糖性白内障相关方法学、病理机制及药物作用研究
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摘要
糖尿病已成为全球流行性疾病,以晶状体混浊为特征的白内障是糖尿病晚期主要的并发症,严重影响患者的生活质量。糖尿病白内障的发病机制不同于普通年龄相关性白内障,主要由微环境中高浓度的葡萄糖引起,而不完全是氧化应激。半乳糖性白内障与糖尿病性白内障具有相似的病理机制,二者合称为“糖性白内障”。晶状体的渗透性膨胀是糖性白内障早期相对可逆的的病理机制,它的发生同时引发了氧化应激及晶体蛋白的翻译后修饰,加速了真性白内障的形成,但是对于每一个病理过程的确切机制目前尚在研究中。
由于糖性白内障发病机制的不明确性及眼科药理的特殊性,糖性白内障的相关机制研究及药物进展相对缓慢。多元醇通路与糖尿病性白内障之间的关系在过去三四十年中倍受关注,研发了一系列醛糖还原酶抑制剂(ARI),动物实验结果显示这些化合物不仅具有抑制糖尿病白内障的作用,而且对糖尿病肾病及神经病变也有类似作用,然而在临床实验中并没有得到满意的疗效,部分化合物出现严重的毒副作用而被迫终止研发。目前唯一在日本上市的羧酸类ARI—依帕司他(EpaIrestat),主要针对糖尿病肾脏并发症。由于缺乏有效的糖性白内障的治疗药物,目前临床上主要依靠手术来解除患者的痛苦。
本论文以糖性白内障方法学建立及抗糖尿病药物的研究为重点,首先优化并建立一系列方法、模型为后续研究做好准备。在ARI体外筛选体系优化中,缩小反应体系于96孔板中进行;结合酶学反应特点,比较加热、冷却、冰冻、酸化及碱化等终止方法,既能够快捷、有效地终止反应,又不至于使酶失活,不断完善ARI的高通量筛选方法。在细胞水平,尝试多种方法对晶状体前囊膜下方单层排列晶状体上皮细胞(LECs)进行原代培养,最终选择组织块培养法建立大鼠、兔、犬及人四种LECs原代培养方法,观察四种细胞的生长特点。在器官水平,采用多种方法完整取出大鼠、兔及犬三种晶状体并尝试建立离体器官培养方法;在此基础上,分别用半乳糖和各种氧化剂诱导大鼠晶状体形成渗透性膨胀模型及氧化性混浊模型。在大鼠半乳糖性白内障模型改良方面,参考国内外半乳糖性白内障模型形成方法,不断调整半乳糖溶液浓度(10～12.5%)及饮用时间,建立经济、快速、简捷的白内障模型形成方法。在硒性白内障模型建立过程中,为了排除性别干扰,同时方便滴眼剂的药物筛选,不断增加大鼠鼠龄,调整亚硒酸钠的剂量,改良硒性白内障模型。同时观察链脲霉素(STZ)高糖大鼠形成糖尿病性白内障的全过程。
在渗透性膨胀相关机制的探讨中,通过形态及生化指标检测确定高半乳糖/葡萄糖可以引起细胞及晶状体发生明显的渗透性膨胀,并在基因水平检测多元醇通路相关蛋白—AR,水分子代谢相关蛋白—水通道蛋白(AQP0、AQP1)及离子代谢相关蛋白—氯离子通道3亚型(Clcn3)、磷酸化糖蛋白(P-gp)的表达,验证晶状体渗透性膨胀是否与多元醇通路、水平衡失调及离子代谢紊乱相关。
此外,运用ARI高通量筛选模型,对大量非定向合成化合物和天然产物进行体外筛选,发现来源于临床的中药复方ZM及天然化合物DG具有一定的AR抑制活性,随后对二者的抗糖性白内障作用进行系统研究。结果显示,ZM和DG在体外均有良好的AR抑制活性,量效关系较好,IC_(50)分别为27.68μg/ml和4.59μmol/L,除此之外ZM还具有一定的抗氧化活性。在器官水平,ZM和DG对50 mM半乳糖诱导的大鼠晶状体渗透性膨胀均有明显的抑制作用。从整体动物结果分析,ZM无论是作为滴眼剂还是灌胃给药对半乳糖性及糖尿病性大鼠白内障都没有明显的延缓作用;DG作为滴眼剂对半乳糖性大鼠白内障物无明显延缓作用,但是口服给予DG可以在一定程度上延缓半乳糖性及糖尿病性大鼠白内障的发生、进展。
通过上述研究,本论文得出以下主要结论:1.采用组织块培养法可以对大鼠、兔、犬及人四种LECs进行原代培养,四种细胞各具特点。2.后囊法、侧囊法及前囊法可分别将大鼠、兔及犬晶状体完整取出并在体外进行器官培养。3.半乳糖和亚硒酸钠/H_2O_2可分别诱导大鼠晶状体形成渗透性膨胀模型和氧化性混浊模型。4.10～12.5%的半乳糖溶液可以诱导21天龄Wistar大鼠形成快速、稳定的半乳糖性白内障.。5.一次性皮下注射亚硒酸钠(20 mmol/kg)可以诱导16天龄雄性Wistar大鼠形成明显的硒性白内障。6.在半乳糖性及糖尿病性大鼠白内障形成过程中,晶状体会出现明显的渗透性膨胀。7.渗透性膨胀的发生伴随着AR、AQP0、AQP1、P-gp及Clcn3 mRNA的异常表达。8.中药复方ZM在体外具有良好的AR抑制活性和拮抗晶状体渗透性膨胀的作用,但在整体水平,滴眼和灌胃给予ZM对半乳糖性及糖尿病性大鼠白内障均没有明显的延缓作用。9.天然化合物DG不仅在体外具有良好的AR抑制活性和拮抗晶状体渗透性膨胀的作用,而且在整体水平,口服给予DG对半乳糖性及糖尿病性大鼠白内障的发生发展有一定的延缓作用,但是作为滴眼剂对半乳糖性白内障的进展无明显延缓作用。
Diabetes has aleady been the global epidemic disease.Cataract,opacification of the lens,is closely associated with diabetes as one of the major late complications.Diabetic cataract has seriously affected the quality of patients' life.Different from the normal age-related cataract,diabetic cataract is mainly caused by high concentration of glucose in body fluid and tissue,rather than oxidative stress in lens.Diabetic cataract and galactosemic cataract are together called "sugar cataract".Lens osmotic expansion is a relatively irreversible pathological period in the early stage of sugar cataract.It triggers the occurrence of oxidative stress and the post-translational modification of lens proteins,accelerates the formation of frank cataract,but the precise pathological mechanism of each stage is not clear.
