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
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
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DOI：
10.1089/ars.2016.6769
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发表时间：
2017-01-10
影响因子：
6.6
通讯作者：
Mukhtar, Hasan
中科院分区：
文献类型：
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作者：
Chamcheu, Jean Christopher;Adhami, Vaqar M.;Mukhtar, Hasan
目的：银屑病的治疗仍然难以捉摸，强调了识别新的疾病靶点和基于机制的治疗方法的必要性。我们最近报道，PI 3 K/Akt/mTOR通路在许多恶性肿瘤中经常失调，在临床上也与银屑病相关。我们还提供了开发飞燕草素（Del）的基本原理，飞燕草素是一种治疗银屑病的膳食抗氧化剂。本研究利用高通量生物物理和生物化学方法以及体外和体内模型来鉴定银屑病中Del调节的分子靶点。激酶组水平筛选和针对一组102个人类激酶靶点的Kds分析显示，Del结合三种脂质PIK 3CG、PIK 3C 2B和PIK 3CA）和六种丝氨酸/苏氨酸（PIM 1、PIM 3、mTOR、S6 K1、PLK 2和AURKB）激酶，其中五种属于PI 3 K/Akt/mTOR途径。表面等离子体共振和计算机分子建模证实了Del与三种PI 3 K（α/c2 β/γ），mTOR和p70 S6 K的直接相互作用。白细胞介素-22或TPA刺激的正常人表皮角质形成细胞（NHEKs）的Del处理显著抑制增殖、PI 3 K/Akt/mTOR组分的活化以及促炎细胞因子和趋化因子的分泌。为了建立这些发现的体内相关性，采用咪喹莫特（IMQ）诱导的Balb/c小鼠银屑病样皮肤模型。与对照相比，Del的局部治疗显著降低了（i）过度增殖和表皮厚度，（ii）免疫细胞的皮肤浸润，（iii）银屑病相关的细胞因子/趋化因子，（iv）PI 3 K/Akt/mTOR通路活化，和（v）增加的分化。我们观察到Del抑制参与银屑病发病机制的关键激酶，并抑制IMQ诱导的小鼠银屑病。类似疾病提示了一种新的PI 3 K/AKT/mTOR通路调节剂，可以开发用于治疗银屑病。
Aim: 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.Results: 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 (alpha/c2 beta/gamma), 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.