Generic placeholder image

Recent Advances in Inflammation & Allergy Drug Discovery

Author(s): Hussein Kadhem Al-Hakeim*, Hawraa Kadhem Al-Jassas, Gerwyn Morris and Michael Maes

DOI: 10.2174/2772270816666220318103929

DownloadDownload PDF Flyer Cite As
Increased ACE2, sRAGE, and Immune Activation, but Lowered Calcium and Magnesium in COVID-19

Page: [32 - 43] Pages: 12

  • * (Excluding Mailing and Handling)

Abstract

Background: The characterization of new biomarkers that could help externally validate the diagnosis of COVID-19 and optimize treatments is extremely important. Many studies have established changes in immune-inflammatory and antibody levels, but few studies measured the soluble receptor for the advanced glycation end product (sRAGE), angiotensin-converting enzyme 2 (ACE2), calcium, and magnesium in COVID-19.

Objective: To evaluate serum advanced glycation end-product receptor (sRAGE) and angiotensin converting enzyme (ACE)2 and peripheral oxygen saturation (SpO2) and chest CT scan abnormalities (CCTA) in COVID-19.

Methods: sRAGE, ACE2, interleukin (IL)-6, IL-10, C-reactive protein (CRP), calcium, magnesium, and albumin were measured in 60 COVID-19 patients and 30 healthy controls.

Results: COVID-19 is characterized by significantly increased IL-6, CRP, IL-10, sRAGE, ACE2, and lowered SpO2, albumin, magnesium, and calcium. COVID-19 with CCTAs showed lower SpO2 and albumin. SpO2 was significantly inversely correlated with IL-6, IL-10, CRP, sRAGE, and ACE2, and positively with albumin, magnesium, and calcium. Neural networks showed that a combination of calcium, IL-6, CRP, and sRAGE yielded an accuracy of 100% in detecting COVID-19 patients, with calcium being the most important predictor followed by IL-6 and CRP. Patients with positive IgG results showed a significant elevation in the serum level of IL-6, sRAGE, and ACE2 compared to the negatively IgG patient subgroup.

Conclusion: The results show that immune-inflammatory and RAGE pathways biomarkers may be used as an external validating criterion for the diagnosis of COVID-19. Those pathways coupled with lowered SpO2, calcium, and magnesium are drug targets that may help reduce the consequences of COVID-19.

Keywords: COVID-19, sRAGE, ACE2, inflammation, CT-scan, and biomarkers.

