PubMed

Ying Yong Sheng Tai Xue Bao. 2023 Mar;34(3):853-864. doi: 10.13287/j.1001-9332.202303.030.ABSTRACTIn recent years, antibiotics have been continuously detected in waterbodies and thus has become an environmental problem, especially in China. However, current knowledge regarding the ecological hazards of antibiotics is mainly focusing on the induction of resistance in pathogenic microorganisms, treating antibiotic contamination as a public safety problem that seriously endangers human health, but relatively ignores its potential risk to aquatic organisms. As an important component of aquatic ecosystems, plankton play an important role in maintaining the stability of aquatic ecosystems. Meanwhile, plankton are very sensitive to environmental changes. Therefore, understanding the impact of antibiotics on plankton is the basis for assessing their ecological risk. To this end, we summarized current status of antibiotic contamination in China's aquatic environments, and analyzed the impacts of antibiotics on planktons. In addition to using metabolomics technology to reveal the negative impacts of antibiotics at the individual level, monitoring of antibiotics and plankton communities in the field needs to be strengthened in the future.PMID:37087670 | DOI:10.13287/j.1001-9332.202303.030

Crit Care. 2023 Mar 1;27(1):79. doi: 10.1186/s13054-023-04378-w.ABSTRACTOBJECTIVE: Community-acquired pneumonia (CAP) is the primary cause of death for children under five years of age globally. Hence, it is essential to investigate new early biomarkers and potential mechanisms involved in disease severity.METHODS: Proteomics combined with metabolomics was performed to identify biomarkers suitable for early diagnosis of severe CAP. In the training cohort, proteomics and metabolomics were performed on serum samples obtained from 20 severe CAPs (S-CAPs), 15 non-severe CAPs (NS-CAPs) and 15 healthy controls (CONs). In the verification cohort, selected biomarkers and their combinations were validated using ELISA and metabolomics in an independent cohort of 129 subjects. Finally, a combined proteomics and metabolomics analysis was performed to understand the major pathological features and reasons for severity of CAP.RESULTS: The proteomic and metabolic signature was markedly different between S-CAPs, NS-CAPs and CONs. A new serum biomarker panel including 2 proteins [C-reactive protein (CRP), lipopolysaccharide (LBP)] and 3 metabolites [Fasciculol C, PE (14:0/16:1(19Z)), PS (20:0/22:6(4Z, 7Z, 10Z, 13Z, 16Z, 19Z))] was developed to identify CAP and to distinguish severe pneumonia. Pathway analysis of changes revealed activation of the cell death pathway, a dysregulated complement system, coagulation cascade and platelet function, and the inflammatory responses as contributors to tissue damage in children with CAP. Additionally, activation of glycolysis and higher levels of nucleotides led to imbalanced deoxyribonucleotide pools contributing to the development of severe CAP. Finally, dysregulated lipid metabolism was also identified as a potential pathological mechanism for severe progression of CAP.CONCLUSION: The integrated analysis of the proteome and metabolome might open up new ways in diagnosing and uncovering the complexity of severity of CAP.PMID:36859478 | DOI:10.1186/s13054-023-04378-w

J Anim Sci Biotechnol. 2023 Mar 2;14(1):28. doi: 10.1186/s40104-023-00836-1.ABSTRACTBACKGROUND: Comparative and comprehensive omics studies have recently been conducted to provide a comprehensive understanding of the biological mechanisms underlying infertility. However, because these huge omics datasets often contain irrelevant information, editing strategies for summarizing and filtering the data are necessary prerequisite steps for identifying biomarkers of male fertility. Here, we attempted to integrate omics data from spermatozoa with normal and below-normal fertility from boars and bulls, including transcriptomic, proteomic, and metabolomic data. Pathway enrichment analysis was conducted and visualized using g:Profiler, Cytoscape, EnrichmentMap, and AutoAnnotation to determine fertility-related biological functions according to species.RESULTS: In particular, gamete production and protein biogenesis-associated pathways were enriched in bull spermatozoa with below-normal fertility, whereas mitochondrial-associated metabolic pathways were enriched in boar spermatozoa with normal fertility. These results indicate that below-normal fertility may be determined by aberrant regulation of protein synthesis during spermatogenesis, and the modulation of reactive oxygen species generation to maintain capacitation and the acrosome reaction governs boar sperm fertility.CONCLUSION: Overall, this approach demonstrated that distinct molecular pathways drive sperm fertility in mammals in a species-dependent manner. Moreover, we anticipate that searching for species-specific signaling pathways may aid in the discovery of fertility-related biomarkers within large omics datasets.PMID:36859388 | DOI:10.1186/s40104-023-00836-1

