Biomedical Research and Therapy Biomedical Research and Therapy http://www.bmrat.org/ Biomedical Research and Therapy 10.15419/bmrat.v10i9.829 Endocrine-disrupting pesticides and SARS-CoV-2 infection: Role of ACE2, TMPRSS2 and CD147 Dixit Swati 1 Ahsan Haseeb drhahsan@gmail.com 2 Khan Fahim Halim fahimhkhan@rediffmail.com 1 Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India Department of Biochemistry, Faculty of Dentistry, Jamia Millia Islamia, New Delhi, India 10 9 5876 5883 Abstract

COVID-19 is a global pandemic caused by severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2). The three main receptors used by SARS-CoV-2 to bind and gain entry into human cells are ACE, TMPRSS2, and CD147. These molecular factors have crucial roles in human metabolism and homeostasis, but the upregulation of these factors causes severe diseases such as myocarditis, prostate cancer, and other endocrine-related cancers. Studies have found that once humans come into contact with SARS-CoV-2, the chances of being affected by such disorders increase; indeed, infection with the virus is associated with increased morbidity and mortality from heart attacks and pulmonary inflammation. Notably, exposure to some pesticides, such as chlorpyrifos, cypermethrin, and imidacloprid, which are identified as potential endocrine disruptors, causes such disorders by interfering with hormonal signaling pathways, such as the insulin-glucagon pathway and the thyroid pathway. This review focuses on the potential role of pesticides in exacerbating the comorbidities linked with SARS-CoV-2 and their effect on the molecular factors associated with SARS-CoV-2. Understanding the potential therapeutic implications of this link between SARS-CoV-2 severity and pesticides requires further clinical trials and investigations.

Keywords ACE2 cancer CD147 endocrine disruptors Pesticides SARS-CoV-2 TMPRSS2 Introduction

The year 2019 witnessed one of the major catastrophes of the world. Spreading globally, the novel coronavirus has become one of the greatest threats to humankind. This coronavirus belongs to the severe acute respiratory syndrome coronavirus (SARS-CoV) family1. First identified following an outbreak in 20042 in Yunnan, China, SARS is responsible for multiple respiratory diseases such as the common cold, bronchitis, and pneumonia caused by severe acute respiratory syndrome coronavirus (SARS-CoV), which also caused the viral pandemic outbreak in 2019 (COVID-19)3. Owing to the high nucleotide substitution and recombination capacity of coronaviruses, SARS-CoV-2 is still mutating and evolving rapidly4, 2. The severe outbreak of the novel strain SARS-CoV-2 in December 2019 in Wuhan Province of China caused a global breakdown in the economy while still posing a threat to human health, leading to unpredictable disastrous consequences5. SARS-CoVs are generally enveloped viruses with a single-stranded RNA genome6. The International Committee for Taxonomy of Viruses has classified the human coronavirus under the Coronaviridae family, which is genotypically and serologically further divided into four major genera: alpha-CoV, beta-CoV, gamma-CoV, and delta-CoV2. Before the emergence of human coronavirus, there was evidence for the presence and harboring of coronavirus in various animals, such as bovine coronavirus (BCoV) and feline infectious peritonitis virus (FIPV)7. Over time, the parallel development of poultry farming and urbanization, and the frequent close contact of animals with one another and their exposure to humans contributed to the evolution and transmission of coronavirus in other species, such as bats8, 9. Direct contact of humans with these coronavirus-harboring bats in 2019 has been suggested as a possible mode of transmission of the virus in humans10. Since then, SARS-CoV, which causes COVID-19, has affected many countries globally11. SARS-CoV-2 relies on ACE2, TMPRSS2, and CD147 to gain entry into human cells (Figure 1)12. ACE2, TMPRSS2, and CD147 receptors are present on the cells of various organs13 and, by attaching itself to these receptors through various mechanisms, SARS-CoV-2 is able to enter various organs of the human body14.

<bold id="s-81e7320c79cc">A representation of mechanism of SARS-CoV-2 interacting with host factors ACE2, TMPRSS2 and CD147 leading to organ dysfunction.</bold>

Abbreviations: ACE2: Angiotensin-Converting Enyzme 2; TMPRSS2: Transmembrane Serine Protease 2; CD147: Cluster of Differentiation 147

SARS-CoV-2 is composed of a phosphorylated nucleocapsid (N) protein containing genomic RNA5. This core unit is packed by a phospholipid bilayer envelope to form particles varying in shape and size ranging between 80-120 nm15. The characteristic feature of this assembly is characterized by sharp projections known as spike or spike proteins (S) present on the outer surface16. Regarding its protein composition, SARS-CoV-2 is composed of four structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins1. Only three viral proteins, S, E, and M, are embedded in the viral envelope, while the N protein is located in the core of the virus bound to the viral genomic RNA17. The S protein is a glycoprotein assembled as a trimeric unit and mediates receptor binding and membrane fusion, allowing the penetration and entry of the virus into host cells18. The genetic composition of SARS-CoV-2 is nonsegmented plus-sense single-stranded 26-31 kb RNA with varied G+C content (32%–43%)19. The genome composition is: 5′-leader-UTR-replicase/transcriptase-spike (S)-envelope (E)-membrane (M)-nucleocapsid (N)-3′UTR-poly (A) tail20. The 5′UTR and 3′UTR are involved in RNA-RNA interactions during the binding of viruses with other cellular proteins21.