Graphical Abstract

[1]
Azkur AK, Akdis M, Azkur D, et al. Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy 2020; 75(7): 1564-81.
[http://dx.doi.org/10.1111/all.14364] [PMID: 32396996]
[2]
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020; 395(10229): 1054-62.
[http://dx.doi.org/10.1016/S0140-6736(20)30566-3] [PMID: 32171076]
[3]
Song J-W, Zhang C, Fan X, et al. Immunological and inflammatory profiles in mild and severe cases of COVID-19. Nat Commun 2020; 11(1): 3410.
[http://dx.doi.org/10.1038/s41467-020-17240-2] [PMID: 32641700]
[4]
Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; 8(4): 420-2.
[http://dx.doi.org/10.1016/S2213-2600(20)30076-X] [PMID: 32085846]
[5]
Oliveira BA, Oliveira LC, Sabino EC, Okay TS. SARS-CoV-2 and the COVID-19 disease: A mini review on diagnostic methods. Rev Inst Med Trop São Paulo 2020; 62: e44.
[http://dx.doi.org/10.1590/s1678-9946202062044] [PMID: 32609256]
[6]
Zainol Rashid Z, Othman SN, Abdul Samat MN, Ali UK, Wong KK. Diagnostic performance of COVID-19 serology assays. Malays J Pathol 2020; 42(1): 13-21.
[PMID: 32342927]
[7]
Pan F, Ye T, Sun P, et al. Time course of lung changes on chest CT during recovery from 2019 novel coronavirus (COVID-19) pneumonia. Radiology 2020; 2020: 200370.
[8]
Dai WC, Zhang HW, Yu J, et al. CT imaging and differential diagnosis of COVID-19. Can Assoc Radiol J 2020; 71(2): 195-200.
[http://dx.doi.org/10.1177/0846537120913033] [PMID: 32129670]
[9]
Adams HJA, Kwee TC, Yakar D, Hope MD, Kwee RM. Chest CT imaging signature of coronavirus disease 2019 infection: In pursuit of the scientific evidence. Chest 2020; 158(5): 1885-95.
[http://dx.doi.org/10.1016/j.chest.2020.06.025] [PMID: 32592709]
[10]
Shenoy N, Luchtel R, Gulani P. Considerations for target oxygen saturation in COVID-19 patients: Are we under-shooting? BMC Med 2020; 18(1): 260.
[http://dx.doi.org/10.1186/s12916-020-01735-2] [PMID: 32814566]
[11]
Luks AM, Swenson ER. COVID-19 lung injury and high-altitude pulmonary edema. A false equation with dangerous implications. Ann Am Thorac Soc 2020; 17(8): 918-21.
[http://dx.doi.org/10.1513/AnnalsATS.202004-327CME] [PMID: 32735170]
[12]
Al-Jassas HK, Al-Hakeim HK, Maes M. Intersections between pneumonia, lowered oxygen saturation percentage and immune activation mediate depression, anxiety, and chronic fatigue syndrome-like symptoms due to COVID-19: A nomothetic network approach. J Affect Disord 2022; 297: 233-45.
[http://dx.doi.org/10.1016/j.jad.2021.10.039] [PMID: 34699853]
[13]
Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in china. N Engl J Med 2020; 382(18): 1708-20.
[http://dx.doi.org/10.1056/NEJMoa2002032] [PMID: 32109013]
[14]
MacLaren G, Fisher D, Brodie D. Preparing for the most critically ill patients with COVID-19: The potential role of extracorporeal membrane oxygenation. JAMA 2020; 323(13): 1245-6.
[http://dx.doi.org/10.1001/jama.2020.2342] [PMID: 32074258]
[15]
Patel SK, Juno JA, Lee WS, et al. Plasma ACE2 activity is persistently elevated following SARS-CoV-2 infection: Implications for COVID-19 pathogenesis and consequences. Eur Resp J 2021. [Epub ahead of print].
[16]
Nagy B Jr, Fejes Z, Szentkereszty Z, et al. A dramatic rise in serum ACE2 activity in a critically ill COVID-19 patient. Int J Infect Dis 2021; 103: 412-4.
[http://dx.doi.org/10.1016/j.ijid.2020.11.184] [PMID: 33249290]
[17]
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181(2): 271-280.e8.
[http://dx.doi.org/10.1016/j.cell.2020.02.052] [PMID: 32142651]
[18]
Zhu Z, Zhang Z, Chen W, et al. Predicting the receptor-binding domain usage of the coronavirus based on kmer frequency on spike protein. Infect Genet Evol 2018; 61: 183-4.
[http://dx.doi.org/10.1016/j.meegid.2018.03.028] [PMID: 29625240]
