BACKGROUND: Associations between metabolic status and metabolic changes with the risk of cardiovascular outcomes have been reported. However, the role of genetic susceptibility underlying these associations remains unexplored. We aimed to examine how metabolic status, metabolic transitions, and genetic susceptibility collectively impact cardiovascular outcomes and all-cause mortality across diverse body mass index (BMI) categories.
METHODS: In our analysis of the UK Biobank, we included a total of 481,576 participants (mean age: 56.55; male: 45.9%) at baseline. Metabolically healthy (MH) status was defined by the presence of < 3 abnormal components (waist circumstance, blood pressure, blood glucose, triglycerides, and high-density lipoprotein cholesterol). Normal weight, overweight, and obesity were defined as 18.5 ≤ BMI < 25 kg/m2, 25 ≤ BMI < 30 kg/m2, and BMI ≥ 30 kg/m2, respectively. Genetic predisposition was estimated using the polygenic risk score (PRS). Cox regressions were performed to evaluate the associations of metabolic status, metabolic transitions, and PRS with cardiovascular outcomes and all-cause mortality across BMI categories.
RESULTS: During a median follow-up of 14.38 years, 31,883 (7.3%) all-cause deaths, 8133 (1.8%) cardiovascular disease (CVD) deaths, and 67,260 (14.8%) CVD cases were documented. Among those with a high PRS, individuals classified as metabolically healthy overweight had the lowest risk of all-cause mortality (hazard ratios [HR] 0.70; 95% confidence interval [CI] 0.65, 0.76) and CVD mortality (HR 0.57; 95% CI 0.50, 0.64) compared to those who were metabolically unhealthy obesity, with the beneficial associations appearing to be greater in the moderate and low PRS groups. Individuals who were metabolically healthy normal weight had the lowest risk of CVD morbidity (HR 0.54; 95% CI 0.51, 0.57). Furthermore, the inverse associations of metabolic status and PRS with cardiovascular outcomes and all-cause mortality across BMI categories were more pronounced among individuals younger than 65 years (Pinteraction < 0.05). Additionally, the combined protective effects of metabolic transitions and PRS on these outcomes among BMI categories were observed.
CONCLUSIONS: MH status and a low PRS are associated with a lower risk of adverse cardiovascular outcomes and all-cause mortality across all BMI categories. This protective effect is particularly pronounced in individuals younger than 65 years. Further research is required to confirm these findings in diverse populations and to investigate the underlying mechanisms involved.

UNASSIGNED: Postoperative complications in aging patients remain a significant cause of increased costs, hospital length of stay, and patient distress. Although alterations in energy metabolism have been closely linked to aging process and surgery, it is still unclear whether metabolic changes during surgery is associated with postoperative complications in elderly patients. This study was conducted to investigate whether metabolic changes during surgery predicts postoperative complications in elderly patients.
UNASSIGNED: We conducted a prospective single-center observational cohort study. 244 adults (aged ≥65 years) who were scheduled for elective major non-cardiac surgery were recruited. Blood samples for each patient were taken before and after surgery. All patients were randomly divided into two groups (122 in each group), then oxygen consumption rate (OCR) or extracellular acidification rate (ECAR) was measured on isolated monocytes in each group.
UNASSIGNED: 14 of 110 (12.7%) patients went through OCR measurement and 15 of 122 patients (12.3%) went through ECAR measurement experienced moderate to severe complications. Overall, there was an intensification of glycolysis in monocytes after surgery. Among all variables, only the change (preoperative -postoperative) of glycolytic reserve (GR)/glycolysis (G) and GR/non-glycolytic acidification (NG) were predictors of moderate to severe complications (AUC = 0.70; 95% CI, 0.56-0.81; P = 0.019 and AUC = 0.67; 95% CI, 0.55-0.80; P = 0.031). Decreased postoperative GR/G were associated with worse postoperative complications (RR = 9.08; 95% CI, 1.23-66.81; P = 0.024).
UNASSIGNED: Compared with mitochondria function, the change of glycolytic function in monocyte was more valuable in predicting postoperative complications after major abdominal surgery. Our study gave us a new insight into identifying patients at high risk in aging patients.

