姜黄素对碱烧伤诱导的兔眼角膜新生血管抑制作用的实验研究
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摘要
目的探讨姜黄素对碱烧伤诱导的大耳兔眼角膜新生血管(CNV)的影响及其机制。方法采用碱烧伤法制备CNV模型。模型制作成功后,采用数字表法将健康的成年雄性日本大耳兔48只随机平均分为4组,对照组给予二甲基亚砜,实验1组给予40μmol/L姜黄素,实验2组给予80μmol/L姜黄素,实验3组给予160μmol/L姜黄素。右眼分别滴眼相应药物,所有滴眼药物用量均为20μl,4次/d,连续用药14 d。用裂隙灯显微镜观察CNV的生长情况。采用酶联免疫吸附试验检测大耳兔眼碱烧伤2 d、4 d、7 d及14 d后的房水中血管内皮生长因子(VEGF)、4E结合蛋白(4EBP1)因子的蛋白含量;采用逆转录-聚合酶链反应检测眼角膜组织中4EBP1、S6蛋白激酶(P70S6K)、雷帕霉素靶蛋白(mTOR)的信使核糖核酸(mRNA)的相对表达量。组间比较采用两因素重复测量方差分析,当差异有统计学意义时,进一步采用SNK法两两比较。计算Spearman相关系数判断4EBP1与VEGF蛋白之间的相关性。结果大耳兔眼角膜碱烧伤后4 d时,各实验组与对照组的平均CNV面积无统计学差异(F=0.592,P>0.05);眼角膜碱烧伤后7 d、14 d时,则各实验组与对照组平均CNV面积差异有统计学意义(F=27.5,28.64;P<0.05)。大耳兔眼角膜碱烧伤后2 d时,各实验组房水中的4EBP1、VEGF蛋白含量与对照组的差异无统计学意义(F=2.46,3.62;P>0.05)。大耳兔眼角膜碱烧伤后4 d、7 d、14 d时,各实验组房水中的4EBP1、VEGF蛋白含量与对照组相比,差异具有统计学意义(F=10.73,49.15,62.37,17.55,106.61,202.13;P<0.05),且4EBP1与VEGF的蛋白表达呈线性正相关(r=0.969,0.803,0.67,0.972;P<0.05)。大耳兔眼角膜碱烧伤后7 d时,实验1组的角膜组织中mTOR、4EBP1及P70S6K的mRNA相对表达量为(0.73±0.26)、(0.58±0.19)和(0.52±0.29);实验2组的相对表达量分别为(0.48±0.13)、(0.39±0.21)和(0.41±0.18);实验3组的相对表达量分别为(0.36±0.09)、(0.22±0.09)和(0.18±0.07)。大耳兔眼角膜碱烧伤后14 d时,各实验组mTOR、4EBP1和P70S6K的mRNA表达量较眼角膜碱烧伤后7 d时的mRNA表达量降低;且随着姜黄素浓度的增高,mTOR、4EBP1和P70S6K在mRNA水平的相对表达量依次降低。结论姜黄素可通过抑制mTOR信号传导通路降低VEGF蛋白的表达,从而抑制眼角膜碱烧伤后新生血管的生长。
Objective The aim of this study was to investigate the effects and its mechanism of curcumin on corneal neovascularization(CNV) after alkali burn in rabbit corneal. Methods The alkali burn models were established by alkali. After that, forty-eight rabbits were distributed randomly into 4 groups. The rabbits of DMSO group were treated with dimethyl sulfoxide; those of experimental group 1 st were treated with 40 μmol/L curcumin; those of experimental group 2 nd were treated with 80 μmol/L curcumin and those of experimental group 3 rd were treated with 160 μmol/L curcumin. Right eye was dripped with the drug, 1 drop/time, 4 times/day, for 14 days. The corneal neovascularization was observed by the slit-lamp microscopy after alkali burn. The enzyme-linked immunoassay was used to detect VEGF, 4 EBP1 factor of protein content from the aqueous humor of rabitts burn by alkali after 2, 4, 7, and 14 days.The reverse transcription polymerase chain reaction was used to detect relative expression of 4 EBP1-P70 S6 KmT OR factor gene in corneal tissue of rabbits burn by alkali after 7 and 14 days. To compare the two groups,two-factor repeated measurement analysis of variance was used. SNK method was used to compare when the difference was statistically significant. Spearman correlation coefficient was calculated to determine the correlation between 4 EBP1 and VEGF protein. Results The area of CNV among expertmental groups and DMSO group had no significant difference when cornea alkali was burned after 4 days( F = 0. 592,P >0. 05). The area of CNV after cornea alkali burned for 7 days and 14 days had significant difference between them( F = 27. 5,28. 64; P < 0. 05). Additionally,there was no significant difference on the amount of 4 EBP1 and expression of VEGF protein in the aqueous humor( F = 2. 462,3. 617; P > 0. 