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Han H, Kim JE, Lee HJ. Effect of apigetrin in pseudo-SARS-CoV-2-induced inflammatory and pulmonary fibrosis in vitro model. Sci Rep 2024; 14:14545. [PMID: 38914619 PMCID: PMC11196261 DOI: 10.1038/s41598-024-65447-w] [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: 04/09/2024] [Accepted: 06/20/2024] [Indexed: 06/26/2024] Open
Abstract
SARS-CoV-2 has become a global public health problem. Acute respiratory distress syndrome (ARDS) is the leading cause of death due to the SARS-CoV-2 infection. Pulmonary fibrosis (PF) is a severe and frequently reported COVID-19 sequela. In this study, an in vitro model of ARDS and PF caused by SARS-CoV-2 was established in MH-S, THP-1, and MRC-5 cells using pseudo-SARS-CoV-2 (PSCV). Expression of proinflammatory cytokines (IL-6, IL-1β, and TNF-α) and HIF-1α was increased in PSCV-infected MH-S and THP-1 cells, ARDS model, consistent with other profiling data in SARS-CoV-2-infected patients have been reported. Hypoxia-inducible factor-1 alpha (HIF-1α) siRNA and cobalt chloride were tested using this in vitro model. HIF-1α knockdown reduces inflammation caused by PSCV infection in MH-S and THP-1 cells and lowers elevated levels of CTGF, COLA1, and α-SMA in MRC-5 cells exposed to CPMSCV. Furthermore, apigetrin, a glycoside bioactive dietary flavonoid derived from several plants, including Crataegus pinnatifida, which is reported to be a HIF-1α inhibitor, was tested in this in vitro model. Apigetrin significantly reduced the increased inflammatory cytokine (IL-6, IL-1β, and TNF-α) expression and secretion by PSCV in MH-S and THP-1 cells. Apigetrin inhibited the binding of the SARS-CoV-2 spike protein RBD to the ACE2 protein. An in vitro model of PF induced by SARS-CoV-2 was produced using a conditioned medium of THP-1 and MH-S cells that were PSCV-infected (CMPSCV) into MRC-5 cells. In a PF model, CMPSCV treatment of THP-1 and MH-S cells increased cell growth, migration, and collagen synthesis in MRC-5 cells. In contrast, apigetrin suppressed the increase in cell growth, migration, and collagen synthesis induced by CMPSCV in THP-1 and MH-S MRC-5 cells. Also, compared to control, fibrosis-related proteins (CTGF, COLA1, α-SMA, and HIF-1α) levels were over two-fold higher in CMPSV-treated MRC-5 cells. Apigetrin decreased protein levels in CMPSCV-treated MRC-5 cells. Thus, our data suggest that hypoxia-inducible factor-1 alpha (HIF-1α) might be a novel target for SARS-CoV-2 sequela therapies and apigetrin, representative of HIF-1alpha inhibitor, exerts anti-inflammatory and PF effects in PSCV-treated MH-S, THP-1, and CMPVSC-treated MRC-5 cells. These findings indicate that HIF-1α inhibition and apigetrin would have a potential value in controlling SARS-CoV-2-related diseases.
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Affiliation(s)
- Hengmin Han
- Department of Cancer Preventive Material Development, Graduate School, College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Korea
| | - Jung-Eun Kim
- Department of Science in Korean Medicine, Graduate School, College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Korea
| | - Hyo-Jeong Lee
- Department of Cancer Preventive Material Development, Graduate School, College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Korea.
- Department of Science in Korean Medicine, Graduate School, College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Korea.
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Dimnjaković J, Buble T, Ivanko P, Poljičanin T, Karanović Štambuk S, Brborović H, Brborović O. Association of anti-diabetic drugs and covid-19 outcomes in patients with diabetes mellitus type 2 and chronic kidney disease: Nationwide registry analysis. PLoS One 2024; 19:e0301056. [PMID: 38536830 PMCID: PMC10971752 DOI: 10.1371/journal.pone.0301056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 03/08/2024] [Indexed: 01/03/2025] Open
Abstract
INTRODUCTION Patients with diabetes mellitus type 2 and chronic kidney disease (T2DM-CKD) have a 5 times higher risk of developing severe SARS-CoV-2 infection than those without these 2 diseases. The goal of this study is to provide information on T2DM-CKD and COVID-19 outcomes, with an emphasis on the association with anti-diabetic medications. METHODOLOGY Study is designed as a retrospective cohort analysis covering the years 2020 and 2021. Data from the National Diabetes Registry (CroDiab) were linked to hospital data, primary healthcare data, Causes of Death Registry data, the SARS-CoV-2 vaccination database, and the SARS-CoV-2 test results database. Study outcomes were cumulative incidence of SARS-CoV-2 positivity, COVID-19 hospitalizations, and COVID-19 deaths. For outcome predictors, logistic regression models were developed. RESULTS Of 231 796 patients with diabetes mellitus type 2 in the database, 7 539 were T2DM-CKD (3.25%). The 2-year cumulative incidences of all three studies' outcomes were higher in T2DM-CKD than in diabetes patients without CKD (positivity 18.1% vs. 14.4%; hospitalization 9.7% vs. 4.2%; death 3.3% vs. 1.1%, all p<0.001). For COVID-19 hospitalization, protective factors were SGLT-2 inhibitors use (OR 0.430; 95%CI 0.257-0.719) and metformin use (OR 0.769; 95% CI 0.643-0.920), risk factors were insulin use (1.411; 95%CI 1.167-1.706) and sulfonylureas use (OR 1.226; 95% CI 1.027-1.464). For SARS-CoV-2 positivity protective factors were SGLT-2 inhibitors (0.607; 95% CI 0.448-0.823), repaglinide use (OR 0.765; 95% CI 0.593-0.986) and metformin use (OR 0.857; 95% CI 0.770-0.994). DPP-4 inhibitors showed a non-significant decrease in risk for COVID-19 death (OR 0.761; 95% CI 0.568-1.019). CONCLUSION T2DM-CKD are heavily burdened by COVID-19 disease. Our results suggest no association between antidiabetic drugs and COVID-19 death outcome while SGLT-2 and metformin show to be protective against COVID-19 hospitalization and infection, repaglinide against infection, and insulin and sulfonylureas show to be risk factors for COVID-19 hospitalization and infection. Further research in T2DM-CKD is needed.
