發(fā)布時(shí)間：2018-05-11 14:11

  本文選題：芍藥內(nèi)酯苷 + 泡沫細(xì)胞��； 參考：《吉林大學(xué)》2017年博士論文

【摘要】：目的:近年來(lái),隨著人們生活水平的提高及飲食習(xí)慣的改變,動(dòng)脈粥樣硬化(AS)的發(fā)生率逐年上升,成為導(dǎo)致人類(lèi)死亡主要原因之一。單核細(xì)胞源性巨噬細(xì)胞在AS的發(fā)生發(fā)展中發(fā)揮著極其重要的作用,血液中單核細(xì)胞在各種外界因素的刺激下穿過(guò)血管內(nèi)膜并分化為巨噬細(xì)胞,當(dāng)機(jī)體脂質(zhì)代謝發(fā)生紊亂,血液中脂質(zhì)濃度過(guò)高時(shí),巨噬細(xì)胞通過(guò)其表面A型清道夫受體吞噬大量氧化低密度脂蛋白(ox-LDL),造成其胞質(zhì)內(nèi)的脂質(zhì)沉積最終形成泡沫細(xì)胞,泡沫細(xì)胞為AS斑塊中具有特征性的病理細(xì)胞,在AS斑塊中大量存在。大量研究證實(shí),AS的發(fā)生為機(jī)體脂質(zhì)代謝紊亂及慢性炎癥反應(yīng)共同作用的結(jié)果,并且另有研究表明LPS可通過(guò)激活TLR4/NF-κB通路加劇AS的發(fā)生。芍藥內(nèi)酯苷為一種中藥成分,臨床研究顯示其具有良好的抗炎作用,并對(duì)一些炎癥疾病如腸炎、類(lèi)風(fēng)濕性關(guān)節(jié)炎等具有很好的治療效果。本研究通過(guò)建立體外泡沫細(xì)胞模型及小鼠動(dòng)脈粥樣硬化模型并給予芍藥內(nèi)酯苷處理,觀察芍藥內(nèi)酯苷對(duì)泡沫細(xì)胞的形成及AS的發(fā)生的影響,并探究其具體作用機(jī)制。方法:1.芍藥內(nèi)酯苷對(duì)THP-1源性泡沫細(xì)胞形成的影響1)為研究芍藥內(nèi)酯苷對(duì)泡沫細(xì)胞形成的影響,需建立穩(wěn)定的THP-1源性泡沫細(xì)胞模型,將THP-1細(xì)胞分為兩組分別為T(mén)HP-1組及巨噬細(xì)胞組,巨噬細(xì)胞組細(xì)胞給予160nmol/L的PMA并孵育24小時(shí),通過(guò)鏡下觀察細(xì)胞形態(tài)和對(duì)細(xì)胞進(jìn)行CD14免疫熒光染色來(lái)對(duì)誘導(dǎo)成的細(xì)胞進(jìn)行鑒定。隨后將誘導(dǎo)后的細(xì)胞分為兩組分別為巨噬細(xì)胞組及泡沫細(xì)胞組,泡沫細(xì)胞組細(xì)胞給予ox-LDL處理48小時(shí),并分別對(duì)細(xì)胞進(jìn)行油紅O染色,觀察細(xì)胞胞質(zhì)內(nèi)脂質(zhì)沉積情況。2)為研究芍藥內(nèi)酯苷對(duì)泡沫細(xì)胞形成的影響,將經(jīng)PMA誘導(dǎo)成功的巨噬細(xì)胞分為三組:巨噬細(xì)胞組(對(duì)照組);泡沫細(xì)胞組:將巨噬細(xì)胞以50mg/L ox-LDL,靜置培養(yǎng)48小時(shí),誘導(dǎo)為泡沫細(xì)胞;芍藥內(nèi)酯苷組:將巨噬細(xì)胞以芍藥內(nèi)酯苷預(yù)處理1小時(shí)后,加入50mg/L ox-LDL共同孵育48小時(shí),通過(guò)油紅O染色分別觀察各組細(xì)胞胞質(zhì)脂質(zhì)沉積情況,并對(duì)細(xì)胞裂解液中膽固醇(TC)及甘油三脂(TG)含量進(jìn)行測(cè)定。3)為研究泡沫細(xì)胞形成過(guò)程中LOX-1/NF-κB通路的變化,將THP-1經(jīng)PMA誘導(dǎo)后形成的巨噬細(xì)胞分別以不同濃度的ox-LDL(25/50/100mg/L)處理48小時(shí),以未經(jīng)處理的巨噬細(xì)胞作為對(duì)照組。收集各處理組細(xì)胞總RNA及胞質(zhì)蛋白,分別以定量PCR及western blot方法測(cè)定細(xì)胞表達(dá)的LOX-1及NF-κB在轉(zhuǎn)錄及蛋白水平的表達(dá)量。并測(cè)定NF-κB信號(hào)通路下游IL-6及TNF-a的變化情況。4)為進(jìn)一步確定LOX-1/NF-κB在泡沫細(xì)胞形成過(guò)程中的作用,將細(xì)胞分為四組:巨噬細(xì)胞組(對(duì)照組);ox-LDL組:細(xì)胞給予50mg/L ox-LDL處理48小時(shí);LOX-1中和抗體組:細(xì)胞給予LOX-1中和抗體預(yù)處理1小時(shí),再加入50mg/L ox-LDL處理48小時(shí),抗體終濃度為10ug/ml;NF-κB抑制劑(PDTC)組:給予細(xì)胞NF-κB抑制劑預(yù)處理24小時(shí),再加入50mg/L ox-LDL處理48小時(shí),抑制劑終濃度為40umol/L。油紅O染色觀察各組細(xì)胞胞質(zhì)脂質(zhì)沉積情況,并分別以定量PCR及western blot方法測(cè)定細(xì)胞表達(dá)的LOX-1及NF-κB在轉(zhuǎn)錄及蛋白水平的表達(dá)量。5)為觀察芍藥內(nèi)酯苷在泡沫細(xì)胞形成過(guò)程中對(duì)LOX-1/NF-κB通路的影響,將THP-1細(xì)胞經(jīng)PMA誘導(dǎo)成的巨噬細(xì)胞分為三組,分別為巨噬細(xì)胞組:對(duì)照組;泡沫細(xì)胞組:將巨噬細(xì)胞以50mg/L ox-LDL,靜置培養(yǎng)48小時(shí),誘導(dǎo)為泡沫細(xì)胞;芍藥內(nèi)酯苷組:將巨噬細(xì)胞以芍藥內(nèi)酯苷預(yù)處理1小時(shí)后,加入50mg/L ox-LDL共同孵育48小時(shí)。分別提取細(xì)胞總RNA及細(xì)胞蛋白,定量PCR及western blot檢測(cè)細(xì)胞LOX-1和NF-κB在轉(zhuǎn)錄及蛋白水平的表達(dá)量,并測(cè)定NF-κB信號(hào)通路下游IL-6及TNF-a的變化情況。2.芍藥內(nèi)酯苷對(duì)小鼠動(dòng)脈粥樣硬化模型的影響1)為研究芍藥內(nèi)酯苷對(duì)小鼠動(dòng)脈粥樣硬化形成的影響,將ApoE-/-小鼠隨機(jī)分成三組,分別為:對(duì)照組(NC)、高脂組+生理鹽水組(HFD)、高脂組+芍藥內(nèi)酯苷組(HFD+A)。