05). When cornea alkali was burned after 4 d,7 d,14 d,there was significant difference on the amount of 4 EBP1 and expression of VEGF protein in the aqueous humor( F = 10. 734,49. 154,62. 367,17. 552,106. 607,202. 130; P < 0. 05). Line Pearson correlation analysis found that 4 EBP1 in aqueous humor is linear positive correlation with VEGF protein expression( r = 0. 969,0. 803,0. 67,0. 972). The expression of mT OR,4 EBP1,P70 S6 K in corneal tissue at mRNA level on 7 days after alkali burn in experimental group 1 st were( 0. 73 ± 0. 26),( 0. 58 ± 0. 19),( 0. 52 ± 0. 29); those of experimental group 2 nd were( 0. 48 ± 0. 13),( 0. 39 ± 0. 21),( 0. 41 ± 0. 18); those of experimental group 3 rd were( 0. 36 ± 0. 09),( 0. 22 ± 0. 09),( 0. 18 ± 0. 07). The expression of mT OR,4 EBP1,P70 S6 K in corneal tissue at mRNA level after alkali burn for 14 days was lower than that of after alkali burn for 7 days. With the concentration of curcumin increasing,the expression quantity of mT OR,4 EBP1,P70 S6 K in corneal tissue at mRNA level reduced in turn. Conclusion Curcumin might reduce the expression of VEGF by inhibiting mT OR signaling pathways,and thus could inhibit the CNV growth after alkali burn.
Objective The aim of this study was to investigate the effects and its mechanism of curcumin on corneal neovascularization(CNV) after alkali burn in rabbit corneal. Methods The alkali burn models were established by alkali. After that, forty-eight rabbits were distributed randomly into 4 groups. The rabbits of DMSO group were treated with dimethyl sulfoxide; those of experimental group 1 st were treated with 40 μmol/L curcumin; those of experimental group 2 nd were treated with 80 μmol/L curcumin and those of experimental group 3 rd were treated with 160 μmol/L curcumin. Right eye was dripped with the drug, 1 drop/time, 4 times/day, for 14 days. The corneal neovascularization was observed by the slit-lamp microscopy after alkali burn. The enzyme-linked immunoassay was used to detect VEGF, 4 EBP1 factor of protein content from the aqueous humor of rabitts burn by alkali after 2, 4, 7, and 14 days.The reverse transcription polymerase chain reaction was used to detect relative expression of 4 EBP1-P70 S6 KmT OR factor gene in corneal tissue of rabbits burn by alkali after 7 and 14 days. To compare the two groups,two-factor repeated measurement analysis of variance was used. SNK method was used to compare when the difference was statistically significant. Spearman correlation coefficient was calculated to determine the correlation between 4 EBP1 and VEGF protein. Results The area of CNV among expertmental groups and DMSO group had no significant difference when cornea alkali was burned after 4 days( F = 0. 592,P >0. 05). The area of CNV after cornea alkali burned for 7 days and 14 days had significant difference between them( F = 27. 5,28. 64; P < 0. 05). Additionally,there was no significant difference on the amount of 4 EBP1 and expression of VEGF protein in the aqueous humor( F = 2. 462,3. 617; P > 0. 05). When cornea alkali was burned after 4 d,7 d,14 d,there was significant difference on the amount of 4 EBP1 and expression of VEGF protein in the aqueous humor( F = 10. 