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Li S, Pan M, Zhao H, Li Y. Role of CCL2/CCR2 axis in pulmonary fibrosis induced by respiratory viruses. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2025:S1684-1182(25)00036-2. [PMID: 39955168 DOI: 10.1016/j.jmii.2025.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 01/23/2025] [Accepted: 02/08/2025] [Indexed: 02/17/2025]
Abstract
Respiratory virus infection is an important cause of both community acquired pneumonia and hospital-acquired pneumonia. Various respiratory viruses, including influenza virus, avian influenza virus, respiratory syncytial virus (RSV), SARS-CoV, MERS-CoV, and SARS-CoV-2, result in severe fibrosis sequelae after the acute phase. Since the COVID-19 pandemic, respiratory virus infection, as an important cause of pulmonary fibrosis, has attracted increasing attention around the world. Respiratory virus infection usually triggers robust inflammation responses, leading to large amounts of proinflammatory mediator production, such as chemokine (C-C motif) ligand 2 (CCL2), a critical chemokine involved in the recruitment of various inflammatory cells. Moreover, CCL2 plays a pivotal role in the pathogenesis of fibrosis progression, through regulating recruitment of bone marrow-derived monocytes and increasing the expression of extracellular matrix proteins. This review provided a concise overview of the common fibrosis sequelae after virus infection. Then we discussed the elevated levels of CCL2 in various respiratory virus infection, underscoring its potent profibrotic role. Targeting the CCL2/CCR2 axis holds promise for alleviating fibrosis sequelae post-acute virus infection and warrants further investigation.
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Affiliation(s)
- Shuangyan Li
- Beijing Hospital, National Centre of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, 100730, Beijing, China.
| | - Mingming Pan
- Department of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, 100730, Beijing, China.
| | - Hui Zhao
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, 100071, Beijing, China.
| | - Yanming Li
- Department of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, 100730, Beijing, China.
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Lovre D, Qadir MMF, Bateman K, Saltzman LY, Sherman M, Mauvais-Jarvis F. Acute estradiol and progesterone therapy in hospitalized adults to reduce COVID-19 severity: a randomized control trial. Sci Rep 2024; 14:22732. [PMID: 39349554 PMCID: PMC11442588 DOI: 10.1038/s41598-024-73263-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 09/16/2024] [Indexed: 10/02/2024] Open
Abstract
COVID-19 outcomes are less severe in women than men suggesting that female sex is protective. The steroids estradiol (E2) and progesterone (P4) promote anti-inflammatory immune responses and their therapeutic use for COVID-19 has been under investigation. The aim of the study was to evaluate the efficacy of a short systemic E2 and P4 combination in mitigating COVID-19 severity in hospitalized men and women. In a phase 2, single center, double blind, randomized placebo-controlled trial, ten male and female participants hospitalized for COVID-19 with scores 3-5 on the 9-point WHO ordinal scale were randomized to receive either (1) E2 cypionate (5 mg, IM) and micronized P4 (200 mg, PO), or (2) placebo-equivalent, in addition to standard of care (SOC). The primary outcome was the proportion of patients whose WHO scores improved to 1-2 on the day of discharge. Secondary outcomes included length of hospital stay (LOS), days on oxygen therapy (DOT), readmission rates (RR), adverse events (AEs), and change in circulating biomarkers using untargeted proteomics and cytokine profiling. There were no significant changes between the groups in primary outcome, LOS, DOT, RR or AEs. The E2P4 group exhibited a decrease in biomarker pathways of respiratory and gastrointestinal disease inflammation, infection by coronavirus, and immune cell trafficking and inflammatory response. A short-term E2P4 treatment in patients hospitalized for COVID-19 decreases biomarkers of inflammation. Considering the availability, low cost, and safety of E2 and P4, our results warrant additional studies to explore their effects in mitigating other viral pandemics. Clinical Trial Registration NCT04865029, ClinicalTrials.gov; (First trial registration 29/04/2021).
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Affiliation(s)
- Dragana Lovre
- Section of Endocrinology and Metabolism, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
- Section of Endocrinology, Department of Medicine, Southeast Louisiana Veterans Health Care System, New Orleans, LA, 70119, USA.
- Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, LA, 70112, USA.
| | - M M Fahd Qadir
- Section of Endocrinology and Metabolism, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA
- Section of Endocrinology, Department of Medicine, Southeast Louisiana Veterans Health Care System, New Orleans, LA, 70119, USA
- Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, LA, 70112, USA
| | - Kristin Bateman
- Section of General Internal Medicine and Geriatrics, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Leia Y Saltzman
- Tulane University School of Social Work, New Orleans, LA, 70112, USA
| | - Mya Sherman
- Institutional Review Board - Health Science Research, University of Virginia, Charlottesville, VA, 22908, USA
| | - Franck Mauvais-Jarvis
- Section of Endocrinology and Metabolism, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
- Section of Endocrinology, Department of Medicine, Southeast Louisiana Veterans Health Care System, New Orleans, LA, 70119, USA.
- Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, LA, 70112, USA.
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Donald J, Bilasy SE, Yang C, El-Shamy A. Exploring the Complexities of Long COVID. Viruses 2024; 16:1060. [PMID: 39066223 PMCID: PMC11281588 DOI: 10.3390/v16071060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 06/24/2024] [Accepted: 06/27/2024] [Indexed: 07/28/2024] Open
Abstract
Since the emergence of the SARS-CoV-2 virus in 2019, nearly 700 million COVID-19 cases and 7 million deaths have been reported globally. Despite most individuals recovering within four weeks, the Center for Disease Control (CDC) estimates that 7.5% to 41% develop post-acute infection syndrome (PAIS), known as 'Long COVID'. This review provides current statistics on Long COVID's prevalence, explores hypotheses concerning epidemiological factors, such as age, gender, comorbidities, initial COVID-19 severity, and vaccine interactions, and delves into potential mechanisms, including immune responses, viral persistence, and gut dysbiosis. Moreover, we conclude that women, advanced age, comorbidities, non-vaccination, and low socioeconomic status all appear to be risk factors. The reasons for these differences are still not fully understood and likely involve a complex relationship between social, genetic, hormonal, and other factors. Furthermore, individuals with Long COVID-19 seem more likely to endure economic hardship due to persistent symptoms. In summary, our findings further illustrate the multifaceted nature of Long COVID and underscore the importance of understanding the epidemiological factors and potential mechanisms needed to develop effective therapeutic strategies and interventions.
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Affiliation(s)
- Jackson Donald
- College of Graduate Studies, California Northstate University, 9700 West Taron Drive, Elk Grove, CA 95757, USA; (J.D.); (C.Y.)
| | - Shymaa E. Bilasy
- College of Dental Medicine, California Northstate University, 9700 West Taron Drive, Elk Grove, CA 95757, USA;
| | - Catherine Yang
- College of Graduate Studies, California Northstate University, 9700 West Taron Drive, Elk Grove, CA 95757, USA; (J.D.); (C.Y.)
| | - Ahmed El-Shamy
- College of Graduate Studies, California Northstate University, 9700 West Taron Drive, Elk Grove, CA 95757, USA; (J.D.); (C.Y.)
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Xiao H, Wei J, Yuan L, Li J, Zhang C, Liu G, Liu X. Sex hormones in COVID-19 severity: The quest for evidence and influence mechanisms. J Cell Mol Med 2024; 28:e18490. [PMID: 38923119 PMCID: PMC11194454 DOI: 10.1111/jcmm.18490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 05/20/2024] [Accepted: 05/30/2024] [Indexed: 06/28/2024] Open
Abstract
Studies have reported variable effects of sex hormones on serious diseases. Severe disease and mortality rates in COVID-19 show marked gender differences that may be related to sex hormones. Sex hormones regulate the expression of the viral receptors ACE2 and TMPRSS2, which affect the extent of viral infection and consequently cause variable outcomes. In addition, sex hormones have complex regulatory mechanisms that affect the immune response to viruses. These hormones also affect metabolism, leading to visceral obesity and severe disease can result from complications such as thrombosis. This review presents the latest researches on the regulatory functions of hormones in viral receptors, immune responses, complications as well as their role in COVID-19 progression. It also discusses the therapeutic possibilities of these hormones by reviewing the recent findings of clinical and assay studies.
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Affiliation(s)
- Haiqing Xiao
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory & Center for Molecular Imaging and Translational Medicine, Institute of Artificial Intelligence, School of Public HealthXiamen UniversityXiamenChina
| | - Jiayi Wei
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory & Center for Molecular Imaging and Translational Medicine, Institute of Artificial Intelligence, School of Public HealthXiamen UniversityXiamenChina
| | - Lunzhi Yuan
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory & Center for Molecular Imaging and Translational Medicine, Institute of Artificial Intelligence, School of Public HealthXiamen UniversityXiamenChina
| | - Jiayuan Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory & Center for Molecular Imaging and Translational Medicine, Institute of Artificial Intelligence, School of Public HealthXiamen UniversityXiamenChina
| | - Chang Zhang
- Clinical Center for Biotherapy, Zhongshan Hospital (Xiamen)Fudan UniversityXiamenChina
| | - Gang Liu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory & Center for Molecular Imaging and Translational Medicine, Institute of Artificial Intelligence, School of Public HealthXiamen UniversityXiamenChina
| | - Xuan Liu
- Clinical Center for Biotherapy, Zhongshan Hospital (Xiamen)Fudan UniversityXiamenChina
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Qiang X, Chen W, Zhu CS, Li J, Qi T, Lou L, Wang P, Tracey KJ, Wang H. Therapeutic potential of procathepsin L-inhibiting and progesterone-entrapping dimethyl-β-cyclodextrin nanoparticles in treating experimental sepsis. Front Immunol 2024; 15:1368448. [PMID: 38550581 PMCID: PMC10972846 DOI: 10.3389/fimmu.2024.1368448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 03/04/2024] [Indexed: 04/02/2024] Open
Abstract
The pathogenic mechanisms of bacterial infections and resultant sepsis are partly attributed to dysregulated inflammatory responses sustained by some late-acting mediators including the procathepsin-L (pCTS-L). It was entirely unknown whether any compounds of the U.S. Drug Collection could suppress pCTS-L-induced inflammation, and pharmacologically be exploited into possible therapies. Here, we demonstrated that a macrophage cell-based screening of a U.S. Drug Collection of 1360 compounds resulted in the identification of progesterone (PRO) as an inhibitor of pCTS-L-mediated production of several chemokines [e.g., Epithelial Neutrophil-Activating Peptide (ENA-78), Monocyte Chemoattractant Protein-1 (MCP-1) or MCP-3] and cytokines [e.g., Interleukin-10 (IL-10) or Tumor Necrosis Factor (TNF)] in primary human peripheral blood mononuclear cells (PBMCs). In vivo, these PRO-entrapping 2,6-dimethal-β-cyclodextrin (DM-β-CD) nanoparticles (containing 1.35 mg/kg PRO and 14.65 mg/kg DM-β-CD) significantly increased animal survival in both male (from 30% to 70%, n = 20, P = 0.041) and female (from 50% to 80%, n = 30, P = 0.026) mice even when they were initially administered at 24 h post the onset of sepsis. This protective effect was associated with a reduction of sepsis-triggered accumulation of three surrogate biomarkers [e.g., Granulocyte Colony Stimulating Factor (G-CSF) by 40%; Macrophage Inflammatory Protein-2 (MIP-2) by 45%; and Soluble Tumor Necrosis Factor Receptor I (sTNFRI) by 80%]. Surface Plasmon Resonance (SPR) analysis revealed a strong interaction between PRO and pCTS-L (KD = 78.2 ± 33.7 nM), which was paralleled with a positive correlation between serum PRO concentration and serum pCTS-L level (ρ = 0.56, P = 0.0009) or disease severity (Sequential Organ Failure Assessment, SOFA; ρ = 0.64, P = 0.0001) score in septic patients. Our observations support a promising opportunity to explore DM-β-CD nanoparticles entrapping lipophilic drugs as possible therapies for clinical sepsis.
