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Oliveira KB, de Souza FMA, de Sá LBM, Pacheco ALD, Prado MR, de Sousa Rodrigues CF, Bassi ÊJ, Santana-Melo I, Silva-Júnior A, Sabino-Silva R, Shetty AK, de Castro OW. Potential Mechanisms Underlying COVID-19-Mediated Central and Peripheral Demyelination: Roles of the RAAS and ADAM-17. Mol Neurobiol 2025; 62:1151-1164. [PMID: 38965171 DOI: 10.1007/s12035-024-04329-8] [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: 12/13/2023] [Accepted: 06/21/2024] [Indexed: 07/06/2024]
Abstract
Demyelination is among the most conspicuous neurological sequelae of SARS-CoV-2 infection (COVID-19) in both the central (CNS) and peripheral (PNS) nervous systems. Several hypotheses have been proposed to explain the mechanisms underlying demyelination in COVID-19. However, none have considered the SARS-CoV-2's effects on the renin-angiotensin-aldosterone system (RAAS). Therefore, our objective in this review is to evaluate how RAAS imbalance, caused by direct and indirect effects of SARS-CoV-2 infection, could contribute to myelin loss in the PNS and CNS. In the PNS, we propose that demyelination transpires from two significant changes induced by SARS-CoV-2 infection, which include upregulation of ADAM-17 and induction of lymphopenia. Whereas, in the CNS, demyelination could result from RAAS imbalance triggering two alterations: (1) a decrease in angiotensin type II receptor (AT2R) activity, responsible for restraining defense cells' action on myelin; (2) upregulation of ADAM-17 activity, leading to impaired maturation of oligodendrocytes and myelin formation. Thus, we hypothesize that increased ADAM-17 activity and decreased AT2R activity play roles in SARS-CoV-2 infection-mediated demyelination in the CNS.
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Affiliation(s)
- Kellysson Bruno Oliveira
- Institute of Biological Sciences and Health, Federal University of Alagoas (UFAL), Av. Lourival de Melo Mota, Km 14, Campus A. C. Simões, Cidade Universitária, Maceió, AL, CEP, 57072-970, Brazil
| | - Fernanda Maria Araujo de Souza
- Institute of Biological Sciences and Health, Federal University of Alagoas (UFAL), Av. Lourival de Melo Mota, Km 14, Campus A. C. Simões, Cidade Universitária, Maceió, AL, CEP, 57072-970, Brazil
| | - Letícia Barros Maurício de Sá
- Institute of Biological Sciences and Health, Federal University of Alagoas (UFAL), Av. Lourival de Melo Mota, Km 14, Campus A. C. Simões, Cidade Universitária, Maceió, AL, CEP, 57072-970, Brazil
| | - Amanda Larissa Dias Pacheco
- Institute of Biological Sciences and Health, Federal University of Alagoas (UFAL), Av. Lourival de Melo Mota, Km 14, Campus A. C. Simões, Cidade Universitária, Maceió, AL, CEP, 57072-970, Brazil
| | - Mariana Reis Prado
- Institute of Biological Sciences and Health, Federal University of Alagoas (UFAL), Av. Lourival de Melo Mota, Km 14, Campus A. C. Simões, Cidade Universitária, Maceió, AL, CEP, 57072-970, Brazil
| | - Célio Fernando de Sousa Rodrigues
- Institute of Biological Sciences and Health, Federal University of Alagoas (UFAL), Av. Lourival de Melo Mota, Km 14, Campus A. C. Simões, Cidade Universitária, Maceió, AL, CEP, 57072-970, Brazil
| | - Ênio José Bassi
- Institute of Biological Sciences and Health, Federal University of Alagoas (UFAL), Av. Lourival de Melo Mota, Km 14, Campus A. C. Simões, Cidade Universitária, Maceió, AL, CEP, 57072-970, Brazil
| | - Igor Santana-Melo
- Institute of Biological Sciences and Health, Federal University of Alagoas (UFAL), Av. Lourival de Melo Mota, Km 14, Campus A. C. Simões, Cidade Universitária, Maceió, AL, CEP, 57072-970, Brazil
| | - Abelardo Silva-Júnior
- Institute of Biological Sciences and Health, Federal University of Alagoas (UFAL), Av. Lourival de Melo Mota, Km 14, Campus A. C. Simões, Cidade Universitária, Maceió, AL, CEP, 57072-970, Brazil
| | - Robinson Sabino-Silva
- Department of Physiology, Institute of Biomedical Sciences, Federal University of Uberlândia (UFU), Uberlândia, MG, Brazil
| | - Ashok K Shetty
- Institute for Regenerative Medicine, Department of Cell Biology and Genetics, Texas A&M University School of Medicine, College Station, TX, USA.
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, 77843, USA.
| | - Olagide Wagner de Castro
- Institute of Biological Sciences and Health, Federal University of Alagoas (UFAL), Av. Lourival de Melo Mota, Km 14, Campus A. C. Simões, Cidade Universitária, Maceió, AL, CEP, 57072-970, Brazil.
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Trimarco V, Izzo R, Pacella D, Virginia Manzi M, Trama U, Lembo M, Piccinocchi R, Gallo P, Esposito G, Morisco C, Rozza F, Mone P, Jankauskas SS, Piccinocchi G, Santulli G, Trimarco B. Increased prevalence of cardiovascular-kidney-metabolic syndrome during COVID-19: A propensity score-matched study. Diabetes Res Clin Pract 2024; 218:111926. [PMID: 39536978 DOI: 10.1016/j.diabres.2024.111926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 10/28/2024] [Accepted: 11/10/2024] [Indexed: 11/16/2024]
Abstract
A recent presidential advisory from the American Heart Association (AHA) has introduced the term cardiovascular-kidney-metabolic (CKM) syndrome to describe the complex interplay among health conditions linking heart, kidney, and metabolism. The aim of our study was to compare the prevalence of concurrent CKM syndrome components before and during the COVID-19 pandemic and identify associated risk factors. We conducted a study utilizing data from a real-world population obtained from a primary care database. The study cohort comprised a closed group followed over a 6-year period (2017-2022). A total of 81,051 individuals were included: 32,650 in the pre-pandemic period and 48,401 in the 2020-2022 triennium. After propensity-score matching for sex, age, and BMI, the study included 30,511 participants for each period. 3554 individuals were diagnosed with type 2 diabetes in the pre-pandemic period, compared to 7430 during the pandemic. Hypertension, dyslipidemia, and obesity displayed significant increases in prevalence during the pandemic, and prediabetes had a particularly sharp rise of 170%. Age-stratified analyses revealed a higher burden of CKM conditions with advancing age. Our findings indicate a substantial increase in the prevalence of CKM syndrome during the COVID-19 pandemic, with nearly half of the patients exhibiting one or more CKM syndrome components.
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Affiliation(s)
- Valentina Trimarco
- Department of Neuroscience, Reproductive Sciences, and Dentistry, "Federico II" University, Naples, Italy
| | - Raffaele Izzo
- Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy
| | - Daniela Pacella
- Department of Public Health, "Federico II" University, Naples, Italy
| | - Maria Virginia Manzi
- Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy
| | - Ugo Trama
- Pharmaceutical Department of Campania Region, Naples, Italy
| | - Maria Lembo
- Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy
| | | | - Paola Gallo
- Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy
| | - Giovanni Esposito
- Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy
| | - Carmine Morisco
- Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy; International Translational Research and Medical Education (ITME) Consortium, Academic Research Unit, Naples, Italy; Italian Society for Cardiovascular Prevention (SIPREC), Rome, Italy
| | - Francesco Rozza
- Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy
| | - Pasquale Mone
- Department of Medicine and Health Sciences "Vincenzo Tiberio", Molise University, Campobasso, Italy; Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, The Fleischer Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine, New York City, NY, USA; Casa di Cura "Montevergine", Mercogliano (Avellino), Italy
| | - Stanislovas S Jankauskas
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, The Fleischer Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine, New York City, NY, USA
| | - Gaetano Piccinocchi
- COMEGEN Primary Care Physicians Cooperative, Italian Society of General Medicine (SIMG), Naples, Italy
| | - Gaetano Santulli
- Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy; International Translational Research and Medical Education (ITME) Consortium, Academic Research Unit, Naples, Italy; Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, The Fleischer Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine, New York City, NY, USA; Department of Molecular Pharmacology, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Einstein Institute for Neuroimmunology and Inflammation, Albert Einstein College of Medicine, New York City, NY, USA.
| | - Bruno Trimarco
- Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy; International Translational Research and Medical Education (ITME) Consortium, Academic Research Unit, Naples, Italy; Italian Society for Cardiovascular Prevention (SIPREC), Rome, Italy
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Timofeeva AM, Nikitin AO, Nevinsky GA. Circulating miRNAs in the Plasma of Post-COVID-19 Patients with Typical Recovery and Those with Long-COVID Symptoms: Regulation of Immune Response-Associated Pathways. Noncoding RNA 2024; 10:48. [PMID: 39311385 PMCID: PMC11417918 DOI: 10.3390/ncrna10050048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/23/2024] [Accepted: 08/27/2024] [Indexed: 09/26/2024] Open
Abstract
Following the acute phase of SARS-CoV-2 infection, certain individuals experience persistent symptoms referred to as long COVID. This study analyzed the patients categorized into three distinct groups: (1) individuals presenting rheumatological symptoms associated with long COVID, (2) patients who have successfully recovered from COVID-19, and (3) donors who have never contracted COVID-19. A notable decline in the expression of miR-200c-3p, miR-766-3p, and miR-142-3p was identified among patients exhibiting rheumatological symptoms of long COVID. The highest concentration of miR-142-3p was found in healthy donors. One potential way to reduce miRNA concentrations is through antibody-mediated hydrolysis. Not only can antibodies possessing RNA-hydrolyzing activity recognize the miRNA substrate specifically, but they also catalyze its hydrolysis. The analysis of the catalytic activity of plasma antibodies revealed that antibodies from patients with long COVID demonstrated lower hydrolysis activity against five fluorescently labeled oligonucleotide sequences corresponding to the Flu-miR-146b-5p, Flu-miR-766-3p, Flu-miR-4742-3p, and Flu-miR-142-3p miRNAs and increased activity against the Flu-miR-378a-3p miRNA compared to other patient groups. The changes in miRNA concentrations and antibody-mediated hydrolysis of miRNAs are assumed to have a complex regulatory mechanism that is linked to gene pathways associated with the immune system. We demonstrate that all six miRNAs under analysis are associated with a large number of signaling pathways associated with immune response-associated pathways.