Because of the uncertainty of sugar cataract mechanisms and the specificity of ophthalmic pharmacology,the investigations of sugar cataract and anti-sugar cataract drugs develop relatively slowly.The relationship of polyol pathway and diabetic cataract has engendered extensive investigations over the last several decades.Many drugs with varying AR-inhibiting efficacy(e.g., sorbinil,tolrestat and zopolrestat) have been synthesized and tested.Initial trials in animal models showed significant protection against diabetic complication.ARI,in addition to preventing diabetic or galactosemic cataract,ameliorate some of the features of diabetic nephropathy and neropathy. However,clinical trials with AR inhibitors have yielded uncertain results,in part due to the high nonspecific toxicity of this class of drugs.And now only AR inhibitor,Epalrestat,appears on the Japanese market,which is mainly used to anti-diabetic nephropathy.Since there is no effective drugs to treat diabetic cataract,most patients rely on surgery to remove the suffering.
In this paper,focus on lens osmotic hypothesis occuring in the early stage of sugar cataract.First of all,optimize and set up a series of sugar cataract associated research methods and models. According to the characters of enzyme reaction,comparing the efficiency of heating,cooling,freezing, acidification and alkalization termination methods to improve the screening methods of ARI.On cellular level,try to establish the primary cultivation methods of lens epithelial cells,which are located below the anterior capsule of lens.On organ level,remove the intact lenses of rat,rabbit and dog with different methods,and establish the organ cultivation method in vitro.On the basis of lens culture,using galactose and sodium selenite/hydrogen peroxide to induce the formation of lens osmotic expansion and oxidative turbidity respectively.Establish economic galactosemic cataract model by continuously adjusting the time and concentration of galactose solution(10-12.5%).In order to rule out the gender interference and facilitate the administration of eye drops,gradually increasing the age of newborn rats and regulating the concentration of sodium selenite to improve the selenic cataract model in vivo.At the same time,study the formation of STZ-induced diabetic cataract in vivo.
In the investigation of lens osmotic expansion,morphological changes and biochemical results showed that high concentration of galactose/glucose could induce the osmotic swelling of rat lenses. And also demonstrated the up or down regulations of AR(polyol pathway associated protein),AQP0, AQP1(water metabolism associated proteins),Clcn3 and P-gp(ion metabolism associated proteins) occured during the formation of osmotic expansion.
Besides,180 non-orient synthetic compounds and 44 natural extracts are screened using AR inhibitor high-throughput screening system in vitro,and then investigate the anti sugar cataract of two active samples,one is Chinese traditional medicine recipe,ZM and another is a natural compound, DG.They both have good dose-response relationship,the IC_(50) values of ZM and DG to AR are calculated 27.68μg/ml and 4.59μM respectively.In the lens culture test,ZM and DG can partly prevent the lens osmotic expansion induced by 50 mM galactose.In animal experiments,ZM has no effects to delay or inhibit the progression of galactosemic or diabetic cataract either as eye drops or given orally.As eye drops,DG also has no effect to obviously attenuate the progression of galactosemic cataract.When given orally,DG can partly delay the formation of galactosemic and diabetic cataract.
The present study can be mainly concluded that:1.Using tissue explant technique,we has established the primary culture methods of LECs from rat,rabbit,dog and human.2.The intact lenses of rat,rabbit and dog can be removed gently by post-capsule,anterior-capsule or side-capsule and cultivated in vitro.3.Galactose and sodium selenite/hydrogen peroxide can induce rat lenses to form osmotic expansion or oxidative turbidity respectively.4.Galactosemic cataract can be induced on 21-day old rats by drinking 10-12.5%galactose solution.5.Selenic cataract can be induced on 16-day old rats by one-time subcutaneous injection of sodium selenite solution(20μmol/kg).6.Lens osmotic swelling occurs during the formation of galactosemic cataract and diabetic cataract in vivo.7.With lens osmotic expansion,AR,AQP0,AQP1,P-gp and Clcn3 have been up-regulated or down-regulated in mRNA levels.8.The ZM has strong AR inhibitory activity,and can partly prevent the lens osmotic expansion in vitro;but it can't delay the progression of galactosemic and diabetic cataract in vivo.9.A natural compound,DG possesses a significant AR inhibitory activity,it can partly prevent lens osmotic expansion induced by galactose in vitro;and also obviously delay the onset and slow the progression of galactosemic and diabetic cataract when given orally in vivo.
