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      Antiviral activity of Isatidis Radix derived glucosinolate isomers and their breakdown products against influenza A in vitro/ovo and mechanism of action

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          Abstract

          Ethnopharmacological relevance

          Isatidis Radix, the sun-dried roots of Isatis indigotica Fortune ex Lindl., is one of the most usually used traditional Chinese medicines. For centuries, the herb has been employed in clinical practice for treatment of virus infection and inflammation. However, its active ingredients remain unclear.

          Aim of the study

          In the present study, the anti-influenza virus activity of epiprogoitrin, progoitrin, epigoitrin and goitrin, the Isatidis Radix derived glucosinolate isomers and their breakdown products, was firstly evaluated in vitro and in ovo and their mechanism of action was investigated.

          Materials and methods

          Epiprogoitrin, progoitrin, epigoitrin and goitrin were isolated from Isatidis Radix by chiral separation. In vitro and in ovo evaluations were performed on Madin-Darby canine kidney (MDCK) cells and embryonated eggs respectively, both using protocols including prevention, treatment and virus neutralization. Hemagglutination (HA) and neuraminidase (NA) inhibition assays were performed for further understanding of the antiviral mechanism.

          Results

          Isatidis Radix derived glucosinolate isomers and their breakdown products all exhibited dose-dependent inhibition effect against influenza A virus (H1N1) without toxicity. The antiviral potency of the components was in the order of progoitrin > goitrin > epigoitrin > epiprogoitrin. The attachment of the constituents to the viral envelope conduced to the mechanism of their antiviral action without disturbing viral adsorption or budding.

          Conclusion

          Taken together, these results are promising for further development of Isatidis Radix and may contribute an adjunct to pharmacotherapy for influenza virus infection.

          Graphical abstract

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          Most cited references28

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          Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds

          The 3C-like protease (3CLpro) of SARS-coronavirus mediates the proteolytic processing of replicase polypeptides 1a and 1ab into functional proteins, becoming an important target for the drug development. In this study, Isatis indigotica root extract, five major compounds of I. indigotica root, and seven plant-derived phenolic compounds were tested for anti-SARS-CoV 3CLpro effects using cell-free and cell-based cleavage assays. Cleavage assays with the 3CLpro demonstrated that IC50 values were in micromolar ranges for I. indigotica root extract, indigo, sinigrin, aloe emodin and hesperetin. Sinigrin (IC50: 217 μM) was more efficient in blocking the cleavage processing of the 3CLpro than indigo (IC50: 752 μM) and beta-sitosterol (IC50: 1210 μM) in the cell-based assay. Only two phenolic compounds aloe emodin and hesperetin dose-dependently inhibited cleavage activity of the 3CLpro, in which the IC50 was 366 μM for aloe emodin and 8.3 μM for hesperetin in the cell-based assay.
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            Emerging influenza antiviral resistance threats.

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              Influenza A virus neuraminidase limits viral superinfection.

              Enveloped viruses use multiple mechanisms to inhibit infection of a target cell by more than one virion. These mechanisms may be of particular importance for the evolution of segmented viruses, because superinfection exclusion may limit the frequency of reassortment of viral genes. Here, we show that cellular expression of influenza A virus neuraminidase (NA), but not hemagglutinin (HA) or the M2 proton pump, inhibits entry of HA-pseudotyped retroviruses. Cells infected with H1N1 or H3N2 influenza A virus were similarly refractory to HA-mediated infection and to superinfection with a second influenza A virus. Both HA-mediated entry and viral superinfection were rescued by the neuraminidase inhibitors oseltamivir carboxylate and zanamivir. These inhibitors also prevented the removal of alpha-2,3- and alpha-2,6-linked sialic acid observed in cells expressing NA or infected with influenza A viruses. Our data indicate that NA alone among viral proteins limits influenza A virus superinfection.
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                Author and article information

                Contributors
                Journal
                J Ethnopharmacol
                J Ethnopharmacol
                Journal of Ethnopharmacology
                Elsevier B.V.
                0378-8741
                1872-7573
                7 January 2020
                6 April 2020
                7 January 2020
                : 251
                : 112550
                Affiliations
                [a ]Chinese Academy of Medical Science & Peking Union Medical College, Beijing, PR China
                [b ]National Institutes for Food and Drug Control, National Medical Products Administration, Beijing, PR China
                Author notes
                []Corresponding author. National Institutes for Food and Drug Control, No.2, Tiantan Xili, Dongcheng District, Beijing, 10050, PR China. masc@ 123456nifdc.org.cn
                [∗∗ ]Corresponding author. National Institutes for Food and Drug Control, No.2, Tiantan Xili, Dongcheng District, Beijing, 10050, PR China. wyljoe@ 123456126.com
                Article
                S0378-8741(19)33356-2 112550
                10.1016/j.jep.2020.112550
                7126217
                31918015
                9a3d6522-4555-465d-97cd-381776c59f89
                © 2020 Elsevier B.V. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 27 August 2019
                : 24 October 2019
                : 4 January 2020
                Categories
                Article

                Pharmacology & Pharmaceutical medicine
                influenza,antivirals,glucosinolate,isomer,isatidis radix
                Pharmacology & Pharmaceutical medicine
                influenza, antivirals, glucosinolate, isomer, isatidis radix

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