Analysis of differential metabolites in serum metabolomics of patients with aortic dissection.

BACKGROUND: Pathogenesis and diagnostic biomarkers of aortic dissection (AD) can be categorized through the analysis of differential metabolites in serum. Analysis of differential metabolites in serum provides new methods for exploring the early diagnosis and treatment of aortic dissection. OBJECTIVES: This study examined affected metabolic pathways to assess the diagnostic value of metabolomics biomarkers in clients with AD. METHOD: The serum from 30 patients with AD and 30 healthy people was collected. The most diagnostic metabolite markers were determined using metabolomic analysis and related metabolic pathways were explored. RESULTS: In total, 71 differential metabolites were identified. The altered metabolic pathways included reduced phospholipid catabolism and four different metabolites considered of most diagnostic value including N2-gamma-glutamylglutamine, PC(phocholines) (20:4(5Z,8Z,11Z,14Z)/15:0), propionyl carnitine, and taurine. These four predictive metabolic biomarkers accurately classified AD patient and healthy control (HC) samples with an area under the curve (AUC) of 0.9875. Based on the value of the four different metabolites, a formula was created to calculate the risk of aortic dissection. Risk score = (N2-gamma-glutamylglutamine × -0.684) + (PC (20:4(5Z,8Z,11Z,14Z)/15:0) × 0.427) + (propionyl carnitine × 0.523) + (taurine × -1.242). An additional metabolic pathways model related to aortic dissection was explored. CONCLUSION: Metabolomics can assist in investigating the metabolic disorders associated with AD and facilitate a more in-depth search for potential metabolic biomarkers.

Effect of glycerol supplementation in early lactation on metabolic health, milking activity, and production of dairy cows in automated milking system herds.

The objective of this study was to quantify the effects of supplementing early-lactation cows with a dry pure glycerol product, delivered through the automated milking system (AMS) concentrate, in the first 21 d in milk (DIM) on metabolic markers, milking behavior, and milk production. In 5 commercial AMS dairy herds, 389 dairy cows were randomly assigned, controlling for parity, 21 d before expected calving to 1 of 2 treatments, within farm: (1) control group (CON) receiving the standard AMS pellet (n = 213) from 1 to 150 DIM, or (2) glycerol group (GLY) receiving the treatment AMS pellet (n = 176) formulated to deliver 250 as fed g/d of glycerol product from 1 to 21 DIM (mean actual = 249 g/d dry matter [DM]), then they received the standard AMS pellet from 22 to 150 DIM. Across all farms, cows were fed partial mixed rations (PMR) that were similar in ingredient and nutrient composition. One prepartum blood sample and 5 postpartum blood samples were collected from each cow to determine serum nonesterified fatty acids (NEFA), blood ß-hydroxy butyrate (BHB), and blood glucose concentrations. Cow body condition score (BCS) was recorded every 21 d from -21 to 63 DIM. Data were collected and analyzed for the treatment period (1 to 21 DIM) and a follow-up period (22 to 150 DIM). There was no detected treatment effect on serum NEFA concentrations in the first week of lactation. There was a treatment by time interaction for blood BHB and blood glucose, where GLY cows tended to have increased BHB concentrations at 5 DIM and had decreased glucose concentrations at 9 and 12 DIM. There was an interaction of BCS with treatment on the incidence of BHB ≥1.2 mmol/L, whereby over-conditioned CON cows (BCS ≥3.5) were 3.5x more likely to have a high BHB test than CON cows with normal prepartum BCS. During the treatment period GLY cows had 0.1 ± 0.05 more successful milkings/d, were delivered 0.27 ± 0.05 DM kg/d more AMS concentrate and tended to yield 0.8 ± 0.47 kg/d more milk. During the follow-up period GLY cows had 0.1 ± 0.04 more successful milkings/d, were delivered 0.18 ± 0.06 DM kg/d more AMS concentrate, and yielded 1.5 ± 0.53 kg/d more milk than CON cows. Glycerol supplementation allowed cows to maintain better BCS, as GLY cows lost less BCS from calving to 63 DIM than CON cows. Overall, the results of this study demonstrate that supplementing pure glycerol through the AMS concentrate for the first 21 DIM can reduce BCS loss in early lactation, improve milking behavior, and increase milk yield to mid lactation.

Association of co-exposure to organophosphate esters and per- and polyfluoroalkyl substances and mixture with cardiovascular-kidney-liver-metabolic biomarkers among Chinese adults.