由于糖性白内障发病机制的不明确性及眼科药理的特殊性,糖性白内障的相关机制研究及药物进展相对缓慢。多元醇通路与糖尿病性白内障之间的关系在过去三四十年中倍受关注,研发了一系列醛糖还原酶抑制剂(ARI),动物实验结果显示这些化合物不仅具有抑制糖尿病白内障的作用,而且对糖尿病肾病及神经病变也有类似作用,然而在临床实验中并没有得到满意的疗效,部分化合物出现严重的毒副作用而被迫终止研发。目前唯一在日本上市的羧酸类ARI—依帕司他(EpaIrestat),主要针对糖尿病肾脏并发症。由于缺乏有效的糖性白内障的治疗药物,目前临床上主要依靠手术来解除患者的痛苦。
本论文以糖性白内障方法学建立及抗糖尿病药物的研究为重点,首先优化并建立一系列方法、模型为后续研究做好准备。在ARI体外筛选体系优化中,缩小反应体系于96孔板中进行;结合酶学反应特点,比较加热、冷却、冰冻、酸化及碱化等终止方法,既能够快捷、有效地终止反应,又不至于使酶失活,不断完善ARI的高通量筛选方法。在细胞水平,尝试多种方法对晶状体前囊膜下方单层排列晶状体上皮细胞(LECs)进行原代培养,最终选择组织块培养法建立大鼠、兔、犬及人四种LECs原代培养方法,观察四种细胞的生长特点。在器官水平,采用多种方法完整取出大鼠、兔及犬三种晶状体并尝试建立离体器官培养方法;在此基础上,分别用半乳糖和各种氧化剂诱导大鼠晶状体形成渗透性膨胀模型及氧化性混浊模型。在大鼠半乳糖性白内障模型改良方面,参考国内外半乳糖性白内障模型形成方法,不断调整半乳糖溶液浓度(10～12.5%)及饮用时间,建立经济、快速、简捷的白内障模型形成方法。在硒性白内障模型建立过程中,为了排除性别干扰,同时方便滴眼剂的药物筛选,不断增加大鼠鼠龄,调整亚硒酸钠的剂量,改良硒性白内障模型。同时观察链脲霉素(STZ)高糖大鼠形成糖尿病性白内障的全过程。
在渗透性膨胀相关机制的探讨中,通过形态及生化指标检测确定高半乳糖/葡萄糖可以引起细胞及晶状体发生明显的渗透性膨胀,并在基因水平检测多元醇通路相关蛋白—AR,水分子代谢相关蛋白—水通道蛋白(AQP0、AQP1)及离子代谢相关蛋白—氯离子通道3亚型(Clcn3)、磷酸化糖蛋白(P-gp)的表达,验证晶状体渗透性膨胀是否与多元醇通路、水平衡失调及离子代谢紊乱相关。
此外,运用ARI高通量筛选模型,对大量非定向合成化合物和天然产物进行体外筛选,发现来源于临床的中药复方ZM及天然化合物DG具有一定的AR抑制活性,随后对二者的抗糖性白内障作用进行系统研究。结果显示,ZM和DG在体外均有良好的AR抑制活性,量效关系较好,IC_(50)分别为27.68μg/ml和4.59μmol/L,除此之外ZM还具有一定的抗氧化活性。在器官水平,ZM和DG对50 mM半乳糖诱导的大鼠晶状体渗透性膨胀均有明显的抑制作用。从整体动物结果分析,ZM无论是作为滴眼剂还是灌胃给药对半乳糖性及糖尿病性大鼠白内障都没有明显的延缓作用;DG作为滴眼剂对半乳糖性大鼠白内障物无明显延缓作用,但是口服给予DG可以在一定程度上延缓半乳糖性及糖尿病性大鼠白内障的发生、进展。
通过上述研究,本论文得出以下主要结论:1.采用组织块培养法可以对大鼠、兔、犬及人四种LECs进行原代培养,四种细胞各具特点。2.后囊法、侧囊法及前囊法可分别将大鼠、兔及犬晶状体完整取出并在体外进行器官培养。3.半乳糖和亚硒酸钠/H_2O_2可分别诱导大鼠晶状体形成渗透性膨胀模型和氧化性混浊模型。4.10～12.5%的半乳糖溶液可以诱导21天龄Wistar大鼠形成快速、稳定的半乳糖性白内障.。5.一次性皮下注射亚硒酸钠(20 mmol/kg)可以诱导16天龄雄性Wistar大鼠形成明显的硒性白内障。6.在半乳糖性及糖尿病性大鼠白内障形成过程中,晶状体会出现明显的渗透性膨胀。7.渗透性膨胀的发生伴随着AR、AQP0、AQP1、P-gp及Clcn3 mRNA的异常表达。8.中药复方ZM在体外具有良好的AR抑制活性和拮抗晶状体渗透性膨胀的作用,但在整体水平,滴眼和灌胃给予ZM对半乳糖性及糖尿病性大鼠白内障均没有明显的延缓作用。9.天然化合物DG不仅在体外具有良好的AR抑制活性和拮抗晶状体渗透性膨胀的作用,而且在整体水平,口服给予DG对半乳糖性及糖尿病性大鼠白内障的发生发展有一定的延缓作用,但是作为滴眼剂对半乳糖性白内障的进展无明显延缓作用。
Diabetes has aleady been the global epidemic disease.Cataract,opacification of the lens,is closely associated with diabetes as one of the major late complications.Diabetic cataract has seriously affected the quality of patients' life.Different from the normal age-related cataract,diabetic cataract is mainly caused by high concentration of glucose in body fluid and tissue,rather than oxidative stress in lens.Diabetic cataract and galactosemic cataract are together called "sugar cataract".Lens osmotic expansion is a relatively irreversible pathological period in the early stage of sugar cataract.It triggers the occurrence of oxidative stress and the post-translational modification of lens proteins,accelerates the formation of frank cataract,but the precise pathological mechanism of each stage is not clear.
Because of the uncertainty of sugar cataract mechanisms and the specificity of ophthalmic pharmacology,the investigations of sugar cataract and anti-sugar cataract drugs develop relatively slowly.The relationship of polyol pathway and diabetic cataract has engendered extensive investigations over the last several decades.Many drugs with varying AR-inhibiting efficacy(e.g., sorbinil,tolrestat and zopolrestat) have been synthesized and tested.Initial trials in animal models showed significant protection against diabetic complication.ARI,in addition to preventing diabetic or galactosemic cataract,ameliorate some of the features of diabetic nephropathy and neropathy. However,clinical trials with AR inhibitors have yielded uncertain results,in part due to the high nonspecific toxicity of this class of drugs.And now only AR inhibitor,Epalrestat,appears on the Japanese market,which is mainly used to anti-diabetic nephropathy.Since there is no effective drugs to treat diabetic cataract,most patients rely on surgery to remove the suffering.
In this paper,focus on lens osmotic hypothesis occuring in the early stage of sugar cataract.First of all,optimize and set up a series of sugar cataract associated research methods and models. According to the characters of enzyme reaction,comparing the efficiency of heating,cooling,freezing, acidification and alkalization termination methods to improve the screening methods of ARI.On cellular level,try to establish the primary cultivation methods of lens epithelial cells,which are located below the anterior capsule of lens.On organ level,remove the intact lenses of rat,rabbit and dog with different methods,and establish the organ cultivation method in vitro.On the basis of lens culture,using galactose and sodium selenite/hydrogen peroxide to induce the formation of lens osmotic expansion and oxidative turbidity respectively.Establish economic galactosemic cataract model by continuously adjusting the time and concentration of galactose solution(10-12.5%).In order to rule out the gender interference and facilitate the administration of eye drops,gradually increasing the age of newborn rats and regulating the concentration of sodium selenite to improve the selenic cataract model in vivo.At the same time,study the formation of STZ-induced diabetic cataract in vivo.
