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1.
Cell Transplant ; 30: 9636897211049814, 2021.
Article in English | MEDLINE | ID: covidwho-1484237

ABSTRACT

During the past 18 months as the world dealt with the COVID-19 pandemic, articles published in Cell Transplantation (CT) voiced unique perspectives on the disease which have since been supported by additional research. Intrigued by the variability in COVID-19 severity, CT authors explored the influence of variants in angiotensin-converting enzyme 2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2) genes, as well as the role of androgen receptors on disease development. Mesenchymal stem cells (MSC) were offered up as a potential COVID-19 therapy because of their immune modulating characteristics and successful use in other acute respiratory diseases. Two CT author groups gave proof of principle when hospitalized COVID-19 patients were infused with MSC after no other interventions seemed to work. MSC treatment reduced disease severity and shortened hospitalization stays. Lastly, CT authors speculated why we are still in the midst of a pandemic and the consequences of disillusioned comfort as we face new emerging variants that may undermine all we have accomplished thus far.


Subject(s)
COVID-19/immunology , COVID-19/therapy , Mesenchymal Stem Cells/cytology , Serine Endopeptidases/genetics , Angiotensin-Converting Enzyme 2/metabolism , Biomedical Research , Cell Transplantation , Cytokines/metabolism , Hospitalization , Humans , Immune System , Mesenchymal Stem Cells/metabolism , Peptidyl-Dipeptidase A/genetics , Publications , Receptors, Androgen/metabolism , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index
2.
PLoS Pathog ; 17(9): e1009947, 2021 09.
Article in English | MEDLINE | ID: covidwho-1470670

ABSTRACT

Kaposi's sarcoma-associated herpesvirus (KSHV) preferentially infects and causes Kaposi's sarcoma (KS) in male patients. However, the biological mechanisms are largely unknown. This study was novel in confirming the extensive nuclear distribution of the androgen receptor (AR) and its co-localization with viral oncoprotein of latency-associated nuclear antigen in KS lesions, indicating a transcription way of AR in KS pathogenesis. The endogenous AR was also remarkably higher in KSHV-positive B cells than in KSHV-negative cells and responded to the ligand treatment of 5α-dihydrotestosterone (DHT), the agonist of AR. Then, the anti-AR antibody-based chromatin immunoprecipitation (ChIP)-associated sequencing was used to identify the target viral genes of AR, revealing that the AR bound to multiple regions of lytic genes in the KSHV genome. The highest peak was enriched in the core promoter sequence of polyadenylated nuclear RNA (PAN), and the physical interaction was verified by ChIP-polymerase chain reaction (PCR) and the electrophoretic mobility shift assay (EMSA). Consistently, male steroid treatment significantly transactivated the promoter activity of PAN in luciferase reporter assay, consequently leading to extensive lytic gene expression and KSHV production as determined by real-time quantitative PCR, and the deletion of nuclear localization signals of AR resulted in the loss of nuclear transport and transcriptional activity in the presence of androgen and thus impaired the expression of PAN RNA. Oncogenically, this study identified that the AR was a functional prerequisite for cell invasion, especially under the context of KSHV reactivation, through hijacking the PAN as a critical effector. Taken together, a novel mechanism from male sex steroids to viral noncoding RNA was identified, which might provide a clue to understanding the male propensity in KS.


Subject(s)
RNA, Messenger/metabolism , RNA, Viral/metabolism , Receptors, Androgen/metabolism , Sarcoma, Kaposi/metabolism , Sex Characteristics , Carcinogenesis/metabolism , Female , Herpesvirus 8, Human , Humans , Male , RNA, Untranslated/metabolism
3.
Sci Rep ; 11(1): 11130, 2021 05 27.
Article in English | MEDLINE | ID: covidwho-1246392