[19]
Amini Pouya M, Afshani SM, Maghsoudi AS, Hassani S, Mirnia K. Classification of the present pharmaceutical agents based on the possible effective mechanism on the COVID-19 infection. Daru 2020; 28(2): 745-64.
[http://dx.doi.org/10.1007/s40199-020-00359-4] [PMID: 32734518]
[20]
Vlachakis D, Papakonstantinou E, Mitsis T, et al. Molecular mechanisms of the novel coronavirus SARS-CoV-2 and potential anti-COVID19 pharmacological targets since the outbreak of the pandemic. Food Chem Toxicol 2020; 146: 111805.
[http://dx.doi.org/10.1016/j.fct.2020.111805] [PMID: 33038452]
[21]
Lambert DW, Yarski M, Warner FJ, et al. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). J Biol Chem 2005; 280(34): 30113-9.
[http://dx.doi.org/10.1074/jbc.M505111200] [PMID: 15983030]
[22]
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497-506.
[http://dx.doi.org/10.1016/S0140-6736(20)30183-5] [PMID: 31986264]
[23]
Hui DSC, Zumla A. Severe acute respiratory syndrome: Historical, epidemiologic, and clinical features. Infect Dis Clin North Am 2019; 33(4): 869-89.
[http://dx.doi.org/10.1016/j.idc.2019.07.001] [PMID: 31668196]
[24]
Qin C, Zhou L, Hu Z, et al. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis 2020; 71(15): 762-8.
[http://dx.doi.org/10.1093/cid/ciaa248] [PMID: 32161940]
[25]
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020; 395(10229): 1033-4.
[http://dx.doi.org/10.1016/S0140-6736(20)30628-0] [PMID: 32192578]
[26]
Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med 2020; 180(7): 934-43.
[http://dx.doi.org/10.1001/jamainternmed.2020.0994] [PMID: 32167524]
[27]
Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020; 46(5): 846-8.
[http://dx.doi.org/10.1007/s00134-020-05991-x] [PMID: 32125452]
[28]
Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. J Infect 2020; 80(6): 607-13.
[http://dx.doi.org/10.1016/j.jinf.2020.03.037] [PMID: 32283152]
[29]
Huang J, Cheng A, Kumar R, et al. Hypoalbuminemia predicts the outcome of COVID-19 independent of age and co-morbidity. J Med Virol 2020; 92(10): 2152-8.
[http://dx.doi.org/10.1002/jmv.26003] [PMID: 32406952]
[30]
Zhang Y, Zheng L, Liu L, Zhao M, Xiao J, Zhao Q. Liver impairment in COVID-19 patients: A retrospective analysis of 115 cases from a single centre in Wuhan city, China. Liver Int 2020; 40(9): 2095-103.
[http://dx.doi.org/10.1111/liv.14455] [PMID: 32239796]
[31]
Soeters PB, Wolfe RR, Shenkin A. Hypoalbuminemia: Pathogenesis and clinical significance. JPEN J Parenter Enteral Nutr 2019; 43(2): 181-93.
[http://dx.doi.org/10.1002/jpen.1451] [PMID: 30288759]
[32]
Yalcin Kehribar D, Cihangiroglu M, Sehmen E, et al. The receptor for advanced glycation end product (RAGE) pathway in COVID-19. Biomarkers 2021; 26(2): 114-8.
[http://dx.doi.org/10.1080/1354750X.2020.1861099] [PMID: 33284049]
[33]
Vistoli G, De Maddis D, Cipak A, Zarkovic N, Carini M, Aldini G. Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): An overview of their mechanisms of formation. Free Radic Res 2013; 47 (Suppl. 1): 3-27.
[http://dx.doi.org/10.3109/10715762.2013.815348] [PMID: 23767955]
[34]
Tóbon-Velasco JC, Cuevas E, Torres-Ramos MA. Receptor for AGEs (RAGE) as mediator of NF-kB pathway activation in neuroinflammation and oxidative stress. CNS Neurol Disord Drug Targets 2014; 13(9): 1615-26.
[http://dx.doi.org/10.2174/1871527313666140806144831] [PMID: 25106630]
[35]
Macaione V, Aguennouz M, Rodolico C, et al. RAGE-NF-kappaB pathway activation in response to oxidative stress in facioscapulohumeral muscular dystrophy. Acta Neurol Scand 2007; 115(2): 115-21.
[http://dx.doi.org/10.1111/j.1600-0404.2006.00724.x] [PMID: 17212615]
[36]
