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      Oxidative Stress Status in COVID-19 Patients Hospitalized in Intensive Care Unit for Severe Pneumonia. A Pilot Study

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          Abstract

          Background: A key role of oxidative stress has been highlighted in the pathogenesis of COVID-19. However, little has been said about oxidative stress status (OSS) of COVID-19 patients hospitalized in intensive care unit (ICU). Material and Methods: Biomarkers of the systemic OSS included antioxidants (9 assays), trace elements (3 assays), inflammation markers (4 assays) and oxidative damage to lipids (3 assays). Results: Blood samples were drawn after 9 (7–11) and 41 (39–43) days of ICU stay, respectively in 3 and 6 patients. Vitamin C, thiol proteins, reduced glutathione, γ-tocopherol, β-carotene and PAOT ® score were significantly decreased compared to laboratory reference values. Selenium concentration was at the limit of the lower reference value. By contrast, the copper/zinc ratio (as a source of oxidative stress) was higher than reference values in 55% of patients while copper was significantly correlated with lipid peroxides (r = 0.95, p < 0.001). Inflammatory biomarkers (C-reactive protein and myeloperoxidase) were significantly increased when compared to normals. Conclusions: The systemic OSS was strongly altered in critically ill COVID-19 patients as evidenced by increased lipid peroxidation but also by deficits in some antioxidants (vitamin C, glutathione, thiol proteins) and trace elements (selenium).

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          A Novel Coronavirus from Patients with Pneumonia in China, 2019

          Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
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            Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target