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Affiliation(s)
- Xiaoling Qiang
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| | - Weiqiang Chen
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| | - Cassie Shu Zhu
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| | - Jianhua Li
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Timothy Qi
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Li Lou
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Ping Wang
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| | - Kevin J. Tracey
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| | - Haichao Wang
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
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Kotani Y, Landoni G, Scquizzato T, Mohamed N, Baiardo Redaelli M, Sofia R, Fresilli S, Zangrillo A, Azzolini ML. Antiandrogen agents in COVID-19: a meta-analysis of randomized trials. Minerva Med 2024; 115:37-44. [PMID: 37204782 DOI: 10.23736/s0026-4806.23.08538-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
INTRODUCTION Antiandrogen therapy can reduce the expression of transmembrane protease 2, which is essential for severe acute respiratory syndrome coronavirus-2 to enter the host cells. Prior trials suggested the efficacy of antiandrogen agents in patients with COVID-19. We investigated whether antiandrogen agents reduce mortality compared to placebo or usual care. EVIDENCE ACQUISITION We searched for randomized controlled trials comparing antiandrogen agents with placebo or usual care alone in adults with COVID-19 in PubMed, EMBASE, the Cochrane Library, the reference lists of retrieved articles, and publications by manufacturers of antiandrogen agents. The primary outcome was mortality at the longest follow-up available. The secondary outcomes included clinical worsening, the need for invasive mechanical ventilation, admission to the intensive care unit, hospitalization, and thrombotic events. We registered this systematic review and meta-analysis in PROSPERO International Prospective Register of Systematic Reviews (CRD42022338099). EVIDENCE SYNTHESIS We included 13 randomized controlled trials enrolling 1934 COVID-19 patients. We found that antiandrogen agents reduced mortality at the longest follow-up available (91/1021 [8.9%] vs. 245/913 [27%]; risk ratio =0.40; 95% confidence interval, 0.25-0.65; P=0.0002; I2=54%). Antiandrogen therapy also reduced clinical worsening (127/1016 [13%] vs. 298/911 [33%]; risk ratio =0.44; 95% confidence interval, 0.27-0.71; P=0.0007; I2=70%) and hospitalization (97/160 [4.4%] vs. 24/165 [15%]; risk ratio =0.24; 95% confidence interval, 0.10-0.58; P=0.002; I2=44%). There was no significant difference in the other outcomes between the two treatment groups. CONCLUSIONS Antiandrogen therapy reduced mortality and clinical worsening in adult patients with COVID-19.
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Affiliation(s)
- Yuki Kotani
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
- Department of Intensive Care Medicine, Kameda Medical Center, Kamogawa, Japan
| | - Giovanni Landoni
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy -
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
| | - Tommaso Scquizzato
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Nadia Mohamed
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Martina Baiardo Redaelli
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Rosaria Sofia
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Stefano Fresilli
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alberto Zangrillo
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
| | - Maria L Azzolini
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Al‐Kuraishy HM, Al‐Maiahy TJ, Al‐Gareeb AI, Alexiou A, Papadakis M, Elhussieny O, Saad HM, Batiha GE. New insights on the potential effect of progesterone in Covid-19: Anti-inflammatory and immunosuppressive effects. Immun Inflamm Dis 2023; 11:e1100. [PMID: 38018575 PMCID: PMC10683562 DOI: 10.1002/iid3.1100] [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: 04/22/2023] [Revised: 11/08/2023] [Accepted: 11/12/2023] [Indexed: 11/30/2023] Open
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) is a pandemic disease caused by severe acute respiratory syndrome CoV type 2 (SARS-CoV-2). COVID-19 is higher in men than women and sex hormones have immune-modulator effects during different viral infections, including SARS-CoV-2 infection. One of the essential sex hormones is progesterone (P4). AIMS This review aimed to reveal the association between P4 and Covid-19. RESULTS AND DISCUSSION The possible role of P4 in COVID-19 could be beneficial through the modulation of inflammatory signaling pathways, induction of the release of anti-inflammatory cytokines, and inhibition release of pro-inflammatory cytokines. P4 stimulates skew of naïve T cells from inflammatory Th1 toward anti-inflammatory Th2 with activation release of anti-inflammatory cytokines, and activation of regulatory T cells (Treg) with decreased interferon-gamma production that increased during SARS-CoV-2 infection. In addition, P4 is regarded as a potent antagonist of mineralocorticoid receptor (MR), it could reduce MRs that were activated by stimulated aldosterone from high AngII during SARS-CoV-2. P4 active metabolite allopregnanolone is regarded as a neurosteroid that acts as a positive modulator of γ-aminobutyric acid (GABAA ) so it may reduce neuropsychiatric manifestations and dysautonomia in COVID-19 patients. CONCLUSION Taken together, the anti-inflammatory and immunomodulatory properties of P4 may improve central and peripheral complications in COVID-19.
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Affiliation(s)
- Hayder M. Al‐Kuraishy
- Department of Clinical Pharmacology and Therapeutic Medicine, College of MedicineMustansiriyah UniversityBaghdadIraq
| | - Thabat J. Al‐Maiahy
- Department of Gynecology and Obstetrics, College of MedicineAl‐Mustansiriyah UniversityBaghdadIraq
| | - Ali I. Al‐Gareeb
- Department of Clinical Pharmacology and Therapeutic Medicine, College of MedicineMustansiriyah UniversityBaghdadIraq
| | - Athanasios Alexiou
- University Centre for Research & DevelopmentChandigarh UniversityMohaliPunjabIndia
- Department of Science and EngineeringNovel Global Community Educational FoundationHebershamNew South WalesAustralia
- Department of Research & DevelopmentAFNP MedWienAustria
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten‐Herdecke, Heusnerstrasse 40University of Witten‐HerdeckeWuppertalGermany
| | - Omnya Elhussieny
- Department of Histology and Cytology, Faculty of Veterinary MedicineMatrouh UniversityMarsa MatruhEgypt
| | - Hebatallah M. Saad
- Department of Pathology, Faculty of Veterinary MedicineMatrouh UniversityMarsa MatruhEgypt
| | - Gaber El‐Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary MedicineDamanhour University, DamanhourAlBeheiraEgypt
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Liu Y, Li H, Peng Y, Gao L, Liu C, Wei B, Luo Z. Impacts of pregnancy and menopause on COVID-19 severity: a systematic review and meta-analysis of 4.6 million women. QJM 2023; 116:755-765. [PMID: 37228103 DOI: 10.1093/qjmed/hcad106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Indexed: 05/27/2023] Open
Abstract
BACKGROUND Corona Virus Disease 2019 (COVID-19) pandemic is still a public health emergency of international concern. However, whether pregnancy and menopause impact the severity of COVID-19 remain unclear. AIM This study is performed to investigate the truth. DESIGN Study appraisal and synthesis follows PRISMA guideline. Meta-analysis is performed in random-effects model. METHODS PubMed, Embase, Cochrane database, Central, CINAHL, ClinicalTrials.gov, WHO COVID-19 database and WHO-ICTRP are searched until 28 March 2023. RESULTS In total, 57 studies (4 640 275 COVID-19 women) were analyzed. Pregnant women were at a lower risk of severe COVID-19, intensive care unit (ICU) admission and disease mortality compared to those nonpregnant women with comparable comorbidities. In contrast, pregnant women with more prepregnancy comorbidities were at a higher risk of severe COVID-19, ICU admission and invasive mechanical ventilation (IMV). In addition, pregnant women with pregnancy complications had a significantly increased risk of severe COVID-19 and ICU admission. Menopause increased COVID-19 severity, IMV requirement and disease mortality. Hormone replacement therapy inhibited COVID-19 severity in postmenopausal women. Premenopausal and postmenopausal women had a lower chance of severe illness than age-matched men. The impact of pregnancy on COVID-19 severity was significant in Americans and Caucasians, whereas the effect of menopause on COVID-19 severity was only significant in Chinese. CONCLUSIONS Pregnancy and menopause are protective and risk factors for severe COVID-19, respectively. The protective role of pregnancy on COVID-19 is minimal and could be counteracted or masked by prepregnancy or pregnancy comorbidities. The administration of estrogen and progesterone may prevent severe COVID-19.
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Affiliation(s)
- Y Liu
- Department of Endocrinology, China Resources and WISCO General Hospital, Wuhan, China
| | - H Li
- Department of Geratology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Y Peng
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - L Gao
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - C Liu
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - B Wei
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
- Institute of Myocardial Injury and Repair, Wuhan University, Wuhan, China
| | - Z Luo
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
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Lin VHC, Chien A, Chien EJ. The rapid activation of cPKCβII by progesterone results in the negative regulation of Ca 2+ influx in human resting T cells. J Chin Med Assoc 2023; 86:885-891. [PMID: 37496123 DOI: 10.1097/jcma.0000000000000970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/28/2023] Open
Abstract
BACKGROUND Progesterone-stimulated rapid suppression of phytohemagglutinin (PHA)-activated sustained membrane Ca 2+ influx is revealed by Mn 2+ quenching fura-2 fluorescence. Ca 2+ influx suppression results in immunosuppression of T-cell proliferation. Downregulation of protein kinase C (PKC) activity by phorbol 12-myristate 13-acetate (PMA) enhances the PHA-activated increase in sustained intracellular Ca 2+ concentration ([Ca 2+ ] i ) via Ca 2+ influx in T cells. Conventional PKC (cPKC) inhibitors also enhance the [Ca 2+ ] i increase in resting T cells caused by progesterone. This study explores whether cPKC activation by progesterone results in suppression of Ca 2+ influx in resting T cells. METHODS Progesterone, its analogs (R5020/Org OD 02-0), and plasma membrane-impermeable progesterone-bovine serum albumin conjugate were used to stimulate human resting T cells. Inhibitors and PKC downregulation by PMA were used to investigate whether cPKC affects Ca 2+ influx. RESULTS Progesterone and analogs dose-dependently suppressed Ca 2+ influx in T cells. One cPKC inhibitor, Ro318220, attenuated Ca 2+ influx suppression, and enhanced the increase in [Ca 2+ ] i caused by progesterone and analogs. U73122 did not affect Ca 2+ influx suppression but did decrease the [Ca 2+ ] i increase. Ca 2+ influx suppression was not attenuated by the cPKCα/βI isoform-selective inhibitor, Go6976, nevertheless, a cPKCβI/βII isoform-selective inhibitor, LY333531 did. Ca 2+ influx suppression was attenuated by the cPKCβII-specific inhibitor CGP53353. After PKC downregulated by PMA, Ca 2+ influx suppression by progesterone and analogs was almost abolished in parallel with a massive reduction in cPKCβII expression. This suggests cPKCβII activation by progesterone and analogs mediate Ca 2+ influx suppression in resting T cells. CONCLUSION Nongenomic membrane activation of cPKCβII by progesterone causes immunosuppression via negative regulation of Ca 2+ influx into human resting T cells. This prevents resting T-cell activation and proliferation, which protects the fetus from maternal immune attack while decreasing maternal autoimmune disease flare-ups during pregnancy. Thus, cPKCβII modulators might provide a new therapeutic approach to balancing T-cell tolerance and immunity.
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Affiliation(s)
- Veronica Hui-Chen Lin
- Department and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Angela Chien
- Department of Biotechnology, School of Health Technology, Ming Chuan University, Taoyuan, Taiwan, ROC
| | - Eileen Jea Chien
- Department and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
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Sourati J, Evans JA. Accelerating science with human-aware artificial intelligence. Nat Hum Behav 2023; 7:1682-1696. [PMID: 37443269 DOI: 10.1038/s41562-023-01648-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 06/02/2023] [Indexed: 07/15/2023]
Abstract
Artificial intelligence (AI) models trained on published scientific findings have been used to invent valuable materials and targeted therapies, but they typically ignore the human scientists who continually alter the landscape of discovery. Here we show that incorporating the distribution of human expertise by training unsupervised models on simulated inferences that are cognitively accessible to experts dramatically improves (by up to 400%) AI prediction of future discoveries beyond models focused on research content alone, especially when relevant literature is sparse. These models succeed by predicting human predictions and the scientists who will make them. By tuning human-aware AI to avoid the crowd, we can generate scientifically promising 'alien' hypotheses unlikely to be imagined or pursued without intervention until the distant future, which hold promise to punctuate scientific advance beyond questions currently pursued. By accelerating human discovery or probing its blind spots, human-aware AI enables us to move towards and beyond the contemporary scientific frontier.
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Affiliation(s)
- Jamshid Sourati
- Department of Sociology, University of Chicago, Chicago, IL, USA
| | - James A Evans
- Department of Sociology, University of Chicago, Chicago, IL, USA.
