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Stubbs DB, Ruzicka JA, Taylor EW. Modular Polymerase Synthesis and Internal Protein Domain Swapping via Dual Opposed Frameshifts in the Ebola Virus L Gene. Pathogens 2024; 13:829. [PMID: 39452701 PMCID: PMC11510084 DOI: 10.3390/pathogens13100829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/20/2024] [Accepted: 09/23/2024] [Indexed: 10/26/2024] Open
Abstract
Sequence analysis of the Zaire ebolavirus (EBOV) polymerase (L gene) mRNA, using online tools, identified a highly ranked -1 programmed ribosomal frameshift (FS) signal including an ideal slippery sequence heptamer (UUUAAAA), with an overlapping coding region featuring two tandem UGA codons, immediately followed by an RNA region that is the inverse complement (antisense) to a region of the mRNA of the selenoprotein iodothyronine deiodinase II (DIO2). This antisense interaction was confirmed in vitro via electrophoretic gel shift assay, using cDNAs at the EBOV and DIO2 segments. The formation of a duplex between the two mRNAs could trigger the ribosomal frameshift, by mimicking the enhancing role of a pseudoknot structure, while providing access to the selenocysteine insertion sequence (SECIS) element contained in the DIO2 mRNA. This process would allow the -1 frame UGA codons to be recoded as selenocysteine, forming part of a C-terminal module in a low abundance truncated isoform of the viral polymerase, potentially functioning in a redox role. Remarkably, 90 bases downstream of the -1 FS site, an active +1 FS site can be demonstrated, which, via a return to the zero frame, would enable the attachment of the entire C-terminal of the polymerase protein. Using a construct with upstream and downstream reporter genes, spanning a wildtype or mutated viral insert, we show significant +1 ribosomal frameshifting at this site. Acting singly or together, frameshifting at these sites (both of which are highly conserved in EBOV strains) could enable the expression of several modified isoforms of the polymerase. The 3D modeling of the predicted EBOV polymerase FS variants using the AI tool, AlphaFold, reveals a peroxiredoxin-like active site with arginine and threonine residues adjacent to a putative UGA-encoded selenocysteine, located on the back of the polymerase "hand". This module could serve to protect the viral RNA from peroxidative damage.
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Affiliation(s)
| | | | - Ethan W. Taylor
- Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, P.O. Box 26170, Greensboro, NC 27402-6170, USA; (D.B.S.); (J.A.R.)
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Islam MR, Akash S, Jony MH, Alam MN, Nowrin FT, Rahman MM, Rauf A, Thiruvengadam M. Exploring the potential function of trace elements in human health: a therapeutic perspective. Mol Cell Biochem 2023; 478:2141-2171. [PMID: 36637616 DOI: 10.1007/s11010-022-04638-3] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 12/08/2022] [Indexed: 01/14/2023]
Abstract
A trace element, known as a minor element, is a chemical element whose concentration is very low. They are divided into essential and non-essential classes. Numerous physiological and metabolic processes in both plants and animals require essential trace elements. These essential trace elements are so directly related to the metabolic and physiologic processes of the organism that either their excess or deficiency can result in severe bodily malfunction or, in the worst situations, death. Elements can be found in nature in various forms and are essential for the body to carry out its varied functions. Trace elements are crucial for biological, chemical, and molecular cell activity. Nutritional deficits can lead to weakened immunity, increased susceptibility to oral and systemic infections, delayed physical and mental development, and lower productivity. Trace element enzymes are involved in many biological and chemical processes. These compounds act as co-factors for a number of enzymes and serve as centers for stabilizing the structures of proteins and enzymes, allowing them to mediate crucial biological processes. Some trace elements control vital biological processes by attaching to molecules on the cell membrane's receptor site or altering the structure of the membrane to prevent specific molecules from entering the cell. Some trace elements are engaged in redox reactions. Trace elements have two purposes. They are required for the regular stability of cellular structures, but when lacking, they might activate alternate routes and induce disorders. Therefore, thoroughly understanding these trace elements is essential for maintaining optimal health and preventing disease.
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Affiliation(s)
- Md Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, 1207, Dhaka, Bangladesh
| | - Shopnil Akash
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, 1207, Dhaka, Bangladesh
| | - Maruf Hossain Jony
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, 1207, Dhaka, Bangladesh
| | - Md Noor Alam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, 1207, Dhaka, Bangladesh
| | - Feana Tasmim Nowrin
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, 1207, Dhaka, Bangladesh
| | - Md Mominur Rahman
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, 1207, Dhaka, Bangladesh
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Anbar, Khyber Pakhtunkhwa, Pakistan.
| | - Muthu Thiruvengadam
- Department of Applied Bioscience, College of Life and Environmental Sciences, Konkuk University, Seoul, 05029, South Korea.
- Department of Microbiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Science, Chennai, 600077, Tamil Nadu, India.
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John-Olabode SO, Akintan P, Okunade KS, Ajie I. Comparative Assessment of Serum Selenium Status in HIV-Infected and Non-infected Children: A Pilot Study in a Tertiary Hospital in Nigeria. Cureus 2023; 15:e39626. [PMID: 37388617 PMCID: PMC10301851 DOI: 10.7759/cureus.39626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/18/2023] [Indexed: 07/01/2023] Open
Abstract
Background Selenium is an essential micronutrient that plays a crucial role in a wide range of physiological processes, including immune responses. Selenium deficiency has been recognized as an associated factor in the progression of HIV to advanced HIV disease and/or mortality. Although selenium supplementation has been shown to reduce hospitalizations and improve cellular immunity, the evidence remains mixed. This study aimed to determine the prevalence of selenium deficiency and its relationship with HIV disease markers in HIV-infected children at the Lagos University Teaching Hospital. Methodology This is a cross-sectional, comparative, pilot study of plasma concentrations of selenium in HIV-infected (n = 30) and non-infected (n = 20) children enrolled in the pediatric HIV clinic of the Lagos University Teaching Hospital, Lagos, Nigeria, from May 2019 to May 2021. HIV-infected children were on stable antiretroviral therapy (ART) with an undetectable viral load. The serum concentration of selenium was measured using the automated atomic absorption spectrophotometer (hydride generation method). Logistic regression was used to study the effect of selenium status on the levels of HIV disease markers (CD4 count, viral load, weight, opportunistic infections) in the study participants. Results The median age of all participants was nine (4-12) years, with 74% being boys. The mean selenium concentrations were lower in HIV-infected children (91.1 ± 12.0 µg/L) compared to the comparison group without HIV (147.8 ± 4.9 µg/L) (p = 0.001). After controlling for age, ART duration, markers of HIV infection, and other potentially confounding variables, participants with selenium deficiency had approximately 11-fold odds of increased hospital admissions (adjusted odds ratio = 10.57, 95% confidence interval = 1.58 to 70.99; p = 0.015). Conclusions In this study, selenium concentrations were significantly lower in HIV-infected children than in the HIV-negative comparison group. Lower serum selenium concentrations were associated with increased hospitalizations. Although our findings suggest the potential need for selenium supplementation for children living with HIV in Nigeria, further studies are warranted to determine the safety and efficacy of selenium supplementation in this key population.
