School of Chinese Medicine, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
Eur J Pharmacol. 2011 Nov 30;670(2-3):399-408. doi: 10.1016/j.ejphar.2011.09.014. Epub 2011 Sep 21.
Psoriasis is a chronic inflammatory skin disease affecting 1-3% of the world's population. Traditional Chinese medicines have been extensively used for treating psoriasis with promising clinical results. Celastrol, a triterpenoid isolated from a Chinese herb Celastrus orbiculatus caulis, has been known to have diverse pharmacological effects such as anti-inflammatory, anti-cancer and antioxidant activities. The present study aimed at evaluating the anti-proliferative action of celastrol on cultured HaCaT cells and elucidating the mechanisms of action involved. Celastrol was shown to inhibit HaCaT cells growth with an IC₅₀ value of 1.1 μM as measured by MTT assay. The ability of celastrol to induce apoptosis was studied by flow cytometric and western blot analyses. Celastrol was found to be capable of inducing apoptosis in HaCaT cells as characterized by phosphatidyl-serine (PS) externalization, depolarization of mitochondrial membrane potential and activation of caspase-3. The apoptosis induced by celastrol could be suppressed by Z-IETD-FMK and Z-LEHD-FMK, the respective caspase-8 and caspase-9 inhibitor. In addition, western blot analysis revealed a significant augmentation in the protein expression of Bax and attenuation in Bcl-2, suggesting that the celastrol-induced apoptosis acts through both death receptor and mitochondrial pathways. Moreover, western blot analysis on the expression of Rel/NF-κB demonstrated that the celastrol-mediated apoptosis on HaCaT cells was associated with the inhibition of the NF-κB pathway. Taken together, the present project has for the first time identified celastrol as a naturally occurring compound with potent apoptogenic action on cultured human keratinocytes, rendering it a promising candidate for further development into an anti-psoriatic agent.
银屑病是一种慢性炎症性皮肤病，影响世界人口的 1-3%。传统中药已被广泛用于治疗银屑病，具有良好的临床效果。从中药雷公藤中分离得到的三萜类化合物雷公藤红素，具有多种药理作用，如抗炎、抗癌和抗氧化作用。本研究旨在评价雷公藤红素对培养的 HaCaT 细胞的增殖抑制作用，并阐明其作用机制。MTT 法测定雷公藤红素对 HaCaT 细胞生长的 IC₅₀值为 1.1 μM。通过流式细胞术和 Western blot 分析研究了雷公藤红素诱导细胞凋亡的能力。结果表明，雷公藤红素能够诱导 HaCaT 细胞凋亡，表现为磷脂酰丝氨酸（PS）外翻、线粒体膜电位去极化和 caspase-3 激活。Z-IETD-FMK 和 Z-LEHD-FMK（分别为 caspase-8 和 caspase-9 的抑制剂）可抑制雷公藤红素诱导的凋亡。此外，Western blot 分析显示 Bax 蛋白表达显著增加，Bcl-2 蛋白表达减弱，提示雷公藤红素诱导的凋亡既通过死亡受体途径，也通过线粒体途径。此外，Western blot 分析显示 Rel/NF-κB 的表达表明，雷公藤红素介导的 HaCaT 细胞凋亡与 NF-κB 途径的抑制有关。综上所述，本研究首次发现雷公藤红素是一种具有潜在抗银屑病作用的天然化合物，可作为一种有前途的候选药物进一步开发为抗银屑病药物。