The virus assembly consists of 4 structural proteins: nucleocapsid (N), envelope (E), spike (S), and membrane (M) protein1. After the synthesis of the SARS-CoV-2 structural proteins and genomic RNA at the replication site, an unknown mechanism translocates these entities at the ER-Golgi intermediate compartment (ERGIC) for the assembly of the virus and budding22, during which the structural proteins become embedded in the outer structure, while the N protein packs itself along with the genomic RNA, making up the virion23. The E and M proteins of the virus assembly help in budding, whereas the S protein is involved in the initial host-virus interaction24. The first step in the interaction is attachment of the virus to the cell membrane of the host, which is regulated by the S glycoprotein25. The S protein organizes itself in an identical trimeric manner23. Multiple copies of this structure are embedded in the viral envelope membrane, and this glycoprotein moiety is recognized by host cell receptors26. During biosynthesis and maturation in the infected cell, the recognition phase occurs, at which point this trimeric unit is usually cleaved from the viral structure by the protease furin from the Golgi apparatus27, leaving only two subunits behind, i.e., S1 and S2. The S1 subunit is recognized by angiotensin-converting enzyme (ACE2) and binds to it1. After budding, the virus moves to the ERGIC lumen and reaches the plasma membrane, traveling through secretory pathways where the S2 subunit fuses with the membrane mediated by a fusion peptide (FP)28.

 <bold id="strong-1">Involvement of SARS-CoV-2</bold> <bold id="strong-2">-</bold> <bold id="strong-3">associated molecular factors</bold> <bold id="s-aefb2faf2fa9">ACE2</bold>

Angiotensin-converting enzyme 2 (ACE2) is an enzyme found in various locations in the human body29. It is mostly found attached to the cell membranes of the heart, intestines, gall bladder, testes, and kidney30, 31. It exists in two forms: membrane-bound (mACE2) and soluble (sACE2)32, which make up the renin-angiotensin-aldosterone system (RAAS) that maintains the body’s blood pressure33. mACE2 acts on the enzyme ADAM17, cleaving its extracellular domain to create sACE2, which catalyzes the hydrolysis of angiotensin II into angiotensin34. Angiotensin II is a vasoconstrictor peptide angiotensin (1-7)35 and induces vasodilation after binding with MasR receptors, hence lowering blood pressure and antagonizing the effects of ACE236. This phenomenon is a potential target for drugs that are used in cardiovascular disease treatment37. ACE2 (membrane-bound) is also functionally known as the receptor for the spike glycoprotein of the human coronavirus SARS-CoV-238. Recognizing this interaction of ACE2 with SARS-CoV-2 has accelerated some novel therapeutic approaches to reduce ACE2 expression or block the enzyme to prevent the cellular entry of SARS-CoV-2 in the kidney, heart, lung, and brain, where ACE2 is expressed39.

 <bold id="s-5dbdd7c8796f">TMPRSS2</bold>

Transmembrane serine protease 2 (TMPRSS2) is a cell surface protein located in endothelial cells lining the heart, liver, respiratory, and digestive tracts40. As a serine protease, it is functionally involved in the cleavage of peptide bonds of proteins that have serine as the nucleophilic amino acid within the active site41. It is encoded by the TMPRSS2 gene and is a member of the TMPRSS family of transmembrane proteins exhibiting serine protease activity42. The protease activity of this protein is used by SARS-CoV-2 to enter cells43. Mutations of the TMPRSS2 gene can lead to prostate cancer. The overexpression of TMPRSS2 and prostate carcinogenesis involves the interplay of the transcription factors ERG and ETV144, 45. Their enhanced expression stimulates the downregulation of androgen receptor signaling46. The protease activity of TMPRSS2 is exploited by SARS-CoV-2 to gain entry into the heart, liver, and respiratory cells40. The S1 and S2 subunits of the virus are cleaved by the proteolytic activity of TMPRSS229.

 <bold id="s-84440d396957">CD147</bold>

In addition to ACE2 and TMPRSS2, another receptor, CD147, is also responsible for SARS-CoV-2 entry into the epithelial cell lining12. CD147 is a transmembrane receptor that forms a transmembrane supramolecular complex and interacts with several extracellular and intracellular factors47. CD147 suppresses NOD2 and the gamma‐secretase protein complex48. NOD2 is part of the innate immune system, and gamma-secretase is responsible for the cleavage of beta-amyloid precursor from the plasma membrane17. Owing to its diverse interactions, CD147 has crucial roles in cell metabolism, motility, and activation49. The initiation of programmed cell death, lymphopenia, and cellular overactivation is suggested to occur as a result of the CD147-SARS-CoV-2 interaction50. Cyclophilins A and B are the two main extracellular ligands of CD147 that are recognized by the nucleocapsid protein and then bind with the spike protein of SARS-CoV-249. The presence of three Asn glycosylation sites in this receptor is also suggested to bind with the glycosylated spike protein of SARS-CoV-251, 52.

