Metabolomic Profiling Research Articles

Metabolomic insights into the beneficial effects of dietary purple potato on DSS-induced murine colon colitis

Inflammatory bowel disease (IBD) is characterized by disturbance in intestinal flora and metabolomic profiles. Building on previous findings that purple potato (PP) supplementation suppresses inflammation and restores intestinal barrier in dextran sulfate sodium (DSS)-treated mice, this study examined changes in the fecal metabolome in the same cohort. Mice were fed 0 % or 10 % PP for 7 weeks, with DSS administered in the fifth week of dietary treatment followed by one-week normal drinking water recovery. A total of 68 metabolites, including amino acids, fatty acids, organic acids, carbohydrates, and polyamines, were significantly altered across the groups. PP supplementation reversed changes in 13 of the 25 DSS-altered metabolites. Six microbial metabolites derived from PP polyphenols were identified and positively correlated with M2 macrophage polarization. Data suggest that dietary PP is effective in reducing inflammation and improves gut metabolites in DSS-induced colitis mice, offering a potential dietary therapy for managing IBD.

Analysis of the relationship between neonatal birth weight and meconium metabolites based on birth cohort metabolomics

Neonatal birth weight is a crucial indicator of intrauterine growth and development with important implications for child development and adult health. The birth weight of a newborn is closely linked to the nutrition and health of the mother during pregnancy as well as genetic factors. Therefore, assessing the metabolic status of the fetus in utero is greatly significant for understanding the mechanisms responsible for abnormal birth weight. While previous studies often analyzed the impact of maternal metabolism on fetal development using umbilical cord blood from pregnant women, such blood may not accurately reflect the actual intrauterine environment owing to the barrier function of the placenta; moreover, obtaining biological samples during the fetal period is challenging. Meconium, the first feces excreted by a newborn, provides ideal biological material for studying maternal and infant health. Metabolomics can reveal metabolic changes in living organisms by analyzing small molecules in biological samples; hence studying meconium samples using metabolomics technology is expected to reveal fetal metabolic changes during pregnancy, thereby providing new insights into fetal nutritional intake, growth, and development, as well as metabolic pathways related to birth weight. To gain a deeper understanding of the metabolic changes associated with birth weight, this study collected metabolomic data from the meconium of 484 newborns in the established Xiaogan birth cohort using an untargeted metabolomics technique based on liquid chromatography-high resolution mass spectrometry (LC-HRMS) and analyzed the association between meconium metabolites and birth weight. This cohort exhibited incidence rates of low birth weight (<2500 g) and macrosomia (>4000 g) of 3.3% and 7.2%, respectively, which were roughly equivalent to the national average. Orthogonal partial least squares discriminant analysis revealed significant differences between the meconium metabolomes of the low birth weight and macrosomic groups when compared to the normal weight group. We discovered significant distinctions between the differential metabolites of newborns of low birth weight and those of normal weight, as well as between macrosomic and normal weight newborns that point to disparate biological pathways. Newborns with low birth weight exhibited significantly lower levels of critical amino acids, such as glutamate and proline, compared to the normal weight group, which may be associated with placental dysfunction and maternal nutritional deficiencies. Conversely, the meconium of macrosomic newborns contained significantly elevated levels of hormone metabolites such as estrone that reflected the pathophysiological state associated with maternal metabolic diseases or excessive placental hormone levels. Our study suggests that the metabolomic profile of the meconium reflects the metabolic pathways and regulatory mechanisms at play during fetal growth and development, and offers potential metabolic biomarkers and directions for future in-depth research into diseases related to fetal development. However, this study was based solely on the Xiaogan birth cohort, which was limited to specific regions and populations. A multicenter, multiethnic, and multiregional study is expected to help validate the universality of our research findings.

Integrated multi-omics analysis of the microbial profile characteristics associated with pulmonary arterial hypertension in congenital heart disease.

