Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Department of Biology, Faculty of Science, University of Bisha, Bisha 61922, Saudi Arabia.
Biomolecules. 2023 Sep 28;13(10):1465. doi: 10.3390/biom13101465.
Nuclear receptors (NRs) constitute a superfamily of ligand-activated transcription factors with a paramount role in ubiquitous physiological functions such as metabolism, growth, and reproduction. Owing to their physiological role and druggability, NRs are deemed attractive and valid targets for medicinal chemists. Pentacyclic triterpenes (PTs) represent one of the most important phytochemical classes present in higher plants, where oleanolic acid (OA) is the most studied PTs representative owing to its multitude of biological activities against cancer, inflammation, diabetes, and liver injury. PTs possess a lipophilic skeleton that imitates the NRs endogenous ligands. Herein, we report a literature overview on the modulation of metabolic NRs by OA and its semi-synthetic derivatives, highlighting their health benefits and potential therapeutic applications. Indeed, OA exhibited varying pharmacological effects on FXR, PPAR, LXR, RXR, PXR, and ROR in a tissue-specific manner. Owing to these NRs modulation, OA showed prominent hepatoprotective properties comparable to ursodeoxycholic acid (UDCA) in a bile duct ligation mice model and antiatherosclerosis effect as simvastatin in a model of New Zealand white (NZW) rabbits. It also demonstrated a great promise in alleviating non-alcoholic steatohepatitis (NASH) and liver fibrosis, attenuated alpha-naphthol isothiocyanate (ANIT)-induced cholestatic liver injury, and controlled blood glucose levels, making it a key player in the therapy of metabolic diseases. We also compiled OA semi-synthetic derivatives and explored their synthetic pathways and pharmacological effects on NRs, showcasing their structure-activity relationship (SAR). To the best of our knowledge, this is the first review article to highlight OA activity in terms of NRs modulation.
核受体 (NRs) 构成了配体激活转录因子的超家族，在新陈代谢、生长和繁殖等普遍的生理功能中起着至关重要的作用。由于其生理作用和可药性，NRs 被认为是药物化学家有吸引力和有效的靶标。五环三萜 (PTs) 是高等植物中最重要的植物化学类群之一，齐墩果酸 (OA) 是研究最多的 PTs 代表，因为它具有多种抗癌、抗炎、糖尿病和肝损伤的生物活性。PTs 具有模仿 NRs 内源性配体的亲脂骨架。在此，我们报告了 OA 及其半合成衍生物对代谢性 NRs 的调节的文献综述，强调了它们的健康益处和潜在的治疗应用。事实上，OA 以组织特异性方式对 FXR、PPAR、LXR、RXR、PXR 和 ROR 表现出不同的药理作用。由于这些 NRs 的调节，OA 在胆管结扎小鼠模型中表现出与熊去氧胆酸 (UDCA) 相当的显著保肝作用，在新西兰白兔的动脉粥样硬化模型中表现出与辛伐他汀相当的抗动脉粥样硬化作用。它还在缓解非酒精性脂肪性肝炎 (NASH) 和肝纤维化、减轻α-萘酚异硫氰酸酯 (ANIT) 诱导的胆汁淤积性肝损伤以及控制血糖水平方面表现出巨大的潜力，使其成为治疗代谢性疾病的关键药物。我们还汇编了 OA 半合成衍生物，并探索了它们对 NRs 的合成途径和药理作用，展示了它们的结构-活性关系 (SAR)。据我们所知，这是第一篇强调 OA 活性在 NRs 调节方面的综述文章。
