVANCES The number of selenoproteins whose physiological roles, protein partners, expression, evolution, and biosynthesis are characterized is steadily increasing, thus offering a more nuanced view of this specialized family. This review focuses on human membrane selenoproteins, particularly the five least characterized ones: selenoproteins I, K, N, S, and T. CRITICAL ISSUES Membrane-bound selenoproteins are the least understood, as it is challenging to provide the membrane-like environment required for their biochemical and biophysical characterization. Hence, their studies rely mostly on biological rather than structural and biochemical assays. Another aspect that has not received much attention is the particular role that their membrane association plays in their physiological function. FUTURE DIRECTIONS Findings cited in this review show that it is possible to infer the structure and the membrane-binding mode of these lesser-studied selenoproteins and design experiments to examine the role of the rare amino acid selenocysteine.
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Affiliation(s)
- Jun Liu
- Department of Chemistry and Biochemistry, University of Delaware , Newark, Delaware
| | - Sharon Rozovsky
- Department of Chemistry and Biochemistry, University of Delaware , Newark, Delaware
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Sun HY, Liu TB, Wang QC, Wu WQ, He YJ. Single nucleotide polymorphism in the SEPS1 gene may contribute to the risk of various human diseases: a meta-analysis. Ann Hum Biol 2015; 43:469-79. [DOI: 10.3109/03014460.2015.1070903] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Affiliation(s)
- Hong-Yun Sun
- Centers for Disease Control and Prevention of Laiwu City, Laiwu, PR China,
| | - Tai-Bin Liu
- Department of Food Nutrition and Student Health Division, Centers for Disease Control and Prevention of Laiwu City, Laiwu, PR China,
| | - Qing-Chang Wang
- Office of Centers for Disease Control and Prevention of Laiwu City, Laiwu, PR China, and
| | - Wei-Qiang Wu
- Office of Centers for Disease Control and Prevention of Laiwu City, Laiwu, PR China, and
| | - Yu-Jing He
- Immunization Management Division, Centers for Disease Control and Prevention of Laiwu City, Laiwu, PR China
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Li M, Liu B, Li L, Zhang C, Zhou Q. Association studies of SEPS1 gene polymorphisms with Hashimoto's thyroiditis in Han Chinese. J Hum Genet 2015; 60:427-433. [PMID: 26016409 DOI: 10.1038/jhg.2015.42] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Revised: 03/16/2015] [Accepted: 03/23/2015] [Indexed: 12/29/2022]
Abstract
Although the connection between SEPS1 gene variants and Hashimoto's thyroiditis (HT) has been established in Europeans, the relationship between the SEPS1 gene and HT remains unclear in Han Chinese. Here we aimed to investigate the potential association between SEPS1 variants and HT in the Han population. In addition, the effects of SEPS1 haplotypes on the susceptibility of the development of immune-mediated diseases with an inflammatory component will also be evaluated. Seven single-nucleotide polymorphisms (SNPs) with minor allele frequency ⩾0.05 were genotyped in 1013 HT patients and 2998 healthy controls from genetically independent Han Chinese individuals. We identified that the rs28665122 SNP was significantly associated with HT, both in the female group (allelic P=0.002644 and genotypic P=0.010326) and the combined data set (allelic P=0.000518 and genotypic P=0.002731). Further analyses based on haplotypes indicated that a two-SNP haplotype (rs2009895-rs28665122) was significantly associated with HT (global P=0.0036), which was also observed in females (global P=0.0162) but not in males. Our findings provide further supporting evidence that confirms the results of previous studies, which suggested potential roles of the SEPS1 gene in the pathogenesis and etiology of HT.
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Affiliation(s)
- Miao Li
- Department of Ultrasound, Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Bailing Liu
- Department of Ultrasound, Children's Hospital of Xi'an, Xi'an, China
| | - Lu Li
- College of Medicine and Forensics, Xi'an Jiaotong University, Xi'an, China
| | - Chen Zhang
- The First Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Qi Zhou
- Department of Ultrasound, Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
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Mao H, Cui R, Wang X. Association analysis of selenoprotein S polymorphisms in Chinese Han with susceptibility to gastric cancer. Int J Clin Exp Med 2015; 8:10993-10999. [PMID: 26379895 PMCID: PMC4565278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Accepted: 06/25/2015] [Indexed: 06/05/2023]
Abstract
OBJECTIVE selenoprotein S (SelS) gene polymorphism is closely related to a variety of malignant tumours. Here, we evaluate the association between SelS polymorphism and genetic susceptibility to gastric cancer. METHODS A case-control study was conducted to investigate the role of two SelS single nucleotide polymorphisms (SNPs) on the susceptibility to gastric cancer. The genotypes and genotype frequencies of the SelS were determined in 260 gastric cancer patients and 278 age-matched healthy controls. Polymerase chain reaction restriction fragment length of polymorphism (PCR-RFLP) was taken to genotype rs28665122 (G-105A) and rs34713741 (G-254A) within the SelS gene. The differences in the genotypic distribution between gastric cancer patients and healthy controls were analyzed with the Chi-square test for trends. Logistic-regression analysis was used to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusting for age and sex. RESULTS For rs34713741 in SelS, the allele frequencies analysis indicated that the allele frequency of the T was higher in patients than in controls (P=0.001). There were significant differences of genotype frequencies and allele of rs34713741 polymorphism between gastric cancer group and control group (P<0.05). The relative risk of suffering from gastric cancer in T allele was 1.62 times of CC genotype in Hunan Han population (OR=1.62, 95% CI: 1.15~2.29). But there were no differences of genotype frequencies and allele of SelS rs28665122 polymorphism between gastric cancer group and control group. CONCLUSIONS Allele T of SelS rs34713741 polymorphism is significantly associated with an increased risk of gastric cancer in Chinese population.