BACKGROUND: Organophosphate esters (OPEs) and Per- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental contaminants with common exposure sources, leading to their widespread presence in human body. However, evidence on co-exposure to OPEs and PFAS and its impact on cardiovascular-kidney-liver-metabolic biomarkers remains limited. METHODS: In this cross-sectional study, 467 adults were enrolled from January to May 2022 during physical visits in Shijiazhuang, Hebei province. Eleven types of OPEs and twelves types of PFAS were detected, among which eight OPEs and six PFAS contaminants were detected in more than 60% of plasma samples. Seventeen biomarkers were assessed to comprehensively evaluate the cardiovascular-kidney-liver-metabolic function. Multiple linear regression, multipollutant models with sparse partial least squares, and Bayesian kernel machine regression (BKMR) models were applied to examine the associations of individual OPEs and PFAS and their mixtures with organ function and metabolism, respectively. RESULTS: Of the over 400 exposure-outcome associations tested when modelling, we observed robust results across three models that perfluorohexanoic acid (PFHxS) was significantly positively associated with alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and indirect bilirubin (IBIL). Perfluorononanoic acid was significantly associated with decreased AST/ALT and increased very-low-density lipoprotein cholesterol levels. Besides, perfluorodecanoic acid was correlated with increased high lipoprotein cholesterol and perfluoroundecanoic acid was consistently associated with lower glucose level. BKMR analysis showed that OPEs and PFAS mixtures were positively associated with IBIL and TBIL, among which PFHxS was the main toxic chemicals. CONCLUSIONS: Our findings suggest that exposure to OPEs and PFAS, especially PFHxS and PFNA, may disrupt organ function and metabolism in the general population, providing insight into the potential pathophysiological mechanisms of OPEs and PFAS co-exposure and chronic diseases.

Metabolic regulation of prostate cancer heterogeneity and plasticity.

Metabolic reprogramming is one of the main hallmarks of cancer cells. It refers to the metabolic adaptations of tumor cells in response to nutrient deficiency, microenvironmental insults, and anti-cancer therapies. Metabolic transformation during tumor development plays a critical role in the continued tumor growth and progression and is driven by a complex interplay between the tumor mutational landscape, epigenetic modifications, and microenvironmental influences. Understanding the tumor metabolic vulnerabilities might open novel diagnostic and therapeutic approaches with the potential to improve the efficacy of current tumor treatments. Prostate cancer is a highly heterogeneous disease harboring different mutations and tumor cell phenotypes. While the increase of intra-tumor genetic and epigenetic heterogeneity is associated with tumor progression, less is known about metabolic regulation of prostate cancer cell heterogeneity and plasticity. This review summarizes the central metabolic adaptations in prostate tumors, state-of-the-art technologies for metabolic analysis, and the perspectives for metabolic targeting and diagnostic implications.

Clinical metabolomics by NMR revealed serum metabolic signatures for differentiating sarcoidosis from tuberculosis.

BACKGROUND: Pulmonary sarcoidosis (SAR) and tuberculosis (TB) are two granulomatous lung-diseases and often pose a diagnostic challenge to a treating physicians. OBJECTIVE: The present study aims to explore the diagnostic potential of NMR based serum metabolomics approach to differentiate SAR from TB. MATERIALS AND METHOD: The blood samples were obtained from three study groups: SAR (N = 35), TB (N = 28) and healthy normal subjects (NC, N = 56) and their serum metabolic profiles were measured using 1D 1H CPMG (Carr-Purcell-Meiboom-Gill) NMR spectra recorded at 800 MHz NMR spectrometer. The quantitative metabolic profiles were compared employing a combination of univariate and multivariate statistical analysis methods and evaluated for their diagnostic potential using receiver operating characteristic (ROC) curve analysis. RESULTS: Compared to SAR, the sera of TB patients were characterized by (a) elevated levels of lactate, acetate, 3-hydroxybutyrate (3HB), glutamate and succinate (b) decreased levels of glucose, citrate, pyruvate, glutamine, and several lipid and membrane metabolites (such as very-low/low density lipoproteins (VLDL/LDL), polyunsaturated fatty acids, etc.). CONCLUSION: The metabolic disturbances not only found to be well in concordance with various previous reports, these further demonstrated very high sensitivity and specificity to distinguish SAR from TB patients suggesting serum metabolomics analysis can serve as surrogate method in the diagnosis and clinical management of SAR.

