本文選題：終末期腎病　切入點(diǎn)：血管鈣化　出處：《復(fù)旦大學(xué)》2014年博士論文　論文類(lèi)型：學(xué)位論文

【摘要】：第一部分尿毒癥患者血管局部Klotho基因超甲基化與血管鈣化的關(guān)系背景：最新研究證實(shí)人類(lèi)血管平滑肌細(xì)胞是Klotho直接作用的靶點(diǎn),血管局部Klotho表達(dá)下調(diào)參與血管鈣化的發(fā)生發(fā)展,但血管局部Klotho低表達(dá)的原因尚不清楚。DNA甲基化是調(diào)節(jié)基因表達(dá)的一種表觀遺傳方式,啟動(dòng)子區(qū)CpG島(即300～3000 bp富含CpG二核苷酸的區(qū)域的甲基化有沉默基因表達(dá)的作用。本研究旨在以ESRD患者為研究對(duì)象,探討ESRD患者橈動(dòng)脈局部Klotho基因超甲基化與血管鈣化的關(guān)系。方法：2013.1～2013.12在復(fù)旦大學(xué)附屬中山醫(yī)院腎內(nèi)科病房住院治療并行動(dòng)靜脈內(nèi)瘺手術(shù)的30例透析前ESRD患者為尿毒癥組,同期于我院心外科病房行冠狀動(dòng)脈搭橋手術(shù)的10例年齡、性別匹配的患者作為對(duì)照組,均取得患者知情同意。術(shù)中分別取橈動(dòng)脈和同級(jí)別的內(nèi)乳動(dòng)脈行H.E.染色觀察血管內(nèi)中膜厚度和血管管壁厚度/血管直徑,茜素紅鈣鹽沉積染色評(píng)估血管鈣化,免疫組織化學(xué)染色評(píng)價(jià)a-SMA、OPN、Cbfα1、Klotho和DNMT1蛋白的表達(dá)水平。同時(shí)利用焦磷酸測(cè)序方法檢測(cè)血管局部Klotho基因甲基化率和超高效液相色譜檢測(cè)技術(shù)檢測(cè)尿毒癥組患者血清IS濃度。結(jié)果：尿毒癥組患者內(nèi)中膜厚度較對(duì)照組顯著增厚(0.68±053mm vs.0.18±0.13mm,P0.01),血管管壁厚度/血管直徑亦顯著高于對(duì)照組(0.34±0.19 vs.0.23±0.09,P0.01)。尿毒癥組中21例(70%)茜素紅染色陽(yáng)性,均分布在血管中膜,對(duì)照組無(wú)一例發(fā)生血管鈣化(P0.01)。血管局部a-SMA、OPN和Cbfα1染色均主要分布于血管中膜,尿毒癥組αα-SMA染色陽(yáng)性率顯著低于對(duì)照組(30% vs.100%,P0.01),OPN和Cbfα1染色陽(yáng)性率顯著高于對(duì)照組(87% vs.0%,P0.01)(93% vs.0%,P0.01)。尿毒癥組患者血管局部Klotho基因甲基化率顯著高于對(duì)照組(43.2±1.7%,8.7±0.8%,P0.001)。血管局部Klotho、 DNMT1染色均主要分布于血管中膜,尿毒癥組Klotho染色陽(yáng)性率顯著低于對(duì)照組(33.3% vs.100%,P0.01),DNMT1染色陽(yáng)性率顯著高于對(duì)照組(70% vs.0%,P0.01)。其中21例茜素紅染色陽(yáng)性的ESRD患者者血管局部Klotho甲基化率和血清IS濃度顯著高于9例染色陰性者(41.8±3.7% vs.29.4±1.5%,P0.001) (34.6±4.13 pg/m,29.8±4.23 pg/mlP0.001)。進(jìn)一步Pearson單因素相關(guān)分析顯示尿毒癥組患者血清IS濃度與血管局部Klotho甲基化率呈正相關(guān)(r=0.587,P0.01)。結(jié)論：尿毒癥患者普遍存在血管鈣化和血管局部Klotho基因超甲基化,血管局部Klotho基因超甲基化與血管鈣化密切相關(guān)。第二部分Klotho基因超甲基化在硫酸吲哚酚誘導(dǎo)的血管平滑肌細(xì)胞成骨轉(zhuǎn)化中的作用機(jī)制背景：IS與ESRD患者心血管疾病死亡率和總死亡率相關(guān),可通過(guò)誘導(dǎo)血管平滑肌細(xì)胞成骨細(xì)胞轉(zhuǎn)分化而促進(jìn)血管鈣化,但是IS誘導(dǎo)血管鈣化的具體機(jī)制目前尚不清楚。第一部分的研究證明尿毒癥患者普遍存在血管鈣化和血管局部Klotho基因超甲基化,血清IS濃度與血管局部Klotho基因甲基化率密切相關(guān)。本研究旨在以人主動(dòng)脈血管平滑肌細(xì)胞為研究對(duì)象,從細(xì)胞層面探討Klotho基因超甲基化在IS誘導(dǎo)的血管平滑肌細(xì)胞成骨轉(zhuǎn)化中的作用和相關(guān)機(jī)制。方法：體外培養(yǎng)人主動(dòng)脈血管平滑肌細(xì)胞,IS按0、200、500和1000μM的濃度梯度干預(yù)6天,采用茜素紅染色觀察鈣鹽沉積,Real-time PCR和Western blot檢測(cè)a-SMA、OPN、Cbfα1ΟKlotho和不同DNMT的mRNA和蛋白表達(dá)水平,同時(shí)利用焦磷酸測(cè)序方法檢測(cè)HASMC Klotho基因甲基化率。IS1000μM組培養(yǎng)基中加入不同濃度梯度的5-氮雜脫氧胞苷進(jìn)行干預(yù),觀察茜素紅染色、各基因表達(dá)水平和Klotho基因甲基化率的改變。結(jié)果：IS 1000μM組細(xì)胞外基質(zhì)呈橙色,細(xì)胞結(jié)節(jié)處濃染,為鈣鹽沉積染色陽(yáng)性。IS可以下調(diào)HASMC a-SMA mRNA和蛋白表達(dá)水平,上調(diào)OPN和Cbfa1的mRNA和蛋白表達(dá)水平,使HASMC逐漸喪失平滑肌細(xì)胞表型而發(fā)生成骨轉(zhuǎn)化。IS 200、500和1000μM刺激6天可顯著升高HASMC Klotho基因甲基化率(9±1%vs.4±0.7%, P0.01)、(18±1.3 vs.4±0.7%, P0.01)、(41±2%vs.4±0.7%, P0.001)。IS 500和1000gM可顯著下調(diào)HASMC Klotho mRNA和蛋白表達(dá)水平。同時(shí)IS可顯著上調(diào)HASMC DNMT1 mRNA和蛋白表達(dá)水平。5-氮雜脫氧胞苷10μM干預(yù)可減輕IS誘導(dǎo)的細(xì)胞外鈣鹽沉積,上調(diào)a-SMA蛋白表達(dá)水平并下調(diào)Cbfa1蛋白表達(dá)水平,同時(shí)減低HASMC Klotho基因甲基化率(20+1%vs.41±2%,P0.01)、上調(diào)HASMC Klotho蛋白表達(dá)水平,提示HASMC Klotho超甲基化可減輕硫酸吲哚酚誘導(dǎo)的血管平滑肌細(xì)胞成骨轉(zhuǎn)化。結(jié)論：硫酸吲哚酚可誘導(dǎo)血管平滑肌細(xì)胞成骨轉(zhuǎn)化,并可通過(guò)上調(diào)血管平滑肌細(xì)胞DNMT11的活性誘導(dǎo)Kloth o超甲基化,下調(diào)Klotho蛋白表達(dá)水平,阻斷Klotho超甲基化可減輕硫酸吲哚酚誘導(dǎo)的血管平滑肌細(xì)胞成骨轉(zhuǎn)化。第三部分Klotho基因超甲基化在硫酸吲哚酚誘導(dǎo)的尿毒癥大鼠血管鈣化中的作用機(jī)制背景：尿毒癥患者普遍存在血管鈣化和血管局部Klotho基因超甲基化,血清IS濃度與血管局部Klotho基因甲基化率密切相關(guān)。