Dual Inhibition of PI3K/Akt and mTOR by the Dietary Antioxidant, Delphinidin, Ameliorates Psoriatic Features In Vitro and in an Imiquimod-Induced Psoriasis-Like Disease in Mice - Université de Lille Accéder directement au contenu
Article Dans Une Revue Antioxidants and Redox Signaling Année : 2017

Dual Inhibition of PI3K/Akt and mTOR by the Dietary Antioxidant, Delphinidin, Ameliorates Psoriatic Features In Vitro and in an Imiquimod-Induced Psoriasis-Like Disease in Mice

Jean Christopher Chamcheu
  • Fonction : Auteur
Vaqar M Adhami
  • Fonction : Auteur
Mario Sechi
  • Fonction : Auteur
Imtiaz A Siddiqui
  • Fonction : Auteur
Kenneth A Satyshur
  • Fonction : Auteur
Deeba N Syed
  • Fonction : Auteur
Shah-Jahan M Dodwad
  • Fonction : Auteur
Maria-Ines Chaves-Rodriquez
  • Fonction : Auteur
B Jack Longley
  • Fonction : Auteur
Gary S Wood
  • Fonction : Auteur
Hasan Mukhtar
  • Fonction : Auteur

Résumé

The treatment of psoriasis remains elusive, underscoring the need for identifying novel disease targets and mechanism-based therapeutic approaches. We recently reported that the PI3K/Akt/mTOR pathway that is frequently deregulated in many malignancies is also clinically relevant for psoriasis. We also provided rationale for developing delphinidin (Del), a dietary antioxidant for the management of psoriasis. This study utilized high-throughput biophysical and biochemical approaches and in vitro and in vivo models to identify molecular targets regulated by Del in psoriasis. A kinome-level screen and Kds analyses against a panel of 102 human kinase targets showed that Del binds to three lipid (PIK3CG, PIK3C2B, and PIK3CA) and six serine/threonine (PIM1, PIM3, mTOR, S6K1, PLK2, and AURKB) kinases, five of which belong to the PI3K/Akt/mTOR pathway. Surface plasmon resonance and in silico molecular modeling corroborated Del's direct interactions with three PI3Ks (α/c2β/γ), mTOR, and p70S6K. Del treatment of interleukin-22 or TPA-stimulated normal human epidermal keratinocytes (NHEKs) significantly inhibited proliferation, activation of PI3K/Akt/mTOR components, and secretion of proinflammatory cytokines and chemokines. To establish the in vivo relevance of these findings, an imiquimod (IMQ)-induced Balb/c mouse psoriasis-like skin model was employed. Topical treatment of Del significantly decreased (i) hyperproliferation and epidermal thickness, (ii) skin infiltration by immune cells, (iii) psoriasis-related cytokines/chemokines, (iv) PI3K/Akt/mTOR pathway activation, and (v) increased differentiation when compared with controls. Innovation and Conclusion: Our observation that Del inhibits key kinases involved in psoriasis pathogenesis and alleviates IMQ-induced murine psoriasis-like disease suggests a novel PI3K/AKT/mTOR pathway modulator that could be developed to treat psoriasis. Antioxid. Redox Signal. 26, 49-69.

Dates et versions

hal-04614200 , version 1 (17-06-2024)

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Citer

Jean Christopher Chamcheu, Vaqar M Adhami, Stéphane Esnault, Mario Sechi, Imtiaz A Siddiqui, et al.. Dual Inhibition of PI3K/Akt and mTOR by the Dietary Antioxidant, Delphinidin, Ameliorates Psoriatic Features In Vitro and in an Imiquimod-Induced Psoriasis-Like Disease in Mice. Antioxidants and Redox Signaling, 2017, Antioxidants and Redox Signaling, 26, pp.49-69. ⟨10.1089/ars.2016.6769⟩. ⟨hal-04614200⟩

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