檢測(cè)試劑盒測(cè)定其血清中甘油三酯(TG)、膽固醇(TC)、低密度脂蛋白(LDL)及高密度脂蛋白(HDL)的含量變化,并通過(guò)對(duì)胸主動(dòng)脈組織進(jìn)行HE及油紅O染色,觀察主動(dòng)脈病理變化及脂質(zhì)沉積情況。2)為研究芍藥內(nèi)酯苷對(duì)小鼠動(dòng)脈粥樣硬化模型LOX-1/NF-κB通路的影響,將ApoE-/-小鼠隨機(jī)分成三組,分別為:對(duì)照組(NC)、高脂組+生理鹽水組(HFD)、高脂組+芍藥內(nèi)酯苷組(HFD+A)。分離胸主動(dòng)脈組織蛋白及總RNA,定量PCR及western blot測(cè)定其LOX-1和NF-κB表達(dá)水平的變化,并測(cè)定NF-κB信號(hào)通路下游IL-6及TNF-a的變化情況。結(jié)果:1.芍藥內(nèi)酯苷對(duì)THP-1源性泡沫細(xì)胞形成的影響1)通過(guò)PMA對(duì)THP-1細(xì)胞處理后,鏡下觀察細(xì)胞呈貼壁生長(zhǎng),大量細(xì)胞生出偽足,成巨噬細(xì)胞樣改變,免疫熒光染色細(xì)胞大量表達(dá)CD14。給予PMA誘導(dǎo)后的巨噬細(xì)胞ox-LDL處理后,油紅O染色細(xì)胞胞質(zhì)大量脂質(zhì)沉積。THP-1源性泡沫細(xì)胞模型成功建立。2)ox-LDL誘導(dǎo)巨噬細(xì)胞形成泡沫細(xì)胞的過(guò)程中給予芍藥內(nèi)酯苷預(yù)處理結(jié)果發(fā)現(xiàn),其胞質(zhì)中脂質(zhì)沉積與未芍藥內(nèi)酯苷處理的細(xì)胞相比明顯減少,并且細(xì)胞裂解液中膽固醇(TC)及甘油三酯(TG)含量也顯著降低。3)以不同濃度ox-LDL處理巨噬細(xì)胞后,定量PCR及western blot結(jié)果發(fā)現(xiàn)LOX-1及NF-κB的表達(dá)水平隨著ox-LDL的濃度的增加也具有上升趨勢(shì),并且下游IL-6及TNF-a的表達(dá)量也隨之上調(diào)。4)在以ox-LDL誘導(dǎo)泡沫細(xì)胞形成的過(guò)程中給予LOX-1中和抗體及NF-κB抑制劑處理后,油紅O染色發(fā)現(xiàn)胞質(zhì)脂質(zhì)沉積情況明顯改善,定量PCR及western blot結(jié)果發(fā)現(xiàn)LOX-1及NF-κB的表達(dá)水平明顯下降,并且下游IL-6及TNF-a的表達(dá)量也顯著下調(diào)。5)在以ox-LDL誘導(dǎo)泡沫細(xì)胞形成的過(guò)程中給予芍藥內(nèi)酯苷處理后,定量PCR及western blot結(jié)果發(fā)現(xiàn)LOX-1及NF-κB的表達(dá)水平明顯下降,并且下游IL-6及TNF-a的表達(dá)量也顯著下調(diào)。2.芍藥內(nèi)酯苷對(duì)小鼠動(dòng)脈粥樣硬化模型的影響1)給予小鼠動(dòng)脈粥樣硬化模型芍藥內(nèi)酯苷處理后,小鼠血清甘油三酯(TG)、膽固醇(TC)、低密度脂蛋白(LDL)及高密度脂蛋白(HDL)的含量下降,胸主動(dòng)脈組織進(jìn)行HE及油紅O染色結(jié)果發(fā)現(xiàn),病理變化及組織脂質(zhì)沉積明顯改善。2)給予小鼠動(dòng)脈粥樣硬化模型芍藥內(nèi)酯苷處理后,胸主動(dòng)脈組織LOX-1及NF-κB的表達(dá)水平明顯下降,并且下游IL-6及TNF-a的表達(dá)量也顯著下調(diào)。結(jié)論:1.芍藥內(nèi)酯苷通過(guò)調(diào)節(jié)LOX-1/NF-κB信號(hào)通路在巨噬細(xì)胞吞噬大量ox-LDL后減少其胞質(zhì)內(nèi)脂質(zhì)堆積,阻斷其泡沫化進(jìn)程。2.ox-LDL通過(guò)上調(diào)LOX-1的表達(dá)進(jìn)而激活NF-κB的表達(dá)促進(jìn)泡沫細(xì)胞的形成,芍藥內(nèi)酯苷在此過(guò)程中通過(guò)調(diào)節(jié)LOX-1/NF-κB通路及炎癥分子的表達(dá)抑制動(dòng)脈粥樣硬化斑塊的形成。
[Abstract]:Objective: in recent years, with the improvement of people's living standard and the change of dietary habits, the incidence of atherosclerosis (AS) is increasing year by year, which has become one of the main causes of human death. Monocyte derived macrophages play an extremely important role in the development of AS, and the mononuclear cells in the blood are in various external factors. When the lipid metabolism of the body is disorganized and the macrophage is differentiated, when the body's lipid metabolism is disturbed and the lipid concentration in the blood is too high, the macrophage phagocytosis a large amount of oxidized low density lipoprotein (ox-LDL) through its surface A type scavenger receptor, resulting in the formation of the lipid deposition in the cytoplasm at the end of the foam cells, and the foam cells are special in the AS plaques. A large number of studies have proved that the occurrence of AS is the result of the common effect of lipid metabolism