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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

Antiviral activity of combined ivy extract and oseltamivir treatment against PR8 virus in vitro and in vivo.A: CPE reduction assay using SRB assay in A549 cells infected with PR8 virus were treated with oseltamivir for 48 h at the concentrations indicated. (***P<0.0001) B: Antiviral activity of ivy extract (at the concentrations indicated) combined with 25 μg/mL oseltamivir PR8-infected A549 cells. (***P<0.001) C: HSF, HSB, and hederacoside C were used in the presence of 25 μg/mL oseltamivir to identify its anti-PR8 virus activity in A549 cells. After 48 h of incubation, the antiviral activity was investigated by CPE reduction assay using SRB. (***P<0.001), and the antiviral activity was calculated based on the viability of virus infected cells as a percentage of the corresponding untreated control. Data are expressed as the mean ± SD of the percentage values obtained from 3 independent experiments carried out in triplicate. (***P<0.001). D: Survival of mice (n = 5/group) was monitored as depicted in Materials and Methods after treating PR8-infected mice with PBS, oseltamivir, or HSF (*P<0.05, log-rank analysis of Mantel-Cox data). E: Mice were infected with 5 x 103 pfu/mouse of PR8, orally coadministered with HSF and/or oseltamivir from 2 days after PR8 infection for 5 days. Mice were sacrificed at 6h after final administration, and lung sections were prepared as described in Materials and Methods. Representative H&E stained samples of lung section were shown (left). Pathological grade of each mouse was evaluated (right). CPE, cytopathic effect; HSB, hederasaponin B; HSF, hederasaponin F; SRB, sulforhodamane B; H&E, hematoxylin and eosin. (*P<0.05) using one-way ANOVA with Tukey’s post hoc test.
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pone.0131089.g002: Antiviral activity of combined ivy extract and oseltamivir treatment against PR8 virus in vitro and in vivo.A: CPE reduction assay using SRB assay in A549 cells infected with PR8 virus were treated with oseltamivir for 48 h at the concentrations indicated. (***P<0.0001) B: Antiviral activity of ivy extract (at the concentrations indicated) combined with 25 μg/mL oseltamivir PR8-infected A549 cells. (***P<0.001) C: HSF, HSB, and hederacoside C were used in the presence of 25 μg/mL oseltamivir to identify its anti-PR8 virus activity in A549 cells. After 48 h of incubation, the antiviral activity was investigated by CPE reduction assay using SRB. (***P<0.001), and the antiviral activity was calculated based on the viability of virus infected cells as a percentage of the corresponding untreated control. Data are expressed as the mean ± SD of the percentage values obtained from 3 independent experiments carried out in triplicate. (***P<0.001). D: Survival of mice (n = 5/group) was monitored as depicted in Materials and Methods after treating PR8-infected mice with PBS, oseltamivir, or HSF (*P<0.05, log-rank analysis of Mantel-Cox data). E: Mice were infected with 5 x 103 pfu/mouse of PR8, orally coadministered with HSF and/or oseltamivir from 2 days after PR8 infection for 5 days. Mice were sacrificed at 6h after final administration, and lung sections were prepared as described in Materials and Methods. Representative H&E stained samples of lung section were shown (left). Pathological grade of each mouse was evaluated (right). CPE, cytopathic effect; HSB, hederasaponin B; HSF, hederasaponin F; SRB, sulforhodamane B; H&E, hematoxylin and eosin. (*P<0.05) using one-way ANOVA with Tukey’s post hoc test.

Mentions: To assess and verify in vitro antiviral activity of ivy extract in combination with oseltamivir, we first monitored the change in CPE induced by treatment with different concentrations of oseltamivir in PR8-infected A549 cells. The antiviral activity of oseltamivir against PR8 was determined using a 2-fold diluted concentration that ranged from 3.1 to 100 μg/mL. PR8 infection dramatically induced cell death in A549 cells, and treatment with oseltamivir increased the viability of virus-infected cells in a dose-dependent manner (Fig 2A). Based on our findings, we decided to use 25 μg/mL oseltamivir for the coadministration with ivy extract in vitro. Coadministration of 25 μg/mL oseltamivir and 50 μg/mL ivy extract exhibited significant antiviral activity against PR8 infection (Fig 2B).