Wang Y, Liu L. The membrane protein of severe acute respiratory syndrome coronavirus functions as a novel cytosolic pathogen-associated molecular pattern to promote beta interferon induction via a toll-like-receptor-related traf3-independent mechanism. MBio 2016; 7(1): e01872-15.
[http://dx.doi.org/10.1128/mBio.01872-15] [PMID: 26861016]
[37]
Zhang L, Bukulin M, Kojro E, et al. Receptor for advanced glycation end products is subjected to protein ectodomain shedding by metalloproteinases. J Biol Chem 2008; 283(51): 35507-16.
[http://dx.doi.org/10.1074/jbc.M806948200] [PMID: 18952609]
[38]
Sterenczak KA, Willenbrock S, Barann M, et al. Cloning, characterisation, and comparative quantitative expression analyses of receptor for advanced glycation end products (RAGE) transcript forms. Gene 2009; 434(1-2): 35-42.
[http://dx.doi.org/10.1016/j.gene.2008.10.027] [PMID: 19061941]
[39]
Lim A, Radujkovic A, Weigand MA, Merle U. Soluble receptor for advanced glycation end products (sRAGE) as a biomarker of COVID-19 disease severity and indicator of the need for mechanical ventilation, ARDS and mortality. Ann Intensive Care 2021; 11(1): 50.
[http://dx.doi.org/10.1186/s13613-021-00836-2] [PMID: 33751264]
[40]
Cappellini F, Brivio R, Casati M, Cavallero A, Contro E, Brambilla P. Low levels of total and ionized calcium in blood of COVID-19 patients. Clin Chem Lab Med 2020; 58(9): e171-3.
[http://dx.doi.org/10.1515/cclm-2020-0611] [PMID: 32459190]
[41]
Lippi G, South AM, Henry BM. Electrolyte imbalances in patients with severe coronavirus disease 2019 (COVID-19). Ann Clin Biochem 2020; 57(3): 262-5.
[http://dx.doi.org/10.1177/0004563220922255] [PMID: 32266828]
[42]
Di Filippo L, Formenti AM, Rovere-Querini P, et al. Hypocalcemia is highly prevalent and predicts hospitalization in patients with COVID-19. Endocrine 2020; 68(3): 475-8.
[http://dx.doi.org/10.1007/s12020-020-02383-5] [PMID: 32533508]
[43]
Nieto-Torres JL, Verdiá-Báguena C, Jimenez-Guardeño JM, et al. Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology 2015; 485: 330-9.
[http://dx.doi.org/10.1016/j.virol.2015.08.010] [PMID: 26331680]
[44]
Deng B, Zhang S, Geng Y, et al. Cytokine and chemokine levels in patients with severe fever with thrombocytopenia syndrome virus. PLoS One 2012; 7(7): e41365.
[http://dx.doi.org/10.1371/journal.pone.0041365] [PMID: 22911786]
[45]
Zhou Y, Frey TK, Yang JJ. Viral calciomics: Interplays between Ca2+ and virus. Cell Calcium 2009; 46(1): 1-17.
[http://dx.doi.org/10.1016/j.ceca.2009.05.005] [PMID: 19535138]
[46]
Civitelli R, Ziambaras K. Calcium and phosphate homeostasis: Concerted interplay of new regulators. J Endocrinol Invest 2011; 34(7): 3-7.
[PMID: 21985972]
[47]
Görlach A, Bertram K, Hudecova S, Krizanova O. Calcium and ROS: A mutual interplay. Redox Biol 2015; 6: 260-71.
[http://dx.doi.org/10.1016/j.redox.2015.08.010] [PMID: 26296072]
[48]
Quilliot D, Bonsack O, Jaussaud R, Mazur A. Dysmagnesemia in Covid-19 cohort patients: Prevalence and associated factors. Magnes Res 2020; 33(4): 114-22.
[http://dx.doi.org/10.1684/mrh.2021.0476] [PMID: 33678604]
[49]
Abiri B, Vafa M. Effects of vitamin D and/or magnesium supplementation on mood, serum levels of BDNF, inflammatory biomarkers, and SIRT1 in obese women: A study protocol for a double-blind, randomized, placebo-controlled trial. Trials 2020; 21(1): 225.
[http://dx.doi.org/10.1186/s13063-020-4122-9] [PMID: 32102680]
[50]
Güzel A, Doğan E, Türkçü G, et al. Dexmedetomidine and magnesium sulfate: A good combination treatment for acute lung injury? J Invest Surg 2019; 32(4): 331-42.
[http://dx.doi.org/10.1080/08941939.2017.1422575] [PMID: 29359990]
[51]
Romani A, Scarpa A. Regulation of cell magnesium. Arch Biochem Biophys 1992; 298(1): 1-12.
[http://dx.doi.org/10.1016/0003-9861(92)90086-C] [PMID: 1524417]
[52]
