基于蛋白质组学淫羊藿苷防治骨质疏松作用机理及药对“淫羊藿仙茅”配伍机制研究
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摘要
淫羊藿仙茅是临床常用的温补肾阳的药对。两药均为我国传统中药，2010版《中华人民共和国药典》中均有收录。淫羊藿和仙茅配伍相须为用，相得益彰。使补肾壮阳，强筋健骨，祛风除湿功力增强。淫羊藿的抗骨质疏松作用已有较多报道，其活性部位淫羊藿总黄酮和活性成分淫羊藿苷能显著促进成骨细胞活性，抑制破骨细胞活性，减少骨质的丢失；能促进下丘脑，海马及骨组织中雌激素受体(ER)表达和增强骨组织护骨素(OPG)表达。仙茅作为补肾壮阳的药物，具有确切的防治骨质疏松作用。仙茅能够抑制骨吸收、降低去卵巢大鼠的骨丢失；仙茅苯甲酸酯类总酚苷能够增加成骨细胞的增殖和碱性磷酸酶活性；仙茅苷降低破骨细胞的形成分化和抗酒石酸酸性磷酸酶的活性。仙茅酚苷类成分具有抗氧化、调节免疫和植物雌激素等作用。
本实验在明确二仙汤对骨质疏松确切防治作用的基础上，对二仙汤内君药药对淫羊藿仙茅抗骨质疏松的配伍机制进行了研究。主要包括：
一、基于蛋白组学研究淫羊藿苷防治骨质疏松作用机理
淫羊藿苷对下丘脑-垂体-性腺(甲状腺，肾上腺)轴靶器官(下丘脑，垂体，子宫，骨骼)的蛋白质组学结果显示，差异蛋白功能与细胞凋亡，能量代谢，细胞骨架，蛋白质聚集、折叠，分子伴侣，氧化应激以及MAPK通路等相关。揭示淫羊藿苷多靶点、多途径的作用机制。
二、淫羊藿仙茅药对抗骨质疏松活性成分筛选
本研究考察了淫羊藿苷、淫羊藿次苷、宝藿苷和朝藿定C、仙茅苷、仙茅素、苔黑酚葡萄糖苷和苔黑酚龙胆二糖苷的成骨细胞活性和破骨细胞活性。主要内容为对新生大鼠颅盖骨成骨细胞成骨细胞增殖、碱性磷酸酶(ALP)活性的影响；对新生大鼠颅盖骨成骨细胞为模型，骨髓单核细胞经1,25-(OH)2-VD3和地塞米松共同诱导而得到的破骨细胞进行TRAP酶活性的影响；并观察了对骨髓单核细胞经细胞因子M-SCF、RANKL诱导的破骨细胞和成骨细胞的细胞线粒体膜电势、细胞内ATP含量及细胞骨架结构的影响，筛选得出仙茅苷和淫羊藿苷的作用明显。
三、淫羊藿总黄酮及仙茅苯甲酸酯类总酚苷配伍防治骨质疏松作用研究
本研究采用去卵巢骨质疏松大鼠模型(OVX)，通过骨密度，骨组织形态计量学，血清、尿液骨相关生化指标(Ca、P、Cr含量，ALP活性，孕激素含量)，血清中氧化应激相关酶活性(谷胱甘肽过氧化酶、超氧化物歧化酶、一氧化氮合酶)及丙二醛的含量)等指标来考察淫羊藿总黄酮、仙茅苯甲酸酯类总酚苷以及配伍前后防治骨质疏松的作用；通过观察靶器官(子宫、阴道、乳腺)切片和考察这些中器官雌激素表达的变化，确定淫羊藿总黄酮和仙茅苯甲酸酯类总酚苷以及配伍后有无显著毒性作用。结果显示，不论是有效性或安全性，配伍后均体现为相加作用。我们还通过代谢组学考察了OVX大鼠和给药大鼠血浆及尿液中代谢产物变化，结果显示，淫羊藿总黄酮组以及配伍组能显著改善OVX导致的尿液和血液的代谢物变化这些显著变化的代谢物仙茅苯甲酸酯类总酚苷主要与能量代谢、氨基酸代谢、氧化应激和脂肪代谢相关。
四、淫羊藿苷和仙茅苷防治骨质疏松配伍作用研究
根据蛋白组研究结果，骨质疏松参与调控能量代谢、细胞骨架形成。因此，我们观察了淫羊藿苷和仙茅苷以及配伍对成骨细胞和破骨细胞作用线粒体膜电势，ATP含量以及细胞骨架的作用。结果显示，成骨细胞活性包括(增殖、ALP活性，骨结节)体现相加关系，破骨细胞活性(破骨细胞数目，TRAP活性，CK活性)体现显著的协同作用。依据骨质疏松发生的原理，进一步考察了淫羊藿苷和仙茅苷以及配伍对破骨细胞MAPK通路及OPG/RANKL通路的影响。结果显示显著的协同作用。
综上所述，骨质疏松与能量代谢、细胞骨架关系密切。淫羊藿总黄酮和仙茅苯甲酸酯类总酚苷配伍，对骨质疏松整体动物有效性和安全性总体呈现相加作用。淫羊藿苷和仙茅苷配伍对成骨细胞活性体现相加作用，破骨细胞活性体现协同作用。本实验为复方二仙汤有效成分间的关联性研究提供方法和思路。
Drug pair composed of Epimedium brevicornum Maxim.(Berberidaceae, whole herb)and Curculigo orchioides Gaertn.(Amaryllidaceae, rhizome), Warming kidney andReinforcing Yang, has been widely used for the clinical treatment of osteoporosis disordersand menopausal syndrome for several decades. Both Epimedium brevicornum and Curculigoorchioides, Traditional Chinese Medicine, were recorded in Pharmacopoeia of people'sRepublic of China. In the present study, we investigated the antiosteoporotic activity andmechanism of the main active constituents. Total Flavones of Epimedium and total phenolicglycosides of curculigo, icariin and curculigoside was the main constituent respectively, wererecongnized as effective drugs for osteoporosis in many published papers. The thesisincluding four parts:
