The continued objective of this proposal is to determine the critical role of PI3K/Akt/mTOR in psoriasis pathogenesis and to develop delphinidin for the management of psoriasis, a common chronic inflammatory skin disorder that affects 125 million people worldwide. Although psoriasis is not life- threatening, it presents disabling physical and psychosocial discomfort and global disease burden associated with psoriatic arthritis and cardiovascular disease risks. Being multifactorial, it is unlikely that hiting a single target will significantly benefit patients, thus the need for developing effective mechanism and target-based agents to treat psoriasis. Among the many signaling networks implicated in psoriasis disease, the PI3K/AKT/mTOR pathway has emerged as clinically relevant target, as it may cooperatively promote psoriasis. Using retrospective human psoriatic and imiquimod (IMQ)-induced murine psoriasis-like skin lesional tissues we observed activation of AKT/mTOR signaling compared to matched controls. These observations form the basis of our proposal that simultaneous targeting of PI3K/Akt/mTOR may be an effective approach for treating psoriasis. In line with this hypothesis and in our pursuit for non-toxic natural agents endowed with pro- differentiation and anti-inflammatory properties in skin, we recently made some novel and exciting observations with delphinidin. Delphinidin treatment of human keratinocytes pre-stimulated with/without IL-22 inhibited PI3K, Akt and mTOR activation. Further competitive binding and in silico docking analyses revealed that delphindin physically interacts with the PI3K, mTOR and p70S6K kinases with binding energy of -7 to -8.9Kcal/mol range, In this application, we propose to take advantage of the multi-pronged ability of delphinidin and is designed to: 1) Examine the involvement of PI3K/Akt/mTOR and secondary signaling in psoriasis pathogenesis; 2) Investigate the efficacy of delphinidin using (i) in-vitro 2D cultures, i) 3D reconstituted human skin models of psoriasis, and iii) in-vivo IMQ-induced Balbc and TPA-induced K14/VEGF transgenic murine psoriasiform models that recapitulates many features of human psoriasis. A successful completion of this proposal may result in our understanding of mechanism of psoriasis pathogenesis via dissecting interaction of PI3K/AKT/mTOR and the development of delphindin as a novel agent against proliferative keratinizing disorders, including psoriasis.
Psoriasis is a common chronic inflammatory skin disorder that affects 125 million people worldwide. Although psoriasis is not life-threatening, it presents disabling physical and psychosocial discomfort. These studies proposed are designed to investigate the mechanism of PI3K/Akt/mTOR interaction and to develop delphinidin, a dietary anthocyanidin for the management of psoriasis. A successful completion of studies in this proposal will contribute to our understanding of mechanism of psoriasis pathogenesis and the development of delphinidin as an agent against proliferative disorders, including psoriasis.
|Chamcheu, Jean Christopher; Siddiqui, Imtiaz A; Adhami, Vaqar M et al. (2018) Chitosan-based nanoformulated (-)-epigallocatechin-3-gallate (EGCG) modulates human keratinocyte-induced responses and alleviates imiquimod-induced murine psoriasiform dermatitis. Int J Nanomedicine 13:4189-4206|
|Syed, Deeba N; Aljohani, Ahmed; Waseem, Durdana et al. (2018) Ousting RAGE in melanoma: A viable therapeutic target? Semin Cancer Biol 49:20-28|
|Khan, Mohammad Imran; Rath, Suvasmita; Adhami, Vaqar Mustafa et al. (2018) Hypoxia driven glycation: Mechanisms and therapeutic opportunities. Semin Cancer Biol 49:75-82|
|Chamcheu, Jean Christopher; Adhami, Vaqar M; Esnault, Stephane et al. (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. Antioxid Redox Signal 26:49-69|
|Chamcheu, Jean Christopher; Siddiqui, Imtiaz A; Mukhtar, Hasan (2016) Chemical chaperone therapy, a new strategy for genetic skin fragility disorders. Exp Dermatol 25:183-4|
|Syed, Deeba N; Adhami, Vaqar Mustafa; Khan, Naghma et al. (2016) Exploring the molecular targets of dietary flavonoid fisetin in cancer. Semin Cancer Biol 40-41:130-140|
|Chamcheu, Jean Christopher; Chaves-Rodriquez, Maria-Ines; Adhami, Vaqar M et al. (2016) Upregulation of PI3K/AKT/mTOR, FABP5 and PPAR?/? in Human Psoriasis and Imiquimod-induced Murine Psoriasiform Dermatitis Model. Acta Derm Venereol 96:854-6|
|Chamcheu, Jean Christopher; Pal, Harish C; Siddiqui, Imtiaz A et al. (2015) Prodifferentiation, anti-inflammatory and antiproliferative effects of delphinidin, a dietary anthocyanidin, in a full-thickness three-dimensional reconstituted human skin model of psoriasis. Skin Pharmacol Physiol 28:177-88|
|Pal, H C; Chamcheu, J C; Adhami, V M et al. (2015) Topical application of delphinidin reduces psoriasiform lesions in the flaky skin mouse model by inducing epidermal differentiation and inhibiting inflammation. Br J Dermatol 172:354-64|
|Syed, Deeba N; Chamcheu, Jean-Christopher; Khan, Mohammad Imran et al. (2014) Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: findings from 3-D melanoma skin equivalents and computational modeling. Biochem Pharmacol 89:349-60|
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