- Santa Fe Institute, Santa Fe, NM, USA.
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11
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Babu TM, Wald A, Restar AJ. Health equity necessitates the inclusion of gender identity data in COVID-19 clinical trials. Ann Epidemiol 2023; 85:3-5. [PMID: 37391114 PMCID: PMC10303319 DOI: 10.1016/j.annepidem.2023.06.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 06/14/2023] [Accepted: 06/26/2023] [Indexed: 07/02/2023]
Abstract
COVID-19 has highlighted the importance of studying differences by sex and gender. The under-reporting of gender identity in COVID-19 studies limits the generalizability of study results to nonbinary persons. Some of the data on sex-assigned associated complications of both COVID-19 infection and COVID-19 immunizations is presented in this manuscript.
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Affiliation(s)
- Tara M Babu
- Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle; Department of Behavioral and Social Sciences, Yale University School of Public Health, New Haven, CT.
| | - Anna Wald
- Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle; Department of Laboratory Medicine and Pathology, University of Washington, Seattle; Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Epidemiology, School of Public Health, University of Washington, Seattle; Department of Behavioral and Social Sciences, Yale University School of Public Health, New Haven, CT
| | - Arjee J Restar
- Department of Epidemiology, School of Public Health, University of Washington, Seattle; Department of Behavioral and Social Sciences, Yale University School of Public Health, New Haven, CT
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12
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Vinson AJ, Anzalone A, Schissel M, Dai R, French ET, Olex AL, Mannon RB. Hormone replacement therapy and COVID-19 outcomes in solid organ transplant recipients compared with the general population. Am J Transplant 2023; 23:1035-1047. [PMID: 37105315 PMCID: PMC10129906 DOI: 10.1016/j.ajt.2023.04.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 04/17/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023]
Abstract
Exogenous estrogen is associated with reduced coronavirus disease (COVID) mortality in nonimmunosuppressed/immunocompromised (non-ISC) postmenopausal females. Here, we examined the association of estrogen or testosterone hormone replacement therapy (HRT) with COVID outcomes in solid organ transplant recipients (SOTRs) compared to non-ISC individuals, given known differences in sex-based risk in these populations. SOTRs ≥45 years old with COVID-19 between April 1, 2020 and July 31, 2022 were identified using the National COVID Cohort Collaborative. The association of HRT use in the last 24 months (exogenous systemic estrogens for females; testosterone for males) with major adverse renal or cardiac events in the 90 days post-COVID diagnosis and other secondary outcomes were examined using multivariable Cox proportional hazards models and logistic regression. We repeated these analyses in a non-ISC control group for comparison. Our study included 1135 SOTRs and 43 383 immunocompetent patients on HRT with COVID-19. In non-ISC, HRT use was associated with lower risk of major adverse renal or cardiac events (adjusted hazard ratio [aHR], 0.61; 95% confidence interval [CI], 0.57-0.65 for females; aHR, 0.70; 95% CI, 0.65-0.77 for males) and all secondary outcomes. In SOTR, HRT reduced the risk of acute kidney injury (aHR, 0.79; 95% CI, 0.63-0.98) and mortality (aHR, 0.49; 95% CI, 0.28-0.85) in males with COVID but not in females. The potentially modifying effects of immunosuppression on the benefits of HRT requires further investigation.
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Affiliation(s)
| | | | | | - Ran Dai
- University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Evan T French
- Virginia Commonwealth University, Richmond, Virginia, USA
| | - Amy L Olex
- Virginia Commonwealth University, Richmond, Virginia, USA
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13
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Lott N, Gebhard CE, Bengs S, Haider A, Kuster GM, Regitz-Zagrosek V, Gebhard C. Sex hormones in SARS-CoV-2 susceptibility: key players or confounders? Nat Rev Endocrinol 2023; 19:217-231. [PMID: 36494595 PMCID: PMC9734735 DOI: 10.1038/s41574-022-00780-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/10/2022] [Indexed: 12/14/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has a clear sex disparity in clinical outcomes. Hence, the interaction between sex hormones, virus entry receptors and immune responses has attracted major interest as a target for the prevention and treatment of SARS-CoV-2 infections. This Review summarizes the current understanding of the roles of androgens, oestrogens and progesterone in the regulation of virus entry receptors and disease progression of coronavirus disease 2019 (COVID-19) as well as their therapeutic value. Although many experimental and clinical studies have analysed potential mechanisms by which female sex hormones might provide protection against SARS-CoV-2 infectivity, there is currently no clear evidence for a sex-specific expression of virus entry receptors. In addition, reports describing an influence of oestrogen, progesterone and androgens on the course of COVID-19 vary widely. Current data also do not support the administration of oestradiol in COVID-19. The conflicting evidence and lack of consensus results from a paucity of mechanistic studies and clinical trials reporting sex-disaggregated data. Further, the influence of variables beyond biological factors (sex), such as sociocultural factors (gender), on COVID-19 manifestations has not been investigated. Future research will have to fill this knowledge gap as the influence of sex and gender on COVID-19 will be essential to understanding and managing the long-term consequences of this pandemic.
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Affiliation(s)
- Nicola Lott
- Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | | | - Susan Bengs
- Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | - Achi Haider
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, Boston, MA, USA
- Department of Radiology, Harvard Medical School, Boston, MA, USA
| | - Gabriela M Kuster
- Department of Cardiology and Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland
| | - Vera Regitz-Zagrosek
- Charité, Universitätsmedizin Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany
| | - Catherine Gebhard
- Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland.
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.
- Department of Cardiology, Inselspital Bern University Hospital, Bern, Switzerland.
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14
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Qaderi K, Hosseinirad H, Kalhor M, Zangeneh S, Pournaghi M, Khodavirdilou R, Keshavarz M, Eghdampour F, Mirmolaei ST, Jesmani Y, Barjasteh S, Mallah MA, Shamsabadi A. The relationship between sex steroids (E2, progesterone, and AMH) levels and severity and fatality of COVID-19: A systematic review. Heliyon 2023; 9:e14218. [PMID: 36873532 PMCID: PMC9974207 DOI: 10.1016/j.heliyon.2023.e14218] [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: 08/21/2022] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/05/2023] Open
Abstract
Sex steroids are powerful modulators of the immune system and they may affect the immune response and inflammatory consequences of COVID-19. This systematic review aims to explore the impact of sex steroids on COVID-19 mortality and complications. We looked up the keywords of the study in Scopus, PubMed, and Web of Science. All related original articles published in English, as of October 16, 2021, were reviewed to be included in our research. Concerns regarding the effect of sex hormones on COVID-19, eight full texts have been identified for the conclusion. In these studies, the relationship between estradiol and COVID-19 mortality has been mentioned. The most significant findings were the higher COVID-19 mortality rate in men, compared to women; also, in menopausal women compared to younger women and who received estradiol. In two studies, oral contraceptive pills had a protective effect on the morbidity of SARS-CoV-2 infection. In a randomized controlled trial, subcutaneous injection of progesterone in hospitalized men significantly reduced their symptoms and need for oxygen therapy. Hormone replacement therapy was positively associated with reducing COVID-19 symptoms. Although the results were insufficient for a conclusion, this study represents estrogen as an appropriate pharmacological method for preventing and diminishing the inflammation related to COVID-19 disease. However, future prospective studies and clinical trials are needed to clarify and approve this protective effect.
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Affiliation(s)
- Kowsar Qaderi
- PhD in Reproductive Health, Midwifery Department, School of Nursing and Midwifery, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hossein Hosseinirad
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehri Kalhor
- PhD in Reproductive Health, Department of Midwifery, School of Nursing and Midwifery, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sanaz Zangeneh
- Midwifery and Reproductive Health Department, Student Research Committee, School of Nursing and Midwifery, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Marjaneh Pournaghi
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rasa Khodavirdilou
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Keshavarz
- School of Nursing and Midwifery, Iran University of Medical Sciences, Tehran, Iran
| | | | - Seyedeh Tahereh Mirmolaei
- Department of Midwifery and Reproductive Health, Nursing and Midwifery School, Tehran University of Medical Sciences, Tehran, Iran
| | - Younes Jesmani
- Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Samira Barjasteh
- Reproductive Health Researcher Center, Clinical Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Manthar Ali Mallah
- College of Public Health, Zhengzhou University, 100 Kexue Ave, Zhongyuan District, Zhengzhou 450001, China
| | - Ahmadreza Shamsabadi
- Department of Health Information Technology, Esfarayen Faculty of Medical Science, Esfarayen, Iran
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15
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Lei S, Chen X, Wu J, Duan X, Men K. Small molecules in the treatment of COVID-19. Signal Transduct Target Ther 2022; 7:387. [PMID: 36464706 PMCID: PMC9719906 DOI: 10.1038/s41392-022-01249-8] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 11/02/2022] [Accepted: 11/08/2022] [Indexed: 12/11/2022] Open
Abstract
The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies and economies. Until now, effective therapeutics against COVID-19 are in high demand. Along with our improved understanding of the structure, function, and pathogenic process of SARS-CoV-2, many small molecules with potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition of viral proteins such as RdRp and Mpro, interference of host enzymes including ACE2 and proteases, and blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, and NLRP3 pathways, are regarded feasible in drug development. The development of small molecules to treat COVID-19 has been achieved by several strategies, including computer-aided lead compound design and screening, natural product discovery, drug repurposing, and combination therapy. Several small molecules representative by remdesivir and paxlovid have been proved or authorized emergency use in many countries. And many candidates have entered clinical-trial stage. Nevertheless, due to the epidemiological features and variability issues of SARS-CoV-2, it is necessary to continue exploring novel strategies against COVID-19. This review discusses the current findings in the development of small molecules for COVID-19 treatment. Moreover, their detailed mechanism of action, chemical structures, and preclinical and clinical efficacies are discussed.
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Affiliation(s)
- Sibei Lei
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Xiaohua Chen
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Jieping Wu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Xingmei Duan
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
| | - Ke Men
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
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16
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Coelingh Bennink HJ, Egberts JF, Debruyne FM. Testosterone suppression combined with high dose estrogen as potential treatment of SARS-CoV-2. A mini review. Heliyon 2022; 8:e12376. [PMID: 36540359 PMCID: PMC9754753 DOI: 10.1016/j.heliyon.2022.e12376] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 10/06/2022] [Accepted: 12/07/2022] [Indexed: 12/23/2022] Open
Abstract
Compared to females, males experience severe acute respiratory syndrome due to COVID-19 (SARS-CoV-2) more often, and also die more frequently from COVID-19. Testosterone has inhibitory and estrogens have favorable effects on the immune system. Both ACE2 and TMPRSS2 are specific host-cellular proteins stimulating viral entry in cells and SARS-CoV-2. Both proteins can be suppressed by inhibition of testosterone levels and by stimulation of estrogen levels. Therefore, both androgen-deprivation therapy (ADT) and estrogen therapy (ET) may decrease COVID-19 virus cell entry. Literature was searched for evidence of COVID-19 treatment benefits with estrogens, progesterone, androgen deprivation, and anti-androgens. Data supporting the effect of ADT on SARS-CoV-2 are sparse and inconsistent. The benefit of anti-androgen therapy is inconsistent. Data on the effect of ET were not found. Indirect estrogen data related to menopausal hormone therapy and hormonal contraception are favorable. In a small study, progesterone had some beneficial effects. The combination of ADT and ET (ADET) has never been studied as a treatment option for SARS-CoV-2. Based on the mode of action of the combination, it is hypothesized that ADET may be an effective and safe treatment of SARS-CoV-2, to be confirmed in a clinical trial.
