Zhang Wen-Jing, Song Zhen-Bo, Bao Yong-Li, Li Wen-Liang, Yang Xiao-Guang, Wang Qi, Yu Chun-Lei, Sun Lu-Guo, Huang Yan-Xin, Li Yu-Xin
National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun 130024, China.
Biochem Pharmacol. 2016 Apr 1;105:66-79. doi: 10.1016/j.bcp.2016.02.001. Epub 2016 Feb 3.
Psoriasis is a multifactorial skin disease that inconveniences many patients. Considering the side effects and drug resistance of the current therapy, it is urgent to discover more effective and safer anti-psoriatic drugs. In the present study, we screened over 250 traditional Chinese medicine compounds for their ability to inhibit the cell viability of cultured human HaCaT keratinocytes, a psoriasis-relevant in vitro model, and found that periplogenin was highly effective. Mechanistic studies revealed that apoptosis and autophagy were not induced by periplogenin in HaCaT cells. However, periplogenin caused PI to permeate into cells, increased lactate LDH release and rapidly increased the number of necrotic cells. Additionally, the typical characteristics of necrosis were observed in the periplogenin-treated HaCaT cells. Notably, the necroptosis inhibitor Nec-1 and NSA were able to rescue the cells from necrotic cell death, supporting that necroptosis was involved in periplogenin-induced cell death. Furthermore, the ROS levels were elevated in the periplogenin-treated cells, NAC (an antioxidant) and Nec-1 could inhibit the ROS levels, and NAC could attenuate necroptotic cell death, indicating that the periplogenin-induced necroptotic cell death was mediated by oxidative stress. More importantly, in the murine models of TPA-induced epidermal hyperplasia and IMQ-induced skin inflammation, topical administration of periplogenin ameliorated skin lesions and inflammation. In sum, our results indicate, for the first time, that periplogenin is a naturally occurring compound with potent anti-psoriatic effects in vitro and in vivo, making it a promising candidate for future drug research.
银屑病是一种多因素的皮肤病，给许多患者带来不便。考虑到当前治疗方法的副作用和耐药性，迫切需要发现更有效、更安全的抗银屑病药物。在本研究中，我们筛选了250多种中药化合物，检测它们抑制培养的人HaCaT角质形成细胞（一种与银屑病相关的体外模型）细胞活力的能力，发现杠柳毒苷具有高效性。机制研究表明，杠柳毒苷在HaCaT细胞中不会诱导凋亡和自噬。然而，杠柳毒苷导致PI渗入细胞，增加乳酸脱氢酶（LDH）释放，并迅速增加坏死细胞数量。此外，在经杠柳毒苷处理的HaCaT细胞中观察到坏死的典型特征。值得注意的是，坏死性凋亡抑制剂Nec-1和NSA能够挽救细胞免于坏死性细胞死亡，这支持坏死性凋亡参与了杠柳毒苷诱导的细胞死亡。此外，经杠柳毒苷处理的细胞中活性氧（ROS）水平升高，NAC（一种抗氧化剂）和Nec-1可以抑制ROS水平，并且NAC可以减轻坏死性凋亡细胞死亡，表明杠柳毒苷诱导的坏死性凋亡细胞死亡是由氧化应激介导的。更重要的是，在佛波酯（TPA）诱导的表皮增生和咪喹莫特（IMQ）诱导的皮肤炎症的小鼠模型中，局部应用杠柳毒苷可改善皮肤病变和炎症。总之，我们的结果首次表明，杠柳毒苷是一种天然存在的化合物，在体外和体内均具有强大的抗银屑病作用，使其成为未来药物研究的有希望的候选物。
