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Coadministration of Hedera helix L. Extract Enabled Mice to Overcome Insufficient Protection against Influenza A/PR/8 Virus Infection under Suboptimal Treatment with Oseltamivir.

Hong EH, Song JH, Shim A, Lee BR, Kwon BE, Song HH, Kim YJ, Chang SY, Jeong HG, Kim JG, Seo SU, Kim H, Kwon Y, Ko HJ - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea.

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.

No MeSH data available.


Related in: MedlinePlus

Anti-influenza virus activity of combined treatment with oseltamivir and fraction of ivy extract in mice.Representative H&E stained samples of lung section from uninfected or PR8-infected mice shown at 200x magnification. A and C: Infected mice were treated with oseltamivir alone or oseltamivir and fraction 4 of ivy extract (n = 4 per group) for 2 (A) or 5 (C) days. B and D: Pathological grade of mice that received oral drug administration for 2 (B) and 5 (D) days. *P<0.05;**p<0.01;***p<0.001; n.s., not significant. one-way ANOVA with Tukey’s post hoc test.
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pone.0131089.g004: Anti-influenza virus activity of combined treatment with oseltamivir and fraction of ivy extract in mice.Representative H&E stained samples of lung section from uninfected or PR8-infected mice shown at 200x magnification. A and C: Infected mice were treated with oseltamivir alone or oseltamivir and fraction 4 of ivy extract (n = 4 per group) for 2 (A) or 5 (C) days. B and D: Pathological grade of mice that received oral drug administration for 2 (B) and 5 (D) days. *P<0.05;**p<0.01;***p<0.001; n.s., not significant. one-way ANOVA with Tukey’s post hoc test.

Mentions: We performed histological analysis on lung tissue obtained from uninfected mice and PR8-infected mice treated with 30 mg/kg fraction 4 and 5 mg/kg oseltamivir for 2 or 5 consecutive days. Lungs from uninfected C57BL/6 mice exhibited typical pulmonary tissue, whereas PR8-infected mice had inflammatory lesions characteristic of viral infection, including necrotizing bronchiolitis and interstitial pneumonia (Fig 4A and 4C). On the contrary, PR8-infected mice treated with a combination of oseltamivir and fraction 4 for 5 days had moderate inflammation with reduced necrosis, inflammatory cells infiltrates, and pulmonary edema compared with untreated PR8-infected mice 7 days post-infection (Fig 4C and 4D). We did not observe significant improvements in PR8-infected mice receiving combined fraction 4 and oseltamivir treatment for 2 consecutive days (Fig 4A and 4B). Although oseltamivir could successfully remove the virus from mice, our results indicate that oseltamivir treatment alone could not prevent pulmonary inflammation in PR8-infected mice. In contrast, combined treatment of PR8-infected mice with oseltamivir and the HSF-containing fraction 4 significantly reduced lung inflammation at post-infection day 7. In addition to the direct anti-influenza activity of HSF, combined oseltamivir and fraction 4 treatment might reduce pulmonary inflammation in the latter stage of PR8 virus infection. In addition, the disease symptom of PR8-infected mice was significantly alleviated by the combined treatment of fraction 4 with oseltamivir as compared with oseltamivir alone (Fig 5A), suggesting the complementary antiviral and anti-inflammatory activity of fraction 4 under suboptimal oseltamivir treatment.


Coadministration of Hedera helix L. Extract Enabled Mice to Overcome Insufficient Protection against Influenza A/PR/8 Virus Infection under Suboptimal Treatment with Oseltamivir.

Hong EH, Song JH, Shim A, Lee BR, Kwon BE, Song HH, Kim YJ, Chang SY, Jeong HG, Kim JG, Seo SU, Kim H, Kwon Y, Ko HJ - PLoS ONE (2015)

Anti-influenza virus activity of combined treatment with oseltamivir and fraction of ivy extract in mice.Representative H&E stained samples of lung section from uninfected or PR8-infected mice shown at 200x magnification. A and C: Infected mice were treated with oseltamivir alone or oseltamivir and fraction 4 of ivy extract (n = 4 per group) for 2 (A) or 5 (C) days. B and D: Pathological grade of mice that received oral drug administration for 2 (B) and 5 (D) days. *P<0.05;**p<0.01;***p<0.001; n.s., not significant. one-way ANOVA with Tukey’s post hoc test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476699&req=5

pone.0131089.g004: Anti-influenza virus activity of combined treatment with oseltamivir and fraction of ivy extract in mice.Representative H&E stained samples of lung section from uninfected or PR8-infected mice shown at 200x magnification. A and C: Infected mice were treated with oseltamivir alone or oseltamivir and fraction 4 of ivy extract (n = 4 per group) for 2 (A) or 5 (C) days. B and D: Pathological grade of mice that received oral drug administration for 2 (B) and 5 (D) days. *P<0.05;**p<0.01;***p<0.001; n.s., not significant. one-way ANOVA with Tukey’s post hoc test.
Mentions: We performed histological analysis on lung tissue obtained from uninfected mice and PR8-infected mice treated with 30 mg/kg fraction 4 and 5 mg/kg oseltamivir for 2 or 5 consecutive days. Lungs from uninfected C57BL/6 mice exhibited typical pulmonary tissue, whereas PR8-infected mice had inflammatory lesions characteristic of viral infection, including necrotizing bronchiolitis and interstitial pneumonia (Fig 4A and 4C). On the contrary, PR8-infected mice treated with a combination of oseltamivir and fraction 4 for 5 days had moderate inflammation with reduced necrosis, inflammatory cells infiltrates, and pulmonary edema compared with untreated PR8-infected mice 7 days post-infection (Fig 4C and 4D). We did not observe significant improvements in PR8-infected mice receiving combined fraction 4 and oseltamivir treatment for 2 consecutive days (Fig 4A and 4B). Although oseltamivir could successfully remove the virus from mice, our results indicate that oseltamivir treatment alone could not prevent pulmonary inflammation in PR8-infected mice. In contrast, combined treatment of PR8-infected mice with oseltamivir and the HSF-containing fraction 4 significantly reduced lung inflammation at post-infection day 7. In addition to the direct anti-influenza activity of HSF, combined oseltamivir and fraction 4 treatment might reduce pulmonary inflammation in the latter stage of PR8 virus infection. In addition, the disease symptom of PR8-infected mice was significantly alleviated by the combined treatment of fraction 4 with oseltamivir as compared with oseltamivir alone (Fig 5A), suggesting the complementary antiviral and anti-inflammatory activity of fraction 4 under suboptimal oseltamivir treatment.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea.

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.

No MeSH data available.


Related in: MedlinePlus