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Affiliation(s)
- Sarah O John-Olabode
- Haematology and Blood Transfusion, College of Medicine, University of Lagos, Lagos, NGA
| | - Patricia Akintan
- Paediatrics, College of Medicine, University of Lagos, Lagos, NGA
| | - Kehinde S Okunade
- Obstetrics and Gynaecology, College of Medicine, University of Lagos, Lagos, NGA
| | - Iwuchukwu Ajie
- Clinical Pathology, College of Medicine, University of Lagos, Lagos, NGA
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Mal’tseva VN, Goltyaev MV, Turovsky EA, Varlamova EG. Immunomodulatory and Anti-Inflammatory Properties of Selenium-Containing Agents: Their Role in the Regulation of Defense Mechanisms against COVID-19. Int J Mol Sci 2022; 23:ijms23042360. [PMID: 35216476 PMCID: PMC8880504 DOI: 10.3390/ijms23042360] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/18/2022] [Accepted: 02/19/2022] [Indexed: 02/04/2023] Open
Abstract
The review presents the latest data on the role of selenium-containing agents in the regulation of diseases of the immune system. We mainly considered the contributions of selenium-containing compounds such as sodium selenite, methylseleninic acid, selenomethionine, and methylselenocysteine, as well as selenoproteins and selenium nanoparticles in the regulation of defense mechanisms against various viral infections, including coronavirus infection (COVID-19). A complete description of the available data for each of the above selenium compounds and the mechanisms underlying the regulation of immune processes with the active participation of these selenium agents, as well as their therapeutic and pharmacological potential, is presented. The main purpose of this review is to systematize the available information, supplemented by data obtained in our laboratory, on the important role of selenium compounds in all of these processes. In addition, the presented information makes it possible to understand the key differences in the mechanisms of action of these compounds, depending on their chemical and physical properties, which is important for obtaining a holistic picture and prospects for creating drugs based on them.
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In Vitro Anti-SARS-CoV-2 Activity of Selected Metal Compounds and Potential Molecular Basis for Their Actions Based on Computational Study. Biomolecules 2021; 11:biom11121858. [PMID: 34944502 PMCID: PMC8699537 DOI: 10.3390/biom11121858] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/07/2021] [Accepted: 12/08/2021] [Indexed: 12/24/2022] Open
Abstract
Metal-based drugs represent a rich source of chemical substances of potential interest for the treatment of COVID-19. To this end, we have developed a small but representative panel of nine metal compounds, including both synthesized and commercially available complexes, suitable for medical application and tested them in vitro against the SARS-CoV-2 virus. The screening revealed that three compounds from the panel, i.e., the organogold(III) compound Aubipyc, the ruthenium(III) complex KP1019, and antimony trichloride (SbCl3), are endowed with notable antiviral properties and an acceptable cytotoxicity profile. These initial findings prompted us to perform a computational study to unveil the likely molecular basis of their antiviral actions. Calculations evidenced that the metalation of nucleophile sites in SARS-CoV-2 proteins or nucleobase strands, induced by Aubipyc, SbCl3, and KP1019, is likely to occur. Remarkably, we found that only the deprotonated forms of Cys and Sec residues can react favorably with these metallodrugs. The mechanistic implications of these findings are discussed.
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Tomo S, Saikiran G, Banerjee M, Paul S. Selenium to selenoproteins - role in COVID-19. EXCLI JOURNAL 2021; 20:781-791. [PMID: 34040501 PMCID: PMC8144537 DOI: 10.17179/excli2021-3530] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 04/07/2021] [Indexed: 12/14/2022]
Abstract
The disruption of antioxidant defense has been demonstrated in severe acute respiratory syndrome due to SARS-CoV infection. Selenium plays a major role in decreasing the ROS produced in response to various viral infections. Selenoprotein enzymes are essential in combating oxidative stress caused due to excessive generation of ROS. Selenium also has a role in inhibiting the activation of NF-κB, thus alleviating inflammation. In viral infections, selenoproteins have also been found to inhibit type I interferon responses, modulate T cell proliferation and oxidative burst in macrophages, and inhibit viral transcriptional activators. Potential virally encoded selenoproteins have been identified by computational analysis in different viral genomes like HIV-1, Japanese encephalitis virus (JEV), and hepatitis C virus. This review discusses the role and the possible mechanisms of selenium, selenoproteins, and virally encoded selenoproteins in the pathogenicity of viral infections. Identification of potential selenoproteins in the COVID 19 genome by computational tools will give insights further into their role in the pathogenesis of viral infections.
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Affiliation(s)
- Sojit Tomo
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India
| | - Gangam Saikiran
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India
| | - Mithu Banerjee
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India
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Hiffler L, Rakotoambinina B. Selenium and RNA Virus Interactions: Potential Implications for SARS-CoV-2 Infection (COVID-19). Front Nutr 2020; 7:164. [PMID: 33015130 PMCID: PMC7498630 DOI: 10.3389/fnut.2020.00164] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Accepted: 08/10/2020] [Indexed: 12/13/2022] Open
Abstract
SARS-CoV-2 is an RNA virus responsible for the COVID-19 pandemic that already claimed more than 340,000 lives worldwide as of May 23, 2020, the majority of which are elderly. Selenium (Se), a natural trace element, has a key and complex role in the immune system. It is well-documented that Se deficiency is associated with higher susceptibility to RNA viral infections and more severe disease outcome. In this article, we firstly present evidence on how Se deficiency promotes mutations, replication and virulence of RNA viruses. Next, we review how Se might be beneficial via restoration of host antioxidant capacity, reduction of apoptosis and endothelial cell damages as well as platelet aggregation. It also appears that low Se status is a common finding in conditions considered at risk of severe COVID-19, especially in the elderly. Finally, we present a rationale for Se use at different stages of COVID-19. Se has been overlooked but may have a significant place in COVID-19 spectrum management, particularly in vulnerable elderly, and might represent a game changer in the global response to COVID-19.
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Himoto T, Masaki T. Current Trends of Essential Trace Elements in Patients with Chronic Liver Diseases. Nutrients 2020; 12:nu12072084. [PMID: 32674425 PMCID: PMC7400835 DOI: 10.3390/nu12072084] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/16/2020] [Accepted: 06/29/2020] [Indexed: 02/06/2023] Open
Abstract
Essential trace elements play crucial roles in the maintenance of health, since they are involved in many metabolic pathways. A deficiency or an excess of some trace elements, including zinc, selenium, iron, and copper, frequently causes these metabolic disorders such as impaired glucose tolerance and dyslipidemia. The liver largely regulates most of the metabolism of trace elements, and accordingly, an impairment of liver functions can result in numerous metabolic disorders. The administration or depletion of these trace elements can improve such metabolic disorders and liver dysfunction. Recent advances in molecular biological techniques have helped to elucidate the putative mechanisms by which liver disorders evoke metabolic abnormalities that are due to deficiencies or excesses of these trace elements. A genome-wide association study revealed that a genetic polymorphism affected the metabolism of a specific trace element. Gut dysbiosis was also responsible for impairment of the metabolism of a trace element. This review focuses on the current trends of four trace elements in chronic liver diseases, including chronic hepatitis, liver cirrhosis, nonalcoholic fatty liver disease, and autoimmune liver diseases. The novel mechanisms by which the trace elements participated in the pathogenesis of the chronic liver diseases are also mentioned.
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Affiliation(s)
- Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, 281-1, Hara, Mure-Cho, Takamatsu, Kagawa 761-0123, Japan
- Correspondence: ; Tel.: +81-87-870-1240; Fax: +81-87-870-1202
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0123, Japan;
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Hiffler L, Rakotoambinina B. Selenium and RNA Virus Interactions: Potential Implications for SARS-CoV-2 Infection (COVID-19). Front Nutr 2020. [PMID: 33015130 DOI: 10.2139/ssrn.3594240] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2023] Open
Abstract
SARS-CoV-2 is an RNA virus responsible for the COVID-19 pandemic that already claimed more than 340,000 lives worldwide as of May 23, 2020, the majority of which are elderly. Selenium (Se), a natural trace element, has a key and complex role in the immune system. It is well-documented that Se deficiency is associated with higher susceptibility to RNA viral infections and more severe disease outcome. In this article, we firstly present evidence on how Se deficiency promotes mutations, replication and virulence of RNA viruses. Next, we review how Se might be beneficial via restoration of host antioxidant capacity, reduction of apoptosis and endothelial cell damages as well as platelet aggregation. It also appears that low Se status is a common finding in conditions considered at risk of severe COVID-19, especially in the elderly. Finally, we present a rationale for Se use at different stages of COVID-19. Se has been overlooked but may have a significant place in COVID-19 spectrum management, particularly in vulnerable elderly, and might represent a game changer in the global response to COVID-19.