硫酸吲哚酚可誘導(dǎo)血管平滑肌細(xì)胞成骨轉(zhuǎn)化,并可通過(guò)上調(diào)血管平滑肌細(xì)胞DNMT1的活性誘導(dǎo)Klotho超甲基化,下調(diào)Klotho蛋白表達(dá)水平,阻斷Klotho超甲基化可減輕硫酸吲哚酚誘導(dǎo)的血管平滑肌細(xì)胞成骨轉(zhuǎn)化。本研究旨在以尿毒癥大鼠為研究對(duì)象,從體內(nèi)層面探討Klotho基因超甲基化在IS誘導(dǎo)的尿毒癥大鼠血管鈣化中的作用和相關(guān)機(jī)制。方法：采用硫酸吲哚酚聯(lián)合5/6腎切除的方法構(gòu)建尿毒癥大鼠血管鈣化模型,24只SD大鼠采用兩步法行5/6腎切除術(shù),隨機(jī)分為對(duì)照組、IS組和IS+5Aza-2dc組。24周后留取血液和尿液標(biāo)本,大鼠處死后留取胸主動(dòng)脈標(biāo)本。行H.E.染色觀察血管內(nèi)中膜厚度和血管管壁厚度/血管直徑,茜素紅鈣鹽沉積染色評(píng)估血管鈣化,免疫組織化學(xué)染色、Real-time PCR和Western blot評(píng)價(jià)a-SMA、 OPN、 Cbfα1、Klotho和DNMT1基因mRNA和蛋白的表達(dá)水平。同時(shí)利用焦磷酸測(cè)序方法檢測(cè)胸主動(dòng)脈Klotho基因甲基化率和超高效液相色譜檢測(cè)技術(shù)檢測(cè)血清IS濃度。結(jié)果：IS組胸主動(dòng)脈IMT和血管管壁厚度/血管直徑顯著高于對(duì)照組(0.21±0.03mm vs.0.14±0.02mm, P0.05) (0.34±0.19 vs.0.22±0.07, P0.05), 對(duì)照組2例(25%)茜素紅鈣鹽沉積染色陽(yáng)性,IS組8例(100%)陽(yáng)性,IS組陽(yáng)性率顯著高于對(duì)照組(P0.01)。IS組胸主動(dòng)脈a-SMA蛋白表達(dá)水平較對(duì)照組顯著下調(diào),IS組胸主動(dòng)脈Cbfα1蛋白表達(dá)水平較對(duì)照組顯著上調(diào)。IS組胸主動(dòng)脈Klotho甲基化率較對(duì)照組顯著升高(29±5% vs.6±2%,P0.001),IS組胸主動(dòng)脈Klotho蛋白表達(dá)水平較對(duì)照組顯著下調(diào),DNMT1蛋白表達(dá)水平較對(duì)照組顯著上調(diào)。5-氮雜脫氧胞苷干預(yù)后,IS+5-Aza-2dc組胸主動(dòng)脈IMT和血管管壁厚度/血管直徑顯著低于IS組(0.21±0.03 mm vs.0.15±0.05mm, P0.05) (0.34±0.19 vs 0.23±0.09, P0.05),茜素紅鈣鹽沉積染色5例(62.5%)陽(yáng)性,顯著低于IS組(P0.01)。IS+5Aza-2dc組胸主動(dòng)脈a-SMA蛋白表達(dá)水平較IS組顯著上調(diào),Cbfα1蛋白表達(dá)水平較IS組顯著下調(diào),與對(duì)照組無(wú)差異。IS+5Aza-2dc組胸主動(dòng)脈Klotho甲基化率較IS組顯著降低(11±2% vs.29±5%,P0.01),與對(duì)照組無(wú)顯著差異,且Klotho蛋白表達(dá)水平較IS組顯著上調(diào),與對(duì)照組無(wú)差異。結(jié)論：硫酸吲哚酚可誘導(dǎo)尿毒癥大鼠血管鈣化,并可通過(guò)上調(diào)血管局部DNMT11的活性誘導(dǎo)Klotho超甲基化,下調(diào)Klotho蛋白表達(dá)水平,阻斷Klotho超甲基化可減輕硫酸吲哚酚誘導(dǎo)的尿毒癥大鼠血管鈣化。
[Abstract]:The first part background uremic vessel local hypermethylation of Klotho gene and vascular calcification: new research confirmed that human vascular smooth muscle cells are targets of direct action of Klotho, Klotho expression of local vessels involved in the occurrence and development of vascular calcification, but the cause of local vascular Klotho low expression is unclear.DNA methylation in the regulation of gene expression an epigenetic, promoter region CpG island methylation (i.e. 300~3000 BP CpG rich regions are dinucleotide silencing gene expression. This study aims to ESRD patients as the research object, to explore the relationship between the radial artery in patients with ESRD. The local hypermethylation of Klotho gene and vascular calcification method: 2013.1 ~ 2013.12 in the Department of Nephrology Zhongshan Hospital Affiliated to Fudan University ward hospitalization and surgery for arteriovenous fistula in 30 cases of ESRD patients before hemodialysis for uremia group, compared to me 10 cases of hospital cardiac surgery ward underwent coronary artery bypass surgery, sex matched patients as control group, were respectively to obtain informed consent of patients. The same level of radial artery and internal mammary artery were performed in H.E. staining to observe the intima-media thickness and vascular wall thickness / vascular diameter, the deposition of calcium salt staining Alizarin red the assessment of vascular calcification, immunohistochemical evaluation