{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:42:55Z","timestamp":1791996175490,"version":"4.4.0"},"reference-count":73,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T00:00:00Z","timestamp":1635897600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Men are disproportionately affected by the coronavirus disease-2019 (COVID-19), and face higher odds of severe illness and death compared to women. The vascular effects of androgen signaling and inflammatory cytokines in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated endothelial injury are not defined. We determined the effects of SARS-CoV-2 spike protein-mediated endothelial injury under conditions of exposure to androgen dihydrotestosterone (DHT) and tumor necrosis factor-a (TNF-\u03b1) and tested potentially therapeutic effects of mineralocorticoid receptor antagonism by spironolactone. Circulating endothelial injury markers VCAM-1 and E-selectin were measured in men and women diagnosed with COVID-19. Exposure of endothelial cells (ECs) in vitro to DHT exacerbated spike protein S1-mediated endothelial injury transcripts for the cell adhesion molecules E-selectin, VCAM-1 and ICAM-1 and anti-fibrinolytic PAI-1 (p &lt; 0.05), and increased THP-1 monocyte adhesion to ECs (p = 0.032). Spironolactone dramatically reduced DHT+S1-induced endothelial activation. TNF-\u03b1 exacerbated S1-induced EC activation, which was abrogated by pretreatment with spironolactone. Analysis from patients hospitalized with COVID-19 showed concordant higher circulating VCAM-1 and E-Selectin levels in men, compared to women. A beneficial effect of the FDA-approved drug spironolactone was observed on endothelial cells in vitro, supporting a rationale for further evaluation of mineralocorticoid antagonism as an adjunct treatment in COVID-19.<\/jats:p>","DOI":"10.3390\/v13112209","type":"journal-article","created":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T21:57:49Z","timestamp":1635976669000},"page":"2209","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["SARS-CoV-2 Spike Protein S1-Mediated Endothelial Injury and Pro-Inflammatory State Is Amplified by Dihydrotestosterone and Prevented by Mineralocorticoid Antagonism"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0153-3493","authenticated-orcid":false,"given":"Nitin","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zuo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srilakshmi","family":"Yalavarthi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina L.","family":"Hunker","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason S.","family":"Knight","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5660-5194","authenticated-orcid":false,"given":"Yogendra","family":"Kanthi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7613-2366","authenticated-orcid":false,"given":"Andrea T.","family":"Obi","sequence":"additional","affiliation":[{"name":"Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santhi K.","family":"Ganesh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.ejim.2020.04.037","article-title":"The pivotal link between ACE2 deficiency and SARS-CoV-2 infection","volume":"76","author":"Verdecchia","year":"2020","journal-title":"Eur. J. Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.jaad.2020.04.032","article-title":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is likely to be androgen mediated","volume":"83","author":"Wambier","year":"2020","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_3","first-page":"450","article-title":"Mice transgenic for human angiotensin-converting enzyme 2 provide a model for SARS coronavirus infection","volume":"57","author":"Yang","year":"2007","journal-title":"Comp. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/nature02145","article-title":"Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus","volume":"426","author":"Li","year":"2003","journal-title":"Nature"},{"key":"ref_5","first-page":"e01815","article-title":"TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection","volume":"93","author":"Okamura","year":"2019","journal-title":"J. Virol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/s41586-020-2700-3","article-title":"Sex differences in immune responses that underlie COVID-19 disease outcomes","volume":"588","author":"Takahashi","year":"2020","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1038\/s41577-020-0348-8","article-title":"Considering how biological sex impacts immune responses and COVID-19 outcomes","volume":"20","author":"Scully","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6317","DOI":"10.1038\/s41467-020-19741-6","article-title":"Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission","volume":"11","author":"Peckham","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/nri.2016.90","article-title":"Sex differences in immune responses","volume":"16","author":"Klein","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/s41420-020-0276-1","article-title":"ACE2 expression and sex disparity in COVID-19","volume":"6","author":"Gagliardi","year":"2020","journal-title":"Cell