Dysregulation of immune and inflammatory cells around blood vessels and metabolic dysfunction are key mechanisms in the development of pulmonary arterial hypertension (PAH). The homeostasis of the human microbiome plays a crucial role in regulating immune responses and the progression of diseases. For pulmonary arterial hypertension associated with congenital heart disease involving body-lung shunt (PAH-CHD), the potential impact of the microbiome on the "gut-lung axis" remains underexplored. This study recruited 15 healthy individuals and 15 patients with pulmonary arterial hypertension due to congenital heart disease from Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences, and Kunming Children's Hospital. We performed differential analyses of metabolites and microbiota from both the gut and lower respiratory tract for these two groups. The goal was to investigate the "gut-lung axis" microbiome and metabolome profiles in children with PAH-CHD and to analyze the interrelationships between these profiles. Ultimately, we aim to propose the potential value of these profiles in aiding diagnosis. The results indicated that the gut and pulmonary microbiota of children with PAH-CHD are characterized by an increased abundance of beneficial symbionts, which are closely linked to changes in the metabolome. Metabolite functional enrichment analysis revealed energy metabolism reprogramming in the PAH-CHD group, with active metabolic pathways associated with bile acid secretion and carnitine homeostasis. Moreover, the differential expression of metabolites was correlated with right heart function and growth development.IMPORTANCEPrevious studies have primarily focused on the relationship between the gut microbiome and PAH. However, the impact of microbial homeostasis on the progression of PAH-CHD from the perspective of the gut-lung axis has not been adequately elucidated. Our study utilizes an integrated multi-omics approach to report on the differential characteristics of gut and lung microbiota between children with PAH-CHD and reference subjects. We found that microbiota influence the pathological changes and disease manifestations of PAH-CHD through their metabolic activity. Additionally, alterations in metabolites impact the microbial ecological structure. Our findings suggest that modulating the microbiome composition may have positive implications for maintaining and regulating the immune environment and pathological progression of PAH-CHD.

Multi-omics evaluation of clinical-grade human umbilical cord-derived mesenchymal stem cells in synergistic improvement of aging related disorders in a senescence-accelerated mouse model

BackgroundThe prevalence of age-related disorders, particularly in neurological and cardiovascular systems, is an increasing global health concern. Mesenchymal stem cell (MSC) therapy, particularly using human umbilical cord-derived MSCs (HUCMSCs), has shown promise in mitigating these disorders. This study investigates the effects of HUCMSCs on aging-related conditions in a senescence-accelerated mouse model (SAMP8), with a focus on DNA damage, gut microbiota alterations, and metabolic changes.MethodsSAMP8 mice were treated with clinical-grade HUCMSCs via intraperitoneal injections. Behavioral and physical assessments were conducted to evaluate cognitive and motor functions. The Single-Strand Break Mapping at Nucleotide Genome Level (SSiNGLe) method was employed to assess DNA single-strand breaks (SSBs) across the genome, with particular attention to exonic regions and transcription start sites. Gut microbiota composition was analyzed using 16S rRNA sequencing, and carboxyl metabolomic profiling was performed to identify changes in circulating metabolites.ResultsHUCMSC treatment significantly improved motor coordination and reduced anxiety in SAMP8 mice. SSiNGLe analysis revealed a notable reduction in DNA SSBs in MSC-treated mice, especially in critical genomic regions, suggesting that HUCMSCs may mitigate age-related DNA damage. The functional annotation of the DNA breaktome indicated a potential link between reduced DNA damage and altered metabolic pathways. Additionally, beneficial alterations in gut microbiota were observed, including an increase in short-chain fatty acid (SCFA)-producing bacteria, which correlated with improved metabolic profiles.ConclusionThe administration of HUCMSCs in SAMP8 mice not only reduces DNA damage but also induces favorable changes in gut microbiota and metabolism. The observed alterations in DNA break patterns, along with specific changes in microbiota and metabolic profiles, suggest that these could serve as potential biomarkers for evaluating the efficacy of HUCMSCs in treating age-related disorders. This highlights a promising avenue for the development of new therapeutic strategies that leverage these biomarkers, to enhance the effectiveness of HUCMSC-based treatments for aging-associated diseases.

Novel metabolomic predictors of incident colorectal cancer in men and women.

Metabolomic profiles may influence colorectal cancer (CRC) development. Few studies have performed pre-diagnostic metabolome-wide analyses with CRC risk. We conducted a nested case-control study among women (Nurses' Health Study (NHS)) and men (Health Professionals Follow-up Study (HPFS)) who provided blood between 1989 and 1995. Over 22.9 years, 684 (409 NHS, 275 HPFS) incident CRC cases occurred and were matched 1:1 to controls. Liquid chromatography-mass spectrometry (LC-MS) identified 255 plasma metabolites after quality control. Cohort-specific and combined metabolite association analyses were performed using conditional logistic regression. Metabolite set enrichment analysis (MSEA) was used to identify differential abundance in metabolite classes. Weighted Correlation Network Analysis (WGCNA) provided modules of covarying metabolites, which were tested for CRC association. MSEA identified specific acylcarnitines associated with higher CRC risk and triacylglycerols with lower CRC risk among women and men. Further, phosphatidylcholines were associated with a higher risk of CRC among men. In an analysis restricted to CRC cases diagnosed two years after blood draw, myristoleic acid (OR = 1.37; 95%CI = 1.15-1.62; FDR = 0.072) and C60:12 triacylglycerol (OR = 0.75; 95%CI = 0.64-0.88; FDR = 0.072 were associated with CRC risk in women. WGCNA identified amino acids associated with CRC in men, fatty acid esters (carnitines) with distal CRC in men, and triradylcglycerols inversely associated with CRC in women. We identified pre-diagnostic CRC-associated metabolites with distinct sex-specific profiles. These results provide insight into CRC etiopathogenesis and have implications for risk prediction strategies.