Micronutrient, Metabolic, and Inflammatory Biomarkers through 24 Months of Age in Infants Receiving Formula with Added Bovine Milk Fat Globule Membrane through the First Year of Life: A Randomized Controlled Trial.

BACKGROUND: Bovine milk fat globule membrane (MFGM) added in infant formula supports typical growth and safety through 24 mo of age in term infants. OBJECTIVES: To assess micronutrient (zinc, iron, ferritin, transferrin receptor), metabolic [glucose, insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), insulin-like growth factor-1 (IGF-1), triglycerides (TGs), total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C)], and inflammatory (leptin, adiponectin, high sensitivity C-reactive protein) secondary outcomes through 24 mo of age in infants who received standard cow's milk-based infant formula (SF), similar formula with added bovine MFGM (EF), or human milk (HM) through 1 y. METHODS: Infants whose parents agreed to a blood draw at baseline (<120 d of age) (SF = 80; EF = 80; HM = 83) were included. Subsequent collections (2-4 h fasting) occurred at D180, D365, and D730. Biomarker concentrations were analyzed and group changes tested using generalized estimating equations models. RESULTS: Only serum iron (+22.1 µg/dL) and HDL-C (+2.5 mg/dL) were significantly higher for EF compared with SF at D730. Prevalence of zinc deficiency for EF (-17.4%) and SF (-16.6%) at D180 and depleted iron stores for SF (+21.4%) at D180 and EF (-34.6%) and SF (-28.0%) at D365 were significantly different compared with HM. IGF-1 (ng/mL) for EF and SF was significantly higher at D180 (+8.9) and for EF (+8.8) at D365, and (+14.5) at D730 compared with HM. Insulin (µUI/mL) for EF (+2.5) and SF (+5.8) and HOMA-IR for EF (+0.5) and SF (+0.6) were significantly higher compared with HM at D180. TGs (mg/dL) for SF (+23.9) at D180, for EF (+19.0) and SF (+17.8) at D365, and EF (+17.3) and SF (+14.5) at D730 were significantly higher compared with HM. Zinc, ferritin, glucose, LDL-C and total cholesterol changes were higher in formula groups compared with HM between various time points. CONCLUSIONS: Micronutrient, metabolic, and inflammatory biomarkers were generally similar through 2 y in infants who received infant formula with or without added bovine MFGM. Over the 2 y, differences were observed between infant formulas and HM reference group. This trial was registered at clinicaltrials.gov as NTC02626143.

Maternal circulating metabolic biomarkers and their prediction performance for gestational diabetes mellitus related macrosomia.

INTRODUCTION: Gestational diabetes mellitus (GDM), a metabolism-related pregnancy complication, is significantly associated with an increased risk of macrosomia. We hypothesized that maternal circulating metabolic biomarkers differed between women with GDM and macrosomia (GDM-M) and women with GDM and normal neonatal weight (GDM-N), and had good prediction performance for GDM-M. METHODS: Plasma samples from 44 GDM-M and 44 GDM-N were analyzed using Olink Proseek multiplex metabolism assay targeting 92 biomarkers. Combined different clinical characteristics and Olink markers, LASSO regression was used to optimize variable selection, and Logistic regression was applied to build a predictive model. Nomogram was developed based on the selected variables visually. Receiver operating characteristic (ROC) curve, calibration plot, and clinical impact curve were used to validate the model. RESULTS: We found 4 metabolism-related biomarkers differing between groups [CLUL1 (Clusterin-like protein 1), VCAN (Versican core protein), FCRL1 (Fc receptor-like protein 1), RNASE3 (Eosinophil cationic protein), FDR <  0.05]. Based on the different clinical characteristics and Olink markers, a total of nine predictors, namely pre-pregnancy body mass index (BMI), weight gain at 24 gestational weeks (gw), parity, oral glucose tolerance test (OGTT) 2 h glucose at 24 gw, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) at 24 gw, and plasma expression of CLUL1, VCAN and RNASE3 at 24 gw, were identified by LASSO regression. The model constructed using these 9 predictors displayed good prediction performance for GDM-M, with an area under the ROC of 0.970 (sensitivity = 0.955, specificity = 0.886), and was well calibrated (P Hosmer-Lemeshow test = 0.897). CONCLUSION: The Model included pre-pregnancy BMI, weight gain at 24 gw, parity, OGTT 2 h glucose at 24 gw, HDL and LDL at 24 gw, and plasma expression of CLUL1, VCAN and RNASE3 at 24 gw had good prediction performance for predicting macrosomia in women with GDM.

