{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T23:28:33Z","timestamp":1784762913484,"version":"3.55.0"},"reference-count":72,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T00:00:00Z","timestamp":1722384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Anter-onlus","award":["ATE-0581, 2023"],"award-info":[{"award-number":["ATE-0581, 2023"]}]},{"name":"NWG Energy","award":["ATE-0581, 2023"],"award-info":[{"award-number":["ATE-0581, 2023"]}]},{"name":"Fondo di Ateneo","award":["ATE-0581, 2023"],"award-info":[{"award-number":["ATE-0581, 2023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>The overlap between the geographic distribution of COVID-19 outbreaks and pollution levels confirmed a correlation between exposure to atmospheric particulate matter (PM) and the SARS-CoV-2 pandemic. The RAS system is essential in the pathogenesis of inflammatory diseases caused by pollution: the ACE\/AngII\/AT1 axis activates a pro-inflammatory pathway, which is counteracted by the ACE2\/Ang(1-7)\/MAS axis, which activates an anti-inflammatory and protective pathway. However, ACE2 is also known to act as a receptor through which SARS-CoV-2 enters host cells to replicate. Furthermore, in vivo systems have demonstrated that exposure to PM increases ACE2 expression. In this study, the effects of acute and sub-acute exposure to ultrafine particles (UFP), originating from different anthropogenic sources (DEP and BB), on the levels of ACE2, ACE, COX-2, HO-1, and iNOS in the lungs and other organs implicated in the pathogenesis of COVID-19 were analyzed in the in vivo BALB\/c male mice model. Exposure to UFP alters the levels of ACE2 and\/or ACE in all examined organs, and exposure to sub-acute DEP also results in the release of s-ACE2. Furthermore, as evidenced in this and our previous works, COX-2, HO-1, and iNOS levels also demonstrated organ-specific alterations. These proteins play a pivotal role in the UFP-induced inflammatory and oxidative stress responses, and their dysregulation is linked to the development of severe symptoms in individuals infected with SARS-CoV-2, suggesting a heightened vulnerability or a more severe clinical course of the disease. UFP and SARS-CoV-2 share common pathways; therefore, in a \u201crisk stratification\u201d concept, daily exposure to air pollution may significantly increase the likelihood of developing a severe form of COVID-19, explaining, at least in part, the greater lethality of the virus observed in highly polluted areas.<\/jats:p>","DOI":"10.3390\/toxics12080560","type":"journal-article","created":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T10:34:43Z","timestamp":1722422083000},"page":"560","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Correlation between Exposure to UFP and ACE\/ACE2 Pathway: Looking for Possible Involvement in COVID-19 Pandemic"],"prefix":"10.3390","volume":"12","author":[{"given":"Laura","family":"Botto","sequence":"first","affiliation":[{"name":"School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2832-6961","authenticated-orcid":false,"given":"Alessandra","family":"Bulbarelli","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy"},{"name":"POLARIS Research Centre, University of Milano-Bicocca, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4579-7397","authenticated-orcid":false,"given":"Elena","family":"Lonati","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5006-2280","authenticated-orcid":false,"given":"Emanuela","family":"Cazzaniga","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1045-8838","authenticated-orcid":false,"given":"Paola","family":"Palestini","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy"},{"name":"POLARIS Research Centre, University of Milano-Bicocca, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"163272","DOI":"10.1016\/j.scitotenv.2023.163272","article-title":"Particulate matter air pollution and COVID-19 infection, severity, and mortality: A systematic review and meta-analysis","volume":"880","author":"Sheppard","year":"2023","journal-title":"Sci. Total Environ."},{"key":"ref_2","unstructured":"(2024, March 28). WHO Air Pollution. Available online: https:\/\/www.who.int\/health-topics\/air-pollution#tab=tab_1."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.envres.2018.11.014","article-title":"Particle deposition in the human lung: Health implications of particulate matter from different sources","volume":"169","author":"Deng","year":"2019","journal-title":"Environ. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1080\/15569543.2018.1513034","article-title":"Characteristics, sources, and health risks of atmospheric PM10-bound heavy metals in a populated middle eastern city","volume":"39","author":"Idani","year":"2020","journal-title":"Toxin Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"eabd4049","DOI":"10.1126\/sciadv.abd4049","article-title":"Air pollution and COVID-19 mortality in the United States: Strengths and limitations of an ecological regression analysis","volume":"6","author":"Wu","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s12940-021-00714-1","article-title":"Acute and chronic exposure to air pollution in relation with incidence, prevalence, severity and mortality of COVID-19: A rapid systematic review","volume":"20","author":"Katoto","year":"2021","journal-title":"Environ. Health"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.tox.2007.10.013","article-title":"Examination of mRNA expression in rat hearts and lungs for analyses of effects of exposure to concentrated ambient particles on cardiovascular function","volume":"243","author":"Ito","year":"2008","journal-title":"Toxicology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.toxlet.2009.03.003","article-title":"Winter fine particulate matter from Milan induces morphological and functional alterations in human pulmonary epithelial cells (A549)","volume":"188","author":"Gualtieri","year":"2009","journal-title":"Toxicol. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"402","DOI":"10.3109\/08958370903527908","article-title":"Inflammation and tissue damage in mouse lung by single and repeated dosing of urban air coarse and fine particles collected from six European cities","volume":"22","author":"Happo","year":"2010","journal-title":"Inhal. Toxicol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1016\/j.chemosphere.2009.12.071","article-title":"Seasonal variations in chemical composition and in vitro biological effects of fine PM from Milan","volume":"78","author":"Perrone","year":"2010","journal-title":"Chemosphere"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13866","DOI":"10.1007\/s11356-015-5666-1","article-title":"Traffic aerosol lobar doses deposited in the human respiratory system","volume":"24","author":"Manigrasso","year":"2017","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1289\/ehp.7339","article-title":"Nanotoxicology: An emerging discipline evolving from studies of ultrafine particles","volume":"113","year":"2005","journal-title":"Environ. Health Perspect."},{"key":"ref_13","unstructured":"ARPA Lombardia (2024, March 28). INEMAR: INventario EMissioni ARia. Available online: https:\/\/www.arpalombardia.it\/temi-ambientali\/aria\/inventario\/inventario-delle-emissioni\/."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Longhin, E.M., Mantecca, P., and Gualtieri, M. (2020). Fifteen Years of Airborne Particulates in Vitro Toxicology in Milano: Lessons and Perspectives Learned. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072489"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.4209\/aaqr.2016.08.0344","article-title":"Mass Concentration and Size-Distribution of Atmospheric Particulate Matter in an Urban Environment","volume":"17","author":"Rovelli","year":"2017","journal-title":"Aerosol Air Qual. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1080\/10473289.2007.10465322","article-title":"Source apportionment of daily fine particulate matter at Jefferson Street, Atlanta, GA, during summer and winter","volume":"57","author":"Zheng","year":"2007","journal-title":"J. Air Waste Manag. Assoc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.envpol.2016.05.015","article-title":"Physico-chemical properties and biological effects of diesel and biomass particles","volume":"215","author":"Longhin","year":"2016","journal-title":"Environ. Pollut."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Farina, F., Lonati, E., Milani, C., Massimino, L., Ballarini, E., Donzelli, E., Crippa, L., Marmiroli, P., Botto, L., and Corsetto, P.A. (2019). In Vivo Comparative Study on Acute and Sub-acute Biological Effects Induced by Ultrafine Particles of Different Anthropogenic Sources in BALB\/c Mice. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20112805"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Milani, C., Farina, F., Botto, L., Massimino, L., Lonati, E., Donzelli, E., Ballarini, E., Crippa, L., Marmiroli, P., and Bulbarelli, A. (2020). Systemic Exposure to Air Pollution Induces Oxidative Stress and Inflammation in Mouse Brain, Contributing to Neurodegeneration Onset. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103699"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"112261","DOI":"10.1016\/j.envres.2021.112261","article-title":"Exposure to particulate matter: Direct and indirect role in the COVID-19 pandemic","volume":"206","author":"Colom","year":"2022","journal-title":"Environ. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1016\/S0140-6736(21)00869-2","article-title":"Ten scientific reasons in support of airborne transmission of SARS-CoV-2","volume":"397","author":"Greenhalgh","year":"2021","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.toxlet.2009.05.023","article-title":"Lung toxicity induced by intratracheal instillation of size-fractionated tire particles","volume":"189","author":"Mantecca","year":"2009","journal-title":"Toxicol. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.mrrev.2014.09.001","article-title":"Oxidative stress and inflammation generated DNA damage by exposure to air pollution particles","volume":"762","author":"Danielsen","year":"2014","journal-title":"Mutat. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1165\/rcmb.2002-0115OC","article-title":"Interaction between respiratory syncytial virus and particulate matter in guinea pig alveolar macrophages","volume":"28","author":"Kaan","year":"2003","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Li, C.-H., Tsai, M.-L., Clair Chiou, H.-Y., Lin, Y.-C., Liao, W.-T., and Hung, C.-H. (2022). Role of Macrophages in Air Pollution Exposure Related Asthma. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012337"},{"key":"ref_26","first-page":"27","article-title":"How COVID-19 induces cytokine storm with high mortality","volume":"40","author":"Shintaro","year":"2020","journal-title":"Inflamm. Regen."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"253","DOI":"10.7150\/ijbs.23489","article-title":"Instillation of particulate matter 2.5 induced acute lung injury and attenuated the injury recovery in ACE2 knockout mice","volume":"14","author":"Lin","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Hikmet, F., M\u00e9ar, L., Edvinsson, \u00c5., Micke, P., Uhl\u00e9n, M., and Lindskog, C. (2020). The protein expression profile of ACE2 in human tissues. Mol. Syst. Biol., 16.","DOI":"10.15252\/msb.20209610"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1038\/hr.2010.147","article-title":"The counterregulating role of ACE2 and ACE2-mediated angiotensin 1-7 signaling against angiotensin II stimulation in vascular cells","volume":"33","author":"Hayashi","year":"2010","journal-title":"Hypertens. Res."},{"key":"ref_30","first-page":"5524098","article-title":"A Correlation among the COVID-19 Spread, Particulate Matters, and Angiotensin-Converting Enzyme 2: A Review","volume":"2021","author":"Zafran","year":"2021","journal-title":"J. Environ. Public Health"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12989-021-00404-3","article-title":"Upregulation of ACE2 and TMPRSS2 by particulate matter and idiopathic pulmonary fibrosis: A potential role in severe COVID-19","volume":"18","author":"Li","year":"2021","journal-title":"Part. Fibre Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"165059","DOI":"10.1016\/j.scitotenv.2023.165059","article-title":"Experimental and in silico evaluations of the possible molecular interaction between airborne particulate matter and SARS-CoV-2","volume":"895","author":"Romeo","year":"2023","journal-title":"Sci. Total Environ."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"108131","DOI":"10.1016\/j.envint.2023.108131","article-title":"On fine particulate matter and COVID-19 spread and severity: An in vitro toxicological plausible mechanism","volume":"179","author":"Marchetti","year":"2023","journal-title":"Environ. Int."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Botto, L., Lonati, E., Russo, S., Cazzaniga, E., Bulbarelli, A., and Palestini, P. (2023). Effects of PM2.5 Exposure on the ACE\/ACE2 Pathway: Possible Implication in COVID-19 Pandemic. Int. J. Environ. Res. Public Health, 20.","DOI":"10.3390\/ijerph20054393"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Farina, F., Sancini, G., Battaglia, C., Tinaglia, V., Mantecca, P., Camatini, M., and Palestini, P. (2013). Milano summer particulate matter (PM10) triggers lung inflammation and extra pulmonary adverse events in mice. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0056636"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Sancini, G., Farina, F., Battaglia, C., Cifola, I., Mangano, E., Mantecca, P., Camatini, M., and Palestini, P. (2014). Health Risk Assessment for Air Pollutants: Alterations in Lung and Cardiac Gene Expression in Mice Exposed to Milano Winter Fine Particulate Matter (PM2.5). PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0109685"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Rizzo, A.M., Corsetto, P.A., Farina, F., Montorfano, G., Pani, G., Battaglia, C., Sancini, G., and Palestini, P. (2014). Repeated intratracheal instillation of PM10 induces lipid reshaping in lung parenchyma and in extra-pulmonary tissues. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0106855"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Hubrecht, R.C., and Carter, E. (2019). The 3Rs and Humane Experimental Technique: Implementing Change. Animals, 9.","DOI":"10.3390\/ani9100754"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1289\/ehp.8266","article-title":"Instillation of Six Different Ultrafine Carbon Particles Indicates a Surface Area Threshold Dose for Acute Lung Inflammation in Mice","volume":"114","author":"Stoeger","year":"2006","journal-title":"Environ. Health Perspect."