ABSTRACT

The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide administration. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Lung/drug effects , Receptors, Androgen/metabolism , Serine Endopeptidases/metabolism , Androgen Receptor Antagonists/pharmacology , Androgens , Angiotensin-Converting Enzyme 2/genetics , Animals , Benzamides/pharmacology , COVID-19/genetics , Cell Line, Tumor , Chromatin Immunoprecipitation Sequencing , Female , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Humans , Immunohistochemistry , Lung/metabolism , Lung/virology , Male , Mice , Nitriles/pharmacology , Phenylthiohydantoin/pharmacology , Serine Endopeptidases/genetics , Smokers
4.
Cell Cycle ; 19(24): 3632-3638, 2020 12.
Article in English | MEDLINE | ID: covidwho-1066164

ABSTRACT

PT150 is a clinical-stage molecule, taken orally, with a strong safety profile having completed Phase 1 and Phase 2 clinical trials for its original use as an antidepressant. It has an active IND for COVID-19. Antiviral activities have been found for PT150 and other members of its class in a variety of virus families; thus, it was now tested against SARS-CoV-2 in human bronchial epithelial lining cells and showed effective 90% inhibitory antiviral concentration (EC90) of 5.55 µM. PT150 is a member of an extended platform of novel glucocorticoid receptor (GR) and androgen receptor (AR) modulating molecules. In vivo, their predominant net effect is one of systemic glucocorticoid antagonism, but they also show direct downregulation of AR and minor GR agonism at the cellular level. We hypothesize that anti-SARS-CoV-2 activity depends in part on this AR downregulation through diminished TMPRSS2 expression and modulation of ACE2 activity. Given that hypercortisolemia is now suggested to be a significant co-factor for COVID-19 progression, we also postulate an additive role for its potent immunomodulatory effects through systemic antagonism of cortisol.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Receptors, Androgen/metabolism , Receptors, Glucocorticoid/metabolism , SARS-CoV-2/drug effects , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/virology , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/therapeutic use , Cell Line , Disease Progression , Down-Regulation , Glucocorticoids/antagonists & inhibitors , Glucocorticoids/metabolism , Humans , Hydrocortisone/antagonists & inhibitors , Immunologic Factors/pharmacology , Immunologic Factors/therapeutic use , Middle East Respiratory Syndrome Coronavirus/drug effects , Receptors, Glucocorticoid/agonists , Serine Endopeptidases/metabolism
5.
Infect Genet Evol ; 88: 104669, 2021 03.
Article in English | MEDLINE | ID: covidwho-1065472

ABSTRACT

Members of Coronaviridae family have been the source of respiratory illnesses. The outbreak of SARS-CoV-2 that produced a severe lung disease in afflicted patients in China and other countries was the reason for the incredible attention paid toward this viral infection. It is known that SARS-CoV-2 is dependent on TMPRSS2 activity for entrance and subsequent infection of the host cells and TMPRSS2 is a host cell molecule that is important for the spread of viruses such as coronaviruses. Different factors can increase the risk of prostate cancer, including older age, a family history of the disease. Androgen receptor (AR) initiates a transcriptional cascade which plays a serious role in both normal and malignant prostate tissues. TMPRSS2 protein is highly expressed in prostate secretory epithelial cells, and its expression is dependent on androgen signals. One of the molecular signs of prostate cancer is TMPRSS2-ERG gene fusion. In TMPRSS2-ERG-positive prostate cancers different patterns of changed gene expression can be detected. The possible molecular relation between fusion positive prostate cancer patients and the increased risk of lethal respiratory viral infections especially SARS-CoV-2 can candidate TMPRSS2 as an attractive drug target. The studies show that some molecules such as nicotinamide, PARP1, ETS and IL-1R can be studied deeper in order to control SARS-CoV-2 infection especially in prostate cancer patients. This review attempts to investigate the possible relation between the gene expression pattern that is produced through TMPRSS2-ERG fusion positive prostate cancer and the possible influence of these fluctuations on the pathogenesis and development of viral infections such as SARS-CoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Oncogene Proteins, Fusion/genetics , Prostatic Neoplasms/genetics , Serine Endopeptidases/genetics , Spike Glycoprotein, Coronavirus/genetics , Aged , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , COVID-19/pathology , COVID-19/virology , Dihydrotestosterone/metabolism , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Humans , Male , Oncogene Proteins, Fusion/metabolism , Prostatic Neoplasms/complications , Prostatic Neoplasms/pathology , Prostatic Neoplasms/virology , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Serine Endopeptidases/metabolism , Signal Transduction , Spike Glycoprotein, Coronavirus/metabolism , Transcription, Genetic , Virus Internalization
6.
Cell Transplant ; 30: 963689721991477, 2021.
Article in English | MEDLINE | ID: covidwho-1058182

