Shikonin

Shikonin is a quinone-containing natural product. Shikonin is a potent TMEM16A chloride channel inhibitor with an IC₅₀ of 6.5μM^[1]. Shikonin exerts an anti-inflammatory effect by inhibiting tumor necrosis factor-α (TNF-α) and prevents activation of nuclear factor-κB (NF-κB) pathway via proteasome inhibition. Shikonin inhibits AIM2 inflammasome activation^[2][3].

Shikonin (1µM) induced caspase-dependent apoptosis in U937 cells after 6h with an increase in DNA fragmentation, intracellular ROS, low mitochondrial membrane potential, and with the expression of Noxa and tBid proapoptotic proteins^[3]. Treatment of non-small cell lung cancer A549 cells with 8µM Shikonin significantly inhibited cell proliferation, reduced the expression of integrin β1 and inhibited the phosphorylation of ERK1/2 at both mRNA and protein levels^[4]. The treatment of PC12 cells (rat pheochromocytoma) with Shikonin (10µM) protected nearly 70 % of the cells against toxicity, via both glutathione-dependent and direct anti-apoptotic pathways^[5].

Topical treatment with Shikonin (1.0mg per ear) decreased 12-O-Tetradecanoylphorbol 13-acetate (TPA)-induced translocation of protein kinase Cα along with the phosphorylation and activation of ERK1/2, the nuclear translocation of NF-κB, and the TPA-induced NF-κB-DNA-binding activity in mouse skin^[6].In the mouse model of acute pancreatitis induced by penicillin, Shikonin (50mg/kg) significantly reduced pancreatic histological scores and serum amylase and lipase activities, and the production of cytokines TNF-α, IL-1β and IL-6 and MPO activity were also significantly reduced^[7]. In the acute lung injury model, Shikonin (50mg/kg) reduced the production of proinflammatory cytokines TNF-α and IL-1β and the concentrations of MPO and NO in mice with acute lung injury induced by LPS. Pretreatment of mice with Shikonin significantly inhibited LPS-induced activation of COX-2 and iNOS, as well as NF-κB DNA binding activity in lung tissues^[8].

References:
[1]. Jiang Y, Yu B, Yang H, et al. Shikonin inhibits intestinal calcium-activated chloride channels and prevents rotaviral diarrhea[J]. Frontiers in Pharmacology, 2016, 7: 270.
[2]. Zorman J, Sušjan P, Hafner-Bratkovič I. Shikonin suppresses NLRP3 and AIM2 inflammasomes by direct inhibition of caspase-1[J]. PloS one, 2016, 11(7): e0159826.
[3]. Andújar I, Ríos J L, Giner R M, et al. Pharmacological properties of shikonin–a review of literature since 2002[J]. Planta medica, 2013, 79(18): 1685-1697.
[4]. Wang H, Wu C, Wan S, et al. Shikonin attenuates lung cancer cell adhesion to extracellular matrix and metastasis by inhibiting integrin β1 expression and the ERK1/2 signaling pathway[J]. Toxicology, 2013, 308: 104-112.
[5]. Esmaeilzadeh E, Gardaneh M, Gharib E, et al. Shikonin protects dopaminergic cell line PC12 against 6-hydroxydopamine-mediated neurotoxicity via both glutathione-dependent and independent pathways and by inhibiting apoptosis[J]. Neurochemical research, 2013, 38: 1590-1604.
[6]. Andújar I, Recio M C, Bacelli T, et al. Shikonin reduces oedema induced by phorbol ester by interfering with IκBα degradation thus inhibiting translocation of NF‐κB to the nucleus[J]. British Journal of Pharmacology, 2010, 160(2): 376-388.
[7]. Xiong J, Ni J, Hu G, et al. Shikonin ameliorates cerulein-induced acute pancreatitis in mice[J]. Journal of Ethnopharmacology, 2013, 145(2): 573-580.
[8]. Bai G Z, Yu H T, Ni Y F, et al. Shikonin attenuates lipopolysaccharide-induced acute lung injury in mice[J]. Journal of Surgical Research, 2013, 182(2): 303-311.

Shikonin是一种含醌的天然产物。Shikonin是一种有效的TMEM16A氯离子通道抑制剂，IC₅₀为6.5μM^[1]。Shikonin通过抑制肿瘤坏死因子-α(TNF-α)发挥抗炎作用，并通过蛋白酶体抑制阻止核因子-κB（NF-κB)通路的激活。Shikonin可抑制AIM2炎症小体活化^[2][3]。

Shikonin（1µM）在诱导U937细胞6小时后，细胞中caspase依赖性凋亡启动，DNA碎片增加，细胞内ROS增加，线粒体膜电位降低，Noxa和tBid促凋亡蛋白表达增加^[3]。用8µM Shikonin治疗非小细胞肺癌A549细胞可显著抑制细胞增殖，降低整合素β1的表达，并在mRNA和蛋白质水平上抑制ERK1/2的磷酸化^[4]。Shikonin（10μM）处理PC12细胞（大鼠嗜铬细胞瘤），可通过谷胱甘肽依赖性和直接抗凋亡途径保护近70%的细胞免受毒性^[5]。

局部用Shikonin（每耳1.0mg）可降低小鼠皮肤中12-O-Tetradecanoylphorbol 13-acetate（TPA）诱导的蛋白激酶Cα易位、ERK1/2磷酸化和活化、NF-κB核易位和TPA诱导的NF-κB-DNA结合活性^[6]。在青霉素诱发的小鼠急性胰腺炎模型中，Shikonin（50mg/kg）可显著降低小鼠胰腺组织学评分、血清淀粉酶和脂肪酶活性，细胞因子TNF-α、IL-1β和IL-6的产生以及MPO活性也显著降低^[7]。在急性肺损伤模型中，Shikonin（50mg/kg）可降低LPS诱发的急性肺损伤小鼠促炎细胞因子TNF-α和IL-1β的产生以及MPO和NO的浓度。用Shikonin预先处理小鼠可以显著抑制LPS诱导的肺组织中COX-2和iNOS的激活，以及NF-κB DNA结合活性^[8]。