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Affiliation(s)
- Huajie Mao
- Department of Laboratory Medicine, Xiang-Ya Medical School, Central South University Changsha 410013, Hunan, China
| | - Ruifang Cui
- Department of Laboratory Medicine, Xiang-Ya Medical School, Central South University Changsha 410013, Hunan, China
| | - Xiaochun Wang
- Department of Laboratory Medicine, Xiang-Ya Medical School, Central South University Changsha 410013, Hunan, China
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Selenium and chronic diseases: a nutritional genomics perspective. Nutrients 2015; 7:3621-51. [PMID: 25988760 PMCID: PMC4446770 DOI: 10.3390/nu7053621] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 04/28/2015] [Accepted: 05/06/2015] [Indexed: 01/10/2023] Open
Abstract
Mechanistic data have revealed a key role for selenium (Se) and selenoproteins in biological pathways known to be altered in multifactorial diseases, such as cellular maintenance, response to oxidative stress and correct protein folding. Although epidemiological studies indicate that low Se intake is linked to increased risk for various chronic diseases, supplementation trials have given confusing outcomes, suggesting that additional genetic factors could affect the relationship between Se and health. Genetic data support this hypothesis, as risk for several chronic diseases, in particular cancer, was linked to a number of single nucleotide polymorphisms (SNP) altering Se metabolism, selenoprotein synthesis or activity. Interactions between SNPs in selenoprotein genes, SNPs in related molecular pathways and biomarkers of Se status were found to further modulate the genetic risk carried by the SNPs. Taken together, nutritional genomics approaches uncovered the potential implication of some selenoproteins as well as the influence of complex interactions between genetic variants and Se status in the aetiology of several chronic diseases. This review discusses the results from these genetic associations in the context of selenoprotein functions and epidemiological investigations and emphasises the need to assess in future studies the combined contribution of Se status, environmental stress, and multiple or individual SNPs to disease risk.
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Association of selenoprotein S gene polymorphism with ischemic stroke in a Chinese case–control study. Blood Coagul Fibrinolysis 2015; 26:131-5. [DOI: 10.1097/mbc.0000000000000202] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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Du XA, Wang HM, Dai XX, Kou Y, Wu RP, Chen Q, Cao JL, Mo XY, Xiong YM. Role of selenoprotein S (SEPS1) -105G>A polymorphisms and PI3K/Akt signaling pathway in Kashin-Beck disease. Osteoarthritis Cartilage 2015; 23:210-6. [PMID: 25433273 DOI: 10.1016/j.joca.2014.11.017] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Revised: 11/07/2014] [Accepted: 11/14/2014] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To investigate the relationship between SEPS1 polymorphism and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in Kashin-Beck disease (KBD) and further explore the pathogenesis of KBD. METHODS Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect SEPS1 -105G>A polymorphism in 232 cases and 331 controls. The protein expressions of PI3K/Akt signaling molecules in whole blood and chondrocytes were detected by Western blot. RESULTS The frequencies of SEPS1 -105G>A genotype AA (21.1% vs 3.0%) and minor allele A (34.1% vs 16.0%) in KBD are significantly higher than those in controls (OR: 8.020, 95% confidence interval (95% CI) 6.341-10.290, P < 0.0001; OR: 2.470, 95% CI 2.001-4.463, P < 0.0001, respectively). SEPS1 AA genotype was an independent risk factor for KBD (adjusted OR: 9.345, 95% CI 4.254-20.529; P < 0.0001). The expression of Gβγ, PI3Kp110, pAkt and pGSK3β in KBD group were higher than that in control group (all P < 0.05). Gβγ, pAkt and pGSK3β protein expression of AA and GA increased than GG (all P < 0.05). Cell apoptosis was increasing and molecule expression of PI3K/Akt signaling pathway were up-regulated in the tert-Butyl hydroperoxide (tBHP)-injured group, the cell apoptosis and expression levels of PI3K/Akt in Na2SeO3 group were decreased. CONCLUSIONS The SEPS1 -105G>A is associated with an increased risk of KBD and influences the expression of PI3K/Akt signaling pathway in KBD patients. Apoptosis induced by tBHP in chondrocyte might be mediated via up-regulation of PI3K/Akt, Na2SeO3 has an effect of anti-apoptosis by down-regulating of PI3K/Akt signaling pathway.
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Affiliation(s)
- X A Du
- Institute of Endemic Diseases, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China
| | - H M Wang
- Institute of Endemic Diseases, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China
| | - X X Dai
- Institute of Endemic Diseases, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China
| | - Y Kou
- School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, PR China
| | - R P Wu
- Institute of Endemic Diseases, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China
| | - Q Chen
- Institute of Endemic Diseases, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China
| | - J L Cao
- Institute of Endemic Diseases, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China
| | - X Y Mo
- School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, PR China
| | - Y M Xiong
- Institute of Endemic Diseases, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China.