In the investigation of lens osmotic expansion,morphological changes and biochemical results showed that high concentration of galactose/glucose could induce the osmotic swelling of rat lenses. And also demonstrated the up or down regulations of AR(polyol pathway associated protein),AQP0, AQP1(water metabolism associated proteins),Clcn3 and P-gp(ion metabolism associated proteins) occured during the formation of osmotic expansion.
Besides,180 non-orient synthetic compounds and 44 natural extracts are screened using AR inhibitor high-throughput screening system in vitro,and then investigate the anti sugar cataract of two active samples,one is Chinese traditional medicine recipe,ZM and another is a natural compound, DG.They both have good dose-response relationship,the IC_(50) values of ZM and DG to AR are calculated 27.68μg/ml and 4.59μM respectively.In the lens culture test,ZM and DG can partly prevent the lens osmotic expansion induced by 50 mM galactose.In animal experiments,ZM has no effects to delay or inhibit the progression of galactosemic or diabetic cataract either as eye drops or given orally.As eye drops,DG also has no effect to obviously attenuate the progression of galactosemic cataract.When given orally,DG can partly delay the formation of galactosemic and diabetic cataract.
The present study can be mainly concluded that:1.Using tissue explant technique,we has established the primary culture methods of LECs from rat,rabbit,dog and human.2.The intact lenses of rat,rabbit and dog can be removed gently by post-capsule,anterior-capsule or side-capsule and cultivated in vitro.3.Galactose and sodium selenite/hydrogen peroxide can induce rat lenses to form osmotic expansion or oxidative turbidity respectively.4.Galactosemic cataract can be induced on 21-day old rats by drinking 10-12.5%galactose solution.5.Selenic cataract can be induced on 16-day old rats by one-time subcutaneous injection of sodium selenite solution(20μmol/kg).6.Lens osmotic swelling occurs during the formation of galactosemic cataract and diabetic cataract in vivo.7.With lens osmotic expansion,AR,AQP0,AQP1,P-gp and Clcn3 have been up-regulated or down-regulated in mRNA levels.8.The ZM has strong AR inhibitory activity,and can partly prevent the lens osmotic expansion in vitro;but it can't delay the progression of galactosemic and diabetic cataract in vivo.9.A natural compound,DG possesses a significant AR inhibitory activity,it can partly prevent lens osmotic expansion induced by galactose in vitro;and also obviously delay the onset and slow the progression of galactosemic and diabetic cataract when given orally in vivo.
引文
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[7]Suryanarayana P,Krishnaswamy K,Reddy GB:Effect of curcumin on galactose-induced cataractogenesis in rats.Molecular vision 2003,9:223-230.
[8]Huang R,Shi F,Lei T,Song Y,Hughes CL,Liu G:Effect of the isoflavone genistein against galactose-induced cataracts in rats.Experimental biology and medicine (Maywood,NJ 2007,232(1):118-125.
[9]Suryanarayana P,Saraswat M,Mrudula T,Krishna TP,Krishnaswamy K,Reddy GB:Curcumin and turmeric delay streptozotocin-induced diabetic cataract in rats.Investigative ophthalmology & visual science 2005,46(6):2092-2099.
[10]Hayman S,Kinoshita JH:Isolation and Properties of Lens Aldose Reductase.The Journal of biological chemistry 1965,240:877-882.
[11]Ueda H,Kuroiwa E,Tachibana Y,Kawanishi K,Ayala F,Moriyasu M:Aldose reductase inhibitors from the leaves of Myrciaria dubia (H.B.& K.)McVaugh.Phytomedicine 2004,11(7-8):652-656.
[12]Sato S,Kador PF:NADPH-dependent reductases of the dog lens.Experimental eye research 1990,50(6):629-634.
[13]Haider N,Joshi S,Gupta SK:Lens aldose reductase inhibiting potential of some indigenous plants.Journal of ethnopharmacology 2003,86(1):113-116.
[14]Da Settimo F,Primofiore G,La Motta C,Salerno S,Novellino E,Greco G,Lavecchia A,Laneri S,Boldrini E:Spirohydantoin derivatives of thiopyrano[2,3-b]pyridin-4(4H)-one as potent in vitro and in vivo aldose reductase inhibitors.Bioorganic & medicinal chemistry 2005,13(2):491-499.
[15]Lee AY,Chung SK,Chung SS:Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens.Proceedings of the National Academy of Sciences of the United States of America 1995,92(7):2780-2784.
[16]Takamura Y,Kubo E,Tsuzuki S,Akagi Y:Apoptotic cell death in the lens epithelium of rat sugar cataract.Experimental eye research 2003,77(1):51-57.
[17]Cho HJ,Yoo J:Rho activation is required for transforming growth factor-beta-induced epithelial-mesenchymal transition in lens epithelial cells.Cell biology international 2007,31(10):1225-1230.
[18]Liu Y,Liu X,Zhang T,Luna C,Liton PB,Gonzalez P:Cytoprotective effects of proteasome beta5 subunit overexpression in lens epithelial cells.Molecular vision 2007,13:31-38.
[19]Kim YS,Kim NH,Lee SW,Lee YM,Jang DS,Kim JS:Effect of protocatechualdehyde on receptor for advanced glycation end products and TGF-betal expression in human lens epithelial cells cultured under diabetic conditions and on lens opacity in streptozotocin-diabetic rats.European journal of pharmacology 2007,569(3):171-179.
[20]Secchi EF,Lizak MJ,Sato S,Kador PF:3-Fluoro-3-deoxy-D-galactose:a new probe for studies on sugar cataract.Current eye research 1999,18(4):277-282.
[21]Chen Z,John M,Subramanian S,Chen H,Carper D:17Beta-estradiol confers a protective effect against transforming growth factor-beta2-induced cataracts in female but not male lenses.Experimental eye research 2004,78(1):67-74.