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Affiliation(s)
- Anna M. Timofeeva
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 630090 Novosibirsk, Russia
- Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia
| | - Artem O. Nikitin
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 630090 Novosibirsk, Russia
| | - Georgy A. Nevinsky
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 630090 Novosibirsk, Russia
- Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia
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Mone P, Jankauskas SS, Manzi MV, Gambardella J, Coppola A, Kansakar U, Izzo R, Fiorentino G, Lombardi A, Varzideh F, Sorriento D, Trimarco B, Santulli G. Endothelial Extracellular Vesicles Enriched in microRNA-34a Predict New-Onset Diabetes in Coronavirus Disease 2019 (COVID-19) Patients: Novel Insights for Long COVID Metabolic Sequelae. J Pharmacol Exp Ther 2024; 389:34-39. [PMID: 38336381 PMCID: PMC10949163 DOI: 10.1124/jpet.122.001253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 01/15/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Emerging evidence indicates that the relationship between coronavirus disease 2019 (COVID-19) and diabetes is 2-fold: 1) it is known that the presence of diabetes and other metabolic alterations poses a considerably high risk to develop a severe COVID-19; 2) patients who survived a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have an increased risk of developing new-onset diabetes. However, the mechanisms underlying this association are mostly unknown, and there are no reliable biomarkers to predict the development of new-onset diabetes. In the present study, we demonstrate that a specific microRNA (miR-34a) contained in circulating extracellular vesicles released by endothelial cells reliably predicts the risk of developing new-onset diabetes in COVID-19. This association was independent of age, sex, body mass index (BMI), hypertension, dyslipidemia, smoking status, and D-dimer. SIGNIFICANCE STATEMENT: We demonstrate for the first time that a specific microRNA (miR-34a) contained in circulating extracellular vesicles released by endothelial cells is able to reliably predict the risk of developing diabetes after having contracted coronavirus disease 2019 (COVID-19). This association was independent of age, sex, body mass index (BMI), hypertension, dyslipidemia, smoking status, and D-dimer. Our findings are also relevant when considering the emerging importance of post-acute sequelae of COVID-19, with systemic manifestations observed even months after viral negativization (long COVID).
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Affiliation(s)
- Pasquale Mone
- Department of Medicine, Einstein-Sinai Diabetes Research Center, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research (P.M., S.S.J., J.G., U.K., A.L., F.V., G.S.) and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (G.S.), Albert Einstein College of Medicine, New York, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education, "Federico II" University, Naples, Italy (M.V.M., J.G., R.I., D.S., B.T., G.S.); Clinica Montevergine, Mercogliano, Avellino (P.M.); and COVID-19 Division, A.O.R.N. Ospedali dei Colli, Naples, Italy (A.C., G.F.)
| | - Stanislovas S Jankauskas
- Department of Medicine, Einstein-Sinai Diabetes Research Center, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research (P.M., S.S.J., J.G., U.K., A.L., F.V., G.S.) and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (G.S.), Albert Einstein College of Medicine, New York, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education, "Federico II" University, Naples, Italy (M.V.M., J.G., R.I., D.S., B.T., G.S.); Clinica Montevergine, Mercogliano, Avellino (P.M.); and COVID-19 Division, A.O.R.N. Ospedali dei Colli, Naples, Italy (A.C., G.F.)
| | - Maria Virginia Manzi
- Department of Medicine, Einstein-Sinai Diabetes Research Center, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research (P.M., S.S.J., J.G., U.K., A.L., F.V., G.S.) and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (G.S.), Albert Einstein College of Medicine, New York, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education, "Federico II" University, Naples, Italy (M.V.M., J.G., R.I., D.S., B.T., G.S.); Clinica Montevergine, Mercogliano, Avellino (P.M.); and COVID-19 Division, A.O.R.N. Ospedali dei Colli, Naples, Italy (A.C., G.F.)
| | - Jessica Gambardella
- Department of Medicine, Einstein-Sinai Diabetes Research Center, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research (P.M., S.S.J., J.G., U.K., A.L., F.V., G.S.) and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (G.S.), Albert Einstein College of Medicine, New York, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education, "Federico II" University, Naples, Italy (M.V.M., J.G., R.I., D.S., B.T., G.S.); Clinica Montevergine, Mercogliano, Avellino (P.M.); and COVID-19 Division, A.O.R.N. Ospedali dei Colli, Naples, Italy (A.C., G.F.)
| | - Antonietta Coppola
- Department of Medicine, Einstein-Sinai Diabetes Research Center, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research (P.M., S.S.J., J.G., U.K., A.L., F.V., G.S.) and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (G.S.), Albert Einstein College of Medicine, New York, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education, "Federico II" University, Naples, Italy (M.V.M., J.G., R.I., D.S., B.T., G.S.); Clinica Montevergine, Mercogliano, Avellino (P.M.); and COVID-19 Division, A.O.R.N. Ospedali dei Colli, Naples, Italy (A.C., G.F.)
| | - Urna Kansakar
- Department of Medicine, Einstein-Sinai Diabetes Research Center, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research (P.M., S.S.J., J.G., U.K., A.L., F.V., G.S.) and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (G.S.), Albert Einstein College of Medicine, New York, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education, "Federico II" University, Naples, Italy (M.V.M., J.G., R.I., D.S., B.T., G.S.); Clinica Montevergine, Mercogliano, Avellino (P.M.); and COVID-19 Division, A.O.R.N. Ospedali dei Colli, Naples, Italy (A.C., G.F.)
| | - Raffaele Izzo
- Department of Medicine, Einstein-Sinai Diabetes Research Center, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research (P.M., S.S.J., J.G., U.K., A.L., F.V., G.S.) and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (G.S.), Albert Einstein College of Medicine, New York, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education, "Federico II" University, Naples, Italy (M.V.M., J.G., R.I., D.S., B.T., G.S.); Clinica Montevergine, Mercogliano, Avellino (P.M.); and COVID-19 Division, A.O.R.N. Ospedali dei Colli, Naples, Italy (A.C., G.F.)
| | - Giuseppe Fiorentino
- Department of Medicine, Einstein-Sinai Diabetes Research Center, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research (P.M., S.S.J., J.G., U.K., A.L., F.V., G.S.) and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (G.S.), Albert Einstein College of Medicine, New York, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education, "Federico II" University, Naples, Italy (M.V.M., J.G., R.I., D.S., B.T., G.S.); Clinica Montevergine, Mercogliano, Avellino (P.M.); and COVID-19 Division, A.O.R.N. Ospedali dei Colli, Naples, Italy (A.C., G.F.)
| | - Angela Lombardi
- Department of Medicine, Einstein-Sinai Diabetes Research Center, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research (P.M., S.S.J., J.G., U.K., A.L., F.V., G.S.) and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (G.S.), Albert Einstein College of Medicine, New York, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education, "Federico II" University, Naples, Italy (M.V.M., J.G., R.I., D.S., B.T., G.S.); Clinica Montevergine, Mercogliano, Avellino (P.M.); and COVID-19 Division, A.O.R.N. Ospedali dei Colli, Naples, Italy (A.C., G.F.)
| | - Fahimeh Varzideh
- Department of Medicine, Einstein-Sinai Diabetes Research Center, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research (P.M., S.S.J., J.G., U.K., A.L., F.V., G.S.) and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (G.S.), Albert Einstein College of Medicine, New York, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education, "Federico II" University, Naples, Italy (M.V.M., J.G., R.I., D.S., B.T., G.S.); Clinica Montevergine, Mercogliano, Avellino (P.M.); and COVID-19 Division, A.O.R.N. Ospedali dei Colli, Naples, Italy (A.C., G.F.)
| | - Daniela Sorriento
- Department of Medicine, Einstein-Sinai Diabetes Research Center, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research (P.M., S.S.J., J.G., U.K., A.L., F.V., G.S.) and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (G.S.), Albert Einstein College of Medicine, New York, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education, "Federico II" University, Naples, Italy (M.V.M., J.G., R.I., D.S., B.T., G.S.); Clinica Montevergine, Mercogliano, Avellino (P.M.); and COVID-19 Division, A.O.R.N. Ospedali dei Colli, Naples, Italy (A.C., G.F.)
| | - Bruno Trimarco
- Department of Medicine, Einstein-Sinai Diabetes Research Center, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research (P.M., S.S.J., J.G., U.K., A.L., F.V., G.S.) and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (G.S.), Albert Einstein College of Medicine, New York, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education, "Federico II" University, Naples, Italy (M.V.M., J.G., R.I., D.S., B.T., G.S.); Clinica Montevergine, Mercogliano, Avellino (P.M.); and COVID-19 Division, A.O.R.N. Ospedali dei Colli, Naples, Italy (A.C., G.F.)
| | - Gaetano Santulli
- Department of Medicine, Einstein-Sinai Diabetes Research Center, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research (P.M., S.S.J., J.G., U.K., A.L., F.V., G.S.) and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (G.S.), Albert Einstein College of Medicine, New York, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education, "Federico II" University, Naples, Italy (M.V.M., J.G., R.I., D.S., B.T., G.S.); Clinica Montevergine, Mercogliano, Avellino (P.M.); and COVID-19 Division, A.O.R.N. Ospedali dei Colli, Naples, Italy (A.C., G.F.)
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Izzo R, Pacella D, Trimarco V, Manzi MV, Lombardi A, Piccinocchi R, Gallo P, Esposito G, Lembo M, Piccinocchi G, Morisco C, Santulli G, Trimarco B. Incidence of type 2 diabetes before and during the COVID-19 pandemic in Naples, Italy: a longitudinal cohort study. EClinicalMedicine 2023; 66:102345. [PMID: 38143804 PMCID: PMC10746394 DOI: 10.1016/j.eclinm.2023.102345] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 10/31/2023] [Accepted: 11/15/2023] [Indexed: 12/26/2023] Open
Abstract
Background The association of COVID-19 with the development of new-onset diabetes has been recently investigated by several groups, yielding controversial results. Population studies currently available in the literature are mostly focused on type 1 diabetes (T1D), comparing patients with a SARS-CoV-2 positive test to individuals without COVID-19, especially in paediatric populations. In this study, we sought to determine the incidence of type 2 diabetes (T2D) before and during the COVID-19 pandemic. Methods In this longitudinal cohort study, we analysed a cohort followed up over a 6-year period using an Interrupted Time Series approach, i.e. 3-years before and 3-years during the COVID-19 pandemic. We analysed data obtained from >200,000 adults in Naples (Italy) from January 1st 2017 to December 31st 2022. In this manner, we had the opportunity to compare the incidence of newly diagnosed T2D before (2017-2019) and during (2020-2022) the COVID-19 pandemic. The key inclusion criteria were age >18-year-old and data availability for the period of observation; patients with a diagnosis of diabetes obtained before 2017 were excluded. The main outcome of the study was the new diagnosis of T2D, as defined by the International Classification of Diseases 10 (ICD-X), including prescription of antidiabetic therapies for more than 30 days. Findings A total of 234,956 subjects were followed-up for at least 3-years before or 3-years during the COVID-19 pandemic and were included in the study; among these, 216,498 were analysed in the pre-pandemic years and 216,422 in the pandemic years. The incidence rate of T2D was 4.85 (95% CI, 4.68-5.02) per 1000 person-years in the period 2017-2019, vs 12.21 (95% CI, 11.94-12.48) per 1000 person-years in 2020-2022, with an increase of about twice and a half. Moreover, the doubling time of the number of new diagnoses of T2D estimated by unadjusted Poisson model was 97.12 (95% CI, 40.51-153.75) months in the prepandemic period vs 23.13 (95% CI, 16.02-41.59) months during the COVID-19 pandemic. Interestingly, these findings were also confirmed when examining patients with prediabetes. Interpretation Our data from this 6-year study on more than 200,000 adult participants indicate that the incidence of T2D was significantly higher during the pandemic compared to the pre-COVID-19 phase. As a consequence, the epidemiology of the disease may change in terms of rates of outcomes as well as public health costs. COVID-19 survivors, especially patients with prediabetes, may require specific clinical programs to prevent T2D. Funding The US National Institutes of Health (NIH: NIDDK, NHLBI, NCATS), Diabetes Action Research and Education Foundation, Weill-Caulier and Hirschl Trusts.