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Song B, Duan ZY, Zhong YH, Lei N, Yang YQ, Luo KY. Meta-analysis of the MDM2 T309G polymorphism and gastric cancer risk. Asian Pac J Cancer Prev 2015; 14:6649-51. [PMID: 24377582 DOI: 10.7314/apjcp.2013.14.11.6649] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Mdm2 binds to the amino-terminus of p53 to induce its degradation and a single nucleotide polymorphism in the MDM2 promoter region (T309G) has been reported to increase the risk of several carcinomas, such as gastric cancer. However, the results of published studies to analyze the association between MDM2 T309G and gastric cancer havve often conflicted. METHODS To better illustrate the filiation between MDM2 T309G and gastric cancer, we performed a meta-analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the relationship. The pooled ORs were performed for 4 models, additive, recessive, co-dominant model, and dominant. RESULTS Nine published case-control studies including 3,225 gastric cancer cases and 4,118 controls were identified. The MDM2 T309G polymorphism was associated with a significantly increased risk of gastric cancer risk when all studies were pooled into the meta-analysis (GG versus TT, OR=1.57; 95%CI=1.57-2.12; p=0.003) and GG versus GT/TT, OR=1.52; 95%CI=1.217-1.90; p<0.001). Furthermore, Egger<s test did not show any evidence of publication bias (P = 0.608 for GG versus TT). CONCLUSION Our results suggest that the MDM2 T309G polymorphism is indeed associated with a significantly increased risk of gastric cancer.
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Affiliation(s)
- Bo Song
- Department of General Surgery, The Fourth Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China E-mail :
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Selenoprotein S is involved in maintenance and transport of multiprotein complexes. Biochem J 2014; 462:555-65. [PMID: 24897171 DOI: 10.1042/bj20140076] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
SelS (Selenoprotein S) is a selenocysteine-containing protein with roles in ER (endoplasmic reticulum) function and inflammation. It has been implicated in ERAD (ER-associated protein degradation), and clinical studies revealed an association of its promoter polymorphism with cytokine levels and human diseases. However, the pathways and interacting proteins that could shed light on pathogenesis of SelS-associated diseases have not been studied systematically. We performed a large-scale affinity isolation of human SelS and its mutant forms and analysed the proteins that interact with them. All previously known SelS targets and nearly two hundred additional proteins were identified that were remarkably enriched for various multiprotein complexes. Subsequent chemical cross-linking experiments identified the specific interacting sites in SelS and its several targets. Most of these interactions involved coiled-coil domains. The data suggest that SelS participates in intracellular membrane transport and maintenance of protein complexes by anchoring them to the ER membrane.
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Labunskyy VM, Hatfield DL, Gladyshev VN. Selenoproteins: molecular pathways and physiological roles. Physiol Rev 2014; 94:739-77. [PMID: 24987004 DOI: 10.1152/physrev.00039.2013] [Citation(s) in RCA: 900] [Impact Index Per Article: 81.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Selenium is an essential micronutrient with important functions in human health and relevance to several pathophysiological conditions. The biological effects of selenium are largely mediated by selenium-containing proteins (selenoproteins) that are present in all three domains of life. Although selenoproteins represent diverse molecular pathways and biological functions, all these proteins contain at least one selenocysteine (Sec), a selenium-containing amino acid, and most serve oxidoreductase functions. Sec is cotranslationally inserted into nascent polypeptide chains in response to the UGA codon, whose normal function is to terminate translation. To decode UGA as Sec, organisms evolved the Sec insertion machinery that allows incorporation of this amino acid at specific UGA codons in a process requiring a cis-acting Sec insertion sequence (SECIS) element. Although the basic mechanisms of Sec synthesis and insertion into proteins in both prokaryotes and eukaryotes have been studied in great detail, the identity and functions of many selenoproteins remain largely unknown. In the last decade, there has been significant progress in characterizing selenoproteins and selenoproteomes and understanding their physiological functions. We discuss current knowledge about how these unique proteins perform their functions at the molecular level and highlight new insights into the roles that selenoproteins play in human health.
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Affiliation(s)
- Vyacheslav M Labunskyy
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and Molecular Biology of Selenium Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Dolph L Hatfield
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and Molecular Biology of Selenium Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Vadim N Gladyshev
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and Molecular Biology of Selenium Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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Cho M, Eze O, Xu R. Molecular genetics of gastric adenocarcinoma in clinical practice. World J Med Genet 2014; 4:58-68. [DOI: 10.5496/wjmg.v4.i3.58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Accepted: 05/16/2014] [Indexed: 02/06/2023] Open
Abstract
The molecular genetics of gastric carcinoma (GC) dictates their biology and clinical behavior. The two morphologically distinct types of gastric carcinoma by Lauren classification, i.e., intestinal and diffuse cell types, have a significant difference in clinical outcome. These two types of GC have different molecular pathogenetic pathways with unique genetic alterations. In addition to environmental and other etiologies, intestinal type GC is associated with Helicobacter pylori (H. pylori) infection and involves a multistep molecular pathway driving the normal epithelium to intestinal metaplasia, dysplasia, and malignant transformation by chromosomal and/or microsatellite instability (MSI), mutation of tumor suppressor genes, and loss of heterozygosity among others. Diffuse type shows no clear causal relationship with H. pylori infection, but is commonly associated with deficiency of cell-cell adhesion due to mutation of the E-cadherin gene (CDH1), and a manifestation of the hereditary gastric cancer syndrome. Thus, detection of CDH1 mutation or loss of expression of E-cadherin may aid in early diagnosis or screening of diffuse type GC. Detection of certain genetic markers, for example, MSI and matrix metalloproteinases, may provide prognostic information, particularly for intestinal type. The common genetic alterations may offer therapeutic targets for treatment of GC. Polymorphisms in Thymidylate synthase to metabolize 5-fluorouracil, glutathione S-transferase for degradation of Cisplatin, and amplification/overexpression of human epidermal growth factor receptor 2 targeted by monoclonal antibody Trastuzumab, are a few examples. P13K/Akt/mTOR pathway, c-Met pathways, epidermal growth factor receptor, insulin-like growth factor receptor, vascular endothelial growth factor receptor fibroblast growth factor receptor, and micro RNAs are several potential therapeutic biomarkers for GC under investigation.