Longitudinal metabolomic profiles reveal sex-specific adjustments to long-duration spaceflight and return to Earth.

Spaceflight entails a variety of environmental and psychological stressors that may have long-term physiological and genomic consequences. Metabolomics, an approach that investigates the terminal metabolic outputs of complex physiological alterations, considers the dynamic state of the human body and allows the identification and quantification of down-stream metabolites linked to up-stream physiological and genomic regulation by stress. Employing a metabolomics-based approach, this study investigated longitudinal metabolic perturbations of male (n = 40) and female (n = 11) astronauts on 4-6-month missions to the International Space Station (ISS). Proton nuclear magnetic resonance (1H-NMR) spectroscopy followed by univariate, multivariate and machine learning analyses were used on blood serum to examine sex-specific metabolic changes at various time points throughout the astronauts' missions, and the metabolic effects of long-duration space travel. Space travel resulted in sex-specific changes in energy metabolism, bone mineral and muscle regulation, immunity, as well as macromolecule maintenance and synthesis. Additionally, metabolic signatures suggest differential metabolic responses-especially during the recovery period-with females requiring more time to adjust to return to Earth. These findings provide insight into the perturbations in glucose and amino acid metabolism and macromolecule biosynthesis that result from the stressors of long-duration spaceflight. Metabolomic biomarkers may provide a viable approach to predicting and diagnosing health risks associated with prolonged space travel and other physiological challenges on Earth.

Environmental concentrations of cadmium and zinc and associating metabolomics profile alternations in urine of pregnant women in the first trimester: A prospective cohort study in Taiyuan, North China.

especially to pregnant women. In recent years, zinc (Zn) supplementation has attracted increasing attention among pregnant women. Thus, understanding the effects and interactions of Cd and Zn in pregnant women is critical. This study aimed to assess the urinary levels of Cd and Zn in pregnant women during early pregnancy, examine associated alterations in urine metabolomics, and identify potential metabolic biomarkers among distinct Cd and Zn groups. Urine samples from 185 pregnant women were collected, and inductively coupled plasma mass spectrometry (ICP-MS) was used to detect Cd and Zn contents. The women were then divided into four groups according to median contents of Cd and Zn. Alterations in the metabolite profile were assessed using a liquid chromatograph mass spectrometer (LC-MS). The results showed that the gravidity of pregnant women was closely related to urinary Cd levels and that the urinary Zn contents of pregnant women with morning sickness in the first trimester were lower than that of non-morning-sick pregnant women. A total of 51 metabolites exhibited significant differential expression in the high level of Cd and Zn (HCdHZn) compared with low level of Cd and Zn (LCdLZn), the diagnostic performance of these 51 metabolites were assessed using receiver operating characteristic curve analysis and revealed that octadecylamine was a promising diagnostic indicator for evaluating the combined effects of Zn and Cd. Metabolomics analysis showed that the arginine and proline pathways were upregulated in HCdHZn compared with that in LCdLZn, suggesting a potential risk of obesity. Although higer levels of bovinic acid in HCdHZn vs. HCdLZn (high level of Cd and low level of Zn) indicated that Zn has antioxidant and anti-inflammatory properties, excessive Zn may still cause harmful effect to the human health and should be supplemented with caution. The study findings may be valuable for potential risk ahissessment of the combined effects of Cd-Zn and their interactions in pregnant women.

Relationships between blood bone metabolic biomarkers and anemia in patients with chronic kidney disease.