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Affiliation(s)
- Raffaele Izzo
- Department of Advanced Biomedical Sciences, “Federico II” University, Naples, Italy
| | - Daniela Pacella
- Department of Public Health, “Federico II” University, Naples, Italy
| | - Valentina Trimarco
- Department of Neuroscience, Reproductive Sciences, and Dentistry, “Federico II” University, Naples, Italy
| | - Maria Virginia Manzi
- Department of Advanced Biomedical Sciences, “Federico II” University, Naples, Italy
| | - Angela Lombardi
- Department of Microbiology and Immunology, Fleischer Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine, New York City, NY, USA
| | | | - Paola Gallo
- Department of Public Health, “Federico II” University, Naples, Italy
| | - Giovanni Esposito
- Department of Advanced Biomedical Sciences, “Federico II” University, Naples, Italy
| | - Maria Lembo
- Department of Advanced Biomedical Sciences, “Federico II” University, Naples, Italy
| | - Gaetano Piccinocchi
- COMEGEN Primary Care Physicians Cooperative, Italian Society of General Medicine (SIMG), Naples, Italy
| | - Carmine Morisco
- Department of Advanced Biomedical Sciences, “Federico II” University, Naples, Italy
- International Translational Research and Medical Education (ITME) Consortium, Academic Research Unit, Naples, Italy
- Italian Society for Cardiovascular Prevention (SIPREC), Rome, Italy
| | - Gaetano Santulli
- Department of Advanced Biomedical Sciences, “Federico II” University, Naples, Italy
- International Translational Research and Medical Education (ITME) Consortium, Academic Research Unit, Naples, Italy
- Department of Medicine, Wilf Family Cardiovascular Research Institute, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York City, NY, USA
- Department of Molecular Pharmacology, Einstein Institute for Aging Research, Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York City, NY, USA
| | - Bruno Trimarco
- Department of Advanced Biomedical Sciences, “Federico II” University, Naples, Italy
- International Translational Research and Medical Education (ITME) Consortium, Academic Research Unit, Naples, Italy
- Italian Society for Cardiovascular Prevention (SIPREC), Rome, Italy
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6
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Li M, Wu X, Shi J, Niu Y. Endothelium dysfunction and thrombosis in COVID-19 with type 2 diabetes. Endocrine 2023; 82:15-27. [PMID: 37392341 DOI: 10.1007/s12020-023-03439-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 06/21/2023] [Indexed: 07/03/2023]
Abstract
SARS-CoV-2 can directly or indirectly damage endothelial cells. Endothelial injury, especially phosphatidylserine (PS) exposure on the outer membrane of cells, can more easily promote thrombosis. Type 2 diabetes(T2D) patients were more susceptible to COVID-19, they had more severe symptoms, higher risk of thrombotic complications, and longer duration of post-COVID-19 sequelae. This review provided a detailed overview of the mechanisms underlying endothelial dysfunction in T2D patients with COVID-19 (including long COVID), which may be influenced by hyperglycemia, hypoxia, and pro-inflammatory environments. The mechanisms of thrombosis in T2D patients with COVID-19 are also explored, particularly the effects of increased numbers of PS-exposing particles, blood cells, and endothelial cells on hypercoagulability. Given the high risk of thrombosis in T2D patients with COVID-19, early antithrombotic therapy can both minimize the impact of the disease on patients and maximize the chances of improvement, thereby alleviating patient suffering. We provided detailed guidance on antithrombotic drugs and dosages for mild, moderate, and severe patients, emphasizing that the optimal timing of thromboprophylaxis is a critical factor in influencing prognosis. Considering the potential interactions between antidiabetic, anticoagulant, and antiviral drugs, we proposed practical and comprehensive management recommendations to supplement the incomplete efficacy of vaccines in the diabetic population, reduce the incidence of post-COVID-19 sequelae, and improve patient quality of life.
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Affiliation(s)
- Mengdi Li
- Department of Endodontics, The First Hospital, Harbin Medical University, Harbin, China
- Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China
| | - Xiaoming Wu
- Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China
| | - Jialan Shi
- Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China
- Department of Research, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Yumei Niu
- Department of Endodontics, The First Hospital, Harbin Medical University, Harbin, China.
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7
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Agewall S. Cardiovascular preventive actions. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2023; 9:497-498. [PMID: 37727121 DOI: 10.1093/ehjcvp/pvad054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 07/28/2023] [Indexed: 09/21/2023]
Affiliation(s)
- Stefan Agewall
- Department of Clinical Sciences, Danderyd Hospital Karolinska Institute, Stockholm, Sweden
- Institute of Clinical Sciences, University of Oslo, Oslo, Norway
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8
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Petrache I, Pujadas E, Ganju A, Serban KA, Borowiec A, Babbs B, Bronova IA, Egersdorf N, Hume PS, Goel K, Janssen WJ, Berdyshev EV, Cordon-Cardo C, Kolesnick R. Marked elevations in lung and plasma ceramide in COVID-19 linked to microvascular injury. JCI Insight 2023; 8:e156104. [PMID: 37212278 PMCID: PMC10322682 DOI: 10.1172/jci.insight.156104] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 04/05/2023] [Indexed: 05/23/2023] Open
Abstract
The pathogenesis of the marked pulmonary microvasculature injury, a distinguishing feature of COVID-19 acute respiratory distress syndrome (COVID-ARDS), remains unclear. Implicated in the pathophysiology of diverse diseases characterized by endothelial damage, including ARDS and ischemic cardiovascular disease, ceramide and in particular palmitoyl ceramide (C16:0-ceramide) may be involved in the microvascular injury in COVID-19. Using deidentified plasma and lung samples from COVID-19 patients, ceramide profiling by mass spectrometry was performed. Compared with healthy individuals, a specific 3-fold C16:0-ceramide elevation in COVID-19 patient plasma was identified. Compared with age-matched controls, autopsied lungs of individuals succumbing to COVID-ARDS displayed a massive 9-fold C16:0-ceramide elevation and exhibited a previously unrecognized microvascular ceramide-staining pattern and markedly enhanced apoptosis. In COVID-19 plasma and lungs, the C16-ceramide/C24-ceramide ratios were increased and reversed, respectively, consistent with increased risk of vascular injury. Indeed, exposure of primary human lung microvascular endothelial cell monolayers to C16:0-ceramide-rich plasma lipid extracts from COVID-19, but not healthy, individuals led to a significant decrease in endothelial barrier function. This effect was phenocopied by spiking healthy plasma lipid extracts with synthetic C16:0-ceramide and was inhibited by treatment with ceramide-neutralizing monoclonal antibody or single-chain variable fragment. These results indicate that C16:0-ceramide may be implicated in the vascular injury associated with COVID-19.
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Affiliation(s)
- Irina Petrache
- Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, Colorado, USA
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, Colorado, USA
| | - Elisabet Pujadas
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Aditya Ganju
- Laboratory of Signal Transduction, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Karina A. Serban
- Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, Colorado, USA
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, Colorado, USA
| | - Alexander Borowiec
- Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, Colorado, USA
| | - Beatrice Babbs
- Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, Colorado, USA
| | - Irina A. Bronova
- Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, Colorado, USA
| | - Nicholas Egersdorf
- Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, Colorado, USA
| | - Patrick S. Hume
- Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, Colorado, USA
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, Colorado, USA
| | - Khushboo Goel
- Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, Colorado, USA
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, Colorado, USA
| | - William J. Janssen
- Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, Colorado, USA
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, Colorado, USA
| | - Evgeny V. Berdyshev
- Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, Colorado, USA
| | - Carlos Cordon-Cardo
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Richard Kolesnick
- Laboratory of Signal Transduction, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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9
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Tsounis EP, Triantos C, Konstantakis C, Marangos M, Assimakopoulos SF. Intestinal barrier dysfunction as a key driver of severe COVID-19. World J Virol 2023; 12:68-90. [PMID: 37033148 PMCID: PMC10075050 DOI: 10.5501/wjv.v12.i2.68] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/08/2022] [Accepted: 01/16/2023] [Indexed: 03/21/2023] Open
Abstract
The intestinal lumen harbors a diverse consortium of microorganisms that participate in reciprocal crosstalk with intestinal immune cells and with epithelial and endothelial cells, forming a multi-layered barrier that enables the efficient absorption of nutrients without an excessive influx of pathogens. Despite being a lung-centered disease, severe coronavirus disease 2019 (COVID-19) affects multiple systems, including the gastrointestinal tract and the pertinent gut barrier function. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can inflict either direct cytopathic injury to intestinal epithelial and endothelial cells or indirect immune-mediated damage. Alternatively, SARS-CoV-2 undermines the structural integrity of the barrier by modifying the expression of tight junction proteins. In addition, SARS-CoV-2 induces profound alterations to the intestinal microflora at phylogenetic and metabolomic levels (dysbiosis) that are accompanied by disruption of local immune responses. The ensuing dysregulation of the gut-lung axis impairs the ability of the respiratory immune system to elicit robust and timely responses to restrict viral infection. The intestinal vasculature is vulnerable to SARS-CoV-2-induced endothelial injury, which simultaneously triggers the activation of the innate immune and coagulation systems, a condition referred to as “immunothrombosis” that drives severe thrombotic complications. Finally, increased intestinal permeability allows an aberrant dissemination of bacteria, fungi, and endotoxin into the systemic circulation and contributes, to a certain degree, to the over-exuberant immune responses and hyper-inflammation that dictate the severe form of COVID-19. In this review, we aim to elucidate SARS-CoV-2-mediated effects on gut barrier homeostasis and their implications on the progression of the disease.