Death Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s40249-020-00662-x","article-title":"Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues","volume":"9","author":"Li","year":"2020","journal-title":"Infect. Dis. Poverty"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1093\/eurheartj\/ehaa373","article-title":"Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors","volume":"41","author":"Sama","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"588618","DOI":"10.3389\/fmolb.2020.588618","article-title":"ACE2 in the Era of SARS-CoV-2: Controversies and Novel Perspectives","volume":"7","author":"Saponaro","year":"2020","journal-title":"Front. Mol. Biosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1016\/j.annonc.2020.04.479","article-title":"Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: A population-based study (N = 4532)","volume":"31","author":"Montopoli","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1093\/cvr\/cvaa230","article-title":"Endothelial dysfunction in COVID-19: A position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science","volume":"116","author":"Evans","year":"2020","journal-title":"Cardiovasc. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1016\/S0140-6736(20)30937-5","article-title":"Endothelial cell infection and endotheliitis in COVID-19","volume":"395","author":"Varga","year":"2020","journal-title":"Lancet"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.7326\/L20-0882","article-title":"Cardiac Endotheliitis and Multisystem Inflammatory Syndrome After COVID-19","volume":"173","author":"Fox","year":"2020","journal-title":"Ann. Intern. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1093\/infdis\/jiaa528","article-title":"Circulating Endothelial Cells as a Marker of Endothelial Injury in Severe COVID-19","volume":"222","author":"Guervilly","year":"2020","journal-title":"J. Infect. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e575","DOI":"10.1016\/S2352-3026(20)30216-7","article-title":"Endotheliopathy in COVID-19-associated coagulopathy: Evidence from a single-centre, cross-sectional study","volume":"7","author":"Goshua","year":"2020","journal-title":"Lancet Haematol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1161\/ATVBAHA.120.314860","article-title":"Endothelial Dysfunction and Thrombosis in Patients with COVID-19-Brief Report","volume":"40","author":"Nagashima","year":"2020","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Shi, H., Zuo, Y., Navaz, S., Harbaugh, A., Hoy, C., Gandhi, A.A., Sule, G., Yalavarthi, S., Gockman, K., and Madison, J.A. (2021). Endothelial cell-activating antibodies in COVID-19. medRxiv.","DOI":"10.1101\/2021.01.18.21250041"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1097\/FJC.0000000000000960","article-title":"Is spironolactone the preferred renin-angiotensin-aldosterone inhibitor for protection against COVID-19?","volume":"77","author":"Wilcox","year":"2020","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"143","DOI":"10.3389\/fcvm.2020.00143","article-title":"Renin-Angiotensin System and Coronavirus Disease 2019: A Narrative Review","volume":"7","author":"Mascolo","year":"2020","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.regpep.2010.09.005","article-title":"Telmisartan attenuates aortic hypertrophy in hypertensive rats by the modulation of ACE2 and profilin-1 expression","volume":"166","author":"Zhong","year":"2011","journal-title":"Regul. Pept."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1161\/CIRCRESAHA.120.317134","article-title":"Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients with Hypertension Hospitalized with COVID-19","volume":"126","author":"Zhang","year":"2020","journal-title":"Circ. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1001\/jama.2020.11301","article-title":"Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use with COVID-19 Diagnosis and Mortality","volume":"324","author":"Fosbol","year":"2020","journal-title":"JAMA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s12575-021-00153-9","article-title":"Investigation of Interaction between the Spike Protein of SARS-CoV-2 and ACE2-Expressing Cells Using an In Vitro Cell Capturing System","volume":"23","author":"Shang","year":"2021","journal-title":"Biol. Proced. Online"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e0079421","DOI":"10.1128\/JVI.00794-21","article-title":"SARS-CoV-2 Spike Protein Induces Paracrine Senescence and Leukocyte Adhesion in Endothelial Cells","volume":"95","author":"Meyer","year":"2021","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"L477","DOI":"10.1152\/ajplung.00223.2021","article-title":"The SARS-CoV-2 spike protein subunit S1 induces COVID-19-like acute lung injury in Kappa18-hACE2 transgenic mice and barrier dysfunction in human endothelial cells","volume":"321","author":"Solopov","year":"2021","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6013","DOI":"10.1038\/s41467-020-19808-4","article-title":"SARS-CoV-2 spike-protein D614G mutation increases virion spike density and infectivity","volume":"11","author":"Zhang","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_32","first-page":"257","article-title":"Free SARS-CoV-2 Spike Protein S1 Particles May Play a Role in the Pathogenesis of COVID-19 Infection","volume":"86","author":"Letarov","year":"2021","journal-title":"Biochemistry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1161\/CIRCRESAHA.121.318902","article-title":"SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2","volume":"128","author":"Lei","year":"2021","journal-title":"Circ. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"105131","DOI":"10.1016\/j.nbd.2020.105131","article-title":"The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier","volume":"146","author":"Buzhdygan","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.virusres.2009.01.005","article-title":"SARS coronavirus spike protein-induced innate immune response occurs via activation of the NF-kappaB pathway in human monocyte macrophages in vitro","volume":"142","author":"Dosch","year":"2009","journal-title":"Virus. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.1210\/en.2005-1318","article-title":"Protective effect of spironolactone on endothelial cell apoptosis","volume":"147","author":"Williams","year":"2006","journal-title":"Endocrinology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1161\/01.CIR.99.17.2317","article-title":"Androgen exposure increases human monocyte adhesion to vascular endothelium and endothelial cell expression of vascular cell adhesion molecule-1","volume":"99","author":"McCrohon","year":"1999","journal-title":"Circulation"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1161\/hq0202.104001","article-title":"Tumor necrosis factor-alpha inhibits growth factor-mediated cell proliferation through SHP-1 activation in endothelial cells","volume":"22","author":"Nakagami","year":"2002","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1093\/cvr\/cvp091","article-title":"Valsartan regulates the interaction of angiotensin II type 1 receptor and endothelial nitric oxide synthase via Src\/PI3K\/Akt signalling","volume":"82","author":"Su","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0950-351X(98)80478-3","article-title":"Natural potent androgens: Lessons from human genetic models","volume":"12","author":"Zhu","year":"1998","journal-title":"Baillieres Clin. Endocrinol. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1210\/endo-97-1-52","article-title":"Antiandrogenic effect of spirolactones: Mechanism of action","volume":"97","author":"Corvol","year":"1975","journal-title":"Endocrinology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/path.1570","article-title":"Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis","volume":"203","author":"Hamming","year":"2004","journal-title":"J. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1007\/s00011-013-0633-0","article-title":"TNF-alpha signalling and inflammation: Interactions between old acquaintances","volume":"62","author":"Zelova","year":"2013","journal-title":"Inflamm. Res."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Seeland, U., Coluzzi, F., Simmaco, M., Mura, C., Bourne, P.E., Heiland, M., Preissner, R., and Preissner, S. (2020). Evidence for treatment with estradiol for women with SARS-CoV-2 infection. BMC Med., 18.","DOI":"10.1186\/s12916-020-01851-z"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1017\/S1049023X20000837","article-title":"An Insight into the Sex Differences in COVID-19 Patients: What are the Possible Causes?","volume":"35","author":"Sadoughi","year":"2020","journal-title":"Prehosp. Disaster Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"H1569","DOI":"10.1152\/ajpheart.00396.2018","article-title":"Sex differences in endothelial function important to vascular health and overall cardiovascular disease risk across the lifespan","volume":"315","author":"Stanhewicz","year":"2018","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/s41443-019-0163-6","article-title":"Effect of treatment with testosterone on endothelial function in hypogonadal men: A systematic review and meta-analysis","volume":"32","author":"Sansone","year":"2020","journal-title":"Int. J. Impot. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"R1055","DOI":"10.1152\/ajpregu.00459.2002","article-title":"Androgen-mediated induction of the kidney arachidonate hydroxylases is associated with the development of hypertension","volume":"284","author":"Nakagawa","year":"2003","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1161\/HYPERTENSIONAHA.107.089599","article-title":"Vascular cytochrome P450 4A expression and 20-hydroxyeicosatetraenoic acid synthesis contribute to endothelial dysfunction in androgen-induced hypertension","volume":"50","author":"Singh","year":"2007","journal-title":"Hypertension"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Poblete, S., and Guzman, H.V. (2021). Structural 3D Domain Reconstruction of the RNA Genome from Viruses with Secondary Structure Models. Viruses, 13.","DOI":"10.3390\/v13081555"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1146\/annurev.med.45.1.361","article-title":"Endothelial-leukocyte adhesion molecules in human disease","volume":"45","author":"Bevilacqua","year":"1994","journal-title":"Annu. Rev. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5086","DOI":"10.1038\/s41467-020-18854-2","article-title":"Two distinct immunopathological profiles in autopsy lungs of COVID-19","volume":"11","author":"Nienhold","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.trsl.2020.04.007","article-title":"Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases","volume":"220","author":"Magro","year":"2020","journal-title":"Transl. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/s41577-020-0343-0","article-title":"COVID-19: The vasculature unleashed","volume":"20","author":"Teuwen","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_56","first-page":"1686","article-title":"Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia","volume":"61","author":"Afar","year":"2001","journal-title":"Cancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1038\/s41433-020-0939-4","article-title":"Expression of SARS-CoV-2 receptor ACE2 and TMPRSS2 in human primary conjunctival and pterygium cell lines and in mouse cornea","volume":"34","author":"Ma","year":"2020","journal-title":"Eye"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1021\/acschemneuro.0c00210","article-title":"Expression of the SARS-CoV-2 Entry Proteins, ACE2 and TMPRSS2, in Cells of the Olfactory Epithelium: Identification of Cell Types and Trends with Age","volume":"11","author":"Bilinska","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.cell.2020.04.035","article-title":"SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues","volume":"181","author":"Ziegler","year":"2020","journal-title":"Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1038\/s42003-020-1088-9","article-title":"Sex differences in SARS-CoV-2 infection rates and the potential link to prostate cancer","volume":"3","author":"Chakravarty","year":"2020","journal-title":"Commun. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.stem.2020.11.009","article-title":"Androgen Signaling Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men","volume":"27","author":"Samuel","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.ccr.2012.11.010","article-title":"The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man","volume":"23","author":"Sharma","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2431","DOI":"10.1056\/NEJMoa2006923","article-title":"Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19","volume":"382","author":"Mancia","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1161\/01.CIR.101.18.2149","article-title":"Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction","volume":"101","author":"Ridker","year":"2000","journal-title":"Circulation"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1016\/S0140-6736(20)30858-8","article-title":"Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed","volume":"395","author":"Feldmann","year":"2020","journal-title":"Lancet"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1038\/s41598-020-80010-z","article-title":"Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients","volume":"11","author":"Zuo","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"110112","DOI":"10.1016\/j.mehy.2020.110112","article-title":"Spironolactone may provide protection from SARS-CoV-2: Targeting androgens, angiotensin converting enzyme 2 (ACE2), and renin-angiotensin-aldosterone system (RAAS)","volume":"143","author":"Cadegiani","year":"2020","journal-title":"Med. Hypotheses"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"227","DOI":"10.4330\/wjc.v6.i5.227","article-title":"Management of hypertension in primary aldosteronism","volume":"6","author":"Aronova","year":"2014","journal-title":"World J. Cardiol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1161\/01.HYP.0000259805.18468.8c","article-title":"Effect of spironolactone on blood pressure in subjects with resistant hypertension","volume":"49","author":"Chapman","year":"2007","journal-title":"Hypertension"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.det.2010.03.011","article-title":"Innovative use of spironolactone as an antiandrogen in the treatment of female pattern hair loss","volume":"28","author":"Rathnayake","year":"2010","journal-title":"Dermatol. Clin."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/j.jaad.2015.05.026","article-title":"Evidence-based approach to cutaneous hyperandrogenism in women","volume":"73","author":"Schmidt","year":"2015","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Vicenzi, M., Ruscica, M., Iodice, S., Rota, I., Ratti, A., Di Cosola, R., Corsini, A., Bollati, V., Aliberti, S., and Blasi, F. (2020). The Efficacy of the Mineralcorticoid Receptor Antagonist Canrenone in COVID-19 Patients. J. Clin. Med., 9.","DOI":"10.21203\/rs.3.rs-45837\/v1"},{"key":"ref_73","first-page":"e13047","article-title":"Early Antiandrogen Therapy with Dutasteride Reduces Viral Shedding, Inflammatory Responses, and Time-to-Remission in Males with COVID-19: A Randomized, Double-Blind, Placebo-Controlled Interventional Trial (EAT-DUTA AndroCoV Trial\u2014Biochemical)","volume":"13","author":"Cadegiani","year":"2021","journal-title":"Cureus"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/11\/2209\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:25:05Z","timestamp":1760167505000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/11\/2209"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,3]]},"references-count":73,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["v13112209"],"URL":"https:\/\/doi.org\/10.3390\/v13112209","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,3]]}}}