Search Results (22)

Ophiocordyceps sinensis is a fungus that is cultured through fermentation from wild Chinese cordyceps. While studies have examined its metabolites, the evaluation of its antioxidant capacity remains to be conducted. The antioxidant results of O. sinensis indicate that the ferric ion-reducing antioxidant power (FRAP), antioxidant capacity (2.74 ± 0.12 μmol Trolox/g), 2,2-diphenyl-1-picrylhydrazyl (DPPH•) free radical scavenging rate (60.21 ± 0.51%), and the hydroxyl free radical scavenging rate (91.83 ± 0.68%) reached a maximum on day 30. Using LC-MS/MS to measure the metabolites on D24, D30, and D36, we found that the majority of the differential accumulated metabolites (DAMs) primarily accumulate in lipids, organoheterocyclic compounds, and organic acids and their derivatives. Notably, the DAMs exhibiting high peaks include acetylcarnitine, glutathione, linoleic acid, and L-propionylcarnitine, among others. The transcriptome analysis results indicate that the differentially expressed genes (DEGs) exhibiting high expression peaks on D30 primarily included lnaA, af470, and ZEB1; high expression peaks on D24 comprised SPBC29A3.09c and YBT1; high expression peaks on D36 included dtxS1, PA1538, and katG. The combined analysis revealed significant and extremely significant positive and negative correlations between all the DAMs and DEGs. The primary enriched pathways (p < 0.05) included glutathione metabolism, tryptophan metabolism, carbon metabolism, biosynthesis of secondary metabolites, and phenylalanine metabolism. The metabolic pathway map revealed that the DAMs and DEGs influencing the antioxidant activity of O. sinensis were significantly up-regulated on D30 but down-regulated on D36. The correlation analysis suggests that an increase in the content of DEGs and DAMs promotes an increase in the levels of enzyme and non-enzyme substances, ultimately enhancing the antioxidant capacity of O. sinensis. These findings serve as a reference of how DAMs and DEGs affect the antioxidant activity of O. sinensis. This may contribute to the enhanced development and application of O. sinensis. Full article

Background: Plasma metabolites could be suitable as predictive biomarkers for cardiovascular pathologies or death, thereby improving the prediction of protein biomarkers. The release of acylcarnitines may be altered after coronary artery disease (CAD) in subjects with recurrent clinical outcomes, and this could be used as a prognosis tool. Methods: Patients with stable coronary artery disease (SCAD) who had suffered an acute coronary syndrome 6–9 months before were followed for up to 4.3 years for adverse events. Soluble pro-inflammatory/fibrotic proteins, and a panel of 13 amino acids and 13 acylcarnitines, were evaluated by ELISA and metabolomics analyses as potential predictors of a primary outcome [heart failure (HF) or death]. Results: Among 139 patients (67.0 years old, BMI = 28.6 kg/m², and 71.2% male), 25 developed the primary outcome after a mean follow-up of 2.2 years. These patients showed increased plasma levels of NT-proBNP (1300 vs. 250 pg/mL; p < 0.001), pro-inflammatory/fibrotic MCP-1 (1.7 vs. 1.4 × 10² pg/mL; p = 0.043), Gal-3 (12.7 vs. 7.9 ng/mL; p < 0.001), and NGAL (2.7 vs. 1.6 × 10² ng/mL; p < 0.001), and lower acetyl- and propionylcarnitines (0.59 vs. 0.99 µM, p = 0.007, and 3.22 vs. 6.49 × 10⁻² µM, p < 0.001, respectively). Instead, plasma amino acids were not significantly changed. Through a multivariable logistic regression analysis, a combined model of age, Gal-3, and the NGAL/propionylcarnitine ratio showed the highest prediction for HF or death (AUC = 0.88, sensitivity = 0.8, and specificity = 0.81; p < 0.001). Conclusions: Patients with SCAD led to recurrent HF or all-cause death. Interestingly, increased levels of plasma NGAL and Gal-3, and a reduction in propionylcarnitine, could predict the occurrence of these events. Full article

