厚朴同步调整糖脂代谢药效物质基础及其核受体效应机制

Peroxisome proliferative activated receptors (PPARs), which belong to the nuclear receptor superfamily, are ligand-dependent-activated nuclear transcription factor, and is now found to be α, β/δ and γ of three subtypes. PPARs were confirmed in a number of pathophysiological processes playing regulatory role, such as the regulation of glucose, lipid and cholesterol metabolism, and were proved to be a key target for the treatment of human metabolic disease. In spite of observed clinical effectiveness, the currently used PPARγ agonists represented by thiazolidinediones (e.g. pioglitazone) have serious side effects (e.g., weight gain), making the retrieval of new PPARs agonists highly relevant. Particularly ligands acting as dual and/or pan-PPAR agonists by activating PPARα/γ dual and/or all the three PPAR subtypes (PPARα, PPARβ/δ, and PPARγ), as well as ligands acting as partial agonists inducing submaximal receptor activation, have demonstrated great promise by retaining efficacy with reduced side effects. Utilizing pharmacophore-based virtual screening, followed by actual confirmation on the molecular level, we have recently identified neolignans as a novel class of selective partial PPARγ agonists, To further clarify the chemical basis and evaluate the efficacy of active components of the Magnolia bark, in this project, we will continue isolate neolignan compounds systemically from Magnolia officinalis. To further study the structural determinants underlying the activity of neolignans from Magnolia bark, the activation profile of the natural and/or synthetic structurally related compounds will be investigated on the three PPAR subtypes, and in a cell model relevant for metabolic disease. The ability of the isolated compounds to stimulate glucose uptake and lipid accumulation in 3T3-L1 adipocytes with the full PPARγ agonist pioglitazone will also be compared. This activity pattern will finally be further tested and confirmed in vivo with diabetic KKAy mice.

过氧物酶体增殖体激活受体（PPARs）是核受体超家族配体依赖激活核转录因子。目前已发现有α、β/δ和γ三种亚型。PPARs被证实在很多病理生理过程中发挥调控作用，如糖、脂及胆固醇代谢,PPARs是治疗人类代谢疾病关键靶点。由于目前临床应用的胰岛素增敏剂专属和完全激动PPARγ受体，因而在发挥治疗2型糖尿病疗效同时，具有增加体重、心衰等严重不良反应。PPARα、γ双和/或PPARα、γ、δ 三靶点部分激动剂可以克服这一局限，因而寻找PPAR双和/或三靶点部分激动剂成为该领域研究热点。本项目在前期虚拟筛选和分子水平实际筛选证明厚朴新木脂素类天然分子为PPARα、γ双和/或PPARα、γ、δ三靶点激动剂的基础上，对厚朴中新木脂素类成分进行系统分离，并探索其作用机制和构效关系，进而从分子、细胞和整体动物水平验证其药效，为发现具有优良性能的新型胰岛素增敏剂，阐明厚朴治疗代谢性疾病的物质基础提供依据。