Characteristics of amino acid metabolism in myeloid-derived suppressor cells in septic mice / 北京大学学报(医学版)

OBJECTIVE@#To explore the amino acid metabolomics characteristics of myeloid-derived suppressor cells (MDSCs) in mice with sepsis induced by the cecal ligation and puncture (CLP).@*METHODS@#The sepsis mouse model was prepared by CLP, and the mice were randomly divided into a sham operation group (sham group, n = 10) and a CLP model group (n = 10). On the 7th day after the operation, 5 mice were randomly selected from the surviving mice in each group, and the bone marrow MDSCs of the mice were isolated. Bone marrow MDSCs were separated to measure the oxygen consumption rate (OCR) by using Agilent Seahorse XF technology and to detect the contents of intracellular amino acids and oligopeptides through ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) technology. Different metabolites and potential biomarkers were analyzed by univariate statistical analysis and multivariate statistical analysis. The major metabolic pathways were enriched using the small molecular pathway database (SMPDB).@*RESULTS@#The proportion of MDSCs in the bone marrow of CLP group mice (75.53% ± 6.02%) was significantly greater than that of the sham group (43.15%± 7.42%, t = 7.582, P < 0.001), and the basal respiratory rate [(50.03±1.20) pmol/min], maximum respiration rate [(78.07±2.57) pmol/min] and adenosine triphosphate (ATP) production [(25.30±1.21) pmol/min] of MDSCs in the bone marrow of CLP group mice were significantly greater than the basal respiration rate [(34.53±0.96) pmol/min, (t = 17.41, P < 0.001)], maximum respiration rate [(42.57±1.87) pmol/min, (t = 19.33, P < 0.001)], and ATP production [(12.63±0.96) pmol/min, (t = 14.18, P < 0.001)] of sham group. Leucine, threonine, glycine, etc. were potential biomarkers of septic MDSCs (all P < 0.05). The increased amino acids were mainly enriched in metabolic pathways, such as malate-aspartate shuttle, ammonia recovery, alanine metabolism, glutathione metabolism, phenylalanine and tyrosine metabolism, urea cycle, glycine and serine metabolism, β-alanine metabolism, glutamate metabolism, arginine and proline metabolism.@*CONCLUSION@#The enhanced mitochondrial oxidative phosphorylation, malate-aspartate shuttle and alanine metabolism in MDSCs of CLP mice may provide raw materials for mitochondrial aerobic respiration, thereby promoting the immunosuppressive function of MDSCs. Blocking the above metabolic pathways may reduce the risk of secondary infection in sepsis and improve the prognosis.

A preliminary study of amino acid metabolomics using LC-MS/MS to predict the che-motherapeutic response of patients with advanced breast cancer / 中国肿瘤临床

Objective:To investigate the value of amino acid metabolomics in evaluating chemotherapeutic response of patients with ad-vanced breast cancer, the changes in the levels of 32 amino acids in the circulating serum of patients before (baseline) and after the first cycle (prognosis) of chemotherapy were tested. Methods:Seventy-three advanced breast cancer patients with local recurrence and distant metastasis admitted at the Liaoning Cancer Hospital from March 2015 to October 2016 were enrolled. Peripheral blood samples (2 mL) were collected before and after the first cycles of chemotherapy from each patient. Thirty-two amino acids in the se-rum were tested using the ultra-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Patients were catego-rized into the improvement or deterioration groups, based on the first imaging test after 2-4 cycles of chemotherapy. The changes in amino acids levels were analyzed in different prognosis groups. Results:The levels of the 32 amino acids ranged 3-180000 pmol/L. Compared to their baseline levels, both glycine and L-glutamine increased in the improvement group, but decreased in the deteriora-tion group. Sarcosine was significantly reduced in the improvement group, while differences in its levels were not obvious in the deteri-oration group. L-threonine, taurine, iminodiacetic acid, and L-glutamic acid were increased in both groups. Conclusion:Changes in the serum levels of glycine, sarcosine, and the other amino acids before and after the first cycles of chemotherapy can predict chemothera-peutic response in patients with advanced breast cancer. Amino acid metabolomics may become a potential biomarker for predicting the efficacy of chemotherapy earlier than that of imaging tests, and thereby help improve therapeutic strategies for advanced breast cancer.