Abstract
Human influenza virus infections occur annually worldwide and are associated with high morbidity and mortality. Hence, development of novel anti-influenza drugs is urgently required. Rice Power® extract developed by the Yushin Brewer Co. Ltd. is a novel aqueous extract of rice obtained via saccharization and fermentation with various microorganisms, such as Aspergillus oryzae, yeast [such as Saccharomyces cerevisiae], and lactic acid bacteria, possessing various biological and pharmacological properties. In our previous experimental screening with thirty types of Rice Power® extracts, we observed that the 30th Rice Power® (Y30) extract promoted the survival of influenza A virus-infected Madin-Darby canine kidney (MDCK) cells. Therefore, to identify compounds for the development of novel anti-influenza drugs, we aimed to investigate whether the Y30 extract exhibits anti-influenza A virus activity. In the present study, we demonstrated that the Y30 extract strongly promoted the survival of influenza A H1N1 Puerto Rico 8/34 (A/PR/8/34), California 7/09, or H3N2 Aichi 2/68 (A/Aichi/2/68) viruses-infected MDCK cells and inhibited A/PR/8/34 or A/Aichi/2/68 viruses infection and growth in the co-treatment and pre-infection experiments. The pre-treatment of Y30 extract on MDCK cells did not induce anti-influenza activity in the cell. The Y30 extract did not significantly affect influenza A virus hemagglutination, and neuraminidase and RNA-dependent RNA polymerase activities. Interestingly, the electron microscopy experiment revealed that the Y30 extract disrupts the integrity of influenza A virus particles by permeabilizing the viral membrane envelope, suggesting that Y30 extract has a direct virucidal effect against influenza A virus. Furthermore, we observed that compared to the ethyl acetate (EtOAc) extract, the water extract of Y30 extract considerably promoted the survival of cells infected with A/PR/8/34 virus. These results indicated that more anti-influenza components were present in the water extract of Y30 extract than in the EtOAc extract. Our results highlight the potential of a rice extract fermented with A. oryzae and S. cerevisiae as an anti-influenza medicine and a drug source for the development of anti-influenza compounds.
Highlights
The World Health Organization Fact sheet shows that approximately 3–5 million cases of severe influenza infection occur annually, out of which approximately 290,000 to 650,000 cases result in mortality [1]
Compared to Madin-Darby canine kidney (MDCK) cells exposed to only water, MDCK cells treated with the 25% Y30 extract showed significant reduction in viability after 24 (Fig 1A) and 72 h (Fig 1B) of incubation (p < 0.001 each), whereas the 0.4–12.5% Y30 extracts did not affect cell viability
The above results demonstrated that cells pre-treated with Y30 extract did not inhibit influenza A H1N1 virus infection and growth, suggesting that this extract has a direct effect on influenza viruses or host factors that inhibit the replication, assembly, and/or release of influenza A virus when used against influenza viruses or to treat influenza virusesinfected host cells
Summary
The World Health Organization Fact sheet shows that approximately 3–5 million cases of severe influenza infection occur annually, out of which approximately 290,000 to 650,000 cases result in mortality [1]. Two classes of anti-influenza virus drugs are currently available: neuraminidase (NA) inhibitors, such as oseltamivir, zanamivir, and peramivir, and M2 proton channel inhibitors, such as amantadine and rimantadine of the adamantane family of antiviral drugs. Considering that adamantane-resistant influenza strains have been frequently reported [1,2,3,4], the use of NA inhibitors is currently recommended for influenza treatment. Baloxavir marboxil, which inhibits the cap-dependent endonuclease activity of influenza polymerase acidic (PA) protein, is a novel antiviral drug against influenza A and B strains and was approved in 2018 [8]. Baloxavir-resistant influenza A H1N1 and H3N2 viruses with I38T-substituted PA have been detected [9], and the H3N2 virus with PA-I38T substitution can be transmitted among humans [10]. Development of novel anti-influenza drugs for preventing and controlling potential influenza epidemics and pandemics is urgently required
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