ETHNOPHARMACOLOGICAL RELEVANCE Salvia mirzayanii Rech. f. & Esfand. is an endemic plant, which is only distributed in the south of Iran. In traditional Iranian medicine, the aerial parts of Salvia mirzayanii have been used for infections, inflammatory diseases, and as a tonic. From this plant, the sesquiterpene teuclatriol was isolated by bioactivity-guided fractionation due to its anti-proliferative actions on human lymphocytes. The guaiane sesquiterpene is lacking the methylene-γ-lactone function that is typically involved in the inhibiting properties of sesquiterpenes on NF-κB, a pivotal transcription factor in inflammatory processes. We here investigated anti-inflammatory effects of teuclatriol on human macrophage-like and endothelial cells. MATERIALS AND METHODS Non-toxic doses of teuclatriol were determined for both cell types by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)-assay. The effect of teuclatriol on the activity of NF-κB in LPS-stimulated human monocytic THP-1 cells was studied using infrared electrophoretic mobility shift assay (IR-EMSA) using curcumin as positive control (32µM). THP-1 were differentiated into macrophage-like cells and evaluated for TNF-α secretion by L929 bioassay following stimulation with LPS and treatment with teuclatriol. Inflammatory gene expression in human umbilical vein endothelial cells (HUVEC), modeling target cells for TNF-α-induced inflammatory gene activation, was investigated by real-time RT-PCR. RESULTS The LPS-induced DNA binding activity of NF-κB in THP-1 was significantly decreased by non-toxic doses of teuclatriol (312 and 390µM). Teuclatriol reduced the production of TNF-α in a dose-dependent manner. mRNA levels of both monocyte chemoattractant protein (MCP)-1 and toll-like receptor (TLR)2 were decreased in TNF-α-activated HUVEC. CONCLUSION These data show an inhibitory effect of teuclatriol on NF-κB signaling at doses of 312µM and higher, validating the traditional use of Salvia mirzayanii in the treatment of inflammatory diseases. Future work on the mode of action of teuclatriol may provide new lead structures with NF-κB inhibiting properties, lacking possible side effects mediated via alkylating centers of sesquiterpene lactones.

中文翻译：

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丹参三萜中的倍半萜烯萜三醇对核因子-κB活化和炎症介质表达的抑制作用。

民族药理关系Salvia mirzayanii Rech。F。＆Esfand。是一种特有植物，仅分布在伊朗南部。在传统的伊朗医学中，丹参的地上部分已被用于感染，炎症性疾病和滋补品。由于其对人淋巴细胞的抗增殖作用，因此通过生物活性指导的分级分离从该植物中提取倍半萜烯三醇。愈创树倍半萜缺乏亚甲基-γ-内酯功能，该功能通常与倍半萜对炎性过程中的关键转录因子NF-κB的抑制作用有关。我们在这里研究了teuclatriol对人类巨噬细胞样和内皮细胞的抗炎作用。材料和方法采用MTT（3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑溴化物）测定法测定两种细胞类型的替克拉三醇的无毒剂量。以姜黄素为阳性对照（32μM），采用红外电泳迁移率变动分析（IR-EMSA）研究了替考三醇对LPS刺激的人单核细胞THP-1细胞中NF-κB活性的影响。将THP-1分化为巨噬细胞样细胞，并在LPS刺激和替克拉三醇处理后，通过L929生物测定法评估TNF-α分泌。通过实时RT-PCR研究了人脐静脉内皮细胞（HUVEC）中的炎性基因表达，该靶细胞模拟了TNF-α诱导的炎性基因激活的靶细胞。结果无毒剂量的替克拉三醇（312和390µM）可显着降低LPS诱导的THP-1中NF-κB的DNA结合活性。替克拉三醇以剂量依赖性方式减少了TNF-α的产生。在TNF-α激活的HUVEC中，单核细胞趋化蛋白（MCP）-1和toll样受体（TLR）2的mRNA水平均降低。结论这些数据表明，当剂量为312μM或更高时，替克拉三醇对NF-κB信号有抑制作用，这证实了丹参在治疗炎性疾病中的传统用途。未来对替考三醇的作用方式的研究可能会提供具有NF-κB抑制特性的新的先导结构，但缺乏通过倍半萜内酯烷基化中心介导的可能的副作用。在TNF-α激活的HUVEC中，单核细胞趋化蛋白（MCP）-1和toll样受体（TLR）2的mRNA水平均降低。结论这些数据表明，当剂量为312μM或更高时，替克拉三醇对NF-κB信号有抑制作用，这证实了丹参在治疗炎性疾病中的传统用途。未来对替考三醇的作用方式的研究可能会提供具有NF-κB抑制特性的新的先导结构，但缺乏通过倍半萜内酯烷基化中心介导的可能的副作用。在TNF-α激活的HUVEC中，单核细胞趋化蛋白（MCP）-1和toll样受体（TLR）2的mRNA水平均降低。结论这些数据表明，当剂量为312μM或更高时，替克拉三醇对NF-κB信号有抑制作用，这证实了丹参在治疗炎性疾病中的传统用途。未来对替考三醇的作用方式的研究可能会提供具有NF-κB抑制特性的新的先导结构，但缺乏通过倍半萜内酯烷基化中心介导的可能的副作用。验证了丹参在炎性疾病治疗中的传统用途。未来对替考三醇的作用方式的研究可能会提供具有NF-κB抑制特性的新的先导结构，但缺乏通过倍半萜内酯烷基化中心介导的可能的副作用。验证了丹参在炎性疾病治疗中的传统用途。未来对替考三醇的作用方式的研究可能会提供具有NF-κB抑制特性的新的先导结构，但缺乏通过倍半萜内酯烷基化中心介导的可能的副作用。