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17
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Ataei A, Derakhshan MM, Razmjooie M, Zare F, Amiresmaeili H, Salehi N, Namakkoobi N, Mirhosseini H, Karim B, Iravani S. Androgens' Role in Severity and Mortality Rates of COVID-19. Horm Metab Res 2022; 54:813-826. [PMID: 36195265 DOI: 10.1055/a-1954-5605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
By the end of December 2019 new corona virus began to spread from Wuhan, China and caused a worldwide pandemic. COVID-19 deaths and prevalence represented sex discrepant patterns with higher rate of deaths and infection in males than females which could be justified by androgen-mediated mechanisms. This review aimed to assess the role of androgens in COVID-19 severity and mortality. Androgens increase expressions of Type II transmembrane Serine Protease (TMPRSS2) and Angiotensin Converting Enzyme 2 (ACE2), which both facilitate new corona virus entry into host cell and their expression is higher in young males than females. According to observational studies, prevalence of COVID-19 infections and deaths was more in androgenic alopecic patients than patients without androgenic alopecia. The COVID-19 mortality rates in aged men (>60 years) were substantially higher than aged females and even young males caused by high inflammatory activities such as cytokine storm due to hypogonadism in this population. Use of anti-androgen and TMPRSS2 inhibitor drugs considerably modified COVID-19 symptoms. Androgen deprivation therapy also improved COVID-19 symptoms in prostate cancer: overall the role of androgens in severity of COVID-19 and its associated mortality seemed to be very important. So, more studies in variety of populations are required to define the absolute role of androgens.
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Affiliation(s)
- Ali Ataei
- School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | - Mohammad Moein Derakhshan
- Student Research Committee, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | | | - Fateme Zare
- Reproductive Immunology Research Center, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Habibe Amiresmaeili
- Nursing Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Negin Salehi
- School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Negar Namakkoobi
- Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Hamid Mirhosseini
- Research Center of Addiction and Behavioral Sciences, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Bardia Karim
- Student Research Committee, Babol University of Medical Science, Babol, Iran
| | - Sima Iravani
- School of Paramedical Sciences, Yazd University of Medical Science, Yazd, Iran
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18
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Ranjbar M, Rahimi A, Baghernejadan Z, Ghorbani A, Khorramdelazad H. Role of CCL2/CCR2 axis in the pathogenesis of COVID-19 and possible Treatments: All options on the Table. Int Immunopharmacol 2022; 113:109325. [PMID: 36252475 PMCID: PMC9561120 DOI: 10.1016/j.intimp.2022.109325] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 10/05/2022] [Accepted: 10/05/2022] [Indexed: 11/05/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is cause of the novel coronavirus disease (COVID-19). In the last two years, SARS-CoV-2 has infected millions of people worldwide with different waves, resulting in the death of many individuals. The evidence disclosed that the host immune responses to SARS-CoV-2 play a pivotal role in COVID-19 pathogenesis and clinical manifestations. In addition to inducing antiviral immune responses, SARS-CoV-2 can also cause dysregulated inflammatory responses characterized by the noticeable release of proinflammatory mediators in COVID-19 patients. Among these proinflammatory mediators, chemokines are considered a subset of cytokines that participate in the chemotaxis process to recruit immune and non-immune cells to the site of inflammation and infection. Researchers have demonstrated that monocyte chemoattractant protein-1 (MCP-1/CCL2) and its receptor (CCR2) are involved in the recruitment of monocytes and infiltration of these cells into the lungs of patients suffering from COVID-19. Moreover, elevated levels of CCL2 have been reported in the bronchoalveolar lavage fluid (BALF) obtained from patients with severe COVID-19, initiating cytokine storm and promoting CD163+ myeloid cells infiltration in the airways and further alveolar damage. Therefore, CCL2/CCR axis plays a key role in the immunopathogenesis of COVID-19 and targeted therapy of involved molecules in this axis can be a potential therapeutic approach for these patients. This review discusses the biology of the CCL2/CCR2 axis as well as the role of this axis in COVID-19 immunopathogenesis, along with therapeutic options aimed at inhibiting CCL2/CCR2 and modulating dysregulated inflammatory responses in patients with severe SARS-CoV-2 infection.
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Affiliation(s)
- Mitra Ranjbar
- Department of Infectious Disease, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Rahimi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zeinab Baghernejadan
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Atousa Ghorbani
- Department of Biology, East Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
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19
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Ferraro JJ, Reynolds A, Edoigiawerie S, Seu MY, Horen SR, Aminzada A, Hamidian Jahromi A. Impact of gender-affirming hormone therapy on the development of COVID-19 infections and associated complications: A systematic review. World J Methodol 2022; 12:465-475. [PMID: 36479311 PMCID: PMC9720351 DOI: 10.5662/wjm.v12.i6.465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 07/14/2022] [Accepted: 10/05/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can produce a wide range of clinical manifestations from asymptomatic to life-threatening. Various researchers have worked to elucidate the pathogenic mechanisms underlying these variable presentations. Differences in individual responses to systemic inflammation and coagulopathy appear to be modulated by several factors, including sex steroid hormones. Transgender men or non-binary individuals who undergo gender-affirming hormone therapy (GAHT) are a unique population of interest for exploring the androgen-mediated coronavirus disease 2019 (COVID-19) hypothesis. As the search for reliable and effective COVID-19 treatments continues, understanding the risks and benefits of GAHT may mitigate COVID-19 related morbidity and mortality in this patient population. AIM To investigate the potential role of GAHT in the development of COVID-19 infections and complications. METHODS This systematic review implemented an algorithmic approach using PRISMA guidelines. PubMed, Scopus, Google Scholar top 100 results, and archives of Plastic and Reconstructive Surgery was on January 12, 2022 using the key words "gender" AND "hormone" AND "therapy" AND "COVID-19" as well as associated terms. Non-English articles, articles published prior to 2019 (prior to COVID-19), and manuscripts in the form of reviews, commentaries, or letters were excluded. References of the selected publications were screened as well. RESULTS The database search resulted in the final inclusion of 14 studies related to GAHT COVID-19. Of the included studies, only two studies directly involved and reported on COVID-19 in transgender patients. Several clinical trials looked at the relationship between testosterone, estrogen, and progesterone in COVID-19 infected cis-gender men and women. It has been proposed that androgens may facilitate initial COVID-19 infection, however, once this occurs, testosterone may have a protective effect. Multiple clinical studies have shown that low baseline testosterone levels in men with COVID-19 are associated with worsening outcomes. The role of female sex hormones, including estrogen and progesterone have also been proposed as potential protective factors in COVID-19 infection. This was exemplified in multiple studies investigating different outcomes in pre- and post-menopausal women as well as those taking hormone replacement therapy. Two studies related specifically to transgender patients and GAHT found that estrogen and progesterone could help protect men against COVID-19, and that testosterone hormone therapy may increase the risk of contracting COVID-19. CONCLUSION Few studies were found related to the role of GAHT in COVID-19 infections. Additional research is necessary to enhance our understanding of this relationship and provide better care for transgender patients.
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Affiliation(s)
- Jennifer J Ferraro
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Rush University Medical Center, Chicago, IL 60612, United States
| | - Allie Reynolds
- Undergraduate Studies, Princeton University, Princeton, NJ 08544, United States
| | - Sylvia Edoigiawerie
- Medical School, The University of Chicago Pritzker School of Medicine, Chicago, IL 60637, United States
| | - Michelle Y Seu
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Rush University Medical Center, Chicago, IL 60612, United States
| | - Sydney R Horen
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Rush University Medical Center, Chicago, IL 60612, United States
| | - Amir Aminzada
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Rush University Medical Center, Chicago, IL 60612, United States
| | - Alireza Hamidian Jahromi
- Division of Plastic and Reconstructive Surgery, Temple University Health System, Philadelphia, PA 19140, United States
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20
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Punjani N, Flannigan R. Androgens and COVID-19: exploring the role of testosterone replacement therapy. Int J Impot Res 2022; 34:649-651. [PMID: 35094017 DOI: 10.1038/s41443-021-00524-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 12/16/2021] [Accepted: 12/20/2021] [Indexed: 11/09/2022]
Affiliation(s)
- Nahid Punjani
- Department of Urology, Weill Cornell Medicine, New York, NY, USA.
| | - Ryan Flannigan
- Department of Urology, Weill Cornell Medicine, New York, NY, USA
- Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
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21
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Wang ZP, Hua M, Jiu T, Ge RL, Bai Z. Biofunctional roles of estrogen in coronavirus disease 2019: Beyond a steroid hormone. Front Pharmacol 2022; 13:1003469. [PMID: 36339571 PMCID: PMC9626865 DOI: 10.3389/fphar.2022.1003469] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/06/2022] [Indexed: 09/26/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), epidemic poses a major global public health threat with more than one million daily new infections and hundreds of deaths. To combat this global pandemic, efficient prevention and management strategies are urgently needed. Together with the main characteristics of COVID-19, impaired coagulation with dysfunctions of the immune response in COVID-19 pathophysiology causes high mortality and morbidity. From recent clinical observations, increased expression of specific types of estrogen appears to protect patients from SARS-CoV-2 infection, thereby, reducing mortality. COVID-19 severity is less common in women than in men, particularly in menopausal women. Furthermore, estrogen levels are negatively correlated with COVID-19 severity and mortality. These findings suggest that estrogen plays a protective role in the pathophysiology of COVID-19. In this review, we discuss the potential roles of estrogen in blocking the SARS-CoV-2 from invading alveolar cells and replicating, and summarize the potential mechanisms of anti-inflammation, immune modulation, reactive oxygen species resistance, anti-thrombosis, vascular dilation, and vascular endothelium protection. Finally, the potential therapeutic effects of estrogen against COVID-19 are reviewed. This review provides insights into the role of estrogen and its use as a potential strategy to reduce the mortality associated with COVID-19, and possibly other viral infections and discusses the possible challenges and pertinent questions.
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Affiliation(s)
- Zhong-Ping Wang
- Clinical Medicine, School of Medicine, Qinghai University, Xining, China
- Department of Respiratory and Critical Diseases, Affiliated Hospital of Qinghai University, Xining, China
| | - Mao Hua
- Department of Respiratory and Critical Diseases, Affiliated Hospital of Qinghai University, Xining, China
| | - Tai Jiu
- Department of Respiratory and Critical Diseases, Affiliated Hospital of Qinghai University, Xining, China
| | - Ri-Li Ge
- Research Center of High-Altitude Medicine, School of Medicine, Qinghai University, Xining, China
- Joint Lab of Qinghai-Utah for High Altitude Medicine, School of Medicine, Qinghai University, Xining, China
| | - Zhenzhong Bai
- Clinical Medicine, School of Medicine, Qinghai University, Xining, China
- Research Center of High-Altitude Medicine, School of Medicine, Qinghai University, Xining, China
- Joint Lab of Qinghai-Utah for High Altitude Medicine, School of Medicine, Qinghai University, Xining, China
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22
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Fedotcheva TA, Fedotcheva NI, Shimanovsky NL. Progesterone as an Anti-Inflammatory Drug and Immunomodulator: New Aspects in Hormonal Regulation of the Inflammation. Biomolecules 2022; 12:biom12091299. [PMID: 36139138 PMCID: PMC9496164 DOI: 10.3390/biom12091299] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/10/2022] [Accepted: 09/11/2022] [Indexed: 11/25/2022] Open
Abstract
The specific regulation of inflammatory processes by steroid hormones has been actively studied in recent years, especially by progesterone (P4) and progestins. The mechanisms of the anti-inflammatory and immunomodulatory P4 action are not fully clear. The anti-inflammatory effects of P4 can be defined as nonspecific, associated with the inhibition of NF-κB and COX, as well as the inhibition of prostaglandin synthesis, or as specific, associated with the regulation of T-cell activation, the regulation of the production of pro- and anti-inflammatory cytokines, and the phenomenon of immune tolerance. The specific anti-inflammatory effects of P4 and its derivatives (progestins) can also include the inhibition of proliferative signaling pathways and the antagonistic action against estrogen receptor beta-mediated signaling as a proinflammatory and mitogenic factor. The anti-inflammatory action of P4 is accomplished through the participation of progesterone receptor (PR) chaperones HSP90, as well as immunophilins FKBP51 and FKBP52, which are the validated targets of clinically approved immunosuppressive drugs. The immunomodulatory and anti-inflammatory effects of HSP90 inhibitors, tacrolimus and cyclosporine, are manifested, among other factors, due to their participation in the formation of an active ligand–receptor complex of P4 and their interaction with its constituent immunophilins. Pharmacological agents such as HSP90 inhibitors can restore the lost anti-inflammatory effect of glucocorticoids and P4 in chronic inflammatory and autoimmune diseases. By regulating the activity of FKBP51 and FKBP52, it is possible to increase or decrease hormonal signaling, as well as restore it during the development of hormone resistance. The combined action of immunophilin suppressors with steroid hormones may be a promising strategy in the treatment of chronic inflammatory and autoimmune diseases, including endometriosis, stress-related disorders, rheumatoid arthritis, and miscarriages. Presumably, the hormone receptor- and immunophilin-targeted drugs may act synergistically, allowing for a lower dose of each.
