title: Coadministration of Hedera helix L. Extract Enabled Mice to Overcome Insufficient Protection against Influenza A/PR/8 Virus Infection under Suboptimal Treatment with Oseltamivir.
abstract: Several anti-influenza drugs that reduce disease manifestation exist, and although these drugs provide clinical benefits in infected patients, their efficacy is limited by the emergence of drug-resistant influenza viruses. In the current study, we assessed the therapeutic strategy of enhancing the antiviral efficacy of an existing neuraminidase inhibitor, oseltamivir, by coadministering with the leaf extract from Hedera helix L, commonly known as ivy. Ivy extract has anti-inflammatory, antibacterial, antifungal, and antihelminthic properties. In the present study, we investigated its potential antiviral properties against influenza A/PR/8 (PR8) virus in a mouse model with suboptimal oseltamivir that mimics a poor clinical response to antiviral drug treatment. Suboptimal oseltamivir resulted in insufficient protection against PR8 infection. Oral administration of ivy extract with suboptimal oseltamivir increased the antiviral activity of oseltamivir. Ivy extract and its compounds, particularly hedrasaponin F, significantly reduced the cytopathic effect in PR8-infected A549 cells in the presence of oseltamivir. Compared with oseltamivir treatment alone, coadministration of the fraction of ivy extract that contained the highest proportion of hedrasaponin F with oseltamivir decreased pulmonary inflammation in PR8-infected mice. Inflammatory cytokines and chemokines, including tumor necrosis factor-alpha and chemokine (C-C motif) ligand 2, were reduced by treatment with oseltamivir and the fraction of ivy extract. Analysis of inflammatory cell infiltration in the bronchial alveolar of PR8-infected mice revealed that CD11b+Ly6G+ and CD11b+Ly6Cint cells were recruited after virus infection; coadministration of the ivy extract fraction with oseltamivir reduced infiltration of these inflammatory cells. In a model of suboptimal oseltamivir treatment, coadministration of ivy extract fraction that includes hedrasaponin F increased protection against PR8 infection that could be explained by its antiviral and anti-inflammatory activities.
authors.affiliation: Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea.
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Hong
authors.affiliation: Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea.
authors.forename: Jae-Hyoung
authors.initials: JH
authors.lastname: Song
authors.affiliation: Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea.
authors.forename: Aeri
authors.initials: A
authors.lastname: Shim
authors.affiliation: Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea.
authors.forename: Bo-Ra
authors.initials: BR
authors.lastname: Lee
authors.affiliation: Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea.
authors.forename: Bo-Eun
authors.initials: BE
authors.lastname: Kwon
authors.affiliation: Natural Medicine Research Center, Korea Research Institute Bioscience and Biotechnology, Chungcheongbuk-do, Korea.
authors.forename: Hyuk-Hwan
authors.initials: HH
authors.lastname: Song
authors.affiliation: College of Pharmacy, Inje University, Gimhae, South Korea.
authors.forename: Yeon-Jeong
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Ajou University, Suwon, South Korea.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Chang
authors.affiliation: Ahngook pharm., R&D Center, Seoul, Korea.
authors.forename: Hyeon Gun
authors.initials: HG
authors.lastname: Jeong
authors.affiliation: Ahngook pharm., R&D Center, Seoul, Korea.
authors.forename: Jong Geal
authors.initials: JG
authors.lastname: Kim
authors.affiliation: Mucosal Immunology Section, International Vaccine Institute, Seoul, South Korea.
authors.forename: Sang-Uk
authors.initials: SU
authors.lastname: Seo
authors.affiliation: Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea.
authors.forename: HyunPyo
authors.initials: H
authors.lastname: Kim
authors.affiliation: Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea.
authors.forename: YongSoo
authors.initials: Y
authors.lastname: Kwon
authors.affiliation: Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea.
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Ko
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D035981:Hedera; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D009980:Influenza A virus / Q000187:drug effects* / Q000472:pathogenicity; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D053139:Oseltamivir / Q000008:administration & dosage*; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage; D012503:Saponins / Q000008:administration & dosage
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D010936:Plant Extracts; D012503:Saponins; D053139:Oseltamivir; D009439:Neuraminidase