<bold id="s-f61f2cb746ad">The relation between pesticides induced metabolic disorders associated with SARS-CoV-2 severity and the involvement of some receptors (ACE2, TMPRSS2, CD147).</bold>

Abbreviations: ACE2: Angiotensin-Converting Enyzme 2; TMPRSS2: Transmembrane Serine Protease 2; CD147: Cluster of Differentiation 147

<bold id="strong-5">Effect of </bold> <bold id="strong-6">pesticide</bold> <bold id="strong-7"> exposure on ACE2, TMPRSS2 </bold> <bold id="strong-8">and</bold> <bold id="strong-9"> CD147</bold> <bold id="strong-10"> </bold>

Endocrine disruptors (EDs) are chemicals that disturb normal human body metabolism by interfering with hormones in the endocrine system53. These chemicals are known to cause developmental, neurological, reproductive, and immunological disorders54 and are present in plasticware, detergents, cosmetics, and pesticides55. This review focuses on pesticides as endocrine disruptors. Human exposure to such chemicals can cause cardiometabolic diseases, hypertension, diabetes, and other endocrine-related cancers56. With the expansion of SARS-CoV-2 worldwide, the risk of severe diseases such as asthma, cancer, cardiovascular disease, hypertension, diabetes57, and obesity also increased, suggesting a possible connection of these chemicals with SARS-CoV-2.

Although these relationships have not yet been explored to any great extent, several studies hint at the possible involvement of ED chemicals in SARS-CoV-2 susceptibility. Pesticides such as chlorpyrifos, deltamethrin, cypermethrin, and imidacloprid have been identified as possible endocrine disruptors58. Using computational approaches, some of the pathways have been identified as potential targets of endocrine disruptors that contribute to COVID-19 severity59. These signaling pathways include TNF60, insulin resistance, endocrine resistance, MAPK61, IL-17, and prolactin pathways62. Ivermectin is an insecticide that has been identified to show mosquitocidal effects. A study by Lehrer et al. showed the interaction of ivermectin binding with the SARS-CoV-2 spike-RBD-ACE2 complex63. A study of cotton aphids exposed to omethoate, an insecticide, was found to downregulate ACE2 mRNA64. The insecticide methamidophos has been shown to affect ACE2 levels in Oomyzus sokolowskii 65, while some organophosphates have been found to affect ACE2 via RNA interference (RNAi)66.

Pesticides are a broad range of chemicals widely used in domestic settings and agriculture67. Exposure to pesticides such as organochlorines, pyrethroids, organophosphates, and carbamates results in disturbances in the normal hormonal functioning of the human body68. Therefore, these chemicals are also classified as endocrine disruptors67. Exposure to these chemicals with human mitochondrial metabolic factors such as ACE2, TMRPSS2, and CD147 also opens the door for SARS-CoV-2 involvement69 (Figure 2). The novel beta-SARS-CoV-2 caused the global health crisis COVID-192. When the virus comes into contact with its living host, it targets ACE2, TMPRSS2, and CD14770. Environmental pollutants can have a wide range of effects on human metabolism. It has been reported that particulate matter from smoking or factories can increase SARS-CoV-2 severity71, but it is unclear whether these pesticides can make organs more susceptible to SARS-CoV-272. Studies have revealed that activation of the IL-8/CXCR1/2 pathway in lung fibroblasts is triggered by pesticides and air pollutants62, resulting in upregulation of ACE2 and TMPRSS2 levels, thereby increasing the risk of SARS-CoV-2 infection. The upregulation was prevented by blocking the IL-8/CXCR1/2 pathway73. Clinical trials are required to determine whether pesticides are linked with SARS-CoV-2 severity and, if yes, it is important to directly or indirectly uncover the underlying mechanisms and pathways74. Given the importance of TMPRSS2 in SARS-CoV-2 infection, a number of studies have considered potential therapeutic approaches that might target this receptor. Certain selective bioactive compounds, from organisms such as P. grandiflorus, show promise as an alternative treatment option against SARS-CoV-2 infections by targeting TMPRSS275. Similarly, designing peptide-mimicking compounds that can inhibit TMPRSS2 activity is another possible approach76. α-Terthienyl, a new-generation insecticide, downregulates TMPRSS2 by reducing its mRNA and protein expression77 but increases the expression of p27, a tumor suppressor gene78. Some anti-CD147 drugs, such as meplazumab, inhibit SARS-CoV-2 in patients with COVID‐19 pneumonia79. Another approach is the truncation of the cytoplasmic tail of CD147 to prevent the entry of SARS‐CoV‐280. As discussed, some environmental toxicants (pesticides) are known to modulate ACE2, TMPRSS2, and CD147 expression thus, further preclinical studies and clinical trials are required to assess inhibitory compounds against these toxicants81.