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10
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Hiffler L, Rakotoambinina B. Selenium and RNA Virus Interactions: Potential Implications for SARS-CoV-2 Infection (COVID-19). Front Nutr 2020. [PMID: 33015130 DOI: 10.31219/osf.io/vaqz6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2023] Open
Abstract
SARS-CoV-2 is an RNA virus responsible for the COVID-19 pandemic that already claimed more than 340,000 lives worldwide as of May 23, 2020, the majority of which are elderly. Selenium (Se), a natural trace element, has a key and complex role in the immune system. It is well-documented that Se deficiency is associated with higher susceptibility to RNA viral infections and more severe disease outcome. In this article, we firstly present evidence on how Se deficiency promotes mutations, replication and virulence of RNA viruses. Next, we review how Se might be beneficial via restoration of host antioxidant capacity, reduction of apoptosis and endothelial cell damages as well as platelet aggregation. It also appears that low Se status is a common finding in conditions considered at risk of severe COVID-19, especially in the elderly. Finally, we present a rationale for Se use at different stages of COVID-19. Se has been overlooked but may have a significant place in COVID-19 spectrum management, particularly in vulnerable elderly, and might represent a game changer in the global response to COVID-19.
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11
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Qian F, Misra S, Prabhu KS. Selenium and selenoproteins in prostanoid metabolism and immunity. Crit Rev Biochem Mol Biol 2019; 54:484-516. [PMID: 31996052 PMCID: PMC7122104 DOI: 10.1080/10409238.2020.1717430] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 01/13/2020] [Accepted: 01/14/2020] [Indexed: 02/06/2023]
Abstract
Selenium (Se) is an essential trace element that functions in the form of the 21st amino acid, selenocysteine (Sec) in a defined set of proteins. Se deficiency is associated with pathological conditions in humans and animals, where incorporation of Sec into selenoproteins is reduced along with their expression and catalytic activity. Supplementation of Se-deficient population with Se has shown health benefits suggesting the importance of Se in physiology. An interesting paradigm to explain, in part, the health benefits of Se stems from the observations that selenoprotein-dependent modulation of inflammation and efficient resolution of inflammation relies on mechanisms involving a group of bioactive lipid mediators, prostanoids, which orchestrate a concerted action toward maintenance and restoration of homeostatic immune responses. Such an effect involves the interaction of various immune cells with these lipid mediators where cellular redox gatekeeper functions of selenoproteins further aid in not only dampening inflammation, but also initiating an effective and active resolution process. Here we have summarized the current literature on the multifaceted roles of Se/selenoproteins in the regulation of these bioactive lipid mediators and their immunomodulatory effects.
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Affiliation(s)
- Fenghua Qian
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences and The Penn State Cancer Institute, The Pennsylvania State University, University Park, PA. 16802, USA
| | - Sougat Misra
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences and The Penn State Cancer Institute, The Pennsylvania State University, University Park, PA. 16802, USA
| | - K. Sandeep Prabhu
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences and The Penn State Cancer Institute, The Pennsylvania State University, University Park, PA. 16802, USA
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Guillin OM, Vindry C, Ohlmann T, Chavatte L. Selenium, Selenoproteins and Viral Infection. Nutrients 2019; 11:nu11092101. [PMID: 31487871 PMCID: PMC6769590 DOI: 10.3390/nu11092101] [Citation(s) in RCA: 255] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 08/23/2019] [Accepted: 08/27/2019] [Indexed: 02/07/2023] Open
Abstract
Reactive oxygen species (ROS) are frequently produced during viral infections. Generation of these ROS can be both beneficial and detrimental for many cellular functions. When overwhelming the antioxidant defense system, the excess of ROS induces oxidative stress. Viral infections lead to diseases characterized by a broad spectrum of clinical symptoms, with oxidative stress being one of their hallmarks. In many cases, ROS can, in turn, enhance viral replication leading to an amplification loop. Another important parameter for viral replication and pathogenicity is the nutritional status of the host. Viral infection simultaneously increases the demand for micronutrients and causes their loss, which leads to a deficiency that can be compensated by micronutrient supplementation. Among the nutrients implicated in viral infection, selenium (Se) has an important role in antioxidant defense, redox signaling and redox homeostasis. Most of biological activities of selenium is performed through its incorporation as a rare amino acid selenocysteine in the essential family of selenoproteins. Selenium deficiency, which is the main regulator of selenoprotein expression, has been associated with the pathogenicity of several viruses. In addition, several selenoprotein members, including glutathione peroxidases (GPX), thioredoxin reductases (TXNRD) seemed important in different models of viral replication. Finally, the formal identification of viral selenoproteins in the genome of molluscum contagiosum and fowlpox viruses demonstrated the importance of selenoproteins in viral cycle.
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Affiliation(s)
- Olivia M Guillin
- CIRI, Centre International de Recherche en Infectiologie, CIRI, 69007 Lyon, France
- Institut National de la Santé et de la Recherche Médicale (INSERM) Unité U1111, 69007 Lyon, France
- Ecole Normale Supérieure de Lyon, 69007 Lyon, France
- Université Claude Bernard Lyon 1 (UCBL1), 69622 Lyon, France
- Unité Mixte de Recherche 5308 (UMR5308), Centre national de la recherche scientifique (CNRS), 69007 Lyon, France
| | - Caroline Vindry
- CIRI, Centre International de Recherche en Infectiologie, CIRI, 69007 Lyon, France
- Institut National de la Santé et de la Recherche Médicale (INSERM) Unité U1111, 69007 Lyon, France
- Ecole Normale Supérieure de Lyon, 69007 Lyon, France
- Université Claude Bernard Lyon 1 (UCBL1), 69622 Lyon, France
- Unité Mixte de Recherche 5308 (UMR5308), Centre national de la recherche scientifique (CNRS), 69007 Lyon, France
| | - Théophile Ohlmann
- CIRI, Centre International de Recherche en Infectiologie, CIRI, 69007 Lyon, France
- Institut National de la Santé et de la Recherche Médicale (INSERM) Unité U1111, 69007 Lyon, France
- Ecole Normale Supérieure de Lyon, 69007 Lyon, France
- Université Claude Bernard Lyon 1 (UCBL1), 69622 Lyon, France
- Unité Mixte de Recherche 5308 (UMR5308), Centre national de la recherche scientifique (CNRS), 69007 Lyon, France
| | - Laurent Chavatte
- CIRI, Centre International de Recherche en Infectiologie, CIRI, 69007 Lyon, France.
- Institut National de la Santé et de la Recherche Médicale (INSERM) Unité U1111, 69007 Lyon, France.
- Ecole Normale Supérieure de Lyon, 69007 Lyon, France.
- Université Claude Bernard Lyon 1 (UCBL1), 69622 Lyon, France.
- Unité Mixte de Recherche 5308 (UMR5308), Centre national de la recherche scientifique (CNRS), 69007 Lyon, France.
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Gupta S, Read SA, Shackel NA, Hebbard L, George J, Ahlenstiel G. The Role of Micronutrients in the Infection and Subsequent Response to Hepatitis C Virus. Cells 2019; 8:E603. [PMID: 31212984 PMCID: PMC6627053 DOI: 10.3390/cells8060603] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 06/13/2019] [Indexed: 12/13/2022] Open
Abstract
Micronutrient deficiencies develop for a variety of reasons, whether geographic, socioeconomic, nutritional, or as a result of disease pathologies such as chronic viral infection. As micronutrients are essential for a strong immune response, deficiencies can significantly dampen both the innate and the adaptive arms of antiviral immunity. The innate immune response in particular is crucial to protect against hepatitis C virus (HCV), a hepatotropic virus that maintains chronic infection in up to 80% of individuals if left untreated. While many micronutrients are required for HCV replication, an overlapping group of micronutrients are also necessary to enact a potent immune response. As the liver is responsible for the storage and metabolism of many micronutrients, HCV persistence can influence the micronutrients' steady state to benefit viral persistence both directly and by weakening the antiviral response. This review will focus on common micronutrients such as zinc, iron, copper, selenium, vitamin A, vitamin B12, vitamin D and vitamin E. We will explore their role in the pathogenesis of HCV infection and in the response to antiviral therapy. While chronic hepatitis C virus infection drives deficiencies in micronutrients such as zinc, selenium, vitamin A and B12, it also stimulates copper and iron excess; these micronutrients influence antioxidant, inflammatory and immune responses to HCV.