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Affiliation(s)
- Jelena Dimnjaković
- Division for Health Informatics and Biostatistics, Department for Biostatistics, Croatian Institute of Public Health, Zagreb, Croatia
| | - Tamara Buble
- Division for Health Informatics and Biostatistics, Department for Biostatistics, Croatian Institute of Public Health, Zagreb, Croatia
| | - Pero Ivanko
- Division for Health Informatics and Biostatistics, Department for Biostatistics, Croatian Institute of Public Health, Zagreb, Croatia
| | | | - Sandra Karanović Štambuk
- Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, Zagreb, Croatia
- Department of Internal Medicine, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Hana Brborović
- Department of Environmental and Occupational Health and Sports Medicine, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ognjen Brborović
- Department of Social Medicine and Organization of Health Care, School of Medicine, University of Zagreb, Zagreb, Croatia
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Gonikman D, Kustovs D. Antidiabetic Drug Efficacy in Reduction of Mortality during the COVID-19 Pandemic. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1810. [PMID: 37893528 PMCID: PMC10608676 DOI: 10.3390/medicina59101810] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/06/2023] [Accepted: 10/09/2023] [Indexed: 10/29/2023]
Abstract
Background and Objectives: The COVID-19 pandemic caused by the Coronavirus SARS-CoV-2 is a complex challenge for the existing scientific and medical landscape. It is an ongoing public health crisis, with over 245,373,039 confirmed cases globally, including 4,979,421 deaths as of 29 October 2021. Exploring molecular mechanisms correlated with the disease's severity has demonstrated significant factors of immune compromise, noted in diabetic patients with SARS-CoV-2 infections. Among diabetics, the altered function of the immune system allows for better penetration of the virus into epithelial cells, increased viral binding affinity due to hyperglycemia, reduced T cell function, decreased viral clearance, high risks of cytokine storm, and hyper-inflammatory responses, altogether increasing the susceptibility of these patients to an extreme COVID-19 disease course. Materials and Methods: This research involved a systematic literature search among various databases comprising PubMed and Google Scholar in determining credible studies about the effects of antidiabetic drugs on the high mortality rates among diabetic patients infected with COVID-19. The primary search found 103 results. Duplicated results, non-pertinent articles, and the unavailability of full text were excluded. Finally, we included 74 articles in our review. The inclusion criteria included articles published during 2020-2023, studies that reported a low risk of bias, and articles published in English. Exclusion criteria included studies published in non-peer-reviewed sources, such as conference abstracts, thesis papers, or non-academic publications. Results: Among the studied anti-diabetic drugs, Metformin, the Glucagon-like peptide 1 receptor agonist (GLP-1RA), and Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) have demonstrated decreased mortality rates among diabetic patients infected with COVID-19. Insulin and Dipeptidyl peptidase 4 inhibitors (DPP-4i) have demonstrated increased mortality rates, while Sulfonylureas, Thiazolidinedione (TZD), and Alpha-glucosidase inhibitors (AGI) have demonstrated mortality-neutral results.
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Affiliation(s)
- Daniel Gonikman
- Student of Faculty of Medicine, Riga Stradins University, LV-1007 Riga, Latvia
| | - Dmitrijs Kustovs
- Department of Pharmacology, Riga Stradins University, LV-1007 Riga, Latvia;
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Popovic DS, Papanas N, Koufakis T, Kotsa K, Mahmeed WA, Al-Rasadi K, Al-Alawi K, Banach M, Banerjee Y, Ceriello A, Cesur M, Cosentino F, Firenze A, Galia M, Goh SY, Janez A, Kalra S, Kempler P, Kapoor N, Lessan N, Lotufo P, Rizvi AA, Sahebkar A, Santos RD, Stoian AP, Toth PP, Viswanathan V, Rizzo M. Glucometabolic Perturbations in Type 2 Diabetes Mellitus and Coronavirus Disease 2019: Causes, Consequences, and How to Counter Them Using Novel Antidiabetic Drugs - The CAPISCO International Expert Panel. Exp Clin Endocrinol Diabetes 2023; 131:260-267. [PMID: 36693416 DOI: 10.1055/a-2019-1111] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The growing amount of evidence suggests the existence of a bidirectional relation between coronavirus disease 2019 (COVID-19) and type 2 diabetes mellitus (T2DM), as these two conditions exacerbate each other, causing a significant healthcare and socioeconomic burden. The alterations in innate and adaptive cellular immunity, adipose tissue, alveolar and endothelial dysfunction, hypercoagulation, the propensity to an increased viral load, and chronic diabetic complications are all associated with glucometabolic perturbations of T2DM patients that predispose them to severe forms of COVID-19 and mortality. Severe acute respiratory syndrome coronavirus 2 infection negatively impacts glucose homeostasis due to its effects on insulin sensitivity and β-cell function, further aggravating the preexisting glucometabolic perturbations in individuals with T2DM. Thus, the most effective ways are urgently needed for countering these glucometabolic disturbances occurring during acute COVID-19 illness in T2DM patients. The novel classes of antidiabetic medications (dipeptidyl peptidase 4 inhibitors (DPP-4is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are considered candidate drugs for this purpose. This review article summarizes current knowledge regarding glucometabolic disturbances during acute COVID-19 illness in T2DM patients and the potential ways to tackle them using novel antidiabetic medications. Recent observational data suggest that preadmission use of GLP-1 RAs and SGLT-2is are associated with decreased patient mortality, while DPP-4is is associated with increased in-hospital mortality of T2DM patients with COVID-19. Although these results provide further evidence for the widespread use of these two classes of medications in this COVID-19 era, dedicated randomized controlled trials analyzing the effects of in-hospital use of novel antidiabetic agents in T2DM patients with COVID-19 are needed.