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Mocchegiani E, Costarelli L, Giacconi R, Malavolta M, Basso A, Piacenza F, Ostan R, Cevenini E, Gonos ES, Monti D. Micronutrient-gene interactions related to inflammatory/immune response and antioxidant activity in ageing and inflammation. A systematic review. Mech Ageing Dev 2014; 136-137:29-49. [PMID: 24388876 DOI: 10.1016/j.mad.2013.12.007] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Revised: 12/06/2013] [Accepted: 12/20/2013] [Indexed: 02/07/2023]
Abstract
Recent longitudinal studies in dietary daily intake in human centenarians have shown that a satisfactory content of some micronutrients within the cells maintain several immune functions, a low grade of inflammation and preserve antioxidant activity. Micronutrients (zinc, copper, selenium) play a pivotal role in maintaining and reinforcing the performances of the immune and antioxidant systems as well as in affecting the complex network of the genes (nutrigenomic) with anti- and pro-inflammatory tasks. Genes of pro- and anti-inflammatory cytokines and some key regulators of trace elements homeostasis, such as Metallothioneins (MT), are involved in the susceptibility to major geriatric disease/disorders. Moreover, the genetic inter-individual variability may affect the nutrients' absorption (nutrigenetic) with altered effects on inflammatory/immune response and antioxidant activity. The interaction between genetic factors and micronutrients (nutrigenomic and nutrigenetic approaches) may influence ageing and longevity because the micronutrients may become also toxic. This review reports the micronutrient-gene interactions in ageing and their impact on the healthy state with a focus on the method of protein-metal speciation analysis. The association between micronutrient-gene interactions and the protein-metal speciation analysis can give a complete picture for a personalized nutrient supplementation or chelation in order to reach healthy ageing and longevity.
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Affiliation(s)
- Eugenio Mocchegiani
- Translation Center of Research in Nutrition and Ageing, Scientific and Technological Pole, Italian National Research Centres on Ageing (INRCA), Via Birarelli 8, 60121 Ancona, Italy.
| | - Laura Costarelli
- Translation Center of Research in Nutrition and Ageing, Scientific and Technological Pole, Italian National Research Centres on Ageing (INRCA), Via Birarelli 8, 60121 Ancona, Italy
| | - Robertina Giacconi
- Translation Center of Research in Nutrition and Ageing, Scientific and Technological Pole, Italian National Research Centres on Ageing (INRCA), Via Birarelli 8, 60121 Ancona, Italy
| | - Marco Malavolta
- Translation Center of Research in Nutrition and Ageing, Scientific and Technological Pole, Italian National Research Centres on Ageing (INRCA), Via Birarelli 8, 60121 Ancona, Italy
| | - Andrea Basso
- Translation Center of Research in Nutrition and Ageing, Scientific and Technological Pole, Italian National Research Centres on Ageing (INRCA), Via Birarelli 8, 60121 Ancona, Italy
| | - Francesco Piacenza
- Translation Center of Research in Nutrition and Ageing, Scientific and Technological Pole, Italian National Research Centres on Ageing (INRCA), Via Birarelli 8, 60121 Ancona, Italy
| | - Rita Ostan
- Department of Experimental Diagnostic and Specialty Medicine (DIMES) and Interdepartmental Centre "L. Galvani" (CIG), University of Bologna, Via San Giacomo, 12, 40126 Bologna, Italy
| | - Elisa Cevenini
- Department of Experimental Diagnostic and Specialty Medicine (DIMES) and Interdepartmental Centre "L. Galvani" (CIG), University of Bologna, Via San Giacomo, 12, 40126 Bologna, Italy
| | - Efstathios S Gonos
- National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, 48 Vas. Constantinou Ave., Athens 11635, Greece
| | - Daniela Monti
- Department of Clinical and Experimental Biomedical Sciences, University of Florence, Viale Morgagni, 50, 50134 Florence, Italy
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Abstract
Selenium (Se) is an essential micronutrient that is incorporated into selenoproteins. Although epidemiological studies suggest that low Se intake is associated with increased risk of various cancers, the results of supplementation trials have been confusing. These conflicting results may be due to different baseline Se status and/or genetic factors. In addition, mechanistic links between Se intake, selenoproteins and carcinogenesis are not clear. In this article, we discuss the functional significance of single-nucleotide polymorphisms (SNP) in selenoprotein genes and the evidence as to whether or not they influence risk of colorectal, prostate, lung or breast cancers. Both in vitro and in vivo studies have shown that a small number of SNPs in genes encoding glutathione peroxidases 1 and 4, selenoprotein P, selenoprotein S and 15-kDa selenoprotein have functional consequences. Data from case-control studies suggest that a variant at codon 198 in glutathione peroxidase 1 influences the effect of Se status on prostate cancer and risk, and it has also been associated with breast cancer and lung cancer risk, whereas variants in glutathione peroxidase 4, selenoprotein P and selenoprotein S may influence the risk of colorectal cancer. In addition, the results of gene microarray (transcriptomic) studies have identified novel selenoprotein biomarkers of Se status and novel downstream Se-targeted pathways. The work highlights the need to take baseline Se status and genetic factors into account in the design of future intervention trials.
