title: Bakuchiol Is a Phenolic Isoprenoid with Novel Enantiomer-selective Anti-influenza A Virus Activity Involving Nrf2 Activation.
abstract: Influenza represents a substantial threat to human health and requires novel therapeutic approaches. Bakuchiol is a phenolic isoprenoid compound present in Babchi (Psoralea corylifolia L.) seeds. We examined the anti-influenza viral activity of synthetic bakuchiol using Madin-Darby canine kidney cells. We found that the naturally occurring form, (+)-(S)-bakuchiol, and its enantiomer, (-)-(R)-bakuchiol, inhibited influenza A viral infection and growth and reduced the expression of viral mRNAs and proteins in these cells. Furthermore, these compounds markedly reduced the mRNA expression of the host cell influenza A virus-induced immune response genes, interferon-β and myxovirus-resistant protein 1. Interestingly, (+)-(S)-bakuchiol had greater efficacy than (-)-(R)-bakuchiol, indicating that chirality influenced anti-influenza virus activity. In vitro studies indicated that bakuchiol did not strongly inhibit the activities of influenza surface proteins or the M2 ion channel, expressed in Chinese hamster ovary cells. Analysis of luciferase reporter assay data unexpectedly indicated that bakuchiol may induce some host cell factor(s) that inhibited firefly and Renilla luciferases. Next generation sequencing and KeyMolnet analysis of influenza A virus-infected and non-infected cells exposed to bakuchiol revealed activation of transcriptional regulation by nuclear factor erythroid 2-related factor (Nrf), and an Nrf2 reporter assay showed that (+)-(S)-bakuchiol activated Nrf2. Additionally, (+)-(S)-bakuchiol up-regulated the mRNA levels of two Nrf2-induced genes, NAD(P)H quinone oxidoreductase 1 and glutathione S-transferase A3. These findings demonstrated that bakuchiol had enantiomer-selective anti-influenza viral activity involving a novel effect on the host cell oxidative stress response.
authors.affiliation: From the Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, and.
authors.forename: Masaki
authors.initials: M
authors.lastname: Shoji
authors.affiliation: From the Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, and.
authors.forename: Yumie
authors.initials: Y
authors.lastname: Arakaki
authors.affiliation: the Institute of Pharmacognosy, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Esumi
authors.affiliation: the Department of Neurophysiology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Kagawa 769-2193, Japan.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Kohnomi
authors.affiliation: the Institute of Pharmacognosy, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yamamoto
authors.affiliation: the Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba 277-8568, Japan, and.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: the Division of Enzyme Chemistry, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan.
authors.forename: Etsuhisa
authors.initials: E
authors.lastname: Takahashi
authors.affiliation: the Department of Neurophysiology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Kagawa 769-2193, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Konishi
authors.affiliation: the Division of Enzyme Chemistry, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kido
authors.affiliation: From the Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, and kuzuhara@ph.bunri-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuzuhara
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D005982:Glutathione Transferase / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects*; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects*; D007251:Influenza, Human / Q000821:virology*; D016899:Interferon-beta / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D016660:NAD(P)H Dehydrogenase (Quinone); D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000821:virology; D018384:Oxidative Stress / Q000187:drug effects*; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects; D012367:RNA, Viral / Q000187:drug effects; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology*; D014158:Transcription, Genetic
chemical_list: D000998:Antiviral Agents; D051267:NF-E2-Related Factor 2; D010636:Phenols; D012333:RNA, Messenger; D012367:RNA, Viral; D013729:Terpenes; D016899:Interferon-beta; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase; C012765:bakuchiol
keywords: antiviral agent; bakuchiol; enantiomer-selective; infectious disease; influenza; influenza virus; nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2); virus