Orally active multi-functional antioxidants delay cataract formation in streptozotocin (type 1) diabetic and gamma-irradiated rats.
Orally active multi-functional antioxidants delay cataract formation in streptozotocin (type 1) diabetic and gamma-irradiated rats.
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DOI：
10.1371/journal.pone.0018980
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发表时间：
2011-04-26
期刊：
影响因子：
3.7
通讯作者：
Kador PF
中科院分区：
文献类型：
--
作者：
Randazzo J;Zhang P;Makita J;Blessing K;Kador PF
糖尿病相关性白内障是一个世界性的健康问题，其进展与氧化应激和氧化还原活性金属的积累有关。由于人类年龄相关性白内障没有特定的动物模型，因此必须使用多种动物模型来评价可能延迟和/或预防白内障形成的潜在疗法。进行了概念验证研究，以评估4-（5-羟基嘧啶-2-基）-N，N-二甲基-3，5-二氧哌嗪-1-磺酰胺（化合物4）和4-（5-羟基-4，6-二甲氧基嘧啶-2-基）-N，N-二甲基-3，5-二氧代哌嗪-1-磺酰胺（化合物8），可独立螯合氧化还原金属和淬灭自由基的多功能抗氧化剂，它们延缓糖尿病“糖”白内障和伽马辐射诱发的白内障的进展的能力。在15戈伊的全头部照射之前，选择的Long Evans大鼠组接受含有化合物4或8的饮食，或单次腹膜内注射泛酰巯基乙胺（一种辐射防护剂）。与未处理的辐射大鼠相比，用泛硫乙胺、4和8处理分别延迟了4、47和38天的初始透镜变化，并分别延迟了23、53和58天的后囊下混浊的平均形成。在第二项研究中，向选定组的糖尿病Sprague道利大鼠施用含有化合物4、8或醛糖还原酶抑制剂AL 1576的食物。正如预期，AL 1576治疗通过抑制透镜中山梨醇的形成来预防白内障。然而，与未处理的大鼠相比，化合物4和8分别延迟空泡形成20天和12天，并且分别延迟皮质性白内障形成8天和3天，而不减少豆状山梨醇。使用体外透镜培养物在30 mM木糖中模拟糖尿病“糖”白内障形成，蛋白质印迹证实多功能抗氧化剂减少内质网应激。多功能抗氧化剂在两种不同大鼠模型中延迟白内障形成。这些研究提供了一个概念的证据，即可以开发一种集中于减少氧化应激而不是白内障发生的特定机制的一般白内障治疗。
Age-related cataract is a worldwide health care problem whose progression has been linked to oxidative stress and the accumulation of redox-active metals. Since there is no specific animal model for human age-related cataract, multiple animal models must be used to evaluate potential therapies that may delay and/or prevent cataract formation. Proof of concept studies were conducted to evaluate 4-(5-hydroxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 4) and 4-(5-hydroxy-4,6-dimethoxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 8), multi-functional antioxidants that can independently chelate redox metals and quench free radicals, on their ability to delay the progression of diabetic “sugar” cataracts and gamma radiation-induced cataracts. Prior to 15 Gy of whole head irradiation, select groups of Long Evans rats received either diet containing compound 4 or 8, or a single i.p. injection of panthethine, a radioprotective agent. Compared to untreated, irradiated rats, treatment with pantethine, 4 and 8 delayed initial lens changes by 4, 47, and 38 days, respectively, and the average formation of posterior subcapsular opacities by 23, 53 and 58 days, respectively. In the second study, select groups of diabetic Sprague Dawley rats were administered chow containing compounds 4, 8 or the aldose reductase inhibitor AL1576. As anticipated, treatment with AL1576 prevented cataract by inhibiting sorbitol formation in the lens. However, compared to untreated rats, compounds 4 and 8 delayed vacuole formation by 20 days and 12 days, respectively, and cortical cataract formation by 8 and 3 days, respectively, without reducing lenticular sorbitol. Using in vitro lens culture in 30 mM xylose to model diabetic “sugar” cataract formation, western blots confirmed that multi-functional antioxidants reduced endoplasmic reticulum stress. Multi-functional antioxidants delayed cataract formation in two diverse rat models. These studies provide a proof of concept that a general cataract treatment focused on reducing oxidative stress instead of a specific mechanism of cataractogenesis can be developed.
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影响因子：
3.4
作者：
Clark, JI;Livesey, JC;Steele, JE
通讯作者：
Steele, JE
影响因子：
3.4
作者：
Chan, Alfred W. H.;Ho, Ye-shih;Chung, Stephen S. M.
通讯作者：
Chung, Stephen S. M.
影响因子：
64.8
作者：
KINOSHITA, JH;DIKMAK, E;MEROLA, LO
通讯作者：
MEROLA, LO
影响因子：
3.4
作者：
Kador, PF;Inoue, J;Sato, S
通讯作者：
Sato, S
DOI：
10.1016/0006-291x(83)91366-9
发表时间：
1983-01-01
影响因子：
3.1
作者：
BUCHER, JR;TIEN, M;AUST, SD
通讯作者：
AUST, SD