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Sun LH, Li JG, Zhao H, Shi J, Huang JQ, Wang KN, Xia XJ, Li L, Lei XG. Porcine serum can be biofortified with selenium to inhibit proliferation of three types of human cancer cells. J Nutr 2013; 143:1115-22. [PMID: 23677865 PMCID: PMC3681546 DOI: 10.3945/jn.113.177410] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Our objectives were to determine if porcine serum could be enriched with selenium (Se) by feeding pigs with high concentrations of dietary Se and if the Se-biofortified serum inhibited proliferation of 3 types of human cancer cells. In Expt. 1, growing pigs (8 wk old, n = 3) were fed 0.02 or 3.0 mg Se/kg (as sodium selenite) for 16 wk and produced serum with 0.5 and 5.4 μmol/L Se, respectively. In Expt. 2, growing pigs (5 wk old, n = 6) were fed 0.3 or 1.0 mg Se/kg (as Se-enriched yeast) for 6 wk and produced serum with 2.6 and 6.2 μmol/L Se, respectively. After the Se-biofortified porcine sera were added at 16% in RPMI 1640 to treat NCI-H446, DU145, and HTC116 cells for 144 h, they decreased (P < 0.05) the viability of the 3 types of human cancer cells by promoting apoptosis, compared with their controls. This effect was replicated only by adding the appropriate amount of methylseleninic acid to the control serum and was mediated by a downregulation of 8 cell cycle arrest genes and an upregulation of 7 apoptotic genes. Along with 6 previously reported selenoprotein genes, selenoprotein T (Selt), selenoprotein M (Selm), selenoprotein H (Selh), selenoprotein K (Selk), and selenoprotein N (Sepn1) were revealed to be strongly associated with the cell death-related signaling induced by the Se-enriched porcine serum. In conclusion, porcine serum could be biofortified with Se to effectively inhibit the proliferation of 3 types of human cancer cells and the action synchronized with a matrix of coordinated functional expression of multiple selenoprotein genes.
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Affiliation(s)
- Lv-Hui Sun
- International Research Center of Future Agriculture for Human Health, Sichuan Agricultural University, Chengdu, China,Department of Animal Science, Cornell University, Ithaca, NY; and
| | - Jun-Gang Li
- International Research Center of Future Agriculture for Human Health, Sichuan Agricultural University, Chengdu, China
| | - Hua Zhao
- International Research Center of Future Agriculture for Human Health, Sichuan Agricultural University, Chengdu, China
| | - Jing Shi
- International Research Center of Future Agriculture for Human Health, Sichuan Agricultural University, Chengdu, China
| | - Jia-Qiang Huang
- International Research Center of Future Agriculture for Human Health, Sichuan Agricultural University, Chengdu, China
| | - Kang-Ning Wang
- International Research Center of Future Agriculture for Human Health, Sichuan Agricultural University, Chengdu, China
| | - Xin-Jie Xia
- International Research Center of Future Agriculture for Human Health, Sichuan Agricultural University, Chengdu, China
| | - Li Li
- Robert W. Holley Center for Agriculture and Health, Agricultural Research Service, USDA, Ithaca, NY
| | - Xin Gen Lei
- International Research Center of Future Agriculture for Human Health, Sichuan Agricultural University, Chengdu, China,Department of Animal Science, Cornell University, Ithaca, NY; and,To whom correspondence should be addressed. E-mail:
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Wang Y, Yang X, Zheng Y, Wu ZH, Zhang XA, Li QP, He XY, Wang CZ, Feng ZC. The SEPS1 G-105A polymorphism is associated with risk of spontaneous preterm birth in a Chinese population. PLoS One 2013; 8:e65657. [PMID: 23776519 PMCID: PMC3679159 DOI: 10.1371/journal.pone.0065657] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 04/25/2013] [Indexed: 11/23/2022] Open
Abstract
Inflammation plays an important role in the etiology and pathophysiology of spontaneous preterm birth (SPTB), and selenoprotein S (SEPS1) is involved in regulating the inflammatory response. Recently the G-105A promoter polymorphism in SEPS1 was shown to increase pro-inflammatory cytokine expression. We examined whether this functional polymorphism was related to the risk of SPTB in a Chinese population. We also examined the impact of premature rupture of membranes (PROM) on susceptibility to SPTB. The SEPS1 G-105A polymorphism was genotyped in 569 preterm singleton neonates and 673 term neonates by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. χ2 tests and logistic regression analyses were used to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs). We observed that, compared with the GG genotype, –105A positive genotypes (GA + AA genotypes) were associated with significantly increased susceptibility to SPTB (adjusted OR, 1.87; 95% CI, 1.36–2.57; P<0.001). The –105A positive genotypes were also significantly associated with increased susceptibility to SPTB, both in the patients with PROM (adjusted OR, 2.65; 95% CI, 1.73–4.03; P<0.001) and in those without PROM (adjusted OR, 1.56; 95% CI, 1.09–2.24; P = 0.015). The –105A positive genotypes were also significantly associated with increased susceptibility to SPTB between extremely preterm neonates and controls (adjusted OR, 4.46; 95% CI, 1.86–10.73; P = 0.002) and between moderately preterm neonates and controls (adjusted OR, 1.76; 95% CI, 1.25–2.47; P = 0.001). Our findings suggest that the SEPS1 G-105A polymorphism contributes to the risk of developing SPTB in a Chinese population.
