Fakhrudin N, Waltenberger B, Cabaravdic M, Atanasov A G, Malainer C, Schachner D, Heiss E H, Liu R, Noha S M, Grzywacz A M, Mihaly-Bison J, Awad E M, Schuster D, Breuss J M, Rollinger J M, Bochkov V, Stuppner H, Dirsch V M
Department of Pharmacognosy, University of Vienna, Vienna, Austria; Department of Pharmaceutical Biology, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia.
Br J Pharmacol. 2014 Apr;171(7):1676-86. doi: 10.1111/bph.12558.
The transcription factor NF-κB orchestrates many pro-inflammatory signals and its inhibition is considered a promising strategy to combat inflammation. Here we report the characterization of the natural product plumericin as a highly potent inhibitor of the NF-κB pathway with a novel chemical scaffold, which was isolated via a bioactivity-guided approach, from extracts of Himatanthus sucuuba, an Amazonian plant traditionally used to treat inflammation-related disorders.
A NF-κB luciferase reporter gene assay was used to identify NF-κB pathway inhibitors from H. sucuuba extracts. Monitoring of TNF-α-induced expression of the adhesion molecules VCAM-1, ICAM-1 and E-selectin by flow cytometry was used to confirm NF-κB inhibition in endothelial cells, and thioglycollate-induced peritonitis in mice to confirm effects in vivo. Western blotting and transfection experiments were used to investigate the mechanism of action of plumericin.
Plumericin inhibited NF-κB-mediated transactivation of a luciferase reporter gene (IC50 1 μM), abolished TNF-α-induced expression of the adhesion molecules VCAM-1, ICAM-1 and E-selectin in endothelial cells and suppressed thioglycollate-induced peritonitis in mice. Plumericin exerted its NF-κB pathway inhibitory effect by blocking IκB phosphorylation and degradation. Plumericin also inhibited NF-κB activation induced by transfection with the constitutively active catalytic subunit of the IκB kinase (IKK-β), suggesting IKK involvement in the inhibitory action of this natural product.
Plumericin is a potent inhibitor of NF-κB pathways with a new chemical scaffold. It could be further explored as a novel anti-inflammatory lead compound.
转录因子NF-κB可协调多种促炎信号，对其进行抑制被认为是对抗炎症的一种有前景的策略。在此，我们报告了天然产物倒捻子素的特性，它是一种具有新型化学骨架的高效NF-κB通路抑制剂，通过生物活性导向法从传统上用于治疗炎症相关疾病的亚马逊植物红鸡蛋花提取物中分离得到。
采用NF-κB荧光素酶报告基因检测法从红鸡蛋花提取物中鉴定NF-κB通路抑制剂。通过流式细胞术监测肿瘤坏死因子-α诱导的黏附分子血管细胞黏附分子-1（VCAM-1）、细胞间黏附分子-1（ICAM-1）和E-选择素的表达，以确认其对内皮细胞中NF-κB的抑制作用，并通过小鼠巯基乙酸盐诱导的腹膜炎来确认其体内作用。采用蛋白质免疫印迹法和转染实验研究倒捻子素的作用机制。
倒捻子素抑制NF-κB介导的荧光素酶报告基因的反式激活（半数抑制浓度为1 μM），消除肿瘤坏死因子-α诱导的内皮细胞中黏附分子VCAM-1、ICAM-1和E-选择素的表达，并抑制小鼠巯基乙酸盐诱导的腹膜炎。倒捻子素通过阻断IκB磷酸化和降解发挥其NF-κB通路抑制作用。倒捻子素还抑制由IκB激酶（IKK-β）的组成型活性催化亚基转染诱导的NF-κB激活，提示IKK参与了这种天然产物的抑制作用。
倒捻子素是一种具有新型化学骨架的NF-κB通路强效抑制剂。它可作为一种新型抗炎先导化合物进行进一步研究。