of a-SMA, OPN, Cbf alpha 1, the expression level of Klotho and DNMT1 protein. At the same time using the pyrosequencing method to detect the Klotho gene methylation rate of local vascular examination and detection technology of ultra high performance liquid chromatography to measure the serum concentration of IS in patients with uremia group. Results: the intima-media thickness in patients with uremia group compared with the control group increased significantly (0.68 + 053mm vs.0.18 + 0.13MM, P0.01), vascular wall thickness / vascular diameter was significantly higher than that of the control group (0.34 + 0.19 vs.0.23 + 0.09, P0.01). In 21 cases of uremia group (70%). Pigment red staining, are distributed in the intima, the control group with no occurrence of vascular calcification (P0.01). The local a-SMA vessels, OPN and Cbf alpha 1 staining were mainly distributed in the intima, the positive rate of uremia group alpha alpha -SMA staining was significantly lower than the control group (30% vs.100%, P0.01), the positive rate of OPN alpha 1 and Cbf staining was significantly higher than the control group (87% vs.0%, P0.01) (93% vs.0%, P0.01). Patients with uremia group vascular Klotho gene methylation rate was significantly higher than that of the control group (43.2 + 1.7%, 8.7 + 0.8%, P0.001). The local Klotho vessels, DNMT1 staining was mainly distributed in the intima, positive rate the uremia group Klotho staining was significantly lower than the control group (33.3% vs.100%, P0.01), the positive rate of DNMT1 was significantly higher than that of the control group (70% vs.0%, P0.01). 21 cases of alizarin red staining was positive in ESRD patients with local vascular Klotho methylation rate and serum IS concentration was significantly higher than that of negative staining in 9 cases (41.8. 3.7% vs.29.4 + 1.5%), P0.001 (34.6 + 4.13 + 4.23 pg/m, 29.8 pg/mlP0.001). Further Pearson single factor correlation analysis showed that serum IS concentration in patients with uremia and vascular local Klotho methylation rate was positively correlated (r=0.587, P0.01). Conclusion: uremic patients with widespread vascular calcification and vascular local hypermethylation of Klotho gene Klotho, the local vascular gene is closely related with methyl vascular calcification. Part second of the Klotho gene hypermethylation in vascular smooth muscle cells induced by indoxyl sulfate into the background in the transformation mechanism of bone: IS and ESRD in patients with cardiovascular disease and total mortality, bone cell transdifferentiation and promote vascular calcification induced by vascular smooth muscle cells, but the specific mechanism of IS induced vascular calcification is unclear. The first part of the study that is prevalent in patients with vascular calcification and uremia Local vascular Klotho hypermethylation, serum concentration of IS and vascular Klotho gene methylation rate was closely related. The purpose of this research is to human aortic vascular smooth muscle cells as the research object, to explore the hypermethylation of Klotho gene in osteoblast conversion role and related mechanisms in vascular smooth muscle cells