Pharmacometabolomics Approach to Explore Pharmacokinetic Variation and Clinical Characteristics of a Single Dose of Desvenlafaxine in Healthy Volunteers

This study investigated the effects of a single dose of desvenlafaxine via oral administration on the pharmacokinetic parameters and clinical and laboratory characteristics in healthy volunteers using a pharmacometabolomics approach. In order to optimize desvenlafaxine’s therapeutic use and minimize potential adverse effects, this knowledge is essential. Methods: Thirty-five healthy volunteers were enrolled after a health trial and received a single dose of desvenlafaxine (Pristiq®, 100 mg). First, liquid chromatography coupled to tandem mass spectrometry was used to determine the main pharmacokinetic parameters. Next, ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry was used to identify plasma metabolites with different relative abundances in the metabolome at pre-dose and when the desvenlafaxine peak plasma concentration was reached (pre-dose vs. post-dose). Results: Correlations were observed between metabolomic profiles, such as tyrosine, sphingosine 1-phosphate, and pharmacokinetic parameters, as well as acetoacetic acid and uridine diphosphate glucose associated with clinical characteristics. Our findings suggest that desvenlafaxine may have a broader effect than previously thought by acting on the proteins responsible for the transport of various molecules at the cellular level, such as the solute carrier SLC and adenosine triphosphate synthase binding cassette ABC transporters. Both of these molecules have been associated with PK parameters and adverse events in our study. Conclusions: This altered transporter activity may be related to the reported side effects of desvenlafaxine, such as changes in blood pressure and liver function. This finding may be part of the explanation as to why people respond differently to the drug.

Human epicardial adipose tissue secretome alters metabolomic profile and induces endothelial-to-mesenchymal transition in human lymphatic endothelial cells

Abstract Background Cardiac lymphatic systems play an important role in maintaining myocardial fluid homeostasis during inflammation. We have recently reported the epicardial adipose tissue (EAT)-derived factor induces inflammation and fibrosis in atrial myocardium, which lead to atrial fibrillation (AF). However, the direct effect of EAT on the cardiac lymphatic endothelial cells (LECs) remains unknown. Objective To elucidate the effect of EAT on cardiac LECs, as one of the potential causes of AF. Methods Human EAT samples were collected from 18 consecutive patients with or without AF patients during cardiovascular surgery. They were categorized into the sinus rhythm (SR) group (n=9, 72.7±8.6 years) and the AF group (n=9, 73.3±7.4 years). Preadipocytes were extracted from EAT by homogenization and collagenase treatment, and cultured to confluence. After differentiation to mature adipocytes, cell culture supernatant was collected, and cultured with human LECs. Cell permeability was measured by using FITC-dextran assay. Tube forming ability was analyzed by seeding LECs on the extracellular matrix gels. Metabolomic profiling of LECs was performed by GC-MS system. Results RT-PCR analysis revealed that cell culture supernatant from mature adipocytes of AF patients significantly increased mRNA expression of mesenchymal marker, TAGLN/SM22a (p&amp;lt;0.01) in human LECs, whereas mRNA expression of lymphatic endothelial markers, LYVE1 (p=0.0552) and PROX1 (p=0.0231) were decreased in human LECs, compared to those from mature adipocytes of SR patients. These data suggest cell culture supernatant from mature adipocytes of AF patients highly induce endothelial-to-mesenchymal transition (EndMT) of LECs. When assessing the endothelial barrier function by using FITC-dextran, cell culture supernatant from mature adipocytes of AF patients significantly decreased cell barrier function (p&amp;lt;0.01) compared to those from mature adipocytes of SR patients. Furthermore, cell culture supernatant from mature adipocytes of AF patients significantly decreased the tube forming ability of LECs (p&amp;lt;0.01) compared to those from mature adipocytes of SR patients. To assess the metabolomic changes in human LECs by EAT-secretome, we conducted the GC/MS analysis. Cell culture supernatant from mature adipocytes of AF patients significantly decreased several amino acids including branched-chain amino acid (BCAA; valine, leucine and isoleucine), compared to those from mature adipocytes of SR patients. Conclusion Our study with human EAT and LECs demonstrated that EAT-secretome from AF patients altered metabolomic profile in LECs, and highly caused EndMT in LECs, leading to impaired barrier function and the tube forming ability. Defects of lymphangiogenesis could be a therapeutic target for atrial cardiomyopathy.

Metabolic alterations in human pulmonary artery smooth muscle cells treated with PDGF-BB.