ABSTRACT

TRANSLATIONAL RELEVANCE: No prophylactic treatments for COVID-19 have been clearly proven and found. In this pandemic context, cancer patients constitute a particularly fragile population that would benefit the best from such treatments, a present unmet need. TMPRSS2 is essential for COVID-19 replication cycle and it is under androgen control. Estrogen and androgen receptor dependent cues converge on TMPRSS2 regulation through different mechanisms of action that can be blocked by the use of hormonal therapies. We believe that there is enough body of evidence to foresee a prophylactic use of hormonal therapies against COVID-19 and this hypothesis can be easily tested on cohorts of breast and prostate cancer patients who follow those regimens. In case of pandemic, if the protective effect of hormonal therapies will be proven on cancer patients, the use of specific hormonal therapies could be extended to other oncological groups and to healthy individuals to decrease the overall risk of infection by SARS-CoV-2.Given the COVID-19 coronavirus emergency, a special focus is needed on the impact of this rapidly spreading viral infection on cancer patients. Androgen receptor (AR) signaling in the transmembrane protease serine 2 (TMPRSS2) regulation is emerging as an important determinant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility. In our study, we analyzed AR and TMPRSS2 expression in 17,352 normal and 9,556 cancer tissues from public repositories and stratified data according to sex and age. The emerging picture is that some patient groups may be particularly susceptible to SARS-CoV-2 infection and may benefit from antiandrogen- or tamoxifen-based therapies. These findings are relevant to choose proper treatments in order to protect cancer patients from concomitant SARS-CoV-2 contagion and related symptoms and put forward the idea that hormonal therapies could be used as prophylactic agents against COVID-19.


Subject(s)
Androgen Receptor Antagonists/therapeutic use , Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/complications , COVID-19/complications , Estrogen Antagonists/therapeutic use , Prostatic Neoplasms/complications , Tamoxifen/therapeutic use , Androgen Receptor Antagonists/pharmacology , Antineoplastic Agents, Hormonal/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , COVID-19/drug therapy , COVID-19/metabolism , Drug Discovery , Estrogen Antagonists/pharmacology , Female , Humans , Male , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Receptors, Androgen/analysis , Receptors, Androgen/metabolism , Serine Endopeptidases/analysis , Serine Endopeptidases/metabolism , Signal Transduction/drug effects , Tamoxifen/pharmacology
7.
Curr Drug Targets ; 22(10): 1149-1157, 2021.
Article in English | MEDLINE | ID: covidwho-948015

ABSTRACT

A novel betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV- -2), which caused a large disease outbreak in Wuhan, China in December 2019, is currently spreading across the world. Along with binding of the virus spike with the host cell receptor, fusion of the viral envelope with host cell membranes is a critical step in establishing successful infection of SARS-CoV-2. In this entry process, a diversity of host cell proteases and androgen receptor play a very important role directly or indirectly. These features of SARS-CoV-2 entry contribute to its rapid spread and severe symptoms, high fatality rates among infected patients. This review is based on the latest published literature including review articles, research articles, hypothetical manuscript, preprint articles and official documents. The literature search was made from various published papers on physiological aspects relevant to SARS-CoV and SARS-CoV-2. In this report, we focus on the role of host cell proteases (ACE2, ADAM17, TMPRSS2) and androgen receptor (AR) in SARS-CoV-2 infection. The hypotheses put forth by us are based on the role played by the proteases ACE2, ADAM17, TMPRSS2 and AR in SARS-CoV-2 infection, which were deduced based on various studies. We have also summarized how these host proteins increase the pathology and the infective ability of SARS-CoV-2 and we posit that their inhibition may be a therapeutic option for preventing SARS-CoV-2 infection.