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Affiliation(s)
- Tatiana A. Fedotcheva
- Science Research Laboratory of Molecular Pharmacology, Medical Biological Faculty, Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Ostrovityanova St. 1, Moscow 117997, Russia
- Correspondence: ; Tel.: +7-9169353196
| | - Nadezhda I. Fedotcheva
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya Str. 3, Pushchino 142290, Russia
| | - Nikolai L. Shimanovsky
- Science Research Laboratory of Molecular Pharmacology, Medical Biological Faculty, Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Ostrovityanova St. 1, Moscow 117997, Russia
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23
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Ho JQ, Sepand MR, Bigdelou B, Shekarian T, Esfandyarpour R, Chauhan P, Serpooshan V, Beura LK, Hutter G, Zanganeh S. The immune response to COVID-19: Does sex matter? Immunology 2022; 166:429-443. [PMID: 35470422 PMCID: PMC9111683 DOI: 10.1111/imm.13487] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 03/14/2022] [Indexed: 01/08/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has created unprecedented challenges worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 and has a complex interaction with the immune system, including growing evidence of sex-specific differences in the immune response. Sex-disaggregated analyses of epidemiological data indicate that males experience more severe symptoms and suffer higher mortality from COVID-19 than females. Many behavioural risk factors and biological factors may contribute to the different immune response. This review examines the immune response to SARS-CoV-2 infection in the context of sex, with emphasis on potential biological mechanisms explaining differences in clinical outcomes. Understanding sex differences in the pathophysiology of SARS-CoV-2 infection will help promote the development of specific strategies to manage the disease.
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Affiliation(s)
- Jim Q. Ho
- Department of MedicineAlbert Einstein College of MedicineBronxNew YorkUSA
| | - Mohammad Reza Sepand
- Department of BioengineeringUniversity of Massachusetts DartmouthDartmouthMassachusettsUSA
| | - Banafsheh Bigdelou
- Department of BioengineeringUniversity of Massachusetts DartmouthDartmouthMassachusettsUSA
| | - Tala Shekarian
- Department of NeurosurgeryUniversity Hospital BaselBaselSwitzerland
| | - Rahim Esfandyarpour
- Department of Electrical EngineeringUniversity of California IrvineIrvineCaliforniaUSA
- Department of Biomedical EngineeringUniversity of California IrvineIrvineCaliforniaUSA
| | - Prashant Chauhan
- Laboratory of Functional Biology of Protists, Institute of ParasitologyBiology Centre of the Czech Academy of SciencesČeské BudějoviceCzech Republic
| | - Vahid Serpooshan
- Wallace H. Coulter Department of Biomedical EngineeringEmory University School of Medicine and Georgia Institute of TechnologyAtlantaGeorgiaUSA
| | - Lalit K. Beura
- Department of Molecular Microbiology and ImmunologyBrown UniversityProvidenceRhode IslandUSA
| | - Gregor Hutter
- Department of NeurosurgeryUniversity Hospital BaselBaselSwitzerland
| | - Steven Zanganeh
- Department of BioengineeringUniversity of Massachusetts DartmouthDartmouthMassachusettsUSA
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24
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Effect of Norelgestromin and Ethinylestradiol in Transdermal Patches on the Clinical Outcomes and Biochemical Parameters of COVID-19 Patients: A Clinical Trial Pilot Study. Pharmaceuticals (Basel) 2022; 15:ph15060757. [PMID: 35745676 PMCID: PMC9228088 DOI: 10.3390/ph15060757] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 06/10/2022] [Accepted: 06/14/2022] [Indexed: 12/15/2022] Open
Abstract
The disease caused by SARS-CoV-2 is still considered a global pandemic. Transdermal patches (TP) with immunoregulators such as estrogen and progesterone compounds could be a feasible option to treat COVID-19 because of their accessibility and relative safety. The objective of the current study was to evaluate the additional treatment with norelgestromin and ethinylestradiol in TP on the clinical and biochemical evolution of COVID-19 patients. The present is a clinical-trial pilot study that included subjects diagnosed with COVID-19, randomized into two groups; the experimental Evra® TP (norelgestromin 6 mg and ethinylestradiol 0.60 mg) was administered such that it was applied on arrival and replaced at day 8 and day 15. The control continued with the conventional COVID-19 treatment protocol. A blood sample was taken each week in order to evaluate relevant biochemical parameters, clinical signs, and evolution. In total, 44 subjects participated in this study, 30 in the experimental group and 14 in the control group. Both groups were homogeneous in terms of age and comorbidities. The experimental group had a significantly lower hospital stay (p = 0.01), high flow supplemental oxygen (p = 0.001), mechanical ventilation (p = 0.003), and intubation (p = 0.01), and the oxygen saturation significantly increased (p = 0.01) in comparison with control group when patients were exposed to room air. A decrease in ferritin (p < 0.05) was observed, with no significant increase in ESR (p > 0.05), D dimer (p > 0.05) and platelets (p > 0.05) in an auto-controlled analysis in the experimental group. Norelgestromin and ethinylestradiol TP could be a safe and effective treatment for moderate and severe COVID-19 patients.
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25
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Hashimoto Y, Suzuki T, Hashimoto K. Mechanisms of action of fluvoxamine for COVID-19: a historical review. Mol Psychiatry 2022; 27:1898-1907. [PMID: 34997196 PMCID: PMC8739627 DOI: 10.1038/s41380-021-01432-3] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 12/13/2021] [Accepted: 12/23/2021] [Indexed: 12/18/2022]
Abstract
The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) accelerates the discovery of prophylactic and therapeutic drugs for persons infected with the virus. Drug repurposing for the COVID-19 pandemic has received particular attention. Increasing clinical data suggest that antidepressant use in early-stage subjects with COVID-19 might be associated with a reduced risk of intubation or death. Among the antidepressants, fluvoxamine is the most attractive drug for mild to moderate subjects with COVID-19. In this article, we review the mechanisms of action (i.e., serotonin transporter, sigma-1 receptor, and acid sphingomyelinase) of fluvoxamine for COVID-19. Furthermore, we discuss a possible link between maternal COVID-19 infection and a risk for neuropsychiatric disorders (i.e., autism spectrum disorder and schizophrenia) in offspring.
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Affiliation(s)
- Yaeko Hashimoto
- Department of Respirology, Chiba University Graduate School of Medicine, Chiba, 260-8670, Japan
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan
| | - Takuji Suzuki
- Department of Respirology, Chiba University Graduate School of Medicine, Chiba, 260-8670, Japan
| | - Kenji Hashimoto
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan.
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26
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Hu T, Tang C, Stern S, Yang L, Du T. 17α-Hydroxyprogesterone Caproate Inhibits Cytokine Production via Suppression of NF-κB Activation. Front Pharmacol 2022; 13:831315. [PMID: 35330839 PMCID: PMC8940231 DOI: 10.3389/fphar.2022.831315] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 02/08/2022] [Indexed: 11/24/2022] Open
Abstract
Cytokine release syndrome (CRS) is one of the leading causes of morbidity and mortality in COVID-19 patients with elevated levels of circulating cytokines contributing to various clinical symptoms. Favorable control of CRS represents a promising and effective strategy to mitigate the clinical outcomes of hospitalized patients with moderate to severe pneumonia. Using in vivo cytokine release assay in human peripheral blood mononuclear cell (PBMC)-engrafted immunodeficient mice, we reported that 17α-hydroxyprogesterone caproate (17-OHPC), a synthetic progestogen, exhibited significant inhibition of OKT-3-stimulated production of numerous cytokines including TNF-α, IFN-γ, IL-2, IL-4, IL-6, IL-10, and GM-CSF. Furthermore, 17-OHPC inhibited in vitro production of IFN-γ, IL-1β, IL-2, IL-6, and IL-10 in human PBMCs stimulated with OKT3, while exhibiting down-regulation of the mRNA levels of TNF-α, IFN-γ, IL-2, IL-6, and IL-10. Using the same human PBMCs, additional stimulators anti-CD28 antibody or PHA treatments led to substantial cytokine production, which was also attenuated by 17-OHPC. OKT3-stimulated phosphorylation of IκBα and nuclear translocation of NF-κB p65 in human PBMCs were also reversed by 17-OHPC, suggesting its inhibition on NF-κB signaling in immune cells. Taken together, this work reported both in vivo and in vitro inhibition of cytokine production by 17-OHPC, presumably by virtue of its suppression of NF-κB signaling. These findings provide pharmacological evidence to support the potential application of 17-OHPC in treating CRS associated with COVID-19.
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Affiliation(s)
- Tao Hu
- Evergreen Therapeutics, Inc., Bethesda, MD, United States
| | - Chengjifu Tang
- Evergreen Therapeutics, Inc., Bethesda, MD, United States
| | - Sydney Stern
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, United States
| | - Luan Yang
- Evergreen Therapeutics, Inc., Bethesda, MD, United States
| | - Tom Du
- Evergreen Therapeutics, Inc., Bethesda, MD, United States
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27
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Bechmann N, Barthel A, Schedl A, Herzig S, Varga Z, Gebhard C, Mayr M, Hantel C, Beuschlein F, Wolfrum C, Perakakis N, Poston L, Andoniadou CL, Siow R, Gainetdinov RR, Dotan A, Shoenfeld Y, Mingrone G, Bornstein SR. Sexual dimorphism in COVID-19: potential clinical and public health implications. Lancet Diabetes Endocrinol 2022; 10:221-230. [PMID: 35114136 PMCID: PMC8803381 DOI: 10.1016/s2213-8587(21)00346-6] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 11/16/2021] [Accepted: 12/03/2021] [Indexed: 01/19/2023]
Abstract
Current evidence suggests that severity and mortality of COVID-19 is higher in men than in women, whereas women might be at increased risk of COVID-19 reinfection and development of long COVID. Differences between sexes have been observed in other infectious diseases and in the response to vaccines. Sex-specific expression patterns of proteins mediating virus binding and entry, and divergent reactions of the immune and endocrine system, in particular the hypothalamic-pituitary-adrenal axis, in response to acute stress might explain the higher severity of COVID-19 in men. In this Personal View, we discuss how sex hormones, comorbidities, and the sex chromosome complement influence these mechanisms in the context of COVID-19. Due to its role in the severity and progression of SARS-CoV-2 infections, we argue that sexual dimorphism has potential implications for disease treatment, public health measures, and follow-up of patients predisposed to the development of long COVID. We suggest that sex differences could be considered in future pandemic surveillance and treatment of patients with COVID-19 to help to achieve better disease stratification and improved outcomes.
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Affiliation(s)
- Nicole Bechmann
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Andreas Barthel
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Medicover Bochum, Bochum, Germany
| | - Andreas Schedl
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Université Côte d'Azur, INSERM, CNRS, iBV, Nice, France
| | - Stephan Herzig
- Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Joint Heidelberg-IDC Translational Diabetes Program Inner Medicine I, Neuherberg, Germany
| | - Zsuzsanna Varga
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Catherine Gebhard
- Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland; Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
| | - Manuel Mayr
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; King's British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine and Sciences, King's College London, London, UK
| | - Constanze Hantel
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
| | - Felix Beuschlein
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland; Department for Endocrinology, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University, Munich, Germany
| | - Christian Wolfrum
- Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland
| | - Nikolaos Perakakis
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Lucilla Poston
- Division of Women's Health, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Cynthia L Andoniadou
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Centre for Craniofacial and Regenerative Biology, Faculty of Dental, Oral, and Craniofacial Sciences, King's College London, London, UK
| | - Richard Siow
- King's British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine and Sciences, King's College London, London, UK; Vascular Biology and Inflammation Section, School of Cardiovascular Medicine and Sciences, King's College London, London, UK
| | - Raul R Gainetdinov
- Institute of Translational Biomedicine and St Petersburg University Hospital, St Petersburg State University, St Petersburg, Russia
| | - Arad Dotan
- The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ramat Gan, Israel
| | - Yehuda Shoenfeld
- The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ramat Gan, Israel; Ariel University, Ariel, Israel
| | - Geltrude Mingrone
- Department of Diabetes, School of Life Course Science and Medicine, King's College London, London, UK; Fondazione Policlinico Universitario Agostino Gemelli Istituto Di Ricovero e Cura a Carattere Scientifico, Rome, Italy; Department of Internal Medicine, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Stefan R Bornstein
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Diabetes, School of Life Course Science and Medicine, King's College London, London, UK.