Kwee TC, Kwee RM. Chest CT in COVID-19: What the radiologist needs to know. Radiographics 2020; 40(7): 1848-65.
[http://dx.doi.org/10.1148/rg.2020200159] [PMID: 33095680]
[53]
Hansell DM, Bankier AA, MacMahon H, McLoud TC, Müller NL, Remy J. Fleischner Society: Glossary of terms for thoracic imaging. Radiology 2008; 246(3): 697-722.
[http://dx.doi.org/10.1148/radiol.2462070712] [PMID: 18195376]
[54]
Franquet T. Imaging of pulmonary viral pneumonia. Radiology 2011; 260(1): 18-39.
[http://dx.doi.org/10.1148/radiol.11092149] [PMID: 21697307]
[55]
Benjamini Y, Hochberg Y. Controlling the false discovery rate: A practical and powerful approach to multiple testing. J R Stat Soc B 1995; 57(1): 289-300.
[http://dx.doi.org/10.1111/j.2517-6161.1995.tb02031.x]
[56]
Moustafa SR, Al-Rawi KF, Stoyanov D, et al. The endogenous opioid system in schizophrenia and treatment resistant schizophrenia: Increased plasma endomorphin 2, and κ and μ opioid receptors are associated with interleukin-6. Diagnostics (Basel) 2020; 10(9): 633.
[http://dx.doi.org/10.3390/diagnostics10090633] [PMID: 32858974]
[57]
Han H, Ma Q, Li C, et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect 2020; 9(1): 1123-30.
[http://dx.doi.org/10.1080/22221751.2020.1770129] [PMID: 32475230]
[58]
Kuba K, Imai Y, Ohto-Nakanishi T, Penninger JM. Trilogy of ACE2: A peptidase in the renin-angiotensin system, a SARS receptor, and a partner for amino acid transporters. Pharmacol Ther 2010; 128(1): 119-28.
[http://dx.doi.org/10.1016/j.pharmthera.2010.06.003] [PMID: 20599443]
[59]
Jia H. Pulmonary angiotensin-converting enzyme 2 (ACE2) and inflammatory lung disease. Shock 2016; 46(3): 239-48.
[http://dx.doi.org/10.1097/SHK.0000000000000633] [PMID: 27082314]
[60]
Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir Med 2020; 8(5): 475-81.
[http://dx.doi.org/10.1016/S2213-2600(20)30079-5] [PMID: 32105632]
[61]
Tetro JA. Is COVID-19 receiving ADE from other coronaviruses? Microbes Infect 2020; 22(2): 72-3.
[http://dx.doi.org/10.1016/j.micinf.2020.02.006] [PMID: 32092539]
[62]
Li G, Fan Y, Lai Y, et al. Coronavirus infections and immune responses. J Med Virol 2020; 92(4): 424-32.
[http://dx.doi.org/10.1002/jmv.25685] [PMID: 31981224]
[63]
Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020; 395(10223): 507-13.
[http://dx.doi.org/10.1016/S0140-6736(20)30211-7] [PMID: 32007143]
[64]
Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA 2020; 323(11): 1061-9.
[http://dx.doi.org/10.1001/jama.2020.1585] [PMID: 32031570]
[65]
Gao Y, Li T, Han M, et al. Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19. J Med Virol 2020; 92(7): 791-6.
[http://dx.doi.org/10.1002/jmv.25770] [PMID: 32181911]
[66]
Li L, Li S, Xu M, et al. Risk factors related to hepatic injury in patients with corona virus disease 2019. MedRxiv 2020.
[http://dx.doi.org/10.1101/2020.02.28.20028514]
[67]
Ronit A, Kirkegaard-Klitbo DM, Dohlmann TL, et al. Plasma albumin and incident cardiovascular disease: Results from the CGPS and an updated meta-analysis. Arterioscler Thromb Vasc Biol 2020; 40(2): 473-82.
[http://dx.doi.org/10.1161/ATVBAHA.119.313681] [PMID: 31852221]
[68]
Maes M, Galecki P, Chang YS, Berk M. A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35(3): 676-92.
[http://dx.doi.org/10.1016/j.pnpbp.2010.05.004] [PMID: 20471444]
[69]
Paar M, Rossmann C, Nusshold C, et al. Anticoagulant action of low, physiologic, and high albumin levels in whole blood. PLoS One 2017; 12(8): e0182997.
[http://dx.doi.org/10.1371/journal.pone.0182997] [PMID: 28800610]
[70]
Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost 2020; 18(5): 1023-6.
[http://dx.doi.org/10.1111/jth.14810] [PMID: 32338827]
[71]