Ecotoxicol Environ Saf. 2023 Feb 27;253:114703. doi: 10.1016/j.ecoenv.2023.114703. Online ahead of print.ABSTRACTBisphenol P (BPP), structurally similar to bisphenol A, is commonly identified in the samples of environment, food, and humans. Unfortunately, very little information is currently available on adverse effects of BPP. The obesogenic effects and underlying mechanisms of BPP on mice were investigated in this study. Compared with the control, high-resolution microcomputed tomography (micro-CT) scans displayed that the visceral fat volume of mice was significantly increased at a dose of 5 mg/kg/day after BPP exposure for 14 days, whereas the subcutaneous fat volume remained unchanged. Nontargeted metabolomic analysis revealed that BPP significantly perturbed the metabolic pathways of mouse livers, and acetyl-CoA was identified as the potential key metabolite responsible for the visceral fat induced by BPP. These findings recommend that a great deal of attention should be paid to the obesogenic properties of BPP as a result of its widely utilized and persistence in the environment.PMID:36857923 | DOI:10.1016/j.ecoenv.2023.114703

Ecotoxicol Environ Saf. 2023 Feb 27;253:114680. doi: 10.1016/j.ecoenv.2023.114680. Online ahead of print.ABSTRACTFenitrothion (FNT), an organophosphorus insecticide, is widely detected in the living environment. The reproductive and endocrine toxicity of FNT to biological communities has been ever reported, but potential mechanism and reproductive toxicity dose effect remain unclear. In our study, we constructed Caenorhabditis elegans model to analyze the reproductive toxicity mechanism of FNT based on metabolomics and evaluated its reproductive toxicity dose effect using benchmark dose (BMD)method. Our results showed that FNT exposure significantly reduced brood size, number of germ cells, and delayed gonadal development in nematodes. Non-targeted metabolomics revealed that FNT exposure caused significant metabolic disturbances in nematodes, leading to a significant reduction in the synthesis of cortisol and melatonin, and the latter played a mediating role in the effects of FNT on number of germ cells. We further found that the levels of these two hormones were significantly negative correlated with the expression of the androgen receptor nhr-69 and affected the meiosis of germ cells by regulating the nhr-69/ fbf-1/2 /gld-3 /fog-1/3 pathway. Meanwhile, the study found the BMDL10s for N2 and him-5 mutant were 0.411 μg/L by number of germ cells and 0.396 μg/L by number of germ cells in the meiotic zone, respectively, providing a more protective reference dose for ecological risk assessment of FNT. This study suggested that FNT can affect androgen receptor expression by inhibiting cortisol and melatonin secretion, which further mediate the meiotic pathway to affect sperm formation and exert reproductive toxicity, and provides a basis for setting reproductive toxicity limits for FNT.PMID:36857914 | DOI:10.1016/j.ecoenv.2023.114680

J Hazard Mater. 2023 Feb 26;450:131092. doi: 10.1016/j.jhazmat.2023.131092. Online ahead of print.ABSTRACTThe use of thermophilic bacteria for treating paper black liquor seems to be an efficient bioremediation strategy. In our previous work, the lignin-degrading bacterium Serratia sp. AXJ-M exhibited excellent heat tolerance ability. However, the molecular mechanism of its response to heat stress is unknown. Therefore, the heat stress response of AXJ-M was investigated using morphological and analytical methods. A comparative genomics analysis revealed interesting insights into the adaptability of the genetic basis of AXJ-M to harsh environments. Moreover, TMT quantitative proteomic analysis and parallel reaction monitoring (PRM) assays revealed that proteins related to both component systems, ABC transporters, carbohydrate, and amino metabolism, energy metabolism, etc., were differentially expressed. The non-targeted metabolome analysis revealed that the metabolic pathways associated with the fatty acid and amino acid biosynthesis and metabolism, together with the TCA cycle were most significantly enriched. Furthermore, integrated omics suggested that AXJ-M made metabolic adaptations to compensate for the increased energy demand caused by adverse environmental stimuli. The dominant heat regulator HspQ mediated heat adaptation of AXJ-M at high temperatures and modulated DyP expression. To summarize, the present study sheds light on the effect of high temperature on the lignin-degrading bacterium and its tolerance and underlying regulatory mechanisms.PMID:36857821 | DOI:10.1016/j.jhazmat.2023.131092