Metabolic abnormalities are considered to play a key regulatory role in vascular remodeling of pulmonary arterial hypertension. However, to date, there is a paucity of research documenting the changes in metabolome profiles within the supernatants of pulmonary artery smooth muscle cells (PASMC) during their transition from a contractile to a synthetic phenotype. CCK-8 and Edu staining assays were used to evaluate the cell viability and proliferation of human PASMCs. IncuCyte ZOOM imaging system was used to continuously and automatically detect the migration of the PASMCs. A targeted metabolomics profiling was performed to quantitatively analyze 121 metabolites in the supernatant. Orthogonal partial least squares discriminant analysis was used to discriminate between PDGF-BB-induced PASMCs and controls. Metabolite set enrichment analysis was adapted to exploit the most disturbed metabolic pathways. Human PASMCs exhibited a transformation from contractile phenotype to synthetic phenotype after PDGF-BB induction, along with a significant increase in cell viability, proliferation, and migration. Metabolites in the supernatants of PASMCs treated with or without PDGF-BB were well profiled. Eleven metabolites were found to be significantly upregulated, whereas seven metabolites were downregulated in the supernatants of PASMCs induced by PDGF-BB compared to the vehicle-treated cells. Fourteen pathways were involved, and pyruvate metabolism pathway was ranked first with the highest enrichment impact followed by glycolysis/gluconeogenesis and pyrimidine metabolism. Significant and extensive metabolic abnormalities occurred during the phenotypic transformation of PASMCs. Disturbance of pyruvate metabolism pathway might contribute to pulmonary vascular remodeling.

Cardiac Urea Cycle Activation by Time-Restricted Feeding Protects Against Pressure Overload-Induced Heart Failure.

Heart failure is a leading cause of mortality worldwide, necessitating the development of novel therapeutic and lifestyle interventions. Recent studies highlight a potential role of time-restricted feeding (TRF) in the prevention and treatment of cardiac diseases. Here, it is found that TRF protected against heart failure at different stages in mice. Metabolomic profiling revealed that TRF upregulated most circulating amino acids, and amino acid supplementation protected against heart failure. In contrast, TRF showed a mild effect on cardiac amino acid profile, but increased cardiac amino acid utilization and activated the cardiac urea cycle through upregulating argininosuccinate lyase (ASL) expression. Cardiac-specific ASL knockout abolished the cardioprotective effects afforded by TRF. Circulating amino acids also protected against heart failure through activation of the urea cycle. Additionally, TRF upregulated cardiac ASL expression through transcription factor Yin Yang 1, and urea cycle-derived NO contributes to TRF-afforded cardioprotection. Furthermore, arteriovenous gradients of circulating metabolites across the human hearts were measured, and found that amino acid utilization and urea cycle activity were impaired in patients with decreased cardiac function. These results suggest that TRF is a promising intervention for heart failure, and highlight the importance of urea cycle in regulation of cardiac function.

Dual inhibition of SGLT 1 and 2 alleviates intracellular sodium overload in uraemic cardiomyopathy

Abstract Background Chronic kidney disease (CKD) is a leading cause of mortality with the risk of developing cardiovascular disease higher than progression to kidney failure. The aetiology of uraemic cardiomyopathy is multifactorial and includes metabolic derangement. It was previously shown that elevated intracellular sodium (Nai) is causally linked to cardiac metabolic impairment and that targeting sodium homeostasis can reprogramme cardiac metabolism. Dual inhibition of sodium-glucose co-transporters (SGLT) 1 and 2 is an emerging therapy for CKD, however the impact on intracellular sodium and cardiac metabolism is yet to be elucidated. Purpose This study aimed to assess whether dual SGLT1/2 inhibitor sotagliflozin impacts cardiometabolic phenotype in CKD. Methods CKD was surgically induced by 5/6 nephrectomy in Wistar rats (n=46) for a period of 4 weeks, with chronic sotagliflozin treatment (5mg/kg) given for the last 3 weeks. Upon termination, hearts were Langendorff-perfused and studied using 31P and 23Na NMR spectroscopy (Sham n=7, CKD n=6, CKD+sotagliflozin n=5). To assess the cardiac-specific effect of the drug, acute sotagliflozin treatment (30mM) was delivered in the Langendorff perfusate to an additional group of CKD hearts (n=5). Furthermore, the effect of chronic sotagliflozin treatment on in vivo cardiac function (echocardiography n=23) and metabolic profile (1H NMR spectroscopy n=15) was assessed. Results CKD animals were characterized by significant renal dysfunction (2-fold increase in urea and creatinine vs sham, p&amp;lt;0.05), and HFpEF (EF(%) sham 82±2 vs CKD 80±1 p&amp;gt;0.05; diastolic dysfunction (E/A) sham 1.39±0.03 vs CKD 1.11±0.01, p=0.0018). Myocardial Nai was significantly elevated in CKD animals compared to sham controls (TQF 23Na 3.04±0.18 vs 2.01±0.32 arb units, p=0.03). Chronic sotagliflozin treatment didn’t impact renal or cardiac dysfunction. Neither chronic nor acute drug treatment impacted baseline CKD cardiac energetics (PCr/ATP sham 1.53±0.22, CKD 1.25±0.13, chronic 1.16±0.14, acute 1.18±0.13, p&amp;gt;0.05; ΔGATP (kJ/mol) sham -64±4, CKD -66±8, chronic -56±1, acute -59±3, p&amp;gt;0.05). However, both chronic and acute sotagliflozin treatment normalised the increased myocardial Nai (TQF 23Na chronic 2.17±0.12, acute 2.23±0.14 arb units, p&amp;gt;0.05 vs sham). Chronic drug dosing altered the systemic metabolic profile of CKD animals reducing the levels of circulating triglycerides and FFA (p&amp;lt;0.05) as well as altering metabolomic profile of liver, muscle and kidneys. Conclusion(s) We have shown that uraemic cardiomyopathy is characterised by HFpEF, elevated myocardial Nai and altered systemic metabolic profile. Both chronic and acute treatment with dual SGLT1/2 inhibitor sotagliflozin normalised myocardial Nai. The alleviation of Nai load could lead to improved cardiometabolic outcomes in CKD.