Muntadher MA. Hussein Kadhem Al-H Jawad KH. Serum HMGB1, DKK1, and ACE2 as a function of lung injuries in COVID-19 patients. Hayati J Biosci 2022; 29: 40-6.
[72]
Zhang C, Wang J, Ma X, et al. ACE2-EPC-EXs protect ageing ECs against hypoxia/reoxygenation-induced injury through the miR-18a/Nox2/ROS pathway. J Cell Mol Med 2018; 22(3): 1873-82.
[http://dx.doi.org/10.1111/jcmm.13471] [PMID: 29363860]
[73]
Narula S, Yusuf S, Chong M, et al. Plasma ACE2 and risk of death or cardiometabolic diseases: A case-cohort analysis. Lancet 2020; 396(10256): 968-76.
[http://dx.doi.org/10.1016/S0140-6736(20)31964-4] [PMID: 33010842]
[74]
Oudit GY, Pfeffer MA. Plasma angiotensin-converting enzyme 2: Novel biomarker in heart failure with implications for COVID-19. Eur Heart J 2020; 41(19): 1818-20.
[http://dx.doi.org/10.1093/eurheartj/ehaa414] [PMID: 32388547]
[75]
Walls AC, Park Y-J, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020; 2020: 281-92.
[76]
Yeung ML, Teng JLL, Jia L, et al. Soluble ACE2-mediated cell entry of SARS-CoV-2 via interaction with proteins related to the renin-angiotensin system 2021; 184: 2212-28.
[http://dx.doi.org/10.1016/j.cell.2021.02.053]
[77]
Glowacka I, Bertram S, Herzog P, et al. Differential downregulation of ACE2 by the spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus NL63. J Virol 2010; 84(2): 1198-205.
[http://dx.doi.org/10.1128/JVI.01248-09] [PMID: 19864379]
[78]
Brest P, Mograbi B, Hofman P, Milano G. More light on cancer and COVID-19 reciprocal interaction. Br J Cancer 2021; 124(8): 1344-5.
[http://dx.doi.org/10.1038/s41416-020-01246-0] [PMID: 33531686]
[79]
Dozio E, Sitzia C, Pistelli L, et al. Soluble receptor for advanced glycation end products and its forms in COVID-19 patients with and without diabetes mellitus: A pilot study on their role as disease biomarkers. J Clin Med 2020; 9(11): E3785.
[http://dx.doi.org/10.3390/jcm9113785] [PMID: 33238596]
[80]
Uchida T, Shirasawa M, Ware LB, et al. Receptor for advanced glycation end-products is a marker of type I cell injury in acute lung injury. Am J Respir Crit Care Med 2006; 173(9): 1008-15.
[http://dx.doi.org/10.1164/rccm.200509-1477OC] [PMID: 16456142]
[81]
Oczypok EA, Perkins TN, Oury TD. All the “RAGE” in lung disease: The receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses. Paediatr Respir Rev 2017; 23: 40-9.
[http://dx.doi.org/10.1016/j.prrv.2017.03.012] [PMID: 28416135]
[82]
Yang WI, Lee D, Lee DL, et al. Blocking the receptor for advanced glycation end product activation attenuates autoimmune myocarditis. Circ J 2014; 78(5): 1197-205.
[http://dx.doi.org/10.1253/circj.CJ-13-1235] [PMID: 24599045]
[83]
Zhang H, Tasaka S, Shiraishi Y, et al. Role of soluble receptor for advanced glycation end products on endotoxin-induced lung injury. Am J Respir Crit Care Med 2008; 178(4): 356-62.
[http://dx.doi.org/10.1164/rccm.200707-1069OC] [PMID: 18535257]
[84]
Izushi Y, Teshigawara K, Liu K, et al. Soluble form of the receptor for advanced glycation end-products attenuates inflammatory pathogenesis in a rat model of lipopolysaccharide-induced lung injury. J Pharmacol Sci 2016; 130(4): 226-34.
[http://dx.doi.org/10.1016/j.jphs.2016.02.005] [PMID: 27038888]
[85]
Sukkar MB, Wood LG, Tooze M, et al. Soluble RAGE is deficient in neutrophilic asthma and COPD. Eur Respir J 2012; 39(3): 721-9.
[http://dx.doi.org/10.1183/09031936.00022011] [PMID: 21920897]
[86]
Ekong U, Zeng S, Dun H, et al. Blockade of the receptor for advanced glycation end products attenuates acetaminophen-induced hepatotoxicity in mice. J Gastroenterol Hepatol 2006; 21(4): 682-8.
[http://dx.doi.org/10.1111/j.1440-1746.2006.04225.x] [PMID: 16677153]
[87]
Zhang F, Su X, Huang G, et al. sRAGE alleviates neutrophilic asthma by blocking HMGB1/RAGE signalling in airway dendritic cells. Sci Rep 2017; 7(1): 14268.