Ⅰ. Proteomic protocol involved of2-DE, image analysis and spectrometry detection wasset up. Proteomics studies of icariin on the target organs of HPA axies (includinghypothalamus, pituitary gland, uterus and bone) shows that: Proteins separation intwo-dimensional gel meet the requirement of PDQuest2-D Analysis Software.Bioinformatics and literature review showed that differentially expressed proteins functionsrelated to apoptosis, cell proliferation, cell differentiation, proteins aggregation, proteinsfolding, molecular chaperones, cytoskeleton formation, cell proliferation signals transduction,oxidative stress and mineral crystal fiber et al.
Ⅱ. Icariin, icariside, baohuoganⅡ, Epimedin C, curculigoside, curculigoside A, Orcinolglucoside and Orcinol rhamnoside of10-8~10-10mol/L, were evaluated for their activity onosteoblast proliferation and differentiation in neonatal rat calvaria cultures, TRAP activitywere determined in the concentration of10-5~10-7mol/L on the multinucleated osteoclastsderived from rat marrow cells induced by1,25-(OH)2-D3and dexamethasone. ATP contentsand mitochondrial membrane potential and cytoskeleton of cells were also observed in theconcentration of10-6mol/L. Considering of all aspects, we chose icariin and curculigoside asthe compounds of effective components to study their interaction on osteoblast and osteoclast.
Ⅲ. We selected the3months old ovariectomized rat model to investigate theanti-osteoporosis effect of total Flavones of Epimedium and total phenolic glycosides ofcurculigo, and analyzed the indexes include total femur bone mineral density,histomorphometry, the Ca, P, Cr content and ALP activity in serum and urine； Serumprogesterone levels; examine serum antioxidant enzymes Activity (glutathione peroxidase, superoxide dismutase, nitric oxide synthase) and MDA content. The results show that theindicators are effective when treated with total Flavones of Epimedium, total phenolicglycosides of curculigo and their combination, they show certain mutual enhancement. Wealso investigated the changes of metabolites in plasma and urine by metabolomics. The resultshows the osteoporosis-related metabolites mainly relevant with energy metabolism and lipidmetabolism.
Ⅳ.Icariin and curculigoside could not only promote the proliferation and ALP activity ofOB, but also increase the quantity of bone nodules. They show mutual enhancement onosteoblastic activity. For osteoclasts, they can decrease the number of mature osteoclasts,suppress the marker enzyme activity (TRAP and Cathepsin K), reduce the bone resorption pitarea. The morphous of osteoclast and its nucleis (actin ring and nuclear staining), proteinexpression of key regulatory factor (OPG and RANKL), the relative proteins includingNF-κB、MAPK(ERK、P38、JNK)、PI3K/Akt, belonging to the routes of RANK, were alsoevaluted. Results showed that icariin and curculigoside showed the strongest suppressingactivity. They show mutual assistance.