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Affiliation(s)
- Efthymios P Tsounis
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University Hospital of Patras, Patras 26504, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University Hospital of Patras, Patras 26504, Greece
| | - Christos Konstantakis
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University Hospital of Patras, Patras 26504, Greece
| | - Markos Marangos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, Patras 26504, Greece
| | - Stelios F Assimakopoulos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, Patras 26504, Greece
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10
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Beneficial Effects of L-Arginine in Patients Hospitalized for COVID-19: New Insights from a Randomized Clinical Trial. Pharmacol Res 2023; 191:106702. [PMID: 36804278 PMCID: PMC9928676 DOI: 10.1016/j.phrs.2023.106702] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 02/03/2023] [Accepted: 02/14/2023] [Indexed: 02/17/2023]
Abstract
We have recently demonstrated in a double-blind randomized trial the beneficial effects of L-Arginine in patients hospitalized for COVID-19. We hypothesize that one of the mechanisms underlying the favorable effects of L-Arginine is its action on inflammatory cytokines. To verify our hypothesis, we measured longitudinal plasma levels of pro-inflammatory and anti-inflammatory cytokines implied in the pathophysiology of COVID-19 in patients randomized to receive oral L-Arginine or placebo. The study was successfully completed by 169 patients. Patients in the L-Arginine arm had a reduced respiratory support evaluated at 10 and 20 days; moreover, the time to hospital discharge was significantly shorter in the L-Arginine group. The assessment of circulating cytokines revealed that L-Arginine significantly reduced the circulating levels of pro-inflammatory IL-2, IL-6, and IFN-γ and increased the levels of the anti-inflammatory IL-10. Taken together, these findings indicate that adding L-Arginine to standard therapy in COVID-19 patients markedly reduces the need of respiratory support and the duration of in-hospital stay; moreover, L-Arginine significantly regulates circulating levels of pro-inflammatory and anti-inflammatory cytokines.
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11
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Oliveira KB, de Melo IS, da Silva BRM, Oliveira KLDS, Sabino-Silva R, Anhezini L, Katayama PL, Santos VR, Shetty AK, de Castro OW. SARS-CoV-2 and Hypertension: Evidence Supporting Invasion into the Brain Via Baroreflex Circuitry and the Role of Imbalanced Renin-Angiotensin-Aldosterone-System. Neurosci Insights 2023; 18:26331055231151926. [PMID: 36756280 PMCID: PMC9900164 DOI: 10.1177/26331055231151926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 01/04/2023] [Indexed: 02/05/2023] Open
Abstract
Hypertension is considered one of the most critical risk factors for COVID-19. Evidence suggests that SARS-CoV-2 infection produces intense effects on the cardiovascular system by weakening the wall of large vessels via vasa-vasorum. In this commentary, we propose that SARS-CoV-2 invades carotid and aortic baroreceptors, leading to infection of the nucleus tractus solitari (NTS) and paraventricular hypothalamic nucleus (PVN), and such dysregulation of NTS and PVN following infection causes blood pressure alteration at the central level. We additionally explored the hypothesis that SARS-CoV-2 favors the internalization of membrane ACE2 receptors generating an imbalance of the renin-angiotensin-aldosterone system (RAAS), increasing the activity of angiotensin II (ANG-II), disintegrin, and metalloproteinase 17 domain (ADAM17/TACE), eventually modulating the integration of afferents reaching the NTS from baroreceptors and promoting increased blood pressure. These mechanisms are related to the increased sympathetic activity, which leads to transient or permanent hypertension associated with SARS-CoV-2 invasion, contributing to the high number of deaths by cardiovascular implications.
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Affiliation(s)
- Kellysson Bruno Oliveira
- Department of Physiology, Institute of
Biological Sciences and Health, Federal University of Alagoas (UFAL), Maceió,
Alagoas, Brazil
| | - Igor Santana de Melo
- Department of Physiology, Institute of
Biological Sciences and Health, Federal University of Alagoas (UFAL), Maceió,
Alagoas, Brazil
| | - Bianca Rodrigues Melo da Silva
- Department of Physiology, Institute of
Biological Sciences and Health, Federal University of Alagoas (UFAL), Maceió,
Alagoas, Brazil
| | - Keylla Lavínia da Silva Oliveira
- Department of Physiology, Institute of
Biological Sciences and Health, Federal University of Alagoas (UFAL), Maceió,
Alagoas, Brazil
| | - Robinson Sabino-Silva
- Department of Physiology, Institute of
Biomedical Sciences, Federal University of Uberlandia (UFU), Uberlândia, Minas
Gerais, Brazil
| | - Lucas Anhezini
- Department of Histology, Institute of
Biological Sciences and Health, Federal University of Alagoas, Maceió, Alagoas,
Brazil
| | - Pedro Lourenco Katayama
- Department of Physiology and Pathology,
Dentistry School of Araraquara, São Paulo State University, Araraquara, São Paulo,
Brazil
| | - Victor Rodrigues Santos
- Department of Morphology, Institute of
Biological Science, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas
Gerais, Brazil
| | - Ashok K Shetty
- Institute for Regenerative Medicine,
Department of Cell Biology and Genetics, Texas A&M University School of
Medicine, College Station, TX, USA
| | - Olagide Wagner de Castro
- Department of Physiology, Institute of
Biological Sciences and Health, Federal University of Alagoas (UFAL), Maceió,
Alagoas, Brazil,Olagide Wagner de Castro, Institute of
Biological Sciences and Health, Federal University of Alagoas (UFAL), Av.
Lourival de Melo Mota, km 14, Campus A. C. Simões, Cidade Universitária, Maceió,
Alagoas CEP 57072-970, Brazil.
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12
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Jankauskas SS, Kansakar U, Sardu C, Varzideh F, Avvisato R, Wang X, Matarese A, Marfella R, Ziosi M, Gambardella J, Santulli G. COVID-19 Causes Ferroptosis and Oxidative Stress in Human Endothelial Cells. Antioxidants (Basel) 2023; 12:326. [PMID: 36829885 PMCID: PMC9952002 DOI: 10.3390/antiox12020326] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/17/2023] [Accepted: 01/30/2023] [Indexed: 02/03/2023] Open
Abstract
Oxidative stress and endothelial dysfunction have been shown to play crucial roles in the pathophysiology of COVID-19 (coronavirus disease 2019). On these grounds, we sought to investigate the impact of COVID-19 on lipid peroxidation and ferroptosis in human endothelial cells. We hypothesized that oxidative stress and lipid peroxidation induced by COVID-19 in endothelial cells could be linked to the disease outcome. Thus, we collected serum from COVID-19 patients on hospital admission, and we incubated these sera with human endothelial cells, comparing the effects on the generation of reactive oxygen species (ROS) and lipid peroxidation between patients who survived and patients who did not survive. We found that the serum from non-survivors significantly increased lipid peroxidation. Moreover, serum from non-survivors markedly regulated the expression levels of the main markers of ferroptosis, including GPX4, SLC7A11, FTH1, and SAT1, a response that was rescued by silencing TNFR1 on endothelial cells. Taken together, our data indicate that serum from patients who did not survive COVID-19 triggers lipid peroxidation in human endothelial cells.
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Affiliation(s)
- Stanislovas S. Jankauskas
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Urna Kansakar
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Celestino Sardu
- University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
| | - Fahimeh Varzideh
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Roberta Avvisato
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
- “Federico II” University, 80131 Naples, Italy
| | - Xujun Wang
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | | | | | | | - Jessica Gambardella
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
- “Federico II” University, 80131 Naples, Italy
| | - Gaetano Santulli
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
- “Federico II” University, 80131 Naples, Italy
- Department of Molecular Pharmacology, Einstein Institute for Neuroimmunology and Inflammation (INI), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Fleischer Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine, New York, NY 10461, USA
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13
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Gambardella J, Kansakar U, Sardu C, Messina V, Jankauskas SS, Marfella R, Maggi P, Wang X, Mone P, Paolisso G, Sorriento D, Santulli G. Exosomal miR-145 and miR-885 Regulate Thrombosis in COVID-19. J Pharmacol Exp Ther 2023; 384:109-115. [PMID: 35772782 PMCID: PMC9827505 DOI: 10.1124/jpet.122.001209] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 05/06/2022] [Accepted: 05/09/2022] [Indexed: 01/13/2023] Open
Abstract
We hypothesized that exosomal microRNAs could be implied in the pathogenesis of thromboembolic complications in coronavirus disease 2019 (COVID-19). We isolated circulating exosomes from patients with COVID-19, and then we divided our population in two arms based on the D-dimer level on hospital admission. We observed that exosomal miR-145 and miR-885 significantly correlate with D-dimer levels. Moreover, we demonstrate that human endothelial cells express the main cofactors needed for the internalization of the "Severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), including angiotensin converting enzyme 2, transmembrane protease serine 2, and CD-147. Interestingly, human endothelial cells treated with serum from COVID-19 patients release significantly less miR-145 and miR-885, exhibit increased apoptosis, and display significantly impaired angiogenetic properties compared with cells treated with non-COVID-19 serum. Taken together, our data indicate that exosomal miR-145 and miR-885 are essential in modulating thromboembolic events in COVID-19. SIGNIFICANCE STATEMENT: This work demonstrates for the first time that two specific microRNAs (namely miR-145 and miR-885) contained in circulating exosomes are functionally involved in thromboembolic events in COVID-19. These findings are especially relevant to the general audience when considering the emerging prominence of post-acute sequelae of COVID-19 systemic manifestations known as Long COVID.