[http://dx.doi.org/10.1038/s41598-017-14667-4] [PMID: 29079726]
[88]
van Zoelen MA, Achouiti A, van der Poll T. The role of receptor for advanced glycation endproducts (RAGE) in infection. Crit Care 2011; 15(2): 208.
[http://dx.doi.org/10.1186/cc9990] [PMID: 21457506]
[89]
Sun JK, Zhang WH, Zou L, et al. Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease 2019. Aging (Albany NY) 2020; 12(12): 11287-95.
[http://dx.doi.org/10.18632/aging.103526] [PMID: 32589164]
[90]
Yang C, Ma X, Wu J, et al. Low serum calcium and phosphorus and their clinical performance in detecting COVID-19 patients. J Med Virol 2021; 93(3): 1639-51.
[http://dx.doi.org/10.1002/jmv.26515] [PMID: 32926424]
[91]
Pal R, Ram S, Zohmangaihi D, et al. High prevalence of hypocalcemia in non-severe COVID-19 Patients: A retrospective case-control study. Front Med (Lausanne) 2021; 7: 590805.
[http://dx.doi.org/10.3389/fmed.2020.590805] [PMID: 33490095]
[92]
di Filippo L, Formenti AM, Doga M, et al. Hypocalcemia is a distinctive biochemical feature of hospitalized COVID-19 patients. Endocrine 2021; 71(1): 9-13.
[http://dx.doi.org/10.1007/s12020-020-02541-9] [PMID: 33165763]
[93]
Kelly A, Levine MA. Hypocalcemia in the critically ill patient. J Intensive Care Med 2013; 28(3): 166-77.
[http://dx.doi.org/10.1177/0885066611411543] [PMID: 21841146]
[94]
Millet JK, Whittaker GR. Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells. Virology 2018; 517: 3-8.
[http://dx.doi.org/10.1016/j.virol.2017.12.015] [PMID: 29275820]
[95]
Straus MR, Tang T, Lai AL, et al. Ca2+ ions promote fusion of middle east respiratory syndrome coronavirus with host cells and increase infectivity. J Virol 2020; 94(13): e00426-20.
[http://dx.doi.org/10.1128/JVI.00426-20] [PMID: 32295925]
[96]
Booth CM, Matukas LM, Tomlinson GA, et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA 2003; 289(21): 2801-9.
[http://dx.doi.org/10.1001/jama.289.21.JOC30885] [PMID: 12734147]
[97]
Chen X, Cao R, Zhong W. Host calcium channels and pumps in viral infections. Cells 2019; 9(1): 94.
[http://dx.doi.org/10.3390/cells9010094] [PMID: 31905994]
[98]
Zhang IX, Ren J, Vadrevu S, Raghavan M, Satin LS. ER stress increases store-operated Ca2+ entry (SOCE) and augments basal insulin secretion in pancreatic beta cells. J Biol Chem 2020; 295(17): 5685-700.
[http://dx.doi.org/10.1074/jbc.RA120.012721] [PMID: 32179650]
[99]
Chen S, Zhang Z, Wu Y, et al. Endoplasmic reticulum stress and store-operated calcium entry contribute to usnic acid-induced toxicity in hepatic cells. Toxicol Sci 2015; 146(1): 116-26.
[http://dx.doi.org/10.1093/toxsci/kfv075] [PMID: 25870318]
[100]
Morris G, Athan E, Walder K, et al. Can endolysosomal deacidification and inhibition of autophagy prevent severe COVID-19? Life Sci 2020; 262: 118541.
[http://dx.doi.org/10.1016/j.lfs.2020.118541] [PMID: 33035581]
[101]
Fung TS, Liu DX. Coronavirus infection, ER stress, apoptosis and innate immunity. Front Microbiol 2014; 5: 296.
[http://dx.doi.org/10.3389/fmicb.2014.00296] [PMID: 24987391]
[102]
Hyser JM, Estes MK. Pathophysiological consequences of calcium-conducting viroporins. Annu Rev Virol 2015; 2(1): 473-96.
[http://dx.doi.org/10.1146/annurev-virology-100114-054846] [PMID: 26958925]
[103]
Nunes P, Demaurex N. Redox regulation of store-operated Ca2+ entry. Antioxid Redox Signal 2014; 21(6): 915-32.
[http://dx.doi.org/10.1089/ars.2013.5615] [PMID: 24053140]
[104]
Morris G, Bortolasci CC, Puri BK, et al. The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach. Life Sci 2020; 258: 118166.
[http://dx.doi.org/10.1016/j.lfs.2020.118166] [PMID: 32739471]
[105]
Dresselhaus EC, Meffert MK. Cellular Specificity of NF-κB Function in the Nervous System. Front Immunol 2019; 10: 1043.