INTRODUCTION: Blood bone metabolic biomarkers are noninvasive indices for evaluating metabolic bone diseases. We investigated the relationships between blood bone metabolic biomarkers and anemia in chronic kidney disease (CKD) patients and analyzed the effects of parathyroidectomy (PTX) on the above indices. METHODS: In this cross-sectional study, 100 healthy controls and 239 CKD patients, including 46 secondary hyperparathyroidism (SHPT) patients with PTX, were enrolled. Moreover, a prospective study was conducted in which 28 PTX patients were followed up. The degree of anemia was classified as mild, moderate, or severe based on the tertiles of hemoglobin (Hb) levels of the anemic CKD patients, with cutoff values of 83 g/L and 102 g/L. Bone metabolic biomarkers, including calcium (Ca), phosphorus (P), intact parathyroid hormone (iPTH), fibroblast growth factor 23 (FGF23), and α-klotho, were tested. RESULTS: The mean estimated glomerular filtration rate (eGFR) in CKD patients was 25.7 ± 36.0 ml/min/1.73 m2, and 84.10% of CKD patients had anemia. The baseline Hb levels in the mild, moderate, and severe anemia subgroups were 110.86 ± 5.99 g/L, 92.71 ± 5.96 g/L, and 67.38 ± 10.56 g/L, respectively. CKD patients had higher adjusted Ca, P, alkaline phosphatase (ALP), iPTH, and FGF23 levels and lower α-klotho levels than controls. Baseline adjusted Ca, P, iPTH, and α-klotho levels were associated with Hb levels in CKD patients. Blood adjusted Ca, P, and iPTH levels were correlated with anemia severity. After PTX (median interval: 6.88 months), anemia and high blood adjusted Ca, P, iPTH, and FGF23 levels were ameliorated, while α-klotho levels were increased. CONCLUSIONS: Blood adjusted Ca, P, iPTH, and α-klotho levels were correlated with Hb levels in CKD patients. Correction of bone metabolic disorders may be a therapeutic strategy for anemia treatment.

Predictive metabolic networks reveal sex- and APOE genotype-specific metabolic signatures and drivers for precision medicine in Alzheimer's disease.

INTRODUCTION: Late-onset Alzheimer's disease (LOAD) is a complex neurodegenerative disease characterized by multiple progressive stages, glucose metabolic dysregulation, Alzheimer's disease (AD) pathology, and inexorable cognitive decline. Discovery of metabolic profiles unique to sex, apolipoprotein E (APOE) genotype, and stage of disease progression could provide critical insights for personalized LOAD medicine. METHODS: Sex- and APOE-specific metabolic networks were constructed based on changes in 127 metabolites of 656 serum samples from the Alzheimer's Disease Neuroimaging Initiative cohort. RESULTS: Application of an advanced analytical platform identified metabolic drivers and signatures clustered with sex and/or APOE ɛ4, establishing patient-specific biomarkers predictive of disease state that significantly associated with cognitive function. Presence of the APOE ɛ4 shifts metabolic signatures to a phosphatidylcholine-focused profile overriding sex-specific differences in serum metabolites of AD patients. DISCUSSION: These findings provide an initial but critical step in developing a diagnostic platform for personalized medicine by integrating metabolomic profiling and cognitive assessments to identify targeted precision therapeutics for AD patient subgroups through computational network modeling.

Untargeted Metabolomics Identifies Biomarkers for MCADD Neonates in Dried Blood Spots.

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common inherited mitochondrial metabolic disease of fatty acid ß-oxidation, especially in newborns. MCADD is clinically diagnosed using Newborn Bloodspot Screening (NBS) and genetic testing. Still, these methods have limitations, such as false negatives or positives in NBS and the variants of uncertain significance in genetic testing. Thus, complementary diagnostic approaches for MCADD are needed. Recently, untargeted metabolomics has been proposed as a diagnostic approach for inherited metabolic diseases (IMDs) due to its ability to detect a wide range of metabolic alterations. We performed an untargeted metabolic profiling of dried blood spots (DBS) from MCADD newborns (n = 14) and healthy controls (n = 14) to discover potential metabolic biomarkers/pathways associated with MCADD. Extracted metabolites from DBS samples were analyzed using UPLC-QToF-MS for untargeted metabolomics analyses. Multivariate and univariate analyses were used to analyze the metabolomics data, and pathway and biomarker analyses were also performed on the significantly identified endogenous metabolites. The MCADD newborns had 1034 significantly dysregulated metabolites compared to healthy newborns (moderated t-test, no correction, p-value ≤ 0.05, FC 1.5). A total of 23 endogenous metabolites were up-regulated, while 84 endogenous metabolites were down-regulated. Pathway analyses showed phenylalanine, tyrosine, and tryptophan biosynthesis as the most affected pathways. Potential metabolic biomarkers for MCADD were PGP (a21:0/PG/F1alpha) and glutathione, with an area under the curve (AUC) of 0.949 and 0.898, respectively. PGP (a21:0/PG/F1alpha) was the first oxidized lipid in the top 15 biomarker list affected by MCADD. Additionally, glutathione was chosen to indicate oxidative stress events that could happen during fatty acid oxidation defects. Our findings suggest that MCADD newborns may have oxidative stress events as signs of the disease. However, further validations of these biomarkers are needed in future studies to ensure their accuracy and reliability as complementary markers with established MCADD markers for clinical diagnosis.