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28
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Female sex hormone, progesterone, ameliorates the severity of SARS-CoV-2-caused pneumonia in the Syrian hamster model. Signal Transduct Target Ther 2022; 7:47. [PMID: 35165265 PMCID: PMC8844354 DOI: 10.1038/s41392-021-00860-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 12/02/2021] [Accepted: 12/13/2021] [Indexed: 01/02/2023] Open
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29
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Choi SW, Kim J, Lee JH, Kim SK, Lee SR, Kim SH, Chae HD. Hormone Therapy in the Era of the COVID-19 Pandemic: A Review. J Menopausal Med 2022; 28:1-8. [PMID: 35534425 PMCID: PMC9086346 DOI: 10.6118/jmm.21036] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 03/12/2022] [Accepted: 03/13/2022] [Indexed: 11/05/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has impacted the medical, social, and reproductive health of millions of people since its outbreak. The causative virus transmits, reproduces, and manifests through the respiratory tract. COVID-19 can invade any system of the body, including the cardiovascular and endocrine systems, through a secondary immune response. In particular, because the fatality rate is high in those over the age of 50 years, special attention is required during the medical care of this population. However, considering the benefit of therapy and the risk of COVID-19, high-quality evidence regarding individualized management in relation to hormone therapy is still insufficient in the field of gynecology. Furthermore, this review aims to serve as a reference for clinical application by analyzing and summarizing the results of studies reported to date regarding female hormone therapy in the context of the COVID-19 pandemic.
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Affiliation(s)
- Sung Wook Choi
- Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Juhee Kim
- Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jae Hoon Lee
- Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Seul Ki Kim
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Sa Ra Lee
- Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung Hoon Kim
- Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hee Dong Chae
- Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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30
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Cenko E, Badimon L, Bugiardini R, Claeys MJ, De Luca G, de Wit C, Derumeaux G, Dorobantu M, Duncker DJ, Eringa EC, Gorog DA, Hassager C, Heinzel FR, Huber K, Manfrini O, Milicic D, Oikonomou E, Padro T, Trifunovic-Zamaklar D, Vasiljevic-Pokrajcic Z, Vavlukis M, Vilahur G, Tousoulis D. Cardiovascular disease and COVID-19: a consensus paper from the ESC Working Group on Coronary Pathophysiology & Microcirculation, ESC Working Group on Thrombosis and the Association for Acute CardioVascular Care (ACVC), in collaboration with the European Heart Rhythm Association (EHRA). Cardiovasc Res 2021; 117:2705-2729. [PMID: 34528075 PMCID: PMC8500019 DOI: 10.1093/cvr/cvab298] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 09/10/2021] [Indexed: 01/08/2023] Open
Abstract
The cardiovascular system is significantly affected in coronavirus disease-19 (COVID-19). Microvascular injury, endothelial dysfunction, and thrombosis resulting from viral infection or indirectly related to the intense systemic inflammatory and immune responses are characteristic features of severe COVID-19. Pre-existing cardiovascular disease and viral load are linked to myocardial injury and worse outcomes. The vascular response to cytokine production and the interaction between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and angiotensin-converting enzyme 2 receptor may lead to a significant reduction in cardiac contractility and subsequent myocardial dysfunction. In addition, a considerable proportion of patients who have been infected with SARS-CoV-2 do not fully recover and continue to experience a large number of symptoms and post-acute complications in the absence of a detectable viral infection. This conditions often referred to as 'post-acute COVID-19' may have multiple causes. Viral reservoirs or lingering fragments of viral RNA or proteins contribute to the condition. Systemic inflammatory response to COVID-19 has the potential to increase myocardial fibrosis which in turn may impair cardiac remodelling. Here, we summarize the current knowledge of cardiovascular injury and post-acute sequelae of COVID-19. As the pandemic continues and new variants emerge, we can advance our knowledge of the underlying mechanisms only by integrating our understanding of the pathophysiology with the corresponding clinical findings. Identification of new biomarkers of cardiovascular complications, and development of effective treatments for COVID-19 infection are of crucial importance.
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Affiliation(s)
- Edina Cenko
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via Giuseppe Massarenti 9, 40134 Bologna, Italy
| | - Lina Badimon
- Cardiovascular Program ICCC-Research Institute Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, CiberCV, Barcelona, Spain
| | - Raffaele Bugiardini
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via Giuseppe Massarenti 9, 40134 Bologna, Italy
| | - Marc J Claeys
- Department of Cardiology, University Hospital Antwerp, Edegem, Belgium
| | - Giuseppe De Luca
- Cardiovascular Department of Cardiology, Ospedale “Maggiore della Carità”, Eastern Piedmont University, Novara, Italy
| | - Cor de Wit
- Institut für Physiologie, Universität zu Lübeck, Lübeck, Germany
- Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) e.V. (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany
| | - Geneviève Derumeaux
- IMRB U955, UPEC, Créteil, France
- Department of Physiology, AP-HP, Henri-Mondor Teaching Hospital, Créteil, France
- Fédération Hospitalo-Universitaire « SENEC », Créteil, France
| | - Maria Dorobantu
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
| | - Dirk J Duncker
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Etto C Eringa
- Department of Physiology, Amsterdam Cardiovascular Science Institute, Amsterdam University Medical Centres, Amsterdam, The Netherlands
- Department of Physiology, Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands
| | - Diana A Gorog
- Faculty of Medicine, National Heart and Lung Institute, Imperial College, London, UK
- Department of Postgraduate Medicine, University of Hertfordshire, Hatfield, UK
| | - Christian Hassager
- Department of Cardiology, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Frank R Heinzel
- Department of Cardiology, Charité-Universitaetsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany
- Berlin Institute of Health, Berlin, Germany
| | - Kurt Huber
- 3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminen Hospital, Vienna, Austria
- Medical School, Sigmund Freud University, Vienna, Austria
| | - Olivia Manfrini
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via Giuseppe Massarenti 9, 40134 Bologna, Italy
| | - Davor Milicic
- Department of Cardiovascular Diseases, University Hospital Centre Zagreb, University of Zagreb, Zagreb, Croatia
| | - Evangelos Oikonomou
- Department of Cardiology, ‘Hippokration’ General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Teresa Padro
- Cardiovascular Program ICCC-Research Institute Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, CiberCV, Barcelona, Spain
| | - Danijela Trifunovic-Zamaklar
- Cardiology Department, Clinical Centre of Serbia, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | | | - Marija Vavlukis
- University Clinic of Cardiology, Medical Faculty, Ss' Cyril and Methodius University in Skopje, Skopje, Republic of Macedonia
| | - Gemma Vilahur
- Cardiovascular Program ICCC-Research Institute Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, CiberCV, Barcelona, Spain
| | - Dimitris Tousoulis
- Department of Cardiology, ‘Hippokration’ General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
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31
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Bengs S, Rossi A, Haberecker M, Mikail N, Meisel A, Haider A, Grämer M, Portmann A, Todorov A, Schönenberger C, Gebhard CE, Kuster GM, Regitz-Zagrosek V, Gebhard C. Immunoreactivity of the SARS-CoV-2 entry proteins ACE-2 and TMPRSS-2 in murine models of hormonal manipulation, ageing, and cardiac injury. Sci Rep 2021; 11:23993. [PMID: 34907257 PMCID: PMC8671541 DOI: 10.1038/s41598-021-03181-3] [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: 06/24/2021] [Accepted: 11/22/2021] [Indexed: 12/24/2022] Open
Abstract
Previous work indicates that SARS-CoV-2 virus entry proteins angiotensin-converting enzyme 2 (ACE-2) and the cell surface transmembrane protease serine 2 (TMPRSS-2) are regulated by sex hormones. However, clinical studies addressing this association have yielded conflicting results. We sought to analyze the impact of sex hormones, age, and cardiovascular disease on ACE-2 and TMPRSS-2 expression in different mouse models. ACE-2 and TMPRSS-2 expression was analyzed by immunostaining in a variety of tissues obtained from FVB/N mice undergoing either gonadectomy or sham-surgery and being subjected to ischemia-reperfusion injury or transverse aortic constriction surgery. In lung tissues sex did not have a significant impact on the expression of ACE-2 and TMPRSS-2. On the contrary, following myocardial injury, female sex was associated to a lower expression of ACE-2 at the level of the kidney tubules. In addition, after myocardial injury, a significant correlation between younger age and higher expression of both ACE-2 and TMPRSS-2 was observed for lung alveoli and bronchioli, kidney tubules, and liver sinusoids. Our experimental data indicate that gonadal hormones and biological sex do not alter ACE-2 and TMPRSS-2 expression in the respiratory tract in mice, independent of disease state. Thus, sex differences in ACE-2 and TMPRSS-2 protein expression observed in mice may not explain the higher disease burden of COVID-19 among men.
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Affiliation(s)
- Susan Bengs
- Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | - Alexia Rossi
- Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | - Martina Haberecker
- Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Nidaa Mikail
- Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | - Alexander Meisel
- Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | - Achi Haider
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, and Department of Radiology, Harvard Medical School, Boston, MA, USA
| | - Muriel Grämer
- Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | - Angela Portmann
- Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | - Atanas Todorov
- Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | | | | | - Gabriela M Kuster
- Department of Cardiology, University Hospital Basel, Basel, Switzerland
- Department of Biomedicine, Myocardial Research, University of Basel, Basel, Switzerland
| | - Vera Regitz-Zagrosek
- Charité, Universitätsmedizin Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Catherine Gebhard
- Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland.
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.
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Zou P, Heath A, Sewell C, Lu Y, Tran D, Seo SK. EXOGENOUS Sex Hormones and Sex Hormone Receptor Modulators in COVID-19: Rationale and Clinical Pharmacology Considerations. Clin Pharmacol Ther 2021; 111:559-571. [PMID: 34888850 DOI: 10.1002/cpt.2508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 12/03/2021] [Indexed: 11/12/2022]
Abstract
Male patients with coronavirus disease 2019 (COVID-19) fare much worse than female patients in COVID-19 severity and mortality according to data from several studies. Because of this sex disparity, researchers hypothesize that the use of exogenous sex hormone therapy and sex hormone receptor modulators might provide therapeutic potential for patients with COVID-19. Repurposing approved drugs or drug candidates at late-stage clinical development could expedite COVID-19 therapy development because their clinical formulation, routes of administration, dosing regimen, clinical pharmacology, and potential adverse events have already been established or characterized in humans. A number of exogenous sex hormones and sex hormone receptor modulators are currently or will be under clinical investigation for COVID-19 therapy. In this review, we discuss the rationale for exogenous sex hormones and sex hormone receptor modulators in COVID-19 treatment, summarize ongoing and planned clinical trials, and discuss some of the clinical pharmacology considerations on clinical study design. To inform clinical study design and facilitate the clinical development of exogenous sex hormones and sex hormone receptor modulators for COVID-19 therapy, clinical investigators should pay attention to clinical pharmacology factors, such as dosing regimen, special populations (i.e., geriatrics, pregnancy, lactation, and renal/hepatic impairment), and drug interactions.
