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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

Anthraquinone derivative suppresses AHR and inflammation.(A) Scheme of chemical synthesis of the anthraquinone derivative O,O´-didodecanoyl-1,4-dihydroxyanthraquinone. (B) AHR, (C) total and (D) differential number of BALF cells, (E) T (CD4, CD8) and B (CD19) cell numbers in lung homogenates and (F) peribronchial lymph node cells in HDM sensitized and challenged mice treated with 1 mg/kg of mitoxantrone or analog. * 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-g001: Anthraquinone derivative suppresses AHR and inflammation.(A) Scheme of chemical synthesis of the anthraquinone derivative O,O´-didodecanoyl-1,4-dihydroxyanthraquinone. (B) AHR, (C) total and (D) differential number of BALF cells, (E) T (CD4, CD8) and B (CD19) cell numbers in lung homogenates and (F) peribronchial lymph node cells in HDM sensitized and challenged mice treated with 1 mg/kg of mitoxantrone or analog. * p<0.05 when compared to vehicle. Data represent the mean±SEM of at least two independent experiments n=6.

Mentions: The ability of mitoxantrone to intercalate with the DNA through hydrogen binding was precluded by synthesizing a novel anthraquinone derivative, O,O´-didodecanoyl-1,4-dihydroxyanthraquinone (Figure 1A). Consequently, this analog did not exhibit any in-vitro cytotoxicity on transformed macrophage cell lines or cytotoxic effects in-vivo (data not shown). In order to investigate the anti-inflammatory properties of mitoxantrone and its analog on AAD, we sensitized and challenged BALB/c mice with HDM via the airway route which resulted in the development of AHR (Figure 1B) and increased cellularity in BAL fluid (Figure 1C) consisting of eosinophils, lymphocytes, and neutrophils (Figure 1D). Treatment with mitoxantrone or its non-cytotoxic analog significantly reduced AHR and airways inflammation (Figure 1C and D). To further investigate the effect of mitoxantrone and its analog on accumulation of lymphocyte subsets in the lungs and peribronchial lymph nodes (PBLN) FACS analysis was performed. Both mitoxantrone and its analog impaired recruitment of T cells (CD3+), CD4+ and CD8+ T helper cells, and CD19+ B cells into the lungs (Figure 1E) while those cells accumulated in the PBLN (Figure 1F). Mucus hypersecretion, Muc5ac expression, and mast cell influx were also significantly reduced upon mitoxantrone or analog treatment (Figure 2 A to K).


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)

Anthraquinone derivative suppresses AHR and inflammation.(A) Scheme of chemical synthesis of the anthraquinone derivative O,O´-didodecanoyl-1,4-dihydroxyanthraquinone. (B) AHR, (C) total and (D) differential number of BALF cells, (E) T (CD4, CD8) and B (CD19) cell numbers in lung homogenates and (F) peribronchial lymph node cells in HDM sensitized and challenged mice treated with 1 mg/kg of mitoxantrone or analog. * 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-g001: Anthraquinone derivative suppresses AHR and inflammation.(A) Scheme of chemical synthesis of the anthraquinone derivative O,O´-didodecanoyl-1,4-dihydroxyanthraquinone. (B) AHR, (C) total and (D) differential number of BALF cells, (E) T (CD4, CD8) and B (CD19) cell numbers in lung homogenates and (F) peribronchial lymph node cells in HDM sensitized and challenged mice treated with 1 mg/kg of mitoxantrone or analog. * p<0.05 when compared to vehicle. Data represent the mean±SEM of at least two independent experiments n=6.
Mentions: The ability of mitoxantrone to intercalate with the DNA through hydrogen binding was precluded by synthesizing a novel anthraquinone derivative, O,O´-didodecanoyl-1,4-dihydroxyanthraquinone (Figure 1A). Consequently, this analog did not exhibit any in-vitro cytotoxicity on transformed macrophage cell lines or cytotoxic effects in-vivo (data not shown). In order to investigate the anti-inflammatory properties of mitoxantrone and its analog on AAD, we sensitized and challenged BALB/c mice with HDM via the airway route which resulted in the development of AHR (Figure 1B) and increased cellularity in BAL fluid (Figure 1C) consisting of eosinophils, lymphocytes, and neutrophils (Figure 1D). Treatment with mitoxantrone or its non-cytotoxic analog significantly reduced AHR and airways inflammation (Figure 1C and D). To further investigate the effect of mitoxantrone and its analog on accumulation of lymphocyte subsets in the lungs and peribronchial lymph nodes (PBLN) FACS analysis was performed. Both mitoxantrone and its analog impaired recruitment of T cells (CD3+), CD4+ and CD8+ T helper cells, and CD19+ B cells into the lungs (Figure 1E) while those cells accumulated in the PBLN (Figure 1F). Mucus hypersecretion, Muc5ac expression, and mast cell influx were also significantly reduced upon mitoxantrone or analog treatment (Figure 2 A to K).

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