Glycation-mediated protein crosslinking and stiffening in mouse lenses are inhibited by carboxitin in vitro.
Glycation-mediated protein crosslinking and stiffening in mouse lenses are inhibited by carboxitin in vitro.
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卡波西汀在体外抑制小鼠晶状体中糖基化介导的蛋白质交联和硬化。
DOI：
10.1007/s10719-020-09961-9
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发表时间：
2021-06
影响因子：
3
通讯作者：
Nagaraj RH
中科院分区：
文献类型：
--
作者：
Nandi SK;Rankenberg J;Rakete S;Nahomi RB;Glomb MA;Linetsky MD;Nagaraj RH
晶状体中的蛋白质几乎没有变化，因此在衰老过程中逐渐积累化学修饰。羰基和氧化应激相互复杂地联系在一起，主导着这种修饰。氧化应激导致谷胱甘肽（GSH）的损失和抗坏血酸的降解；这反过来导致高活性二羰基化合物的形成，二羰基化合物与蛋白质反应形成晚期糖基化终产物（AGEs）。AGEs的形成导致蛋白质的交联和聚集，从而导致晶状体老化和白内障的形成。为了抑制AGE的形成，我们开发了一种连接谷胱甘肽二酯和巯基胍的二硫化合物，并将其命名为carboxitin。用碳西汀培养的牛晶状体器官显示晶状体核中谷胱甘肽和巯基胍的含量较高。carboxtin抑制赤藓糖介导的小鼠晶状体蛋白交联、AGE的形成和3-脱氧苏酮的形成，3-脱氧苏酮是人晶状体中抗坏血酸衍生的AGE的主要前体。carboxtin抑制糖基化介导的器官培养小鼠晶状体硬度增加，采用压缩机械应变测量。向晶状体输送碳西丁可增加谷胱甘肽水平，捕获二羰基化合物并抑制AGE的形成。碳西汀的这些特性可以用来开发一种治疗AGEs的形成和硬度的增加，从而导致老化的晶状体老花眼。
Proteins in the eye lens have negligible turnover and therefore progressively accumulate chemical modifications during aging. Carbonyls and oxidative stresses, which are intricately linked to one another, predominantly drive such modifications. Oxidative stress leads to the loss of glutathione (GSH) and ascorbate degradation; this in turn leads to the formation of highly reactive dicarbonyl compounds that react with proteins to form advanced glycation end products (AGEs). The formation of AGEs leads to the crosslinking and aggregation of proteins contributing to lens aging and cataract formation. To inhibit AGE formation, we developed a disulfide compound linking GSH diester and mercaptoethylguanidine, and we named it carboxitin. Bovine lens organ cultured with carboxitin showed higher levels of GSH and mercaptoethylguanidine in the lens nucleus. Carboxitin inhibited erythrulose-mediated mouse lens protein crosslinking, AGE formation and the formation of 3-deoxythreosone, a major ascorbate-derived AGE precursor in the human lens. Carboxitin inhibited the glycation-mediated increase in stiffness in organ-cultured mouse lenses measured using compressive mechanical strain. Delivery of carboxitin into the lens increases GSH levels, traps dicarbonyl compounds and inhibits AGE formation. These properties of carboxitin could be exploited to develop a therapy against the formation of AGEs and the increase in stiffness that causes presbyopia in aging lenses.
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影响因子：
3.5
作者：
Lederer, MO;Klaiber, RG
通讯作者：
Klaiber, RG
影响因子：
1.2
作者：
Cheng, Catherine;Gokhin, David S.;Fowler, Velia M.
通讯作者：
Fowler, Velia M.
影响因子：
4.4
作者：
Hains, Peter G.;Truscott, Roger J. W.
通讯作者：
Truscott, Roger J. W.
影响因子：
4.8
作者：
Biemel, KM;Friedl, DA;Lederer, MO
通讯作者：
Lederer, MO
影响因子：
--
作者：
Chang D;Zhang X;Rong S;Sha Q;Liu P;Han T;Pan H
通讯作者：
Pan H