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Affiliation(s)
- Sunil Gupta
- Blacktown Clinical School, Western Sydney University, Blacktown, NSW 2148, Australia.
| | - Scott A Read
- Blacktown Clinical School, Western Sydney University, Blacktown, NSW 2148, Australia.
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead 2145, Australia.
| | - Nicholas A Shackel
- Department of Medicine, University of New South Wales, Kensington, NSW 2052, Australia.
| | - Lionel Hebbard
- Department of Molecular and Cell Biology, Centre for Molecular Therapeutics, James Cook University, Australian Institute of Tropical Health and Medicine, Townsville, QLD 4814, Australia.
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead 2145, Australia.
| | - Golo Ahlenstiel
- Blacktown Clinical School, Western Sydney University, Blacktown, NSW 2148, Australia.
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead 2145, Australia.
- Department of Medicine, Blacktown Hospital, Blacktown, NSW 2148, Australia.
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The genomics of selenium: Its past, present and future. Biochim Biophys Acta Gen Subj 2018; 1862:2427-2432. [DOI: 10.1016/j.bbagen.2018.05.020] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 04/29/2018] [Accepted: 05/24/2018] [Indexed: 12/13/2022]
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Taylor EW, Ruzicka JA, Premadasa L, Zhao L. Cellular Selenoprotein mRNA Tethering via Antisense Interactions with Ebola and HIV-1 mRNAs May Impact Host Selenium Biochemistry. Curr Top Med Chem 2016; 16:1530-5. [PMID: 26369818 PMCID: PMC4997913 DOI: 10.2174/1568026615666150915121633] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Revised: 08/23/2015] [Accepted: 08/25/2015] [Indexed: 02/06/2023]
Abstract
Regulation of protein expression by non-coding RNAs typically involves effects on mRNA degradation and/or ribosomal translation. The possibility of virus-host mRNA-mRNA antisense tethering interactions (ATI) as a gain-of-function strategy, via the capture of functional RNA motifs, has not been hitherto considered. We present evidence that ATIs may be exploited by certain RNA viruses in order to tether the mRNAs of host selenoproteins, potentially exploiting the proximity of a captured host selenocysteine insertion sequence (SECIS) element to enable the expression of virally-encoded selenoprotein modules, via translation of in-frame UGA stop codons as selenocysteine. Computational analysis predicts thermodynamically stable ATIs between several widely expressed mammalian selenoprotein mRNAs (e.g., isoforms of thioredoxin reductase) and specific Ebola virus mRNAs, and HIV-1 mRNA, which we demonstrate via DNA gel shift assays. The probable functional significance of these ATIs is further supported by the observation that, in both viruses, they are located in close proximity to highly conserved in-frame UGA stop codons at the 3′ end of open reading frames that encode essential viral proteins (the HIV-1 nef protein and the Ebola nucleoprotein). Significantly, in HIV/AIDS patients, an inverse correlation between serum selenium and mortality has been repeatedly documented, and clinical benefits of selenium in the context of multi-micronutrient supplementation have been demonstrated in several well-controlled clinical trials. Hence, in the light of our findings, the possibility of a similar role for selenium in Ebola pathogenesis and treatment merits serious investigation.
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Affiliation(s)
- Ethan Will Taylor
- Dept. of Nanoscience, University of North Carolina at Greensboro, Joint School of Nanoscience and Nanoengineering, 2907 E. Gate City Blvd., Greensboro, NC 27401 USA.
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16
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Cheng Z, Zhi X, Sun G, Guo W, Huang Y, Sun W, Tian X, Zhao F, Hu K. Sodium selenite suppresses hepatitis B virus transcription and replication in human hepatoma cell lines. J Med Virol 2015; 88:653-63. [PMID: 26331371 PMCID: PMC7167125 DOI: 10.1002/jmv.24366] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/25/2015] [Indexed: 12/30/2022]
Abstract
Hepatitis B virus (HBV) infection is one of the most serious and prevalent health problems worldwide. Current anti‐HBV medications have a number of drawbacks, such as adverse effects and drug resistance; thus, novel potential anti‐HBV reagents are needed. Selenium (Se) has been shown to be involved in both human immunodeficiency virus and hepatitis C virus infections, but its role in HBV infection remains unclear. To address this, sodium selenite (Na2SeO3) was applied to three HBV cell models: HepG2.2.15 cells, and HuH‐7 cells transfected with either 1.1 or 1.3× HBV plasmids. Cytotoxicity of Na2SeO3 was examined by Cell Counting Kit‐8. Levels of viral antigen expression, transcripts, and encapsidated viral DNA were measured by enzyme‐linked immunosorbent assay, northern blot, and Southern blot, respectively. There was no obvious cytotoxicity in either HepG2.2.15 or HuH‐7 cells with <2.5 µM Na2SeO3. Below this concentration, Na2SeO3 suppressed HBsAg and HBeAg production, HBV transcript level, and amount of genomic DNA in all three tested models, and suppression level was enhanced in line with increases in Na2SeO3 concentration or treatment time. Moreover, the inhibitory effect of Na2SeO3 on HBV replication can be further enhanced by combined treatment with lamivudine, entecavir, or adefovir. Thus, the present study clearly proves that Na2SeO3 suppresses HBV protein expression, transcription, and genome replication in hepatoma cell models in a dose‐ and time‐dependent manner. J. Med. Virol. 88:653–663, 2016. © 2015 Wiley Periodicals, Inc.
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Affiliation(s)
- Zhikui Cheng
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
| | - Xiaoguang Zhi
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
| | - Ge Sun
- Sino-Germany Biomedical Center, Hubei University of Technology, Wuhan, 430068, China
| | - Wei Guo
- Department of Infectious Disease and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Tongji, China
| | - Yayun Huang
- Sino-Germany Biomedical Center, Hubei University of Technology, Wuhan, 430068, China
| | - Weihua Sun
- Sino-Germany Biomedical Center, Hubei University of Technology, Wuhan, 430068, China
| | - Xiaohui Tian
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
| | - Fei Zhao
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
| | - Kanghong Hu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.,Sino-Germany Biomedical Center, Hubei University of Technology, Wuhan, 430068, China
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17
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Gać P, Pawlas N, Poręba R, Poręba M, Pawlas K. The relationship between environmental exposure to cadmium and lead and blood selenium concentration in randomly selected population of children inhabiting industrial regions of Silesian Voivodship (Poland). Hum Exp Toxicol 2013; 33:661-9. [PMID: 23956355 DOI: 10.1177/0960327113499169] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
This study aimed at determining the relationship between environmental exposure to lead (Pb) and cadmium (Cd) and blood selenium (Se) concentration in randomly selected population of children inhabiting the industrial regions of Silesian Voivodship, Poland. The study was conducted on a group of consecutive randomly selected 349 children aged below 15 years and inhabiting the industrial regions in Upper Silesia. The examined variables included whole blood Cd concentration (Cd-B), whole blood Pb concentration (Pb-B) and whole blood Se concentration (Se-B). The concentration of Cd-B, Pb-B and Se-B in the studied group of children amounted to 0.26 ± 0.14, 37.62 ± 25.30 and 78.31 ± 12.82 μg/L, respectively. In the entire examined group a statistically significant negative linear relationship was noted between Pb-B and Se-B (r = -0.12, p < 0.05). Also, a statistically insignificant negative correlation was detected between Cd-B and Se-B (r = -0.02, p > 0.05) and a statistically insignificant positive correlation between Pb-B and Cd-B (r = 0.08, p > 0.05). A multivariate backward stepwise regression analysis demonstrated that in the studied group of children higher Pb-B and a more advanced age-represented independent risk factors for a decreased Se-B. Environmental exposure to Pb may represent an independent risk factor for Se deficit in blood of the studied population of children. In children, the lowered Se-B may create one of the mechanisms in which Pb unfavourably affects human body.
