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      Hesperidin and SARS-CoV-2: New Light on the Healthy Function of Citrus Fruits

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          Abstract

          Among the many approaches to Coronavirus disease 2019 (COVID-19) prevention, the possible role of nutrition has so far been rather underestimated. Foods are very rich in substances, with a potential beneficial effect on health, and some of these could have an antiviral action or be important in modulating the immune system and in defending cells from the oxidative stress associated with infection. This short review draws the attention on some components of citrus fruits, and especially of the orange ( Citrus sinensis), well known for its vitamin and flavonoid content. Among the flavonoids, hesperidin has recently attracted the attention of researchers, because it binds to the key proteins of the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several computational methods, independently applied by different researchers, showed that hesperidin has a low binding energy, both with the coronavirus “spike” protein, and with the main protease that transforms the early proteins of the virus (pp1a and ppa1b) into the complex responsible for viral replication. The binding energy of hesperidin to these important components is lower than that of lopinavir, ritonavir, and indinavir, suggesting that it could perform an effective antiviral action. Furthermore, both hesperidin and ascorbic acid counteract the cell damaging effects of the oxygen free radicals triggered by virus infection and inflammation. There is discussion about the preventive efficacy of vitamin C, at the dose achievable by the diet, but recent reviews suggest that this substance can be useful in the case of strong immune system burden caused by viral disease. Computational methods and laboratory studies support the need to undertake apposite preclinical, epidemiological, and experimental studies on the potential benefits of citrus fruit components for the prevention of infectious diseases, including COVID-19.

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          Extrapulmonary manifestations of COVID-19

          Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.
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            Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

            SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths. There are currently no registered therapies for treating coronavirus infections. Because of time consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases. We systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homology modeling. By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compound libraries including ZINC drug database and our own database of natural products. Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were discussed in detail. In addition, a database of 78 commonly used anti-viral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed. Possible targets of these compounds and potential drugs acting on a certain target were predicted. This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2, new insights for those drugs currently ongoing clinical studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.
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              SARS-CoV-2 productively infects human gut enterocytes

              The virus severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) can cause coronavirus disease 2019 (COVID-19), an influenza-like disease that is primarily thought to infect the lungs with transmission via the respiratory route. However, clinical evidence suggests that the intestine may present another viral target organ. Indeed, the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2) is highly expressed on differentiated enterocytes. In human small intestinal organoids (hSIOs), enterocytes were readily infected by SARS-CoV and SARS-CoV-2 as demonstrated by confocal- and electron-microscopy. Consequently, significant titers of infectious viral particles were detected. mRNA expression analysis revealed strong induction of a generic viral response program. Hence, intestinal epithelium supports SARS-CoV-2 replication, and hSIOs serve as an experimental model for coronavirus infection and biology
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                Author and article information

                Journal
                Antioxidants (Basel)
                Antioxidants (Basel)
                antioxidants
                Antioxidants
                MDPI
                2076-3921
                13 August 2020
                August 2020
                : 9
                : 8
                : 742
                Affiliations
                [1 ]Department of Medicine, Section of General Pathology, University of Verona Medical School, Strada Le Grazie 8, 37134 Verona, Italy
                [2 ]Medical Doctor, Scientific Committee of Fondazione Allineare Sanità e Salute, 20122 Milano, Italy; adonzelli@ 123456ats-milano.it
                Author notes
                Article
                antioxidants-09-00742
                10.3390/antiox9080742
                7465267
                32823497
                6be6dd05-94f1-4af7-b5d7-ce19b28c9e30
                © 2020 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
                : 25 July 2020
                : 11 August 2020
                Categories
                Review

                citrus fruits,citrus sinensis,hesperidin,virus and oxidative stress,covid-19,vitamin c,sars-cov-2,sweet orange

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