Yang Gangqiang, Mi Xiaoliang, Wang Yunxiao, Li Shuang, Yu Liping, Huang Xinru, Tan Shuai, Yu Hui
School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai 264005, China.
School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai 264005, China.
Bioorg Chem. 2023 May;134:106467. doi: 10.1016/j.bioorg.2023.106467. Epub 2023 Mar 15.
Ginsenosides are a promising group of secondary metabolites for developing anti-inflammatory agents. In this study, Michael acceptor was fused into the aglycone A-ring of protopanoxadiol (PPD)-type ginsenosides (MAAG), the main pharmacophore of ginseng, and its liver metabolites to produce novel derivatives and assess their anti-inflammatory activity in vitro. The structure-activity relationship of MAAG derivatives was assessed based on their NO-inhibition activities. Of these, a 4-nitrobenzylidene derivative of PPD (2a) was the most effective and dose-dependently inhibited the release of proinflammatory cytokines. Further studies indicated that 2a-induced downregulation on lipopolysaccharide (LPS)-induced iNOS protein expression and cytokine release may be related to its inhibitory effect on MAPK and NF-κB signaling pathways. Importantly, 2a almost completely inhibited LPS-induced production of mitochondrial reactive oxygen species (mtROS) and LPS-induced NLRP3 upregulation. This inhibition was higher than that by hydrocortisone sodium succinate, a glucocorticoid drug. Overall, the fusion of Michael acceptors into the aglycone of ginsenosides greatly enhanced the anti-inflammatory activities of the derivatives, and 2a alleviated inflammation considerably. These findings could be attributed to the inhibition of LPS-induced mtROS to block abnormal activation of the NLRP3 pathway.
人参皂苷是一类很有前景的次生代谢产物，可用于开发抗炎药物。在本研究中，将迈克尔受体融合到原人参二醇（PPD）型人参皂苷（MAAG）的苷元A环中，人参的主要药效基团及其肝脏代谢产物，以产生新型衍生物并评估其体外抗炎活性。基于其对一氧化氮的抑制活性评估了MAAG衍生物的构效关系。其中，PPD的4-硝基亚苄基衍生物（2a）最为有效，且能剂量依赖性地抑制促炎细胞因子的释放。进一步研究表明，2a诱导的对脂多糖（LPS）诱导的诱导型一氧化氮合酶（iNOS）蛋白表达和细胞因子释放的下调可能与其对丝裂原活化蛋白激酶（MAPK）和核因子κB（NF-κB）信号通路的抑制作用有关。重要的是，2a几乎完全抑制了LPS诱导的线粒体活性氧（mtROS）的产生以及LPS诱导的NLRP3上调。这种抑制作用高于糖皮质激素药物琥珀酸钠氢化可的松。总体而言，将迈克尔受体融合到人参皂苷的苷元中极大地增强了衍生物的抗炎活性，并且2a显著减轻了炎症。这些发现可能归因于对LPS诱导的mtROS的抑制，从而阻断了NLRP3途径的异常激活。