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Affiliation(s)
- P Gać
- Department of Hygiene, Wroclaw Medical University, Wrocław, Poland
| | - N Pawlas
- Institute of Occupational Medicine and Environmental Health, Sosnowiec, Poland
| | - R Poręba
- Department of Internal Medicine, Occupational Diseases and Hypertension, Wroclaw Medical University, Wrocław, Poland
| | - M Poręba
- Department of Pathophysiology, Wroclaw Medical University, Wrocław, Poland
| | - K Pawlas
- Department of Hygiene, Wroclaw Medical University, Wrocław, Poland Institute of Occupational Medicine and Environmental Health, Sosnowiec, Poland
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18
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Abstract
Selenium is an essential micronutrient in mammals, but is also recognized as toxic in excess. It is a non-metal with properties that are intermediate between the chalcogen elements sulfur and tellurium. Selenium exerts its biological functions through selenoproteins. Selenoproteins contain selenium in the form of the 21st amino acid, selenocysteine (Sec), which is an analog of cysteine with the sulfur-containing side chain replaced by a Se-containing side chain. Sec is encoded by the codon UGA, which is one of three termination codons for mRNA translation in non-selenoprotein genes. Recognition of the UGA codon as a Sec insertion site instead of stop requires a Sec insertion sequence (SECIS) element in selenoprotein mRNAs and a unique selenocysteyl-tRNA, both of which are recognized by specialized protein factors. Unlike the 20 standard amino acids, Sec is biosynthesized from serine on its tRNA. Twenty-five selenoproteins are encoded in the human genome. Most of the selenoprotein genes were discovered by bioinformatics approaches, searching for SECIS elements downstream of in-frame UGA codons. Sec has been described as having stronger nucleophilic and electrophilic properties than cysteine, and Sec is present in the catalytic site of all selenoenzymes. Most selenoproteins, whose functions are known, are involved in redox systems and signaling pathways. However, several selenoproteins are not well characterized in terms of their function. The selenium field has grown dramatically in the last few decades, and research on selenium biology is providing extensive new information regarding its importance for human health.
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Affiliation(s)
- Suguru Kurokawa
- Department of Cell & Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, 96813, USA,
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19
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Ismail NA, Okasha SH, Dhawan A, Rahman AMOA, Hamid NA, Shaker O. Glutathione peroxidase, superoxide dismutase and catalase activities in children with chronic hepatitis. ACTA ACUST UNITED AC 2012. [DOI: 10.4236/abb.2012.327119] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Shen H, Thomas PR, Ensley SM, Kim WI, Loynachan AT, Halbur PG, Opriessnig T. Vitamin E and selenium levels are within normal range in pigs diagnosed with mulberry heart disease and evidence for viral involvement in the syndrome is lacking. Transbound Emerg Dis 2011; 58:483-91. [PMID: 21518323 PMCID: PMC7169668 DOI: 10.1111/j.1865-1682.2011.01224.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Mulberry heart disease (MHD) in pigs is characterized by lesions of acute haemorrhagic myocarditis and myocardial necrosis. The objectives of this study were to determine the levels of vitamin E and selenium and 13 other trace minerals in heart and liver tissues and to determine the prevalence of certain viral infections in heart tissues from MHD-affected and MHD-unaffected pigs and the vitamin E and selenium concentration in feed samples from selected farms with MHD. Based on the pathological examination, 114 pigs were separated into MHD lesion-negative (L-NEG) (n = 57) and MHD lesion-positive (L-POS) (n = 57) groups. Seventy-three samples (40 L-NEG and 33 L-POS) were subjected to chemical analysis, and 66 (32 L-NEG and 34 L-POS) were subjected to PCR detection for viral pathogens. Lower (P < 0.05) levels of myocardial copper, lower (P < 0.05) levels of hepatic magnesium and higher (P < 0.05) levels of myocardial and hepatic sodium were detected in the L-POS cases. Although lower (P < 0.05) levels of hepatic selenium were detected in L-POS group, all were within the normal range. Analysis of feed samples (n = 22) revealed that selenium levels in all the samples were above the legal limit (0.3 ppm) for pigs. Vitamin E levels in all feed samples were above 20 IU/kg. Among the 66 pigs subjected to PCR detection, there were 19, 4, 13, 8, 2 and 1 animals positive for porcine circovirus type 2, porcine reproductive and respiratory syndrome virus, pan-herpes virus, porcine enterovirus, pan-pestivirus and porcine parvovirus, respectively. Clear evidence of viral association with L-POS was lacking.
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Affiliation(s)
- H Shen
- Department of Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames, USA
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21
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Abstract
HIV infection is a global disease that disproportionately burdens populations with nutritional vulnerabilities. Laboratory experiments have shown that selenium has an inhibitory effect on HIV in vitro through antioxidant effects of glutathione peroxidase and other selenoproteins. Numerous studies have reported low selenium status in HIV-infected individuals, and serum selenium concentration declines with disease progression. Some cohort studies have shown an association between selenium deficiency and progression to AIDS or mortality. In several randomized controlled trials, selenium supplementation has reduced hospitalizations and diarrheal morbidity, and improved CD4(+) cell counts, but the evidence remains mixed. Additional trials are recommended to study the effect of selenium supplementation on opportunistic infections, and other HIV disease-related comorbidities in the context of highly active antiretroviral therapy in both developing and developed countries.
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Affiliation(s)
- Cosby A Stone
- School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA.
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22
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Abstract
Following the publication of the landmark trial of Clark et al. in 1996 that appeared to show that Se could reduce the risk of cancer, awareness of the importance of Se to human health has markedly increased. As a result, there is now much more aggressive marketing of Se supplements and functional foods, even in situations where additional consumption of Se is inappropriate. The present review addresses how Se gets into the food chain, the wide variability in Se content of foods and the very different levels of intake between countries and regions. Though it is clear that there are adverse consequences for health of both deficient and excessive intake, health effects at intermediate levels of intake are less certain. Thus it is difficult to define optimal intake which depends on a large number of factors, such as which functions of Se are most relevant to a particular disease state, which species of Se is most prominent in the Se source, which health condition is being considered, the adequacy or otherwise of intake of other nutrients, the presence of additional stressors, and lastly whether the ability to make selenoproteins may be compromised. These complexities need to be understood, particularly by policy makers, in order to make informed judgments. Potential solutions for increasing Se intake, where required, include agronomic biofortification and genetic biofortification or, for individuals, increased intake of naturally Se-rich foods, functional foods or supplements. The difficulties of balancing the risks and benefits in relation to Se intake are highlighted.
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Cooper LT, Rader V, Ralston NVC. The roles of selenium and mercury in the pathogenesis of viral cardiomyopathy. ACTA ACUST UNITED AC 2007; 13:193-9. [PMID: 17673870 DOI: 10.1111/j.1527-5299.2007.06410.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Research on the pathogenesis of nonischemic dilated cardiomyopathy (DCM) has largely been focused on the role of viral pathogens and altered immunity. Trace elements have only rarely been considered; however, clinical observations that trace elements influence cardiovascular disease have been made in populations with extreme dietary deficiency or occupational exposure. Recently, animal models of DCM have been used to explore interactions among trace elements, viral pathogens, and the immune system. Discovery of interactions of trace elements with causes for DCM has heightened awareness of potential contributions of environmental variables to DCM pathogenesis. This article reviews the present knowledge regarding trace elements, in particular selenium and mercury, in the pathogenesis of viral and immune-mediated DCM. Based on recent studies, the authors propose a novel paradigm for the pathogenesis of viral DCM that incorporates trace element imbalance and its interactions with the cellular physiology of viral-induced cardiomyocyte dysfunction.
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Affiliation(s)
- Leslie T Cooper
- Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA.
