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Filip R, Bélanger É, Chen X, Lefebvre D, Uguccioni SM, Pezacki JP. LYPLAL1 enzyme activity is linked to hepatic glucose metabolism. Biochem Biophys Res Commun 2025; 759:151656. [PMID: 40147354 DOI: 10.1016/j.bbrc.2025.151656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 03/14/2025] [Accepted: 03/17/2025] [Indexed: 03/29/2025]
Abstract
The serine hydrolase LYPLAL1 is a poorly characterised enzyme with emerging roles in hepatic metabolism. A multitude of association studies have shown links between variants of this gene locus and metabolic conditions such as obesity and insulin resistance. However, the enzyme's function is still largely unknown. Recent biochemical studies have revealed that it may play a role in hepatic glucose metabolism and that its activity is allosterically regulated. Herein, we use a selective activity-based probe to delineate LYPLAL1's involvement in hepatic metabolism. We show that the enzyme's activity is modulated during metabolic stress, specifically pointing to a putative role in negatively regulating gluconeogenesis and upregulating glycolysis. We also determine that knock-out of the enzyme does not affect liver lipid profiles and bring forth evidence for insulin-mediated control of LYPLAL1 in HepG2 cells. Furthermore, LYPLAL1 activity appears to be largely post-translationally regulated as gene expression levels remain largely constant under insulin and glucagon treatments. Taken together these data point to an enzymatic role in regulating glucose metabolism that may be part of a feedback mechanism of signal transduction.
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Affiliation(s)
- Roxana Filip
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, K1N 6N5, Canada
| | - Étienne Bélanger
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, K1N 6N5, Canada
| | - Xinhzu Chen
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, K1N 6N5, Canada
| | - David Lefebvre
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, K1N 6N5, Canada
| | - Spencer M Uguccioni
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, K1N 6N5, Canada
| | - John Paul Pezacki
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, K1N 6N5, Canada.
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Kasai H, Yamashita A, Akaike Y, Tanaka T, Matsuura Y, Moriishi K. HCV infection activates the proteasome via PA28γ acetylation and heptamerization to facilitate the degradation of RNF2, a catalytic component of polycomb repressive complex 1. mBio 2024; 15:e0169124. [PMID: 39329491 PMCID: PMC11559043 DOI: 10.1128/mbio.01691-24] [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: 06/03/2024] [Accepted: 08/26/2024] [Indexed: 09/28/2024] Open
Abstract
We previously reported that hepatitis C virus (HCV) infection or HCV core protein expression induces HOX gene expression by impairing histone H2A monoubiquitination via a proteasome-dependent reduction in the level of RNF2, a key catalytic component of polycomb repressive complex 1 (H. Kasai, K. Mochizuki, T. Tanaka, A. Yamashita, et al., J Virol 95:e01784-20, 2021, https://doi.org/10.1128/jvi.01784-20). In this study, we aimed to investigate the mechanism by which HCV infection accelerates RNF2 degradation. Yeast two-hybrid screening and an immunoprecipitation assay revealed that RNF2 is a PA28γ-binding protein. The proteasome activator PA28γ destabilized the RNF2 protein in a proteasome-dependent manner, since RNF2 degradation was impaired by PA28γ knockout or MG132 treatment. HCV infection or core protein expression reduced the levels of RNF2 and histone H2A K119 monoubiquitination and induced the expression of HOX genes in the presence of PA28γ, while PA28γ knockout reversed these changes. Treatment with a lysine acetyltransferase inhibitor inhibited the acetylation of PA28γ at K195 and the degradation of the RNF2 protein, while treatment with a lysine deacetylase inhibitor accelerated these events in a PA28γ-dependent manner. RNF2 protein degradation was increased by expression of the acetylation mimetic PA28γ mutant but not by expression of the acetylation-defective mutant or the proteasome activation-defective mutant. Furthermore, HCV infection or core protein expression facilitated the interaction between PA28γ and the lysine acetyltransferase CBP/p300 and then accelerated PA28γ acetylation and heptazmerization to promote RNF2 degradation. These data suggest that HCV infection accelerates the acetylation-dependent heptamerization of PA28γ to increase the proteasomal targeting of RNF2.IMPORTANCEHCV is a causative agent of HCV-related liver diseases, including hepatic steatosis, cirrhosis, and hepatocellular carcinoma. PA28γ, which, in heptameric form, activates the 20S core proteasome for the degradation of PA28γ-binding proteins, is responsible for HCV-related liver diseases. HCV core protein expression or HCV infection accelerates RNF2 degradation, leading to the induction of HOX gene expression via a decrease in the level of H2Aub on HOX gene promoters. However, the mechanism of RNF2 degradation in HCV-infected cells has not been clarified. The data presented in this study suggest that PA28γ acetylation and heptamerization are promoted by HCV infection or by core protein expression to activate the proteasome for the degradation of RNF2 and are responsible for HCV propagation. This study provides novel insights valuable for the development of therapies targeting both HCV propagation and HCV-related diseases.