Anal Chem. 2023 Mar 1. doi: 10.1021/acs.analchem.2c05351. Online ahead of print.ABSTRACTStudying the mechanisms of drug antitumor activity at the single-cell level can provide information about the responses of cell subpopulations to drug therapy, which is essential for the accurate treatment of cancer. Due to the small size of single cells and the low contents of metabolites, metabolomics-based approaches to studying the mechanisms of drug action at the single-cell level are lacking. Herein, we develop a label-free platform for studying the mechanisms of drug action based on single-cell metabolomics (sMDA-scM) by integrating intact living-cell electro-launching ionization mass spectrometry (ILCEI-MS) with metabolomics analysis. Using this platform, we reveal that non-small-cell lung cancer (NSCLC) cells treated by gefitinib can be clustered into two cell subpopulations with different metabolic responses. The glutathione metabolic pathway of the subpopulation containing 14.4% of the cells is not significantly affected by gefitinib, exhibiting certain resistance characteristics. The presence of these cells masked the judgment of whether cysteine and methionine metabolic pathway was remarkably influenced in the analysis of overall average results, revealing the heterogeneity of the response of single NSCLC cells to gefitinib treatment. The findings provide a basis for evaluating the early therapeutic effects of clinical medicines and insights for overcoming drug resistance in NSCLC subpopulations.PMID:36857711 | DOI:10.1021/acs.analchem.2c05351

J Proteome Res. 2023 Mar 1. doi: 10.1021/acs.jproteome.2c00762. Online ahead of print.ABSTRACTIntact protein analysis by mass spectrometry is important for several applications such as assessing post-translational modifications and biotransformation. In particular, intact protein analysis allows the detection of proteoforms that are commonly missed by other approaches such as proteolytic digestion followed by bottom-up analysis. Two quantification methods are mainly used for intact protein data quantification, namely the extracted ion and deconvolution approaches. However, a consensus with regard to a single best practice for intact protein data processing is lacking. Furthermore, many data processing tools are not fit-for-purpose and, as a result, the analysis of intact proteins is laborious and lacks the throughput required to be implemented for the analysis of clinical cohorts. Therefore, in this study, we investigated the application of a software-assisted data analysis and processing workflow in order to streamline intact protein integration, annotation, and quantification via deconvolution. In addition, the assessment of orthogonal data sets generated via middle-up and bottom-up analysis enabled the cross-validation of cleavage proteoform assignments present in seminal prostate-specific antigen (PSA). Furthermore, deconvolution quantification of PSA from patients' urine revealed results that were comparable with manually performed quantification based on extracted ion electropherograms. Overall, the presented workflow allows fast and efficient processing of intact protein data. The raw data is available on MassIVE using the identifier MSV000086699.PMID:36857466 | DOI:10.1021/acs.jproteome.2c00762

Cell Rep. 2023 Feb 28;42(3):112183. doi: 10.1016/j.celrep.2023.112183. Online ahead of print.ABSTRACTCircadian oscillation of gut microbiota exerts significant influence on host physiology, but the host factors that sustain microbial oscillations are rarely reported. We compared the gut microbiome and metabolome of wild-type and BMAL1-deficient cynomolgus monkeys during a diurnal cycle by performing 16S rRNA sequencing and untargeted fecal metabolomics and uncovered the influence of intestinal H2O2 on microbial compositions. Ablation of BMAL1 induced expansion of Bacteroidota at midnight and altered microbial oscillations. Some important fecal metabolites changed significantly, and we investigated their correlations with microbes. Further analyses revealed that disturbed rhythmicity of NOX1-derived intestinal H2O2 was responsible for the altered microbial oscillations in BMAL1-deficient monkeys. Mechanistic studies showed that BMAL1 transactivated NOX1 via binding to the E1-E2 site in its promoter. Notably, BMAL1-dependent activation of NOX1 was conserved in cynomolgus monkeys and humans. Our study demonstrates the importance of intestine clock-controlled H2O2 rhythmicity on the rhythmic oscillation of gut microbiota.PMID:36857177 | DOI:10.1016/j.celrep.2023.112183