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24
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Ravikumar Naik TR, Bhojya Naik HS, Gopala Krishna Naik SR. One pot solvent-free synthesis of 2H-pyrano, 2H-thiopyrano, 2H-selenopyrano[2,3-b]-1,8-naphthyridin-2-ones on solid phase catalyst under microwave irradiation. J Sulphur Chem 2007. [DOI: 10.1080/17415990701312279] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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25
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Foster HD. Host-pathogen evolution: Implications for the prevention and treatment of malaria, myocardial infarction and AIDS. Med Hypotheses 2007; 70:21-5. [PMID: 17590522 DOI: 10.1016/j.mehy.2007.05.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2007] [Accepted: 05/02/2007] [Indexed: 11/24/2022]
Abstract
Humans have evolved complex immune systems to protect against infection by pathogens. However, pathogens possess a remarkable genetic versatility that allows them to gain new vigour and so escape such population immunity. Conflicting pathogen-host objectives, therefore, lead to the evolutionary equivalent of an "arms race". Typically, in this struggle, pathogens attempt to deplete their host of specific nutrients that are essential for immune system function. After infection, the resulting deficiency of nutrient(s) may cause many of the disease symptoms and sequela. In malaria, Plasmodium falciparum, for example, depletes its host of Vitamin A, possibly resulting in blindness in some cases. However, 200,000 International Units of Vitamin A, given to children every three months can reduce significantly their susceptibility to malaria. This would seem to be a minimum child dosage for the treatment of the disease. In contrast, the Coxsackie B virus causes a selenium deficiency that may result in myocardial infarction or Keshan disease. However, table salt fortified with 15ppm anhydrous sodium selenite can cause dramatic drops in the incidence of Keshan disease, while selenium supplementation also reduces re-infarction rates. HIV-1 depletes its host of four nutrients: selenium, cysteine, glutamine and tryptophan, resulting in symptoms known as AIDS. Open and closed clinical trials in South Africa, Zambia and Uganda, involving daily adult doses of 600mcg l-selenomethione, and some 500mg l-glutamine, hydroxytryptophan and N-acetyl cysteine, however, have shown that such supplementation can reverse the symptoms of AIDS and prevent HIV-1 infected patients declining into this disease. It is obvious, therefore, that supplementation of diet with specific nutrients can reduce infection by particular pathogens. In addition, if infection still occurs, their use as a treatment may prevent many of the symptoms and sequela commonly associated with diseases such as malaria, myocardial infarction and AIDS.
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Affiliation(s)
- Harold D Foster
- Department of Geography, University of Victoria, P.O. Box 3050, Victoria, BC, Canada V8W 3P5.
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26
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Bulska E, Wysocka IA, Wierzbicka MLGH, Proost K, Janssens K, Falkenberg G. In Vivo Investigation of the Distribution and the Local Speciation of Selenium inAlliumcepa L. by Means of Microscopic X-ray Absorption Near-Edge Structure Spectroscopy and Confocal Microscopic X-ray Fluorescence Analysis. Anal Chem 2006; 78:7616-24. [PMID: 17105151 DOI: 10.1021/ac060380s] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
In this work, microscopic X-ray absorption near-edge structure spectroscopy (mu-XANES) and confocal microscopic X-ray fluorescence analysis (mu-XRF) were used for the in vivo determination of the distribution of total selenium and for the local speciation of selenium in roots and leaves of onion. Selected Allium cepa L. plants were grown hydroponically in a standard medium containing inorganic selenium compounds (selenite or selenate). The measurements were performed in vivo, that is, on living plants without the need for any form of sampling or sample pretreatment and without the necessity for cutting plant tissues into pieces. Distinct energy differences of the XANES spectra of various selenium reference compounds having different oxidation states allow adjusting the excitation energies used for mu-XRF mapping in such a manner that the distribution of selenium in various oxidation states is obtained with a spatial resolution of a few tens of micrometers within the virtual cross section of the onion tissues. We find that the ratio of inorganic to amino acid selenium compounds differs in various subparts of the plant. Detailed in vivo investigation of the distribution of various selenium species in virtual cross sections of root tips and green leaf shows that the selenium transport takes place via different mechanisms, depending on the nature of the selenium compounds originally taken up.
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Affiliation(s)
- Ewa Bulska
- Faculty of Chemistry, Warsaw University, Warsaw, Poland. ebulska@ chem.uw.edu.pl
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27
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Abstract
In an alternate reading frame overlapping the viral envelope gene, HIV-1 has been shown to encoded a truncated glutathione peroxidase (GPx) module. Essential active site residues of the catalytic core regions of mammalian GPx sequences are conserved in the putative viral GPx (vGPx, encoded by the env-fs gene). Cells transfected with an HIV-1 env-fs construct show up to a 100% increase in GPx enzyme activity, and are protected against the loss of mitochondrial transmembrane potential and subsequent cell death induced by exogenous oxidants or mitochondrial reactive oxygen species. An intact vGPx gene was observed to be more common in HIV-1-infected long-term non-progressors, as compared to HIV-1 isolates from patients developing AIDS. An antioxidant/antiapoptotic protective role of the vGPx is also consistent with the observation that -1 frameshifting induced by the HIV-1 env-fs sequence AAAAAGA (which contains a potential "hungry" arginine codon, AGA) increases during arginine deficiency, which has been associated with increased oxidative stress. Under arginine-limited conditions, nitric oxide synthase generates superoxide, which rapidly combines with NO to form peroxynitrite, which can cause activated T-cells to undergo apoptosis. Thus, biosynthesis of the HIV-1 GPx as an adaptive response to low arginine conditions might delay oxidant-induced apoptotic cell death, providing an enhanced opportunity for viral replication.
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Affiliation(s)
- Lijun Zhao
- Office of Research and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, PO Box 26170, Greensboro, NC 27402-6170, USA
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28
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Ko WS, Guo CH, Yeh MS, Lin LY, Hsu GSW, Chen PC, Luo MC, Lin CY. Blood micronutrient, oxidative stress, and viral load in patients with chronic hepatitis C. World J Gastroenterol 2005; 11:4697-702. [PMID: 16094713 PMCID: PMC4615414 DOI: 10.3748/wjg.v11.i30.4697] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the extent of micronutrient and oxidative stress in blood and to examine their linkages with viral loads in chronic hepatitis C patients.
METHODS: Hepatitis C virus (HCV)-RNA levels were quantified in the serum from 37 previously untreated patients with chronic hepatitis C. The plasma and erythrocyte micronutrients (zinc, selenium, copper, and iron) were estimated, and malondialdehyde (MDA) contents were determined as a marker to detect oxidative stress. Antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPX) and glutathione reductase (GR) activities in blood were also measured. The control group contained 31 healthy volunteers.
RESULTS: The contents of zinc (Zn), and selenium (Se) in plasma and erythrocytes were significantly lower in hepatitis C patients than in the controls. On the contrary, copper (Cu) levels were significantly higher. Furthermore, plasma and erythrocyte MDA levels, and the SOD and GR activities in erythrocytes significantly increased in hepatitis C patients compared to the controls. However, the plasma GPX activity in patients was markedly lower. Plasma Se (r = -0.730, P < 0.05), Cu (r = 0.635), and GPX (r = -0.675) demonstrated correlations with HCV-RNA loads. Significant correlation coefficients were also observed between HCV-RNA levels and erythrocyte Zn (r = -0.403), Se (r = -0.544), Cu (r = 0.701) and MDA (r = 0.629) and GR (r = 0.441).
CONCLUSION: The levels of Zn, Se, Cu, and oxidative stress (MDA), as well as related anti-oxidative enzymes (GR and GPX) in blood have important impact on the viral factors in chronic hepatitis C. The distribution of these parameters might be significant biomarkers for HCV.