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Affiliation(s)
- Jessica Gambardella
- Department of Medicine, Wilf Family Cardiovascular Research Institute (J.G., U.K., S.S.J., X.W., P.Mo.) and Department of Molecular Pharmacology, Einstein-Sinai Diabetes Research Center (ES-DRC), Institute for Neuroimmunology and Inflammation (INI), Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research (G.S.), Albert Einstein College of Medicine, New York City, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education (ITME) Consortium, "Federico II" University, Naples, Italy (J.G., D.S., G.S.); Department of Advanced Medical and Surgical Sciences (C.S., R.M., P. Ma., G.P.), and Department of Mental and Physical Health and Preventive Medicine (P.Ma.) University of Campania, Naples, Italy; Infectious Disease Unit, "Sant'Anna and San Sebastiano" Hospital, Caserta, Italy (V.M.)
| | - Urna Kansakar
- Department of Medicine, Wilf Family Cardiovascular Research Institute (J.G., U.K., S.S.J., X.W., P.Mo.) and Department of Molecular Pharmacology, Einstein-Sinai Diabetes Research Center (ES-DRC), Institute for Neuroimmunology and Inflammation (INI), Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research (G.S.), Albert Einstein College of Medicine, New York City, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education (ITME) Consortium, "Federico II" University, Naples, Italy (J.G., D.S., G.S.); Department of Advanced Medical and Surgical Sciences (C.S., R.M., P. Ma., G.P.), and Department of Mental and Physical Health and Preventive Medicine (P.Ma.) University of Campania, Naples, Italy; Infectious Disease Unit, "Sant'Anna and San Sebastiano" Hospital, Caserta, Italy (V.M.)
| | - Celestino Sardu
- Department of Medicine, Wilf Family Cardiovascular Research Institute (J.G., U.K., S.S.J., X.W., P.Mo.) and Department of Molecular Pharmacology, Einstein-Sinai Diabetes Research Center (ES-DRC), Institute for Neuroimmunology and Inflammation (INI), Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research (G.S.), Albert Einstein College of Medicine, New York City, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education (ITME) Consortium, "Federico II" University, Naples, Italy (J.G., D.S., G.S.); Department of Advanced Medical and Surgical Sciences (C.S., R.M., P. Ma., G.P.), and Department of Mental and Physical Health and Preventive Medicine (P.Ma.) University of Campania, Naples, Italy; Infectious Disease Unit, "Sant'Anna and San Sebastiano" Hospital, Caserta, Italy (V.M.)
| | - Vincenzo Messina
- Department of Medicine, Wilf Family Cardiovascular Research Institute (J.G., U.K., S.S.J., X.W., P.Mo.) and Department of Molecular Pharmacology, Einstein-Sinai Diabetes Research Center (ES-DRC), Institute for Neuroimmunology and Inflammation (INI), Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research (G.S.), Albert Einstein College of Medicine, New York City, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education (ITME) Consortium, "Federico II" University, Naples, Italy (J.G., D.S., G.S.); Department of Advanced Medical and Surgical Sciences (C.S., R.M., P. Ma., G.P.), and Department of Mental and Physical Health and Preventive Medicine (P.Ma.) University of Campania, Naples, Italy; Infectious Disease Unit, "Sant'Anna and San Sebastiano" Hospital, Caserta, Italy (V.M.)
| | - Stanislovas S Jankauskas
- Department of Medicine, Wilf Family Cardiovascular Research Institute (J.G., U.K., S.S.J., X.W., P.Mo.) and Department of Molecular Pharmacology, Einstein-Sinai Diabetes Research Center (ES-DRC), Institute for Neuroimmunology and Inflammation (INI), Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research (G.S.), Albert Einstein College of Medicine, New York City, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education (ITME) Consortium, "Federico II" University, Naples, Italy (J.G., D.S., G.S.); Department of Advanced Medical and Surgical Sciences (C.S., R.M., P. Ma., G.P.), and Department of Mental and Physical Health and Preventive Medicine (P.Ma.) University of Campania, Naples, Italy; Infectious Disease Unit, "Sant'Anna and San Sebastiano" Hospital, Caserta, Italy (V.M.)
| | - Raffaele Marfella
- Department of Medicine, Wilf Family Cardiovascular Research Institute (J.G., U.K., S.S.J., X.W., P.Mo.) and Department of Molecular Pharmacology, Einstein-Sinai Diabetes Research Center (ES-DRC), Institute for Neuroimmunology and Inflammation (INI), Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research (G.S.), Albert Einstein College of Medicine, New York City, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education (ITME) Consortium, "Federico II" University, Naples, Italy (J.G., D.S., G.S.); Department of Advanced Medical and Surgical Sciences (C.S., R.M., P. Ma., G.P.), and Department of Mental and Physical Health and Preventive Medicine (P.Ma.) University of Campania, Naples, Italy; Infectious Disease Unit, "Sant'Anna and San Sebastiano" Hospital, Caserta, Italy (V.M.)
| | - Paolo Maggi
- Department of Medicine, Wilf Family Cardiovascular Research Institute (J.G., U.K., S.S.J., X.W., P.Mo.) and Department of Molecular Pharmacology, Einstein-Sinai Diabetes Research Center (ES-DRC), Institute for Neuroimmunology and Inflammation (INI), Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research (G.S.), Albert Einstein College of Medicine, New York City, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education (ITME) Consortium, "Federico II" University, Naples, Italy (J.G., D.S., G.S.); Department of Advanced Medical and Surgical Sciences (C.S., R.M., P. Ma., G.P.), and Department of Mental and Physical Health and Preventive Medicine (P.Ma.) University of Campania, Naples, Italy; Infectious Disease Unit, "Sant'Anna and San Sebastiano" Hospital, Caserta, Italy (V.M.)
| | - Xujun Wang
- Department of Medicine, Wilf Family Cardiovascular Research Institute (J.G., U.K., S.S.J., X.W., P.Mo.) and Department of Molecular Pharmacology, Einstein-Sinai Diabetes Research Center (ES-DRC), Institute for Neuroimmunology and Inflammation (INI), Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research (G.S.), Albert Einstein College of Medicine, New York City, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education (ITME) Consortium, "Federico II" University, Naples, Italy (J.G., D.S., G.S.); Department of Advanced Medical and Surgical Sciences (C.S., R.M., P. Ma., G.P.), and Department of Mental and Physical Health and Preventive Medicine (P.Ma.) University of Campania, Naples, Italy; Infectious Disease Unit, "Sant'Anna and San Sebastiano" Hospital, Caserta, Italy (V.M.)
| | - Pasquale Mone
- Department of Medicine, Wilf Family Cardiovascular Research Institute (J.G., U.K., S.S.J., X.W., P.Mo.) and Department of Molecular Pharmacology, Einstein-Sinai Diabetes Research Center (ES-DRC), Institute for Neuroimmunology and Inflammation (INI), Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research (G.S.), Albert Einstein College of Medicine, New York City, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education (ITME) Consortium, "Federico II" University, Naples, Italy (J.G., D.S., G.S.); Department of Advanced Medical and Surgical Sciences (C.S., R.M., P. Ma., G.P.), and Department of Mental and Physical Health and Preventive Medicine (P.Ma.) University of Campania, Naples, Italy; Infectious Disease Unit, "Sant'Anna and San Sebastiano" Hospital, Caserta, Italy (V.M.)
| | - Giuseppe Paolisso
- Department of Medicine, Wilf Family Cardiovascular Research Institute (J.G., U.K., S.S.J., X.W., P.Mo.) and Department of Molecular Pharmacology, Einstein-Sinai Diabetes Research Center (ES-DRC), Institute for Neuroimmunology and Inflammation (INI), Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research (G.S.), Albert Einstein College of Medicine, New York City, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education (ITME) Consortium, "Federico II" University, Naples, Italy (J.G., D.S., G.S.); Department of Advanced Medical and Surgical Sciences (C.S., R.M., P. Ma., G.P.), and Department of Mental and Physical Health and Preventive Medicine (P.Ma.) University of Campania, Naples, Italy; Infectious Disease Unit, "Sant'Anna and San Sebastiano" Hospital, Caserta, Italy (V.M.)
| | - Daniela Sorriento
- Department of Medicine, Wilf Family Cardiovascular Research Institute (J.G., U.K., S.S.J., X.W., P.Mo.) and Department of Molecular Pharmacology, Einstein-Sinai Diabetes Research Center (ES-DRC), Institute for Neuroimmunology and Inflammation (INI), Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research (G.S.), Albert Einstein College of Medicine, New York City, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education (ITME) Consortium, "Federico II" University, Naples, Italy (J.G., D.S., G.S.); Department of Advanced Medical and Surgical Sciences (C.S., R.M., P. Ma., G.P.), and Department of Mental and Physical Health and Preventive Medicine (P.Ma.) University of Campania, Naples, Italy; Infectious Disease Unit, "Sant'Anna and San Sebastiano" Hospital, Caserta, Italy (V.M.)
| | - Gaetano Santulli
- Department of Medicine, Wilf Family Cardiovascular Research Institute (J.G., U.K., S.S.J., X.W., P.Mo.) and Department of Molecular Pharmacology, Einstein-Sinai Diabetes Research Center (ES-DRC), Institute for Neuroimmunology and Inflammation (INI), Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research (G.S.), Albert Einstein College of Medicine, New York City, New York; Department of Advanced Biomedical Sciences, International Translational Research and Medical Education (ITME) Consortium, "Federico II" University, Naples, Italy (J.G., D.S., G.S.); Department of Advanced Medical and Surgical Sciences (C.S., R.M., P. Ma., G.P.), and Department of Mental and Physical Health and Preventive Medicine (P.Ma.) University of Campania, Naples, Italy; Infectious Disease Unit, "Sant'Anna and San Sebastiano" Hospital, Caserta, Italy (V.M.)
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14
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Izzo C, Visco V, Gambardella J, Ferruzzi GJ, Rispoli A, Rusciano MR, Toni AL, Virtuoso N, Carrizzo A, Di Pietro P, Iaccarino G, Vecchione C, Ciccarelli M. Cardiovascular Implications of microRNAs in Coronavirus Disease 2019. J Pharmacol Exp Ther 2023; 384:102-108. [PMID: 35779946 DOI: 10.1124/jpet.122.001210] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 06/11/2022] [Accepted: 06/15/2022] [Indexed: 01/13/2023] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to be a global challenge due to resulting morbidity and mortality. Cardiovascular (CV) involvement is a crucial complication in coronavirus disease 2019 (COVID-19), and no strategies are available to prevent or specifically address CV events in COVID-19 patients. The identification of molecular partners contributing to CV manifestations in COVID-19 patients is crucial for providing early biomarkers, prognostic predictors, and new therapeutic targets. The current report will focus on the role of microRNAs (miRNAs) in CV complications associated with COVID-19. Indeed, miRNAs have been proposed as valuable biomarkers and predictors of both cardiac and vascular damage occurring in SARS-CoV-2 infection. SIGNIFICANCE STATEMENT: It is essential to identify the molecular mediators of coronavirus disease 2019 (COVID-19) cardiovascular (CV) complications. This report focused on the role of microRNAs in CV complications associated with COVID-19, discussing their potential use as biomarkers, prognostic predictors, and therapeutic targets.
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Affiliation(s)
- Carmine Izzo
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Valeria Visco
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Jessica Gambardella
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Germano Junior Ferruzzi
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Antonella Rispoli
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Maria Rosaria Rusciano
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Anna Laura Toni
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Nicola Virtuoso
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Albino Carrizzo
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Paola Di Pietro
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Guido Iaccarino
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Carmine Vecchione
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Michele Ciccarelli
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
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15
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Kansakar U, Gambardella J, Varzideh F, Avvisato R, Jankauskas SS, Mone P, Matarese A, Santulli G. miR-142 Targets TIM-1 in Human Endothelial Cells: Potential Implications for Stroke, COVID-19, Zika, Ebola, Dengue, and Other Viral Infections. Int J Mol Sci 2022; 23:10242. [PMID: 36142146 PMCID: PMC9499484 DOI: 10.3390/ijms231810242] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 08/30/2022] [Accepted: 09/02/2022] [Indexed: 11/30/2022] Open
Abstract
T-cell immunoglobulin and mucin domain 1 (TIM-1) has been recently identified as one of the factors involved in the internalization of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human cells, in addition to angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), neuropilin-1, and others. We hypothesized that specific microRNAs could target TIM-1, with potential implications for the management of patients suffering from coronavirus disease 2019 (COVID-19). By combining bioinformatic analyses and functional assays, we identified miR-142 as a specific regulator of TIM-1 transcription. Since TIM-1 has been implicated in the regulation of endothelial function at the level of the blood-brain barrier (BBB) and its levels have been shown to be associated with stroke and cerebral ischemia-reperfusion injury, we validated miR-142 as a functional modulator of TIM-1 in human brain microvascular endothelial cells (hBMECs). Taken together, our results indicate that miR-142 targets TIM-1, representing a novel strategy against cerebrovascular disorders, as well as systemic complications of SARS-CoV-2 and other viral infections.