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Affiliation(s)
- Hirotake Kasai
- Department of Microbiology, Faculty of Medicine, Graduate Faculty of Interdisciplinary Research, University of Yamanashi, Yamanashi, Japan
| | - Atsuya Yamashita
- Department of Microbiology, Faculty of Medicine, Graduate Faculty of Interdisciplinary Research, University of Yamanashi, Yamanashi, Japan
| | - Yasunori Akaike
- Department of Microbiology, Faculty of Medicine, Graduate Faculty of Interdisciplinary Research, University of Yamanashi, Yamanashi, Japan
| | - Tomohisa Tanaka
- Department of Microbiology, Faculty of Medicine, Graduate Faculty of Interdisciplinary Research, University of Yamanashi, Yamanashi, Japan
- Division of Hepatitis Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Yoshiharu Matsuura
- Laboratory of Virus Control, Research Institute for Microbial Diseases (RIMD), Osaka University, Osaka, Japan
- Center for Infectious Diseases Education and Research (CiDER), Osaka University, Osaka, Japan
| | - Kohji Moriishi
- Department of Microbiology, Faculty of Medicine, Graduate Faculty of Interdisciplinary Research, University of Yamanashi, Yamanashi, Japan
- Division of Hepatitis Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
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Perakakis N, Harb H, Hale BG, Varga Z, Steenblock C, Kanczkowski W, Alexaki VI, Ludwig B, Mirtschink P, Solimena M, Toepfner N, Zeissig S, Gado M, Abela IA, Beuschlein F, Spinas GA, Cavelti-Weder C, Gerber PA, Huber M, Trkola A, Puhan MA, Wong WWL, Linkermann A, Mohan V, Lehnert H, Nawroth P, Chavakis T, Mingrone G, Wolfrum C, Zinkernagel AS, Bornstein SR. Mechanisms and clinical relevance of the bidirectional relationship of viral infections with metabolic diseases. Lancet Diabetes Endocrinol 2023; 11:675-693. [PMID: 37524103 DOI: 10.1016/s2213-8587(23)00154-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 05/09/2023] [Accepted: 05/19/2023] [Indexed: 08/02/2023]
Abstract
Viruses have been present during all evolutionary steps on earth and have had a major effect on human history. Viral infections are still among the leading causes of death. Another public health concern is the increase of non-communicable metabolic diseases in the last four decades. In this Review, we revisit the scientific evidence supporting the presence of a strong bidirectional feedback loop between several viral infections and metabolic diseases. We discuss how viruses might lead to the development or progression of metabolic diseases and conversely, how metabolic diseases might increase the severity of a viral infection. Furthermore, we discuss the clinical relevance of the current evidence on the relationship between viral infections and metabolic disease and the present and future challenges that should be addressed by the scientific community and health authorities.
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Affiliation(s)
- Nikolaos Perakakis
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany; Paul Langerhans Institute Dresden, Helmholtz Munich, Technische Universität Dresden, Dresden 01307, Germany; German Center for Diabetes Research, Neuherberg, Germany.