734,49. 154,62. 367,17. 552,106. 607,202. 130; P < 0. 05). Line Pearson correlation analysis found that 4 EBP1 in aqueous humor is linear positive correlation with VEGF protein expression( r = 0. 969,0. 803,0. 67,0. 972). The expression of mT OR,4 EBP1,P70 S6 K in corneal tissue at mRNA level on 7 days after alkali burn in experimental group 1 st were( 0. 73 ± 0. 26),( 0. 58 ± 0. 19),( 0. 52 ± 0. 29); those of experimental group 2 nd were( 0. 48 ± 0. 13),( 0. 39 ± 0. 21),( 0. 41 ± 0. 18); those of experimental group 3 rd were( 0. 36 ± 0. 09),( 0. 22 ± 0. 09),( 0. 18 ± 0. 07). The expression of mT OR,4 EBP1,P70 S6 K in corneal tissue at mRNA level after alkali burn for 14 days was lower than that of after alkali burn for 7 days. With the concentration of curcumin increasing,the expression quantity of mT OR,4 EBP1,P70 S6 K in corneal tissue at mRNA level reduced in turn. Conclusion Curcumin might reduce the expression of VEGF by inhibiting mT OR signaling pathways,and thus could inhibit the CNV growth after alkali burn.
引文
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[23] Epstein RJ,Stulting RD,Hendricks RL,et al.Corneal neovascularization.Pathogenesis and inhibition[J].Cornea,1987,6(4):250-257.
[24] Cursiefen C,Rummelt C,Kuchle M.Immunohis-tochemical localization of vascular endothelial growth factor,transforming growth factor alpha,and transforming growth factor beta1 in human corneas with neovascularization[J].Cornea,2000,19(4):526-533.
[25] Sarchahi AA,Maimandi A,Tafti AK,et al.Effects of acetylcysteine and dexamethasone on experimental corneal wounds in rabbits[J].Ophthalmic Res,2008,40(1):41-48.
[26] Guidera AC,Luchs JI,Udell IJ.Keratitis,ulceration,and perforation associated with topical nonsteroidal anti-inflammatory drugs[J].Ophthalmology,2001,108(5):936-944.
[27] Kim SW,Ha BJ,Kim EK,et al.The effect of topical bevacizumab on corneal neovascularization[J].Ophthalmology,2008,115(6):e33-e38.
[28] Waisbourd M,Levinger E,Varssano D,et al.High-dose topical bevacizumab for corneal neovascularization[J].Pharmacology,2013,92(5/6):310-314.
[29] Kim EK,Kong SJ,Chung SK.Comparative study of ranibizumab and bevacizumab on corneal neovascularization in rabbits[J].Cornea,2014,33(1):60-64.
[30] Gupta SK,Kumar B,Nag TC,et al.Curcumin prevents experimental diabetic retinopathy in rats through its hypoglycemic,antioxidant,and anti-inflammatory mechanisms[J].J Ocul Pharmacol Ther,2011,27(2):123-130.
[31] 周晶晶,郑昱辰,李明月,等.姜黄素的药理作用研究进展[J].吉林医药学院学报,2016(4):304-307.
[32] Zhao F,Gong Y,Hu Y,et al.Curcumin and its major metabolites inhibit the inflammatory response induced by lipopolysaccharide:translocation of nuclear factor-kappaB as potential target[J].Mol Med Rep,2015,11(4):3087-3093.
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[34] Pescosolido N,Giannotti R,Plateroti AM,et al.Curcumin:therapeutical potential in ophthalmology[J].Planta Med,2014,80(4):249-254.
[35] Gururaj AE,Belakavadi M,Venkatesh DA,et al.Molecular mechanisms of anti-angiogenic effect of curcumin[J].Biochem Biophys Res Commun,2002,297(4):934-942.