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Affiliation(s)
- Peng Zou
- Division of Cardiometabolic and Endocrine Pharmacology, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Agiua Heath
- Division of Urology, Obstetrics, and Gynecology, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Catherine Sewell
- Division of Urology, Obstetrics, and Gynecology, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Yanhui Lu
- Division of Cardiometabolic and Endocrine Pharmacology, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Doanh Tran
- Division of Cardiometabolic and Endocrine Pharmacology, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Shirley K Seo
- Division of Cardiometabolic and Endocrine Pharmacology, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
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Cadegiani FA, Zimerman RA, Fonseca DN, Correia MN, Muller MP, Bet DL, Slaviero MR, Zardo I, Benites PR, Barros RN, Paulain RW, Onety DC, Israel KCP, Gustavo Wambier C, Goren A. Final Results of a Randomized, Placebo-Controlled, Two-Arm, Parallel Clinical Trial of Proxalutamide for Hospitalized COVID-19 Patients: A Multiregional, Joint Analysis of the Proxa-Rescue AndroCoV Trial. Cureus 2021; 13:e20691. [PMID: 34976549 PMCID: PMC8712234 DOI: 10.7759/cureus.20691] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/25/2021] [Indexed: 02/06/2023] Open
Abstract
Background The role of androgens on COVID-19 is well established. Proxalutamide is a second-generation, non-steroidal antiandrogen (NSAA) with the highest antiandrogen potency among NSAAs and concurrent regulation of angiotensin-converting enzyme 2 (ACE2) expression and inflammatory response. Proxalutamide has been demonstrated to be effective to prevent hospitalizations in early COVID-19 in randomized clinical trials (RCTs). Conversely, in hospitalized COVID-19 patients, preliminary results from two different arms of an RCT (The Proxa-Rescue AndroCoV Trial) also demonstrated a reduction in all-cause mortality. This study aims to report the final, joint results of the two arms (North arm and South arm) of the Proxa-Rescue AndroCoV trial of the two arms (North and South arms) combined, and to evaluate whether COVID-19 response to proxalutamide was consistent across different regions (Northern Brazil and Southern Brazil). Materials and methods Upon randomization, hospitalized COVID-19 patients received either proxalutamide 300mg/day or placebo for 14 days, in addition to usual care, in a proxalutamide:placebo ratio of 1:1 in the North arm and 4:1 in the South arm (ratio was modified due to preliminary report of high drug efficacy). Datasets of the South and North arms were combined, and statistical analysis was performed for the overall study population. Proxalutamide was compared to placebo group for 14-day and 28-day recovery (discharge alive from the hospital) and mortality rates, and overall and post-randomization hospitalization stay. Results of proxalutamide and placebo groups were also compared between the North and South arms. Analysis was also performed stratified by sex and baseline WHO COVID Ordinary Score. Results A total of 778 subjects were included (645 from the North, 317 from the proxalutamide group and 328 from the placebo group; 133 from the South arm, 106 from the proxalutamide group and 27 from the placebo group). Recovery rate was 121% higher in proxalutamide than placebo group at day 14 [81.1% vs 36.6%; Recovery ratio (RecR) 2.21; 95% confidence interval (95% CI), 1.92-2.56; p<0.0001], and 81% higher at day 28 (98.1% vs 47.6%; RecR, 1.81; 95% CI, 1.61-2.03; p<0.0001). All-cause mortality rate was 80% lower in proxalutamide than placebo group at Day 14 [8.0% vs 39.2%; Risk ratio (RR), 0.20; 95% CI, 0.14-0.29; p<0.0001], and 78% lower at Day 28 (10.6% vs 48.2%; RR, 0.22; 95% CI 0.16-0.30). Post-randomization time-to-discharge was shorter in proxalutamide [median, 5 days; interquartile range (IQR), 3-8] than placebo group (median, 9 days; IQR, 6-14) (p<0.0001). Results were statistically similar between North and South arms for all measured outcomes. Males and females presented similar results in all outcomes. Patients that did not require oxygen use (scores 3 and 4) did not present statistically significant improvement in recovery and mortality rates, whereas scores 5 and 6 presented significant improvements in all outcomes (p<0.0001 for all). Conclusion Proxalutamide increased recovery rate, reduced mortality rate and shortened hospital stay in hospitalized COVID-19 patients. Results were similar between the two different arms, providing further consistency for the efficacy of proxalutamide when used in late-stage COVID-19.
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Affiliation(s)
| | - Ricardo A Zimerman
- Infectious Disease, Hospital da Brigada Militar de Porto Alegre, Porto Alegre, BRA
| | | | | | | | | | | | - Ivan Zardo
- Cardiology, Hospital Unimed Chapecó, Chapecó, BRA
| | | | - Renan N Barros
- Internal Medicine, Hospital Municipal Jofre Cohen, Parintins, BRA
| | - Raysa W Paulain
- Internal Medicine, Hospital Municipal Jofre Cohen, Parintins, BRA
| | - Dirce C Onety
- Critical Care, Samel & Oscar Nicolau Hospitals, Manaus, BRA
| | | | | | - Andy Goren
- Dermatology, Applied Biology Inc., Irvine, USA
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Masterson JM, Bui C, Zhang Y, Yuan X, Huynh C, Jawanda H, Hasan W, Tourtellotte W, Luthringer D, Garcia MM. Feminising hormone therapy reduces testicular ACE-2 receptor expression: Implications for treatment or prevention of COVID-19 infection in men. Andrologia 2021; 53:e14186. [PMID: 34514615 PMCID: PMC8646357 DOI: 10.1111/and.14186] [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: 05/05/2021] [Revised: 06/22/2021] [Accepted: 06/24/2021] [Indexed: 01/08/2023] Open
Abstract
It has been proposed that men hospitalised with COVID-19 be treated with oestrogen or progesterone to improve COVID-19 outcomes. Transgender women (male-to-female) are routinely treated with oestrogen or oestrogen +progesterone for feminisation which provides a model for the effect of feminising hormones on testicular tissue. Our goal was to analyse differences in ACE-2 expression in testicles of trans-women taking oestrogen or oestrogen +progesterone. Orchiectomy specimens were collected from trans-women undergoing gender-affirming surgery, who were taking oestrogen or oestrogen+progesterone preoperatively. For controls, we used benign orchiectomy specimens from cis-gender men. All specimens were stained with H&E, Trichrome (fibrosis), insulin-like 3 antibody (Leydig cell) and ACE-2 IHC. Cells per high-powered field were counted by cell type (Leydig, Sertoli and Germ). Stain intensity was rated on a 0-2 scale. On immunohistochemistry staining for Leydig cells and ACE-2 staining, the oestrogen+progesterone cohort had fewer Leydig cells compared with controls. The oestrogen+progesterone cohort also had greater degree of tissue fibrosis compared with controls and the oestrogen cohort. This work supports the hopeful possibility that a short course of progesterone (or oestrogen+progesterone) could downregulate ACE-2 to protect men from COVID-19 infection.
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Affiliation(s)
- John M. Masterson
- Department of SurgeryDivision of UrologyCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Chau Bui
- Pathology and Laboratory MedicineCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Yi Zhang
- Biobank and Translational Research, Pathology and Laboratory MedicineCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Xiaopen Yuan
- Biobank and Translational Research, Pathology and Laboratory MedicineCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Carissa Huynh
- Biobank and Translational Research, Pathology and Laboratory MedicineCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Harneet Jawanda
- Biobank and Translational Research, Pathology and Laboratory MedicineCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Wohaib Hasan
- Biobank and Translational Research, Pathology and Laboratory MedicineCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Warren Tourtellotte
- Pathology and Laboratory MedicineCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
- Biobank and Translational Research, Pathology and Laboratory MedicineCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Daniel Luthringer
- Pathology and Laboratory MedicineCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Maurice M. Garcia
- Department of SurgeryDivision of UrologyCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
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Lovre D, Bateman K, Sherman M, Fonseca VA, Lefante J, Mauvais-Jarvis F. Acute estradiol and progesterone therapy in hospitalised adults to reduce COVID-19 severity: a randomised control trial. BMJ Open 2021; 11:e053684. [PMID: 34848523 PMCID: PMC8635865 DOI: 10.1136/bmjopen-2021-053684] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION As of November 2021, COVID-19 has killed more than 5 million people globally, including over 750 000 in the USA. Apart from corticosteroids, most available therapeutic options are at best marginally efficient in reducing disease severity and are extremely expensive. The systematic investigation of clinically approved drugs is a priority to determine what does mitigate disease severity. Oestradiol (E2) and progesterone (P4) produce a state of anti-inflammatory immune responses and immune tolerance, and enhanced antibody production. The goal of this trial is to evaluate the efficacy of a short E2 and P4 therapy, in addition to standard of care (SOC), in mitigating disease severity in COVID-19 hospitalised patients. METHODS AND ANALYSIS Phase 2, randomised, double blind, placebo-controlled, single-centre trial. Patients hospitalised for confirmed COVID-19, with scores 3-5 on the 9-point WHO ordinal scale are randomised between two arms: (1) Oestradiol cypionate intramuscular (IM) and micronised progesterone oral (PO), in addition to SOC, and (2) placebo, in addition to SOC. The primary outcome is the proportion of patients improving to scores 1 or 2 on the WHO scale through day 28. Secondary outcomes include length of hospital stay, duration of mechanical ventilation, cause of death, readmission rates, change in inflammatory biomarkers between admission and occurrence of primary endpoint, and adverse events. Study sample size will be up to 120 participants. The trial is currently recruiting subjects. ETHICS AND DISSEMINATION The sponsor of this study is the Center of Excellence in Sex-Based Biology & Medicine at Tulane University, New Orleans, Louisiana, USA. Ethical approval was obtained from the Tulane institutional review board on 14 May 2021. The study was reviewed by the US Food and Drug Administration and granted Investigational New Drug #152 499. Results of the study will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER NCT04865029; Pre-results.
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Affiliation(s)
- Dragana Lovre
- Section of Endocrinology and Metabolism, John W. Deming Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
- Section of Endocrinology, Department of Medicine, Southeast Louisiana Veterans Health Care System, New Orleans, Louisiana, USA
- Tulane Center of Excellence in Sex-Based Biology & Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
| | - Kristin Bateman
- Section of General Internal Medicine and Geriatrics, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Mya Sherman
- Clinical Translational Unit, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Vivian A Fonseca
- Section of Endocrinology and Metabolism, John W. Deming Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
- Section of Endocrinology, Department of Medicine, Southeast Louisiana Veterans Health Care System, New Orleans, Louisiana, USA
| | - John Lefante
- Department of Biostatistics and Data Science, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA
| | - Franck Mauvais-Jarvis
- Section of Endocrinology and Metabolism, John W. Deming Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
- Section of Endocrinology, Department of Medicine, Southeast Louisiana Veterans Health Care System, New Orleans, Louisiana, USA
- Tulane Center of Excellence in Sex-Based Biology & Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
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Azeez JM, Susmi TR, Remadevi V, Ravindran V, Sasikumar Sujatha A, Ayswarya RNS, Sreeja S. New insights into the functions of progesterone receptor (PR) isoforms and progesterone signaling. Am J Cancer Res 2021; 11:5214-5232. [PMID: 34873457 PMCID: PMC8640821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 10/03/2021] [Indexed: 06/13/2023] Open
Abstract
Progesterone, the ovarian steroid hormone, regulates a plentitude of biological processes in tissues ranging from the brain to bones. Recognizing the role of progesterone and its receptors in physiological processes and maladies can prevent and treat various diseases. Apart from its physiological functions, its role in developing diseases, especially breast cancer, is a recent topic of deliberation. There exists conflicting experimental and epidemiological evidence linking progesterone to breast cancer. This review tries to describe the physiological functions of progesterone and its receptors, genomic and non-genomic signaling, splice variants, and a different aspect of progesterone signaling. Furthermore, we seek to address or attempt to discuss the following pertinent questions on steroid hormone signaling; How does progesterone influence breast cancer progression? How does it change the molecular pathways in breast cancer with different receptor statuses, the specific role of each isoform, and how does the ER/and PR ratio affect progesterone signaling?
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Affiliation(s)
- Juberiya M Azeez
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology Thiruvananthapuram, India
| | | | - Viji Remadevi
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology Thiruvananthapuram, India
| | - Vini Ravindran
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology Thiruvananthapuram, India
| | | | | | - Sreeharshan Sreeja
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology Thiruvananthapuram, India
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Sfera A, Osorio C, Rahman L, Zapata-Martín del Campo CM, Maldonado JC, Jafri N, Cummings MA, Maurer S, Kozlakidis Z. PTSD as an Endothelial Disease: Insights From COVID-19. Front Cell Neurosci 2021; 15:770387. [PMID: 34776871 PMCID: PMC8586713 DOI: 10.3389/fncel.2021.770387] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 10/11/2021] [Indexed: 12/15/2022] Open
Abstract
SARS-CoV-2 virus, the etiologic agent of COVID-19, has affected almost every aspect of human life, precipitating stress-related pathology in vulnerable individuals. As the prevalence rate of posttraumatic stress disorder in pandemic survivors exceeds that of the general and special populations, the virus may predispose to this disorder by directly interfering with the stress-processing pathways. The SARS-CoV-2 interactome has identified several antigens that may disrupt the blood-brain-barrier by inducing premature senescence in many cell types, including the cerebral endothelial cells. This enables the stress molecules, including angiotensin II, endothelin-1 and plasminogen activator inhibitor 1, to aberrantly activate the amygdala, hippocampus, and medial prefrontal cortex, increasing the vulnerability to stress related disorders. This is supported by observing the beneficial effects of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in both posttraumatic stress disorder and SARS-CoV-2 critical illness. In this narrative review, we take a closer look at the virus-host dialog and its impact on the renin-angiotensin system, mitochondrial fitness, and brain-derived neurotrophic factor. We discuss the role of furin cleaving site, the fibrinolytic system, and Sigma-1 receptor in the pathogenesis of psychological trauma. In other words, learning from the virus, clarify the molecular underpinnings of stress related disorders, and design better therapies for these conditions. In this context, we emphasize new potential treatments, including furin and bromodomains inhibitors.
