Multi-omics analyses of red blood cell reveal antioxidation mechanisms associated with hemolytic toxicity of gossypol.
Multi-omics analyses of red blood cell reveal antioxidation mechanisms associated with hemolytic toxicity of gossypol.
复制标题
红细胞的多组学分析揭示了与棉酚溶血毒性相关的抗氧化机制
DOI：
10.18632/oncotarget.21779
复制
发表时间：
2017-11-28
期刊：
影响因子：
--
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Tang C;Meng Q;Zhang K;Zhan T;Zhao Q;Zhang S;Zhang J
棉酚是一种抗增生性药物，由于其溶血毒性，用途有限。在本研究中，观察到用棉酚处理的奶牛有加速溶血的现象。用比较代谢组学方法获得红细胞(RBC)对治疗的反应途径，并通过平行的基于iTRAQ的蛋白质组学分析和酶活性测定进行交叉验证。我们发现棉酚处理显著激活了磷酸戊糖途径(PPP)，增加了核糖-5-磷酸的关键产物，增加了6-磷酸葡萄糖酸脱氢酶、黄素还原酶和核糖-磷酸焦磷酸激酶等几种关键酶的丰度和活性。同时，观察到糖酵解代谢降低，因为棉酚组许多糖酵解的输入代谢物减少，而其远端代谢物没有变化，同时磷酸丙糖异构酶的丰度降低，催化几个远端糖酵解步骤的酶的丰度增加。氧化还原途径也受到了显著的影响，我们发现随着其催化产物半胱氨酸的增加，黄素还原酶底物谷胱甘肽二硫键减少，谷胱甘肽还原酶活性增加，谷胱甘肽S转移酶的丰度和活性增加。我们的结果表明，RBC的糖酵解、PPP和氧化还原途径都参与了RBC对棉酚溶血毒性的反应。
Gossypol is an antiproliferative drug with limited use due to its hemolytic toxicity. In this study, accelerated hemolysis was observed in the cows treated with gossypol. Comparative metabolomics were used to gain responsive pathways in the red blood cell (RBC) to the treatment, which were crossly validated by parallel iTRAQ-based proteomic analysis and enzyme activity assay. We found that gossypol treatment appeared to considerably activate pentose phosphate pathway (PPP) with an increased key product of ribose-5-phosphate and the increased abundance and activity of several key enzymes such as 6-phosphogluconate dehydrogenase, flavin reductase, and ribose-phosphate pyrophesphokinase. Meanwhile, a decreased glycolysis metabolism was observed, as many input metabolites of glycolysis were reduced in the gossypol group, whereas its distal metabolites were unchanged, along with decreased abundance of triosephosphate isomerase and increased abundance of enzymes catalyzing several distal glycolytic steps. Oxidative reduction pathways were also remarkably affected as we found a decreased substrate of flavin reductase, glutathione disulfide, increased glutathione reductase activity, and increased abundance and activity of glutathione S-transferase with the increase of its catalytic product, cysteine. Our results demonstrated that glycolysis, PPP, and oxidative reduction pathways of RBC were all involved in RBC’s response to the hemolytic toxicity of gossypol.
登录
查看更多内容
影响因子：
4.3
作者：
El-Sharaky, A. S.;Wahby, M. M.;El-Shahawy, I. N.
通讯作者：
El-Shahawy, I. N.
影响因子：
3.5
作者：
Mena, H;Santos, JEP;Calhoun, MC
通讯作者：
Calhoun, MC
影响因子：
2.9
作者：
PERCY, AK;SCHMELL, E;LENNARZ, WJ
通讯作者：
LENNARZ, WJ
影响因子：
2
作者：
SMITH, FH;CLAWSON, AJ
通讯作者：
CLAWSON, AJ
影响因子：
6.1
作者：
Gao, Minghui;Cheung, K. L.;Kong, S. K.
通讯作者：
Kong, S. K.