Subject(s)
Biomarkers/metabolism , COVID-19/metabolism , SARS-CoV-2/physiology , ADAM17 Protein/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans , Molecular Targeted Therapy , Receptors, Androgen/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Serine Endopeptidases/metabolism , Virus Internalization/drug effects
8.
Int J Mol Sci ; 21(10)2020 May 21.
Article in English | MEDLINE | ID: covidwho-327277

ABSTRACT

The COVID-19 pandemic is marked by a wide range of clinical disease courses, ranging from asymptomatic to deadly. There have been many studies seeking to explore the correlations between COVID-19 clinical outcomes and various clinical variables, including age, sex, race, underlying medical problems, and social habits. In particular, the relationship between smoking and COVID-19 outcome is controversial, with multiple conflicting reports in the current literature. In this study, we aim to analyze how smoking may affect the SARS-CoV-2 infection rate. We analyzed sequencing data from lung and oral epithelial samples obtained from The Cancer Genome Atlas (TCGA). We found that the receptor and transmembrane protease necessary for SARS-CoV-2 entry into host cells, ACE2 and TMPRSS2, respectively, were upregulated in smoking samples from both lung and oral epithelial tissue. We then explored the mechanistic hypothesis that smoking may upregulate ACE2 expression through the upregulation of the androgen pathway. ACE2 and TMPRSS2 upregulation were both correlated to androgen pathway enrichment and the specific upregulation of central pathway regulatory genes. These data provide a potential model for the increased susceptibility of smoking patients to COVID-19 and encourage further exploration into the androgen and tobacco upregulation of ACE2 to understand the potential clinical ramifications.


Subject(s)
Androgens/metabolism , Coronavirus Infections/metabolism , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/metabolism , Serine Endopeptidases/genetics , Smoking/metabolism , Up-Regulation , Alveolar Epithelial Cells/metabolism , Angiotensin-Converting Enzyme 2 , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/genetics , Humans , Mouth Mucosa/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/epidemiology , Pneumonia, Viral/genetics , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Serine Endopeptidases/metabolism , Smoking/epidemiology , Smoking/genetics
10.
Drug Dev Res ; 81(7): 771-776, 2020 11.
Article in English | MEDLINE | ID: covidwho-263091

ABSTRACT

In this communication, we present arguments for androgen sensitivity as a likely determinant of COVID-19 disease severity. The androgen sensitivity model explains why males are more likely to develop severe symptoms while children are ostensibly resistant to infection. Further, the model explains the difference in COVID-19 mortality rates among different ethnicities. Androgen sensitivity is determined by genetic variants of the androgen receptor. The androgen receptor regulates transcription of the transmembrane protease, serine 2 (TMPRSS2), which is required for SARS-CoV-2 infectivity. TMPRSS2 primes the Spike protein of the virus, which has two consequences: diminishing viral recognition by neutralizing antibodies and activating SARS-CoV-2 for virus-cell fusion. Genetic variants that have been associated with androgenetic alopecia, prostate cancer, benign prostatic hyperplasia and polycystic ovary syndrome could be associated with host susceptibility. In addition to theoretical epidemiological and molecular mechanisms, there are reports of high rates of androgenetic alopecia of from hospitalized COVID-19 patients due to severe symptoms. Androgen sensitivity is a likely determinant of COVID-19 disease severity. We believe that the evidence presented in this communication warrants the initiation of trials using anti-androgen agents.


Subject(s)
Alopecia/etiology , COVID-19/complications , Receptors, Androgen/genetics , Alopecia/genetics , Alopecia/metabolism , COVID-19/genetics , COVID-19/metabolism , Humans , Male , Models, Theoretical , Pandemics , Receptors, Androgen/metabolism , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Severity of Illness Index , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
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