Sepsis is a manifestation of the immune and inflammatory response to infection, which may lead to multi‑organ failure. Health care advances have improved outcomes in critical illness, but it still remains the leading cause of death. Septic cardiomyopathy is heart dysfunction brought on by sepsis. Septic cardiomyopathy is a common consequence of sepsis and has a mortality rate of up to 70%. There is a lack of understanding of septic cardiomyopathy pathogenesis; knowledge of its pathogenesis and the identification of potential therapeutic targets may reduce the mortality rate of patients with sepsis and lead to clinical improvements. The present review aimed to summarize advances in the pathogenesis of cardiac dysfunction in sepsis, with a focus on mitochondrial dysfunction, metabolic changes and cell death modalities and pathways. The present review summarized diagnostic criteria and outlook for sepsis treatment, with the goal of identifying appropriate treatment methods for this disease.

Gastric cancer (GAS) is one of the malignant tumors of the gastrointestinal system. Alterations in metabolite composition can reflect pathological processes of GAS and constitute a basis for diagnosis and treatment improvements. In this study, a total of 301 serum samples from 150 GAS patients at different tumor-node-metastasis (TNM) stages and 151 healthy controls were collected. Mass spectrometry platforms were performed to investigate the changes in GAS-related metabolites and explore the new potential serum biomarkers and the metabolic dysregulation associated with GAS progression. Twelve differential metabolites (ethyl 2,4-dimethyl-1,3-dioxolane-2-acetate, D-urobilinogen, 14-HDoHE, 13-hydroxy-9-methoxy-10-oxo-11-octadecenoic acid, 5,6-dihydroxyprostaglandin F1a, 9\'-carboxy-gamma-tocotrienol, glutaric acid, alanine, tyrosine, C18:2(FFA), adipic acid, and suberic acid) were identified to establish the diagnosis model for GAS. The defined biomarker panel was also statistically significant for GAS progression with different TNM stages. KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment revealed the metabolic dysregulation associated with GAS progression. In conclusion, a diagnostic panel was established and validated, which could be used to further stage the early and advanced GAS patients from healthy controls. These findings may provide useful information for explaining the GAS metabolic alterations and try to facilitate the characterization of GAS patients in the early stage.

The current study applied an untargeted metabolomics approach by ultra high performance liquid chromatography quadrupole-orbitaltrap high resolution mass spectrometry (UHPLC-Q-Oritrap-MS) to identify the chemical composition of irradiated goat meat and investigate the effect of irradiation on its metabolic profile and meat quality. A total of 103 metabolites were identified as differential metabolites responsible for metabolic changes in irradiated goat meat, which were involved in phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism and purine metabolism. Differential metabolites comprising amino acids, nucleotides and their derivatives were determined as the discriminating factors responsible for the meat quality during irradiation. Specifically, the levels of L-phenylalanine, L-isoleucine, L-histidine, guanosine, guanine, creatinine, glutathione and nicotinic acid were increased while inosine 5\'-monophosphate (IMP) and guanosine 5\'-monophosphate (GMP) were decreased. Overall, except for L-phenylalanine and guanine, other related metabolites significantly decreased with storage. This study contributes to a comprehensive understanding of the effect of irradiation doses and storage time on goat meat metabolism at the molecular level, so as to assess the quality of irradiated goat meat. Satisfactory results with linearity (R2 > 0.995), precision (RSD less than 8.9%) and recovery (83%-106%) were obtained, demonstrating that the untargeted mebabolomics approach was appropriate for monitoring the changes of small molecular metabolites in irradiated goat meat and irradiation is a feasible method for goat meat preservation.

