Abstract
Influenza is an infectious respiratory disease with frequent seasonal epidemics that causes a high rate of mortality and morbidity in humans, poultry, and animals. Influenza is a serious economic concern due to the costly countermeasures it necessitates. In this study, we compared the antiviral activities of several flavonols and other flavonoids with similar, but distinct, hydroxyl or methyl substitution patterns at the 3, 3′, and 4′ positions of the 15-carbon flavonoid skeleton, and found that the strongest antiviral effect was induced by isorhamnetin. Similar to quercetin and kaempferol, isorhamnetin possesses a hydroxyl group on the C ring, but it has a 3′-methyl group on the B ring that is absent in quercetin and kaempferol. Co-treatment and pre-treatment with isorhamnetin produced a strong antiviral effect against the influenza virus A/PR/08/34(H1N1). However, isorhamnetin showed the most potent antiviral potency when administered after viral exposure (post-treatment method) in vitro. Isorhamnetin treatment reduced virus-induced ROS generation and blocked cytoplasmic lysosome acidification and the lipidation of microtubule associated protein1 light chain 3-B (LC3B). Oral administration of isorhamnetin in mice infected with the influenza A virus significantly decreased lung virus titer by 2 folds, increased the survival rate which ranged from 70–80%, and decreased body weight loss by 25%. In addition, isorhamnetin decreased the virus titer in ovo using embryonated chicken eggs. The structure-activity relationship (SAR) of isorhamnetin could explain its strong anti-influenza virus potency; the methyl group located on the B ring of isorhamnetin may contribute to its strong antiviral potency against influenza virus in comparison with other flavonoids.
Highlights
The influenza A virus, a causative agent of periodic contagious disease epidemics, is a member of the Orthomyxoviridae family
We investigated the influence of flavonoids treatment on the cell viability of Madin Darby Canine Kidney (MDCK) cells
Influenza virus infection resulted in significant generation of ROS and oxidative stress that was related to the release of cytokines and chemokines from the infected cells [46]
Summary
The influenza A virus, a causative agent of periodic contagious disease epidemics, is a member of the Orthomyxoviridae family. Efficient control of influenza outbreaks requires the discovery and development of novel antiviral drugs [5]. Novel and safe anti-influenza drugs are a focus of drug development programs, and natural antiviral nutrients are of special interest, because they are widely available and may be used as dietary supplements to combat diseases, including influenza infection. There is various flavonoids showed strong anti-influenza virus property in vitro [13,14,15]. It is worth noting that the biological activities and health benefits of the flavonoids are attributed to their potent antioxidant effects in vitro and in vivo [18,19]. We confirmed the anti-influenza virus potency of 3,40dihydroxyflavone against the influenza A virus in vitro and in vivo [23]. We recently showed that the transplantation of induced pluripotent stem cells (iPS cells) pretreated with 3,20-dihydroxyflavone (3,20-DHF iPS) into rats with peripheral nerve injury improved axonal regeneration and functional injury recovery in comparison with the control group [24]
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