Identification of crucial genes of pyrimidine metabolism as biomarkers for gastric cancer prognosis

Background Metabolic reprogramming has been reported in various kinds of cancers and is related to clinical prognosis, but the prognostic role of pyrimidine metabolism in gastric cancer (GC) remains unclear. Methods Here, we employed DEG analysis to detect the differentially expressed genes (DEGs) in pyrimidine metabolic signaling pathway and used univariate Cox analysis, Lasso-penalizes Cox regression analysis, Kaplan–Meier survival analysis, univariate and multivariate Cox regression analysis to explore their prognostic roles in GC. The DEGs were experimentally validated in GC cells and clinical samples by quantitative real-time PCR. Results Through DEG analysis, we found NT5E, DPYS and UPP1 these three genes are highly expressed in GC. This conclusion has also been verified in GC cells and clinical samples. A prognostic risk model was established according to these three DEGs by Univariate Cox analysis and Lasso-penalizes Cox regression analysis. Kaplan–Meier survival analysis suggested that patient cohorts with high risk score undertook a lower overall survival rate than those with low risk score. Stratified survival analysis, Univariate and multivariate Cox regression analysis of this model confirmed that it is a reliable and independent clinical factor. Therefore, we made nomograms to visually depict the survival rate of GC patients according to some important clinical factors including our risk model. Conclusion In a word, our research found that pyrimidine metabolism is dysregulated in GC and established a prognostic model of GC based on genes differentially expressed in pyrimidine metabolism.

Integration of metabolomics and transcriptomics indicates changes in MRSA exposed to terpinen-4-ol

Background This study investigated the effects of terpinen-4-ol on methicillin-resistant Staphylococcus aureus (MRSA) and its biofilm, and the possible mechanisms governing this effect. Results We observed that terpinen-4-ol has good antibacterial activity and inhibits the formation of MRSA biofilm. The MIC and MBC values for terpinen-4-ol against S. aureus were 0.08% ~ 0.32%. And terpinen-4-ol at 0.32% could kill all bacteria and clear all biofilms. Untargeted metabolomic and transcriptomic analyses showed that terpinen-4-ol strongly inhibited DNA and RNA biosynthesis in MRSA at 2 h after treatment by affecting genes and metabolites related to purine and pyrimidine metabolic pathways. Some differential genes which play important roles in DNA synthesis and the production of eDNA from biofilm exposed to terpinen-4-ol was also significantly decreased compared with that of the control. Conclusions Terpinen-4-ol has good antibacterial activity and significantly inhibits the formation of MRSA biofilm by inhibiting purine and pyrimidine metabolism.

Ral GEF with the PH Domain and SH3 Binding Motif 1 Regulated by Splicing Factor Junction Plakoglobin and Pyrimidine Metabolism Are Prognostic in Uterine Carcinosarcoma

Uterine carcinosarcoma (UCS) is a highly invasive malignant tumor that originated from the uterine epithelium. Many studies suggested that the abnormal changes of alternative splicing (AS) of pre-mRNA are related to the occurrence and metastasis of the tumor. This study investigates the mechanism of alternative splicing events (ASEs) in the tumorigenesis and metastasis of UCS. RNA-seq of UCS samples and alternative splicing event (ASE) data of UCS samples were downloaded from The Cancer Genome Atlas (TCGA) and TCGASpliceSeq databases, several times. Firstly, we performed the Cox regression analysis to identify the overall survival-related alternative splicing events (OSRASEs). Secondly, a multivariate model was applied to approach the prognostic values of the risk score. Afterwards, a coexpressed network between splicing factors (SFs) and OSRASEs was constructed. In order to explore the relationship between the potential prognostic signaling pathways and OSRASEs, we fabricated a network between these pathways and OSRASEs. Finally, validations from multidimension platforms were used to explain the results unambiguously. 1,040 OSRASEs were identified by Cox regression. Then, 6 OSRASEs were incorporated in a multivariable model by Lasso regression. The area under the curve (AUC) of the receiver operator characteristic (ROC) curve was 0.957. The risk score rendered from the multivariate model was corroborated to be an independent prognostic factor ( P < 0.001 ). In the network of SFs and ASEs, junction plakoglobin (JUP) noteworthily regulated RALGPS1-87608-AT ( P < 0.001 , R = 0.455 ). Additionally, RALGPS1-87608-AT ( P = 0.006 ) showed a prominent relationship with distant metastasis. KEGG pathways related to prognosis of UCS were selected by gene set variation analysis (GSVA). The pyrimidine metabolism ( P < 0.001 , R = − 0.470 ) was the key pathway coexpressed with RALGPS1. We considered that aberrant JUP significantly regulated RALGPS1-87608-AT and the pyrimidine metabolism pathway might play a significant part in the metastasis and prognosis of UCS.