| | - Hani Harb
- Medical Microbiology and Virology, Technische Universität Dresden, Dresden 01307, Germany
| | - Benjamin G Hale
- Institute of Medical Virology, University of Zürich, Zürich, Switzerland
| | - Zsuzsanna Varga
- Department of Pathology and Molecular Pathology, University of Zürich, Zürich, Switzerland
| | - Charlotte Steenblock
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany
| | - Waldemar Kanczkowski
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany
| | - Vasileia Ismini Alexaki
- Institute for Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden 01307, Germany
| | - Barbara Ludwig
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany; Paul Langerhans Institute Dresden, Helmholtz Munich, Technische Universität Dresden, Dresden 01307, Germany; Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden 01307, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Peter Mirtschink
- Institute for Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden 01307, Germany
| | - Michele Solimena
- Paul Langerhans Institute Dresden, Helmholtz Munich, Technische Universität Dresden, Dresden 01307, Germany; Department of Molecular Diabetology, Technische Universität Dresden, Dresden 01307, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Nicole Toepfner
- Department of Pediatrics, Technische Universität Dresden, Dresden 01307, Germany
| | - Sebastian Zeissig
- Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden 01307, Germany; Department of Medicine I, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany
| | - Manuel Gado
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany; Paul Langerhans Institute Dresden, Helmholtz Munich, Technische Universität Dresden, Dresden 01307, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Irene Alma Abela
- Institute of Medical Virology, University of Zürich, Zürich, Switzerland; Department of Infectious Diseases and Hospital Epidemiology, University of Zürich, Zürich, Switzerland
| | - Felix Beuschlein
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zürich, University of Zürich, Zürich, Switzerland; Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Giatgen A Spinas
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Claudia Cavelti-Weder
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Philipp A Gerber
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Michael Huber
- Institute of Medical Virology, University of Zürich, Zürich, Switzerland
| | - Alexandra Trkola
- Institute of Medical Virology, University of Zürich, Zürich, Switzerland
| | - Milo A Puhan
- Epidemiology, Biostatistics and Prevention Institute, University of Zürich, Zürich, Switzerland
| | - Wendy Wei-Lynn Wong
- and Department of Molecular Life Science, University of Zürich, Zürich, Switzerland
| | - Andreas Linkermann
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany; Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Viswanathan Mohan
- Madras Diabetes Research Foundation and Dr. Mohan's Diabetes Specialties Centre, Chennai, Tamil Nadu, India
| | - Hendrik Lehnert
- Presidential Office, Paris Lodron Universität Salzburg, Salzburg, Austria
| | - Peter Nawroth
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany
| | - Triantafyllos Chavakis
- Paul Langerhans Institute Dresden, Helmholtz Munich, Technische Universität Dresden, Dresden 01307, Germany; Institute for Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden 01307, Germany; German Center for Diabetes Research, Neuherberg, Germany; Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Geltrude Mingrone
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy; Division of Diabetes and Nutritional Sciences, School of Cardiovascular and Metabolic Medicine and Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Christian Wolfrum
- Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology, ETH Zürich, Schwerzenbach, Switzerland
| | - Annelies S Zinkernagel
- Department of Infectious Diseases and Hospital Epidemiology, University of Zürich, Zürich, Switzerland
| | - Stefan R Bornstein
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany; Paul Langerhans Institute Dresden, Helmholtz Munich, Technische Universität Dresden, Dresden 01307, Germany; German Center for Diabetes Research, Neuherberg, Germany; Division of Diabetes and Nutritional Sciences, School of Cardiovascular and Metabolic Medicine and Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
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Mone K, Lasrado N, Sur M, Reddy J. Vaccines against Group B Coxsackieviruses and Their Importance. Vaccines (Basel) 2023; 11:vaccines11020274. [PMID: 36851152 PMCID: PMC9961666 DOI: 10.3390/vaccines11020274] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 02/03/2023] Open
Abstract
The group B coxsackieviruses (CVBs) exist in six serotypes (CVB1 to CVB6). Disease associations have been reported for most serotypes, and multiple serotypes can cause similar diseases. For example, CVB1, CVB3, and CVB5 are generally implicated in the causation of myocarditis, whereas CVB1 and CVB4 could accelerate the development of type 1 diabetes (T1D). Yet, no vaccines against these viruses are currently available. In this review, we have analyzed the attributes of experimentally tested vaccines and discussed their merits and demerits or limitations, as well as their impact in preventing infections, most importantly myocarditis and T1D.
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Affiliation(s)
- Kiruthiga Mone
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Ninaad Lasrado
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
| | - Meghna Sur
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Jay Reddy
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
- Correspondence: ; Tel.: +1-(402)-472-8541
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A Monovalent Mt10-CVB3 Vaccine Prevents CVB4-Accelerated Type 1 Diabetes in NOD Mice. Vaccines (Basel) 2022; 11:vaccines11010076. [PMID: 36679922 PMCID: PMC9864234 DOI: 10.3390/vaccines11010076] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 12/27/2022] [Accepted: 12/27/2022] [Indexed: 12/30/2022] Open
Abstract
Enteroviruses, which include Coxsackieviruses, are a common cause of virus infections in humans, and multiple serotypes of the group B Coxsackievirus (CVB) can induce similar diseases. No vaccines are currently available to prevent CVB infections because developing serotype-specific vaccines is not practical. Thus, developing a vaccine that induces protective immune responses for multiple serotypes is desired. In that direction, we created a live-attenuated CVB3 vaccine virus, designated mutant (Mt)10, that offers protection against myocarditis and pancreatitis induced by CVB3 and CVB4 in disease-susceptible A/J mice. Here, we report that the Mt10 vaccine protected against CVB4-triggered type 1 diabetes (T1D) in non-obese diabetic (NOD) mice but the expected subsequent development of spontaneous T1D in these genetically predisposed NOD mice was not altered. We noted that Mt10 vaccine induced significant amounts of neutralizing antibodies, predominantly of the IgG2c isotype, and the virus was not detected in vaccine-challenged animals. Furthermore, monitoring blood glucose levels-and to a lesser extent, insulin antibodies-was found to be helpful in predicting vaccine responses. Taken together, our data suggest that the monovalent Mt10 vaccine has the potential to prevent infections caused by multiple CVB serotypes, as we have demonstrated in various pre-clinical models.
