title: A novel benzofuran, 4-methoxybenzofuran-5-carboxamide, from Tephrosia purpurea suppressed histamine H1 receptor gene expression through a protein kinase C-δ-dependent signaling pathway.
abstract: Histamine H1 receptor (H1R) gene is upregulated in patients with allergic rhinitis (AR), and its expression level is strongly correlated with the severity of allergic symptoms. We previously reported isolation of the putative anti-allergic compound, 4-methoxybenzofuran-5-carboxamide (MBCA) from Tephrosia purpurea and its chemical synthesis (Shill et al., Bioorg Med Chem 2015;23:6869-6874). However, the mechanism underlying its anti-allergic activity remains to be elucidated. Here, we report the mechanism of MBCA on phorbol 12-myristate-13-acetate (PMA)- or histamine-induced upregulation of H1R gene expression in HeLa cells, and in vivo effects of MBCA were also determined in toluene-2,4-diisocyanate (TDI)-sensitized rats. MBCA suppressed PMA- and histamine-induced upregulation of H1R expression at both mRNA and protein levels and inhibited PMA-induced phosphorylation of PKCδ at Tyr(311) and subsequent translocation to the Golgi. Furthermore, MBCA ameliorated allergic symptoms and suppressed the elevation of H1R and helper T cell type 2 (Th2) cytokine mRNAs in TDI-sensitized rats. Data suggest that MBCA alleviates nasal symptoms in TDI-sensitized rats through the inhibition of H1R and Th2 cytokine gene expression. The mechanism of its H1R gene suppression underlies the inhibition of PKCδ activation.
authors.affiliation: Department of Molecular Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, 1-78-1 Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Manik Chandra
authors.initials: MC
authors.lastname: Shill
authors.affiliation: Department of Molecular Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, 1-78-1 Sho-machi, Tokushima 770-8505, Japan. Electronic address: guchi003@tokushima-u.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizuguchi
authors.affiliation: School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India.
authors.forename: Sanmoy
authors.initials: S
authors.lastname: Karmakar
authors.affiliation: Department of Molecular Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, 1-78-1 Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kadota
authors.affiliation: School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India.
authors.forename: Pulok K
authors.initials: PK
authors.lastname: Mukherjee
authors.affiliation: Department of Otolaryngology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kitamura
authors.affiliation: Department of Parmacognosy, Institute of Biomedical Sciences, Tokushima University Graduate School, 1-78-1 Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kashiwada
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Biomedical Sciences, Tokushima University Graduate School, 1-78-1 Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Nemoto
authors.affiliation: Department of Otolaryngology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Takeda
authors.affiliation: Department of Molecular Studies for Incurable Diseases, Institute of Biomedical Sciences, Tokushima University Graduate School, Fujii Memorial Institute of Medical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fukui
mesh_terms: D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage*; D001572:Benzofurans / Q000008:administration & dosage*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D006632:Histamine / Q000378:metabolism; D006801:Humans; D008297:Male; D051745:Protein Kinase C-delta / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011969:Receptors, Histamine H1 / Q000235:genetics / Q000378:metabolism*; D065631:Rhinitis, Allergic / Q000139:chemically induced / Q000188:drug therapy*; D031304:Tephrosia / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology; D014051:Toluene 2,4-Diisocyanate / Q000276:immunology
chemical_list: C000610442:4-methoxybenzofuran-5-carboxamide; D018926:Anti-Allergic Agents; D001572:Benzofurans; D016207:Cytokines; D011969:Receptors, Histamine H1; D014051:Toluene 2,4-Diisocyanate; D006632:Histamine; D051745:Protein Kinase C-delta
keywords: Allergic disease sensitive gene; Histamine H(1) receptor gene; PKCδ; Pollinosis