Identification of Crucial Genes of Pyrimidine Metabolism as Biomarkers for Gastric Cancer Prognosis

Background Metabolic reprogramming has been reported in various kinds of cancers and is related to clinical prognosis, but the prognostic role of pyrimidine metabolism in gastric cancer (GC) remains unclear. Methods Here, we employed DEG analysis to detect the differentially expressed genes (DEGs) in pyrimidine metabolic signaling pathway and used univariate Cox analysis, Lasso-penalizes Cox regression analysis, Kaplan-Meier survival analysis, univariate and multivariate Cox regression analysis to explore their prognostic roles in GC. The DEGs were experimentally validated in GC cells and clinical samples by quantitative real-time PCR. Results Through DEG analysis, we found NT5E, DPYS and UPP1 these three genes are highly expressed in GC. This conclusion has also been verified in GC cells and clinical samples. A prognostic risk model was established according to these three DEGs by Univariate Cox analysis and Lasso-penalizes Cox regression analysis. Kaplan-Meier survival analysis suggested that patient cohorts with high risk score undertook a lower overall survival rate than those with low risk score. Stratified survival analysis, Univariate and multivariate Cox regression analysis of this model confirmed that it is a reliable and independent clinical factor. Therefore, we made nomograms to visually depict the survival rate of GC patients according to some important clinical factors including our risk model. Conclusion In a word, our research found that pyrimidine metabolism is dysregulated in GC and established a prognostic model of GC based on genes differentially expressed in pyrimidine metabolism.

Study of metabolomics in selenium deprived Przewalski’s Gazelles (P. przewalskii)

To understand why P. przewalskii does not show the same white myopathy as sheep in Se-deficient regions, and to provide reference for feeding nutrition level of artificial population and selection of wild reintroduction areas in the later period, a Se-deficient model was established. The mineral elements content, physiological and biochemical parameters in blood, and serum metabonomics were determined. In the Se-deficient group compared with the control group, the Se content was highly significantly lower (P<0.01), and the Cu content was significantly higher (P<0.05). The activity of glutathione peroxidase (GSH-Px) was significantly lower (P<0.05), but total superoxide dismutase (T-SOD) was significantly higher (P<0.05). Principal component analysis (PCA) revealed significant differences in serum metabolic profiling between the Se-deficient group and control group, orthogonal partial least squares discriminant analysis (OPLS-DA) indicated significant differences in metabolite distribution in the serum between the two groups (P<0.05, variable importance in projection VIP>1). By matching the mass spectrum data of compounds with the Kyoto Encyclopedia of Genes and Genomes (KEGG database), identified 86 types of differential metabolites in the serum. The main metabolic pathways included secondary bile acid biosynthesis, biosynthesis of unsaturated fatty acids and pyrimidine metabolism. Further analysis showed that there were 7 different metabolites in pyrimidine metabolism pathway between the Se-deficient and control group. And there was no significant difference in red blood cell (RBC), hemoglobin (Hb) and total antioxidant capacity (T-AOC) between the two groups (P>0.05). The above results showed that the differential metabolism of substances exhibited complementary functions, thus alleviating some adverse effects and resulting normal activities of P. przewalskii can be carried out under the condition of dietary Se content lower than 0.05mg/kg.