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Affiliation(s)
- Wang-Sheng Ko
- Department of Food and Nutrition, Hung Kuang University, Taichung, Taiwan, China
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29
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Mouret S, Sauvaigo S, Peinnequin A, Favier A, Beani JC, Leccia MT. E6* oncoprotein expression of human papillomavirus type-16 determines different ultraviolet sensitivity related to glutathione and glutathione peroxidase antioxidant defence. Exp Dermatol 2005; 14:401-10. [PMID: 15885075 DOI: 10.1111/j.0906-6705.2005.00296.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Clinical observations of non-melanoma skin cancer in immunocompromised patients, such as organ transplant recipients, suggest co-operative effects of human papillomavirus (HPV) and ultraviolet (UV) radiation. The aim of the present study is to evaluate UV sensitivity and DNA damage formation according to antioxidant status in HPV16-infected keratinocytes. We used SKv cell lines, infected with HPV16 and well characterized for their proliferative and tumorigenic capacities. We showed that SKv cell lines presented various E6* (a truncated form of E6) RNA levels. We demonstrated that the higher oncoprotein RNA expression level was associated with a higher resistance to solar-simulated radiation, more specifically to UVB radiation and to hydrogen peroxide. Moreover, this high resistance was associated with a low oxidative DNA damage formation after UV radiation and was related to high glutathione content and glutathione peroxidase activities. Therefore, the results of our study suggest that E6* levels could modulate the glutathione/glutathione peroxidase pathway providing a mechanism to protect HPV-infected keratinocytes against an environmental oxidative stress, such as UV radiation.
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Affiliation(s)
- Stéphane Mouret
- Laboratoire Oligoéléments et Résistance au Stress Oxydant induit par les Xénobiotiques (ORSOX; UMR UJF-CEA, LRC7 CEA 8 M), Université Joseph Fourier, UFR de Médecine et Pharmacie, La Tronche, France
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30
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Zhong H, Taylor EW. Structure and dynamics of a predicted ferredoxin-like selenoprotein in Japanese encephalitis virus. J Mol Graph Model 2005; 23:223-31. [PMID: 15530818 DOI: 10.1016/j.jmgm.2004.07.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2004] [Revised: 05/25/2004] [Accepted: 07/01/2004] [Indexed: 10/26/2022]
Abstract
Homologues of the selenoprotein glutathione peroxidase (GPx) have been previously identified in poxviruses and in RNA viruses including HIV-1 and hepatitis C virus (HCV). Sequence analysis of the NS4 region of Japanese encephalitis virus (JEV) suggests it may encode a structurally related but functionally distinct selenoprotein gene, more closely related to the iron-binding protein ferredoxin than to GPx, with three highly conserved UGA codons that align with essential Cys residues of ferredoxin. Comparison of the probe JEV sequence to an aligned family of ferredoxin sequences gave an overall 30.3% identity and 45.8% similarity, and was statistically significant at 4.9 S.D. (P < 10(-6)) above the average score computed for randomly shuffled sequences. A 3-dimensional model of the hypothetical JEV protein (JEV model) was constructed by homology modeling using SYBYL, based upon a high resolution X-ray structure of ferredoxin (PDB code: 1awd). The JEV model and the model from 1awd were subsequently subjected to molecular dynamics simulations in aqueous medium using AMBER 6. The solution structure of the JEV model indicates that it could fold into a tertiary structure globally similar to ferredoxin 1awd, with RMSD between the averaged structures of 1.8 A for the aligned regions. The modeling and MD simulations data also indicate that this structure for the JEV protein is energetically favorable, and that it could be quite stable at room temperature. This protein might play a role in JEV infection and replication via TNF and other cellular stimuli mediated via redox mechanisms.
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Affiliation(s)
- Haizhen Zhong
- Center for Biomolecular Structure and Dynamics, and Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, GA 30602, USA
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31
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Fu LH, Wang XF, Eyal Y, She YM, Donald LJ, Standing KG, Ben-Hayyim G. A selenoprotein in the plant kingdom. Mass spectrometry confirms that an opal codon (UGA) encodes selenocysteine in Chlamydomonas reinhardtii gluththione peroxidase. J Biol Chem 2002; 277:25983-91. [PMID: 11973339 DOI: 10.1074/jbc.m202912200] [Citation(s) in RCA: 103] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Selenoproteins that contain the rare amino acid selenocysteine in their primary structure have been identified in diverse organisms such as viruses, bacteria, archea, and mammals, but so far not in yeast or plants. Among the most thoroughly investigated families of selenoenzymes are the animal glutathione peroxidases (GPXs). In the last few years, genes encoding GPX-like homologues from Chlamydomonas and higher plants have been isolated, but, unlike the animal ones, all of them have cysteine (rather than selenocysteine) residues in their catalytic site. In all organisms investigated that contain selenoproteins, selenocysteine is encoded by a UGA opal codon, which is usually a stop codon. We report here that, in Chlamydomonas reinhardtii, the cDNA-cloned sequence of a GPX homologue contains an internal TGA codon in frame to the ATG. Specific mRNA expression, protein production, and enzyme activity are selenium-dependent. Sequence analysis of the peptides produced by proteolytic digestion, performed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), confirmed the presence of a selenocysteine residue at the predicted site and suggest its location in the mitochondria. Thus, our data present the first direct proof that a UGA opal codon is decoded in the plant kingdom to incorporate selenocysteine.
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Affiliation(s)
- Lian-Hai Fu
- Department of Fruit-Tree Breeding and Molecular Genetics, Agricultural Research Organization, Volcani Center, Bet Dagan 50250, Israel
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Abstract
Many viruses have as part of their arsenal the ability to modulate the apoptotic pathways of the host. It is counter-intuitive that such simple organisms would be efficient at regulating this the most crucial pathway within the host, given the relative complexity of the host cells. Yet, viruses have the potential to initiate or stay the onset of programmed cell death through the manipulation of a variety of key apoptotic proteins. It is the intention of this review to provide an overview of viral gene products that are able to promote or inhibit apoptotic death of the host cell and to discuss their mechanisms of action. It is not until recently that the depth at which viruses exploit the apoptotic pathways of their host has been seen. This understanding may provide a great opportunity for future therapeutic ventures.
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Affiliation(s)
- Stewart Hay
- The Fiona Elsey Cancer Research Laboratory, Cancer Research Centre, School of Science, University of Ballarat, St John of God Hospital, 1002 Mair Street, Ballarat, Victoria 3350, Australia1
| | - George Kannourakis
- The Fiona Elsey Cancer Research Laboratory, Cancer Research Centre, School of Science, University of Ballarat, St John of God Hospital, 1002 Mair Street, Ballarat, Victoria 3350, Australia1
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Abstract
The essential trace mineral, Se, is of fundamental importance to human health. As a constituent of selenoproteins it plays both structural and enzymic roles, in the latter context being best known as an antioxidant and catalyst for the production of active thyroid hormone. While Se-deficiency diseases have been recognised for some time, evidence is mounting that less-overt deficiency can also cause adverse health effects and furthermore, that supra-nutritional levels of Se may give additional protection from disease. In the context of these effects, low or diminishing Se status in some parts of the world, notably in some European countries such as the UK, is giving cause for concern. While deficiency has an adverse effect on immunocompetence, Se supplementation appears to enhance the immune response. Se appears to be a key nutrient in counteracting certain viral infections; thus, in a Se-deficient host the benign coxsackie virus becomes virulent, causing heart damage, the influenza virus causes more serious lung pathology and HIV infection progresses more rapidly to AIDS. Long recognised as essential for successful animal reproduction, Se is required for human sperm maturation and sperm motility and may reduce the risk of miscarriage. Deficiency has been linked to adverse mood states. Findings have been equivocal in linking Se to cardiovascular disease risk, although other conditions involving oxidative stress and inflammation have shown some association with Se status. There is growing evidence that higher Se intakes are associated with reduced cancer risk. While persuasive evidence already exists to suggest that additional Se would be beneficial in some health conditions, results from intervention trials underway or planned have the potential to reinforce or refute the argument for increasing Se intake.
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Affiliation(s)
- Margaret P Rayman
- Centre for Nutrition and Food Safety, School of Biomedical and Life Sciences, University of Surrey, Guildford GU2 7XH, UK.