 Conclusion

The receptors ACE2, TMPRSS2 and CD147 are the main entry for the SARS-CoV-2 in humans. These molecular factors play a crucial role in human metabolism and homeostatis but their overexpression and upregulation leads to various pathophysiological conditions. The endocrine disrupting pesticides such as chlorpyripos, cypermethrin, imidacloprid modulate the expression of ACE2, TMPRSS2 and CD147. The COVID-19 is associated with severe inflammatory conditions leading to cardiovascular and pulmonary pathologies. Hence, the exposure of these endocrine disrupting pesticides will increase the comorbidities associated with SARS-CoV-2 infection by interfering with the hormonal signaling pathways. Hence, the present review article explores the link between pesticide exposure and endocrine receptors associated with SARS-CoV-2 infection.

 Abbreviations

ACE2: angiotensin onverting enzyme 2; CD147: cluster of differentiation 147; COVID-19: coronavirus disease-2019; ED: endocrine disrupting/disruptors; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TMPRSS2: transmembrane serine protease 2

 Acknowledgments

None.

 Author’s contributions

SD: data collection; analysis and interpretation of results; draft manuscript preparation. HA: study conception and design; analysis and interpretation of results; draft manuscript preparation; correction and proofreading of manuscript. FHK: study conception and design; analysis and interpretation of results; All authors approved the final version of the manuscript for submission.

 Funding

None.