Hydrogen Peroxide Affects Growth of S. aureus Through Downregulation of Genes Involved in Pyrimidine Biosynthesis

Reactive oxygen species (ROS) play a crucial role in the cellular defense against S. aureus, as evidenced by the importance of this pathogen in patients lacking the ROS-generating phagocyte NADPH oxidase NOX2. ROS concentrations required to kill S. aureus in vitro are much higher than those found in the phagosome. We therefore hypothesized that sublethal ROS concentrations may play a role in S. aureus gene dysregulation and investigated the in vitro transcriptomic response of S. aureus to sublethal concentrations of hydrogen peroxide (H2O2). A striking observation of these experiments was a coordinated and massive downregulation of genes involved in pyrimidine metabolism. Using transposon insertion mutants, we demonstrated that deletion of carA, a gene involved in pyrimidine synthesis, led to a significant growth defect and to an increased sensitivity of S. aureus to added H2O2. The phenotype of the carA mutant could be reversed through supplementation with the pyrimidine precursor uracil, or with a multicopy vector encoding carA. As opposed to the impact of ROS on extracellular survival, carA deletion did not affect the intracellular survival in neutrophils. Our results raise the possibility that ROS-dependent downregulation of pyrimidine metabolism might be a survival strategy of S. aureus, allowing colonization through intracellular survival, while decreasing the risk of killing the host through dampened extracellular growth.

A Study on Gentiana dahurica Fisch Ethanol Extract Alleviating Alcoholic Liver Disease in Mice: A Metabolomic Analysis of the Liver

We clarified the hepatoprotective effect of Gentiana dahurica Fisch ethanol extract (GDEE) in our previous study, and we further revealed the mechanism with the help of metabolomics technology in this study. The livers from Control group, Alcohol group, and Alcohol + GDEE group were analyzed by metabolomics. The metabolites in the liver were separated by ultra-high-performance liquid chromatography (UHPLC) and were tentatively identified using mass spectrometry (MS)/MS analysis. Differential metabolites were defined with VIP > 1 and P < 0.05 . Principal component analysis (PCA) and orthogonal partial least square discriminant analysis (OPLS-DA) were applied to analyze differences among these groups. The results showed that the groups could be clearly distinguished by PCA and OPLS-DA analysis. Alcohol and GDEE could change the overall profile of liver metabolites. Alterations in liver tissues of ALD mice induced by alcohol were mainly involved in the dipeptides, purine and pyrimidine metabolism and glucose and lipid metabolism, which could be partly affected by GDEE. This study revealed that the mechanism of GDEE in alleviating ALD had the characteristics of multitarget and multipathway.

Anxiety disturbs the blood plasma metabolome in acute coronary syndrome patients

Coronary heart disease (CHD) is the result of a complex metabolic disorder caused by various environmental and genetic factors, and often has anxiety as a comorbidity. Rupture of atherosclerotic plaque in CHD patients can lead to acute coronary syndrome (ACS). Anxiety is a known independent risk factor for the adverse cardiovascular events and mortality in ACS, but it remains unclear how stress-induced anxiety behavior impacts their blood plasma metabolome and contributes to worsening of CHD. The present study aimed to determine the effect of anxiety on the plasma metabolome in ACS patients. After receiving ethical approval 26 ACS patients comorbid anxiety were recruited and matched 26 ACS patients. Blood plasma samples were collected from the patients and stored at − 80 °C until metabolome profiling. Metabolome analysis was performed by liquid chromatography mass spectrometry (LC–MS), and the data were subjected to multivariate analysis. Disturbance of 39 plasma metabolites was noted in the ACS with comorbid anxiety group compared to the ACS group. These disturbed metabolites were mainly involved in tryptophan metabolism, pyrimidine metabolism, glycerophospholipid metabolism, pentose phosphate pathway, and pentose and glucuronate interconversions. The most significantly affected pathway was tryptophan metabolism including the down-regulation of tryptophan and serotonin. Glycerophospholipids metabolism, pentose and glucuronate interconversions, and pentose phosphate pathway were also greatly affected. These results suggest that anxiety can disturb three translation of material in ACS patients. Besides the above metabolism pathways pyrimidine metabolism was significantly disturbed. Based on the present findings the plasma metabolites monitoring can be recommended and may be conducive to early biomarkers detection for personalized treatment anxiety in CHD patients in future.