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Sparvoli JMH, Sparvoli AC, Dumith SDC, Pereira AA, Paula ALMD, Garcia L, Belarmino V, Hora VPD, Martínez AMBD, Gonçalves CV. Impact of hepatitis C virus eradication with direct-acting antivirals on glycidic metabolism. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2022; 67:314-322. [PMID: 36468927 DOI: 10.20945/2359-3997000000543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Objective To compare the glucose metabolism of patients with chronic hepatitis C virus infection treated with direct-acting antivirals (DAAs) in pretreatment and sustained viral response (SVR) periods. Materials and methods This was an intervention pre-post study of 273 patients with chronic hepatitis C virus infection treated with DAAs from March 2018 to December 2019. Glycidic metabolism was evaluated through homeostasis model assessment (HOMA) - insulin resistance (IR) and HOMA-β indices and assessments of insulinemia and HbA1c levels. These parameters were analyzed with a T test by paired comparison of the means of the variables and Wilcoxon's test paired for the median; in the variables with an abnormal distribution, the Z score was generated for the mean in both the pretreatment and SVR periods. Statistical significance was considered at p ≤ 0.05. Results Among 273 participants, 125 (45.8%) had prediabetes, and 50 (18.3%) had diabetes. In SVR, there was a significant increase in platelets, albumin, alkaline phosphatase, cholesterol and triglycerides and a significant decrease in aspartate aminotransferase, alanine aminotransferase, gamma GT and bilirubin. The HOMA-IR and HOMA-β indices increased in SVR from 1.95 to 2.29 (p = 0.087) and 71.20 to 82.60 (p = 0.001), respectively. Insulinemia increased from 7.60 μU/mL to 8.90 μU/mL (p = 0.011). HbA1c decreased from 5.6 to 5.4 (p < 0.001). Among patients with prediabetes and those with diabetes, the reduction in HbA1c values was significant (p = 0.006 and p = 0.026, respectively). Conclusion SVR significantly impacts and leads to improvement in glucose metabolism in patients with chronic liver disease induced by hepatitis C virus.
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Krogvold L, Genoni A, Puggioni A, Campani D, Richardson SJ, Flaxman CS, Edwin B, Buanes T, Dahl-Jørgensen K, Toniolo A. Live enteroviruses, but not other viruses, detected in human pancreas at the onset of type 1 diabetes in the DiViD study. Diabetologia 2022; 65:2108-2120. [PMID: 35953727 PMCID: PMC9630231 DOI: 10.1007/s00125-022-05779-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 04/14/2022] [Indexed: 01/11/2023]
Abstract
AIMS/HYPOTHESIS Enterovirus (EV) infection of pancreatic islet cells is one possible factor contributing to type 1 diabetes development. We have reported the presence of EV genome by PCR and of EV proteins by immunohistochemistry in pancreatic sections. Here we explore multiple human virus species in the Diabetes Virus Detection (DiViD) study cases using innovative methods, including virus passage in cell cultures. METHODS Six recent-onset type 1 diabetes patients (age 24-35) were included in the DiViD study. Minimal pancreatic tail resection was performed under sterile conditions. Eleven live cases (age 43-83) of pancreatic carcinoma without diabetes served as control cases. In the present study, we used EV detection methods that combine virus growth in cell culture, gene amplification and detection of virus-coded proteins by immunofluorescence. Pancreas homogenates in cell culture medium were incubated with EV-susceptible cell lines for 3 days. Two to three blind passages were performed. DNA and RNA were extracted from both pancreas tissue and cell cultures. Real-time PCR was used for detecting 20 different viral agents other than EVs (six herpesviruses, human polyomavirus [BK virus and JC virus], parvovirus B19, hepatitis B virus, hepatitis C virus, hepatitis A virus, mumps, rubella, influenza A/B, parainfluenza 1-4, respiratory syncytial virus, astrovirus, norovirus, rotavirus). EV genomes were detected by endpoint PCR using five primer pairs targeting the partially conserved 5' untranslated region genome region of the A, B, C and D species. Amplicons were sequenced. The expression of EV capsid proteins was evaluated in cultured cells using a panel of EV antibodies. RESULTS Samples from six of six individuals with type 1 diabetes (cases) and two of 11 individuals without diabetes (control cases) contained EV genomes (p<0.05). In contrast, genomes of 20 human viruses other than EVs could be detected only once in an individual with diabetes (Epstein-Barr virus) and once in an individual without diabetes (parvovirus B19). EV detection was confirmed by immunofluorescence of cultured cells incubated with pancreatic extracts: viral antigens were expressed in the cytoplasm of approximately 1% of cells. Notably, infection could be transmitted from EV-positive cell cultures to uninfected cell cultures using supernatants filtered through 100 nm membranes, indicating that infectious agents of less than 100 nm were present in pancreases. Due to the slow progression of infection in EV-carrying cell cultures, cytopathic effects were not observed by standard microscopy but were recognised by measuring cell viability. Sequences of 5' untranslated region amplicons were compatible with EVs of the B, A and C species. Compared with control cell cultures exposed to EV-negative pancreatic extracts, EV-carrying cell cultures produced significantly higher levels of IL-6, IL-8 and monocyte chemoattractant protein-1 (MCP1). CONCLUSIONS/INTERPRETATION Sensitive assays confirm that the pancreases of all DiViD cases contain EVs but no other viruses. Analogous EV strains have been found in pancreases of two of 11 individuals without diabetes. The detected EV strains can be passaged in series from one cell culture to another in the form of poorly replicating live viruses encoding antigenic proteins recognised by multiple EV-specific antibodies. Thus, the early phase of type 1 diabetes is associated with a low-grade infection by EVs, but not by other viral agents.