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Affiliation(s)
- Djordje S Popovic
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre of Vojvodina, Novi Sad, Serbia
- Medical Faculty, University of Novi Sad, Novi Sad, Serbia
| | - Nikolaos Papanas
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece
| | - Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Wael Al Mahmeed
- Heart and Vascular Institute, Cleveland Clinic, Abu Dhabi, United Arab Emirates
| | | | - Kamila Al-Alawi
- Department of Training and Studies, Royal Hospital, Ministry of Health, Muscat, Oman
| | - Maciej Banach
- Department of Preventive Cardiology and Lipidology, Medical University of Lodz (MUL), Poland
- Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
- Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland
| | - Yajnavalka Banerjee
- Department of Biochemistry, Mohammed Bin Rashid University, Dubai, United Arab Emirates
| | | | - Mustafa Cesur
- Clinic of Endocrinology, Ankara Güven Hospital, Ankara, Turkey
| | - Francesco Cosentino
- Unit of Cardiology, Karolinska Institute and Karolinska University Hospital, University of Stockholm, Sweden
| | - Alberto Firenze
- Unit of Research and International Cooperation, University Hospital of Palermo, Italy
| | - Massimo Galia
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (Bind), University of Palermo, Italy
| | - Su-Yen Goh
- Department of Endocrinology, Singapore General Hospital, Singapore
| | - Andrej Janez
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, Slovenia
| | - Sanjay Kalra
- Department of Endocrinology, Bharti Hospital, Karnal, India
| | - Peter Kempler
- Department of Medicine and Oncology, Semmelweis University, Budapest, Hungary
| | - Nitin Kapoor
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, India
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Nader Lessan
- The Research Institute, Imperial College London Diabetes Centre, Abu Dhabi, United Arab Emirates
| | - Paulo Lotufo
- Center for Clinical and Epidemiological Research, University Hospital, University of São Paulo, Brazil
| | - Ali A Rizvi
- Department of Medicine, University of Central Florida College of Medicine, Orlando, Florida, USA
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Raul D Santos
- Heart Institute (InCor) University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil
- Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Anca Pantea Stoian
- Faculty of Medicine, Diabetes, Nutrition and Metabolic Diseases, Carol Davila University, Bucharest, Romania
| | - Peter P Toth
- Cicarrone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Manfredi Rizzo
- Department of Biochemistry, Mohammed Bin Rashid University, Dubai, United Arab Emirates
- Faculty of Medicine, Diabetes, Nutrition and Metabolic Diseases, Carol Davila University, Bucharest, Romania
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (Promise), School of Medicine, University of Palermo, Italy
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Human Coronavirus Cell Receptors Provide Challenging Therapeutic Targets. Vaccines (Basel) 2023; 11:vaccines11010174. [PMID: 36680018 PMCID: PMC9862439 DOI: 10.3390/vaccines11010174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/06/2023] [Accepted: 01/11/2023] [Indexed: 01/15/2023] Open
Abstract
Coronaviruses interact with protein or carbohydrate receptors through their spike proteins to infect cells. Even if the known protein receptors for these viruses have no evolutionary relationships, they do share ontological commonalities that the virus might leverage to exacerbate the pathophysiology. ANPEP/CD13, DPP IV/CD26, and ACE2 are the three protein receptors that are known to be exploited by several human coronaviruses. These receptors are moonlighting enzymes involved in several physiological processes such as digestion, metabolism, and blood pressure regulation; moreover, the three proteins are expressed in kidney, intestine, endothelium, and other tissues/cell types. Here, we spot the commonalities between the three enzymes, the physiological functions of the enzymes are outlined, and how blocking either enzyme results in systemic deregulations and multi-organ failures via viral infection or therapeutic interventions is addressed. It can be difficult to pinpoint any coronavirus as the target when creating a medication to fight them, due to the multiple processes that receptors are linked to and their extensive expression.
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Krumpolec P, Kodada D, Nyáriová N, Repiská V, Minárik G. COVID-19 and Diabetes Mellitus: Mutual Interplay of Two Diseases. Curr Diabetes Rev 2023; 19:e130922208761. [PMID: 36100987 DOI: 10.2174/1573399819666220913113146] [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: 05/20/2022] [Revised: 07/16/2022] [Accepted: 08/09/2022] [Indexed: 11/22/2022]
Abstract
Currently, when the world is fighting against the rapidly spreading pandemic of COVID-19, the silent epidemic of diabetes should not be set aside. In comparison, while COVID- 19 led to about 6 million deaths in 2021, diabetes caused 6.7 million deaths in the same year. Diabetes mellitus is a serious risk factor for worse outcomes in COVID-19 patients. Moreover, it seems that there is a bidirectional relationship between pre-existing diabetes pandemic and the rapidly spreading COVID-19 pandemic. In this article, we summarize mechanisms by which SARS-CoV-2 infects the host cell and discuss the bidirectional relationship between diabetes and COVID-19. We also focus on clinical variables in which diabetic patients differ from non-diabetic patients and which could have promising predictive value for the course and outcome of diabetic COVID-19 patients' therapy management.
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Affiliation(s)
| | - Dominik Kodada
- Medirex Group Academy n.p.o., Novozamocka 67, Nitra, Slovakia
- Faculty of Medicine, Department of Clinical Biology, Genetics and Clinical Genetics, Comenius University in Bratislava, Sasinkova 4, Bratislava, Slovakia
| | - Nikola Nyáriová
- Medirex Group Academy n.p.o., Novozamocka 67, Nitra, Slovakia
- Faculty of Medicine, Department of Clinical Biology, Genetics and Clinical Genetics, Comenius University in Bratislava, Sasinkova 4, Bratislava, Slovakia
| | - Vanda Repiská
- Faculty of Medicine, Department of Clinical Biology, Genetics and Clinical Genetics, Comenius University in Bratislava, Sasinkova 4, Bratislava, Slovakia
| | - Gabriel Minárik
- Medirex Group Academy n.p.o., Novozamocka 67, Nitra, Slovakia
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de Matos PH, da Silva TP, Mansano AB, Gancedo NC, Tonin FS, Pelloso FC, Petruco MV, de Melo EB, Fernandez-Llimos F, Sanches ACC, de Mello JCP, Chierrito D, de Medeiros Araújo DC. Bioactive compounds as potential angiotensin-converting enzyme II inhibitors against COVID-19: a scoping review. Inflamm Res 2022; 71:1489-1500. [PMID: 36307652 PMCID: PMC9616414 DOI: 10.1007/s00011-022-01642-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/29/2022] [Accepted: 09/10/2022] [Indexed: 11/28/2022] Open
Abstract
OBJECTIVE AND DESIGN The current study aimed to summarize the evidence of compounds contained in plant species with the ability to block the angiotensin-converting enzyme 2 (ACE-II), through a scoping review. METHODS PubMed and Scopus electronic databases were used for the systematic search and a manual search was performed RESULTS: Studies included were characterized as in silico. Among the 200 studies retrieved, 139 studies listed after the exclusion of duplicates and 74 were included for the full read. Among them, 32 studies were considered eligible for the qualitative synthesis. The most evaluated class of secondary metabolites was flavonoids with quercetin and curcumin as most actives substances and terpenes (isothymol, limonin, curcumenol, anabsinthin, and artemisinin). Other classes that were also evaluated were alkaloid, saponin, quinone, substances found in essential oils, and primary metabolites as the aminoacid L-tyrosine and the lipidic compound 2-monolinolenin. CONCLUSION This review suggests the most active substance from each class of metabolites, which presented the strongest affinity to the ACE-II receptor, what contributes as a basis for choosing compounds and directing the further experimental and clinical investigation on the applications these compounds in biotechnological and health processes as in COVID-19 pandemic.
