淫羊藿素通过下调雌激素缺失状态下的铁过载而调节骨type I胶原合成分泌与降解抗绝经后骨质疏松研究

Postmenopausal osteoporosis (PMOP) is a serious disease that affects the health of older women. Postmenopausal estrogen deficiency causes the body to iron level (Fe3+) overload. Under estrogen deficiency, iron overload induces osteoporosis. Previous studies have found that iron overload in the absence of estrogen can promote the degradation of bone type I collagen and induce PMOP. Icaritin (IT) has the activity of anti-PMOP. In the structure of IT, there’s one 4-carbonyl and one 5-hydroxy which can give lone pair electrons and act as a ligand. Meanwhile, Fe3+ is a vacancy ion that can accept these lone pair electrons and form complexes with IT. Thus, it is hypothesized that IT can react with excess Fe3+ in vivo to promote iron excretion and reduce iron overload in the absence of estrogen, thereby reverse what the iron overload caused the increase in type I collagen degradation and the decrease in type I collagen synthesis and secretion, and finally exhibit the effect of anti - PMOP. This project described the distribution and excretion of the complexes formed by IT and Fe3+ in vivo under estrogen deficiency. The Pharmacokinetics - Pharmacodynamics (PK-PD) mode was used to study the Dose - Effect relationship of IT on down-regulating iron overload and promoting type I collagen synthesis secretion after the reduction of iron overload. Finally, the zebra-fish and estrogen deficient rat models were used to demonstrate that IT reversed what the iron overload caused the increase in type I collagen degradation and the decrease in type I collagen synthesis and secretion, and then exerted the effect of anti - PMOP.

绝经后骨质疏松(PMOP)是危害中老年妇女健康的严重疾病。绝经后的雌激素缺失导致机体铁(Fe3+)水平负荷过载，即铁过载。前期研究发现，铁过载可促进骨type I 胶原降解而诱导PMOP。淫羊藿素(IT)具有抗PMOP活性，且其结构中含有4-羰基、5-羟基可给出孤对电子并作为配体，与接受这些电子的空位离子(Fe3+)形成络合物。因此，提出假说：在雌激素缺失状态下，IT能与体内过载的Fe3+生成络合物以促进铁的排泄而下调铁过载，从而逆转铁过载所致type I胶原降解增加、合成分泌减少抗PMOP。本项目阐述雌激素缺失状态下IT与Fe3+体内络合物的结构解析、组织分布与排泄，采用药动学-药效学(PK-PD)结合模型研究IT下调铁过载及下调铁过载后的促type I胶原合成分泌的量-效关系，采用斑马鱼及大鼠模型阐明IT逆转铁过载所致type I胶原降解增加、合成分泌减少而抗PMOP作用。

绝经后骨质疏松(PMOP)是危害中老年妇女健康的严重疾病。绝经后的雌激素缺失导致机体铁(Fe3+)水平负荷过载，即铁过载。前期研究发现，铁过载可促进骨type I 胶原降解而诱导PMOP。淫羊藿素(IT)具有抗PMOP活性，且其结构中含有4-羰基、5-羟基可给出孤对电子并作为配体，与接受这些电子的空位离子(Fe3+)形成络合物。因此，提出假说：在雌激素缺失状态下，IT能与体内过载的Fe3+生成络合物以促进铁的排泄而下调铁过载，从而逆转铁过载所致type I胶原降解增加、合成分泌减少抗PMOP。本项目阐述雌激素缺失状态下IT与Fe3+体内络合物的结构解析、组织分布与排泄，采用药动学-药效学(PK-PD)结合模型研究IT下调铁过载及下调铁过载后的促type I胶原合成分泌的量-效关系，采用斑马鱼及大鼠模型阐明IT逆转铁过载所致type I胶原降解增加、合成分泌减少而抗PMOP作用。. 本项目以卵巢切除雌激素缺失大鼠模型(OVX)进行一系列实验，对淫羊藿素(IT)在OVX大鼠血浆、胆汁、尿液和粪便中的代谢产物进行解析，阐释了雌激素缺失状态下IT的体内代谢机制；随后，通过体外模拟实验以验证IT与Fe3+的络合作用，并借助紫外全波长扫描和UPLC-QTOF-MS确定了IT与Fe3+的络合位点、络合物的分子式和分子量；紧接着将IT经灌胃给药给予高铁模型OVX大鼠，再分别于不同时间点采取大鼠血清，进行IT- Fe3+络合物筛查，对不同时间点的大鼠血清IT- Fe3+络合物进行了半定量；接着先后获得了IT在高铁模型OVX大鼠体内的药动学(PK)特征和下调Fe3+水平的药效学特征(PD)，并对PK-PD进行拟合，阐释了IT下调铁过载、调节type I胶原代谢的量效关系和有效剂量范围；最后，分别采用斑马鱼模型和高铁OVX大鼠模型验证了IT可以通过下调铁过载而调节type I胶原代谢而发挥抗绝经后骨质疏松作用。. 通过本项目的研究，目前已发表相关论文6篇，其中SCI 4篇，中文核心2篇；参与获得江苏中医药科学技术奖一等奖1项、中国商业联合会科学技术奖一等奖1项。本项目为中药或天然活性黄酮类化合物的抗骨质疏松药物研发提供了重要数据，具有重要的实用价值。