LB1121 Prodifferentiative and anti-inflammatory effects of fisetin in 2D and 3D human skin model of psoriasis are associated with inhibition of PI3K/Akt/mTOR and MAPK signaling

Abstract

Psoriasis is a chronic immune-mediated skin disorder with high cost for therapies often complicated with serious adverse effects, thus there is a need to develop cheaper, safe and effective mechanism and target-based agents for its treatment. Natural agents that can rescind molecular defects associated with psoriasis could be developed as agents for its management. We examined the associated mechanism of fisetin-induced anti-proliferative and anti-inflammatory responses in 2D normal human epidermal keratinocytes(NHEK), peripheral blood mononuclear cells(PBMCs) and CD4+ T-cell cultures, and in T-cell activated 3D full-thickness human skin model of psoriasis. Fisetin(0-20mM) treatment significantly inhibited cytokines and activators-induced i) proliferation of NHEK, ii) production of Th1/Th-17 pro-inflammatory cytokines by NHEK, PBMCs and CD4+ T-cells(p<0.001) while promoting differentiation comparable to that of Vitamin-D3(0.1mM). These effects were associated with the downregulation of activated components of the PI3K/Akt/mTOR and MAPKs. Fisetin(30uM) treatment of 3D human psoriatic skin model, significantly modulated psoriatic features including reduction in: i) epidermal thickness, ii) proliferation, iii) antimicrobial peptide(psoriasin) expression, iv) inflammatory cytokine IL-17A production in media(p<0.001), and (v) activated mTOR effector, p70S6K. These observations are similar to that seen with Vitamin-D3. In summary, we found that fisetin-induced promotion of differentiation and inhibition of proliferation and inflammatory responses in 2D cultures and in 3D skin model of psoriasis is associated with down-regulation of components of the PI3K/AkT/mTOR signaling. These results highlight the mechanistic potential of fisetin that could be exploited for its development for the treatment of psoriasis and possibly other related cutaneous inflammatory disorders.

Enhancing stability and antioxidant efficacy of fisetin by encapsulating as β-cyclodextrin inclusion complex with porous polylactic acid film from breath figure

“…At present, fisetin (FIT) (3,3',4',7-tetrahydroxyflavone, 2-(3,4dihydroxyphenyl)-3,7-dihydroxy-chromen-4-one, Figure 1 [1]) is widely used for several beneficial human actions in terms of health due to its therapeutic activities and harmacological properties, such as antibacteria [2], anti cancer [3,4], anti-inflammatory [5,6] and antiangiogenic [7]. In addtition, fisetin's property as an anti-oxidant agent is able to prevent and delay the oxidation reaction of free radicals and to eliminate the molecules.…”