induced by IS from the cell level. Methods: aortic vascular smooth muscle cells cultured in vitro by IS 0200500 concentration gradient and 1000 M intervention for 6 days, using alizarin red staining calcium salt deposition, Real-time PCR and Western blot detection of a-SMA, OPN, Cbf, Klotho and alpha 1 April mRNA and protein expression level of DNMT, while using the pyrosequencing method for detecting HASMC Klotho the methylation rate of.IS1000 gene M were cultured with different concentration gradient in 5- - deoxycitydine intervention, observed by alizarin red staining, the level of gene expression and Klotho gene The methylation rate changes. Results: IS 1000 M group of extracellular matrix orange cell nodules stain for the deposition of calcium salt staining positive.IS can downregulate the level of HASMC a-SMA mRNA and protein expression level, protein expression level of mRNA and upregulation of OPN and Cbfa1, the HASMC gradually lose the phenotype of smooth muscle cell and osteoblast conversion of.IS 200500 and 1000 M stimulation for 6 days can significantly increase the HASMC Klotho gene methylation rate (9 + 1%vs.4 + 0.7%, P0.01), (18 + 1.3 vs.4 + 0.7%, P0.01), (41 + 2%vs.4 + 0.7%, P0.001).IS 500 and 1000gM can significantly lower HASMC Klotho mRNA and protein expression level. At the same time, IS significantly increased HASMC DNMT1 mRNA and protein expression level of.5- aza deoxycytidine 10 M intervention can reduce the extracellular calcium salt deposition induced by IS, expression of a-SMA and down-regulation of Cbfa1 protein expression level of HASMC, while reducing the Klotho gene methylation rate (20+1%v S.41 + 2%, P0.01), HASMC up-regulated the expression level of Klotho protein, suggesting that HASMC Klotho hypermethylation can relieve the vascular smooth muscle cells of indoxyl sulfate induced osteoblast conversion. Conclusion: indoxyl sulfate can induce osteogenic transformation of vascular smooth muscle cells, and vascular smooth muscle cells through upregulation of DNMT11 activity induced by Kloth o methyl and reduce the expression of Klotho protein, blocking Klotho hypermethylation can relieve the vascular smooth muscle cells of indoxyl sulfate induced osteoblast conversion. Part third of the Klotho gene hypermethylation background mechanism of vascular calcification in uremic rats induced by indoxyl sulfate in uremic patients: vascular calcification is a common vascular and local Klotho gene hypermethylation, the concentration of serum IS and vascular local methylation rate of Klotho gene is closely related. Indoxyl sulfate can be transformed into bone induced vascular smooth muscle cells, and can pass DNMT1 up-regulated the activity of vascular smooth muscle cells induced by Klotho hypermethylation, down regulated expression of Klotho protein, blocking Klotho hypermethylation can relieve the vascular smooth muscle cells of indoxyl sulfate induced osteoblast conversion. The purpose of this study was to uremic rats as the research object, to explore the hypermethylation of Klotho gene in vascular calcification in uremic rats induced by IS the role and mechanism of in vivo level. Methods: the vascular