[22]Moghaddam MS,Kumar PA,Reddy GB,Ghole VS:Effect of Diabecon on sugar-induced lens opacity in organ culture:mechanism of action.Journal of ethnopharmacology 2005,97(2):397-403.
[23]Cheng Q,Gerald Robison W,Samuel Zigler J:Geranylgeranyl pyrophosphate counteracts the cataractogenic effect of lovastatin on cultured rat lenses.Experimental eye research 2002,75(5):603-609.
[24]Nakajima E,Walkup RD,Ma H,Shearer TR,Azuma M:Low activity by the calpain system in primate lenses causes resistance to calcium-induced proteolysis.Experimental eye research 2006,83(3):593-601.
[25]Devamanoharan PS,Henein M,Ali AH,Varma SD:Attenuation of sugar cataract by ethyl pyruvate.Molecular and cellular biochemistry 1999,200(1-2):103-109.
[26]Zatechka DS,Jr.,Kador PF,Garcia-Castineiras S,Lou MF:Diabetes can alter the signal transduction pathways in the lens of rats.Diabetes 2003,52(4):1014-1022.
[27]Yagci R,Aydin B,Erdurmus M,Karadag R,Gurel A,Durmus M,Yigitoglu R:Use of melatonin to prevent selenite-induced cataract formation in rat eyes.Current eye research 2006,31(10):845-850.
[28]Fris M,Tessem MB,Saether O,Midelfart A:Biochemical changes in selenite cataract model measured by high-resolution MAS H NMR spectroscopy.Acta ophthalmologica Scandinavica 2006,84(5):684-692.
[29]Shearer TR,Ma H,Fukiage C,Azuma M:Selenite nuclear cataract:review of the model.Molecular vision 1997,3:8.
[30]Ostadalova I,Babicky A,Obenberger J:Cataract induced by administration of a single dose of sodium selenite to suckling rats.Experientia 1978,34(2):222-223.
[31]Javadzadeh A,Ghorbanihaghjo A,Bonyadi S,Rashidi MR,Mesgari M,Rashtchizadeh N,Argani H:Preventive effect of onion juice on selenite-induced experimental cataract.Indian journal of ophthalmology 2009,57(3):185-189.
[1]Takamura Y,Kubo E,Tsuzuki S,Akagi Y:Apoptotic cell death in the lens epithelium of rat sugar cataract.Experimental eye research 2003,77(1):51-57.
[2]Suryanarayana P,Krishnaswamy K,Reddy GB:Effect of curcumin on galactose-induced cataractogenesis in rats.Molecular vision 2003,9:223-230.
[3]Mulhern ML,Madson CJ,Kador PF,Randazzo J,Shinohara T:Cellular osmolytes reduce lens epithelial cell death and alleviate cataract formation in galactosemic rats.Molecular vision 2007,13:1397-1405.
[4]Ajani EO,Salako AA,Sharlie PD,Akinleye WA,Adeoye AO,Salau BA,Adebawo OO:Chemopreventive and remediation effect of Hydrocotyl bonariensis Comm.Ex Lam (Apiaceae)leave extract in galactose-induced cataract.Journal of ethnopharmacology 2009,123(1):134-142.
[5]Anil Kumar P,Bhanuprakash Reddy G:Focus on molecules:aldose reductase.Experimental eye research 2007,85(6):739-740.
[6]Hayman S,Kinoshita JH:Isolation and Properties of Lens Aldose Reductase.The Journal of biological chemistry 1965,240:877-882.
[7]Kyselova Z,Stefek M,Bauer V:Pharmacological prevention of diabetic cataract.Journal of diabetes and its complications 2004,18(2):129-140.
[8]Chung YS,Choi YH,Lee SJ,Choi SA,Lee JH,Kim H,Hong EK:Water extract of Aralia elata prevents cataractogenesis in vitro and in vivo.Journal of ethnopharmacology 2005,101(l-3):49-54.
[9]Zhang Z,FerrARI JD,Brooks HL,Brisc I,Burg MB:Expression of osmotic stress-related genes in tissues of normal and hyposmotic rats.American journal of physiology 2003,285(4):F688-693.
[10]Kuper C,Steinert D,Fraek ML,Beck FX,Neuhofer W:EGF receptor signaling is involved in expression of osmoprotective TonEBP target gene aldose reductase under hypertonic conditions.American journal of physiology 2009,296(5):F1100-1108.
[11]Fazlina N,Maha A,Zarina AL,Hamidah A,Zulkifli SZ,Cheong SK,Ainoon O,Jamal R,Hamidah NH:Assessment of P-gp and MRP1 activities using MultiDrugQuant Assay Kit:a preliminary study of correlation between protein expressions and its functional activities in newly diagnosed acute leukaemia patients.The Malaysian journal of pathology 2008,30(2):87-93.
[12]Idriss HT,Hannun YA,Boulpaep E,Basavappa S:Regulation of volume-activated chloride channels by P-glycoprotein:phosphorylation has the final say! The Journal of physiology 2000,524 Pt 3:629-636.
[13]Sardini A.Amey JS,Weylandt KH.Nobles M,Valverde MA,Higgins CF:Cell volume regulation and swelling-activated chloride channels.Biochimica et biophysica acta 2003.1618(2):153-162.
[14]Marin M,Poret A,Maillet G,Leboulenger F,Le Foil F:Regulation of volume-sensitive Clchannels in multi-drug resistant MCF7 cells.Biochemical and biophysical research communications 2005,334(4):1266-1278.
[15]Guan YY,Wang GL,Zhou JG:The C1C-3 CI-channel in cell volume regulation,proliferation and apoptosis in vascular smooth muscle cells.Trends in pharmacological sciences 2006,27(6):290-296.
[16]Nilius B,Eggermont J,Voets T,Droogmans G:Volume-activated CI-channels.General pharmacology 1996,27(7):1131-1140.
[17]Vanoye CG,Altenberg GA,Reuss L:P-glycoprotein is not a swelling-activated CI-channel;possible role as a CI-channel regulator.The Journal of physiology 1997,502 (Pt 2):249-258.