Aqueous metabolome of tissue-specific conditional Pten-knockout mouse prostate cancer and TRAMP neuroendocrine carcinoma.

BACKGROUND: Metabolic reprograming is now a recognized hallmark of cancer. The prostate-specific phosphatase and tensin homolog deleted on chromosome 10 (Pten) gene-conditional knockout (KO) mouse carcinogenesis model is highly desirable for studying prostate cancer biology and prevention due to its close resemblance of primary molecular defects and histopathological features of human prostate cancer. We have recently published macromolecular profiling of this model by proteomics and transcriptomics, denoting a preeminence of inflammation and myeloid suppressive immune cell features. Here, we performed metabolomic analyses of Pten-KO prostate versus wild type (WT) counterpart for discernable changes in the aqueous metabolites and contrasted to those in the TRAMP neuroendocrine carcinoma (NECa). METHODS: Three matched pairs of tissue-specific conditional Pten-KO mouse prostate and WT prostate of litter/cage-mates at 20-22 weeks of age and three pairs of TRAMP NECa versus WT (28-31 weeks) were profiled for their global aqueous metabolite changes, using hydrophilic interaction liquid chromatography-tandem mass spectrometry. RESULTS: The Pten-KO prostate increased purine nucleotide pools, cystathionine, and both reduced and oxidized glutathione (GSH, GSSG), and gluconate/glucuronate species in addition to cholesteryl sulfate and polyamine precursor ornithine. On the contrary, Pten-KO prostate contained diminished pools of glycolytic intermediates and phosphorylcholine derivatives, select amino acids, and their metabolites. Bioinformatic integration revealed a significant shunting of glucose away from glycolysis-citrate cycle and glycerol-lipid genesis to pentose phosphate cycle for NADPH/GSH/GSSG redox and pentose moieties for purine and pyrimidine nucleotides, and glycosylation/glucuronidation. Implicit arginine catabolism to ornithine was consistent with immunosuppression in Pten-KO model. While also increased in cystathionine-GSH/GSSG, purine, and pyrimidine nucleotide pools and glucuronidation at the expense of glycolysis-citrate cycle, the TRAMP NECa increased abundance of many amino acids, methyl donor S-adenosyl-methionine, and intermediates for phospholipids without increasing cholesteryl sulfate or ornithine. CONCLUSIONS: The aqueous metabolomic patterns in Pten-KO prostate and TRAMP NECa shared similarities in the greater pools of cystathionine, GSH/GSSG redox pair, and nucleotides and shunting away from glycolysis-citrate cycle in both models. Remarkable metabolic distinctions between them included metabolisms of many amino acids (protein synthesis; arginine-ornithine/immune suppression) and cholesteryl sulfate and methylation donor for epigenetic regulations.

Integrative metabolomic profiling reveals aberrations in myometrium associated with adenomyosis: a pilot study.

BACKGROUND: Uterine adenomyosis is a common gynecologic disease in premenopausal women, the pathological mechanism of which remains largely unknown. The aim of this study was to identify metabolic biomarkers significantly altered in the myometrium of adenomyosis patients. METHODS: The comprehensive metabolomic profiles of 17 myometrium specimens from adenomyosis patients and 25 control specimens were analyzed using untargeted approach by combination of gas chromatography-mass spectrometry and high performance liquid chromatography-mass spectrometry. Metabolic data were filtered using orthogonal partial least square-discriminant analysis and univariate statistics. RESULTS: We firstly demonstrated that the myometrial metabolome of women with adenomyosis is distinct from that of women without adenomyosis. A total of 106 metabolites, mainly including nucleosides, lipids (including acylcarnitines), amino acids, organic acids and carbohydrates, were found to be differentially expressed in myometrium of uteri with adenomyosis compared to the control subjects. Functional inferences of these perturbed metabolites indicated that inflammation, oxidative stress, cell proliferation and apoptosis, and energy metabolism appeared to be involved in the progress of adenomyosis. CONCLUSION: This study firstly described the integrated metabolic signatures of the adenomyosis uterus, which provided novel insights for the pathogenesis study of this disease.

Training and retention effects of paced and music-synchronised walking exercises on pre-older females: an interventional study.

