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Metabonomics analysis of drought resistance of wheat seedlings induced by β-aminobutyric acid-modified chitooligosaccharide derivative.
Yin, X, Liu, S, Qin, Y, Xing, R, Li, K, Yu, C, Chen, X, Li, P
Carbohydrate polymers. 2021;:118437
Abstract
Chitooligosaccharide grafted with β-aminobutyric acid based on the idea of bioactive molecular splicing was prepared, and the differences in drought resistance activity before and after grafting were compared. The mechanism was investigated by comparing the differences of the derivative with the Control and Drought about metabolomes. The results showed that the expected derivative was successfully synthesized, named COS-BABA, and had better drought resistance-inducing activity than the raw materials. We suggest that COS-BABA induced drought resistance through second messenger-induced activation of signaling pathways related to traumatic acid and indol-3-lactic acid, which enhanced nucleic acid metabolism to accumulate nucleotides and decreased some amino acids to facilitate protein synthesis. These proteins are regulated to strengthen photosynthesis, resulting in the promotion of carbohydrate metabolism. The accumulation of unsaturated fatty acids stabilized the cell membrane structure and prevented nonstomatal water dissipation. This study provides ideas for the development of more effective drought resistance inducers.
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Loss of SETD2 Induces a Metabolic Switch in Renal Cell Carcinoma Cell Lines toward Enhanced Oxidative Phosphorylation.
Liu, J, Hanavan, PD, Kras, K, Ruiz, YW, Castle, EP, Lake, DF, Chen, X, O'Brien, D, Luo, H, Robertson, KD, et al
Journal of proteome research. 2019;(1):331-340
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Abstract
SETD2, a histone H3 lysine trimethyltransferase, is frequently inactivated and associated with recurrence of clear cell renal cell carcinoma (ccRCC). However, the impact of SETD2 loss on metabolic alterations in ccRCC is still unclear. In this study, SETD2 null isogenic 38E/38F clones derived from 786-O cells were generated by zinc finger nucleases, and subsequent metabolic, genomic, and cellular phenotypic changes were analyzed by targeted metabolomics, RNA sequencing, and biological methods, respectively. Our results showed that compared with parental 786-O cells, 38E/38F cells had elevated levels of MTT/Alamar blue levels, ATP, glycolytic/mitochondrial respiratory capacity, citrate synthase (CS) activity, and TCA metabolites such as aspartate, malate, succinate, fumarate, and α-ketoglutarate. The 38E/38F cells also utilized alternative sources beyond pyruvate to generate acetyl-CoA for the TCA cycle. Moreover, 38E/38F cells showed disturbed gene networks mainly related to mitochondrial metabolism and the oxidation of fatty acids and glucose, which was associated with increased PGC1α, mitochondrial mass, and cellular size/complexity. Our results indicate that SETD2 deficiency induces a metabolic switch toward enhanced oxidative phosphorylation in ccRCC, which can be related to PGC1α-mediated metabolic networks. Therefore, this current study lays the foundation for the further development of a global metabolic analysis of cancer cells in individual patients, which ultimately will have significant potential for the discovery of novel therapeutics and precision medicine in SETD2-inactivated ccRCC.
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1H NMR based pharmacometabolomics analysis of metabolic phenotype on predicting metabolism characteristics of losartan in healthy volunteers.
He, C, Liu, Y, Wang, Y, Tang, J, Tan, Z, Li, X, Chen, Y, Huang, Y, Chen, X, Ouyang, D, et al
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences. 2018;:15-23
Abstract
Inter-individual variability in drug metabolism and disposition is common in both preclinical and clinical researches. Losartan and its active metabolite EXP3174 present a high degree of inter-individual differences in blood concentrations that affect drug efficacy and side effect. Pharmacometabolomics has been increasingly applied on predicting the drug responses by analyzing the differences in metabolic profile. A pre-dose metabolic phenotype was investigated to interpret inter-individual variations in the metabolism characteristics of losartan. 1H Nuclear Magnetic Resonance (NMR) spectroscopy-based metabolic profiles were performed on 36 healthy Chinese male volunteers by measuring their pre-dose plasma samples. After oral administration of losartan, the concentrations of losartan and its bioactive metabolite EXP3174 were monitored by liquid chromatography-mass spectrometry (LC-MS). Orthogonal partial least-squares (O-PLS) model was conducted to select potential biomarkers that substantially contributed to the inter-individual variations in the metabolism features via analyzing the ratio of pharmacokinetics (PK) parameters of its metabolite to parent drug. Potential metabolites such as glycine, phosphorylcholine, choline, creatine, creatinine, lactate, citrate, α-glucose, and lipids showed strong correlations with metabolism features of losartan. In addition, the pathway analysis revealed that baseline lipid metabolism, the glycine, serine and threonine pathway, and glycolysis or gluconeogenesis metabolism pathway were significantly associated with the ratio of PK parameters of EXP3174 to losartan. Step-wise multiple linear regression (MLR) was constructed to investigate the potential roles of the selected biomarkers in predicting individualized metabolism characteristics of losartan. These results showed that the pre-dose individual metabolic traits may be a useful approach for characterizing individual differences in losartan metabolism characteristics and therefore for expediting personalized dose-setting in further clinical studies.
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Stable isotope labeling strategy for curcumin metabolite study in human liver microsomes by liquid chromatography-tandem mass spectrometry.
Gao, D, Chen, X, Yang, X, Wu, Q, Jin, F, Wen, H, Jiang, Y, Liu, H
Journal of the American Society for Mass Spectrometry. 2015;(4):686-94
Abstract
The identification of drug metabolites is very important in drug development. Nowadays, the most widely used methods are isotopes and mass spectrometry. However, the commercial isotopic labeled reagents are usually very expensive, and the rapid and convenient identification of metabolites is still difficult. In this paper, an (18)O isotope labeling strategy was developed and the isotopes were used as a tool to identify drug metabolites using mass spectrometry. Curcumin was selected as a model drug to evaluate the established method, and the (18)O labeled curcumin was successfully synthesized. The non-labeled and (18)O labeled curcumin were simultaneously metabolized in human liver microsomes (HLMs) and analyzed by liquid chromatography/mass spectrometry (LC-MS). The two groups of chromatograms obtained from metabolic reaction mixture with and without cofactors were compared and analyzed using Metabolynx software (Waters Corp., Milford, MA, USA). The mass spectra of the newly appearing chromatographic peaks in the experimental sample were further analyzed to find the metabolite candidates. Their chemical structures were confirmed by tandem mass spectrometry. Three metabolites, including two reduction products and a glucuronide conjugate, were successfully detected under their specific HLMs metabolic conditions, which were in accordance with the literature reported results. The results demonstrated that the developed isotope labeling method, together with post-acquisition data processing using Metabolynx software, could be used for fast identification of new drug metabolites.