[36] 孟崇.姜黄素对原发性肝癌模型大鼠组织VEGF及微血管密度影响研究[J].辽宁中医药大学学报,2017,19(2):21-24.
[37] Kim JS,Choi JS,Chung SK.The effect of curcumin on corneal neovascularization in rabbit eyes[J].Cur Eye Res,2010,35(4):274-280.
[38] 林小俊,谢平,袁冬青,等.姜黄素抑制小鼠脉络膜新生血管的实验研究[J].现代生物医学进展,2014,14(1):52-56,+12.
[39] 陈洪菊,唐彬秩,屈艺,等.mTOR信号通路调节HIF-1α及VEGF[J].生命的化学,2011(6):838-843.
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[2] Zhao F,Gong Y,Hu Y,et al.Curcumin and its major metabolites inhibit the inflammatory response induced by lipopolysaccharide:translocation of nuclear factor-kappaB as potential target[J].Mol Med Rep,2015,11(4):3087-3093.
[3] Subash M,Sheth HG.Rapid,accurate and easy pH assessment in ocular chemical injury[J].J Emer Med,2011,41(3):301.
[4] D′Amato RJ,Loughnan MS,Flynn E,et al.Thalidomide is an inhibitor of angiogenesis[J].Proc Natl Acad Sci USA,1994,91(9):4082-4085.
[5] 周芳,肖启国.TLR-2、TLR-4与大鼠角膜碱烧伤早期炎症反应相关性研究[J].眼科新进展,2007,7(3):1-4.
[6] 王军梅,孙艳,周明明,等.兔角膜碱烧伤后角膜基质注射脐带间充质干细胞的疗效[J].眼科新进展,2016,36(7):622-625.
[7] 吴艳,叶芬,黄振平.不同浓度KH902对兔碱烧伤后角膜新生血管的抑制作用[J].眼科新进展,2016,36(8):720-724.
[8] 杨世琳.角膜碱烧伤相关研究进展[J].中国中医眼科杂志,2006,16(1):60-62.
[9] 张宏,孙勇,安晓,等.干眼与CC趋化因子受体5和CXC趋化因子受体3及其配体介导的炎性反应的关系[J].中华实验眼科杂志,2015,33(7):633-637.
[10] Murphy G,Houbrechts A,Cockett MI,et al.The N-terminal domain of tissue inhibitor of metalloproteinases retains metalloproteinase inhibitory activity[J].Biochemistry,1991,30(33):8097-8102.
[11] Paterson CA,Wells JG,Koklitis PA,et al.Recombinant tissue inhibitor of metalloproteinases type1 suppresses alkali-burn-induced corneal ulceration in rabbits[J].Invest Ophthalmol Vis Sci,1994,35(2) :677-684.
[12] 宋彦华,徐艳春.自由剂与前段烧伤[J].中华医学丛刊,2003,3(1):43-44.
[13] 邱培瑾,姚克,朱丽君,等.大鼠角膜碱烧伤后碱性成纤维细胞生长因子在角膜中的表达及意义[J].眼科研究,2002,20(2):101-104.
[14] He J,Bazan NG,Bazan HE.Alkali-induced corneal stromal melting prevention by a novel platelet-activating factor receptor antagonist[J].Arch Ophthalmol,2006,124(1):70-78.
[15] Brodovsky SC,Mccarty CA,Snibson G,et al.Management of alkali burns:an 11-year retrospective review[J].Ophthalmology,2000,107(10):1829-1835.
[16] 王朋,吴志鸿.角膜碱烧伤的药物治疗研究进展[J].中国急救复苏与灾害医学杂志,2016,11(7):735-738.
[17] Lu P,Li L,Liu G,et al.Opposite roles of CCR2 and CX3CR1 macrophages in alkali-induced corneal neovascularization[J].Cornea,2009,28(5):562-569.
[18] von Marschall Z,Cramer T,Hocker M,et al.Dual mechanism of vascular endothelial growth factor upregulation by hypoxia in human hepatocellular carcinoma[J].Gut,2001,48(1):87-96.