The objective of this study was to investigate the regulatory effects of a high-fiber content feed on the productive performance, meat quality, and fat acid composition. A total of 18 120-day-old Yushan pigs with similar initial body weight were randomly allotted into high-concentrate diet (high energy, HE) and high-fiber diet (low energy, LE) treatments for the determination of regulatory effects on productive performance, meat quality, and fatty acid content. Further, blood metabolomic, gut microbiota, and liver energy-related gene expression measurements were used to investigate the underlying mechanisms. Results showed that the LE treatment significantly increased ADFI while decreasing carcass weight, fat percentage, and IMF. Metabolomic results showed that the high-fiber treatment significantly down-regulated metabolites that participated in lipid metabolism such as cyclic ADP-ribose and hippuric acid, while up-regulated metabolites were mainly enriched in nitrogen metabolism such as DL-arginine and propionylcarnitine (p < 0.05). Microbial results showed relative abundances of Lactobacillus and Bifidobacterium are significantly proliferated in the high-fiber feeding treatments (p < 0.05). Transcriptomic results showed that genes mainly enriched into the lipid metabolism are significantly up-regulated under the high-fiber dietary treatment (p < 0.05). Conclusion: higher dietary fiber significantly reduced dietary energy provision, effectively decreased the backfat and abdominal fat content of Yushan pigs through proliferating intestinal fiber-degradable bacteria, and up-regulating the hepatic lipolysis-related gene expression. Full article

Methylmalonyl-CoA epimerase enzyme (MCEE) is responsible for catalyzing the isomeric conversion between D- and L-methylmalonyl-CoA, an intermediate along the conversion of propionyl-CoA to succinyl-CoA. A dedicated test for MCEE deficiency is not included in the newborn screening (NBS) panels but it can be incidentally identified when investigating methylmalonic acidemia and propionic acidemia. Here, we report for the first time the biochemical description of a case detected by NBS. The NBS results showed increased levels of propionylcarnitine (C3) and 2-methylcitric acid (MCA), while methylmalonic acid (MMA) and homocysteine (Hcy) were within the reference limits. Confirmatory analyses revealed altered levels of metabolites, including MCA and MMA, suggesting a block in the propionate degradation pathway. The analysis of methylmalonic pathway genes by next-generation sequencing (NGS) allowed the identification of the known homozygous nonsense variation c.139C>T (p.R47X) in exon 2 of the MCE gene. Conclusions: Elevated concentrations of C3 with a slight increase in MCA and normal MMA and Hcy during NBS should prompt the consideration of MCEE deficiency in differential diagnosis. Increased MMA levels may be negligible at NBS as they may reach relevant values beyond the first days of life and thus could be identified only in confirmatory analyses. Full article

The genetic and environmental determinants of serum propionylcarnitine concentrations (PC) remain largely unexplored. This study investigated the impact of genetic and environmental factors on serum propionylcarnitine levels in middle-aged and elderly participants from the Ansan/Ansung cohort of the Korean Genome and Epidemiology Study. Our goal was to understand the role of PC on the risk of metabolic syndrome (MetS) leading to cardiovascular disease, particularly concerning branched-chain amino acid (BCAA) metabolism. We analyzed participants’ demographic, lifestyle, and biochemical data with and without MetS. Serum metabolite concentrations, including carnitine, acylcarnitine, and amino acid concentrations, were measured, and the components of MetS were evaluated. Genetic variants associated with low and high PC were selected using genome-wide association studies after adjusting for MetS-related parameters. Further, genetic variants and lifestyle factors that interacted with the polygenic risk score (PRS) were analyzed. Participants with MetS were older and less educated, and their alcohol intake was higher than non-MetS participants. PC was significantly associated with the MetS risk and increased the serum levels of BCAAs and other amino acids. Higher PC positively correlated with MetS components, insulin resistance, and cardiovascular risk factors. Intake of calcium, sodium, and vitamin D were inversely associated with PC, but coffee consumption was positively linked to PC. Multiple C2 And Transmembrane Domain Containing-1 (MCTP1)_rs4290997, Kinesin Family Member-7 (KIF7)_rs2350480, Coagulation Factor-II (F2)_rs2070850, Peroxisomal Biogenesis Factor-3 (PEX3)_rs223231, TBC1 Domain Family Member-22A (TBC1D22A)_rs910543, and Phospholipase A2 Group-IV-C (PLA2G4C)_rs7252136 interact with each other to have a threefold influence on PC. The PRS for the six-genetic variant model also interacted with age; the diet rich in beans, potato, and kimchi; and smoking status, influencing PC. In conclusion, elevated PC was associated with MetS and cardiovascular disease risk, suggesting their potential as disease biomarkers. Full article

