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.
abstract: 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.
authors.affiliation: 1 Department of Dermatology, School of Medicine and Public Health, University of Wisconsin , Madison, Wisconsin.
authors.forename: Jean Christopher
authors.initials: JC
authors.lastname: Chamcheu
authors.affiliation: 1 Department of Dermatology, School of Medicine and Public Health, University of Wisconsin , Madison, Wisconsin.
authors.forename: Vaqar M
authors.initials: VM
authors.lastname: Adhami
authors.affiliation: 2 Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, School of Medicine and Public Health, University of Wisconsin , Madison, Wisconsin.
authors.forename: Stephane
authors.initials: S
authors.lastname: Esnault
authors.affiliation: 3 Department of Chemistry and Pharmacy, University of Sassari , Sassari, Italy .
authors.forename: Mario
authors.initials: M
authors.lastname: Sechi
authors.affiliation: 1 Department of Dermatology, School of Medicine and Public Health, University of Wisconsin , Madison, Wisconsin.
authors.forename: Imtiaz A
authors.initials: IA
authors.lastname: Siddiqui
authors.affiliation: 4 Small Molecule Screening Facility, Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin , Madison, Wisconsin.|5 Middleton VA Medical Center , Madison, Wisconsin.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Satyshur
authors.affiliation: 1 Department of Dermatology, School of Medicine and Public Health, University of Wisconsin , Madison, Wisconsin.
authors.forename: Deeba N
authors.initials: DN
authors.lastname: Syed
authors.affiliation: 1 Department of Dermatology, School of Medicine and Public Health, University of Wisconsin , Madison, Wisconsin.
authors.forename: Shah-Jahan M
authors.initials: SM
authors.lastname: Dodwad
authors.affiliation: 1 Department of Dermatology, School of Medicine and Public Health, University of Wisconsin , Madison, Wisconsin.|6 Centro de Investigación en Biotecnología Instituto Tecnológico de Costa Rica , Cartago, Republica de Costa Rica.
authors.forename: Maria-Ines
authors.initials: MI
authors.lastname: Chaves-Rodriquez
authors.affiliation: 1 Department of Dermatology, School of Medicine and Public Health, University of Wisconsin , Madison, Wisconsin.
authors.forename: B Jack
authors.initials: BJ
authors.lastname: Longley
authors.affiliation: 1 Department of Dermatology, School of Medicine and Public Health, University of Wisconsin , Madison, Wisconsin.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Wood
authors.affiliation: 1 Department of Dermatology, School of Medicine and Public Health, University of Wisconsin , Madison, Wisconsin.
authors.forename: Hasan
authors.initials: H
authors.lastname: Mukhtar
mesh_terms: D000287:Administration, Topical; D000634:Aminoquinolines / Q000009:adverse effects; D000818:Animals; D000872:Anthocyanins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D001706:Biopsy; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D000077271:Imiquimod; D056747:Immunomodulation / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011565:Psoriasis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D000872:Anthocyanins; D000975:Antioxidants; D016207:Cytokines; D000077271:Imiquimod; D018836:Inflammation Mediators; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C017185:delphinidin
keywords: antioxidants; delphinidin; imiquimod model of inflammation; psoriasis