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Affiliation(s)
- Adonis Sfera
- Department of Psychiatry, Loma Linda University, Loma Linda, CA, United States
- Patton State Hospital, San Bernardino, CA, United States
| | - Carolina Osorio
- Department of Psychiatry, Loma Linda University, Loma Linda, CA, United States
| | - Leah Rahman
- Patton State Hospital, San Bernardino, CA, United States
| | | | - Jose Campo Maldonado
- Department of Medicine, The University of Texas Rio Grande Valley, Edinburg, TX, United States
| | - Nyla Jafri
- Patton State Hospital, San Bernardino, CA, United States
| | | | - Steve Maurer
- Patton State Hospital, San Bernardino, CA, United States
| | - Zisis Kozlakidis
- International Agency For Research On Cancer (IARC), Lyon, France
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Spini A, Giudice V, Brancaleone V, Morgese MG, De Francia S, Filippelli A, Ruggieri A, Ziche M, Ortona E, Cignarella A, Trabace L. Sex-tailored pharmacology and COVID-19: Next steps towards appropriateness and health equity. Pharmacol Res 2021; 173:105848. [PMID: 34454035 PMCID: PMC8387562 DOI: 10.1016/j.phrs.2021.105848] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 08/21/2021] [Accepted: 08/22/2021] [Indexed: 12/12/2022]
Abstract
Making gender bias visible allows to fill the gaps in knowledge and understand health records and risks of women and men. The coronavirus disease 2019 (COVID-19) pandemic has shown a clear gender difference in health outcomes. The more severe symptoms and higher mortality in men as compared to women are likely due to sex and age differences in immune responses. Age-associated decline in sex steroid hormone levels may mediate proinflammatory reactions in older adults, thereby increasing their risk of adverse outcomes, whereas sex hormones and/or sex hormone receptor modulators may attenuate the inflammatory response and provide benefit to COVID-19 patients. While multiple pharmacological options including anticoagulants, glucocorticoids, antivirals, anti-inflammatory agents and traditional Chinese medicine preparations have been tested to treat COVID-19 patients with varied levels of evidence in terms of efficacy and safety, information on sex-targeted treatment strategies is currently limited. Women may have more benefit from COVID-19 vaccines than men, despite the occurrence of more frequent adverse effects, and long-term safety data with newly developed vectors are eagerly awaited. The prevalent inclusion of men in randomized clinical trials (RCTs) with subsequent extrapolation of results to women needs to be addressed, as reinforcing sex-neutral claims into COVID-19 research may insidiously lead to increased inequities in health care. The huge worldwide effort with over 3000 ongoing RCTs of pharmacological agents should focus on improving knowledge on sex, gender and age as pillars of individual variation in drug responses and enforce appropriateness.
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Affiliation(s)
- Andrea Spini
- University of Siena, Department of Medicine, Surgery and Neuroscience, 53100 Siena, Italy; University of Bordeaux, Bordeaux Population Health Center, UMR 1219, 33000 Bordeaux, France
| | - Valentina Giudice
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Baronissi, Italy
| | - Vincenzo Brancaleone
- Department of Science, University of Basilicata, via Ateneo Lucano, 85100 Potenza, Italy
| | - Maria Grazia Morgese
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Silvia De Francia
- Department of Clinical and Biological Sciences, S. Luigi Hospital, University of Turin, Italy
| | - Amelia Filippelli
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Baronissi, Italy
| | - Anna Ruggieri
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Marina Ziche
- University of Siena, Department of Medicine, Surgery and Neuroscience, 53100 Siena, Italy; University of Bordeaux, Bordeaux Population Health Center, UMR 1219, 33000 Bordeaux, France; Centro Studi Nazionale Salute e Medicina di Genere, Italy
| | - Elena Ortona
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy; Centro Studi Nazionale Salute e Medicina di Genere, Italy
| | - Andrea Cignarella
- Department of Medicine, University of Padova, via Giustiniani 2, 35128 Padova, Italy; Centro Studi Nazionale Salute e Medicina di Genere, Italy
| | - Luigia Trabace
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy; Centro Studi Nazionale Salute e Medicina di Genere, Italy.
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Felberbaum R, Küpker W. [COVID-19 from the perspective of a gynecological endocrinologist]. GYNAKOLOGISCHE ENDOKRINOLOGIE 2021; 19:311-314. [PMID: 34335125 PMCID: PMC8300072 DOI: 10.1007/s10304-021-00395-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/01/2021] [Indexed: 12/14/2022]
Abstract
Die von SARS-CoV‑2 („severe acute respiratory syndrome coronavirus 2“) ausgelöste infektiöse Atemwegserkrankung COVID-19 („coronavirus disease 2019“) weist in ihrem Verlauf und Schweregrad eine deutliche Abhängigkeit vom Geschlecht der Erkrankten auf. So ist die Inzidenzrate bei Frauen höher als bei Männern, während bei Männern schwere Verlaufsformen erheblich häufiger zu beobachten sind und die Mortalitätsrate bei ihnen signifikant höher ist. Allerdings unterscheiden sich wiederum prämenopausale und postmenopausale Frauen hinsichtlich des Verlaufs. Prämenopausale Frauen müssen seltener hospitalisiert werden und bedürfen seltener maschineller Beatmung. Postmenopausale Frauen, die eine Hormonersatztherapie erhalten, scheinen davon zu profitieren. Ergebnisse der Grundlagenforschung am Mausmodell zeigen, dass die weiblichen Sexualsteroide im Falle der Influenza den Entzündungsverlauf positiv beeinflussen bzw. im Falle von SARS-CoV‑2 die Empfänglichkeit gegenüber dem Virus herabsenken, während Androgene eine Erhöhung der Infektionsrate zur Folge haben. Dies gilt auch für Patientinnen mit polyzystischem Ovarsyndrom. Erste Ergebnisse von Therapiestudie mit Progesteron – wenngleich mit kleinen Patientenzahlen – weisen darauf hin, dass eine Therapie mit diesem Sexualsteroid sich positiv auf den Krankheitsverlauf bei betroffenen Männern auswirken kann. Allerdings zeigt auch die Verteilung der Komplikationen im Zusammenhang mit der Impfung gegen COVID-19 eine deutliche Geschlechterdifferenz, hier mit einem höheren relativen Risiko für jüngere Frauen.
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Affiliation(s)
- Ricardo Felberbaum
- Klinik für Frauenheilkunde und Geburtshilfe, Zentrum für Reproduktionsmedizin und gynäkologische Endokrinologie, Klinikum Kempten & Immenstadt, Klinikverbund Allgäu, Robert-Weixler-Str. 50, 87439 Kempten, Deutschland
| | - Wolfgang Küpker
- Zentrum für Reproduktionsmedizin und gynäkologische Endokrinologie, IVF Baden-Baden, Baden-Baden, Deutschland
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Arulkumaran N, Snow TAC, Kulkarni A, Brealey D, Rickman HM, Rees-Spear C, Spyer MJ, Heaney J, Garr E, Williams B, Cherepanov P, Kassiotis G, Lunn MP, Houlihan C, McCoy LE, Nastouli E, Singer M. Sex differences in immunological responses to COVID-19: a cross-sectional analysis of a single-centre cohort. Br J Anaesth 2021; 127:e75-e78. [PMID: 34140157 PMCID: PMC8156911 DOI: 10.1016/j.bja.2021.05.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 12/12/2022] Open
Affiliation(s)
| | - Timothy A C Snow
- Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK
| | - Adarsh Kulkarni
- Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK
| | - David Brealey
- Department of Clinical Virology, University College London, London, UK; Clinical Research Department, London School of Hygiene and Tropical Medicine, London, UK
| | - Hannah M Rickman
- Department of Clinical Virology, University College London Hospital and Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK
| | - Chloe Rees-Spear
- Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, London, UK; Advanced Pathogen Diagnostics Unit, Department of Clinical Virology, University College London Hospitals NHS Trust, London, UK; Biology of Infection Laboratory, The Francis Crick Institute, London, UK
| | - Moira J Spyer
- Advanced Pathogen Diagnostics Unit, Department of Clinical Virology, University College London Hospitals NHS Trust, London, UK
| | - Judith Heaney
- Neuroimmunology and CSF Laboratory, University College London Hospitals, National Hospital of Neurology and Neurosurgery, London, UK
| | - Edmund Garr
- Biology of Infection Laboratory, The Francis Crick Institute, London, UK
| | - Bryan Williams
- NIHR University College London Hospitals (UCL) Biomedical Research Centre, UK
| | - Peter Cherepanov
- Retroviral Immunology Laboratory, The Francis Crick Institute, London, UK
| | - George Kassiotis
- Neuroimmunology and CSF Laboratory, University College London Hospitals, National Hospital of Neurology and Neurosurgery, London, UK; Centre for Neuromuscular Disease, National Hospital for Neurology and Neurosurgery, London, UK
| | - Michael P Lunn
- Department of Clinical Virology, University College London, London, UK; Department of Clinical Virology, University College London Hospital and Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK
| | - Catherine Houlihan
- Department of Clinical Virology, University College London Hospital and Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK
| | - Laura E McCoy
- Department of Clinical Virology, University College London, London, UK; Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Eleni Nastouli
- Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK
| | - Mervyn Singer
- Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK.
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Hellberg S, Raffetseder J, Rundquist O, Magnusson R, Papapavlou G, Jenmalm MC, Ernerudh J, Gustafsson M. Progesterone Dampens Immune Responses in In Vitro Activated CD4 + T Cells and Affects Genes Associated With Autoimmune Diseases That Improve During Pregnancy. Front Immunol 2021; 12:672168. [PMID: 34054852 PMCID: PMC8149943 DOI: 10.3389/fimmu.2021.672168] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/26/2021] [Indexed: 12/13/2022] Open
Abstract
The changes in progesterone (P4) levels during and after pregnancy coincide with the temporary improvement and worsening of several autoimmune diseases like multiple sclerosis (MS) and rheumatoid arthritis (RA). Most likely immune-endocrine interactions play a major role in these pregnancy-induced effects. In this study, we used next generation sequencing to investigate the direct effects of P4 on CD4+ T cell activation, key event in pregnancy and disease. We report profound dampening effects of P4 on T cell activation, altering the gene and protein expression profile and reversing many of the changes induced during the activation. The transcriptomic changes induced by P4 were significantly enriched for genes associated with diseases known to be modulated during pregnancy such as MS, RA and psoriasis. STAT1 and STAT3 were significantly downregulated by P4 and their downstream targets were significantly enriched among the disease-associated genes. Several of these genes included well-known and disease-relevant cytokines, such as IL-12β, CXCL10 and OSM, which were further validated also at the protein level using proximity extension assay. Our results extend the previous knowledge of P4 as an immune regulatory hormone and support its importance during pregnancy for regulating potentially detrimental immune responses towards the semi-allogenic fetus. Further, our results also point toward a potential role for P4 in the pregnancy-induced disease immunomodulation and highlight the need for further studies evaluating P4 as a future treatment option.
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Affiliation(s)
- Sandra Hellberg
- Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.,Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Johanna Raffetseder
- Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Olof Rundquist
- Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden
| | - Rasmus Magnusson
- Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden
| | - Georgia Papapavlou
- Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Maria C Jenmalm
- Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Jan Ernerudh
- Department of Clinical Immunology and Transfusion Medicine and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Mika Gustafsson
- Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden
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