Metabolomic alterations in the plasma of patients with various clinical manifestations of COVID-19

BackgroundThe metabolomic profiles of individuals with different clinical manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have not been clearly characterized.MethodsWe performed metabolomics analysis of 166 individuals, including 62 healthy controls, 16 individuals with asymptomatic SARS-CoV-2 infection, and 88 patients with moderate (n = 42) and severe (n = 46) symptomatic 2019 coronavirus disease (COVID-19; 17 with short-term and 34 with long-term nucleic-acid test positivity). By examining differential expression, we identified candidate metabolites associated with different SARS-CoV-2 infection presentations. Functional and machine learning analyses were performed to explore the metabolites’ functions and verify their candidacy as biomarkers.ResultsA total of 417 metabolites were detected. We discovered 70 differentially expressed metabolites that may help differentiate asymptomatic infections from healthy controls and COVID-19 patients with different disease severity. Cyclamic acid and N-Acetylneuraminic Acid were identified to distinguish symptomatic infected patients and asymptomatic infected patients. Shikimic Acid, Glycyrrhetinic acid and 3-Hydroxybutyrate can supply significant insights for distinguishing short-term and long-term nucleic-acid test positivity.ConclusionMetabolomic profiling may highlight novel biomarkers for the identification of individuals with asymptomatic SARS-CoV-2 infection and further our understanding of the molecular pathogenesis of COVID-19.

First Insights into the Fecal Metabolome of Healthy, Free-Roaming Giraffes (Giraffa camelopardalis): An Untargeted GCxGC/TOF-MS Metabolomics Study

Background/Objectives: This study provides the first insights to the fecal metabolome of the giraffe (Giraffa camelopardalis). By using untargeted metabolomics via gas chromatography time-of-flight mass spectrometry (GCxGC/TOF-MS), this study primarily aims to provide results of the impact that external stimuli, such as supplemental feeding (SF) practices, seasonal variation and sex, might have on the fecal metabolome composition of healthy, free-roaming giraffes. Methods: Untargeted GCxGC/TOF-MS analysis was applied to the feces collected from thirteen giraffes (six males and seven females) from six different locations within the central Free State Province of South Africa over a period of two years. Statistical analysis of the generated data was used to identify the metabolites that were significantly different between the giraffes located in environments that provided SF and others where the giraffes only fed on the natural available vegetation. The same metabolomics analysis was used to investigate metabolite concentrations that were significantly different between the wet and dry seasons for a single giraffe male provided with SF over the two-year period, as well as for age and sex differences. Results: A total of 2042 features were detected from 26 giraffe fecal samples. Clear variations between fecal metabolome profiles were confirmed, with higher levels of amino acid-related and carbohydrate-related metabolites for giraffes receiving SF. In addition, a separation between the obtained profiles of samples collected from a single adult male giraffe during the wet and dry seasons was identified. Differences, such as higher levels of carbohydrate-related metabolites and organic compounds during the wet season were noted. Distinct variations in profiles were also identified for the metabolites from fecal samples collected from the six males and seven females, with higher concentrations in carbohydrate-related metabolites and alkanes for female giraffes comparatively. Conclusions: This is the first study to investigate the composition of the fecal metabolome of free-roaming giraffes, as well as the effects that external factors, such as environmental exposures, feeding practices, seasonal variations, age and sex, have on it. This novel use of fecal metabolomics assists in developing non-invasive techniques to determine giraffe populations’ health that do not require additional stressors such as capture, restraint and blood collection. Ultimately, such non-invasive advances are beneficial towards the conservation of wildlife species on a larger scale.