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Affiliation(s)
- Urna Kansakar
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Jessica Gambardella
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Fahimeh Varzideh
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Roberta Avvisato
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Stanislovas S. Jankauskas
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Pasquale Mone
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | | | - Gaetano Santulli
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
- Department of Molecular Pharmacology, Institute for Neuroimmunology and Inflammation, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Fleischer Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine, New York, NY 10461, USA
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16
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Izzo R, Trimarco V, Mone P, Aloè T, Capra Marzani M, Diana A, Fazio G, Mallardo M, Maniscalco M, Marazzi G, Messina N, Mininni S, Mussi C, Pelaia G, Pennisi A, Santus P, Scarpelli F, Tursi F, Zanforlin A, Santulli G, Trimarco B. Combining L-Arginine with vitamin C improves long-COVID symptoms: The LINCOLN Survey. Pharmacol Res 2022; 183:106360. [PMID: 35868478 PMCID: PMC9295384 DOI: 10.1016/j.phrs.2022.106360] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/17/2022] [Accepted: 07/18/2022] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Recent evidence suggests that oxidative stress and endothelial dysfunction play critical roles in the pathophysiology of COVID-19 and Long-COVID. We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have favorable effects on Long-COVID symptoms. METHODS We designed a survey (LINCOLN: L-Arginine and Vitamin C improves Long-COVID), assessing several symptoms that have been associated with Long-COVID to be administered nationwide to COVID-19 survivors; the survey also included effort perception, measured using the Borg scale. Patients receiving the survey were divided in two groups, with a 2:1 ratio: the first group included patients that received L-Arginine + Vitamin C, whereas the second group received a multivitamin combination (alternative treatment). RESULTS 1390 patients successfully completed the survey. Following a 30-day treatment in both groups, the survey revealed that patients in the L-Arginine + Vitamin C treatment arm had significantly lower scores compared to patients who had received the multivitamin combination. There were no other significant differences between the two groups. When examining effort perception, we observed a significantly lower value (p < 0.0001) in patients receiving L-Arginine + Vitamin C compared to the alternative-treatment arm. CONCLUSIONS Our survey indicates that the supplementation with L-Arginine + Vitamin C has beneficial effects in Long-COVID, in terms of attenuating its typical symptoms and improving effort perception.
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Affiliation(s)
- Raffaele Izzo
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Valentina Trimarco
- Department of Neuroscience, Reproductive Sciences and Dentistry, Federico II University, Naples, Italy
| | - Pasquale Mone
- Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA
| | | | | | | | | | | | | | | | | | - Simone Mininni
- Associazione Scientifica Interdisciplinare Aggiornamento Medico (ASIAM), Florence, Italy
| | - Chiara Mussi
- Department of Biomedical and Metabolic Sciences and Neuroscience, University of Modena and Reggio Emilia, Modena, Italy
| | - Girolamo Pelaia
- Department of Health Science, Magna Graecia University, Catanzaro, Italy
| | | | | | | | | | | | - Gaetano Santulli
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy; Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA.
| | - Bruno Trimarco
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
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17
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Zha D, Fu M, Qian Y. Vascular Endothelial Glycocalyx Damage and Potential Targeted Therapy in COVID-19. Cells 2022; 11:cells11121972. [PMID: 35741101 PMCID: PMC9221624 DOI: 10.3390/cells11121972] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/10/2022] [Accepted: 06/17/2022] [Indexed: 02/06/2023] Open
Abstract
COVID-19 is a highly infectious respiratory disease caused by a new coronavirus known as SARS-CoV-2. COVID-19 is characterized by progressive respiratory failure resulting from diffuse alveolar damage, inflammatory infiltrates, endotheliitis, and pulmonary and systemic coagulopathy forming obstructive microthrombi with multi-organ dysfunction, indicating that endothelial cells (ECs) play a central role in the pathogenesis of COVID-19. The glycocalyx is defined as a complex gel-like layer of glycosylated lipid–protein mixtures, which surrounds all living cells and acts as a buffer between the cell and the extracellular matrix. The endothelial glycocalyx layer (EGL) plays an important role in vascular homeostasis via regulating vascular permeability, cell adhesion, mechanosensing for hemodynamic shear stresses, and antithrombotic and anti-inflammatory functions. Here, we review the new findings that described EGL damage in ARDS, coagulopathy, and the multisystem inflammatory disease associated with COVID-19. Mechanistically, the inflammatory mediators, reactive oxygen species (ROS), matrix metalloproteases (MMPs), the glycocalyx fragments, and the viral proteins may contribute to endothelial glycocalyx damage in COVID-19. In addition, the potential therapeutic strategies targeting the EGL for the treatment of severe COVID-19 are summarized and discussed.
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Affiliation(s)
- Duoduo Zha
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China;
| | - Mingui Fu
- Shock/Trauma Research Center, Department of Biomedical Sciences, School of Medicine, University of Missouri Kansas City, Kansas City, MO 64108, USA;
| | - Yisong Qian
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China;
- Correspondence:
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18
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Shen L, Qiu L, Wang L, Huang H, Liu D, Xiao Y, Liu Y, Jin J, Liu X, Wang DW, He B, Zhou N. Statin Use and In-hospital Mortality in Patients with COVID-19 and Coronary Heart Disease. Sci Rep 2021; 11:23874. [PMID: 34903765 PMCID: PMC8668894 DOI: 10.1038/s41598-021-02534-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 08/30/2021] [Indexed: 02/08/2023] Open
Abstract
The worsening progress of coronavirus disease 2019 (COVID-19) is attributed to the proinflammatory state, leading to increased mortality. Statin works with its anti-inflammatory effects and may attenuate the worsening of COVID-19. COVID-19 patients were retrospectively enrolled from two academic hospitals in Wuhan, China, from 01/26/2020 to 03/26/2020. Adjusted in-hospital mortality was compared between the statin and the non-statin group by CHD status using multivariable Cox regression model after propensity score matching. Our study included 3133 COVID-19 patients (median age: 62y, female: 49.8%), and 404 (12.9%) received statin. Compared with the non-statin group, the statin group was older, more likely to have comorbidities but with a lower level of inflammatory markers. The Statin group also had a lower adjusted mortality risk (6.44% vs. 10.88%; adjusted hazard ratio [HR] 0.47; 95% CI, 0.29–0.77). Subgroup analysis of CHD patients showed a similar result. Propensity score matching showed an overall 87% (HR, 0.13; 95% CI, 0.05–0.36) lower risk of in-hospital mortality for statin users than nonusers. Such survival benefit of statin was obvious both among CHD and non-CHD patients (HR = 0.30 [0.09–0.98]; HR = 0.23 [0.1–0.49], respectively). Statin use was associated with reduced in-hospital mortality in COVID-19. The benefit of statin was both prominent among CHD and non-CHD patients. These findings may further reemphasize the continuation of statins in patients with CHD during the COVID-19 era.
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Affiliation(s)
- Lan Shen
- Department of Cardiology, Clinical Research Unit, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 200030, China
| | - Lin Qiu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, 430030, China
| | - Li Wang
- Department of Geriatrics, School of Medicine, Shanghai Renji Hospital, Shanghai Jiaotong University, Shanghai, 200127, China
| | - Hengye Huang
- School of Public Health, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025, China
| | - Dong Liu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, 430030, China
| | - Ying Xiao
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, 430030, China
| | - Yi Liu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, 430030, China
| | - Jingjin Jin
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, 430030, China
| | - Xiulan Liu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, 430030, China
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Ben He
- Department of Cardiology, Clinical Research Unit, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 200030, China.
| | - Ning Zhou
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China.
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19
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Fiorentino G, Coppola A, Izzo R, Annunziata A, Bernardo M, Lombardi A, Trimarco V, Santulli G, Trimarco B. Effects of adding L-arginine orally to standard therapy in patients with COVID-19: A randomized, double-blind, placebo-controlled, parallel-group trial. Results of the first interim analysis. EClinicalMedicine 2021; 40:101125. [PMID: 34522871 PMCID: PMC8428476 DOI: 10.1016/j.eclinm.2021.101125] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/11/2021] [Accepted: 08/20/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND We and others have previously demonstrated that the endothelium is a primary target of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and L-arginine has been shown to improve endothelial dysfunction. However, the effects of L-arginine have never been evaluated in coronavirus disease 2019 (COVID-19). METHODS This is a parallel-group, double-blind, randomized, placebo-controlled trial conducted on patients hospitalized for severe COVID-19. Patients received 1.66 g L-arginine twice a day or placebo, administered orally. The primary efficacy endpoint was a reduction in respiratory support assessed 10 and 20 days after randomization. Secondary outcomes were the length of in-hospital stay, the time to normalization of lymphocyte number, and the time to obtain a negative real-time reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 on nasopharyngeal swab. This clinical trial had been registered at ClinicalTrials.gov, identifier: NCT04637906. FINDINGS We present here the results of the initial interim analysis on the first 101 patients. No treatment-emergent serious adverse events were attributable to L-arginine. At 10-day evaluation, 71.1% of patients in the L-arginine arm and 44.4% in the placebo arm (p < 0.01) had the respiratory support reduced; however, a significant difference was not detected 20 days after randomization. Strikingly, patients treated with L-arginine exhibited a significantly reduced in-hospital stay vs placebo, with a median (interquartile range 25th,75th percentile) of 46 days (45,46) in the placebo group vs 25 days (21,26) in the L-arginine group (p < 0.0001); these findings were also confirmed after adjusting for potential confounders including age, duration of symptoms, comorbidities, D-dimer, as well as antiviral and anticoagulant treatments. The other secondary outcomes were not significantly different between groups. INTERPRETATION In this interim analysis, adding oral L-arginine to standard therapy in patients with severe COVID-19 significantly decreases the length of hospitalization and reduces the respiratory support at 10 but not at 20 days after starting the treatment. FUNDING Both placebo and L-arginine were kindly provided by Farmaceutici Damor S.p.A., Naples.