[http://dx.doi.org/10.3389/fimmu.2019.01043] [PMID: 31143184]
[106]
Berry CT, May MJ, Freedman BD. STIM- and orai-mediated calcium entry controls NF-κB activity and function in lymphocytes. Cell Calcium 2018; 74: 131-43.
[http://dx.doi.org/10.1016/j.ceca.2018.07.003] [PMID: 30048879]
[107]
Çiçek G, Açıkgoz SK, Yayla Ç, Kundi H, İleri M. Magnesium as a predictor of acute stent thrombosis in patients with ST-segment elevation myocardial infarction who underwent primary angioplasty. Coron Artery Dis 2016; 27(1): 47-51.
[http://dx.doi.org/10.1097/MCA.0000000000000318] [PMID: 26513291]
[108]
Gromova OA, Torshin IY, Kobalava ZD, et al. Deficit of magnesium and states of hypercoagulation: Intellectual analysis of data obtained from a sample of patients aged 18-50 years from medical and preventive facilities in Russia. Kardiologiia 2018; 58(4): 22-35.
[http://dx.doi.org/10.18087/cardio.2018.4.10106] [PMID: 30704380]
[109]
Nielsen FH. Magnesium deficiency and increased inflammation: Current perspectives. J Inflamm Res 2018; 11: 25-34.
[http://dx.doi.org/10.2147/JIR.S136742] [PMID: 29403302]
[110]
Zheltova AA, Kharitonova MV, Iezhitsa IN, Spasov AA. Magnesium deficiency and oxidative stress: An update. Biomedicine (Taipei) 2016; 6(4): 20.
[http://dx.doi.org/10.7603/s40681-016-0020-6] [PMID: 27854048]
[111]
Sheu JR, Hsiao G, Shen MY, Lee YM, Yen MH. Antithrombotic effects of magnesium sulfate in in vivo experiments. Int J Hematol 2003; 77(4): 414-9.
[http://dx.doi.org/10.1007/BF02982655] [PMID: 12774935]
[112]
Zhang HW, Yu J, Xu HJ, et al. Corona virus international public health emergencies: Implications for radiology management. Acad Radiol 2020; 27(4): 463-7.
[http://dx.doi.org/10.1016/j.acra.2020.02.003] [PMID: 32113880]
[113]
Fang YZH, Xie J, et al. Sensitivity of chest CT for COVID-19: Comparison to RT-PCR. Radiology. Radiology 2020; 296(2): 200432.
[http://dx.doi.org/10.1148/radiol.2020200432]
[114]
Sadhukhan P, Ugurlu MT, Hoque MO. Effect of COVID-19 on lungs: Focusing on prospective malignant phenotypes. Cancers (Basel) 2020; 12(12): 3822.
[http://dx.doi.org/10.3390/cancers12123822] [PMID: 33352869]
[115]
Eltzschig HK, Bratton DL, Colgan SP. Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases. Nat Rev Drug Discov 2014; 13(11): 852-69.
[http://dx.doi.org/10.1038/nrd4422] [PMID: 25359381]
[116]
Guo L, Ren L, Yang S, et al. Profiling early humoral response to diagnose novel coronavirus disease (COVID-19). Clin Infect Dis 2020; 71(15): 778-85.
[http://dx.doi.org/10.1093/cid/ciaa310] [PMID: 32198501]
[117]
Xiao AT, Gao C, Zhang S. Profile of specific antibodies to SARS-CoV-2: The first report. J Infect 2020; 81(1): 147-78.
[http://dx.doi.org/10.1016/j.jinf.2020.03.012] [PMID: 32209385]
[118]
Al-Hakeim HK, Al-Hamami SA, Almulla AF, Maes M. Increased serum thromboxane A2 and prostacyclin but lower complement C3 and C4 levels in COVID-19: Associations with chest ct scan anomalies and lowered peripheral oxygen saturation. COVID 2021; 1(2): 489-502.
[http://dx.doi.org/10.3390/covid1020042]
[119]
Zhou P, Yang X-L, Wang X-G, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579(7798): 270-3.
[http://dx.doi.org/10.1038/s41586-020-2012-7] [PMID: 32015507]
[120]
Maeda K, Mehta H, Drevets DA, Coggeshall KM. IL-6 increases B-cell IgG production in a feed-forward proinflammatory mechanism to skew hematopoiesis and elevate myeloid production. Blood 2010; 115(23): 4699-706.
[http://dx.doi.org/10.1182/blood-2009-07-230631] [PMID: 20351305]
[121]
Zeng F, Dai C, Cai P, et al. A comparison study of SARS-CoV-2 IgG antibody between male and female COVID-19 patients: A possible reason underlying different outcome between gender. BMJ 2019; 2020: 1-13.