BACKGROUND: Metabolomics strategy was perform to identify the novel serum biomarkers linked to schizophrenia with the assistance of transcriptomics analysis.
METHODS: Two analytical platforms, UPLC-Q-TOF MS/MS and 1H NMR, were used to acquire the serum fingerprinting profiles from a total of 112 participants (57 healthy controls and 55 schizophrenia patients). The differential metabolites were primarily selected after statistical analyses. Meanwhile, GSE17612 dataset downloaded from GEO database was implemented WGCNA analysis to discover crucial genes and corresponding biological processes. Based on metabolomics analysis, the metabolic distinctions were explored under the aid of transcriptomics. Then using Boruta algorithm identified the biomarkers, and LASSO regression analysis and Random Forest algorithm were used to evaluate the performance of the diagnostic model constructed by biomarkers selected.
RESULTS: A total of four metabolites (α-CEHC, neuraminic acid, glyceraldehyde and asparagine) were selected as the biomarkers to establish diagnosis model. The performance of this model showed a higher accuracy rate to distinguish schizophrenia patients from healthy controls (area under the receive operating characteristic curve, 0.992; precision recall curve, 1.000, the mean accuracy of random forest algorithm, 95.00%).
CONCLUSIONS: A four-biomarker model (α-CEHC, neuraminic acid, glyceraldehyde and asparagine) seems to be a good model for diagnosing schizophrenia patients. It might be helpful to guide the future studies on permitting early intervention designed to prevent disease progression.

Changes in cellular metabolism accompany tumor therapeutic resistance. Metabolite concentrations specifically reflect the cellular state. Glutathione (GSH) metabolism maintains the redox homeostasis while also confers therapeutic resistance to cancer cells. However, analytical methods for studying GSH metabolism rely on high-resolution-based untargeted metabolomics. Since the aim of untargeted metabolomics studies is covering as much metabolites as possible, these methods lack sensitivity for simultaneous analysis of intracellular GSH-related metabolites with different polarities and structures. In this study, based on cultured lung cancer cells, we described a rapid, robust and sensitive ultra-performance liquid chromatography-triple quadrupole tandem mass spectrographic method (UPLC-QQQ-MS/MS) to simultaneously quantify a repertoire of GSH-related metabolites, including GSH, GSSG, glycine, cysteine, glutamine, glutamate, cystine, γ-glutamyl-cysteine and cysteinyl-glycine. This method avoided the use of derivatization and/or ion-pairing reagents and was validated according to United States Food and Drug Administration (US FDA) criteria. The lower limit of quantification was determined to be 0.5-100 ng/mL with lower limits of detection at 0.14-10.07 ng/mL. The intra- and inter-day precision values for all the analytes were <15% CV, and the accuracy ranged from 85.4% to 114% at three levels of quality control. This method combined simple preparation with rapid analytical procedure (8 min), allowed for high-throughput analysis of GSH metabolism in basic and therapeutic treatment conditions within cultured cells. Our data showed a significant alteration of GSH metabolism in two independent resistant cells compared to sensitive cells. This method monitored the impact of molecularly targeted drugs on GSH metabolism within lung cancer cells and therefore helped identifying potential metabolic vulnerability for the therapeutic resistance in lung cancer.

Background: Investigation on neurochemical changes in the frontal cortex in individuals with Alzheimer\'s disease (AD) and different Apolipoprotein E (APOE) genotypes, using ex vivo solid-state high-resolution NMR analysis, may lead to a better understanding of the neurochemistry associated with AD as well as new AD-specific metabolite biomarkers that might potentially improve the clinical diagnosis of AD. Methods: Intact tissue samples of the frontal cortex were obtained from 11 patients and 11 age-matched non-demented controls. Metabolite profiles in all samples were analyzed ex vivo, using solid-state high-resolution magic angle spinning (HRMAS) 600 MHz 1H nuclear magnetic resonance (NMR). A logistic regression analysis was used to rank metabolites based on their level of contribution in differentiating the AD patient tissues and the controls, and different AD-associated APOE genotypes (APOE ε4 vs. APOE ε3). Results: Tissue samples from the AD patients showed significantly lower NAA/Cr (p = 0.011), Ace/Cr (p = 0.027), GABA/Cr (p = 0.005), Asp/Cr (p < 0.0001), mI/Cr (p < 0.0001), and Tau/Cr (p = 0.021), and higher PCho/Cr (p < 0.0001), GPCho/Cr (p < 0.0001), and α&β-Glc/Cr (p < 0.0001) than the controls did. Specifically, a newly observed resonance at 3.71 ppm, referred to as α&β-Glc, was observed in 90.9% of the AD samples (10/11). Samples with APOE ε4 also exhibited higher PCho/Cr (p = 0.0002), GPCho/Cr (p = 0.0001), α&β-Glc/Cr (p < 0.0001), and lower Asp/Cr (p = 0.004) and GABA/Cr (p = 0.04) than the samples with APOE ε3 did. In the logistic regression analysis, PCho, GPCho, ASP, and α&β-Glc were found to be the most relevant metabolites for differentiating the AD patient tissues and the controls, and different APOE genotypes. Conclusion: HRMAS 1H NMR with high spectral resolution and sensitivity offers a powerful tool to gain quantitative information on AD associated neurochemical changes. There are important neurochemical differences in the frontal cortex between the AD patient tissues and the controls, and between those with different APOE genotypes. The resonance (α&β-Glc) found at 3.71 ppm in the AD patient tissues may be further investigated for its potential in the diagnosis and monitoring of AD.

