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Inhibiting AKT phosphorylation employing non-cytotoxic anthraquinones ameliorates TH2 mediated allergic airways disease and rhinovirus exacerbation.

de Souza Alves CC, Collison A, Hatchwell L, Plank M, Morten M, Foster PS, Johnston SL, da Costa CF, de Almeida MV, Couto Teixeira H, Paula Ferreira A, Mattes J - PLoS ONE (2013)

Bottom Line: Anthraquinone derivatives have been shown to reduce PI3K-mediated AKT phosphorylation in-vitro.Anthraquinone treatment reduced AKT phosphorylation, hypoxia-inducible factor-1α and vascular endothelial growth factor expression, and ameliorated allergen- and RV-induced airways hyprereactivity, neutrophilic and eosinophilic inflammation, cytokine/chemokine expression, mucus hypersecretion, and expression of TH2 proteins in the airways.Anthraquinones also boosted type 1 interferon responses and limited RV replication in the lung.

View Article: PubMed Central - PubMed

Affiliation: Department of Parasitology, Microbiology and Immunology, Institute of Biological Sciences, Federal University of Juiz de Fora, Minas Gerais, Brazil ; Experimental&Translational Respiratory Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia ; Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.

ABSTRACT

Background: Severe asthma is associated with T helper (TH) 2 and 17 cell activation, airway neutrophilia and phosphoinositide-3-kinase (PI3K) activation. Asthma exacerbations are commonly caused by rhinovirus (RV) and also associated with PI3K-driven inflammation. Anthraquinone derivatives have been shown to reduce PI3K-mediated AKT phosphorylation in-vitro.

Objective: To determine the anti-inflammatory potential of anthraquinones in-vivo.

Methods: BALB/c mice were sensitized and challenged with crude house dust mite extract to induce allergic airways disease and treated with mitoxantrone and a novel non-cytotoxic anthraquinone derivative. Allergic mice were also infected with RV1B to induce an exacerbation.

Results: Anthraquinone treatment reduced AKT phosphorylation, hypoxia-inducible factor-1α and vascular endothelial growth factor expression, and ameliorated allergen- and RV-induced airways hyprereactivity, neutrophilic and eosinophilic inflammation, cytokine/chemokine expression, mucus hypersecretion, and expression of TH2 proteins in the airways. Anthraquinones also boosted type 1 interferon responses and limited RV replication in the lung.

Conclusion: Non-cytotoxic anthraquinone derivatives may be of therapeutic benefit for the treatment of severe and RV-induced asthma by blocking pro-inflammatory pathways regulated by PI3K/AKT.

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Related in: MedlinePlus

Rhinovirus-induced exacerbation of AAD is ameliorated by anthraquinone derivative treatment.24hrs after the last HDM challenge, allergic mice were infected with 50µl of RV1B (RV) or UV-inactivated RV1B (UVRV). (A) 24hrs after RV1B infection AHR was determined. (B) Differential number of cells in the BALF. RT-PCRs with RNA isolated from lower airway tissue; data normalized to HPRT, (C) the absolute copy numbers of RV, and the relative expression of (D) IFN-α and (E) IFN-β was calculated relative UVRV expression levels. * p<0.05 when compared to vehicle+RV. Data represent the mean±SEM of at least two independent experiments n=6.
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pone-0079565-g006: Rhinovirus-induced exacerbation of AAD is ameliorated by anthraquinone derivative treatment.24hrs after the last HDM challenge, allergic mice were infected with 50µl of RV1B (RV) or UV-inactivated RV1B (UVRV). (A) 24hrs after RV1B infection AHR was determined. (B) Differential number of cells in the BALF. RT-PCRs with RNA isolated from lower airway tissue; data normalized to HPRT, (C) the absolute copy numbers of RV, and the relative expression of (D) IFN-α and (E) IFN-β was calculated relative UVRV expression levels. * p<0.05 when compared to vehicle+RV. Data represent the mean±SEM of at least two independent experiments n=6.

Mentions: AHR is further exacerbated by RV1B infection of allergic mice as compared to mice exposed to UV-inactivated RV1B (Figure 6A). Notably, treatment with one dose of analog 24hrs before RV exposure resulted in marked attenuation of AHR to levels that are comparable to allergic mice exposed to UV-inactivated RV1B (Figure 6A). This was associated with inhibition of RV-induced exacerbation of eosinophilic and neutrophilic airways inflammation (Figure 6B). Interestingly anthraquinone treatment also impaired RV1B replication (Figure 6C) and increased expression of innate antiviral type 1 IFNs (Figure 6D and E).