 Availability of data and materials

Not applicable.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

 References Jackson C.B. Farzan M. Chen B. Choe H. Mechanisms of SARS-CoV-2 entry into cells Nature Reviews. Molecular Cell Biology 2022 23 1 3 20 1471-0080 https://doi.org/10.1038/s41580-021-00418-x 34611326 Wu F. Zhao S. Yu B. Chen Y.M. Wang W. Song Z.G. Hu Y. Tao Z.W. Tian J.H. Pei Y.Y. Yuan M.L. Zhang Y.L. Dai F.H. Liu Y. Wang Q.M. Zheng J.J. Xu L. Holmes E.C. Zhang Y.Z. A new coronavirus associated with human respiratory disease in China Nature 2020 2020 579 265 580:E7 https://doi.org/10.1038/s41586-020-2008-3 Pene F. Merlat A. Vabret A. Rozenberg F. Buzyn A. Dreyfus F. Coronavirus 229E-related pneumonia in immunocompromised patients Clinical Infectious Diseases 2003 37 7 929 32 1537-6591 https://doi.org/10.1086/377612 13130404 Vijgen L. Keyaerts E. Moës E. Maes P. Duson G. Van Ranst M. Development of one-step, real-time, quantitative reverse transcriptase PCR assays for absolute quantitation of human coronaviruses OC43 and 229E Journal of Clinical Microbiology 2005 43 11 5452 6 0095-1137 https://doi.org/10.1128/JCM.43.11.5452-5456.2005 16272469 Zhou P. Yang X.L. Wang X.G. Hu B. Zhang L. Zhang W. A pneumonia outbreak associated with a new coronavirus of probable bat origin Nature 2020 579 7798 270 3 1476-4687 https://doi.org/10.1038/s41586-020-2012-7 32015507 Masters P.S. The molecular biology of coronaviruses Advances in Virus Research 2006 66 193 292 0065-3527 https://doi.org/10.1016/S0065-3527(06)66005-3 16877062 Saif L.J. Animal coronaviruses: what can they teach us about the severe acute respiratory syndrome? Revue Scientifique et Technique (International Office of Epizootics) 2004 23 2 643 60 0253-1933 https://doi.org/10.20506/rst.23.2.1513 15702725 Xie J. Li Y. Shen X. Goh G. Zhu Y. Cui J. Dampened STING-dependent interferon activation in bats Cell Host & Microbe 2018 23 3 P297 301.e4 1934-6069 https://doi.org/10.1016/j.chom.2018.01.006 29478775 Gouilh M. Ar Puechmaille S.J. Diancourt L. Vandenbogaert M. Serra-Cobo J. Roig M. Lopez consortium EPICOREM SARS-CoV related Betacoronavirus and diverse Alphacoronavirus members found in western old-world Virology 2018 517 88 97 1096-0341 https://doi.org/10.1016/j.virol.2018.01.014 29482919 Banerjee A. Kulcsar K. Misra V. Frieman M. Mossman K. Bats and Coronaviruses Viruses 2019 11 1 41 1999-4915 https://doi.org/10.3390/v11010041 30634396 Kirtipal N. Bharadwaj S. Kang S.G. From SARS to SARS-CoV-2, insights on structure, pathogenicity and immunity aspects of pandemic human coronaviruses Infection, Genetics and Evolution 2020 85 104502 1567-7257 https://doi.org/10.1016/j.meegid.2020.104502 32798769 Wang K. Chen W. Zhou Y.S. SARS‐CoV‐2 invades host cells via a novel route: CD147‐spike protein bioRxiv. 2020:2020.2003.2014.988345. 2020 https://doi.org/10.1101/2020.03.14.988345 Lan J. Ge J. Yu J. Shan S. Zhou H. Fan S. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor Nature 2020 581 7807 215 20 1476-4687 https://doi.org/10.1038/s41586-020-2180-5 32225176 Walls A.C. Park Y.J. Tortorici M.A. Wall A. McGuire A.T. Veesler D. Structure, function, and antigenicity of the SARS- CoV-2 spike glycoprotein Cell 2020 181 2 1097-4172 https://doi.org/10.1016/j.cell.2020.02.058 32155444 Bárcena M. Oostergetel G.T. Bartelink W. Faas F.G. Verkleij A. Rottier P.J. Cryo-electron tomography of mouse hepatitis virus: insights into the structure of the coronavirion Proceedings of the National Academy of Sciences of the United States of America 2009 106 2 582 7 1091-6490 https://doi.org/10.1073/pnas.0805270106 19124777 Neuman B.W. Adair B.D. Yoshioka C. Quispe J.D. Orca G. Kuhn P. Supramolecular architecture of severe acute respiratory syndrome coronavirus revealed by electron cryomicroscopy Journal of Virology 2006 80 16 7918 28 0022-538X https://doi.org/10.1128/JVI.00645-06 16873249 Zhou S. Zhou H. Walian P.J. Jap B.K. CD147 is a regulatory subunit of the gamma-secretase complex in Alzheimer's disease amyloid beta-peptide production Proceedings of the National Academy of Sciences of the United States of America 2005 102 21 7499 504 0027-8424 https://doi.org/10.1073/pnas.0502768102 15890777 Bosch B.J. van der Zee R. de Haan C.A. Rottier P.J. The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex Journal of Virology 2003 77 16 8801 11 0022-538X https://doi.org/10.1128/JVI.77.16.8801-8811.2003 12885899 Yang H. Bartlam M. Rao Z. Drug design targeting the main protease, the Achilles' heel of coronaviruses Current Pharmaceutical Design 2006 12 35 4573 90 1873-4286 https://doi.org/10.2174/138161206779010369 17168763 Mousavizadeh L. Ghasemi S. Genotype and phenotype of COVID-19: Their roles in pathogenesis Journal of Microbiology, Immunology and Infection 2021 54 2 159 63 https://doi.org/10.1016/j.jmii.2020.03.022 Yang D. Leibowitz J.L. The structure and functions of coronavirus genomic 