[18]Merrirnan-Smith BR,Young MA,Jacobs MD,Kistler J,Donaldson PJ:Molecular identification of P-glycoprotein:a role in lens circulation? Investigative ophthalmology & visual science 2002,43(9):3008-3015.
[19]Miyazawa T,Kubo E,Takamura Y,Akagi Y:Up-regulation of P-glycoprotein expression by osmotic stress in rat sugar cataract.Experimental eye research 2007,84(2):246-253.
[20]Dunia I,Smit JJ,van der Valk MA,Bloemendal H,Borst P,Benedetti EL:Human multidrug resistance 3-P-glycoprotein expression in transgenic mice induces lens membrane alterations leading to cataract.The Journal of cell biology 1996,132(4):701-716.
[21]Preston GM,Agre P:Isolation of the cDNA for erythrocyte integral membrane protein of 28 kilodaltons:member of an ancient channel family.Proceedings of the National Academy of Sciences of the United States of America 1991,88(24):! 1110-11114.
[22]King LS,Yasui M:Aquaporins and disease:lessons from mice to humans.Trends in endocrinology and metabolism:TEM 2002,13(8):355-360.
[23]Hamann S,Zeuthen T,La Cour M,Nagelhus EA,Ottersen OP,Agre P,Nielsen S:Aquaporins in complex tissues:distribution of aquaporins 1-5 in human and rat eye.The American journal of physiology 1998,274(5 Pt 1):C1332-1345.
[24]Verkman AS:Role of aquaporin water channels in eye function.Experimental eye research 2003,76(2):137-143.
[25]Verkman AS,Ruiz-Ederra J.Levin MH:Functions of aquaporins in the eye.Progress in retinal and eye research 2008,27(4):420-433.
[26]Okamura T,Miyoshi I,Takahashi K,Mototani Y,Ishigaki S,Kon Y,Kasai N:Bilateral congenital cataracts result from a gain-of-function mutation in the gene for aquaporin-0 in mice.Genomics 2003,81(4):361-368.
[27]Varadaraj K,Kumari SS,Patil R,Wax MB,Mathias RT:Functional characterization of a human aquaporin 0 mutation that leads to a congenital dominant lens cataract.Experimental eye research 2008,87(1):9-21.
[28]Boassa D,Yool AJ:A fascinating tail:cGMP activation of aquaporin-1 ion channels.Trends in pharmacological sciences 2002,23(12):558-562.
[1]晶状体解剖、生化、组织形态学[M]//何守志.晶状体病学.北京:人民卫生出版社,2004:3-11.
[2]Cho HJ,Yoo J.Rho activation is required for transforming growth factor-beta-induced epithelial-mesenchymal transition in lens epithelial cells[J].Cell Biol Int,2007,31(10):1225-30.
[3]Anil Kumar P,Bhanuprakash Reddy G.Focus on Molecules:Aldose reductase[J].Exp Eye Res,2007,85(6):739-40.
[4]Steuber H,Heine A,Klebe G.Structural and thermodynamic study on aldose reductase:nitro-substituted inhibitors with strong enthalpic binding contribution[J].J Mol Biol,2007,368(3):618-38.
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[6]Iwata K,NishinakaT,Matsuno K,et al.The activity of aldose reductase is elevated in diabetic mouse heart[J].J Pharmacol Sci,2007,103(4):408-16.
[7]Srivastava SK,Ramana KV,Bhatnagar A.Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options[J].Endocr Rev,2005,26(3):380-92.
[8]Kubo E,Urakami T,Fatma N,et al.Polyol pathway-dependent osmotic and oxidative stresses in aldose reductase-mediated apoptosis in human lens epithelial cells:role of AOP2[J],Biochem Biophys Res Commun,2004,314(4):1050-6.
[9]Liu W H,Huang H Q,DENG Y H,et al.Effects of berberine on renal function,oxidative stress and renal aldose reductase in rats with diabetic nephropathy[J].Chinese Pharmacological Bulletin,2008,24(7):955-9.
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[11]Suryanarayana P,Krishnaswamy K,Reddy GB.Effect of curcumin on Gal-induced cataractogenesis in rats[J].Mol Vis,2003(9):223-30
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[13]Suryanarayana P,Saraswat M,Mrudula T,et al.Curcumin and turmeric delay streptozotocin-induced diabetic cataract in rats[J].Invest Ophthalmol Vis Sci,2005,46(6): 2092-9.
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[17]Merriman-Smith BR,Young MA,Jacobs MD,et al.Molecular identification of P-glycoprotein:a role in lens circulation? [J],Invest Ophthalmol Vis Sci,2002,43(9):3008-015.
[18]Zhang JJ,Jacob TJ.ATP-activated chloride channel inhibited by an antibody to P glycoprotein [J].Am J Physiol,1994,267(4 Pt 1):C1095-102.
[19]Kubo E,Singh DP,Akagi Y.Gene expression profiling of diabetic and galactosaemic cataractous rat lens by microarray analysis [J].Diabetologia,2005,48(4):790-8.
[20]Miyazawa T,Kubo E,Takamura Y,et al.Up-regulation of P-glycoprotein expression by osmotic stress in rat sugar cataract [J].Exp Eye Res,2007,84(2):246-53.
[21]Verkman AS,Mitra AK.Structure and function of aquaporin water channels [J].Am J Physiol Renal Physiol,2000 Jan;278(1):F13-28.
[22]Verkman AS.Role of aquaporin water channels in eye function [J].Exp Eye Res,2003,76(2):137-43.
[23]King LS,Yasui M.Aquaporins and disease:lessons from mice to humans [J].Trends Endocrinol Metab,2002,13(8):355-60.
[24]Berry V,Francis P,Kaushal S,et al.Missense mutations in MIP underlie autosomal dominant 'polymorphic' and lamellar cataracts linked to 12q [J].Nat Genet,2000,25(1):15-7.
[25]Stamer WD,Snyder RW,Smith BL,et al.Localization of aquaporin CHIP in the human eye:implications in the pathogenesis of glaucoma and other disorders of ocular fluid balance [J].Invest Ophthalmol Vis Sci,1994,35(11):3867-72.
[2]Kanth VR,Lavanya K,Srinivas J:Elevated Expression of indoleamine 2,3-dioxygenase (IDO)and accumulation of kynurenic acid in the pathogenesis of STZ-induced diabetic cataract in Wistar rats.Current eye research 2009,34(4):274-281.