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Affiliation(s)
- Pedro Henrique de Matos
- Centro Universitário Ingá-UNINGÁ, Rodovia PR 317, 6114. Parque Industrial, 200, Maringá,, PR, 87035-510, Brazil
| | - Thalita Prates da Silva
- Departamento de Farmácia, Universidade Estadual de Maringá, Avenida Colombo, Maringá, 5790, Brazil
| | - Amanda Benites Mansano
- Departamento de Farmácia, Universidade Estadual de Maringá, Avenida Colombo, Maringá, 5790, Brazil
| | - Naiara Cássia Gancedo
- Departamento de Farmácia, Universidade Estadual de Maringá, Avenida Colombo, Maringá, 5790, Brazil
| | - Fernanda Stumpf Tonin
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Paraná, Avenida Prefeito Lothário Meissner 632, Curitiba, Brazil
- H&TRC-Health & Technology Research Center, ESTeSL-Escola Superior de Tecnologia da Saúde, Instituto Politécnico de Lisboa, Lisbon, Portugal
| | - Fernando Castilho Pelloso
- Complexo Hospital de Clínicas, Universidade Federal Do Paraná, Rua General Carneiro, Curitiba, 181, Brazil
| | | | - Eduardo Borges de Melo
- Centro de Ciências Médicas e Farmacêuticas, Universidade Estadual do Oeste do Paraná, Rua Universitário 2069, Cascavel, Brazil
| | - Fernando Fernandez-Llimos
- Departamento de Ciências do Medicamento, Universidade do Porto, Praça Gomes Teixeira, Porto, Portugal
| | | | | | - Danielly Chierrito
- Centro Universitário Ingá-UNINGÁ, Rodovia PR 317, 6114. Parque Industrial, 200, Maringá,, PR, 87035-510, Brazil
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Carrondo MC, Moita JJ. Clinical profile of patients with type 2 diabetes after COVID-19 vaccination: A prospective study. OBESITY MEDICINE 2022; 35:100458. [PMID: 36268222 PMCID: PMC9561417 DOI: 10.1016/j.obmed.2022.100458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/23/2022] [Accepted: 10/10/2022] [Indexed: 11/17/2022]
Abstract
The purpose of this study was to characterize the clinical profile of patients with type 2 diabetes after COVID-19 vaccination. This prospective study has involved 100 adult diabetic patients followed in the primary health care. SARS-CoV-2 infection after COVID-19 vaccination was the outcome indicator.
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Affiliation(s)
- Maria Cristina Carrondo
- Polytechnic Institute of Coimbra College of Health Technology of Coimbra, Department Medical, Social, and Human Sciences, Portugal
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Jugulete G, Pacurar D, Pavelescu ML, Safta M, Gheorghe E, Borcoș B, Pavelescu C, Oros M, Merișescu M. Clinical and Evolutionary Features of SARS-CoV-2 Infection (COVID-19) in Children, a Romanian Perspective. CHILDREN (BASEL, SWITZERLAND) 2022; 9:1282. [PMID: 36138590 PMCID: PMC9497796 DOI: 10.3390/children9091282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 08/20/2022] [Accepted: 08/21/2022] [Indexed: 01/08/2023]
Abstract
Background: Given the potential for additional development to clarify a better knowledge of generally influence of COVID-19 upon the pediatric population, the clinical symptoms of SARS-CoV-2 infection in children and adolescents are still being explored. Morbidity in children is characterized by a variable clinical course. Our study’s goal was to compare clinical aspects of 230 pediatric patients who analyzed positive for SARS-CoV-2 and were hospitalized between April 2020 and March 2022. Methods: This retrospective study aimed to compare the clinical characteristics of coronavirus disease 2019, (COVID-19) in two groups of pediatric patients hospitalized in the infectious disease clinical ward IX at the National Institute for Infectious Diseases “Prof. Dr. Matei Bals,” Bucharest, Romania. Clinical characteristics of 88 patients (first group), admitted between April−December 2020 were compared with the second group of 142 children admitted between July 2021 and March 2022. Results: Of 230 children, the median age was 4.5 years, and 53.9% were male. Fever (82.17%) and sore throat (66%) were the most common initial symptoms. Rhinorrhea (42%), cough (34%) and diarrhea (41.74%), with abdominal pain (26%) were also reported in a considerable number of cases. 88 (36.21%) patients (first group) were admitted during the second wave in Romania, mostly aged <5 years old, and experienced digestive manifestations like fever (p = 0.001), and diarrhea (p = 0.004). The second group experienced different clinical signs when compared with the first group, with higher temperature and increased respiratory symptoms analogous to persons who suffer acute respiratory viral infections. The proportion in the second group increased by 23.48% from the first group, and the 0−4 age group for both groups had symptoms for a median interval of 5 days; age (0−4-years old) and length of stay were both proportionally inversely and required longer hospitalization (5 days), for the first group. During study time, the fully vaccinated children for 5−12 years old were 10%, and for 13−18 years old, 14.35% respective. We report two Pediatric Inflammatory Multisystem Syndrome (PIMS) in the second group, with favorable evolution under treatment. Comorbidities (obesity and oncological diseases) were reported in both groups and are risk factors for complications appearing (p < 0.001). All pediatric cases admitted to our clinic evolved favorably and no death was recorded. Conclusions: Clinical characteristics of pediatric patients with COVID-19 are age-related. In the first group, 85.29% of 0−4 years old children experienced digestive symptoms, whereas in the second group 83.78% underwent mild and moderate respiratory symptoms for the 5−12 age range. The potential effects of COVID-19 infection in children older than 5 years should encourage caregivers to vaccinate and improve the prognosis among pediatric patients at risk.