Background: Osteoporosis, which is a bone disease, is characterized by low bone mineral density and an increased risk of fractures. The heel bone mineral density is often used as a representative measure of overall bone mineral density. Lipid metabolism, which includes processes such as fatty acid metabolism, glycerol metabolism, inositol metabolism, bile acid metabolism, carnitine metabolism, ketone body metabolism, sterol and steroid metabolism, etc., may have an impact on changes in bone mineral density. While some studies have reported correlations between lipid metabolism and heel bone mineral density, the overall causal relationship between metabolites and heel bone mineral density remains unclear. Objective: to investigate the causal relationship between lipid metabolites and heel bone mineral density using two-sample Mendelian randomization analysis. Methods: Summary-level data from large-scale genome-wide association studies were extracted to identify genetic variants linked to lipid metabolite levels. These genetic variants were subsequently employed as instrumental variables in Mendelian randomization analysis to estimate the causal effects of each lipid metabolite on heel bone mineral density. Furthermore, metabolites that could potentially be influenced by causal relationships with bone mineral density were extracted from the KEGG and WikiPathways databases. The causal associations between these downstream metabolites and heel bone mineral density were then examined. Lastly, a sensitivity analysis was conducted to evaluate the robustness of the results and address potential sources of bias. Results: A total of 130 lipid metabolites were analyzed, and it was found that acetylcarnitine, propionylcarnitine, hexadecanedioate, tetradecanedioate, myo-inositol, 1-arachidonoylglycerophosphorine, 1-linoleoylglycerophoethanolamine, and epiandrosterone sulfate had a causal relationship with heel bone mineral density (p < 0.05). Furthermore, our findings also indicate an absence of causal association between the downstream metabolites associated with the aforementioned metabolites identified in the KEGG and WikiPathways databases and heel bone mineral density. Conclusion: This work supports the hypothesis that lipid metabolites have an impact on bone health through demonstrating a causal relationship between specific lipid metabolites and heel bone mineral density. This study has significant implications for the development of new strategies to osteoporosis prevention and treatment. Full article

Obesity is a chronic and complex disease, with an increasing incidence worldwide that is associated with metabolic disorders such as type 2 diabetes mellitus (T2DM). Thus, it is important to determine the differences between metabolically healthy obese individuals and those with metabolic disorders. The aim of this study was to perform an untargeted metabolomics assay in women with morbid obesity (MO) compared to a normal weight group, and to differentiate the metabolome of these women with MO who present with T2DM. We carried out a liquid chromatography-mass spectrometry-based untargeted metabolomics assay using serum samples of 209 Caucasian women: 73 with normal weight and 136 with MO, of which 71 had T2DM. First, we found increased levels of choline and acylglycerols and lower levels of bile acids, steroids, ceramides, glycosphingolipids, lysophosphatidylcholines, and lysophosphatidylethanolamines in MO women than in the control group. Then, in MO women with T2DM, we found increased levels of glutamate, propionyl-carnitine, bile acids, ceramides, lysophosphatidylcholine 14:0, phosphatidylinositols and phosphoethanolamines, and lower levels of Phe-Ile/Leu. Thus, we found metabolites with opposite trends of concentration in the two metabolomic analyses. These metabolites could be considered possible new factors of study in the pathogenesis of MO and associated T2DM in women. Full article

Escherichia coli (E. coli) F17 is one of the most common pathogens causing diarrhea in farm livestock. In the previous study, we accessed the transcriptomic and microbiomic profile of E. coli F17-antagonism (AN) and -sensitive (SE) lambs; however, the biological mechanism underlying E. coli F17 infection has not been fully elucidated. Therefore, the present study first analyzed the metabolite data obtained with UHPLC-MS/MS. A total of 1957 metabolites were profiled in the present study, and 11 differential metabolites were identified between E. coli F17 AN and SE lambs (i.e., FAHFAs and propionylcarnitine). Functional enrichment analyses showed that most of the identified metabolites were related to the lipid metabolism. Then, we presented a machine-learning approach (Random Forest) to integrate the microbiome, metabolome and transcriptome data, which identified subsets of potential biomarkers for E. coli F17 infection (i.e., GlcADG 18:0-18:2, ethylmalonic acid and FBLIM1); furthermore, the PCCs were calculated and the interaction network was constructed to gain insight into the crosstalk between the genes, metabolites and bacteria in E. coli F17 AN/SE lambs. By combing classic statistical approaches and a machine-learning approach, our results revealed subsets of metabolites, genes and bacteria that could be potentially developed as candidate biomarkers for E. coli F17 infection in lambs. Full article

