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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

Phosporylated AKT, PIP3, HIF-1α, and VEGF expression after anthraquinone derivative treatment.(A) Protein lung lysates were isolated from allergic mice and levels of p-AKT1/2/3 were determined by western blotting. Signal strength of p-AKT when compared to total actin level. (B) PIP3 activity in lung lysates. (C-D) RT-PCRs with RNA isolated from lower airway tissue; data normalized to HPRT and the relative expression of (C) HIF-1α and (D) VEGF was calculated to saline expression levels. * p<0.05 when compared to vehicle. Data represent the mean±SEM of at least two independent experiments n=6.
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pone-0079565-g005: Phosporylated AKT, PIP3, HIF-1α, and VEGF expression after anthraquinone derivative treatment.(A) Protein lung lysates were isolated from allergic mice and levels of p-AKT1/2/3 were determined by western blotting. Signal strength of p-AKT when compared to total actin level. (B) PIP3 activity in lung lysates. (C-D) RT-PCRs with RNA isolated from lower airway tissue; data normalized to HPRT and the relative expression of (C) HIF-1α and (D) VEGF was calculated to saline expression levels. * p<0.05 when compared to vehicle. Data represent the mean±SEM of at least two independent experiments n=6.

Mentions: In accordance with in vitro observations [26] anthraquinone treatment of allergic mice reduced HIF-1α and VEGF expression along with reduced levels of p-AKT and active PIP3 in the lungs (Figure 5A to D).


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)

Phosporylated AKT, PIP3, HIF-1α, and VEGF expression after anthraquinone derivative treatment.(A) Protein lung lysates were isolated from allergic mice and levels of p-AKT1/2/3 were determined by western blotting. Signal strength of p-AKT when compared to total actin level. (B) PIP3 activity in lung lysates. (C-D) RT-PCRs with RNA isolated from lower airway tissue; data normalized to HPRT and the relative expression of (C) HIF-1α and (D) VEGF was calculated to saline expression levels. * p<0.05 when compared to vehicle. Data represent the mean±SEM of at least two independent experiments n=6.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3818233&req=5

pone-0079565-g005: Phosporylated AKT, PIP3, HIF-1α, and VEGF expression after anthraquinone derivative treatment.(A) Protein lung lysates were isolated from allergic mice and levels of p-AKT1/2/3 were determined by western blotting. Signal strength of p-AKT when compared to total actin level. (B) PIP3 activity in lung lysates. (C-D) RT-PCRs with RNA isolated from lower airway tissue; data normalized to HPRT and the relative expression of (C) HIF-1α and (D) VEGF was calculated to saline expression levels. * p<0.05 when compared to vehicle. Data represent the mean±SEM of at least two independent experiments n=6.
Mentions: In accordance with in vitro observations [26] anthraquinone treatment of allergic mice reduced HIF-1α and VEGF expression along with reduced levels of p-AKT and active PIP3 in the lungs (Figure 5A to D).

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