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Affiliation(s)
| | | | - Raffaele Izzo
- Department of Advanced Biomedical Sciences, “Federico II” University, Naples, Italy
| | - Anna Annunziata
- COVID-19 Division, A.O.R.N. Ospedali dei Colli, Naples, Italy
| | | | - Angela Lombardi
- Department of Medicine, Fleischer Institute for Diabetes and Metabolsim (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY, USA
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY, USA
| | - Valentina Trimarco
- Department of Neuroscience, Reproductive Sciences, and Dentistry, "Federico II" University, Naples, Italy
| | - Gaetano Santulli
- Department of Advanced Biomedical Sciences, “Federico II” University, Naples, Italy
- Department of Medicine, Fleischer Institute for Diabetes and Metabolsim (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY, USA
- Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY, USA
- International Translational Research and Medical Education (ITME) Consortium, Naples, Italy
| | - Bruno Trimarco
- Department of Advanced Biomedical Sciences, “Federico II” University, Naples, Italy
- International Translational Research and Medical Education (ITME) Consortium, Naples, Italy
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20
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D’Alessandro A, Thomas T, Akpan IJ, Reisz JA, Cendali FI, Gamboni F, Nemkov T, Thangaraju K, Katneni U, Tanaka K, Kahn S, Wei AZ, Valk JE, Hudson KE, Roh D, Moriconi C, Zimring JC, Hod EA, Spitalnik SL, Buehler PW, Francis RO. Biological and Clinical Factors Contributing to the Metabolic Heterogeneity of Hospitalized Patients with and without COVID-19. Cells 2021; 10:2293. [PMID: 34571942 PMCID: PMC8467961 DOI: 10.3390/cells10092293] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/24/2021] [Accepted: 08/31/2021] [Indexed: 12/26/2022] Open
Abstract
The Corona Virus Disease 2019 (COVID-19) pandemic represents an ongoing worldwide challenge. The present large study sought to understand independent and overlapping metabolic features of samples from acutely ill patients (n = 831) that tested positive (n = 543) or negative (n = 288) for COVID-19. High-throughput metabolomics analyses were complemented with antigen and enzymatic activity assays on plasma from acutely ill patients collected while in the emergency department, at admission, or during hospitalization. Lipidomics analyses were also performed on COVID-19-positive or -negative subjects with the lowest and highest body mass index (n = 60/group). Significant changes in amino acid and fatty acid/acylcarnitine metabolism emerged as highly relevant markers of disease severity, progression, and prognosis as a function of biological and clinical variables in these patients. Further, machine learning models were trained by entering all metabolomics and clinical data from half of the COVID-19 patient cohort and then tested on the other half, yielding ~78% prediction accuracy. Finally, the extensive amount of information accumulated in this large, prospective, observational study provides a foundation for mechanistic follow-up studies and data sharing opportunities, which will advance our understanding of the characteristics of the plasma metabolism in COVID-19 and other acute critical illnesses.
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Affiliation(s)
- Angelo D’Alessandro
- Department of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO 80045, USA; (J.A.R.); (F.I.C.); (F.G.); (T.N.)
| | - Tiffany Thomas
- Department of Pathology & Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; (T.T.); (J.E.V.); (K.E.H.); (C.M.); (E.A.H.); (S.L.S.); (R.O.F.)
| | - Imo J. Akpan
- Division of Hematology/Oncology, Department of Medicine, Irving Medical Center, Columbia University, New York, NY 10032, USA; (I.J.A.); (S.K.); (A.Z.W.)
| | - Julie A. Reisz
- Department of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO 80045, USA; (J.A.R.); (F.I.C.); (F.G.); (T.N.)
| | - Francesca I. Cendali
- Department of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO 80045, USA; (J.A.R.); (F.I.C.); (F.G.); (T.N.)
| | - Fabia Gamboni
- Department of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO 80045, USA; (J.A.R.); (F.I.C.); (F.G.); (T.N.)
| | - Travis Nemkov
- Department of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO 80045, USA; (J.A.R.); (F.I.C.); (F.G.); (T.N.)
| | - Kiruphagaran Thangaraju
- Center for Blood Oxygen Transport, Department of Pathology, Department of Pediatrics, University of Maryland, Baltimore, MD 21201, USA; (K.T.); (U.K.); (P.W.B.)
| | - Upendra Katneni
- Center for Blood Oxygen Transport, Department of Pathology, Department of Pediatrics, University of Maryland, Baltimore, MD 21201, USA; (K.T.); (U.K.); (P.W.B.)
| | - Kenichi Tanaka
- Department of Anesthesiology, University of Maryland, Baltimore, MD 21201, USA;
- Department of Anesthesiology, University of Oklahoma College of Medicine, Oklahoma City, OK 73126-0901, USA
| | - Stacie Kahn
- Division of Hematology/Oncology, Department of Medicine, Irving Medical Center, Columbia University, New York, NY 10032, USA; (I.J.A.); (S.K.); (A.Z.W.)
| | - Alexander Z. Wei
- Division of Hematology/Oncology, Department of Medicine, Irving Medical Center, Columbia University, New York, NY 10032, USA; (I.J.A.); (S.K.); (A.Z.W.)
| | - Jacob E. Valk
- Department of Pathology & Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; (T.T.); (J.E.V.); (K.E.H.); (C.M.); (E.A.H.); (S.L.S.); (R.O.F.)
| | - Krystalyn E. Hudson
- Department of Pathology & Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; (T.T.); (J.E.V.); (K.E.H.); (C.M.); (E.A.H.); (S.L.S.); (R.O.F.)
| | - David Roh
- Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA;
| | - Chiara Moriconi
- Department of Pathology & Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; (T.T.); (J.E.V.); (K.E.H.); (C.M.); (E.A.H.); (S.L.S.); (R.O.F.)
| | - James C. Zimring
- Department of Pathology, University of Virginia, Charlottesville, VA 22903, USA;
| | - Eldad A. Hod
- Department of Pathology & Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; (T.T.); (J.E.V.); (K.E.H.); (C.M.); (E.A.H.); (S.L.S.); (R.O.F.)
| | - Steven L. Spitalnik
- Department of Pathology & Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; (T.T.); (J.E.V.); (K.E.H.); (C.M.); (E.A.H.); (S.L.S.); (R.O.F.)
| | - Paul W. Buehler
- Center for Blood Oxygen Transport, Department of Pathology, Department of Pediatrics, University of Maryland, Baltimore, MD 21201, USA; (K.T.); (U.K.); (P.W.B.)
| | - Richard O. Francis
- Department of Pathology & Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; (T.T.); (J.E.V.); (K.E.H.); (C.M.); (E.A.H.); (S.L.S.); (R.O.F.)
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21
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Jayaswal SK, Singh S, Malik PS, Venigalla SK, Gupta P, Samaga SN, Hota RN, Bhatia SS, Gupta I. Detrimental effect of diabetes and hypertension on the severity and mortality of COVID-19 infection: A multi-center case-control study from India. Diabetes Metab Syndr 2021; 15:102248. [PMID: 34412000 PMCID: PMC8364674 DOI: 10.1016/j.dsx.2021.102248] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/11/2021] [Accepted: 08/12/2021] [Indexed: 02/06/2023]
Abstract
AIMS This study aims to find a quantitative association between the presence of co-existing diabetes mellitus (DM) and/or hypertension (HTN) with COVID-19 infection severity and mortality. METHODS A total of 813 patients with a positive COVID-19 were included. A case-control design was used to dissect the association between DM and HTN with COVID-19 severity and mortality. RESULTS According to MOHFW guidelines, 535 (65.7%) patients had mild, 160 (19.7%) patients had moderate, and 118 (14.5%) patients had severe disease outcomes including mortality in 52 patients. Age, Neutrophil%, and Diabetes status were significantly associated with severe COVID-19 infection. After adjusting for age, patients with diabetes were 2.46 times more likely to have severe disease (Chi-squared = 18.89, p-value<0.0001) and 2.11 times more likely to have a fatal outcome (Chi-squared = 6.04, p-value = 0.014). However, we did not find evidence for Hypertension modifying the COVID-19 outcomes in Diabetic patients. CONCLUSION COVID-19 severity and mortality both were significantly associated with the status of DM and its risk may not be modified by the presence of HTN.
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Affiliation(s)
- Sneha Kumar Jayaswal
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, Hauz Khas, New Delhi, 110016, India.
| | - Shalendra Singh
- Department of Anesthesiology and Critical Care, Armed Forces Medical College, Pune, 411040, Maharashtra, India.
| | - Prabhat Singh Malik
- Department of Medical Oncology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 10029, India.
| | - Sri Krishna Venigalla
- Department of Anesthesiology and Critical Care, Armed Forces Medical College, Pune, 411040, Maharashtra, India.
| | - Pallavi Gupta
- Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, Bhauri, Madhya Pradesh, 462066, India.
| | - Shreyas N Samaga
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, Hauz Khas, New Delhi, 110016, India.
| | - Rabi Narayan Hota
- Department of Anesthesiology and Critical Care, Armed Forces Medical College, Pune, 411040, Maharashtra, India.
| | | | - Ishaan Gupta
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, Hauz Khas, New Delhi, 110016, India.
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22
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Zanza C, Tassi MF, Romenskaya T, Piccolella F, Abenavoli L, Franceschi F, Piccioni A, Ojetti V, Saviano A, Canonico B, Montanari M, Zamai L, Artico M, Robba C, Racca F, Longhitano Y. Lock, Stock and Barrel: Role of Renin-Angiotensin-Aldosterone System in Coronavirus Disease 2019. Cells 2021; 10:1752. [PMID: 34359922 PMCID: PMC8306543 DOI: 10.3390/cells10071752] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/21/2021] [Accepted: 07/09/2021] [Indexed: 02/06/2023] Open
Abstract
Since the end of 2019, the medical-scientific community has been facing a terrible pandemic caused by a new airborne viral agent known as SARS-CoV2. Already in the early stages of the pandemic, following the discovery that the virus uses the ACE2 cell receptor as a molecular target to infect the cells of our body, it was hypothesized that the renin-angiotensin-aldosterone system was involved in the pathogenesis of the disease. Since then, numerous studies have been published on the subject, but the exact role of the renin-angiotensin-aldosterone system in the pathogenesis of COVID-19 is still a matter of debate. RAAS represents an important protagonist in the pathogenesis of COVID-19, providing the virus with the receptor of entry into host cells and determining its organotropism. Furthermore, following infection, the virus is able to cause an increase in plasma ACE2 activity, compromising the normal function of the RAAS. This dysfunction could contribute to the establishment of the thrombo-inflammatory state characteristic of severe forms of COVID-19. Drugs targeting RAAS represent promising therapeutic options for COVID-19 sufferers.
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Affiliation(s)
- Christian Zanza
- Department of Emergency Medicine, Foundation of Policlinico Agostino Gemelli-IRCCS, Catholic University of Sacred Heart, 00168 Rome, Italy; (F.F.); (A.P.); (V.O.); (A.S.)
- Department of Anesthesia and Critical Care, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy; (T.R.); (F.P.); (F.R.); (Y.L.)
