發(fā)布時(shí)間：2018-02-28 23:04

  本文關(guān)鍵詞： 糖尿病黃斑水腫 康柏西普 二甲雙胍 血-視網(wǎng)膜屏障 VEGF　出處：《天津醫(yī)科大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：目的糖尿病黃斑水腫是成人視力受損的重要原因之一,其發(fā)病機(jī)制主要與血-視網(wǎng)膜屏障受損有關(guān)�？筕EGF藥物玻璃體腔注射已成為治療該病的重要手段之一,但并非所有患者對(duì)該藥物反映良好。二甲雙胍作為一種傳統(tǒng)降糖藥,近年來在抗腫瘤、抗衰老等領(lǐng)域研究頗多。本研究旨在探究康柏西普與二甲雙胍的聯(lián)合應(yīng)用對(duì)視網(wǎng)膜血管內(nèi)皮細(xì)胞的協(xié)同作用及可能機(jī)制,為臨床治療提供理論基礎(chǔ)。方法回顧性分析2016年1月~2016年12月于天津醫(yī)科大學(xué)眼科醫(yī)院因糖尿病黃斑水腫行玻璃體腔注射康柏西普的患者,對(duì)比服用二甲雙胍組與未服用二甲雙胍組視網(wǎng)膜中心凹厚度(CRT)改變情況。體外培養(yǎng)RF/6A,將細(xì)胞分為五個(gè)組:對(duì)照組、VEGF刺激組、VEGF+康柏西普刺激組、VEGF+二甲雙胍刺激組、VEGF+康柏西普+二甲雙胍刺激組。設(shè)置VEGF、康柏西普及二甲雙胍濃度梯度,用1640完全培養(yǎng)基將其稀釋,利用MTT比色法選取藥物最佳濃度及實(shí)驗(yàn)觀測(cè)時(shí)點(diǎn);用MTT細(xì)胞增殖實(shí)驗(yàn)檢測(cè)兩種藥物聯(lián)合應(yīng)用對(duì)VEGF誘導(dǎo)的RF/6A細(xì)胞增殖的影響;通過細(xì)胞劃痕實(shí)驗(yàn)觀察兩種藥物聯(lián)合應(yīng)用對(duì)VEGF誘導(dǎo)的RF/6A細(xì)胞遷移能力的影響;通過FQRT-PCR檢測(cè)藥物作用下RF/6A細(xì)胞血管內(nèi)皮生長(zhǎng)因子受體2(VEGFR2)、蛋白激酶C-α(PKC-α)和蛋白激酶C-β(PKC-β)的基因表達(dá)情況。結(jié)果10例(12眼)患者納入數(shù)據(jù)分析,對(duì)比術(shù)后3月CRT恢復(fù)率,二甲雙胍組明顯優(yōu)于對(duì)照組,差異有統(tǒng)計(jì)學(xué)意義(P0.05)。50ng/ml為VEGF的最佳刺激濃度;2.5ug/ml為康柏西普最佳給藥濃度;2.0mmol/L為二甲雙胍最佳給藥濃度;72h為最佳觀測(cè)時(shí)點(diǎn)。MTT細(xì)胞增殖實(shí)驗(yàn)結(jié)果顯示:與對(duì)照組(0.5136±0.0311)及VEGF刺激組(0.8179±0.0288)相比,干預(yù)組細(xì)胞增殖明顯受到抑制(P0.001);聯(lián)合用藥組(0.2991±0.0323)與單獨(dú)應(yīng)用康柏西普組(0.3408±0.0274)相比,OD值顯著降低(P0.05)。細(xì)胞劃痕實(shí)驗(yàn)結(jié)果顯示:與對(duì)照組相比,VEGF組細(xì)胞遷移率顯著升高(P0.001);與VEGF組相比,干預(yù)組細(xì)胞遷移率顯著降低(P0.05);12h時(shí),聯(lián)合用藥組(0.1085±0.0141)與康柏西普組(0.1324±0.0379)相比,細(xì)胞遷移率顯著降低(P0.05)。FQRT-PCR實(shí)驗(yàn)結(jié)果顯示:與對(duì)照組相比,VEGF組VEGFR2、PKC-α和PKC-β的基因表達(dá)量均顯著升高(P0.01);聯(lián)合用藥組與VEGF組相比,VEGFR2、PKC-α和PKC-β的基因表達(dá)量均顯著降低(P0.05);聯(lián)合用藥組與康柏西普組相比,PKC-α的基因表達(dá)量顯著降低(P0.05)。結(jié)論因糖尿病黃斑水腫行玻璃體腔注射康柏西普的患者,二甲雙胍對(duì)藥效時(shí)間有一定積極作用。聯(lián)合應(yīng)用康柏西普及二甲雙胍,可以抑制VEGF所引起的血管內(nèi)皮細(xì)胞生物學(xué)改變及相關(guān)基因的表達(dá),且作用明顯優(yōu)于單獨(dú)應(yīng)用康柏西普。
[Abstract]:Objective Diabetic macular edema is one of the most important causes of visual impairment in adults, and its pathogenesis is mainly related to the damage of blood-retina barrier. Antidiabetic intravitreal injection of VEGF has become one of the important methods for the treatment of this disease. But not all patients reacted well to the drug. Metformin, as a traditional hypoglycemic drug, has been working on antitumor drugs in recent years. The aim of this study was to explore the synergistic effect and possible mechanism of Compactopril and metformin on retinal vascular endothelial cells (RVEC). Methods from January 2016 to December 2016, the patients with macular edema in Tianjin Medical University were treated with intravitreal injection of Combortopril in the ophthalmology hospital of Tianjin Medical University. The changes of retinal foveal thickness (CRT) were compared between metformin group and non-metformin group. RFR / 6A was cultured in vitro. Compacipe metformin stimulation group. Set up VEGF, Compaq universal