Inhibiting AKT phosphorylation employing non-cytotoxic anthraquinones ameliorates TH2 mediated allergic airways disease and rhinovirus exacerbation.

de Souza Alves CC, Collison A, Hatchwell L, Plank M, Morten M, Foster PS, Johnston SL, da Costa CF, de Almeida MV, Couto Teixeira H, Paula Ferreira A, Mattes J - PLoS ONE (2013)

Rhinovirus-induced exacerbation of AAD is ameliorated by anthraquinone derivative treatment.24hrs after the last HDM challenge, allergic mice were infected with 50µl of RV1B (RV) or UV-inactivated RV1B (UVRV). (A) 24hrs after RV1B infection AHR was determined. (B) Differential number of cells in the BALF. RT-PCRs with RNA isolated from lower airway tissue; data normalized to HPRT, (C) the absolute copy numbers of RV, and the relative expression of (D) IFN-α and (E) IFN-β was calculated relative UVRV expression levels. * p<0.05 when compared to vehicle+RV. Data represent the mean±SEM of at least two independent experiments n=6.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3818233&req=5

pone-0079565-g006: Rhinovirus-induced exacerbation of AAD is ameliorated by anthraquinone derivative treatment.24hrs after the last HDM challenge, allergic mice were infected with 50µl of RV1B (RV) or UV-inactivated RV1B (UVRV). (A) 24hrs after RV1B infection AHR was determined. (B) Differential number of cells in the BALF. RT-PCRs with RNA isolated from lower airway tissue; data normalized to HPRT, (C) the absolute copy numbers of RV, and the relative expression of (D) IFN-α and (E) IFN-β was calculated relative UVRV expression levels. * p<0.05 when compared to vehicle+RV. Data represent the mean±SEM of at least two independent experiments n=6.
Mentions: AHR is further exacerbated by RV1B infection of allergic mice as compared to mice exposed to UV-inactivated RV1B (Figure 6A). Notably, treatment with one dose of analog 24hrs before RV exposure resulted in marked attenuation of AHR to levels that are comparable to allergic mice exposed to UV-inactivated RV1B (Figure 6A). This was associated with inhibition of RV-induced exacerbation of eosinophilic and neutrophilic airways inflammation (Figure 6B). Interestingly anthraquinone treatment also impaired RV1B replication (Figure 6C) and increased expression of innate antiviral type 1 IFNs (Figure 6D and E).

Bottom Line: Anthraquinone derivatives have been shown to reduce PI3K-mediated AKT phosphorylation in-vitro.Anthraquinone treatment reduced AKT phosphorylation, hypoxia-inducible factor-1α and vascular endothelial growth factor expression, and ameliorated allergen- and RV-induced airways hyprereactivity, neutrophilic and eosinophilic inflammation, cytokine/chemokine expression, mucus hypersecretion, and expression of TH2 proteins in the airways.Anthraquinones also boosted type 1 interferon responses and limited RV replication in the lung.

View Article: PubMed Central - PubMed

Affiliation: Department of Parasitology, Microbiology and Immunology, Institute of Biological Sciences, Federal University of Juiz de Fora, Minas Gerais, Brazil ; Experimental&Translational Respiratory Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia ; Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.

ABSTRACT

Background: Severe asthma is associated with T helper (TH) 2 and 17 cell activation, airway neutrophilia and phosphoinositide-3-kinase (PI3K) activation. Asthma exacerbations are commonly caused by rhinovirus (RV) and also associated with PI3K-driven inflammation. Anthraquinone derivatives have been shown to reduce PI3K-mediated AKT phosphorylation in-vitro.

Objective: To determine the anti-inflammatory potential of anthraquinones in-vivo.

Methods: BALB/c mice were sensitized and challenged with crude house dust mite extract to induce allergic airways disease and treated with mitoxantrone and a novel non-cytotoxic anthraquinone derivative. Allergic mice were also infected with RV1B to induce an exacerbation.

Results: Anthraquinone treatment reduced AKT phosphorylation, hypoxia-inducible factor-1α and vascular endothelial growth factor expression, and ameliorated allergen- and RV-induced airways hyprereactivity, neutrophilic and eosinophilic inflammation, cytokine/chemokine expression, mucus hypersecretion, and expression of TH2 proteins in the airways. Anthraquinones also boosted type 1 interferon responses and limited RV replication in the lung.

Conclusion: Non-cytotoxic anthraquinone derivatives may be of therapeutic benefit for the treatment of severe and RV-induced asthma by blocking pro-inflammatory pathways regulated by PI3K/AKT.

Show MeSH
Related in: MedlinePlus