3' and 5' ends Virus Research 2015 206 120 33 1872-7492 https://doi.org/10.1016/j.virusres.2015.02.025 25736566 Stertz S. Reichelt M. Spiegel M. Kuri T. Martínez-Sobrido L. García-Sastre A. The intracellular sites of early replication and budding of SARS-coronavirus Virology 2007 361 2 304 15 0042-6822 https://doi.org/10.1016/j.virol.2006.11.027 17210170 V'kovski P. Kratzel A. Steiner S. Stalder H. Thiel V. Coronavirus biology and replication: implications for SARS-CoV-2 Nature Reviews. Microbiology 2021 19 3 155 70 1740-1534 https://doi.org/10.1038/s41579-020-00468-6 33116300 Goldsmith C.S. Tatti K.M. Ksiazek T.G. Rollin P.E. Comer J.A. Lee W.W. Ultrastructural characterization of SARS coronavirus Emerging Infectious Diseases 2004 10 2 320 6 1080-6040 https://doi.org/10.3201/eid1002.030913 15030705 Shang J. Wan Y. Luo C. Ye G. Geng Q. Auerbach A. Cell entry mechanisms of SARS-CoV-2 Proceedings of the National Academy of Sciences of the United States of America 2020 117 21 11727 34 1091-6490 https://doi.org/10.1073/pnas.2003138117 32376634 Schoeman D. Fielding B.C. Coronavirus envelope protein: current knowledge Virology Journal 2019 16 1 69 1743-422X https://doi.org/10.1186/s12985-019-1182-0 31133031 Hoffmann M. Kleine-Weber H. Pöhlmann S. Multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells Molecular Cell 2020 78 4 1097-4164 https://doi.org/10.1016/j.molcel.2020.04.022 32362314 Fehr A.R. Perlman S. Coronaviruses: an overview of their replication and pathogenesis Methods in Molecular Biology (Clifton, N.J.) 2015 1282 1 23 1940-6029 https://doi.org/10.1007/978-1-4939-2438-7_1 25720466 NCBI "Gene: ACE2, angiotensin I converting enzyme 2". National Center for Biotechnology Information (NCBI). U.S. National Library of Medicine. 2020-02-28 2020 Hikmet F. Méar L. Edvinsson A.A. Micke P. Uhlén M. Lindskog C. The protein expression profile of ACE2 in human tissues Molecular Systems Biology 2020 16 7 e9610 1744-4292 https://doi.org/10.15252/msb.20209610 32715618 Hamming I. Timens W. Bulthuis M.L. Lely A.T. Navis G. van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis The Journal of Pathology 2004 203 2 631 7 0022-3417 https://doi.org/10.1002/path.1570 15141377 Diz D.I. Garcia-Espinosa M.A. Gegick S. Tommasi E.N. Ferrario C.M. Ann Tallant E. Injections of angiotensin-converting enzyme 2 inhibitor MLN4760 into nucleus tractus solitarii reduce baroreceptor reflex sensitivity for heart rate control in rats Experimental Physiology 2008 93 5 694 700 0958-0670 https://doi.org/10.1113/expphysiol.2007.040261 18356558 Dong B. Zhang C. Feng J.B. Zhao Y.X. Li S.Y. Yang Y.P. Overexpression of ACE2 enhances plaque stability in a rabbit model of atherosclerosis Arteriosclerosis, Thrombosis, and Vascular Biology 2008 28 7 1270 6 1524-4636 https://doi.org/10.1161/ATVBAHA.108.164715 18403726 Ferrario C.M. Jessup J. Gallagher P.E. Averill D.B. Brosnihan K.B. Ann Tallant E. Effects of renin-angiotensin system blockade on renal angiotensin-(1-7) forming enzymes and receptors Kidney International 2005 68 5 2189 96 0085-2538 https://doi.org/10.1111/j.1523-1755.2005.00675.x 16221218 Hoffmann M. Kleine-Wever H. Kruger N. Muller M. Drotsten C. Pholhlmann S. The novel coronavirus 2019 (2019-nCoV) uses the SARS coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry in target cells Cell 2020 181 1 10 0092-8674 Garabelli P.J. Modrall J.G. Penninger J.M. Ferrario C.M. Chappell M.C. Distinct roles for angiotensin-converting enzyme 2 and carboxypeptidase A in the processing of angiotensins within the murine heart Experimental Physiology 2008 93 5 613 21 0958-0670 https://doi.org/10.1113/expphysiol.2007.040246 18356559 Jia H.P. Look D.C. Tan P. Shi L. Hickey M. Gakhar L. Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia American Journal of Physiology. Lung Cellular and Molecular Physiology 2009 297 1 84 96 1522-1504 https://doi.org/10.1152/ajplung.00071.2009 19411314 Kuba K. Imai Y. Rao S. Gao H. Guo F. Guan B. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury Nature Medicine 2005 11 8 875 9 1078-8956 https://doi.org/10.1038/nm1267 16007097 Wrapp D. Wang N. Corbett K.S. Goldsmith J.A. Hsieh C.L. Abiona O. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Science 2020 367 6483 1260 3 1095-9203 https://doi.org/10.1126/science.abb2507 32075877 Bertram S. Glowacka I. Blazejewska P. Soilleux E. Allen P. Danisch S. TMPRSS2 and TMPRSS4 facilitate trypsin-independent spread of influenza virus in Caco-2 cells Journal of Virology 2010 84 19 10016 25 1098-5514 https://doi.org/10.1128/JVI.00239-10 20631123 Thunders M. Delahunt B. Gene of the month: TMPRSS2 (transmembrane serine protease 2) Journal of Clinical Pathology 2020 73 12 773 6 1472-4146 https://doi.org/10.1136/jclinpath-2020-206987 32873700 Gierer S. Bertram S. Kaup F. Wrensch F. Heurich A. Krämer-Kühl A. The spike protein of the emerging betacoronavirus EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing antibodies Journal of Virology 2013 87 10 5502 11 1098-5514 https://doi.org/10.1128/JVI.00128-13 23468491 Bossart K.N. Wang L.F. Flora M.N. Chua K.B. Lam S.K. Eaton B.T. Membrane fusion tropism and heterotypic functional activities of the Nipah virus and Hendra virus envelope glycoproteins Journal of Virology 2002 76 22 11186 98 0022-538X https://doi.org/10.1128/JVI.76.22.11186-11198.2002 12388678 Winnes M. Lissbrant E. Damber J.E. Stenman G. Molecular genetic analyses of the TMPRSS2-ERG and TMPRSS2-ETV1 gene fusions in 50 cases of prostate cancer Oncology Reports 2007 17 5 1033 6 1021-335X https://doi.org/10.3892/or.17.5.1033 17390040 Beuzeboc P. Soulié M. Richaud P. Salomon L. Staerman F. Peyromaure M. [Fusion genes and prostate cancer. From discovery to prognosis and therapeutic perspectives] Progres en Urologie 2009 19 11 819 24 1166-7087 https://doi.org/10.1016/j.purol.2009.06.002 19945666 Yu J. Yu J. Mani R.S. Cao Q. Brenner C.J. Cao X. An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression Cancer Cell 2010 17 5 443 54 1878-3686 https://doi.org/10.1016/j.ccr.2010.03.018 20478527 Muramatsu T. Basigin (CD147), a multifunctional transmembrane glycoprotein with various binding partners Journal of Biochemistry 2016 159 5 481 90 1756-2651 https://doi.org/10.1093/jb/mvv127 26684586 Till A. Rosenstiel P. Bräutigam K. Sina C. Jacobs G. Oberg H.H. A role for membrane-bound CD147 in NOD2-mediated recognition of bacterial cytoinvasion Journal of Cell Science 2008 121 Pt 4 487 95 0021-9533 https://doi.org/10.1242/jcs.016980 18256385 Radzikowska U. Ding M. Tan G. Zhakparov D. Peng Y. Wawrzyniak P. Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors Allergy 2020 75 11 2829 45 1398-9995 https://doi.org/10.1111/all.14429 32496587 Goyal P. Choi J.J. Pinheiro L.C. Schenck E.J. Chen R. Jabri A. Clinical Characteristics of Covid-19 in New York City The New England Journal of Medicine 2020 382 24 2372 4 1533-4406 https://doi.org/10.1056/NEJMc2010419 32302078 Huang W. Luo W.J. Zhu P. Tang J. Yu X.L. Cui H.Y. Modulation of CD147-induced matrix metalloproteinase activity: role of CD147 N-glycosylation The Biochemical Journal 2013 449 2 437 48 1470-8728 https://doi.org/10.1042/BJ20120343 23005037 Vankadari N. Wilce J.A. Emerging WuHan (COVID-19) coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26 Emerging Microbes & Infections 2020 9 1 601 4 2222-1751 https://doi.org/10.1080/22221751.2020.1739565 32178593 Dixit S. Zia M.K. Siddiqui T. Ahsan H. Khan F.H. Interaction of Human Alpha-2-Macroglobulin with Pesticide Aldicarb Using Spectroscopy and Molecular Docking Protein and Peptide Letters 2021 28 3 315 22 1875-5305 https://doi.org/10.2174/0929866527666200921165834 32957873 Mnif W. Hassine A.I. Bouaziz A. Bartegi A. Thomas O. Roig B. Effect of endocrine disruptor pesticides: a review International Journal of Environmental Research and Public Health 2011 8 6 2265 303 1660-4601 https://doi.org/10.3390/ijerph8062265 21776230 Darbre P.D. Chemical components of plastics as endocrine disruptors: overview and commentary Birth Defects Research 2020 112 17 1300 7 2472-1727 https://doi.org/10.1002/bdr2.1778 32720473 Zahra A. Sisu C. Silva E. De Aguiar Greca S.C. Randeva H.S. Chatha K. Is There a Link between Bisphenol A (BPA), a Key Endocrine Disruptor, and the Risk for SARS-CoV-2 Infection and Severe COVID-19? Journal of Clinical Medicine 2020 9 10 3296 2077-0383 https://doi.org/10.3390/jcm9103296 33066495 Sandoval M. Nguyen D.T. Vahidy F.S. Graviss E.A. Risk factors for severity of COVID-19 in hospital patients age 18-29 years PLoS One 2021 16 7 e0255544 1932-6203 https://doi.org/10.1371/journal.pone.0255544 34329347 Abdel-Razik R.K. Mosallam E.M. Hamed N.A. Badawy M.E. Abo-El-Saad M.M. Testicular deficiency associated with exposure to cypermethrin, imidacloprid, and chlorpyrifos in adult rats Environmental Toxicology and Pharmacology 2021 87 103724 1872-7077 https://doi.org/10.1016/j.etap.2021.103724 34416397 Wu Q. Coumoul X. Grandjean P. Barouki R. Audouze K. Endocrine disrupting chemicals and COVID-19 relationships: a computational systems biology approach medRxiv 2020 2020 https://doi.org/10.1101/2020.07.10.20150714 Fabregat A. Jupe S. Matthews L. Sidiropoulos K. Gillespie M. Garapati P. The Reactome Pathway Knowledgebase Nucleic Acids Research 2018 46 649 55 1362-4962 https://doi.org/10.1093/nar/gkx1132 29145629 Kanehisa M. Sato Y. Furumichi M. Morishima K. Tanabe M. New approach for understanding genome variations in KEGG Nucleic Acids Research 2019 47 590 5 1362-4962 https://doi.org/10.1093/nar/gky962 30321428 Slenter D.N. Kutmon M. Hanspers K. Riutta A. Windsor J. Nunes N. WikiPathways: a multifaceted pathway database bridging metabolomics to other omics research Nucleic Acids Research 2018 46 661 7 1362-4962 https://doi.org/10.1093/nar/gkx1064 29136241 Lehrer S. Rheinstein P.H. Ivermectin