Title :

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

Author(s) :

Chamcheu, Jean Christopher [Auteur]
Adhami, Vaqar M [Auteur]
Esnault, Stéphane [Auteur]
University of Wisconsin School of Medicine and Public Health
Sechi, Mario [Auteur]
Siddiqui, Imtiaz A [Auteur]
Satyshur, Kenneth A [Auteur]
Syed, Deeba N [Auteur]
Dodwad, Shah-Jahan M [Auteur]
Chaves-Rodriquez, Maria-Ines [Auteur]
Longley, B Jack [Auteur]
Wood, Gary S [Auteur]
Mukhtar, Hasan [Auteur]

Journal title :

Antioxidants and Redox Signaling

Abbreviated title :

Antioxid Redox Signal

Volume number :

26

Pages :

49-69

Publication date :

2017-01-10

ISSN :

1557-7716

English keyword(s) :

Administration, Topical
Aminoquinolines
Animals
Anthocyanins
Antioxidants
Binding Sites
Biopsy
Chemotaxis, Leukocyte
Cytokines
Disease Models, Animal
Imiquimod
Immunomodulation
Inflammation Mediators
Mice
Models, Molecular
Molecular Conformation
Neutrophils
Phosphatidylinositol 3-Kinases
Phosphoinositide-3 Kinase Inhibitors
Protein Binding
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-akt
Psoriasis
Ribosomal Protein S6 Kinases, 70-kDa
Signal Transduction
Skin
TOR Serine-Threonine Kinases
antioxidants
delphinidin
imiquimod model of inflammation
psoriasis

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

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 ...
Show more >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.Show less >

Language :

Anglais

Peer reviewed article :

Oui

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

Université de Lille
Inserm
CHU Lille

Collections :

• Autres travaux scientifiques

Submission date :

2023-10-23T15:16:55Z
2024-06-17T11:00:14Z