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Affiliation(s)
- Gheorghiță Jugulete
- Faculty of Medicine, University of Medicine and Pharmacy, “Carol Davila”, No. 37, Dionisie Lupu Street, 2nd District, 020021 Bucharest, Romania
- “Matei Balş” National Institute for Infectious Diseases, No. 1, Calistrat Grozovici Street, 2nd District, 021105 Bucharest, Romania
| | - Daniela Pacurar
- Faculty of Medicine, University of Medicine and Pharmacy, “Carol Davila”, No. 37, Dionisie Lupu Street, 2nd District, 020021 Bucharest, Romania
- Department of Pediatrics, “Grigore Alexandrescu” Emergency Clinical Hospital for Children, No. 30-32, Iancu de Hunedoara Blvd., 011743 Bucharest, Romania
| | - Mirela Luminița Pavelescu
- Faculty of Medicine, University of Medicine and Pharmacy, “Carol Davila”, No. 37, Dionisie Lupu Street, 2nd District, 020021 Bucharest, Romania
- Department of Pediatrics, “Grigore Alexandrescu” Emergency Clinical Hospital for Children, No. 30-32, Iancu de Hunedoara Blvd., 011743 Bucharest, Romania
| | - Mihaela Safta
- Faculty of Medicine, University of Medicine and Pharmacy, “Carol Davila”, No. 37, Dionisie Lupu Street, 2nd District, 020021 Bucharest, Romania
- “Matei Balş” National Institute for Infectious Diseases, No. 1, Calistrat Grozovici Street, 2nd District, 021105 Bucharest, Romania
| | - Elena Gheorghe
- “Matei Balş” National Institute for Infectious Diseases, No. 1, Calistrat Grozovici Street, 2nd District, 021105 Bucharest, Romania
| | - Bianca Borcoș
- Faculty of Medicine, University of Medicine and Pharmacy, “Carol Davila”, No. 37, Dionisie Lupu Street, 2nd District, 020021 Bucharest, Romania
- “Matei Balş” National Institute for Infectious Diseases, No. 1, Calistrat Grozovici Street, 2nd District, 021105 Bucharest, Romania
| | - Carmen Pavelescu
- Faculty of Medicine, University of Medicine and Pharmacy, “Carol Davila”, No. 37, Dionisie Lupu Street, 2nd District, 020021 Bucharest, Romania
| | - Mihaela Oros
- Ponderas Academic Hospital, No. 85A, Nicolae G. Caramfil Street, 014142 Bucharest, Romania
- Faculty of Medicine, Titu Maiorescu University, No. 67A, Gheorghe Petraşcu Street, 3rd District, 031593 Bucharest, Romania
| | - Mădălina Merișescu
- Faculty of Medicine, University of Medicine and Pharmacy, “Carol Davila”, No. 37, Dionisie Lupu Street, 2nd District, 020021 Bucharest, Romania
- “Matei Balş” National Institute for Infectious Diseases, No. 1, Calistrat Grozovici Street, 2nd District, 021105 Bucharest, Romania
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10
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Carrondo MC. Diabetic women: Inpatient mortality risk before SARS-CoV-2. OBESITY MEDICINE 2022; 32:100413. [PMID: 35480137 PMCID: PMC9023087 DOI: 10.1016/j.obmed.2022.100413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/23/2022] [Accepted: 04/05/2022] [Indexed: 11/15/2022]
Abstract
Background Type 2 diabetes mellitus is a major driver of mortality worldwide. To assess the risk factors associated with diabetes that increase in-hospital mortality. Methods A retrospective cohort study was conducted using the National Hospital Morbidity with a sample of 3904 diabetic women admitted (2018–2019) in public hospitals, in Portugal. The type of comorbidities and the severity of the main disease – type 2 diabetes mellitus – was assessed based on the International Classification of Diseases (ICD-9) and Disease Staging. Cox proportional hazard was used to assess mortality during hospitalization. Mortality rates and mortality risk were the main outcome measures. Results In a total of 3904 diabetic women three hundred and eighty-nine (10.0%) died during hospitalization. Comorbidities bacterial pneumonia and coronary artery disease contributed 73% [Hazard ratio (HR) 1.73, 95% CI 1.32–2.27] and 37% [HR 1.37, 95% CI 1.03–1.81] respectively, to the risk of mortality, as did age over 65 years and severity 3 of the main disease. Conclusions Women with advanced type 2 diabetes mellitus, advanced age, and with comorbidities such as pneumonia and coronary artery disease admitted urgently have a higher risk of mortality during hospitalization.
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11
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Trozzi F, Karki N, Song Z, Verma N, Kraka E, Zoltowski BD, Tao P. Allosteric control of ACE2 peptidase domain dynamics. Org Biomol Chem 2022; 20:3605-3618. [PMID: 35420112 PMCID: PMC9205182 DOI: 10.1039/d2ob00606e] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The Angiotensin Converting Enzyme 2 (ACE2) assists the regulation of blood pressure and is the main target of the coronaviruses responsible for SARS and COVID19. The catalytic function of ACE2 relies on the opening and closing motion of its peptidase domain (PD). In this study, we investigated the possibility of allosterically controlling the ACE2 PD functional dynamics. After confirming that ACE2 PD binding site opening-closing motion is dominant in characterizing its conformational landscape, we observed that few mutations in the viral receptor binding domain fragments were able to impart different effects on the binding site opening of ACE2 PD. This showed that binding to the solvent exposed area of ACE2 PD can effectively alter the conformational profile of the protein, and thus likely its catalytic function. Using a targeted machine learning model and relative entropy-based statistical analysis, we proposed the mechanism for the allosteric perturbation that regulates the ACE2 PD binding site dynamics at atomistic level. The key residues and the source of the allosteric regulation of ACE PD dynamics are also presented.
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Affiliation(s)
- Francesco Trozzi
- Department of Chemistry, Center for Research Computing, Center for Drug Discovery, Design, and Delivery (CD4), Southern Methodist University, Dallas, USA.
| | - Nischal Karki
- Department of Chemistry, Center for Research Computing, Center for Drug Discovery, Design, and Delivery (CD4), Southern Methodist University, Dallas, USA.
| | - Zilin Song
- Department of Chemistry, Center for Research Computing, Center for Drug Discovery, Design, and Delivery (CD4), Southern Methodist University, Dallas, USA.
| | - Niraj Verma
- Department of Chemistry, Center for Research Computing, Center for Drug Discovery, Design, and Delivery (CD4), Southern Methodist University, Dallas, USA.
| | - Elfi Kraka
- Department of Chemistry, Center for Research Computing, Center for Drug Discovery, Design, and Delivery (CD4), Southern Methodist University, Dallas, USA.
| | - Brian D Zoltowski
- Department of Chemistry, Center for Research Computing, Center for Drug Discovery, Design, and Delivery (CD4), Southern Methodist University, Dallas, USA.
| | - Peng Tao
- Department of Chemistry, Center for Research Computing, Center for Drug Discovery, Design, and Delivery (CD4), Southern Methodist University, Dallas, USA.
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12
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Approaches to the Potential Therapy of COVID-19: A General Overview from the Medicinal Chemistry Perspective. Molecules 2022; 27:molecules27030658. [PMID: 35163923 PMCID: PMC8838458 DOI: 10.3390/molecules27030658] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 01/17/2022] [Accepted: 01/19/2022] [Indexed: 02/01/2023] Open
Abstract
In spite of advances in vaccination, control of the COVID-19 pandemic will require the use of pharmacological treatments against SARS-CoV2. Their development needs to consider the existence of two phases in the disease, namely the viral infection and the inflammatory stages. The main targets for antiviral therapeutic intervention are: (a) viral proteins, including the spike (S) protein characteristic of the viral cover and the viral proteases in charge of processing the polyprotein arising from viral genome translation; (b) host proteins, such as those involved in the processes related to viral entry into the host cell and the release of the viral genome inside the cell, the elongation factor eEF1A and importins. The use of antivirals targeted at host proteins is less developed but it has the potential advantage of not being affected by mutations in the genome of the virus and therefore being active against all its variants. Regarding drugs that address the hyperinflammatory phase of the disease triggered by the so-called cytokine storm, the following strategies are particularly relevant: (a) drugs targeting JAK kinases; (b) sphingosine kinase 2 inhibitors; (c) antibodies against interleukin 6 or its receptor; (d) use of the traditional anti-inflammatory corticosteroids.
