Zhu Shengjie, Cheng Linyan, Chen Teng, Liu Xin, Zhang Chen, Aji Abudula, Guo Wanjun, Zhu Jianyong, Chu Yuxia, Guo Dongjie, Li Fulun
Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Phytother Res. 2025 Feb;39(2):661-675. doi: 10.1002/ptr.8399. Epub 2024 Dec 5.
Bergapten (BP) is a plant-derived furocoumarin that has a wide range of pharmacological effects. BP serves as a candidate amplifier in phototherapy against skin inflammation, such as psoriasis and atopic dermatitis. However, the anti-inflammatory role of BP remains elusive. We utilized IL-17A-stimulated keratinocyte line and imiquimod-challenged BALB/c mice to imitate psoriasis-like inflammation. Inflammatory phenotypes were determined by expressions of inflammatory genes and cytokines, histopathological changes and activities of nuclear factor-κB (NF-κB) pathway. An RNA-seq analysis of rodent skin was performed to explore possible mechanism lying behind. SiRNAs and antagonist (TMS) against cytochrome P450 family 1 subfamily B member 1 (CYP1B1) were subsequently used to determine the role of CYP1B1 in psoriasis pathogenesis in vitro and in vivo. Overexpression of CYP1B1 with lentivirus further validate therapeutic effect of BP. BP significantly suppressed activation of the NF-κB pathway by inhibiting p65 phosphorylation and improved the inflammatory phenotype both in vitro and in vivo. We revealed the key role of CYP1B1 in regulating the activation of the NF-κB signaling pathway. Knock-down with siRNAs significantly reduce the expression of inflammatory genes and cytokines. An intraperitoneal injection of TMS partially remediated IMQ-induced inflammation, mainly in terms of skin thickness. Overexpression of Cyp1b1 led to increased expression of the CYP1B1 protein and rescued the therapeutic effect of BP in vitro. This study revealed that BP suppressed expression of Cyp1b1 in keratinocytes and inhibited the activation of NF-κB signaling pathway by blocking the phosphorylation of p65.
补骨脂素（BP）是一种植物来源的呋喃香豆素，具有广泛的药理作用。BP是光疗治疗皮肤炎症（如银屑病和特应性皮炎）的候选增效剂。然而，BP的抗炎作用仍不明确。我们利用白细胞介素-17A刺激的角质形成细胞系和咪喹莫特诱导的BALB/c小鼠来模拟银屑病样炎症。通过炎症基因和细胞因子的表达、组织病理学变化以及核因子-κB（NF-κB）信号通路的活性来确定炎症表型。对啮齿动物皮肤进行RNA测序分析以探索其潜在机制。随后使用针对细胞色素P450家族1亚家族B成员1（CYP1B1）的小干扰RNA（siRNA）和拮抗剂（TMS）来确定CYP1B1在银屑病发病机制中的体内外作用。用慢病毒过表达CYP1B1进一步验证了BP的治疗效果。BP通过抑制p65磷酸化显著抑制NF-κB信号通路的激活，并在体内外改善了炎症表型。我们揭示了CYP1B1在调节NF-κB信号通路激活中的关键作用。用siRNA敲低显著降低了炎症基因和细胞因子的表达。腹腔注射TMS部分缓解了咪喹莫特诱导的炎症，主要体现在皮肤厚度方面。Cyp1b1的过表达导致CYP1B1蛋白表达增加，并挽救了BP在体外的治疗效果。本研究表明，BP抑制角质形成细胞中Cyp1b1的表达，并通过阻断p65的磷酸化抑制NF-κB信号通路的激活。