Untreated vitamin B12 (B12) deficiency may cause delayed development in infants. Several newborn screening (NBS) programs have reported an increased detection rate of B12 deficiency when second-tier dried blood spot (DBS) analyses of total homocysteine (tHcy) and methylmalonic acid (MMA) are included. This is a retrospective study of newborns reported from NBS during 2012–2021 with confirmed B12 deficiency. DBSs were retrieved from the NBS biobank for second-tier MMA and tHcy analysis. Thirty-one newborns were diagnosed with B12 deficiency out of 552970 screened. Twenty-five were ascertained from sixty-one false positive (FP) cases of methylmalonic acidemia and propionic acidemia (PA), and six infants screened positive for other NBS metabolic diseases with propionylcarnitine (C3) in the normal range. In the original DBS, 7/23 (30%) and 12/23 (52%) of B12-deficient newborns with FP methylmalonic acidemia/PA had MMA and tHcy > 99th percentile. B12 deficiency was a common differential diagnosis of screening positive for methylmalonic and PA. C3 failed to identify a subset of newborns with B12 deficiency. Second-tier MMA and tHcy analyses in the DBS showed suboptimal sensitivity for identifying infants with B12 deficiency. The shortcomings of NBS should be acknowledged when considering B12 deficiency as a primary target of NBS panels. Full article

Diagnosing the cause of fatal intoxication by antipsychotic agents is an important task in forensic practice. In the 2020 Annual Report of the American Association of Poison Control Centers, among 40 deaths caused by antipsychotics, 21 cases were diagnosed as “probably responsible”, thereby indicating that more objective diagnostic tools are needed. We used liquid chromatography-mass spectrometry-based integrated metabolomics analysis to measure changes in metabolic profiles in the plasma of mice that died from fatal intoxication due to chlorpromazine (CPZ) or olanzapine (OLA). These results were used to construct a stable discriminative classification model (DCM) comprising L-acetylcarnitine, succinic acid, and propionylcarnitine between fatal intoxication caused by CPZ/OLA and cervical dislocation (control). Performance evaluation of the classification model in mice that suffered fatal intoxication showed relative specificity for different pharmacodynamic drugs and relative sensitivity in different life states (normal, intoxication, fatal intoxication). A stable level of L-acetylcarnitine and variable levels of succinic acid and propionylcarnitine between fatal-intoxication and intoxication groups revealed procedural perturbations in metabolic pathways related to fatal intoxication by CPZ/OLA. Additional stability studies revealed that decomposition of succinic acid in fatal-intoxication samples (especially in the OLA group) could weaken the prediction performance of the binary-classification model; however, levels of these three potential metabolites measured within 6 days in fresh samples kept at 4 °C revealed a good performance of our model. Our findings suggest that metabolomics analysis can be used to explore metabolic alterations during fatal intoxication due to use of antipsychotic agents and provide evidence for the cause of death. Full article

Cord blood metabolites can be predictive of long-term disease risk, but how levels of different metabolites might vary with respect to maternal diet is not well understood. The aim of this study was to evaluate the associations of different dietary patterns during pregnancy with cord blood metabolites (including glycerophospholipid fatty acids, polar lipids, non-esterified fatty acids, amino acids, and the sum of hexoses). Participants from the German LISA birth cohort study, with available data on targeted cord blood metabolomics and maternal diet, were included (n = 739). Maternal diet during the last 4 weeks of pregnancy was assessed by a non-quantitative food-frequency questionnaire. Using factor analysis, ten dietary patterns were identified, which were used in linear regression models exploring associations with cord blood metabolites. After correction for multiple hypothesis testing and adjustment for basic covariates, “fish and shellfish” was associated with higher glycerophospholipid fatty acid C20:5 n3 and lower C22:5 n6, whereas the “meat and potato” pattern was directly associated with propionylcarnitine (C3:0). The observed associations highlight potential metabolic pathways involved in the early programming of health and disease through maternal diet, as well as the potential for establishing quantitative biomarkers for dietary patterns of pregnant women. Full article

Objective: To assess the longitudinal metabolic patterns during the evolution of bronchopulmonary dysplasia (BPD) development. Methods: A case-control dataset of preterm infants (<32-week gestation) was obtained from a multicenter database, including 355 BPD cases and 395 controls. A total of 72 amino acid (AA) and acylcarnitine (AC) variables, along with infants’ calorie intake and growth outcomes, were measured on day of life 1, 7, 28, and 42. Logistic regression, clustering methods, and random forest statistical modeling were utilized to identify metabolic variables significantly associated with BPD development and to investigate their longitudinal patterns that are associated with BPD development. Results: A panel of 27 metabolic variables were observed to be longitudinally associated with BPD development. The involved metabolites increased from 1 predominant different AC by day 7 to 19 associated AA and AC compounds by day 28 and 16 metabolic features by day 42. Citrulline, alanine, glutamate, tyrosine, propionylcarnitine, free carnitine, acetylcarnitine, hydroxybutyrylcarnitine, and most median-chain ACs (C₅:C₁₀) were the most associated metabolites down-regulated in BPD babies over the early days of life, whereas phenylalanine, methionine, and hydroxypalmitoylcarnitine were observed to be up-regulated in BPD babies. Most calorie intake and growth outcomes revealed similar longitudinal patterns between BPD cases and controls over the first 6 weeks of life, after gestational adjustment. When combining with birth weight, the derived metabolic-based discriminative model observed some differences between those with and without BPD development, with c-statistics of 0.869 and 0.841 at day 7 and 28 of life on the test data. Conclusions: The metabolic panel we describe identified some metabolic differences in the blood associated with BPD pathogenesis. Further work is needed to determine whether these compounds could facilitate the monitoring and/or investigation of early-life metabolic status in the lung and other tissues for the prevention and management of BPD. Full article