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.ejpb.2005.04.009","article-title":"Non-invasive pulmonary aerosol delivery in mice by the endotracheal route","volume":"61","author":"Zwier","year":"2005","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.toxlet.2011.01.031","article-title":"The acute toxic effects of particulate matter in mouse lung are related to size and season of collection","volume":"202","author":"Farina","year":"2011","journal-title":"Toxicol. Lett."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.toxlet.2010.07.002","article-title":"Comparative acute lung inflammation induced by atmospheric PM and size-fractionated tire particles","volume":"198","author":"Mantecca","year":"2010","journal-title":"Toxicol. Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"311","DOI":"10.56808\/2985-1130.2191","article-title":"Acute and Sub-acute Pulmonary Effects of Diesel Exhaust Particles in Mice: Pathological Changes and Translocation Pathways to the Circulation","volume":"39","author":"Kaewamatawong","year":"2009","journal-title":"Thai J. Vet. Med."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Nemmar, A., Holme, J.A., Rosas, I., Schwarze, P.E., and Alfaro-Moreno, E. (2013). Recent advances in particulate matter and nanoparticle toxicology: A review of the in vivo and in vitro studies. Biomed. Res. Int., 2013.","DOI":"10.1155\/2013\/279371"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"71","DOI":"10.2131\/jts.38.71","article-title":"Effects of acute single intranasal instillation of secondary organic aerosol on neurological and immunological biomarkers in the brain and lung of BALB\/c mice","volume":"38","author":"Fujitani","year":"2013","journal-title":"J. Toxicol. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Massimino, L., Bulbarelli, A., Corsetto, P.A., Milani, C., Botto, L., Farina, F., Lamparelli, L.A., Lonati, E., Ungaro, F., and Maddipati, K.R. (2022). LSEA Evaluation of Lipid Mediators of Inflammation in Lung and Cortex of Mice Exposed to Diesel Air Pollution. Biomedicines, 10.","DOI":"10.3390\/biomedicines10030712"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.lfs.2013.02.014","article-title":"An old method facing a new challenge: Re-visiting housekeeping proteins as internal reference control for neuroscience research","volume":"92","author":"Li","year":"2013","journal-title":"Life Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1600189","DOI":"10.1002\/pmic.201600189","article-title":"Tubulin or Not Tubulin: Heading Toward Total Protein Staining as Loading Control in Western Blots","volume":"17","author":"Moritz","year":"2017","journal-title":"Proteomics"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1152\/japplphysiol.00236.2004","article-title":"Endothelial cells as early sensors of pul-monary interstitial edema","volume":"97","author":"Daffara","year":"2004","journal-title":"J. Appl. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"105974","DOI":"10.1016\/j.envint.2020.105974","article-title":"Long-term exposure to PM and all cause and cause-specific mortality: A systematic review and meta-analysis","volume":"143","author":"Chen","year":"2020","journal-title":"Environ. Int."},{"key":"ref_51","first-page":"125","article-title":"Long-term exposure to ambient air pollution and the incidence of SARS-CoV-2 infections in Italy: The EpiCovAir study","volume":"47","author":"Ranzi","year":"2023","journal-title":"Epidemiol. Prev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"057004","DOI":"10.1289\/EHP11882","article-title":"Long-Term Exposure to Ambient Air Pollution and Mortality among Four Million COVID-19 Cases in Italy: TheEpiCovAir Study","volume":"31","author":"Stafoggia","year":"2023","journal-title":"Environ. Health Perspect."},{"key":"ref_53","unstructured":"(2024, March 28). WHO Global Air Quality Guidelines. Available online: https:\/\/iris.who.int\/bitstream\/handle\/10665\/345329\/9789240034228-eng.pdf?sequence=1."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Comunian, S., Dongo, D., Milani, C., and Palestini, P. (2020). Air Pollution and COVID-19: The Role of Particulate Matter in the Spread and Increase of COVID-19\u2032s Morbidity and Mortality. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17124487"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2430","DOI":"10.1002\/jcp.30041","article-title":"ACE2: Its potential role and regulation in severe acute respiratory syndrome and COVID-19","volume":"236","author":"Rezaei","year":"2021","journal-title":"J. Cell Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1126\/science.abb2507","article-title":"Cryo-EM structure of the 2019-nCoV spike in the perfusion conformation","volume":"367","author":"Wrapp","year":"2020","journal-title":"Science"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.1016\/j.ajpath.2020.06.010","article-title":"Eicosanoids: The Overlooked Storm in Coronavirus Disease 2019 (COVID-19)?","volume":"190","author":"Hammock","year":"2020","journal-title":"Am. J. Pathol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Hrenak, J., and Simko, F. (2020). Renin-Angiotensin System: An Important Player in the Pathogenesis of Acute Respiratory Distress Syndrome. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218038"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1152\/physrev.00023.2016","article-title":"The ACE2\/Angiotensin-(1\u20137)\/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1\u20137)","volume":"98","author":"Sampaio","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1161\/01.HYP.38.3.665","article-title":"Angiotensin-(1-7): Cardioprotective effect in myocardial ischemia\/reperfusion","volume":"38","author":"Ferreira","year":"2001","journal-title":"Hypertension"},{"key":"ref_61","first-page":"108502","article-title":"Oxidative stress and inflammatory markers in patients with COVID-19: Potential role of RAGE, HMGB1, GFAP and COX-2 in disease severity","volume":"104","author":"Heimfarth","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1111\/j.1440-1746.2008.05461.x","article-title":"Liver disease and the renin-angiotensin system: Recent discoveries and clinical implications","volume":"23","author":"Lubel","year":"2008","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"G99","DOI":"10.1152\/ajpgi.00163.2012","article-title":"Angiotensin-(1-7) reduces the perfusion pressure response to angiotensin II and methoxamine via an endothelial nitric oxide mediated pathway in cirrhotic rat liver","volume":"304","author":"Herath","year":"2013","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3321","DOI":"10.1007\/s00705-014-2201-5","article-title":"Downregulation of inducible nitric oxide synthase (iNOS) expression is implicated in the antiviral activity of acetylsalicylic acid in HCV-expressing cells","volume":"159","year":"2014","journal-title":"Arch. Virol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"F245","DOI":"10.1152\/ajprenal.00477.2006","article-title":"Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2","volume":"293","author":"Gupta","year":"2007","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.apsb.2020.10.006","article-title":"Angiotensin-converting enzyme 2 (ACE2): SARS-CoV-2 receptor and RAS modulator","volume":"11","author":"Bian","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e2213","DOI":"10.1002\/rmv.2213","article-title":"Potential detrimental role of soluble ACE2 in severe COVID-19 comorbid patients","volume":"31","author":"Rahman","year":"2021","journal-title":"Rev. Med. Virol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1007\/s11845-021-02740-x","article-title":"The relationship between mortality and inflammatory markers and the systemic immune inflammatory index in patients in the intensive care unit with a pneumothorax as a complication of COVID-19 disease","volume":"191","author":"Akboga","year":"2022","journal-title":"Ir. J. Med. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1007\/s11845-021-02743-8","article-title":"Thiol level and total oxidant\/antioxidant status in patients with COVID-19 infection","volume":"191","author":"Torun","year":"2022","journal-title":"Ir. J. Med. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Vassiliou, A.G., Zacharis, A., Keskinidou, C., Jahaj, E., Pratikaki, M., Gallos, P., Dimopoulou, I., Kotanidou, A., and Orfanos, S.E. (2021). Soluble Angiotensin Converting Enzyme 2 (ACE2) Is Upregulated and Soluble Endothelial Nitric Oxide Synthase (eNOS) is Downregulated in COVID-19-induced Acute Respiratory Distress Syndrome (ARDS). Pharmaceuticals, 14.","DOI":"10.3390\/ph14070695"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41589-021-00923-2","article-title":"Host glycolipids in SARS-CoV-2 entry","volume":"18","author":"Uraki","year":"2022","journal-title":"Nat. Chem. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/s41589-021-00924-1","article-title":"Sialic acid-containing glycolipids mediate binding and viral entry of SARS-CoV-2","volume":"18","author":"Nguyen","year":"2022","journal-title":"Nat. Chem. Biol."}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/12\/8\/560\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:27:07Z","timestamp":1760110027000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/12\/8\/560"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,31]]},"references-count":72,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["toxics12080560"],"URL":"https:\/\/doi.org\/10.3390\/toxics12080560","relation":{},"ISSN":["2305-6304"],"issn-type":[{"value":"2305-6304","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,31]]}}}