Polyacetylenes from Notopterygium incisum--new selective partial agonists of peroxisome proliferator-activated receptor-gamma.
Polyacetylenes from Notopterygium incisum--new selective partial agonists of peroxisome proliferator-activated receptor-gamma.
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DOI：
10.1371/journal.pone.0061755
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Bauer R
中科院分区：
文献类型：
--
作者：
Atanasov AG;Blunder M;Fakhrudin N;Liu X;Noha SM;Malainer C;Kramer MP;Cocic A;Kunert O;Schinkovitz A;Heiss EH;Schuster D;Dirsch VM;Bauer R
过氧化物酶体增殖物激活受体γ (PPARγ)是葡萄糖和脂质代谢的关键调节因子，因此是对抗代谢性疾病的重要药理靶点。由于目前使用的全PPARγ激动剂显示出严重的副作用，鉴定新的配体，特别是部分激动剂，是高度相关的。为了寻找新的活性化合物，我们研究了中药药用植物切牙Notopterygium incisum地下部分的提取物，并使用PPARγ驱动的荧光素酶报告模型观察到显著的PPARγ激活。对二氯甲烷提取物进行活性引导分离，分离出6种聚乙炔，在荧光素酶报告因子模型中显示出选择性部分PPARγ激动剂的特性。由于这类化合物对PPARγ的激活迄今尚未报道，我们选择了典型的聚乙炔镰镰醇进行进一步的研究。在与PPARγ拮抗剂T0070907（1µM）共处理后，镰孢红醇（10µM）在荧光素酶报告细胞模型中的作用被阻断。Falcarindiol与纯化的人PPARγ受体结合，Ki值为3.07µM。硅对接研究表明，在配体结合位点内存在一种结合模式，除了广泛的疏水相互作用外，还预测与Cys285和Glu295形成氢键。此外，falcarindiol进一步诱导3T3-L1前脂肪细胞分化，并增强胰岛素诱导的分化3T3-L1脂肪细胞的葡萄糖摄取，证实了其在内源性PPARγ表达的细胞模型中的有效性。总之，我们确定了镰镰醇型聚乙炔是一类新的天然部分PPARγ激动剂，具有进一步探索作为药物先导物或膳食补充剂的潜力。
Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of glucose and lipid metabolism and therefore an important pharmacological target to combat metabolic diseases. Since the currently used full PPARγ agonists display serious side effects, identification of novel ligands, particularly partial agonists, is highly relevant. Searching for new active compounds, we investigated extracts of the underground parts of Notopterygium incisum, a medicinal plant used in traditional Chinese medicine, and observed significant PPARγ activation using a PPARγ-driven luciferase reporter model. Activity-guided fractionation of the dichloromethane extract led to the isolation of six polyacetylenes, which displayed properties of selective partial PPARγ agonists in the luciferase reporter model. Since PPARγ activation by this class of compounds has so far not been reported, we have chosen the prototypical polyacetylene falcarindiol for further investigation. The effect of falcarindiol (10 µM) in the luciferase reporter model was blocked upon co-treatment with the PPARγ antagonist T0070907 (1 µM). Falcarindiol bound to the purified human PPARγ receptor with a Ki of 3.07 µM. In silico docking studies suggested a binding mode within the ligand binding site, where hydrogen bonds to Cys285 and Glu295 are predicted to be formed in addition to extensive hydrophobic interactions. Furthermore, falcarindiol further induced 3T3-L1 preadipocyte differentiation and enhanced the insulin-induced glucose uptake in differentiated 3T3-L1 adipocytes confirming effectiveness in cell models with endogenous PPARγ expression. In conclusion, we identified falcarindiol-type polyacetylenes as a novel class of natural partial PPARγ agonists, having potential to be further explored as pharmaceutical leads or dietary supplements.
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影响因子：
5.4
作者：
Liu, Xin;Jiang, Shunyuan;Ding, Lisheng S.
通讯作者：
Ding, Lisheng S.
影响因子：
3.3
作者：
Abbott, Barbara D.
通讯作者：
Abbott, Barbara D.
影响因子：
64.8
作者：
Ge, K;Guermah, M;Roeder, RG
通讯作者：
Roeder, RG
DOI：
10.1161/atvbaha.108.179689
发表时间：
2010-05-01
影响因子：
8.7
作者：
Lalloyer, Fanny;Staels, Bart
通讯作者：
Staels, Bart
影响因子：
3.7
作者：
GRAHAM, FL;VANDEREB, AJ
通讯作者：
VANDEREB, AJ