Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University Graz , Austria.
J Nat Prod. 2014 Apr 25;77(4):842-7. doi: 10.1021/np400943b. Epub 2014 Mar 5.
Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of glucose and lipid metabolism. Agonists of this nuclear receptor are used in the treatment of type 2 diabetes and are also studied as a potential treatment of other metabolic diseases, including nonalcoholic fatty liver disease. Silymarin, a concentrated phenolic mixture from milk thistle (Silybum marianum) seeds, is used widely as a supportive agent in the treatment of a variety of liver diseases. In this study, the PPARγ activation potential of silymarin and its main constituents was investigated. Isosilybin A (3) caused transactivation of a PPARγ-dependent luciferase reporter in a concentration-dependent manner. This effect could be reversed upon co-treatment with the PPARγ antagonist T0070907. In silico docking studies suggested a binding mode for 3 distinct from that of the inactive silymarin constituents, with one additional hydrogen bond to Ser342 in the entrance region of the ligand-binding domain of the receptor. Hence, isosilybin A (3) has been identified as the first flavonolignan PPARγ agonist, suggesting its further investigation as a modulator of this nuclear receptor.
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剂。该核受体的激动剂被用于治疗 2 型糖尿病，也被研究作为其他代谢疾病的潜在治疗方法，包括非酒精性脂肪性肝病。水飞蓟素是奶蓟（Silybum marianum）种子中的一种浓缩酚混合物，被广泛用作治疗各种肝脏疾病的辅助剂。在这项研究中，研究了水飞蓟素及其主要成分对 PPARγ 的激活作用。水飞蓟宾 A（3）以浓度依赖的方式引起 PPARγ 依赖性荧光素酶报告基因的转激活。这种作用可以在用 PPARγ 拮抗剂 T0070907 共同处理时逆转。基于计算机的对接研究表明，3 的结合模式与无活性的水飞蓟素成分不同，与受体配体结合域入口区域的 Ser342 形成一个额外的氢键。因此，水飞蓟宾 A（3）已被鉴定为第一个类黄酮木脂素 PPARγ 激动剂，表明其作为该核受体调节剂的进一步研究。