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Affiliation(s)
- Lars Krogvold
- Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
- Institute of Clinical Dentistry, Faculty of Dentistry, University of Oslo, Oslo, Norway.
| | - Angelo Genoni
- Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Anna Puggioni
- Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Daniela Campani
- Department of Surgical, Medical and Molecular Pathology and Critical Care, University of Pisa, Pisa, Italy
| | - Sarah J Richardson
- Islet Biology Group (IBEx), Exeter Centre of Excellence in Diabetes (EXCEED), University of Exeter College of Medicine and Health, Exeter, UK
| | - Christine S Flaxman
- Islet Biology Group (IBEx), Exeter Centre of Excellence in Diabetes (EXCEED), University of Exeter College of Medicine and Health, Exeter, UK
| | - Bjørn Edwin
- Department for HPB Surgery, Oslo University Hospital, Oslo, Norway
| | - Trond Buanes
- Department for HPB Surgery, Oslo University Hospital, Oslo, Norway
| | - Knut Dahl-Jørgensen
- Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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Kouroumalis E, Voumvouraki A. Hepatitis C virus: A critical approach to who really needs treatment. World J Hepatol 2022; 14:1-44. [PMID: 35126838 PMCID: PMC8790391 DOI: 10.4254/wjh.v14.i1.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/14/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Introduction of effective drugs in the treatment of hepatitis C virus (HCV) infection has prompted the World Health Organization to declare a global eradication target by 2030. Propositions have been made to screen the general population and treat all HCV carriers irrespective of the disease status. A year ago the new severe acute respiratory syndrome coronavirus 2 virus appeared causing a worldwide pandemic of coronavirus disease 2019 disease. Huge financial resources were redirected, and the pandemic became the first priority in every country. In this review, we examined the feasibility of the World Health Organization elimination program and the actual natural course of HCV infection. We also identified and analyzed certain comorbidity factors that may aggravate the progress of HCV and some marginalized subpopulations with characteristics favoring HCV dissemination. Alcohol consumption, HIV coinfection and the presence of components of metabolic syndrome including obesity, hyperuricemia and overt diabetes were comorbidities mostly responsible for increased liver-related morbidity and mortality of HCV. We also examined the significance of special subpopulations like people who inject drugs and males having sex with males. Finally, we proposed a different micro-elimination screening and treatment program that can be implemented in all countries irrespective of income. We suggest that screening and treatment of HCV carriers should be limited only in these particular groups.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, University of Crete Medical School, Heraklion 71500, Crete, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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Garrido-Estepa M, Herruzo R, Flores-Herrera J. Co-infections, comorbidities, and alcohol or other substances abuses in chronic hepatitis C-related hospitalisations in Spain. GASTROENTEROLOGIA Y HEPATOLOGIA 2022; 45:677-689. [DOI: 10.1016/j.gastrohep.2022.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 12/08/2021] [Accepted: 01/14/2022] [Indexed: 11/26/2022]
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Niu B, Yao L, Zhang Y, Xia X, Su H. LncRNA KCNQ1OT1 promoted hepatitis C virus-induced pyroptosis of β-cell through mediating the miR-223-3p/NLRP3 axis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1387. [PMID: 34733939 PMCID: PMC8506540 DOI: 10.21037/atm-21-3862] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/12/2021] [Indexed: 01/10/2023]
Abstract