The conclusion we made in these study is osteoporosis were relate with cytoskeleton andenergy metabolism. The interaction between total Flavones of Epimedium and total phenolicglycosides shows mutual enhancement on OVX rats. Icariin and curculigoside show mutualassistance in osteoclastic activity, mutual enhancement in osteoblastic activity.
本实验在明确二仙汤对骨质疏松确切防治作用的基础上，对二仙汤内君药药对淫羊藿仙茅抗骨质疏松的配伍机制进行了研究。主要包括：
一、基于蛋白组学研究淫羊藿苷防治骨质疏松作用机理
淫羊藿苷对下丘脑-垂体-性腺(甲状腺，肾上腺)轴靶器官(下丘脑，垂体，子宫，骨骼)的蛋白质组学结果显示，差异蛋白功能与细胞凋亡，能量代谢，细胞骨架，蛋白质聚集、折叠，分子伴侣，氧化应激以及MAPK通路等相关。揭示淫羊藿苷多靶点、多途径的作用机制。
二、淫羊藿仙茅药对抗骨质疏松活性成分筛选
本研究考察了淫羊藿苷、淫羊藿次苷、宝藿苷和朝藿定C、仙茅苷、仙茅素、苔黑酚葡萄糖苷和苔黑酚龙胆二糖苷的成骨细胞活性和破骨细胞活性。主要内容为对新生大鼠颅盖骨成骨细胞成骨细胞增殖、碱性磷酸酶(ALP)活性的影响；对新生大鼠颅盖骨成骨细胞为模型，骨髓单核细胞经1,25-(OH)2-VD3和地塞米松共同诱导而得到的破骨细胞进行TRAP酶活性的影响；并观察了对骨髓单核细胞经细胞因子M-SCF、RANKL诱导的破骨细胞和成骨细胞的细胞线粒体膜电势、细胞内ATP含量及细胞骨架结构的影响，筛选得出仙茅苷和淫羊藿苷的作用明显。
三、淫羊藿总黄酮及仙茅苯甲酸酯类总酚苷配伍防治骨质疏松作用研究
本研究采用去卵巢骨质疏松大鼠模型(OVX)，通过骨密度，骨组织形态计量学，血清、尿液骨相关生化指标(Ca、P、Cr含量，ALP活性，孕激素含量)，血清中氧化应激相关酶活性(谷胱甘肽过氧化酶、超氧化物歧化酶、一氧化氮合酶)及丙二醛的含量)等指标来考察淫羊藿总黄酮、仙茅苯甲酸酯类总酚苷以及配伍前后防治骨质疏松的作用；通过观察靶器官(子宫、阴道、乳腺)切片和考察这些中器官雌激素表达的变化，确定淫羊藿总黄酮和仙茅苯甲酸酯类总酚苷以及配伍后有无显著毒性作用。结果显示，不论是有效性或安全性，配伍后均体现为相加作用。我们还通过代谢组学考察了OVX大鼠和给药大鼠血浆及尿液中代谢产物变化，结果显示，淫羊藿总黄酮组以及配伍组能显著改善OVX导致的尿液和血液的代谢物变化这些显著变化的代谢物仙茅苯甲酸酯类总酚苷主要与能量代谢、氨基酸代谢、氧化应激和脂肪代谢相关。
四、淫羊藿苷和仙茅苷防治骨质疏松配伍作用研究
根据蛋白组研究结果，骨质疏松参与调控能量代谢、细胞骨架形成。因此，我们观察了淫羊藿苷和仙茅苷以及配伍对成骨细胞和破骨细胞作用线粒体膜电势，ATP含量以及细胞骨架的作用。结果显示，成骨细胞活性包括(增殖、ALP活性，骨结节)体现相加关系，破骨细胞活性(破骨细胞数目，TRAP活性，CK活性)体现显著的协同作用。依据骨质疏松发生的原理，进一步考察了淫羊藿苷和仙茅苷以及配伍对破骨细胞MAPK通路及OPG/RANKL通路的影响。结果显示显著的协同作用。
综上所述，骨质疏松与能量代谢、细胞骨架关系密切。淫羊藿总黄酮和仙茅苯甲酸酯类总酚苷配伍，对骨质疏松整体动物有效性和安全性总体呈现相加作用。淫羊藿苷和仙茅苷配伍对成骨细胞活性体现相加作用，破骨细胞活性体现协同作用。本实验为复方二仙汤有效成分间的关联性研究提供方法和思路。
Drug pair composed of Epimedium brevicornum Maxim.(Berberidaceae, whole herb)and Curculigo orchioides Gaertn.(Amaryllidaceae, rhizome), Warming kidney andReinforcing Yang, has been widely used for the clinical treatment of osteoporosis disordersand menopausal syndrome for several decades. Both Epimedium brevicornum and Curculigoorchioides, Traditional Chinese Medicine, were recorded in Pharmacopoeia of people'sRepublic of China. In the present study, we investigated the antiosteoporotic activity andmechanism of the main active constituents. Total Flavones of Epimedium and total phenolicglycosides of curculigo, icariin and curculigoside was the main constituent respectively, wererecongnized as effective drugs for osteoporosis in many published papers. The thesisincluding four parts:
Ⅰ. Proteomic protocol involved of2-DE, image analysis and spectrometry detection wasset up. Proteomics studies of icariin on the target organs of HPA axies (includinghypothalamus, pituitary gland, uterus and bone) shows that: Proteins separation intwo-dimensional gel meet the requirement of PDQuest2-D Analysis Software.Bioinformatics and literature review showed that differentially expressed proteins functionsrelated to apoptosis, cell proliferation, cell differentiation, proteins aggregation, proteinsfolding, molecular chaperones, cytoskeleton formation, cell proliferation signals transduction,oxidative stress and mineral crystal fiber et al.
