A Metabolomic and Lipidomic Serum Signature from Nonhuman Primates Administered with a Promising Radiation Countermeasure, Gamma-Tocotrienol

Abstract

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.

Tocotrienol-Rich Fraction (TRF) Improves the Viability of Wild-Type Saccharomyces cerevisiae in the Initial Stationary Phase

“…Although there are no documented findings of the effect of tocotrienol on S. cerevisiae, tocotrienols have been tested on many other organisms. A recent study reported how γ-tocotrienol counter radiation injury by instigating metabolic shifts (Cheema et al 2017). Another study reported δ-tocotrienol causes cell cycle arrest in G1 and G2/M phase simultaneously, leading to an anti-prostate cancer activity (Sato et al 2017).…”

Plasma Derived Exosomal Biomarkers of Exposure to Ionizing Radiation in Nonhuman Primates

“…Plasma samples were prepared as described previously [ 37 ]. Briefly, 25 µL of NHP plasma was mixed with 75 µL of 40% isopropanol +25% methanol +35% water containing internal standards (4-nitrobenzoic acid and debrisoquine).…”

“…Untargeted metabolomics and lipidomics data was acquired as previously described for plasma [ 37 ] and exosomes [ 11 ]. Raw MS data were pre-processed using XCMS (a web-based platform to process untargeted metabolomic data, Scripps Research Institute, La Jolla, CA, USA) in “R.” Intensities were normalized to internal standards and for exosome samples, exosome concentration.…”

Citrulline, A Potential Biomarker of Radiation-Induced Small Intestine Damage

“…2 In some experiments the dose that caused the collapse of the GI system was 6-10 Gy. 10 While some researchers believe that the losing of intestinal crypt cells and breakdown of the mucosal barrier occurs between 5-12Gy. 11 Moreover, from the experimental data of the monkeys listed in Table 1, it can be seen that if different observation time points are selected, different conclusions will be obtained.…”