BACKGROUND: Physical activity at pre-older ages (55-64 years) can greatly affect one's physical fitness, health, physical-activity behaviour, and quality of life at older ages. The objective of this study was to conduct a 24-week walking-exercise programme among sedentary pre-older females and investigate the influence of different walking cadences on cardiorespiratory fitness and associated biomarkers. METHODS: A total of 78 pre-older sedentary female participants were recruited and randomly assigned to normal (n = 36), paced (n = 15), music-synchronised (n = 15) walking, and no-exercise control (n = 12) groups, respectively. The normal, paced, and music-synchronised walking groups walked at a cadence of 120 steps/min, 125 steps/min, and 120-128 steps/min, respectively, under supervised conditions. Anthropometric characteristics, step length, nutrient intake, blood pressure and composition, and cardiorespiratory fitness were measured at baseline, the 12th week of the programme, the 24th week of the programme (completion), and after a 12-week retention period, which began immediately upon completion of the programme and did not feature any supervised exercises. RESULTS: All walking conditions improved high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, step length, maximum oxygen consumption (VO2max), and oxidative capacity at anaerobic threshold (all P < 0.001); however, after the 12-week retention period only the training effects of HDL-C (P < 0.05) and VO2max (P < 0.05) remained robust. Additionally, music-synchronised walking was found to reduce the fat ratio (P = 0.031), while paced walking was found to reduce body mass (P = 0.049). CONCLUSIONS: The significant pre-post changes in health-related outcomes across the 24-week walking intervention, including improved blood composition, longer step length, and better cardiorespiratory capacity, show that this intervention is promising for improving health and fitness. When, during the retention period, the participants resumed their usual lifestyles without supervised exercise, most physiological biomarkers deteriorated. Thus, for sedentary middle-aged females, persistent behavioural change is necessary to retain the health benefits of physical exercise.

Circulating metabolites serve as diagnostic biomarkers for HER2-positive breast cancer and have predictive value for trastuzumab therapy outcomes.

Human epidermal growth factor receptor 2 (HER2)-positive is a particularly aggressive type of the breast cancer. Trastuzumab-based therapy is a standard treatment for HER2-positive breast cancer, but some patients are resistance to the therapy. There are no known diagnostic biomarkers to improve the early diagnosis of HER2-positive breast cancer and the clinical utility of trastuzumab therapy. Using ultrahigh-performance liquid time of flight mass spectrometry (UPLC-TOF-MS)-based serum metabolomics and multivariate statistical analysis, we investigated and identified the circulating metabolites L-arginine and arachidonic acid were elevated in trastuzumab-responsive and trastuzumab-resistant HER2-positive breast cancer patients, and increased until reaching their peaks in trastuzumab-resistant HER2-positive breast cancer patients. Moreover, an equation for assessing the risk scores based on linear logistic regression models involving L-arginine and arachidonic acid was created, which was beneficial for revealing metabolic changes in HER2-positive breast cancer and enhancing current trastuzumab-based therapy. In summary, we develop serum-based metabolic biomarkers for diagnosis of HER2-positive breast cancers and predicts the therapeutic effects of trastuzumab therapy.

Interaction between CETP Taq1B polymorphism and HEI, DQI and DPI on metabolic biomarkers in patients with type 2 diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a multidimensional consequence of environmental and genetic factors. Cholesteryl ester transfer protein (CETP) Taq1B polymorphism has been reported as a main predictor of dyslipidaemia, comprising an important complication in persons with T2DM. However, diet could affect T2DM patients metabolic health. METHODS: We investigated the combination of gene-diet effects on some metabolic biomarkers. In our cross-sectional study, blood samples of 220 patients were collected. Dietary indices (healthy eating index, dietary quality index and dietary phytochemical index) were obtained from a validated semi-quantitative food frequency questionnaire. CETP Taq1B polymorphism was genotyped by a polymerase chain reaction-restriction fragment polymorphism method. Data were analysed by analysis of covariance. RESULTS: The interaction between the CETP Taq1B polymorphism and dietary indices on low density lipoprotein/high density lipoprotein was significant (p < 0.001 both crude and adjusted models). In addition, the interaction between polymorphism and dietary quality index on total antioxidant capacity (p = 0.004 crude model, p = 0.005 after adjusting) and pentraxin 3 (p = 0.01 both crude and adjusted models) was significant. Also, the interaction between polymorphism and healthy eating index on waist circumference (p = 0.005 both crude and adjusted models) and dietary phytochemical index on interleukin-18 (p = 0.03 crude model) was significant. CONCLUSIONS: Our results indicated the effect of CETP Taq1B polymorphism on some inflammatory and anthropometrics markers (total antioxidant capacity, pentraxin 3, interleukin-18, low density lipoprotein/high density lipoprotein and waist circumference) with high and low adherence to dietary incides.