Ⅱ. Icariin, icariside, baohuoganⅡ, Epimedin C, curculigoside, curculigoside A, Orcinolglucoside and Orcinol rhamnoside of10-8~10-10mol/L, were evaluated for their activity onosteoblast proliferation and differentiation in neonatal rat calvaria cultures, TRAP activitywere determined in the concentration of10-5~10-7mol/L on the multinucleated osteoclastsderived from rat marrow cells induced by1,25-(OH)2-D3and dexamethasone. ATP contentsand mitochondrial membrane potential and cytoskeleton of cells were also observed in theconcentration of10-6mol/L. Considering of all aspects, we chose icariin and curculigoside asthe compounds of effective components to study their interaction on osteoblast and osteoclast.
Ⅲ. We selected the3months old ovariectomized rat model to investigate theanti-osteoporosis effect of total Flavones of Epimedium and total phenolic glycosides ofcurculigo, and analyzed the indexes include total femur bone mineral density,histomorphometry, the Ca, P, Cr content and ALP activity in serum and urine； Serumprogesterone levels; examine serum antioxidant enzymes Activity (glutathione peroxidase, superoxide dismutase, nitric oxide synthase) and MDA content. The results show that theindicators are effective when treated with total Flavones of Epimedium, total phenolicglycosides of curculigo and their combination, they show certain mutual enhancement. Wealso investigated the changes of metabolites in plasma and urine by metabolomics. The resultshows the osteoporosis-related metabolites mainly relevant with energy metabolism and lipidmetabolism.
Ⅳ.Icariin and curculigoside could not only promote the proliferation and ALP activity ofOB, but also increase the quantity of bone nodules. They show mutual enhancement onosteoblastic activity. For osteoclasts, they can decrease the number of mature osteoclasts,suppress the marker enzyme activity (TRAP and Cathepsin K), reduce the bone resorption pitarea. The morphous of osteoclast and its nucleis (actin ring and nuclear staining), proteinexpression of key regulatory factor (OPG and RANKL), the relative proteins includingNF-κB、MAPK(ERK、P38、JNK)、PI3K/Akt, belonging to the routes of RANK, were alsoevaluted. Results showed that icariin and curculigoside showed the strongest suppressingactivity. They show mutual assistance.
The conclusion we made in these study is osteoporosis were relate with cytoskeleton andenergy metabolism. The interaction between total Flavones of Epimedium and total phenolicglycosides shows mutual enhancement on OVX rats. Icariin and curculigoside show mutualassistance in osteoclastic activity, mutual enhancement in osteoblastic activity.
引文
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