Delphinidin, a dietary antioxidant, induces human epidermal keratinocyte differentiation but not apoptosis: studies in submerged and three-dimensional epidermal equivalent models.
Delphinidin, a dietary antioxidant, induces human epidermal keratinocyte differentiation but not apoptosis: studies in submerged and three-dimensional epidermal equivalent models.
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DOI：
10.1111/exd.12140
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发表时间：
2013-05
影响因子：
3.6
通讯作者：
Mukhtar H
中科院分区：
文献类型：
--
作者：
Chamcheu JC;Afaq F;Syed DN;Siddiqui IA;Adhami VM;Khan N;Singh S;Boylan BT;Wood GS;Mukhtar H
飞雀素(Delphinidin，Del)[3，5，7，3‘-，4’，5‘-六羟基黄素]是一种广泛存在于有色水果和蔬菜中的花青素和有效的抗氧化剂，在许多癌细胞中具有促凋亡作用。在这里，我们检测了DEL对体外培养的正常人表皮角质形成细胞(NHEKs)生长、凋亡和分化的影响，并在三维(3D)表皮等效(EE)模型中检测了其影响，该模型允许完全分化，使人联想到体内皮肤。DEL(10-40μm，24-48 h)可显著促进角质形成细胞的分化。在DEL处理的细胞中，人总蛋白(HINV)启动子活性显著增加，同时总蛋白和其他表皮分化标志物包括原天冬氨酸氨基转移酶-14和转谷氨酰胺酶-1(TGM1)的mRNA和蛋白表达增加，但对TGM2没有影响。DEL处理NHEKs后，细胞存活率下降幅度很小，与细胞凋亡无关，因为caspase、凋亡相关蛋白(包括bcl2蛋白家族)和聚(ADP-核糖)聚合酶的裂解缺乏调节。为了确定我们在深层培养中观察到的体内相关性，我们随后在3D EE模型中验证了这些效应，在该模型中，DEL被发现显著促进角化并增加角化标志物包括caspase-14和角蛋白1的蛋白表达。我们首次使用一种紧密模拟活体人类皮肤的实验系统证明了DEL诱导表皮分化。这些观察表明，DEL可能是一种有用的药物，用于治疗与表皮屏障缺陷相关的皮肤病，包括牛皮癣和鱼鳞病等皮肤病中观察到的异常角质化、过度增殖或炎症。
Delphinidin (Del), [3,5,7,3′-,4′-,5′-hexahydroxyflavylium], an anthocyanidin and a potent antioxidant abundantly found in pigmented fruits and vegetables exhibits proapoptotic effects in many cancer cells. Here, we determined the effect of Del on growth, apoptosis and differentiation of normal human epidermal keratinocytes (NHEKs) in vitro in submerged cultures and examined its effects in a three-dimensional (3D) epidermal equivalent (EE) model that permits complete differentiation reminiscent of in vivo skin. Treatment of NHEKs with Del (10–40 μm; 24–48 h) significantly enhanced keratinocyte differentiation. In Del-treated cells, there was marked increase in human involucrin (hINV) promoter activity with simultaneous increase in the mRNA and protein expressions of involucrin and other epidermal differentiation markers including procaspase-14 and transglutaminase-1 (TGM1), but without any effect on TGM2. Del treatment of NHEKs was associated with minimal decrease in cell viability, which was not associated with apoptosis as evident by lack of modulation of caspases, apoptosis-related proteins including Bcl-2 family of proteins and poly(ADP-ribose) polymerase cleavage. To establish the in vivo relevance of our observations in submerged cultures, we then validated these effects in a 3D EE model, where Del was found to significantly enhance cornification and increase the protein expression of cornification markers including caspase-14 and keratin 1. For the first time, we show that Del induces epidermal differentiation using an experimental system that closely mimics in vivo human skin. These observations suggest that Del could be a useful agent for dermatoses associated with epidermal barrier defects including aberrant keratinization, hyperproliferation or inflammation observed in skin diseases like psoriasis and ichthyoses.