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Diamond AM, Hu YJ, Mansur DB. Glutathione peroxidase and viral replication: implications for viral evolution and chemoprevention. Biofactors 2001; 14:205-10. [PMID: 11568458 DOI: 10.1002/biof.5520140126] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
It is likely that several of the biological effects of selenium are due to its effects on selenoprotein activity. While the effects of the anti-oxidant selenoprotein glutathione peroxidase (GPx) on inhibiting HIV activation have been well documented, it is clear that increased expression of this enzyme can stimulate the replication and subsequent appearance of cytopathic effects associated with an acutely spreading HIV infection. The effects of GPx on both phases of the viral life cycle are likely mediated via its influence on signaling molecules that use reactive oxygen species, and similar influences on signaling pathways may account for some of the anti-cancer effects of selenium. Similarly, selenium can alter mutagenesis rates in both viral genomes and the DNA of mammalian cells exposed to carcinogens. Comparisons between the effects of selenium and selenoproteins on viral infections and carcinogenesis may yield new insights into the mechanisms of action of this element.
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Affiliation(s)
- A M Diamond
- Department of Human Nutrition and Dietetics, University of Illinois, Chicago, IL 60612, USA.
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Abstract
The essential trace mineral, selenium, is of fundamental importance to human health. As a constituent of selenoproteins, selenium has structural and enzymic roles, in the latter context being best-known as an antioxidant and catalyst for the production of active thyroid hormone. Selenium is needed for the proper functioning of the immune system, and appears to be a key nutrient in counteracting the development of virulence and inhibiting HIV progression to AIDS. It is required for sperm motility and may reduce the risk of miscarriage. Deficiency has been linked to adverse mood states. Findings have been equivocal in linking selenium to cardiovascular disease risk although other conditions involving oxidative stress and inflammation have shown benefits of a higher selenium status. An elevated selenium intake may be associated with reduced cancer risk. Large clinical trials are now planned to confirm or refute this hypothesis. In the context of these health effects, low or diminishing selenium status in some parts of the world, notably in some European countries, is giving cause for concern.
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Affiliation(s)
- M P Rayman
- Centre for Nutrition and Food Safety, School of Biological Sciences, University of Surrey, Guildford, UK
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Zhao L, Cox AG, Ruzicka JA, Bhat AA, Zhang W, Taylor EW. Molecular modeling and in vitro activity of an HIV-1-encoded glutathione peroxidase. Proc Natl Acad Sci U S A 2000; 97:6356-61. [PMID: 10841544 PMCID: PMC18607 DOI: 10.1073/pnas.97.12.6356] [Citation(s) in RCA: 70] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Based on theoretical evidence, it has been proposed that HIV-1 may encode several selenoprotein modules, one of which (overlapping the env gp41-coding region) has highly significant sequence similarity to the mammalian selenoprotein glutathione peroxidase (GPx; EC ). The similarity score of the putative HIV-1 viral GPx homolog relative to an aligned set of known GPx is 6.3 SD higher than expected for random sequences of similar composition. Based on that alignment, a molecular model of the HIV-1 GPx was constructed by homology modeling from the bovine GPx crystal structure. Despite extensive truncation relative to the cellular GPx gene, the structural core and the geometry of the catalytic triad of selenocysteine, glutamine, and tryptophan are well conserved in the viral GPx. All of the insertions and deletions predicted by the alignment proved to be structurally feasible. The model is energetically favorable, with a computed molecular mechanics strain energy close to that of the bovine GPx structure, when normalized on a per-residue basis. However, considering the remote homology, this model is intended only to provide a working hypothesis allowing for a similar active site and structural core. To validate the theoretical predictions, we cloned the hypothetical HIV-1 gene and found it to encode functional GPx activity when expressed as a selenoprotein in mammalian cells. In transfected canine kidney cells, the increase in GPx activity ranged from 21% to 43% relative to controls (average 30%, n = 9, P < 0.0001), whereas, in transfected MCF7 cells, which have low endogenous GPx activity, a near 100% increase was observed (average 99%, n = 3, P < 0.05).
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Affiliation(s)
- L Zhao
- Computational Center for Molecular Structure and Design, and Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, USA
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Berkson BM. A conservative triple antioxidant approach to the treatment of hepatitis C. Combination of alpha lipoic acid (thioctic acid), silymarin, and selenium: three case histories. MEDIZINISCHE KLINIK (MUNICH, GERMANY : 1983) 1999; 94 Suppl 3:84-9. [PMID: 10554539 DOI: 10.1007/bf03042201] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND There has been an increase in the number of adults seeking liver transplantation for hepatitis C in the last few years and the count is going up rapidly. There is no reliable and effective therapy for chronic hepatitis C since interferon and antivirals work no more than 30% of the time, and liver transplant surgery is uncertain and tentative over the long run. This is because, ultimately, residual hepatitis C viremia infects the new liver. Furthermore, liver transplantation can be painful, disabling and extremely costly. TREATMENT PROGRAM The author describes a low cost and efficacious treatment program in 3 patients with cirrhosis, portal hypertension and esophageal varices secondary to chronic hepatitis C infection. This effective and conservative regimen combines 3 potent antioxidants (alpha-lipoic acid [thioctic acid], silymarin, and selenium) that possess antiviral, free radical quenching and immune boosting qualities. CONCLUSION There are no remarkably effective treatments for chronic hepatitis C in general use. Interferon and antivirals have less than a 30% response rate and because of the residual viremia, a newly transplanted liver usually becomes infected again. The triple antioxidant combination of alpha-lipoic acid, silymarin and selenium was chosen for a conservative treatment of hepatitis C because these substances protect the liver from free radical damage, increase the levels of other fundamental antioxidants, and interfere with viral proliferation. The 3 patients presented in this paper followed the triple antioxidant program and recovered quickly and their laboratory values remarkably improved. Furthermore, liver transplantation was avoided and the patients are back at work, carrying out their normal activities, and feeling healthy. The author offers a more conservative approach to the treatment of hepatitis C, that is exceedingly less expensive. One year of the triple antioxidant therapy described in this paper costs less than $2,000, as compared to mor than $300,000 a year for liver transplant surgery. It appears reasonable, that prior to liver transplant surgery evaluation, or during the transplant evaluation process, the conservative triple antioxidant treatment approach should be considered. If these is a significant betterment in the patient's condition, liver transplant surgery may be avoided.
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Affiliation(s)
- B M Berkson
- Integrative Medical Center of New Mexico, New Mexico State University, Las Cruces, USA.
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Zhang W, Cox AG, Taylor EW. Hepatitis C virus encodes a selenium-dependent glutathione peroxidase gene. Implications for oxidative stress as a risk factor in progression to hepatocellular carcinoma. MEDIZINISCHE KLINIK (MUNICH, GERMANY : 1983) 1999; 94 Suppl 3:2-6. [PMID: 10554520 DOI: 10.1007/bf03042181] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
AIM Using structural bioinformatics methods, the aim is to assess the hypothesis that hepatitis C virus (HCV) encodes a glutathione peroxidase (GPx) gene in an overlapping reading frame, linking HCV expression and pathogenesis to the Se status and dietary oxidant/Antioxidant balance of the host. METHODS The putative HCV GPx gene was identified by searching viral sequence databases, using conserved GPx active site sequences as probes, giving particular weight to the UGA (selenocysteine) codon. Multiple sequence alignments were generated and analyzed to validate the sequence similarity, and to establish the degree of conservation of the identified genomic features in HCV. Molecular modeling was used to assess the structural feasibility of the proposed homology. RESULTS The GPx homology region overlaps the NS4 gene, and is well conserved in HCV. The sequence similarity of the conserved active site regions to a set of known GPx is high (4 to 6 SD greater than expected for similar random sequences). The computed strain energy of a molecular model of the HCV GPx is energetically favorable, comparable to the bovine GPx structure. CONCLUSIONS By linking HCV replication and pathogenesis to the Se status and dietary oxidant/antioxidant balance of the host, the existence of a viral GPx gene could help to explain why HCV disease progression is accelerated by oxidant stresses such as alcoholism and iron overload.
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Affiliation(s)
- W Zhang
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, USA
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