            A novel infectious disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was detected in Wuhan, China, in December 2019. The disease (COVID-19) spread rapidly, reaching epidemic proportions in China, and has been found in 27 other countries. As of February 27, 2020, over 82,000 cases of COVID-19 were reported, with > 2800 deaths. No specific therapeutics are available, and current management includes travel restrictions, patient isolation, and supportive medical care. There are a number of pharmaceuticals already being tested [1, 2], but a better understanding of the underlying pathobiology is required. In this context, this article will briefly review the rationale for angiotensin-converting enzyme 2 (ACE2) receptor as a specific target. SARS-CoV-2 and severe acute respiratory syndrome coronavirus (SARS-CoV) use ACE2 receptor to facilitate viral entry into target cells SARS-CoV-2 has been sequenced [3]. A phylogenetic analysis [3, 4] found a bat origin for the SARS-CoV-2. There is a diversity of possible intermediate hosts for SARS-CoV-2, including pangolins, but not mice and rats [5]. There are many similarities of SARS-CoV-2 with the original SARS-CoV. Using computer modeling, Xu et al. [6] found that the spike proteins of SARS-CoV-2 and SARS-CoV have almost identical 3-D structures in the receptor-binding domain that maintains van der Waals forces. SARS-CoV spike protein has a strong binding affinity to human ACE2, based on biochemical interaction studies and crystal structure analysis [7]. SARS-CoV-2 and SARS-CoV spike proteins share 76.5% identity in amino acid sequences [6] and, importantly, the SARS-CoV-2 and SARS-CoV spike proteins have a high degree of homology [6, 7]. Wan et al. [4] reported that residue 394 (glutamine) in the SARS-CoV-2 receptor-binding domain (RBD), corresponding to residue 479 in SARS-CoV, can be recognized by the critical lysine 31 on the human ACE2 receptor [8]. Further analysis even suggested that SARS-CoV-2 recognizes human ACE2 more efficiently than SARS-CoV increasing the ability of SARS-CoV-2 to transmit from person to person [4]. Thus, the SARS-CoV-2 spike protein was predicted to also have a strong binding affinity to human ACE2. This similarity with SARS-CoV is critical because ACE2 is a functional SARS-CoV receptor in vitro [9] and in vivo [10]. It is required for host cell entry and subsequent viral replication. Overexpression of human ACE2 enhanced disease severity in a mouse model of SARS-CoV infection, demonstrating that viral entry into cells is a critical step [11]; injecting SARS-CoV spike into mice worsened lung injury. Critically, this injury was attenuated by blocking the renin-angiotensin pathway and depended on ACE2 expression [12]. Thus, for SARS-CoV pathogenesis, ACE2 is not only the entry receptor of the virus but also protects from lung injury. We therefore previously suggested that in contrast to most other coronaviruses, SARS-CoV became highly lethal because the virus deregulates a lung protective pathway [10, 12]. Zhou et al. [13] demonstrated that overexpressing ACE2 from different species in HeLa cells with human ACE2, pig ACE2, civet ACE2 (but not mouse ACE2) allowed SARS-CoV-2 infection and replication, thereby directly showing that SARS-CoV-2 uses ACE2 as a cellular entry receptor. They further demonstrated that SARS-CoV-2 does not use other coronavirus receptors such as aminopeptidase N and dipeptidyl peptidase 4 [13]. In summary, the SARS-CoV-2 spike protein directly binds with the host cell surface ACE2 receptor facilitating virus entry and replication. Enrichment distribution of ACE2 receptor in human alveolar epithelial cells (AEC) A key question is why the lung appears to be the most vulnerable target organ. One reason is that the vast surface area of the lung makes the lung highly susceptible to inhaled viruses, but there is also a biological factor. Using normal lung tissue from eight adult donors, Zhao et al. [14] demonstrated that 83% of ACE2-expressing cells were alveolar epithelial type II cells (AECII), suggesting that these cells can serve as a reservoir for viral invasion. In addition, gene ontology enrichment analysis showed that the ACE2-expressing AECII have high levels of multiple viral process-related genes, including regulatory genes for viral processes, viral life cycle, viral assembly, and viral genome replication [14], suggesting that the ACE2-expressing AECII facilitate coronaviral replication in the lung. Expression of the ACE2 receptor is also found in many extrapulmonary tissues including heart, kidney, endothelium, and intestine [15–19]. Importantly, ACE2 is highly expressed on the luminal surface of intestinal epithelial cells, functioning as a co-receptor for nutrient uptake, in particular for amino acid resorption from food [20]. We therefore predict that the intestine might also be a major entry site for SARS-CoV-2 and that the infection might have been initiated by eating food from the Wuhan market, the putative site of the outbreak. Whether SARS-CoV-2 can indeed infect the human gut epithelium has important implications for fecal–oral transmission and containment of viral spread. ACE2 tissue distribution in other organs could explain the multi-organ dysfunction observed in patients [21–23]. Of note, however, according to the Centers for Disease Control and Prevention [24], whether a person can get COVID-19 by touching surfaces or objects that have virus on them and then touching mucus membranes is yet to be confirmed. Potential approaches to address ACE2-mediated COVID-19 There are several potential therapeutic approaches (Fig. 1). Spike protein-based vaccine. Development of a spike1 subunit protein-based vaccine may rely on the fact that ACE2 is the SARS-CoV-2 receptor. Cell lines that facilitate viral replication in the presence of ACE2 may be most efficient in large-scale vaccine production. Inhibition of transmembrane protease serine 2 (TMPRSS2) activity. Hoffman et al. [25] recently demonstrated that initial spike protein priming by transmembrane protease serine 2 (TMPRSS2) is essential for entry and viral spread of SARS-CoV-2 through interaction with the ACE2 receptor [26, 27]. The serine protease inhibitor camostat mesylate, approved in Japan to treat unrelated diseases, has been shown to block TMPRSS2 activity [28, 29] and is thus an interesting candidate. Blocking ACE2 receptor. The interaction sites between ACE2 and SARS-CoV have been identified at the atomic level and from studies to date should also hold true for interactions between ACE2 and SARS-CoV-2. Thus, one could target this interaction site with antibodies or small molecules. Delivering excessive soluble form of ACE2. Kuba et al. [10] demonstrated in mice that SARS-CoV downregulates ACE2 protein (but not ACE) by binding its spike protein, contributing to severe lung injury. This suggests that excessive ACE2 may competitively bind with SARS-CoV-2 not only to neutralize the virus but also rescue cellular ACE2 activity which negatively regulates the renin-angiotensin system (RAS) to protect the lung from injury [12, 30]. Indeed, enhanced ACE activity and decreased ACE2 availability contribute to lung injury during acid- and ventilator-induced lung injury [12, 31, 32]. Thus, treatment with a soluble form of ACE2 itself may exert dual functions: (1) slow viral entry into cells and hence viral spread [7, 9] and (2) protect the lung from injury [10, 12, 31, 32]. Notably, a recombinant human ACE2 (rhACE2; APN01, GSK2586881) has been found to be safe, with no negative hemodynamic effects in healthy volunteers and in a small cohort of patients with ARDS [33–35]. The administration of APN01 rapidly decreased levels of its proteolytic target peptide angiotensin II, with a trend to lower plasma IL-6 concentrations. Our previous work on SARS-CoV pathogenesis makes ACE2 a rational and scientifically validated therapeutic target for the current COVID-19 pandemic. The availability of recombinant ACE2 was the impetus to assemble a multinational team of intensivists, scientists, and biotech to rapidly initiate a pilot trial of rhACE2 in patients with severe COVID-19 (Clinicaltrials.gov #NCT04287686). Fig. 1 Potential approaches to address ACE2-mediated COVID-19 following SARS-CoV-2 infection. The finding that SARS-CoV-2 and SARS-CoV use the ACE2 receptor for cell entry has important implications for understanding SARS-CoV-2 transmissibility and pathogenesis. SARS-CoV and likely SARS-CoV-2 lead to downregulation of the ACE2 receptor, but not ACE, through binding of the spike protein with ACE2. This leads to viral entry and replication, as well as severe lung injury. Potential therapeutic approaches include a SARS-CoV-2 spike protein-based vaccine; a transmembrane protease serine 2 (TMPRSS2) inhibitor to block the priming of the spike protein; blocking the surface ACE2 receptor by using anti-ACE2 antibody or peptides; and a soluble form of ACE2 which should slow viral entry into cells through competitively binding with SARS-CoV-2 and hence decrease viral spread as well as protecting the lung from injury through its unique enzymatic function. MasR—mitochondrial assembly receptor, AT1R—Ang II type 1 receptor
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              The Cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system