calcification in uremic rats model by using the method of indoxyl sulfate combined with 5/6 nephrectomy, 24 SD rats using two step method for 5/6 nephrectomy, were randomly divided into control group, IS group and IS+5Aza-2dc group after.24 weeks of blood and urine samples. The rats were sacrificed for thoracic aortic specimens. H.E. staining was used to observe the intima-media thickness and vascular wall thickness / vascular diameter, red calcium salt deposition alizarin staining was used to assess vascular calcification, immune group PCR and Real-time histochemical staining, Western blot OPN, Cbf a-SMA, alpha 1, the expression level of Klotho and DNMT1 gene mRNA and protein. At the same time using the pyrosequencing method for detection of thoracic aortic Klotho gene methylation rate and serum IS ultra high performance liquid chromatography detection concentration. Results: IS group of thoracic aorta IMT and vascular wall thickness / vascular diameter was significantly higher than the control group (0.21 + 0.03mm vs.0.14 + 0.02mm, P0.05) (0.34 + 0.19 vs.0.22 + 0.07, P0.05), the control group of 2 cases (25%) red calcium salt deposition alizarin staining, IS group of 8 cases (100%) positive, the positive rate of IS group was significantly higher than that of the control group (P0.01) group the expression of.IS a-SMA protein in thoracic aorta significantly lower levels than the control group, IS group of thoracic aortic Cbf alpha 1 expression raised significantly compared to the control group.IS group aortic Klotho methylation rate was significantly higher than that of control group (29 + 5% vs.6 + 2%, P0.001), IS group of chest The expression level of Klotho protein in the aorta than in the control group significantly decreased, the expression level of DNMT1 protein was significantly up-regulated.5- - deoxycitydine intervention group IS+5-Aza-2dc thoracic aortic IMT and vascular wall thickness / vascular diameter was significantly lower than that of IS group (0.21 + 0.03 mm vs.0.15 + 0.05mm, P0.05) (0.34 + 0.19 vs 0.23 + 0.09 P0.05, red), the deposition of calcium alizarin staining in 5 cases (62.5%) were significantly lower than those in group IS (P0.01).IS+5Aza-2dc expression level of a-SMA protein in thoracic aorta group than in IS group significantly increased, Cbf protein expression level of alpha 1 decreased significantly compared with IS group,.IS+5Aza-2dc group and control group had no difference between thoracic aortic Klotho methylation rate is the IS group was significantly lower (11 + 2% vs.29 + 5%, P0.01), and the control group had no significant difference, and the expression level of Klotho protein increased significantly compared with IS group, no difference with the control group. Conclusion: indoxyl sulfate can induce vascular calcification in uremic rats, and It can induce Klotho hypermethylation and down regulate the expression level of Klotho protein by up regulating the activity of local DNMT11, and blocking Klotho hypermethylation can reduce the vascular calcification of indolol induced uremic rats.

【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R692.5

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