Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794-5281, USA.
Department of Biochemistry and Cellular Biology, Stony Brook University, Stony Brook, NY 11794-5215, USA.
Int J Mol Sci. 2021 Jun 3;22(11):6043. doi: 10.3390/ijms22116043.
Hyperpigmentation is a dermatological condition characterized by the overaccumulation and/or oversecretion of melanin pigment. The efficacy of curcumin as an anti-melanogenic therapeutic has been recognized, but the poor stability and solubility that have limited its use have inspired the synthesis of novel curcumin analogs. We have previously reported on comparisons of the anti-melanogenic activity of four novel chemically modified curcumin (CMC) analogs, CMC2.14, CMC2.5, CMC2.23 and CMC2.24, with that of parent curcumin (PC), using a B16F10 mouse melanoma cell model, and we have investigated mechanisms of inhibition. In the current study, we have extended our findings using normal human melanocytes from a darkly pigmented donor (HEMn-DP) and we have begun to study aspects of melanosome export to human keratinocytes. Our results showed that all the CMCs downregulated the protein levels of melanogenic paracrine mediators, endothelin-1 (ET-1) and adrenomedullin (ADM) in HaCaT cells and suppressed the phagocytosis of FluoSphere beads that are considered to be melanosome mimics. All the three CMCs were similarly potent (except CMC2.14, which was highly cytotoxic) in inhibiting melanin production; furthermore, they suppressed dendricity in HEMn-DP cells. CMC2.24 and CMC2.23 robustly suppressed cellular tyrosinase activity but did not alter tyrosinase protein levels, while CMC2.5 did not suppress tyrosinase activity but significantly downregulated tyrosinase protein levels, indicative of a distinctive mode of action for the two structurally related CMCs. Moreover, HEMn-DP cells treated with CMC2.24 or CMC2.23 partially recovered their suppressed tyrosinase activity after cessation of the treatment. All the three CMCs were nontoxic to human dermal fibroblasts while PC was highly cytotoxic. Our results provide a proof-of-principle for the novel use of the CMCs for skin depigmentation, since at low concentrations, ranging from 5 to 25 µM, the CMCs (CMC2.24, CMC2.23 and CMC2.5) were more potent anti-melanogenic agents than PC and tetrahydrocurcumin (THC), both of which were ineffective at melanogenesis at similar doses, as tested in HEMn-DP cells (with PC being highly toxic in dermal fibroblasts and keratinocytes). Further studies to evaluate the efficacy of CMCs in human skin tissue and in vivo studies are warranted.
色素沉着是一种皮肤状况，其特征是黑色素色素的过度积累和/或过度分泌。姜黄素作为一种抗黑色素生成治疗剂的功效已得到认可，但由于其较差的稳定性和溶解度限制了其应用，因此激发了新型姜黄素类似物的合成。我们之前曾报道过比较四种新型化学修饰姜黄素（CMC）类似物 CMC2.14、CMC2.5、CMC2.23 和 CMC2.24 与母体姜黄素（PC）的抗黑色素生成活性，使用 B16F10 小鼠黑色素瘤细胞模型，并研究了抑制机制。在本研究中，我们使用来自深色色素沉着供体的正常人黑素细胞（HEMn-DP）扩展了我们的发现，并开始研究黑素体向人角质形成细胞输出的各个方面。我们的结果表明，所有 CMC 均下调了 HaCaT 细胞中黑色素生成旁分泌介质内皮素-1（ET-1）和肾上腺髓质素（ADM）的蛋白水平，并抑制了被认为是黑素体模拟物的 FluoSphere 珠的吞噬作用。所有三种 CMC 都同样有效（除 CMC2.14 外，它的细胞毒性很高），可抑制黑色素生成；此外，它们抑制了 HEMn-DP 细胞中的树突状。CMC2.24 和 CMC2.23 强烈抑制细胞酪氨酸酶活性，但不改变酪氨酸酶蛋白水平，而 CMC2.5 不抑制酪氨酸酶活性，但显著下调酪氨酸酶蛋白水平，表明这两种结构相关的 CMC 具有独特的作用方式。此外，用 CMC2.24 或 CMC2.23 处理的 HEMn-DP 细胞在停止治疗后部分恢复了其受抑制的酪氨酸酶活性。所有三种 CMC 对人真皮成纤维细胞均无毒性，而 PC 则具有高细胞毒性。我们的结果为 CMC 用于皮肤脱色提供了一个原理证明，因为在低浓度（5 至 25 µM）下，CMC（CMC2.24、CMC2.23 和 CMC2.5）比 PC 和四氢姜黄素（THC）更有效，这两种物质在类似剂量下在黑素生成中均无效，在 HEMn-DP 细胞中进行了测试（PC 在真皮成纤维细胞和角质形成细胞中毒性很高）。需要进一步研究以评估 CMC 在人皮肤组织中的功效，并进行体内研究。