[19] Zhang SX,Ma JX.Ocular neovascularization:Implication of endogenous angiogenic inhibitors and potential therapy[J].Prog Retin Eye Res,2007,26(1):31-37.
[20] Gao G,Li Y,Zhang D,et al.Unbalanced expression of VEGF and PEDF in ischemia-induced retinal neovascularization[J].FEBS letters,2001,489(2/3):270-276.
[21] Hosseini H,Nejabat M.A potential therapeutic strategy for inhibition of corneal neovascularization with new anti-VEGF agents[J].Med Hypotheses,2007,68(4):799-801.
[22] Kim WJ,Jeong HO,Chung SK.The effect of bevacizumab on corneal neovascularization in rabbits[J].Kor J Ophthalmol,2010,24(4):230-236.
[23] Epstein RJ,Stulting RD,Hendricks RL,et al.Corneal neovascularization.Pathogenesis and inhibition[J].Cornea,1987,6(4):250-257.
[24] Cursiefen C,Rummelt C,Kuchle M.Immunohis-tochemical localization of vascular endothelial growth factor,transforming growth factor alpha,and transforming growth factor beta1 in human corneas with neovascularization[J].Cornea,2000,19(4):526-533.
[25] Sarchahi AA,Maimandi A,Tafti AK,et al.Effects of acetylcysteine and dexamethasone on experimental corneal wounds in rabbits[J].Ophthalmic Res,2008,40(1):41-48.
[26] Guidera AC,Luchs JI,Udell IJ.Keratitis,ulceration,and perforation associated with topical nonsteroidal anti-inflammatory drugs[J].Ophthalmology,2001,108(5):936-944.
[27] Kim SW,Ha BJ,Kim EK,et al.The effect of topical bevacizumab on corneal neovascularization[J].Ophthalmology,2008,115(6):e33-e38.
[28] Waisbourd M,Levinger E,Varssano D,et al.High-dose topical bevacizumab for corneal neovascularization[J].Pharmacology,2013,92(5/6):310-314.
[29] Kim EK,Kong SJ,Chung SK.Comparative study of ranibizumab and bevacizumab on corneal neovascularization in rabbits[J].Cornea,2014,33(1):60-64.
[30] Gupta SK,Kumar B,Nag TC,et al.Curcumin prevents experimental diabetic retinopathy in rats through its hypoglycemic,antioxidant,and anti-inflammatory mechanisms[J].J Ocul Pharmacol Ther,2011,27(2):123-130.
[31] 周晶晶,郑昱辰,李明月,等.姜黄素的药理作用研究进展[J].吉林医药学院学报,2016(4):304-307.
[32] Zhao F,Gong Y,Hu Y,et al.Curcumin and its major metabolites inhibit the inflammatory response induced by lipopolysaccharide:translocation of nuclear factor-kappaB as potential target[J].Mol Med Rep,2015,11(4):3087-3093.
[33] 李婧,邢怡桥,贺涛,等.姜黄素对氧诱导的视网膜新生血管形成的影响[J].中华眼底病杂志,2010,26(3):227-230.
[34] Pescosolido N,Giannotti R,Plateroti AM,et al.Curcumin:therapeutical potential in ophthalmology[J].Planta Med,2014,80(4):249-254.
[35] Gururaj AE,Belakavadi M,Venkatesh DA,et al.Molecular mechanisms of anti-angiogenic effect of curcumin[J].Biochem Biophys Res Commun,2002,297(4):934-942.
[36] 孟崇.姜黄素对原发性肝癌模型大鼠组织VEGF及微血管密度影响研究[J].辽宁中医药大学学报,2017,19(2):21-24.
[37] Kim JS,Choi JS,Chung SK.The effect of curcumin on corneal neovascularization in rabbit eyes[J].Cur Eye Res,2010,35(4):274-280.
[38] 林小俊,谢平,袁冬青,等.姜黄素抑制小鼠脉络膜新生血管的实验研究[J].现代生物医学进展,2014,14(1):52-56,+12.
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