Recent scientific evidence suggests that chronic pain phenotypes are reflected in metabolomic changes. However, problems associated with chronic pain, such as sleep disorders or obesity, may complicate the metabolome pattern. Such a complex phenotype was investigated to identify common metabolomics markers at the interface of persistent pain, sleep, and obesity in 71 men and 122 women undergoing tertiary pain care. They were examined for patterns in d = 97 metabolomic markers that segregated patients with a relatively benign pain phenotype (low and little bothersome pain) from those with more severe clinical symptoms (high pain intensity, more bothersome pain, and co-occurring problems such as sleep disturbance). Two independent lines of data analysis were pursued. First, a data-driven supervised machine learning-based approach was used to identify the most informative metabolic markers for complex phenotype assignment. This pointed primarily at adenosine monophosphate (AMP), asparagine, deoxycytidine, glucuronic acid, and propionylcarnitine, and secondarily at cysteine and nicotinamide adenine dinucleotide (NAD) as informative for assigning patients to clinical pain phenotypes. After this, a hypothesis-driven analysis of metabolic pathways was performed, including sleep and obesity. In both the first and second line of analysis, three metabolic markers (NAD, AMP, and cysteine) were found to be relevant, including metabolic pathway analysis in obesity, associated with changes in amino acid metabolism, and sleep problems, associated with downregulated methionine metabolism. Taken together, present findings provide evidence that metabolomic changes associated with co-occurring problems may play a role in the development of severe pain. Co-occurring problems may influence each other at the metabolomic level. Because the methionine and glutathione metabolic pathways are physiologically linked, sleep problems appear to be associated with the first metabolic pathway, whereas obesity may be associated with the second. Full article

Wisconsin’s newborn screening program implemented second-tier testing on specimens with elevated propionylcarnitine (C3) to aid in the identification of newborns with propionic and methylmalonic acidemias. The differential diagnosis for elevated C3 also includes acquired vitamin B12 deficiency, which is currently categorized as a false positive screen. The goal of this study was to summarize screening data and evaluate their effectiveness at establishing diagnoses and categorizing false positive cases. All Wisconsin newborns born between 2013 and 2019 with a positive first-tier screen for C3 were included in this study. For each case the first- and second-tier newborn screening data and confirmatory test results were compiled. The clinical determination for each case was reviewed and categorized into groups: inborn error of metabolism, maternal B12 deficiency, infant B12 deficiency, and false positive. A review of the screening data showed a significant overlap in the concentration of biomarkers for newborns with genetic versus acquired disease. Additionally, a review of confirmatory test results showed incomplete ascertainment of maternal vitamin B12 status. The Wisconsin newborn screening program recommended a confirmatory testing algorithm to aid in the diagnosis of inborn errors of metabolism and acquired vitamin B12 deficiency. Full article

About half of patients with Graves’ disease develop an orbitopathy related to an inflammatory expansion of the periorbital adipose tissue and muscles. We used a targeted metabolomic approach measuring 188 metabolites by mass spectrometry to compare the metabolic composition of tears in patients with active (n = 21) versus inactive (n = 24) thyroid-associated orbitopathy. Among the 44 metabolites accurately measured, 8 showed a significant alteration of their concentrations between the two groups. Two short-chain acylcarnitines, propionylcarnitine and butyrylcarnitine, and spermine showed increased concentrations in the tears of patients with active orbitopathy, whereas ornithine, glycine, serine, citrulline and histidine showed decreased concentrations in this group. In addition, the ratio putrescine/ornithine, representing the activity of ornithine decarboxylase, was significantly increased in patients with active compared to inactive orbitopathy (p = 0.0011, fold change 3.75). The specificity of this candidate biomarker was maintained when compared to a control group with unclassified dry eye disease. Our results suggest that the stimulation of ornithine decarboxylase by TSH receptor autoantibodies in orbital fibroblasts could lead to increased synthesis of spermine, through the increased activity of ornithine decarboxylase, that may contribute to periorbital expansion in Graves’ ophthalmopathy. Full article