title: Periplogenin induces necroptotic cell death through oxidative stress in HaCaT cells and ameliorates skin lesions in the TPA- and IMQ-induced psoriasis-like mouse models.
abstract: 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.
authors: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
authors: Wen-Jing
authors: WJ
authors: Zhang
authors: Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun 130024, China.
authors: Zhen-Bo
authors: ZB
authors: Song
authors: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China. Electronic address: baoyl800@nenu.edu.cn.
authors: Yong-Li
authors: YL
authors: Bao
authors: Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun 130024, China.
authors: Wen-Liang
authors: WL
authors: Li
authors: Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China.
authors: Xiao-Guang
authors: XG
authors: Yang
authors: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
authors: Qi
authors: Q
authors: Wang
authors: Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China.
authors: Chun-Lei
authors: CL
authors: Yu
authors: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
authors: Lu-Guo
authors: LG
authors: Sun
authors: Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China.
authors: Yan-Xin
authors: YX
authors: Huang
authors: Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun 130024, China; Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China. Electronic address: liyx486@nenu.edu.cn.
authors: Yu-Xin
authors: YX
authors: Li
mesh_terms: D000634:Aminoquinolines / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004073:Digitoxigenin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D000077271:Imiquimod; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011565:Psoriasis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*
chemical_list: D000634:Aminoquinolines; D004073:Digitoxigenin; C008813:periplogenin; D013755:Tetradecanoylphorbol Acetate; D000077271:Imiquimod
keywords: 3-MA (PubChem CID: 1673); CQ (PubChem CID: 64927); IMQ (PubChem CID: 57469); LY294002 (PubChem CID: 3973); NAC (PubChem CID: 12035); NSA (PubChem CID: 1566236); Nec-1 (PubChem CID: 2828334); Necroptosis; Periplogenin; Periplogenin (PubChem CID: 10574); Psoriasis; ROS; TPA (PubChem CID: 27924); z-VAD-fmk (PubChem CID: 5497173)