              Highlights • COVID-19 pandemic is raging worldwide and is putting health-care systems under severe strain. • The “cytokine storm” and the subsequent Acute Respiratory Distress Syndrome results from the effects of a combination of several immune-active molecules. • the “cytokine storm” appears as one of the most dangerous and potentially life-threatening event related to COVID-19 sustaining its major clinical consequences. • The chemokine system appears to be deeply involved in the pathogenesis of severe clinical sequelae of COVID-19, similarly to what was observed in SARS and MERS epidemics.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Antioxidants (Basel)
                Antioxidants (Basel)
                antioxidants
                Antioxidants
                MDPI
                2076-3921
                07 February 2021
                February 2021
                : 10
                : 2
                : 257
                Affiliations
                [1 ]Clinical Chemistry, CHU of Liège, Sart Tilman, 4000 Liège, Belgium; etienne.cavalier@ 123456chuliege.be (E.C.); e.brevers@ 123456chu.ulg.ac.be (E.B.); c.legoff@ 123456chu.ulg.ac.be (C.L.G.)
                [2 ]Toxicology Department, CHU of Liège, Sart Tilman, 4000 Liège, Belgium; c.charlier@ 123456chuliege.be
                [3 ]Department of Cardiovascular Surgery, CHU of Liège, Sart Tilman, 4000 Liège, Belgium; JP.Cheramy@ 123456chuliege.be (J.-P.C.-B.); a.courtois@ 123456chuliege.be (A.C.); jo.defraigne@ 123456chuliege.be (J.-O.D.)
                [4 ]Service of Diabetology, Nutrition and Metabolic Diseases, CHU of Liège, Sart Tilman, 4000 Liège, Belgium; marjorie.fadeur@ 123456chuliege.be
                [5 ]Institut Européen des Antioxydants, 54000 Nancy, France; smeziane@ 123456ie-antioxydants.com
                [6 ]Intensive Care Department, CHU of Liège, Sart Tilman, 4000 Liège, Belgium; benoit.misset@ 123456chuliege.be (B.M.); afrousseau@ 123456chuliege.be (A.-F.R.)
                [7 ]Biostatistics and Medico-economic Information Department, CHU of Liège, Sart Tilman, 4000 Liège, Belgium; aalbert@ 123456uliege.be
                Author notes
                Author information
                https://orcid.org/0000-0001-5938-2590
                https://orcid.org/0000-0002-4157-6570
                Article
                antioxidants-10-00257
                10.3390/antiox10020257
                7914603
                33562403
                a9a8c001-faee-4579-997e-d718841333ff
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 04 January 2021
                : 02 February 2021
                Categories
                Article

                covid-19,oxidative stress,critical care,vitamin c,lipid peroxides

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