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Affiliation(s)
- Yan Wang
- BaYi Children’s Hospital, General Military Hospital of Beijing PLA, P. R. China
| | - Xiao Yang
- BaYi Children’s Hospital, General Military Hospital of Beijing PLA, P. R. China
| | - Yong Zheng
- The 309 Hospital of PLA, Beijing, P. R. China
| | - Zhi-Hao Wu
- Department of Infectious Disease Control, Beijing Institute of Disease Control and Prevention, Beijing, P. R. China
| | - Xiao-Ai Zhang
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, P. R. China
| | - Qiu-Ping Li
- BaYi Children’s Hospital, General Military Hospital of Beijing PLA, P. R. China
| | - Xi-Yu He
- BaYi Children’s Hospital, General Military Hospital of Beijing PLA, P. R. China
| | - Chun-Zhi Wang
- BaYi Children’s Hospital, General Military Hospital of Beijing PLA, P. R. China
- * E-mail: (ZCF); (CZW)
| | - Zhi-Chun Feng
- BaYi Children’s Hospital, General Military Hospital of Beijing PLA, P. R. China
- * E-mail: (ZCF); (CZW)
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Kim CY, Kim KH. Dexamethasone-induced selenoprotein S degradation is required for adipogenesis. J Lipid Res 2013; 54:2069-2082. [PMID: 23687306 DOI: 10.1194/jlr.m034603] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Although adipogenesis is associated with induction of endoplasmic reticulum (ER) stress, the role of selenoprotein S (SEPS1), an ER resident selenoprotein known to regulate ER stress and ER-associated protein degradation, is unknown. We found an inverse relationship between SEPS1 level in adipose tissue and adiposity in mice. While SEPS1 expression was increased during adipogenesis, a markedly reduced SEPS1 protein level was found in the early phase of adipogenesis due to dexamethasone (DEX)-induced proteosomal degradation of SEPS1. Overexpression of SEPS1 in the early phase of cell differentiation resulted in impairment of adipogenesis with reduced levels of CCAAT/enhancer binding protein α and other adipocyte marker genes during the course of adipogenesis. Conversely, knockdown of SEPS1 resulted in the promotion of adipogenesis. Additionally, altered SEPS1 expression was associated with changes in expression of ER stress marker genes in the early phase of adipogenesis, and ubiquitin-proteasome system (UPS)-related ubiquitination and proteasome function. Our study reveals that SEPS1 is a novel anti-adipogenic selenoprotein that modulates ER stress- and UPS-dependent adipogenesis. Our results also identifies a novel function of DEX in the regulation of adipogenesis through induction of SEPS1 degradation. Taken together, DEX-dependent degradation of SEPS1 in the early phase of adipogenesis is necessary for initiating ER stress- and UPS-dependent maturation of adipocytes.
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Affiliation(s)
- Choon Young Kim
- Department of Food Science, Purdue University, West Lafayette, IN 47907
| | - Kee-Hong Kim
- Department of Food Science, Purdue University, West Lafayette, IN 47907.
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Abstract
The discovery of multiple selenoproteins has raised tantalizing questions about their role in maintaining normal cellular function. Unfortunately, many of these remain inadequately investigated. While they have a role in maintaining redox balance, other functions are becoming increasingly recognized. As the roles of these selenoproteins are further characterized, a better understanding of the true physiological significance of this trace element will arise. This knowledge will be essential in defining optimum intakes to achieve cellular homeostasis in order to optimize health, including a reduction in cancer, for diverse populations. Human variation in the response to selenium likely reflects significant interactions between the type and amounts of selenium consumed with the genome and a host of environmental factors including the totality of the diet, as discussed in this review.
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Affiliation(s)
- Cindy D. Davis
- Nutritional Science Research Group, National Cancer Institute, Rockville, Maryland 20892;,
- Current address: Office of Dietary Supplements, National Institutes of Health, Rockville, Maryland 20892
| | - Petra A. Tsuji
- Department of Biological Sciences, Towson University, Towson, Maryland 21252
| | - John A. Milner
- Nutritional Science Research Group, National Cancer Institute, Rockville, Maryland 20892;,
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Meplan C, Hesketh J. The influence of selenium and selenoprotein gene variants on colorectal cancer risk. Mutagenesis 2012; 27:177-86. [DOI: 10.1093/mutage/ger058] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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Hesketh J, Méplan C. Transcriptomics and functional genetic polymorphisms as biomarkers of micronutrient function: focus on selenium as an exemplar. Proc Nutr Soc 2011; 70:1-9. [PMID: 21557886 DOI: 10.1017/s0029665111000115] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Micronutrients are essential for optimal human health. However, in some cases, raising intake by supplementation has not proven to be beneficial and there is even some evidence that supplementation may increase disease risk, highlighting the importance of assessing the functional status of micronutrients. Techniques such as gene microarrays and single-nucleotide polymorphism analysis have the potential to examine effects of micronutrient intake on patterns of gene expression and inter-individual variation in micronutrient metabolism. Recent genomic research related to selenium (Se) provides examples illustrating how studies of functional single-nucleotide polymorphism and gene expression patterns can reveal novel biomarkers of micronutrient function. Both in vitro and in vivo experiments show that there are functionally relevant polymorphisms in genes encoding glutathione peroxidases 1, 3 and 4, selenoprotein P, selenoprotein S and the 15 kDa selenoprotein. Disease association studies investigating these gene variants have so far been relatively small but an association of a polymorphism in the selenoprotein S gene with colorectal cancer risk has been replicated in two distinct populations. Future disease association studies should examine effects of multiple variants in combination with nutritional status. Gene microarray studies indicate that changes in Se intake alter expression of components of inflammatory, stress response and translation pathways. Our hypothesis is that Se intake and genetic factors have linked effects on stress response, inflammation and apoptotic pathways. Combining such data in a systems biology approach has the potential to identify both biomarkers of micronutrients status and sub-group populations at particular risk.