disorder and chronic inflammatory reaction in the body, and other studies show that LPS can aggravate the occurrence of AS by activating TLR4/NF- kappa B pathway. Paeoniflorin is a kind of traditional Chinese medicine, and the clinical study shows that LPS has good effect. The effect of anti-inflammatory effects on some inflammatory diseases such as enteritis and rheumatoid arthritis is very good. In this study, the effects of paeoniflorin on the formation of foam cells and the occurrence of AS were observed through the establishment of an in vitro foam cell model and a mouse atherosclerosis model, and the effects of paeoniflorin on the formation of foam cells and the specific effects were explored. Mechanism. Method: 1. the effect of paeoniflorin on the formation of THP-1 derived foam cells (1). To study the effect of paeoniflorin on the formation of foam cells, a stable THP-1 derived foam cell model should be established, and the THP-1 cells were divided into two groups, THP-1 and macrophage groups, and the macrophage cells were given 160nmol/L PMA and incubated for 24 small groups. The cell morphology and CD14 immunofluorescence staining were used to identify the cells. Then the induced cells were divided into two groups, macrophage group and foam cell group. The cells of the foam cell group were treated with ox-LDL for 48 hours, and the cells were stained with oil red O, and the cytoplasm was observed. Internal lipid deposition.2) in order to study the effect of paeoniflorin on the formation of foam cells, the macrophages were divided into three groups: macrophage group (control group); foam cell group: macrophages were cultured with 50mg/L ox-LDL, cultured for 48 hours, and induced as foam cells; paeoniflorin group: macrophage with paeoniflorin After 1 hours of pretreatment, 50mg/L ox-LDL was added to incubate for 48 hours. The cytoplasmic lipid deposition of each cell was observed by oil red O staining, and the contents of cholesterol (TC) and glycerol three fat (TG) in the cell lysate were measured.3) to study the changes of LOX-1/NF- kappa B pathway during the formation of the foam cells, and the THP-1 was induced by PMA to form. The macrophages were treated with different concentrations of ox-LDL (25/50/100mg/L) for 48 hours, and the untreated macrophages were used as the control group. The total RNA and cytoplasmic proteins were collected and the expressions of LOX-1 and NF- kappa B expressed in the cells were measured by quantitative PCR and Western blot, and the NF- kappa B signal was measured. The change of IL-6 and TNF-a in the downstream of the channel.4) to further determine the role of LOX-1/NF- kappa B in the formation of foam cells, the cells were divided into four groups: macrophage group (control group); ox-LDL group: the cells were