A Metabolomic and Lipidomic Serum Signature from Nonhuman Primates Administered with a Promising Radiation Countermeasure, Gamma-Tocotrienol
A Metabolomic and Lipidomic Serum Signature from Nonhuman Primates Administered with a Promising Radiation Countermeasure, Gamma-Tocotrienol
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DOI：
10.3390/ijms19010079
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发表时间：
2018-01-01
影响因子：
5.6
通讯作者：
Singh, Vijay K.
中科院分区：
文献类型：
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作者：
Cheema, Amrita K.;Mehta, Khyati Y.;Singh, Vijay K.
在过去的60年里，针对急性辐射综合征(ARS)的辐射对策的发展一直在进行中，导致了多种辐射对策的确定。然而，到目前为止，只有两种生长因子(Neupogen和Neulasta)被美国食品和药物管理局(US FDA)批准用于缓解造血急性辐射综合征(H-ARS)。FDA还没有批准ARS的放射防护剂。γ-生育三烯醇(GT3)已被证明在小鼠和非人灵长类动物(NHP)模型中具有辐射防护效果。目前，GT3正处于高级开发阶段，作为一种辐射防护剂，可以在辐射暴露前给予。我们正在使用NHP模型研究这种药物的安全性和有效性。在这项研究中，我们使用超性能液相色谱(UPLC)四极杆飞行时间质谱仪(QTOF-MS)分析了服用GT3的NHP血清样本中整体代谢和脂组的变化。我们的研究，使用12个NHP，表明代谢产物的变化仅在GT3给药后24小时表现出来。此外，代谢变化与抗氧化剂生物利用度的短暂增加有关，抗氧化剂包括乳酸和胆酸以及抗炎代谢物3脱氧维生素D3和二十二碳六烯酸。综上所述，我们的结果表明，对NHP给予GT3会引起代谢变化，这将为对抗辐射损伤提供整体优势。这项初步评估还强调了代谢组学和脂类组学在确定GT3辐射防护效果所涉及的潜在生理机制方面的作用。
The development of radiation countermeasures for acute radiation syndrome (ARS) has been underway for the past six decades, leading to the identification of multiple classes of radiation countermeasures. However, to date, only two growth factors (Neupogen and Neulasta) have been approved by the United States Food and Drug Administration (US FDA) for the mitigation of hematopoietic acute radiation syndrome (H-ARS). No radioprotector for ARS has been approved by the FDA yet. Gamma-tocotrienol (GT3) has been demonstrated to have radioprotective efficacy in murine as well as nonhuman primate (NHP) models. Currently, GT3 is under advanced development as a radioprotector that can be administered prior to radiation exposure. We are studying this agent for its safety profile and efficacy using the NHP model. In this study, we analyzed global metabolomic and lipidomic changes using ultra-performance liquid chromatography (UPLC) quadrupole time-of-flight mass spectrometry (QTOF-MS) in serum samples of NHPs administered GT3. Our study, using 12 NHPs, demonstrates that alterations in metabolites manifest only 24 h after GT3 administration. Furthermore, metabolic changes are associated with transient increase in the bioavailability of antioxidants, including lactic acid and cholic acid and anti-inflammatory metabolites 3 deoxyvitamin D3, and docosahexaenoic acid. Taken together, our results show that the administration of GT3 to NHPs causes metabolic shifts that would provide an overall advantage to combat radiation injury. This initial assessment also highlights the utility of metabolomics and lipidomics to determine the underlying physiological mechanisms involved in the radioprotective efficacy of GT3.