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13
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Pizzato M, Baraldi C, Boscato Sopetto G, Finozzi D, Gentile C, Gentile MD, Marconi R, Paladino D, Raoss A, Riedmiller I, Ur Rehman H, Santini A, Succetti V, Volpini L. SARS-CoV-2 and the Host Cell: A Tale of Interactions. FRONTIERS IN VIROLOGY 2022. [DOI: 10.3389/fviro.2021.815388] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The ability of a virus to spread between individuals, its replication capacity and the clinical course of the infection are macroscopic consequences of a multifaceted molecular interaction of viral components with the host cell. The heavy impact of COVID-19 on the world population, economics and sanitary systems calls for therapeutic and prophylactic solutions that require a deep characterization of the interactions occurring between virus and host cells. Unveiling how SARS-CoV-2 engages with host factors throughout its life cycle is therefore fundamental to understand the pathogenic mechanisms underlying the viral infection and to design antiviral therapies and prophylactic strategies. Two years into the SARS-CoV-2 pandemic, this review provides an overview of the interplay between SARS-CoV-2 and the host cell, with focus on the machinery and compartments pivotal for virus replication and the antiviral cellular response. Starting with the interaction with the cell surface, following the virus replicative cycle through the characterization of the entry pathways, the survival and replication in the cytoplasm, to the mechanisms of egress from the infected cell, this review unravels the complex network of interactions between SARS-CoV-2 and the host cell, highlighting the knowledge that has the potential to set the basis for the development of innovative antiviral strategies.
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14
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Wei J, Wang R, Ye H, Wang Y, Wang L, Zhang X. Effects of GLP-1 receptor agonists on arrhythmias and its subtypes in patients with type 2 diabetes: A systematic review and meta-analysis. Front Endocrinol (Lausanne) 2022; 13:910256. [PMID: 36034440 PMCID: PMC9403613 DOI: 10.3389/fendo.2022.910256] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/29/2022] [Indexed: 11/13/2022] Open
Abstract
PURPOSE An update of a systematic review and meta-analysis of the risk of arrhythmias and their subtypes in type 2 diabetic patients receiving glucagon-like peptide 1 receptor agonist (GLP-1RA) medication according to data from the Cardiovascular Outcome Trial(CVOT). METHODS Randomized controlled trials (RCT) on GLP-1RA therapy and cardiovascular outcomes in type 2 diabetes mellitus patients published in full-text journal databases such as MEDLINE (via PubMed), Embase, Clinical Trials.gov, and the Cochrane Library from establishment to March 1, 2022 were searched. We assessed the quality of individual studies by the Cochrane risk-of-bias algorithm. RevMan 5.4.1 software was use for calculating meta-analysis. RESULTS A total of 60,081 randomized participants were included in the data of these 8 GLP-1RA cardiovascular outcomes trials. Pooled analysis reported no significant effect on total arrhythmia [RR=0.96, 95% CI (0.96, 1.05), p =0.36], and its subtypes such as atrial fibrillation [RR=0.96, 95% CI (0.86, 1.07), p =0.43], atrial flutter [RR= 0.82, 95% CI (0.57, 1.19), p =0.30], atrial tachycardia [RR=0.64, 95% CI (0.20, 2.01), p =0.44)], sinoatrial node dysfunction [RR=0.74, 95% CI (0.44, 1.25), p =0.26], ventricular preterm systole [RR=1.42, 95% CI (0.62, 3.26), p =0.41], second degree AV block [RR=0.96, 95% CI (0.53, 1.72), p =0.88], complete AV block [RR=0.75, 95% CI (0.49, 1.17), p =0.21], ventricular fibrillation [RR=1.00, 95% CI (0.50, 2.02), p =1.00], ventricular tachycardia [RR=1.37, 95% CI (0.91, 2.08), p =0.13] from treatment with GLP-1RA versus placebo. However, the risk of hypoglycemia was reduced by about 30% [RR=0.70, 95% CI (0.57, 0.87), p=0.001] and the risk of pneumonia by about 25% [RR=0.85, 95% CI (0.75, 0.97), p=0.01], both statistically significant differences. CONCLUSION In type 2 diabetic patients, treatment with GLP-1RA has no significant effect on the risk of major arrhythmias but significantly reduces the risk of hypoglycemia and pneumonia.
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Affiliation(s)
- Jinjing Wei
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Ruxin Wang
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Haowen Ye
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Ying Wang
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Lihong Wang
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Jinan University, Guangzhou, China
- *Correspondence: Xiaofang Zhang, ; Lihong Wang,
| | - Xiaofang Zhang
- Department Clinical Experimental Center, First Affiliated Hospital of Jinan University, Guangzhou, China
- *Correspondence: Xiaofang Zhang, ; Lihong Wang,
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15
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Popovic DS, Papanas N, Pantea Stoian A, Rizvi AA, Janez A, Rizzo M. Use of Novel Antidiabetic Agents in Patients with Type 2 Diabetes and COVID-19: A Critical Review. Diabetes Ther 2021; 12:3037-3054. [PMID: 34699021 PMCID: PMC8546380 DOI: 10.1007/s13300-021-01170-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 10/05/2021] [Indexed: 12/12/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). The latter is a pandemic that has the potential of developing into a severe illness manifesting as systemic inflammatory response syndrome, acute respiratory distress syndrome, multi-organ involvement and shock. In addition, advanced age and male sex and certain underlying health conditions, like type 2 diabetes mellitus (T2DM), predispose to a higher risk of greater COVID-19 severity and mortality. This calls for an urgent identification of antidiabetic agents associated with more favourable COVID-19 outcomes among patients with T2DM, as well as recognition of their potential underlying mechanisms. It is crucial that individuals with T2DM be kept under very stringent glycaemic control in order to avoid developing various cardiovascular, renal and metabolic complications associated with more severe forms of COVID-19 that lead to increased mortality. The use of novel antidiabetic agents dipeptidyl peptidase 4 inhibitors (DPP4i), sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) in subjects with T2DM may have beneficial effects on COVID-19 outcomes. However, relevant studies either show inconsistent results (DPP4i) or are still too few (SGLT2i and GLP-1RAs). Further research is therefore needed to assess the impact of these agents on COVID-19 outcomes.