treated with 50mg/L ox-LDL for 48 hours; LOX-1 neutralization antibody group: fine cell given LOX-1 neutralization antibody for 1 hours, then 50mg/L ox-LD was added. L was treated for 48 hours, the final antibody concentration was 10ug/ml, and the NF- kappa B inhibitor (PDTC) group was treated with NF- kappa B inhibitor for 24 hours and then 50mg/L ox-LDL treatment for 48 hours. The final concentration of the inhibitor was 40umol/L. oil red O staining, and the cell cytoplasmic lipid deposition was observed by 40umol/L. oil red O staining. The expression of OX-1 and NF- kappa B at the transcriptional and protein level.5) was to observe the effect of paeoniflorin on the LOX-1/NF- kappa B pathway during the formation of foam cells. The macrophages induced by PMA in THP-1 cells were divided into three groups: macrophage group, control group, and foam cell group: macrophages were incubated with 50mg/L ox-LDL and cultured for 48 hours, Induced as foam cells; paeoniflorin group: after pretreating macrophages with paeoniflorin for 1 hours, the cells were incubated with 50mg/L ox-LDL for 48 hours. The total RNA and cell protein were extracted respectively. Quantitative PCR and Western blot were used to detect the expression of LOX-1 and NF- kappa B in the transcriptional and protein level, and the downstream IL-6 of NF- kappa B signaling pathway was determined. And the change of TNF-a.2. the effect of paeoniflorin on the atherosclerotic model of mice 1) to study the effect of paeoniflorin on the formation of atherosclerosis in mice. The ApoE-/- mice were randomly divided into three groups: the control group (NC), the high fat group + physiological saline group (HFD), the high fat group + paeoniflorin group (HFD+A) and the detection kit The serum levels of triglyceride (TG), cholesterol (TC), low density lipoprotein (LDL) and high density lipoprotein (HDL) were changed, and the pathological changes of aorta and lipid deposition.2 were observed by HE and oil red O staining on the thoracic aorta tissue. The effect of paeoniflorin on the LOX-1/NF- kappa B pathway in the atherosclerotic model of mice was studied. ApoE-/- mice were randomly divided into three groups: control group (NC), high fat group + physiological saline group (HFD), high fat group + paeoniflorin group (HFD+A), separation of thoracic aorta tissue protein and total RNA, quantitative PCR and Western blot to determine the expression of LOX-1 and NF- kappa B expression, and determine the changes in the downstream of NF- kappa signaling pathway. Fruit: 1. the effect of paeoniflorin on the formation of THP-1 derived foam cells 1. After the treatment of THP-1 cells by PMA, the cells were observed under the microscope, and a large number of cells produced pseudo foot and became macrophage like changes. The