Background Type 2 diabetes is a well described extra-hepatic manifestation of hepatitis C virus (HCV) infection. This study aimed to explore the potential mechanism of KCNQ1 overlapping transcript 1 (KCNQ1OT1) in type 2 diabetes mellitus (T2DM) caused by HCV infection. Methods Min6 cells were infected with HCV to establish a vitro model, and the HCV copy number was detected by real-time quantitative PCR (RT-qPCR). The mRNA and protein expressions of IL-1β, IL-18, NLRP3, caspase-1, and GSDMD were analyzed by RT-qPCR and Western blot. Flow cytometry and TUNEL assay were used to evaluate the pyroptosis of cells and enzyme-linked immunosorbent assay (ELISA) detected the secretion of insulin. A dual luciferase reporter gene assay then verified the targeting relationship of KCNQ1OT1, miRNA-223-3p, and NLRP3. Results KCNQ1OT1 was highly expressed in HCV-infected T2DM patients and HCV-infected β-cells. Silencing KCNQ1OT1 inhibited β-cell pyroptosis by regulating miR-223-3p/NLRP3, and inhibition of miR-223-3p or overexpression of NLRP3 reversed the pyroptosis by silencing KCNQ1OT1. Conclusions Our findings indicate KCNQ1OT1 promotes HCV-infected β-cell pyroptosis through the miRNA-223-3p/NLRP3 axis, effecting the production of insulin and accelerating the occurrence and development of T2DM.Regulating KCNQ1OT1 and its target genes will help to better understand the pathogenesis of T2DM induced by HCV infection and provide new theoretical foundations and therapeutic targets.
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Affiliation(s)
- Ben Niu
- Department of Endocrinology and Metabolism, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Lixuan Yao
- Department of Endocrinology and Metabolism, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Yating Zhang
- Department of Endocrinology and Metabolism, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Xueshan Xia
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China
| | - Heng Su
- Department of Endocrinology and Metabolism, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
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11
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Compagnoni S, Bruno EM, Madonia G, Cannizzaro M, Madonia S. Direct antiviral agents in hepatitis C virus related liver disease: Don't count the chickens before they're hatched. World J Gastroenterol 2021; 27:2771-2783. [PMID: 34135553 PMCID: PMC8173378 DOI: 10.3748/wjg.v27.i21.2771] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/26/2021] [Accepted: 04/28/2021] [Indexed: 02/06/2023] Open
Abstract
Since molecules with direct-acting antiviral (DAA) became available, the landscape of the treatment of hepatitis C virus (HCV) infection has completely changed. The new drugs are extremely effective in eradicating infection, and treatment is very well tolerated with a duration of 8-12 wk. This review aims to report the outstanding clinical benefits of DAA and to highlight their critical disadvantages, identifying some clinically relevant hot topics. First, do the rates of virological response remain as high when patients with more advanced cirrhosis are considered? Large studies have shown slightly lower but still satisfactory rates of response in these patients. Nevertheless, modified schedules with an extended treatment duration and use of ribavirin may be necessary. Second, does the treatment of HCV infection affect the risk of occurrence and recurrence of liver cancer? Incidence is reduced after viral eradication but remains high enough to warrant periodic surveillance for an early diagnosis. In contrast, the risk of recurrence seems to be unaffected by viral clearance; however, DAA treatment improves survival because of the reduced risk of progression of liver disease. Third, can HCV treatment also have favorable effects on major comorbidities? HCV eradication is associated with a reduced incidence of diabetes, an improvement in glycemic control and a decreased risk of cardiovascular events; nevertheless, a risk of hypoglycemia during DAA treatment has been reported. Finally, is it safe to treat patients with HCV/ hepatitis B virus (HBV) coinfection? In this setting, HCV is usually the main driver of viral activity, while HBV replication is suppressed. Because various studies have described HBV reactivation after HCV clearance, a baseline evaluation for HBV coinfection and a specific follow-up is mandatory.