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Affiliation(s)
- Djordje S Popovic
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre of Vojvodina, Novi Sad, Serbia
- Medical Faculty, University of Novi Sad, Novi Sad, Serbia
| | - Nikolaos Papanas
- Diabetes Centre-Diabetic Foot Clinic, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupoli, Greece
| | - Anca Pantea Stoian
- Faculty of Medicine, Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
| | - Ali A Rizvi
- Division of Endocrinology, Metabolism, and Lipids, Emory University School of Medicine, Atlanta, GA, USA
- Division of Endocrinology, Diabetes and Metabolism, University of South Carolina School of Medicine, Columbia, SC, USA
| | - Andrej Janez
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Manfredi Rizzo
- Faculty of Medicine, Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Division of Endocrinology, Diabetes and Metabolism, University of South Carolina School of Medicine, Columbia, SC, USA
- Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
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16
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Feng F, Chen J, Zhao J, Li Y, Li M, Sun C. Killing Two Birds with One Stone by Administration of Soluble ACE2: A Promising Strategy to Treat Both Cardiovascular Diseases and SARS-CoV-2 Infection. Viruses 2021; 13:2243. [PMID: 34835049 PMCID: PMC8622942 DOI: 10.3390/v13112243] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 10/31/2021] [Accepted: 11/02/2021] [Indexed: 12/19/2022] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells mainly by the angiotensin converting enzyme 2 (ACE2) receptor, which can recognize the spike (S) protein by its extracellular domain. Previously, recombinant soluble ACE2 (sACE2) has been clinically used as a therapeutic treatment for cardiovascular diseases. Recent data demonstrated that sACE2 can also be exploited as a decoy to effectively inhibit the cell entry of SARS-CoV-2, through blocking SARS-CoV-2 binding to membrane-anchored ACE2. In this study, we summarized the current findings on the optimized sACE2-based strategies as a therapeutic agent, including Fc fusion to prolong the half-life of sACE2, deep mutagenesis to create high-affinity decoys for SARS-CoV-2, or designing the truncated functional fragments to enhance its safety, among others. Considering that COVID-19 patients are often accompanied by manifestations of cardiovascular complications, we think that administration of sACE2 in COVID-19 patients may be a promising therapeutic strategy to simultaneously treat both cardiovascular diseases and SARS-CoV-2 infection. This review would provide insights for the development of novel therapeutic agents against the COVID-19 pandemic.
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Affiliation(s)
- Fengling Feng
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (F.F.); (J.C.); (J.Z.); (Y.L.); (M.L.)
- Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
| | - Jiaoshan Chen
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (F.F.); (J.C.); (J.Z.); (Y.L.); (M.L.)
- Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
| | - Jin Zhao
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (F.F.); (J.C.); (J.Z.); (Y.L.); (M.L.)
- Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
| | - Yanjun Li
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (F.F.); (J.C.); (J.Z.); (Y.L.); (M.L.)
- Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
| | - Minchao Li
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (F.F.); (J.C.); (J.Z.); (Y.L.); (M.L.)
- Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
| | - Caijun Sun
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (F.F.); (J.C.); (J.Z.); (Y.L.); (M.L.)
- Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
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17
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Sen S, Chakraborty R, Kalita P, Pathak MP. Diabetes mellitus and COVID-19: Understanding the association in light of current evidence. World J Clin Cases 2021; 9:8327-8339. [PMID: 34754842 PMCID: PMC8554438 DOI: 10.12998/wjcc.v9.i28.8327] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 04/12/2021] [Accepted: 07/29/2021] [Indexed: 02/06/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have posed a problematic healthcare situation worldwide since December 2019. Diabetes mellitus is associated with an increased risk and severity of coronavirus disease 2019 (COVID-19). While interacting with various other risk factors, high blood sugar was found to reduce immunity and increase the replication of SARS-CoV-2. Oxidative stress and the release of pro-inflammatory cytokines are greater in diabetic individuals than in healthy people, worsening the outcome of SARS-CoV-2 infection in diabetics. Increased expression of furin and angiotensin converting enzyme 2 (ACE-2) receptor in the hyperglycemic environment may promote the entry of SARS-CoV-2 in the host cell. COVID-19 infection primarily modulates immune and inflammatory responses, and may cause a cytokine storm, resulting in possible lethal outcomes in diabetics. An experimental report suggests that ACE expressed in the pancreas and the SARS-CoV-2 virus invariably destroy β-cells which contain ACE-2 receptors and results in acute diabetes. Moreover, COVID-19 also causes hyperglycemia in an individual with diabetes which may be related to insulin resistance and destruction of β-cells during SARS-CoV-2 infection. Early observations also suggest a correlation between oral hypoglycemic agents and the risk of COVID-19. This review focused on the possible cause and mechanism involved in SARS-CoV-2 infection in diabetics and the role of antidiabetic drugs in COVID-19.
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Affiliation(s)
- Saikat Sen
- Faculty of Pharmaceutical Science, Assam down town University, Guwahati 781026, Assam, India
| | - Raja Chakraborty
- Department of Pharmaceutical Technology, School of Medical Sciences, ADAMAS University, Kolkata 700 126, West Bengal, India
| | - Pratap Kalita
- Department of Pharmacy, Pratiksha Institute of Pharmaceutical Sciences, Guwahati 781026, Assam, India
| | - Manash Pratim Pathak
- Faculty of Pharmaceutical Science, Assam down town University, Guwahati 781026, Assam, India
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18
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Hariyanto TI, Intan D, Hananto JE, Putri C, Kurniawan A. Pre-admission glucagon-like peptide-1 receptor agonist (GLP-1RA) and mortality from coronavirus disease 2019 (Covid-19): A systematic review, meta-analysis, and meta-regression. Diabetes Res Clin Pract 2021; 179:109031. [PMID: 34461139 PMCID: PMC8397482 DOI: 10.1016/j.diabres.2021.109031] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 08/20/2021] [Accepted: 08/26/2021] [Indexed: 12/13/2022]
Abstract
AIMS GLP-1RA has many beneficial properties, including anti-inflammatory, anti-obesogenic, pulmonary protective effects as well as beneficial impact on gut microbiome. However, the evidence regarding the benefit of GLP-1RA in Covid-19 patients with diabetes is still unclear. This study sought to analyze the benefit of pre-admission use of GLP-1RA in altering the mortality outcomes of coronavirus disease 2019 (Covid-19) patients with diabetes mellitus. METHODS Using specific keywords, we comprehensively searched the potential articles on PubMed, Europe PMC, and medRxiv database until June 12th, 2021. All published studies on Covid-19 and GLP-1RA were retrieved. Statistical analysis was conducted using Review Manager 5.4 and Comprehensive Meta-Analysis version 3 software. RESULTS A total of 9 studies with 19,660 diabetes mellitus patients who were infected by SARS-CoV-2 were included in the meta-analysis. Our data suggested that pre-admission use of GLP-1RA was associated with reduction in mortality rate from Covid-19 in patients with diabetes mellitus (OR 0.53; 95 %CI: 0.43-0.66, p < 0.00001, I2 = 0%, random-effect modelling). Further analysis showed that the associations were not influenced by age (p = 0.213), gender (p = 0.421), hypertension (p = 0.131), cardiovascular disease (p = 0.293), nor the use of metformin (p = 0.189) and insulin (p = 0.117). CONCLUSIONS Our study suggests that pre-admission use of GLP-1RA may offer beneficial effects on Covid-19 mortality in patients with diabetes mellitus. However, more randomized clinical trials are required to confirm this conclusion.