Naturally stressed? Glucocorticoid profiles in blubber of blue and gray whales in response to life history parameters.

The goal of the present study was to carry out a thorough methodological validation and describe baseline profiles for glucocorticoid hormones (cortisol and corticosterone) in blubber from blue (n = 77) and gray (n = 103) whales from the eastern North Pacific Ocean. For each species, we modelled cortisol and corticosterone concentrations in response to life history parameters (age, sex, reproductive status) and season or geographic location. In blue whales, cortisol concentrations did not vary significantly by age class, sex, or reproductive status, whereas corticosterone was significantly lower in immature than in adult females (p < .001). In gray whales, cortisol concentrations were significantly higher in lactating whales (p < .05), while corticosterone was significantly different between females and males (p = .001) and elevated in calves (p = .003). In gray whales, corticosterone concentrations were significantly lower in males sampled later in the year (August to November) compared to both sexes sampled between March and August (p = .05), but no seasonal trend occurred in blue whales. Our results indicate that glucocorticoid actions vary between species and sex in large whales. Analysis of multiple hormones improves our understanding of the physiology of maintaining metabolic homeostasis or coping with chronic stressors.

High-throughput metabolomics method based on liquid chromatography-mass spectrometry: Insights into the underlying mechanisms of salinity-alkalinity exposure-induced metabolites changes in Barbus capito.

It is critical to investigate the adaptive development and the physiological mechanism of fish in external stimulation. In this study, the response of Barbus capito to salinity-alkalinity exposure was explored by high-throughput nontargeted and liquid chromatography-mass spectrometry-based metabolomics to investigate metabolic biomarker and pathway changes. Meanwhile, the biochemical indexes of Barbus capito were measured to discover the chronic impairment response to salinity-alkalinity exposures. A total of 29 tissue metabolites were determined to deciphering the endogenous metabolic changes of fishes during the different concentration salinity-alkalinity exposures environment, which were mainly involved in the key metabolism including the phenylalanine, tyrosine, and tryptophan biosynthesis, arachidonic acid metabolism, pyruvate metabolism, citrate cycle, and glycerophospholipid metabolism. Finally, we found the amino acid metabolism as key target was associated with the endogenous metabolites and metabolic pathways of Barbus capito to salinity-alkalinity exposures. In conclusion, metabolomics is a potentially powerful tool to reveal the mechanism information of fish in various exposure environments.

Biomarkers of Glyco-Metabolic Control in Hemodialysis Patients: Glycated Hemoglobin vs. Glycated Albumin.

Background and Objectives: Glycated hemoglobin (HbA1c) dosage is considered the gold standard in glycol-metabolic monitoring, but it presents limits, which can underestimate the glycemia trend. In this regard, it was introduced the glycated albumin (GA). The aim of the study is to verify the predictivity of the GA compared to HbA1c in identifying glyco-metabolic alterations in non-diabetic and diabetic hemodialysis (HD) patients. Materials and Methods: For this purpose, we conducted a multicenter study involving one analysis laboratory and six dialysis centers in the Lazio region (Rome, Italy). Both diabetic and non-diabetic HD patients represent the study population, and the protocol included five time points. Results: The analyzed data highlighted the ability of GA to predict changes in glycemic metabolism in HD patients, and GA values are not significantly influenced, like HbA1c, by dialysis therapy itself and by comorbidities of the uremic state, such as normochromic and normocytic anemia. Thus, GA seems to reflect early glyco-metabolic alterations, both in patients with a previous diagnosis of diabetes and in subjects without diabetes mellitus. As part of this study, we analyzed two HD patients (one diabetic and one non-diabetic) in which GA was more predictive of glycol-metabolic alterations compared to HbA1c. Our study confirms the need to compare classical biomarkers used for the monitoring of glyco-metabolic alterations with new ones, likely more reliable and effective in specific subgroups of patients in which the classic biomarkers can be influenced by the preexisting pathological conditions. Conclusions: In conclusion, our evidence highlights that in uremic patients, GA shows a better ability to predict glyco-metabolic alterations allowing both an earlier diagnosis of DM and a prompt modulation of the hypoglycemic therapy, thus improving the clinical management of these patients.