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Affiliation(s)
- Stella Compagnoni
- Department of Internal Medicine, V. Cervello Hospital, University of Palermo, Palermo 90146, Italy
| | - Erica Maria Bruno
- Department of Internal Medicine, V. Cervello Hospital, University of Palermo, Palermo 90146, Italy
| | - Giorgio Madonia
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo 90127, Italy
| | - Marco Cannizzaro
- Department of Emergency Medicine, A. Ajello Hospital, Trapani 91026, Italy
| | - Salvatore Madonia
- Department of Internal Medicine, V. Cervello Hospital, Palermo 90146, Italy
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12
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Nevola R, Acierno C, Pafundi PC, Adinolfi LE. Chronic hepatitis C infection induces cardiovascular disease and type 2 diabetes: mechanisms and management. Minerva Med 2020; 112:188-200. [PMID: 33205641 DOI: 10.23736/s0026-4806.20.07129-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Despite the availability of effective treatments, hepatitis C virus (HCV) still remains a threat to public health. HCV is capable to trigger, behind liver damage, extrahepatic manifestations, including cardiovascular disease and type 2 diabetes (T2DM). A close association has been reported between HCV infection and cardiovascular disease due to imbalances in metabolic pathways and chronic inflammation. HCV through both direct and indirect mechanisms causes a higher incidence of ischemic stroke, acute coronary syndrome, heart failure and peripheral arterial disease. In addition, a higher risk of death from cardiovascular events has been showed in HCV patients. Insulin resistance is a hallmark of HCV infection and represents the link between HCV and T2DM, which is one of the most frequent HCV-associated extrahepatic manifestations. The pathological basis of the increased risk of T2DM in HCV infection is provided by the alterations of the molecular mechanisms of IR induced both by the direct effects of the HCV proteins, and by the indirect effects mediated by chronic inflammation, oxidative stress and hepatic steatosis. T2DM increases the risk of compensated and decompensate cirrhosis and hepatocellular carcinoma as well as increases the risk of cardiovascular disease, lower limb amputation and end stage renal disease. Current evidence suggests that HCV eradication reduces the incidence and mortality of cardiovascular disease and T2DM, further underling the importance of public health strategies for eradication the infection. The aim of this review was to update evidence and management of interaction between HCV, cardiovascular disease, and T2DM in the era of DAA treatment.
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Affiliation(s)
- Riccardo Nevola
- Unit of Internal Medicine, Department of Advanced Medical and Surgery Sciences, Luigi Vanvitelli University of Campania, Naples, Italy
| | - Carlo Acierno
- Unit of Internal Medicine, Department of Advanced Medical and Surgery Sciences, Luigi Vanvitelli University of Campania, Naples, Italy
| | - Pia C Pafundi
- Unit of Internal Medicine, Department of Advanced Medical and Surgery Sciences, Luigi Vanvitelli University of Campania, Naples, Italy
| | - Luigi E Adinolfi
- Unit of Internal Medicine, Department of Advanced Medical and Surgery Sciences, Luigi Vanvitelli University of Campania, Naples, Italy -
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13
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McPherson S, Gosrani S, Hogg S, Patel P, Wetten A, Welton R, Hallsworth K, Campbell M. Increased cardiovascular risk and reduced quality of life are highly prevalent among individuals with hepatitis C. BMJ Open Gastroenterol 2020; 7:e000470. [PMID: 32847899 PMCID: PMC7451276 DOI: 10.1136/bmjgast-2020-000470] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/15/2020] [Accepted: 07/20/2020] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Hepatitis C virus (HCV) infection is common. Although treatment is effective, with oral antivirals curing >95% of patients, most individuals have comorbidities that persist long term. Therefore, our aim was to determine the prevalence of potentially modifiable health problems in patients with HCV and develop an HCV care bundle to identify and target comorbidities. DESIGN Cross-sectional, observational single-centre study that recruited consecutive patients with HCV from our viral hepatitis clinics. Data were collected on cardiovascular (CV) risk factors, lifestyle behaviours, anthropometry and health-related quality of life (HRQoL). QRISK 3 was used to predict 10-year CV event risk. RESULTS 100 patients were recruited (67% male, 93% white, median age 52 years (range 24-80); 71% were treated for HCV; 34% had cirrhosis; 14% had diabetes; 61% had hypertension; 31% had metabolic syndrome; and 54% were smokers). The median 10-year CV event risk was 8.3% (range 0.3%-63%). 45% had a predicted 10-year CV event risk of >10%. Only 10% of individuals were treated with statins and 27% with antihypertensives. 92% had a predicted 'heart age' greater than their chronological age (median difference +7 (-4 to +26) years). HRQoL was reduced in all SF36v2 domains in the cohort. Factors independently associated with HRQoL included cirrhosis, metabolic syndrome, history of mental health disorder, sedentary behaviour and HCV viraemia. CONCLUSION A large proportion of patients with HCV presented with increased risk of CV events, and rates of smoking and sedentary behaviour were high, while prescribing of primary prophylaxis was infrequent. HRQoL was also reduced in the cohort. A 'care bundle' was developed to provide a structured approach to treating potentially modifiable health problems.