- Foundation Ospedale Alba-Bra and Department of Anesthesia, Critical Care and Emergency Medicine, Pietro and Michele Ferrero Hospital, 12051 Verduno, Italy
| | - Michele Fidel Tassi
- Department of Emergency Medicine, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy;
| | - Tatsiana Romenskaya
- Department of Anesthesia and Critical Care, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy; (T.R.); (F.P.); (F.R.); (Y.L.)
| | - Fabio Piccolella
- Department of Anesthesia and Critical Care, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy; (T.R.); (F.P.); (F.R.); (Y.L.)
| | - Ludovico Abenavoli
- Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy;
| | - Francesco Franceschi
- Department of Emergency Medicine, Foundation of Policlinico Agostino Gemelli-IRCCS, Catholic University of Sacred Heart, 00168 Rome, Italy; (F.F.); (A.P.); (V.O.); (A.S.)
| | - Andrea Piccioni
- Department of Emergency Medicine, Foundation of Policlinico Agostino Gemelli-IRCCS, Catholic University of Sacred Heart, 00168 Rome, Italy; (F.F.); (A.P.); (V.O.); (A.S.)
| | - Veronica Ojetti
- Department of Emergency Medicine, Foundation of Policlinico Agostino Gemelli-IRCCS, Catholic University of Sacred Heart, 00168 Rome, Italy; (F.F.); (A.P.); (V.O.); (A.S.)
| | - Angela Saviano
- Department of Emergency Medicine, Foundation of Policlinico Agostino Gemelli-IRCCS, Catholic University of Sacred Heart, 00168 Rome, Italy; (F.F.); (A.P.); (V.O.); (A.S.)
| | - Barbara Canonico
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy; (B.C.); (M.M.); (L.Z.)
| | - Mariele Montanari
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy; (B.C.); (M.M.); (L.Z.)
| | - Loris Zamai
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy; (B.C.); (M.M.); (L.Z.)
- National Institute for Nuclear Physics (INFN)-Gran Sasso National Laboratory (LNGS), 67100 Assergi L’Aquila, Italy
| | - Marco Artico
- Department of Sensory Organs, Sapienza University of Rome, 00185 Rome, Italy;
| | - Chiara Robba
- Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, 16132 Genoa, Italy;
| | - Fabrizio Racca
- Department of Anesthesia and Critical Care, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy; (T.R.); (F.P.); (F.R.); (Y.L.)
| | - Yaroslava Longhitano
- Department of Anesthesia and Critical Care, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy; (T.R.); (F.P.); (F.R.); (Y.L.)
- Foundation Ospedale Alba-Bra and Department of Anesthesia, Critical Care and Emergency Medicine, Pietro and Michele Ferrero Hospital, 12051 Verduno, Italy
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23
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Sušić L, Maričić L, Vincelj J, Vadoci M, Sušić T. Understanding the association between endothelial dysfunction and left ventricle diastolic dysfunction in development of coronary artery disease and heart failure. ACTA BIO-MEDICA : ATENEI PARMENSIS 2021; 92:e2021204. [PMID: 34212905 PMCID: PMC8343725 DOI: 10.23750/abm.v92i3.11495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 04/07/2021] [Indexed: 11/23/2022]
Abstract
Cardiovascular diseases (CVDs) have been the most common cause of death worldwide for decades. Until recently the most affected patients were middle-aged and elderly, predominantly men, with more frequent ST elevation myocardial infarction (STEMI) caused by obstructive coronary artery disease (CAD). However, in the last two decades we have noticed an increased incidence of ischemia with non-obstructive coronary arteries (INOCA), which includes myocardial infarction with non-obstructive coronary arteries (MINOCA) and non-myocardial infarction syndromes, such as microvascular and vasospastic angina, conditions that have been particularly pronounced in women and young adults - the population we considered low-risky till than. Therefore, it has become apparent that for this group of patients conventional methods of assessing the risk of future cardiovascular (CV) events are no longer specific and sensitive enough. Heart failure with preserved ejection fraction (HFpEF) is another disease, the incidence of which has been rising rapidly during last two decades, and predominantly affects elderly population. Although the etiology and pathophysiology of INOCA and HFpEF are complex and not fully understood, there is no doubt that the underlying cause of both conditions is endothelial dysfunction (ED) which further promotes the development of left ventricular diastolic dysfunction (LVDD). Plasma biomarkers of ED, as well as natriuretic peptides (NPs), have been intensively investigated recently, and some of them have great potential for early detection and better assessment of CV risk in the future.
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Affiliation(s)
- Livija Sušić
- Department of Internal Medicine, Osijek-Baranja County Health Center, Osijek, Croatia and Josip Juraj Strossmayer University of Osijek, Faculty of Medicine, Osijek, Croatia.
| | - Lana Maričić
- Cardiology, University Hospital Centre Osijek, Osijek, Croatia; Josip Juraj Strossmayer University of Osijek, Faculty of Medicine, Osijek, Croatia.
| | - Josip Vincelj
- Josip Juraj Strossmayer University of Osijek, Faculty of Medicine, Osijek, Croatia.
| | - Milena Vadoci
- 1Department of Internal Medicine, Osijek-Baranja County Health Center, Osijek, Croatia.
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24
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Abstract
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associates with a considerable high rate of mortality and represents currently the most important concern in global health. The risk of more severe clinical manifestation of COVID-19 is higher in males and steeply raised with age but also increased by the presence of chronic comorbidities. Among the latter, early reports suggested that arterial hypertension associates with higher susceptibility to SARS-CoV-2 infection, more severe course and increased COVID-19-related deaths. Furthermore, experimental studies suggested that key pathophysiological hypertension mechanisms, such as activation of the renin-angiotensin system (RAS), may play a role in COVID-19. In fact, ACE2 (angiotensin-converting-enzyme 2) is the pivotal receptor for SARS-CoV-2 to enter host cells and provides thus a link between COVID-19 and RAS. It was thus anticipated that drugs modulating the RAS including an upregulation of ACE2 may increase the risk for infection with SARS-CoV-2 and poorer outcomes in COVID-19. Since the use of RAS-blockers, ACE inhibitors or angiotensin receptor blockers, represents the backbone of recommended antihypertensive therapy and intense debate about their use in the COVID-19 pandemic has developed. Currently, a direct role of hypertension, independent of age and other comorbidities, as a risk factor for the SARS-COV-2 infection and COVID-19 outcome, particularly death, has not been established. Similarly, both current experimental and clinical studies do not support an unfavorable effect of RAS-blockers or other classes of first line blood pressure lowering drugs in COVID-19. Here, we review available data on the role of hypertension and its management on COVID-19. Conversely, some aspects as to how the COVID-19 affects hypertension management and impacts on future developments are also briefly discussed. COVID-19 has and continues to proof the critical importance of hypertension research to address questions that are important for global health.
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Affiliation(s)
- Carmine Savoia
- Clinical and Molecular Medicine Department, Division of Cardiology, Sant' Andrea Hospital, Sapienza University of Rome, Rome, Italy (C.S., M.V.)
| | - Massimo Volpe
- Clinical and Molecular Medicine Department, Division of Cardiology, Sant' Andrea Hospital, Sapienza University of Rome, Rome, Italy (C.S., M.V.)
| | - Reinhold Kreutz
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Klinische Pharmakologie und Toxikologie (R.K.)
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25
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Mone P, Gambardella J, Wang X, Jankauskas SS, Matarese A, Santulli G. miR-24 targets SARS-CoV-2 co-factor Neuropilin-1 in human brain microvascular endothelial cells: Insights for COVID-19 neurological manifestations. RESEARCH SQUARE 2021:rs.3.rs-192099. [PMID: 33564755 PMCID: PMC7872362 DOI: 10.21203/rs.3.rs-192099/v1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Neuropilin-1 is a transmembrane glycoprotein that has been implicated in several processes including angiogenesis and immunity. Recent evidence has also shown that it is implied in the cellular internalization of the severe acute respiratory syndrome coronavirus (SARS-CoV-2), which causes the coronavirus disease 2019 (COVID-19). We hypothesized that specific microRNAs can target Neuropilin-1. By combining bioinformatic and functional approaches, we identified miR-24 as a regulator of Neuropilin-1 transcription. Since Neuropilin-1 has been shown to play a key role in the endothelium-mediated regulation of the blood-brain barrier, we validated miR-24 as a functional modulator of Neuropilin-1 in human brain microvascular endothelial cells (hBMECs), which are the most suitable cell line for an in vitro bloodâ€"brain barrier model.
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26
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Mone P, Gambardella J, Wang X, Jankauskas SS, Matarese A, Santulli G. miR-24 Targets the Transmembrane Glycoprotein Neuropilin-1 in Human Brain Microvascular Endothelial Cells. Noncoding RNA 2021; 7:9. [PMID: 33540664 PMCID: PMC7931075 DOI: 10.3390/ncrna7010009] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/29/2021] [Accepted: 01/31/2021] [Indexed: 02/06/2023] Open
Abstract
Neuropilin-1 is a transmembrane glycoprotein that has been implicated in several processes including angiogenesis and immunity. Recent evidence has also shown that it is implied in the cellular internalization of the severe acute respiratory syndrome coronavirus (SARS-CoV-2), which causes the coronavirus disease 2019 (COVID-19). We hypothesized that specific microRNAs can target Neuropilin-1. By combining bioinformatic and functional approaches, we identified miR-24 as a regulator of Neuropilin-1 transcription. Since Neuropilin-1 has been shown to play a key role in the endothelium-mediated regulation of the blood-brain barrier, we validated miR-24 as a functional modulator of Neuropilin-1 in human brain microvascular endothelial cells (hBMECs), which are the most suitable cell line for an in vitro blood-brain barrier model.
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Affiliation(s)
- Pasquale Mone
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA; (P.M.); (J.G.); (X.W.); (S.S.J.)
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80100 Naples, Italy
| | - Jessica Gambardella
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA; (P.M.); (J.G.); (X.W.); (S.S.J.)
- Department of Molecular Pharmacology, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Fleischer Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine, New York, NY 10461, USA
- Department of Advanced Biomedical Science, “Federico II” University, and International Translational Research and Medical Education (ITME), 80131 Naples, Italy
| | - Xujun Wang
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA; (P.M.); (J.G.); (X.W.); (S.S.J.)
- Department of Molecular Pharmacology, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Fleischer Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Stanislovas S. Jankauskas
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA; (P.M.); (J.G.); (X.W.); (S.S.J.)
- Department of Molecular Pharmacology, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Fleischer Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine, New York, NY 10461, USA
| | | | - Gaetano Santulli
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA; (P.M.); (J.G.); (X.W.); (S.S.J.)
- Department of Molecular Pharmacology, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Fleischer Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine, New York, NY 10461, USA
- Department of Advanced Biomedical Science, “Federico II” University, and International Translational Research and Medical Education (ITME), 80131 Naples, Italy
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