[3]Srivastava SK,Ramana KV,Bhatnagar A:Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options.Endocrine reviews 2005,26(3):380-392.
[4]Anil Kumar P,Bhanuprakash Reddy G:Focus on molecules:aldose reductase.Experimental eye research 2007,85(6):739-740.
[5]Kyselova Z,Stefek M,Bauer V:Pharmacological prevention of diabetic cataract.Journal of diabetes and its complications 2004,18(2):129-140.
[6]Matsuoka K,Sakamoto N,Akanuma Y,Hotta N,Shichiri M,Toyota T,Oka Y,Kawamori R,Shigeta Y:A long-term effect of Epalrestat on motor conduction velocity of diabetic patients:ARI-Diabetes Complications Trial (ADCT).Diabetes research and clinical practice 2007,77 Suppl 1.S263-268.
[7]Suryanarayana P,Krishnaswamy K,Reddy GB:Effect of curcumin on galactose-induced cataractogenesis in rats.Molecular vision 2003,9:223-230.
[8]Huang R,Shi F,Lei T,Song Y,Hughes CL,Liu G:Effect of the isoflavone genistein against galactose-induced cataracts in rats.Experimental biology and medicine (Maywood,NJ 2007,232(1):118-125.
[9]Suryanarayana P,Saraswat M,Mrudula T,Krishna TP,Krishnaswamy K,Reddy GB:Curcumin and turmeric delay streptozotocin-induced diabetic cataract in rats.Investigative ophthalmology & visual science 2005,46(6):2092-2099.
[10]Hayman S,Kinoshita JH:Isolation and Properties of Lens Aldose Reductase.The Journal of biological chemistry 1965,240:877-882.
[11]Ueda H,Kuroiwa E,Tachibana Y,Kawanishi K,Ayala F,Moriyasu M:Aldose reductase inhibitors from the leaves of Myrciaria dubia (H.B.& K.)McVaugh.Phytomedicine 2004,11(7-8):652-656.
[12]Sato S,Kador PF:NADPH-dependent reductases of the dog lens.Experimental eye research 1990,50(6):629-634.
[13]Haider N,Joshi S,Gupta SK:Lens aldose reductase inhibiting potential of some indigenous plants.Journal of ethnopharmacology 2003,86(1):113-116.
[14]Da Settimo F,Primofiore G,La Motta C,Salerno S,Novellino E,Greco G,Lavecchia A,Laneri S,Boldrini E:Spirohydantoin derivatives of thiopyrano[2,3-b]pyridin-4(4H)-one as potent in vitro and in vivo aldose reductase inhibitors.Bioorganic & medicinal chemistry 2005,13(2):491-499.
[15]Lee AY,Chung SK,Chung SS:Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens.Proceedings of the National Academy of Sciences of the United States of America 1995,92(7):2780-2784.
[16]Takamura Y,Kubo E,Tsuzuki S,Akagi Y:Apoptotic cell death in the lens epithelium of rat sugar cataract.Experimental eye research 2003,77(1):51-57.
[17]Cho HJ,Yoo J:Rho activation is required for transforming growth factor-beta-induced epithelial-mesenchymal transition in lens epithelial cells.Cell biology international 2007,31(10):1225-1230.
[18]Liu Y,Liu X,Zhang T,Luna C,Liton PB,Gonzalez P:Cytoprotective effects of proteasome beta5 subunit overexpression in lens epithelial cells.Molecular vision 2007,13:31-38.
[19]Kim YS,Kim NH,Lee SW,Lee YM,Jang DS,Kim JS:Effect of protocatechualdehyde on receptor for advanced glycation end products and TGF-betal expression in human lens epithelial cells cultured under diabetic conditions and on lens opacity in streptozotocin-diabetic rats.European journal of pharmacology 2007,569(3):171-179.
[20]Secchi EF,Lizak MJ,Sato S,Kador PF:3-Fluoro-3-deoxy-D-galactose:a new probe for studies on sugar cataract.Current eye research 1999,18(4):277-282.
[21]Chen Z,John M,Subramanian S,Chen H,Carper D:17Beta-estradiol confers a protective effect against transforming growth factor-beta2-induced cataracts in female but not male lenses.Experimental eye research 2004,78(1):67-74.
[22]Moghaddam MS,Kumar PA,Reddy GB,Ghole VS:Effect of Diabecon on sugar-induced lens opacity in organ culture:mechanism of action.Journal of ethnopharmacology 2005,97(2):397-403.
[23]Cheng Q,Gerald Robison W,Samuel Zigler J:Geranylgeranyl pyrophosphate counteracts the cataractogenic effect of lovastatin on cultured rat lenses.Experimental eye research 2002,75(5):603-609.
[24]Nakajima E,Walkup RD,Ma H,Shearer TR,Azuma M:Low activity by the calpain system in primate lenses causes resistance to calcium-induced proteolysis.Experimental eye research 2006,83(3):593-601.
[25]Devamanoharan PS,Henein M,Ali AH,Varma SD:Attenuation of sugar cataract by ethyl pyruvate.Molecular and cellular biochemistry 1999,200(1-2):103-109.
[26]Zatechka DS,Jr.,Kador PF,Garcia-Castineiras S,Lou MF:Diabetes can alter the signal transduction pathways in the lens of rats.Diabetes 2003,52(4):1014-1022.
[27]Yagci R,Aydin B,Erdurmus M,Karadag R,Gurel A,Durmus M,Yigitoglu R:Use of melatonin to prevent selenite-induced cataract formation in rat eyes.Current eye research 2006,31(10):845-850.
[28]Fris M,Tessem MB,Saether O,Midelfart A:Biochemical changes in selenite cataract model measured by high-resolution MAS H NMR spectroscopy.Acta ophthalmologica Scandinavica 2006,84(5):684-692.
[29]Shearer TR,Ma H,Fukiage C,Azuma M:Selenite nuclear cataract:review of the model.Molecular vision 1997,3:8.
[30]Ostadalova I,Babicky A,Obenberger J:Cataract induced by administration of a single dose of sodium selenite to suckling rats.Experientia 1978,34(2):222-223.