Metabolomic profiling of the entire UK Biobank enables interpretation of familial hypercholesterolemia mutations and prediction of severe cardiovascular outcomes

Abstract Background Familial hypercholesterolemia (FH) is an inherited disorder resulting in high levels of LDL-C from birth. Premeature coronary heart disease occurs in half of affected men by age 50 years(1). While many genetic variants that cause FH are well understood, there are also many variants in FH genes that are of uncertain clinical significance. Furthermore, the variability in residual cardiovascular risk of FH carriers after statin treatment is not fully understood. We here investigate whether metabolomic and genomic data from the 500,000 person UK Biobank cohort can aid in interpretation of candidate pathogenic variants for FH, and characterise future risk of severe cardiac events in the carriers of such variants. Methods We have quantified 249 metabolomic parameters in 490,830 blood samples from UK Biobank cohort. Among 186,483 participants with exome sequence data we identified 896 who carried known pathogenic FH variants and 405 who carried variants of unknown significance in an established FH gene. We fitted a logistic predictive model to identify pathogenic mutations using LDL levels, statin use and 17 principal components of the metabolomic parameters. We further tested whether metabolomic and genomic scores for predicting future risk of myocardial infarction (MI), that were trained in the general population (i.e. individuals without FH), could predict risk in FH carriers. Results A model including all metabolites had a higher accuracy at identifying known pathogenic FH variants (36/56 at FDR &amp;lt; 0.05), compared to LDL and statin use alone (30/56). Our model also identified 8 FH variants marked as uncertain significance in ClinVar with significant (FDR &amp;lt; 0.05) evidence of predicted pathogenicity. We found that our metabolomic risk score predicted 10-year risk of MI among FH carriers (HR=1.96 per SD, p = 0.0011). This was indeed stronger than the effect in the general population (HR = 1.64 per SD, p = 2.5e-168). A combined metabolomic and polygenic risk score had an even larger effect at predicting MI in FH carriers (HR = 3.06 per SD, p = 2.0e-6), and this score was significantly better at predicting MI in FH carriers than in non-carriers (HR = 3.06 vs 1.88 per SD, interaction p = 0.042). Conclusion Familial hypercholesterolemia is an important source of risk for early cardiovascular disease. Population-scale metabolomics can help distinguish pathogenic from benign variants that have not yet been characterised. Metabolomic and genomic scores can also identify individuals at most elevated risk, and provide even more information to FH individuals than in the general population.

Effects of Black Soldier Fly Larvae Oil on Growth Performance, Blood Biochemical Parameters, Carcass Quality, and Metabolomics Profile of Breast Muscle of Thai Native Chickens

This study aimed to evaluate the effects of the replacement of rice bran oil (RBO) with black soldier fly larvae oil (BSFLO) on growth performance, blood biochemicals, carcass quality, and metabolomics profile of breast muscle of Thai native chickens. A total of 192 1-day-old, mixed-sex, Pradu Hang Dam (Mor Kor 55) chickens were randomly allocated to one of three dietary groups. Each treatment had four replicates with 16 chicks per replicate (8 males and 8 females). Three dietary treatments were used: (T1) the control group, based on a corn–soybean meal with RBO, and two treatment groups that replaced 50% (T2) and 75% (T3) of RBO in the basal diet with BSFLO, respectively. Results showed that BSFLO inclusion at 50% and 75% did not adversely affect the productive performance of Thai native chickens (p &gt; 0.05). Regarding blood profiles, on day 28, chickens fed 75% BSFLO exhibited significant increases in hemoglobin, hematocrit, and MCHC (mean corpuscular hemoglobin concentration) with lower eosinophil percentages compared to the control group (p &lt; 0.05). Additionally, BSFLO supplementation raised glucose levels but decreased globulin and total protein levels (p &lt; 0.05). On day 63, BSFLO inclusion primarily affected MCV (mean corpuscular volume), with higher values in the 50% BSFLO group (p &lt; 0.05). It also increased globulin and HDL (high-density lipoprotein) levels while lowering AST (aspartate transaminase) concentrations (p &lt; 0.05). For carcass and meat quality, BSFLO supplementation did not affect dressing percentage or edible meat yield (p &gt; 0.05). However, it influenced meat pH and shear force (p &lt; 0.05), with a higher pH at 24 h post-mortem in BSFLO-fed chickens. Metabolomics showed that arginine biosynthesis; phenylalanine, tyrosine, and tryptophan metabolism; alanine, aspartate, and glutamate metabolism; arginine and proline metabolism; and taurine and hypotaurine metabolism were the most differentially abundant. These findings suggest that BSFLO can be used for a partial replacement (50 to 75%) for RBO in Thai native chicken diets, potentially offering benefits for animal health and meat quality without compromising growth performance.