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Affiliation(s)
- John Hesketh
- Institute for Cell and Molecular Biosciences and Human Nutrition Research Centre, The Medical School, Newcastle University, Framlington place, Newcastle upon Tyne NE1 4HH, UK
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Fairweather-Tait SJ, Bao Y, Broadley MR, Collings R, Ford D, Hesketh JE, Hurst R. Selenium in human health and disease. Antioxid Redox Signal 2011; 14:1337-83. [PMID: 20812787 DOI: 10.1089/ars.2010.3275] [Citation(s) in RCA: 813] [Impact Index Per Article: 58.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This review covers current knowledge of selenium in the environment, dietary intakes, metabolism and status, functions in the body, thyroid hormone metabolism, antioxidant defense systems and oxidative metabolism, and the immune system. Selenium toxicity and links between deficiency and Keshan disease and Kashin-Beck disease are described. The relationships between selenium intake/status and various health outcomes, in particular gastrointestinal and prostate cancer, cardiovascular disease, diabetes, and male fertility, are reviewed, and recent developments in genetics of selenoproteins are outlined. The rationale behind current dietary reference intakes of selenium is explained, and examples of differences between countries and/or expert bodies are given. Throughout the review, gaps in knowledge and research requirements are identified. More research is needed to improve our understanding of selenium metabolism and requirements for optimal health. Functions of the majority of the selenoproteins await characterization, the mechanism of absorption has yet to be identified, measures of status need to be developed, and effects of genotype on metabolism require further investigation. The relationships between selenium intake/status and health, or risk of disease, are complex but require elucidation to inform clinical practice, to refine dietary recommendations, and to develop effective public health policies.
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Affiliation(s)
- Susan J Fairweather-Tait
- School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, Norfolk, United Kingdom.
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Fradejas N, Del Carmen Serrano-PÉREZ M, Tranque P, Calvo S. Selenoprotein S expression in reactive astrocytes following brain injury. Glia 2011; 59:959-72. [DOI: 10.1002/glia.21168] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2011] [Accepted: 02/21/2011] [Indexed: 02/05/2023]
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Abstract
Gastric cancer remains a major cause of cancer death worldwide. The discovery of Helicobacter pylori Helicobacter pylori and its association with gastric cancer has opened up new insights into its pathogenesis. Gastric cancer pathogenesis is the result of a complex interplay between bacterial, host and environmental factors resulting in a step wise histological progression to neoplasia. H. pylori is a major factor in the early stages of cancer development and the mechanism of action of its virulence factors are being steadily unravelled. It is also now recognised that host genetic polymorphisms also play a complex role interacting synergistically with the bacterial virulence factors. The role of H. pylori in the causation of gastric cancer also raises the possibility of cancer prevention through screening and eradication, actions which may improve outcomes in high risk populations but which may not be cost-effective in areas of low risk. Ultimately, despite the vast improvements in knowledge, as yet there has not been a corresponding improvement in terms of gastric cancer survival rates.
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Zhang N, Jing W, Cheng J, Cui W, Mu Y, Li K, Lei X. Molecular characterization and NF-κB-regulated transcription of selenoprotein S from the Bama mini-pig. Mol Biol Rep 2010; 38:4281-6. [DOI: 10.1007/s11033-010-0551-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2010] [Accepted: 11/17/2010] [Indexed: 01/22/2023]
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Selenium controls the sex-specific immune response and selenoprotein expression during the acute-phase response in mice. Biochem J 2010; 429:43-51. [PMID: 20370716 DOI: 10.1042/bj20091868] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Selenium modifies inflammatory reactions in rodents and humans. The liver controls metabolism and transport of selenium via hepatically-derived SEPP (selenoprotein P). Intracellular SEPS (selenoprotein S) modifies endoplasmic-reticulum function and immune-cell activity. Polymorphisms in SEPS have been associated with cytokine levels and inflammatory diseases in a subset of clinical studies. In the present study, we hypothesized that sex and selenium represent decisive parameters controlling the immune response and regulation of SEPS expression in vivo. Male and female mice fed a selenium-poor diet were supplemented or not with selenite for 3 days and injected with saline or LPS (lipopolysaccharide) 24 h before analysis. Selenium supplementation mitigated the LPS-induced rise in circulating cytokines in male mice. Serum SepP and selenium concentrations decreased in response to LPS, whereas hepatic SepS was specifically up-regulated despite declining selenium concentrations in the liver. Hepatic SepS induction was mainly controlled by post-transcriptional mechanisms and attributed to hepatocytes by analysing transgenic mice. Notably, selenium supplementation was essential for an optimal SepS induction. We conclude that selenoprotein biosynthesis becomes redirected in hepatocytes during the acute-phase response at the expense of dispensable selenoproteins (e.g. SepP) and in favour of SepS expression, thereby causing declining serum selenium and improving liver function. The selenium status and sex control SepS expression and modify cytokine response patterns in serum, which might explain contradictory results on associations of SEPS genotype and inflammatory diseases in clinical studies.