Maternal diet during pregnancy can influence offspring\'s health by affecting development and metabolism. This study aimed to analyze the influence of maternal folic acid (FA) supplementation on the metabolism of rat pups using targeted metabolomics. Twenty female rats were randomly assigned to a FA supplementation (FAS group, n = 10) or control group (n = 10), which were fed AIN93G diet with 2 or 10 mg/kg FA, respectively. We then measured amino acids and their derivatives, biogenic amines, and fatty acids in the female rats and their pups by ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UHPLC/MS-MS) and gas chromatography-mass spectrometry (GC/MS-MS). In maternal rats, the significant changes of three metabolites (proline, γ-aminobutyric acid and esterified octadecatetraenoic acid, P < 0.05) were observed in FAS group. For the rat pups, FAS pups had significantly lower homocysteine and higher FA levels than control pups. The lower levels of amino acids (leucine, isoleucine, serine, proline) were obtained in FAS pups. Furthermore, there were the decreased esterified fatty acids (arachidonic acid, eicosapentaenoic acid, and docosatetraenoic acid) and free fatty acids (oleic acid, linoleic acid, γ-linolenic acid, octadecatetraenoic acid, arachidonic acid, eicosapentaenoic acid and selacholeic acid) in FAS pups. Metabolic changes in the FAS pups were characterized by changes in fatty acids and amino acids. These results suggested that FA supplementation during pregnancy influenced amino acids and fatty acids metabolism in rat pups. This study provides new insights into the regulation of amino acids and fatty acids metabolism during early life.

In current military conflicts and civilian terrorism, blast-induced traumatic brain injury (bTBI) is the primary cause of neurotrauma. However, the effects and mechanisms of bTBI are poorly understood. Although previous researchers have made significant contributions to establishing animal models for the simulation of bTBI, the precision and controllability of blast-induced injury in animal models must be improved. Therefore, we established a novel rat model to simulate blast-wave injury to the brain. To simulate different extents of bTBI injury, the animals were divided into moderate and severe injury groups. The miniature spherical explosives (pentaerythritol tetranitrate) used in each group were of different sizes (2.5 mm diameter in the moderate injury group and 3.0 mm diameter in the severe injury group). A specially designed apparatus was able to precisely adjust the positions of the miniature explosives and create eight rats with bTBI simultaneously, using a single electric detonator. Neurological functions, gross pathologies, histopathological changes and the expression levels of various biomarkers were examined after the explosion. Compared with the moderate injury group, there were significantly more neurological dysfunctions, cortical contusions, intraparenchymal hemorrhages, cortical expression of S-100β, myelin basic protein, neuron-specific enolase, IL-8, IL-10, inducible nitric oxide synthase, and HIF-1α in the severe injury group. These results demonstrate that we have created a reliable and reproducible bTBI model in rats. This model will be helpful for studying the mechanisms of bTBI and developing strategies for clinical bTBI treatment.