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)

Antiviral activity of combined ivy extract and oseltamivir treatment against PR8 virus in vitro and in vivo.A: CPE reduction assay using SRB assay in A549 cells infected with PR8 virus were treated with oseltamivir for 48 h at the concentrations indicated. (***P<0.0001) B: Antiviral activity of ivy extract (at the concentrations indicated) combined with 25 μg/mL oseltamivir PR8-infected A549 cells. (***P<0.001) C: HSF, HSB, and hederacoside C were used in the presence of 25 μg/mL oseltamivir to identify its anti-PR8 virus activity in A549 cells. After 48 h of incubation, the antiviral activity was investigated by CPE reduction assay using SRB. (***P<0.001), and the antiviral activity was calculated based on the viability of virus infected cells as a percentage of the corresponding untreated control. Data are expressed as the mean ± SD of the percentage values obtained from 3 independent experiments carried out in triplicate. (***P<0.001). D: Survival of mice (n = 5/group) was monitored as depicted in Materials and Methods after treating PR8-infected mice with PBS, oseltamivir, or HSF (*P<0.05, log-rank analysis of Mantel-Cox data). E: Mice were infected with 5 x 103 pfu/mouse of PR8, orally coadministered with HSF and/or oseltamivir from 2 days after PR8 infection for 5 days. Mice were sacrificed at 6h after final administration, and lung sections were prepared as described in Materials and Methods. Representative H&E stained samples of lung section were shown (left). Pathological grade of each mouse was evaluated (right). CPE, cytopathic effect; HSB, hederasaponin B; HSF, hederasaponin F; SRB, sulforhodamane B; H&E, hematoxylin and eosin. (*P<0.05) using 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.g002: Antiviral activity of combined ivy extract and oseltamivir treatment against PR8 virus in vitro and in vivo.A: CPE reduction assay using SRB assay in A549 cells infected with PR8 virus were treated with oseltamivir for 48 h at the concentrations indicated. (***P<0.0001) B: Antiviral activity of ivy extract (at the concentrations indicated) combined with 25 μg/mL oseltamivir PR8-infected A549 cells. (***P<0.001) C: HSF, HSB, and hederacoside C were used in the presence of 25 μg/mL oseltamivir to identify its anti-PR8 virus activity in A549 cells. After 48 h of incubation, the antiviral activity was investigated by CPE reduction assay using SRB. (***P<0.001), and the antiviral activity was calculated based on the viability of virus infected cells as a percentage of the corresponding untreated control. Data are expressed as the mean ± SD of the percentage values obtained from 3 independent experiments carried out in triplicate. (***P<0.001). D: Survival of mice (n = 5/group) was monitored as depicted in Materials and Methods after treating PR8-infected mice with PBS, oseltamivir, or HSF (*P<0.05, log-rank analysis of Mantel-Cox data). E: Mice were infected with 5 x 103 pfu/mouse of PR8, orally coadministered with HSF and/or oseltamivir from 2 days after PR8 infection for 5 days. Mice were sacrificed at 6h after final administration, and lung sections were prepared as described in Materials and Methods. Representative H&E stained samples of lung section were shown (left). Pathological grade of each mouse was evaluated (right). CPE, cytopathic effect; HSB, hederasaponin B; HSF, hederasaponin F; SRB, sulforhodamane B; H&E, hematoxylin and eosin. (*P<0.05) using one-way ANOVA with Tukey’s post hoc test.
Mentions: To assess and verify in vitro antiviral activity of ivy extract in combination with oseltamivir, we first monitored the change in CPE induced by treatment with different concentrations of oseltamivir in PR8-infected A549 cells. The antiviral activity of oseltamivir against PR8 was determined using a 2-fold diluted concentration that ranged from 3.1 to 100 μg/mL. PR8 infection dramatically induced cell death in A549 cells, and treatment with oseltamivir increased the viability of virus-infected cells in a dose-dependent manner (Fig 2A). Based on our findings, we decided to use 25 μg/mL oseltamivir for the coadministration with ivy extract in vitro. Coadministration of 25 μg/mL oseltamivir and 50 μg/mL ivy extract exhibited significant antiviral activity against PR8 infection (Fig 2B).

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