[31]Javadzadeh A,Ghorbanihaghjo A,Bonyadi S,Rashidi MR,Mesgari M,Rashtchizadeh N,Argani H:Preventive effect of onion juice on selenite-induced experimental cataract.Indian journal of ophthalmology 2009,57(3):185-189.
[1]Takamura Y,Kubo E,Tsuzuki S,Akagi Y:Apoptotic cell death in the lens epithelium of rat sugar cataract.Experimental eye research 2003,77(1):51-57.
[2]Suryanarayana P,Krishnaswamy K,Reddy GB:Effect of curcumin on galactose-induced cataractogenesis in rats.Molecular vision 2003,9:223-230.
[3]Mulhern ML,Madson CJ,Kador PF,Randazzo J,Shinohara T:Cellular osmolytes reduce lens epithelial cell death and alleviate cataract formation in galactosemic rats.Molecular vision 2007,13:1397-1405.
[4]Ajani EO,Salako AA,Sharlie PD,Akinleye WA,Adeoye AO,Salau BA,Adebawo OO:Chemopreventive and remediation effect of Hydrocotyl bonariensis Comm.Ex Lam (Apiaceae)leave extract in galactose-induced cataract.Journal of ethnopharmacology 2009,123(1):134-142.
[5]Anil Kumar P,Bhanuprakash Reddy G:Focus on molecules:aldose reductase.Experimental eye research 2007,85(6):739-740.
[6]Hayman S,Kinoshita JH:Isolation and Properties of Lens Aldose Reductase.The Journal of biological chemistry 1965,240:877-882.
[7]Kyselova Z,Stefek M,Bauer V:Pharmacological prevention of diabetic cataract.Journal of diabetes and its complications 2004,18(2):129-140.
[8]Chung YS,Choi YH,Lee SJ,Choi SA,Lee JH,Kim H,Hong EK:Water extract of Aralia elata prevents cataractogenesis in vitro and in vivo.Journal of ethnopharmacology 2005,101(l-3):49-54.
[9]Zhang Z,FerrARI JD,Brooks HL,Brisc I,Burg MB:Expression of osmotic stress-related genes in tissues of normal and hyposmotic rats.American journal of physiology 2003,285(4):F688-693.
[10]Kuper C,Steinert D,Fraek ML,Beck FX,Neuhofer W:EGF receptor signaling is involved in expression of osmoprotective TonEBP target gene aldose reductase under hypertonic conditions.American journal of physiology 2009,296(5):F1100-1108.
[11]Fazlina N,Maha A,Zarina AL,Hamidah A,Zulkifli SZ,Cheong SK,Ainoon O,Jamal R,Hamidah NH:Assessment of P-gp and MRP1 activities using MultiDrugQuant Assay Kit:a preliminary study of correlation between protein expressions and its functional activities in newly diagnosed acute leukaemia patients.The Malaysian journal of pathology 2008,30(2):87-93.
[12]Idriss HT,Hannun YA,Boulpaep E,Basavappa S:Regulation of volume-activated chloride channels by P-glycoprotein:phosphorylation has the final say! The Journal of physiology 2000,524 Pt 3:629-636.
[13]Sardini A.Amey JS,Weylandt KH.Nobles M,Valverde MA,Higgins CF:Cell volume regulation and swelling-activated chloride channels.Biochimica et biophysica acta 2003.1618(2):153-162.
[14]Marin M,Poret A,Maillet G,Leboulenger F,Le Foil F:Regulation of volume-sensitive Clchannels in multi-drug resistant MCF7 cells.Biochemical and biophysical research communications 2005,334(4):1266-1278.
[15]Guan YY,Wang GL,Zhou JG:The C1C-3 CI-channel in cell volume regulation,proliferation and apoptosis in vascular smooth muscle cells.Trends in pharmacological sciences 2006,27(6):290-296.
[16]Nilius B,Eggermont J,Voets T,Droogmans G:Volume-activated CI-channels.General pharmacology 1996,27(7):1131-1140.
[17]Vanoye CG,Altenberg GA,Reuss L:P-glycoprotein is not a swelling-activated CI-channel;possible role as a CI-channel regulator.The Journal of physiology 1997,502 (Pt 2):249-258.
[18]Merrirnan-Smith BR,Young MA,Jacobs MD,Kistler J,Donaldson PJ:Molecular identification of P-glycoprotein:a role in lens circulation? Investigative ophthalmology & visual science 2002,43(9):3008-3015.
[19]Miyazawa T,Kubo E,Takamura Y,Akagi Y:Up-regulation of P-glycoprotein expression by osmotic stress in rat sugar cataract.Experimental eye research 2007,84(2):246-253.
[20]Dunia I,Smit JJ,van der Valk MA,Bloemendal H,Borst P,Benedetti EL:Human multidrug resistance 3-P-glycoprotein expression in transgenic mice induces lens membrane alterations leading to cataract.The Journal of cell biology 1996,132(4):701-716.
[21]Preston GM,Agre P:Isolation of the cDNA for erythrocyte integral membrane protein of 28 kilodaltons:member of an ancient channel family.Proceedings of the National Academy of Sciences of the United States of America 1991,88(24):! 1110-11114.
[22]King LS,Yasui M:Aquaporins and disease:lessons from mice to humans.Trends in endocrinology and metabolism:TEM 2002,13(8):355-360.
[23]Hamann S,Zeuthen T,La Cour M,Nagelhus EA,Ottersen OP,Agre P,Nielsen S:Aquaporins in complex tissues:distribution of aquaporins 1-5 in human and rat eye.The American journal of physiology 1998,274(5 Pt 1):C1332-1345.
[24]Verkman AS:Role of aquaporin water channels in eye function.Experimental eye research 2003,76(2):137-143.
[25]Verkman AS,Ruiz-Ederra J.Levin MH:Functions of aquaporins in the eye.Progress in retinal and eye research 2008,27(4):420-433.
[26]Okamura T,Miyoshi I,Takahashi K,Mototani Y,Ishigaki S,Kon Y,Kasai N:Bilateral congenital cataracts result from a gain-of-function mutation in the gene for aquaporin-0 in mice.Genomics 2003,81(4):361-368.
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