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Fairweather-Tait SJ, Collings R, Hurst R. Selenium bioavailability: current knowledge and future research requirements. Am J Clin Nutr 2010; 91:1484S-1491S. [PMID: 20200264 DOI: 10.3945/ajcn.2010.28674j] [Citation(s) in RCA: 267] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Information on selenium bioavailability is required to derive dietary recommendations and to evaluate and improve the quality of food products. The need for robust data is particularly important in light of recent suggestions of potential health benefits associated with different intakes of selenium. The issue is not straightforward, however, because of large variations in the selenium content of foods (determined by a combination of geologic/environmental factors and selenium supplementation of fertilizers and animal feedstuffs) and the chemical forms of the element, which are absorbed and metabolized differently. Although most dietary selenium is absorbed efficiently, the retention of organic forms is higher than that of inorganic forms. There are also complications in the assessment and quantification of selenium species within foodstuffs. Often, extraction is only partial, and the process can alter the form or forms present in the food. Efforts to improve, standardize, and make more widely available techniques for species quantification are required. Similarly, reliable and sensitive functional biomarkers of selenium status are required, together with improvements in current biomarker methods. This requirement is particularly important for the assessment of bioavailability, because some functional biomarkers respond differently to the various selenium species. The effect of genotype adds a potential further dimension to the process of deriving bioavailability estimates and underlines the need for further research to facilitate the process of deriving dietary recommendations in the future.
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Affiliation(s)
- Susan J Fairweather-Tait
- School of Medicine, Health Policy & Practice, University of East Anglia, Norwich, NR4 7TJ, United Kingdom.
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Shchedrina VA, Zhang Y, Labunskyy VM, Hatfield DL, Gladyshev VN. Structure-function relations, physiological roles, and evolution of mammalian ER-resident selenoproteins. Antioxid Redox Signal 2010; 12:839-49. [PMID: 19747065 PMCID: PMC2864662 DOI: 10.1089/ars.2009.2865] [Citation(s) in RCA: 140] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Selenium is an essential trace element in mammals. The major biological form of this micronutrient is the amino acid selenocysteine, which is present in the active sites of selenoenzymes. Seven of 25 mammalian selenoproteins have been identified as residents of the endoplasmic reticulum, including the 15-kDa selenoprotein, type 2 iodothyronine deiodinase and selenoproteins K, M, N, S, and T. Most of these proteins are poorly characterized. However, recent studies implicate some of them in quality control of protein folding in the ER, retrotranslocation of misfolded proteins from the ER to the cytosol, metabolism of the thyroid hormone, and regulation of calcium homeostasis. In addition, some of these proteins are involved in regulation of glucose metabolism and inflammation. This review discusses evolution and structure-function relations of the ER-resident selenoproteins and summarizes recent findings on these proteins, which reveal the emerging important role of selenium and selenoproteins in ER function.
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Affiliation(s)
- Valentina A Shchedrina
- Redox Biology Center and Department of Biochemistry, University of Nebraska, Lincoln, NE, USA
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Abstract
Gastric cancer is a worldwide health burden, which is still the second most common cause of cancer related deaths with little improvement of long-term survival during the past decades. Understanding the molecular nature of this disease and its precursor lesions has been under intense investigation and our review attempts to highlight recent progress in this field of cancer research. First, host-related genetic susceptibility is dealt with genes involved in inflammation and carcinogen metabolism. Next, role of overexpression of a proinflammatory cytokine (interleukin-1beta) and deletion of a cell-cell adhesion molecule (E-cadherin) are described in experimental mouse models of gastric carcinogenesis. Finally, the role of stem cells in gastric cancer is covered.
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Affiliation(s)
- Marta Correia
- Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias s/n, Porto, Portugal
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Reeves MA, Hoffmann PR. The human selenoproteome: recent insights into functions and regulation. Cell Mol Life Sci 2009; 66:2457-78. [PMID: 19399585 PMCID: PMC2866081 DOI: 10.1007/s00018-009-0032-4] [Citation(s) in RCA: 367] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2009] [Revised: 04/01/2009] [Accepted: 04/03/2009] [Indexed: 12/16/2022]
Abstract
Selenium (Se) is a nutritional trace mineral essential for various aspects of human health that exerts its effects mainly through its incorporation into selenoproteins as the amino acid, selenocysteine. Twenty-five selenoprotein genes have been identified in humans and several selenoproteins are broadly classified as antioxidant enzymes. As progress is made on characterizing the individual members of this protein family, however, it is becoming clear that their properties and functions are quite diverse. This review summarizes recent insights into properties of individual selenoproteins such as tissue distribution, subcellular localization, and regulation of expression. Also discussed are potential roles the different selenoproteins play in human health and disease.
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Affiliation(s)
- M. A. Reeves
- Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, 651 Ilalo Street, Honolulu, HI 96813 USA
| | - P. R. Hoffmann
- Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, 651 Ilalo Street, Honolulu, HI 96813 USA
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Abstract
Selenoproteins are proteins containing selenium in the form of the 21st amino acid, selenocysteine. Members of this protein family have many diverse functions, but their synthesis is dependent on a common set of cofactors and on dietary selenium. Although the functions of many selenoproteins are unknown, several disorders involving changes in selenoprotein structure, activity or expression have been reported. Selenium deficiency and mutations or polymorphisms in selenoprotein genes and synthesis cofactors are implicated in a variety of diseases, including muscle and cardiovascular disorders, immune dysfunction, cancer, neurological disorders and endocrine function. Members of this unusual family of proteins have roles in a variety of cell processes and diseases.
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