metformin concentration gradient, The best concentration and time point were selected by MTT colorimetry, and the effects of two drugs on the proliferation of RF/6A cells induced by VEGF were detected by MTT cell proliferation assay. The effects of combined use of two drugs on the migration of RF/6A cells induced by VEGF were observed by cell scratch assay. FQRT-PCR was used to detect the gene expression of vascular endothelial growth factor receptor (VEGFR2A), protein kinase C- 偽 (PKC- 偽) and protein kinase C- 尾 (PKC- 尾) in RF/6A cells. Results 10 patients (12 eyes) were enrolled in the data analysis, and the recovery rate of CRT was compared on March. Metformin group was superior to control group. The difference was statistically significant (P < 0.05) .50ng / ml was the best stimulating concentration of VEGF. The best concentration of VEGF was 2.5ugr / ml, the best dose of Compactopril was 2.0 mmol / L, the best concentration of metformin was 72 hours. The results of cell proliferation test showed that compared with the control group (0.5136 鹵0.0311) and the VEGF group (0.8179 鹵0.0288), the difference was significant. The cell proliferation was significantly inhibited in the intervention group (P 0.001) and the OD value in the combined treatment group (0.2991 鹵0.0323) was significantly lower than that in the control group (0.3408 鹵0.0274). The cell scratch test showed that the cell migration rate of the VEGF group was significantly higher than that of the control group, and that of the VEGF group was significantly higher than that of the control group. The cell migration rate in the intervention group was significantly lower than that in the control group (0.1085 鹵0.0141) and that in the control group (0.1324 鹵0.0379) at 12h. The results of reverse transcription polymerase chain reaction (RT-PCR) showed that the expression of VEGFR2PKC- 偽 and PKC- 尾 in VEGFR2PKC- 偽 and PKC- 尾 were significantly increased in VEGFR2PKC- 偽 and PKC- 尾, and the expression of PKC- 偽 and PKC- 尾 in VEGFR2PKC- 偽 and PKC- 尾 in combination group were significantly lower than those in VEGF group, and the expression of PKC- 偽 and PKC- 尾 in combination group was significantly lower than that in VEGF group. The expression of PKC- 偽 gene decreased significantly compared with the control group. Conclusion the patients with diabetic macular edema treated by intravitreous injection of Compactopril, and the patients with diabetic macular edema were treated with intravitreous injection of Compactopril, and the expression of PKC- 偽 decreased significantly. Metformin had a positive effect on the time of pharmacodynamics. The combination of Compactyl and metformin could inhibit the biological changes of vascular endothelial cells and the expression of related genes induced by VEGF, and the effect was obviously better than that of Compactopril alone.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R587.2;R774.5

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