Chemical Constituents, Antioxidant, and Enzyme Inhibitory Potentials Supported by In-Silico Studies of the n-Hexane Extract and Essential Oil of Platycladus orientalis (L.) Franco Leaves.

Platycladus orientalis leaves are widely used in traditional medicine to treat different ailments. In the present study, the volatile constituents were obtained by n-hexane extraction and hydrodistillation. Comprehensive metabolomic profiling was performed using GC-MS analysis. Furthermore, in vitro antioxidant potential and enzyme-inhibitory activity were assessed and supported by in silico profiling. Results revealed the predominance of monoterpene hydrocarbons in the hydrodistilled volatile oil (42.30%) followed by oxygenated sesquiterpenes (32.10%); with cedrol as the main component. Diterpenoids (49.70%) and sesquiterpene hydrocarbons (13.43%) were the major components of the n-hexane extract; with vulgarol A, a diterpene alcohol, as the major constituent. The volatile oil demonstrated significantly higher antioxidant potential across all assays, including ABTS and DDPH scavenging activity, CUPRAC, and FRAP assays. However, the n-hexane extract demonstrated broad inhibitory effects against butyrylcholinesterase, tyrosinase, α-amylase, and α-glucosidase enzymes, supported by molecular docking study and predictive ADME profiling. Therefore, it may be concluded that the n-hexane extract is a viable option for treating dysregulated enzyme conditions. In addition, the potential use of volatile oil in the pharmaceutical industries and management of oxidative stress can be inferred. These results warrant further studies to validate the therapeutic potential of the volatile oil and the n-hexane extract.

Identification of metabolic biomarkers in idiopathic pulmonary arterial hypertension using targeted metabolomics and bioinformatics analysis

Pulmonary arterial hypertension (PAH) is a life-threatening disease with a poor prognosis, and metabolic abnormalities play a critical role in its development. This study used metabolomics, machine learning algorithms and bioinformatics to screen for potential metabolic biomarkers associated with the diagnosis of PAH. In this study, plasma samples were collected from 17 patients diagnosed with idiopathic pulmonary arterial hypertension (IPAH) and 20 healthy controls. Plasma metabolomic profiling was performed by high-performance liquid chromatography-mass spectrometry. Gene profiles of PAH patients were obtained from the GEO database. Key differentially expressed metabolites (DEMs) and metabolism-related genes were subsequently identified using machine learning algorithms. Twenty differential plasma metabolites associated with IPAH were identified (VIP score > 1 and p < 0 0.05), and enrichment analysis revealed the arginine biosynthesis pathway as the most altered pathway. Using machine learning models, including least absolute shrinkage and selection operator (LASSO), random forest (RF) and support vector machine (SVM), we extracted key metabolites that correlated with clinical phenotypes. Our results suggested that five metabolites, kynurenine, homoserine, tryptophan, AMP, and spermine, are potential biomarkers for IPAH. Bioinformatics analysis also identified 3 metabolism-related genes, MAPK6, SLC7A11 and CDC42BPA, that are strongly correlated with pulmonary hypertension, demonstrating strong predictive power and clinical relevance. Our findings revealed some key genes associated with metabolism in PH, and provided crucial information about complex metabolic reprogramming signals and may lead to the identification of useful metabolic biomarkers for the diagnosis of PAH.

Deciphering the Metabolic Basis and Molecular Circuitry of the Warburg Paradox in Lymphoma

Background/Objectives: Warburg’s metabolic paradox illustrates that malignant cells require both glucose and oxygen to survive, even after converting glucose into lactate. It remains unclear whether sparing glucose from oxidation intersects with TCA cycle continuity and if this confers any metabolic advantage in proliferating cancers. This study seeks to understand the mechanistic basis of Warburg’s paradox and its overall implications for lymphomagenesis. Methods: Using metabolomics, we first examined the metabolomic profiles, glucose, and glutamine carbon labeling patterns in the metabolism during the cell cycle. We then investigated proliferation-specific metabolic features of malignant and nonmalignant cells. Finally, through bioinformatics and the identification of appropriate pharmacological targets, we established malignant-specific proliferative implications for the Warburg paradox associated with metabolic features in this study. Results: Our results indicate that pyruvate, lactate, and alanine levels surge during the S phase and are correlated with nucleotide synthesis. By using 13C1,2-Glucose and 13C6, 15N2-Glutamine isotope tracers, we observed that the transamination of pyruvate to alanine is elevated in lymphoma and coincides with the entry of glutamine carbon into the TCA cycle. Finally, by using fludarabine as a strong inhibitor of lymphoma, we demonstrate that disrupting the transamination of pyruvate to alanine correlates with the simultaneous suppression of glucose-derived nucleotide biosynthesis and glutamine carbon entry into the TCA cycle. Conclusions: We conclude that the transamination of pyruvate to alanine intersects with reduced glucose oxidation and maintains the TCA cycle as a critical metabolic feature of Warburg’s paradox and lymphomagenesis.