Docks to the SARS-CoV-2 Spike Receptor-binding Domain Attached to ACE2 In Vivo (Athens, Greece) 2020 34 5 3023 6 1791-7549 https://doi.org/10.21873/invivo.12134 32871846 Pan Y. Shang Q. Fang K. Zhang J. Xi J. Down-regulated transcriptional level of Ace1 combined with mutations in Ace1 and Ace2 of Aphis gossypii are related with omethoate resistance Chemico-Biological Interactions 2010 188 3 553 7 1872-7786 https://doi.org/10.1016/j.cbi.2010.07.022 20692243 Zhuang H.M. Li C.W. Wu G. Identification and characterization of ace2-type acetylcholinesterase in insecticide-resistant and -susceptible parasitoid wasp Oomyzus sokolowskii (Hymenoptera: eulophidae) Molecular Biology Reports 2014 41 11 7525 34 1573-4978 https://doi.org/10.1007/s11033-014-3640-5 25074274 Revuelta L. Piulachs M.D. Bellés X. Castañera P. Ortego F. Díaz-Ruíz J.R. RNAi of ace1 and ace2 in Blattella germanica reveals their differential contribution to acetylcholinesterase activity and sensitivity to insecticides Insect Biochemistry and Molecular Biology 2009 39 12 913 9 1879-0240 https://doi.org/10.1016/j.ibmb.2009.11.001 19900550 Dixit S. Ahsan H. Khan F.H. Pesticides and plasma proteins: unexplored dimensions in neurotoxicity International Journal of Pest Management 2021 69 3 278 87 0967-0874 https://doi.org/10.1080/09670874.2021.1917725 Mi H. Muruganujan A. Thomas P.D. PANTHER in 2013: modeling the evolution of gene function, and other gene attributes, in the context of phylogenetic trees Nucleic Acids Research 2013 41 Database issue 377 86 1362-4962 23193289 Yao Y. Lawrence D.A. Susceptibility to COVID-19 in populations with health disparities: posited involvement of mitochondrial disorder, socioeconomic stress, and pollutants Journal of Biochemical and Molecular Toxicology 2021 35 1 e22626 1099-0461 https://doi.org/10.1002/jbt.22626 32905655 Duru C.E. Umar H.I. Duru I.A. Enenebeaku U.E. Ngozi-Olehi L.C. Enyoh C.E. Blocking the interactions between human ACE2 and coronavirus spike glycoprotein by selected drugs: a computational perspective Environmental Analysis, Health and Toxicology 2021 36 2 e2021010 2671-9525 https://doi.org/10.5620/eaht.2021010 34130375 Baraniuk C. Receptors for SARS-CoV-2 Present in Wide Variety of Human Cells Scientist (Philadelphia, Pa.) 2020 0890-3670 Sagawa T. Tsujikawa T. Honda A. Miyasaka N. Tanaka M. Kida T. Exposure to particulate matter upregulates ACE2 and TMPRSS2 expression in the murine lung Environmental Research 2021 195 110722 1096-0953 https://doi.org/10.1016/j.envres.2021.110722 33422505 Li H.H. Liu C.C. Hsu T.W. Lin J.H. Hsu J.W. Li A.F. Upregulation of ACE2 and TMPRSS2 by particulate matter and idiopathic pulmonary fibrosis: a potential role in severe COVID-19 Particle and Fibre Toxicology 2021 18 1 11 1743-8977 https://doi.org/10.1186/s12989-021-00404-3 33706759 South A.M. Diz D.I. Chappell M.C. COVID-19, ACE2, and the cardiovascular consequences American Journal of Physiology. Heart and Circulatory Physiology 2020 318 5 1084 90 1522-1539 https://doi.org/10.1152/ajpheart.00217.2020 32228252 Gurung A.B. Ali M.A. Lee J. Aljowaie R.M. Almutairi S.M. Exploring the phytochemicals of Platycodon grandiflorus for TMPRSS2 inhibition in the search for SARS-CoV-2 entry inhibitors Journal of King Saud University. Science 2022 34 6 102155 2213-686X https://doi.org/10.1016/j.jksus.2022.102155 35702062 Shapira T. Monreal I.A. Dion S.P. Buchholz D.W. Imbiakha B. Olmstead A.D. TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic Nature 2022 605 7909 340 8 1476-4687 https://doi.org/10.1038/s41586-022-04661-w 35344983 Mahoney M. Damalanka V.C. Tartell M.A. Chung D.H. Lourenço A.L. Pwee D. A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells Proceedings of the National Academy of Sciences of the United States of America 2021 118 43 e2108728118 1091-6490 https://doi.org/10.1073/pnas.2108728118 34635581 Gan X. Huang H. Wen J. Liu K. Yang Y. Li X. α-Terthienyl induces prostate cancer cell death through inhibiting androgen receptor expression Biomedicine and Pharmacotherapy 2022 152 113266 1950-6007 https://doi.org/10.1016/j.biopha.2022.113266 35691152 Bian H. Zheng Z.H. Wei D. Meplazumab treats COVID‐19 pneumonia: an open‐labelled, concurrent controlled add‐on clinical trial. medRxiv. 2020:2020.2003.2021.20040691. 2020 https://doi.org/10.1101/2020.03.21.20040691 Pushkarsky T. Yurchenko V. Laborico A. Bukrinsky M. CD147 stimulates HIV-1 infection in a signal-independent fashion Biochemical and Biophysical Research Communications 2007 363 3 495 9 0006-291X https://doi.org/10.1016/j.bbrc.2007.08.192 17888876 Rath S. Perikala V. Jena A.B. Dandapat J. Factors regulating dynamics of angiotensin-converting enzyme-2 (ACE2), the gateway of SARS-CoV-2: epigenetic modifications and therapeutic interventions by epidrugs Biomedicine and Pharmacotherapy 2021 143 112095 1950-6007 https://doi.org/10.1016/j.biopha.2021.112095 34479017