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Affiliation(s)
| | - Denny Intan
- Faculty of Medicine, Pelita Harapan University, Karawaci, Tangerang 15811, Indonesia
| | - Joshua Edward Hananto
- Faculty of Medicine, Pelita Harapan University, Karawaci, Tangerang 15811, Indonesia
| | - Cynthia Putri
- Faculty of Medicine, Pelita Harapan University, Karawaci, Tangerang 15811, Indonesia
| | - Andree Kurniawan
- Department of Internal Medicine, Faculty of Medicine, Pelita Harapan University, Karawaci, Tangerang 15811, Indonesia.
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19
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Effects of the Na +/H + Ion Exchanger on Susceptibility to COVID-19 and the Course of the Disease. JOURNAL OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM : JRAAS 2021. [PMID: 34285709 DOI: 10.1155/2021/4754440.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The Na+/H+ ion exchanger (NHE) pumps Na+ inward the cell and H+ ion outside the cell. NHE activity increases in response to a decrease in intracellular pH, and it maintains intracellular pH in a narrow range. Patients with obesity, diabetes, and hypertension and the elderly are prone to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The angiotensin II (Ang II) level is high in chronic diseases such as diabetes, hypertension, and obesity. Ang II is the main stimulator of NHE, and an increased Ang II level causes prolonged NHE activation in these patients. The long-term increase in NHE activity causes H+ ions to leave the cell in patients with diabetes, hypertension, and obesity. Increasing H+ ions outside the cell lead to an increase in oxidative stress and reactive oxygen species. H+ ion flows into the cell due to the increased oxidative stress. This vicious circle causes intracellular pH to drop. Although NHE is activated when intracellular pH decreases, there is prolonged NHE activation in chronic diseases such as aforementioned. Novel coronavirus disease 2019 (COVID-19) progression may be more severe and mortal in these patients. SARS-CoV-2 readily invades the cell at low intracellular pH and causes infection. The renin-angiotensin system and NHE play a vital role in regulating intracellular pH. The reduction of NHE activity or its prolonged activation may cause susceptibility to SARS-CoV-2 infection by lowering intracellular pH in patients with diabetes, hypertension, and obesity. Prolonged NHE activation in these patients with COVID-19 may worsen the course of the disease. Scientists continue to investigate the mechanism of the disease and the factors that affect its clinical progression.
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20
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Cumhur Cure M, Cure E. Effects of the Na +/H + Ion Exchanger on Susceptibility to COVID-19 and the Course of the Disease. J Renin Angiotensin Aldosterone Syst 2021; 2021:4754440. [PMID: 34285709 PMCID: PMC8265032 DOI: 10.1155/2021/4754440] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 05/14/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
The Na+/H+ ion exchanger (NHE) pumps Na+ inward the cell and H+ ion outside the cell. NHE activity increases in response to a decrease in intracellular pH, and it maintains intracellular pH in a narrow range. Patients with obesity, diabetes, and hypertension and the elderly are prone to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The angiotensin II (Ang II) level is high in chronic diseases such as diabetes, hypertension, and obesity. Ang II is the main stimulator of NHE, and an increased Ang II level causes prolonged NHE activation in these patients. The long-term increase in NHE activity causes H+ ions to leave the cell in patients with diabetes, hypertension, and obesity. Increasing H+ ions outside the cell lead to an increase in oxidative stress and reactive oxygen species. H+ ion flows into the cell due to the increased oxidative stress. This vicious circle causes intracellular pH to drop. Although NHE is activated when intracellular pH decreases, there is prolonged NHE activation in chronic diseases such as aforementioned. Novel coronavirus disease 2019 (COVID-19) progression may be more severe and mortal in these patients. SARS-CoV-2 readily invades the cell at low intracellular pH and causes infection. The renin-angiotensin system and NHE play a vital role in regulating intracellular pH. The reduction of NHE activity or its prolonged activation may cause susceptibility to SARS-CoV-2 infection by lowering intracellular pH in patients with diabetes, hypertension, and obesity. Prolonged NHE activation in these patients with COVID-19 may worsen the course of the disease. Scientists continue to investigate the mechanism of the disease and the factors that affect its clinical progression.
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Affiliation(s)
- Medine Cumhur Cure
- Department of Biochemistry, Private Kucukcekmece Hospital, Istanbul, Turkey
| | - Erkan Cure
- Department of Internal Medicine, Ota&Jinemed Hospital, Istanbul, Turkey
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Sui Y, Li J, Venzon DJ, Berzofsky JA. SARS-CoV-2 Spike Protein Suppresses ACE2 and Type I Interferon Expression in Primary Cells From Macaque Lung Bronchoalveolar Lavage. Front Immunol 2021; 12:658428. [PMID: 34149696 PMCID: PMC8213020 DOI: 10.3389/fimmu.2021.658428] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 05/13/2021] [Indexed: 01/08/2023] Open
Abstract
SARS-CoV-2 virus causes upper and lower respiratory diseases including pneumonia, and in some cases, leads to lethal pulmonary failure. Angiotensin converting enzyme-2 (ACE2), the receptor for cellular entry of SARS-CoV-2 virus, has been shown to protect against severe acute lung failure. Here, we provide evidence that SARS-CoV-2 spike protein S1 reduced the mRNA expression of ACE2 and type I interferons in primary cells of lung bronchoalveolar lavage (BAL) from naïve rhesus macaques. The expression levels of ACE2 and type I interferons were also found to be correlated with each other, consistent with the recent finding that ACE2 is an interferon-inducible gene. Furthermore, induction of ACE2 and type I interferons by poly I:C, an interferon inducer, was suppressed by S1 protein in primary cells of BAL. These observations suggest that the downregulation of ACE2 and type I interferons induced by S1 protein may directly contribute to SARS-CoV-2-associated lung diseases.
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Affiliation(s)
- Yongjun Sui
- Vaccine Branch, Center of Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, United States
| | - Jianping Li
- Vaccine Branch, Center of Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, United States
| | - David J Venzon
- Biostatistics and Data Management Section, Center of Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, United States
| | - Jay A Berzofsky
- Vaccine Branch, Center of Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, United States
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