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Affiliation(s)
- Stuart McPherson
- Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Shion Gosrani
- Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Sarah Hogg
- Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Preya Patel
- Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Aaron Wetten
- Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Rachael Welton
- Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Kate Hallsworth
- Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Matthew Campbell
- School of Food Science and Nutrition, University of Leeds, Leeds, West Yorkshire, UK
- Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
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14
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da Silva CB, Vieira DA, de Melo LF, Chagas ALS, Gomes AD, Faria Jr CLLD, Teixeira R, de Magalhães Queiroz DM, Rocha GA, Soares MMS, Bezerra JMT, Silva LD. Interleukin-6-174G/C polymorphism is associated with a decreased risk of type 2 diabetes in patients with chronic hepatitis C virus. World J Hepatol 2020; 12:137-148. [PMID: 32685106 PMCID: PMC7336292 DOI: 10.4254/wjh.v12.i4.137] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 02/28/2020] [Accepted: 03/22/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Chronic hepatitis C (CHC) is associated with type 2 diabetes mellitus. Although the pathogenesis remains to be elucidated, a growing evidence has suggested a role of pro-inflammatory immune response. Increased serum concentrations of Interleukin 6 (IL-6) have been associated with insulin resistance, type 2 diabetes mellitus as well as advanced forms of liver disease in chronic hepatitis C infection.
AIM To investigate the frequency of IL-6-174G/C (rs1800795) single nucleotide polymorphism (SNP) in CHC patients and in healthy subjects of the same ethnicity. Associations between type 2 diabetes mellitus (dependent variable) and demographic, clinical, nutritional, virological and, IL-6 genotyping data were also investigated in CHC patients.
METHODS Two hundred and forty-five patients with CHC and 179 healthy control subjects (blood donors) were prospectively included. Type 2 diabetes mellitus was diagnosed according to the criteria of the American Diabetes Association. Clinical, biochemical, histological and radiological methods were used for the diagnosis of the liver disease. IL-6 polymorphism was evaluated by Taqman SNP genotyping assay. The data were analysed by logistic regression models.
RESULTS Type 2 diabetes mellitus, blood hypertension and liver cirrhosis were observed in 20.8% (51/245), 40.0% (98/245) and 38.4% (94/245) of the patients, respectively. The frequency of the studied IL-6 SNP did not differ between the CHC patients and controls (P = 0.81) and all alleles were in Hardy-Weinberg equilibrium (P = 0.38). In the multivariate analysis, type 2 diabetes mellitus was inversely associated with GC and CC genotypes of IL-6-174 (OR = 0.42; 95%CI = 0.22-0.78; P = 0.006) and positively associated with blood hypertension (OR = 5.56; 95%CI = 2.79-11.09; P < 0.001).
CONCLUSION This study was the first to show that GC and CC genotypes of IL-6-174 SNP are associated with a decreased risk of type 2 diabetes mellitus in patients chronically infected with hepatitis C virus. The identification of potential inflammatory mediators involved in the crosstalk between hepatitis C virus and the axis pancreas-liver remains important issues that deserve further investigations.
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Affiliation(s)
- Cliviany Borges da Silva
- Sciences Applied to Adult Health Care Post-Graduate Programme, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
- Outpatient Clinic of Viral Hepatitis, Instituto Alfa de Gastroenterologia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Diego Alves Vieira
- Medical undergraduate student, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
- Outpatient Clinic of Viral Hepatitis, Instituto Alfa de Gastroenterologia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Luisa Freitas de Melo
- Medical undergraduate student, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
- Outpatient Clinic of Viral Hepatitis, Instituto Alfa de Gastroenterologia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Anna Luiza Soares Chagas
- Medical undergraduate student, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
- Outpatient Clinic of Viral Hepatitis, Instituto Alfa de Gastroenterologia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Adriana Dias Gomes
- Laboratory of Research in Bacteriology, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - César Lúcio Lopes de Faria Jr
- Laboratory of Research in Bacteriology, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Rosângela Teixeira
- Outpatient Clinic of Viral Hepatitis, Instituto Alfa de Gastroenterologia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
- Department of Internal Medicine, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Dulciene Maria de Magalhães Queiroz
- Laboratory of Research in Bacteriology, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Gifone Aguiar Rocha
- Laboratory of Research in Bacteriology, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Maria Marta Sarquis Soares
- Division of Endocrinology, Department of Internal Medicine, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Juliana Maria Trindade Bezerra
- Epidemiology of Infectious and Parasitic Diseases Laboratory, Department of Parasitology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Luciana Diniz Silva
- Outpatient Clinic of Viral Hepatitis, Instituto Alfa de Gastroenterologia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
- Department of Internal Medicine, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
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15
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Merza M. Seroprevalence and risk factors of hepatitis B and C viruses among diabetes mellitus patients in Duhok province, Iraqi Kurdistan. J Family Med Prim Care 2020; 9:642-646. [PMID: 32318396 PMCID: PMC7114067 DOI: 10.4103/jfmpc.jfmpc_1158_19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 01/10/2020] [Accepted: 01/23/2020] [Indexed: 01/08/2023] Open
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