immunofluorescent staining cells expressed a large number of CD14. to PMA induced macrophage ox-LDL treatment, and the cytoplasm of the oil red O staining cells was large. The lipid deposition.THP-1 derived foam cell model successfully established.2) in the process of ox-LDL induced macrophage formation of foam cells, the results showed that the lipid deposition in the cytoplasm decreased significantly compared with the cells treated with paeoniflorin, and the content of cholesterol (TC) and triglyceride (TG) content in the cell lysate. After treating macrophages with different concentrations of ox-LDL, the results of quantitative PCR and Western blot showed that the expression level of LOX-1 and NF- kappa B also increased with the increase of ox-LDL concentration, and the expression of IL-6 and TNF-a downstream of the downstream was also up regulation of.4) in the process of inducing the formation of foam cells. After the treatment of the antibody and NF- kappa B inhibitor, the oil red O staining showed that the cytoplasmic lipid deposition was obviously improved. The quantitative PCR and Western blot results showed that the expression level of LOX-1 and NF- kappa B decreased obviously, and the downstream IL-6 and TNF-a expressed the.5) in the process of inducing the formation of foam cells. The results of quantitative PCR and Western blot showed that the expression level of LOX-1 and NF- kappa B decreased significantly, and the expression of IL-6 and TNF-a in the lower reaches significantly reduced the effect of.2. paeoniflorin on the atherosclerotic model in mice. 1) after the mice were treated with paeoniflorin, the serum triglyceride (TG) and cholesterol (TC) in mice were given. The levels of low density lipoprotein (LDL) and high density lipoprotein (HDL) were decreased. The results of HE and oil red O staining in thoracic aorta tissue showed that the pathological changes and tissue lipid deposition significantly improved.2). The expression level of LOX-1 and NF- kappa B in the thoracic active vein tissue decreased significantly after the treatment of paeoniflorin in the atherosclerotic model of the mice. The expression of IL-6 and TNF-a decreased significantly. Conclusion: 1. paeoniflorin can reduce the accumulation of lipid in the cytoplasm of macrophages by regulating the LOX-1/NF- kappa B signaling pathway and blocking its foaming process.2.ox-LDL by up regulation of the expression of LOX-1 and activating the expression of NF- kappa B to promote the formation of foamy cells, paeoniflorin During this process, the formation of atherosclerotic plaques was inhibited by regulating the expression of LOX-1/NF- - B pathway and inflammatory molecules.

【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R543.5

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