Multi-omics analyses of red blood cell reveal antioxidation mechanisms associated with hemolytic toxicity of gossypol
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Chaohua Tang1,2, Qingshi Meng1,2, Kai Zhang1,2, Tengfei Zhan1,2, Qingyu Zhao1,2, Sheng Zhang3 and Junmin Zhang1,2
1State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China
2Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China, Ministry of Agriculture, Beijing, China
3Institute of Biotechnology, Cornell University, Ithaca, NY, USA
Junmin Zhang, email: [email protected]
Keywords: gossypol, red blood cell, hemolytic toxicity, metabolomics, proteomics
Received: July 21, 2017 Accepted: September 21, 2017 Published: October 10, 2017
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.
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