Arabidopsis METHYLENETETRAHYDROFOLATE REDUCTASE 2 functions independently of PENETRATION 2 during primary immunity against rice blast.

Nonhost resistance (NHR) is the most durable and robust form of innate immunity, with a surge of interest in crop improvement. Of the NHR genes identified against rice blast, a devastating disease caused by Magnaporthe oryzae, Arabidopsis PEN2 is indispensable for pre-penetration resistance against M. oryzae, while a consortium of genes orchestrates post-penetration resistance via lesser-known mechanisms. We identified M. oryzae-susceptible mosA (mthfr2 pen2-3) from a randomly mutagenized Arabidopsis pen2-3 population using forward genetics. Analysis of T-DNA inserted mthfr2 lines and pen2-3 complemented mosA lines enunciated that MTHFR2-dependent resistance to M. oryzae is independent of PEN2. MTHFR2-defective plants exhibited higher ROS accumulation and expression of SA-dependent defense markers. MTHFR2-ligand docking revealed that A55V nonsynonymous substitution in mosA altered ligand binding efficiency. This further affected the metabolomic profile of mosA, effectively allowing in vitro germination and development of M. oryzae conidia. Moreover, the loss of function mutation in mthfr2 (involved in 1C metabolic pathway) potentiated mosA immunity against Pst DC3000. In conclusion, our findings assert MTHFR2 as a positive modulator of NHR against M. oryzae. This work documents another layer of conserved yet divergent metabolomic defense in Arabidopsis regulated by folate-mediated 1C metabolism that has the potential to revolutionize crop improvement.

Targeted Metabolic Profiling in Determining the Metabolic Heterogeneity in Human Biopsies of Different Grades of Glioma.

Gliomas are intricate tumors with numerous metabolic and genetic abnormalities contributing to their aggressive phenotypes and poor prognoses. The study aims at identifying the key molecular metabolic as well as gene expressional variations that could be used to differentiate between different grades of glioma to obtain deeper insights theabout metabolic status of glioma that may serve as good candidates of diagnosis in future. In the present study, the metabolomic profiling along with clinical and expressional analyses of glioma biopsies (n = 52; patients comprising both of benign and malignant lesions) was analyzed. The biopsies were subjected to gene/protein expressional analysis using RT-PCR and western blotting and also were subjected to metabolite analyses. The results of the gene/protein expressional analysis exhibited elevated levels of carnitine palmitoyltransferase, monoglyceride lipase, human phosphofructokinase, and isocitrate dehydrogenase in higher grades of glioma when compared to those of control. Our study suggested that the metabolites and gene/protein expressional levels were found to be discriminative among the grades of glioma. The study is deemed as a provider of deeper insights that are essential for differential therapeutic approaches that specifically target the dysregulated metabolome to the benefit of patients.

Earlier Age at Menopause, Plasma Metabolome, and Risk of Premature Mortality

Background/Objectives: Menopause and related metabolites are associated with mortality. However, the relationship between earlier menopause, premature mortality, and the role of metabolomic signatures remains underexplored. This study investigated the association between earlier menopause and premature mortality, and the mediating effect of metabolomic signatures. Methods: This prospective cohort study used data from the UK Biobank, including 33,687 post-menopausal women aged 40–69 years. Age at menopause was obtained from a baseline self-reported questionnaire and analyzed both as a continuous variable and in categories (&lt;40, 40–49, and ≥50 years). Premature mortality was defined as deaths before 75 years. Cox regression was used to estimate hazard ratios (HRs), and elastic net regression identified metabolomic signatures related to menopause age. Mediation analysis was conducted to assess the proportion of the association explained by the metabolomic signature. Results: During a median follow-up of 13.7 years, 1612 cases of premature mortality occurred. Compared to menopause at ≥50 years, earlier menopause (HR 1.17, 95% CI 1.04–1.30) and premature menopause (HR 1.60, 95% CI 1.28–2.00) were associated with higher risks of premature mortality. A metabolomic signature inversely associated with premature mortality (HR per SD increment, 0.79; 95% CI, 0.75–0.83) mediated 13.6% (95% CI, 1.9%–28.3%) of the association between earlier menopause and premature mortality. Conclusions: Earlier menopause is associated with an increased risk of premature mortality, partially mediated by a metabolomic signature related to age at menopause. These findings highlight the importance of metabolomic profiling in understanding menopause and mortality risks.