Transplantation. 2023 Mar 1:e004529. doi: 10.1097/TP.0000000000004529. Online ahead of print.ABSTRACTBACKGROUND: Ischemia-free liver transplantation (IFLT) has been innovated to avoid graft ischemia during organ procurement, preservation, and implantation. However, the metabolism activity of the donor livers between in the in situ and ex situ normothermic machine perfusion (NMP) conditions, and between standard criteria donor and extend criteria donor remains unknown.METHODS: During IFLT, plasma samples were collected both at the portal vein and hepatic vein of the donor livers in situ during procurement and ex situ during NMP. An ultra-high performance liquid chromatography-mass spectrometry was conducted to investigate the common and distinct intraliver metabolite exchange.RESULTS: Profound cysteine and methionine metabolism, and aminoacyl-tRNA biosynthesis were found in both in situ and ex situ conditions. However, obvious D-arginine and D-ornithine metabolism, arginine and proline metabolism were only found in the in situ condition. The suppressed activities of the urea cycle pathway during ex situ condition were confirmed in an RNA expression level. In addition, compared with extend criteria donor group, standard criteria donor group had more active intraliver metabolite exchange in metabonomics level. Furthermore, we found that the relative concentration of p-cresol, allocystathionine, L-prolyl-L-proline in the ex situ group was strongly correlated with peak alanine aminotransferase and aspartate aminotransferase at postoperative days 1-7.CONCLUSIONS: In the current study, we show the common and distinct metabolism activities during IFLT. These findings might provide insights on how to modify the design of NMP device, improve the perfusate components, and redefine the criteria of graft viability.PMID:36857152 | DOI:10.1097/TP.0000000000004529

Transplantation. 2023 Mar 1:e004530. doi: 10.1097/TP.0000000000004530. Online ahead of print.NO ABSTRACTPMID:36857151 | DOI:10.1097/TP.0000000000004530

FASEB J. 2023 Apr;37(4):e22846. doi: 10.1096/fj.202201469R.ABSTRACTColchicine is a broad-acting anti-inflammatory agent that has attracted interest for repurposing in atherosclerotic cardiovascular disease. Here, we studied its ability at a human equivalent dose of 0.5 mg/day to modify plaque formation and composition in murine atherosclerosis and investigated its actions on macrophage responses to atherogenic stimuli in vitro. In atherosclerosis induced by high-cholesterol diet, Apoe-/- mice treated with colchicine had 50% reduction in aortic oil Red O+ plaque area compared to saline control (p = .001) and lower oil Red O+ staining of aortic sinus lesions (p = .03). In vitro, addition of 10 nM colchicine inhibited foam cell formation from murine and human macrophages after treatment with oxidized LDL (ox-LDL). Mechanistically, colchicine downregulated glycosylation and surface expression of the ox-LDL uptake receptor, CD36, and reduced CD36+ staining in aortic sinus plaques. It also decreased macrophage uptake of cholesterol crystals, resulting in lower intracellular lysosomal activity, inhibition of the NLRP3 inflammasome, and reduced secretion of IL-1β and IL-18. Colchicine's anti-atherosclerotic actions were accentuated in a mouse model of unstable plaque induced by carotid artery tandem stenosis surgery, where it decreased lesion size by 48% (p = .01), reduced lipid (p = .006) and necrotic core area (p = .007), increased collagen content and cap-to-necrotic core ratio (p = .05), and attenuated plaque neutrophil extracellular traps (p < .001). At low dose, colchicine's effects were not accompanied by the evidence of microtubule depolymerization. Together, these results show that colchicine exerts anti-atherosclerotic and plaque-stabilizing effects at low dose by inhibiting foam cell formation and cholesterol crystal-induced inflammation. This provides a new framework to support its repurposing for atherosclerotic cardiovascular disease.PMID:36856983 | DOI:10.1096/fj.202201469R

Mol Genet Genomics. 2023 Mar 1. doi: 10.1007/s00438-023-02001-9. Online ahead of print.ABSTRACTOuabain is a cardiac glycoside long studied for treating heart diseases, but the attempts to evaluate its anti-psoriatic activity have not been reported. We aimed to explore the effects of ouabain on proliferation and metabolism towards psoriatic keratinocytes. In human HaCaT keratinocytes, ouabain potently decreased viability, promoted apoptosis and caused G2/M cycle arrest. Metabolomics analysis indicated that ouabain markedly impaired glutathione metabolism. The solute carrier family 7 member 11 (SLC7A11) is an amino acid transporter highly specific to cysteine, which is critical for glutathione synthesis. Ouabain downregulated SLC7A11, reduced cysteine uptake and subsequently inhibited glutathione synthesis, probably through inhibiting Akt/mTOR/beclin axis that regulate protein activity of SLC7A11. The impaired glutathione synthesis and oxidative stress caused by ouabain may contribute to its cytotoxicity towards psoriatic keratinocytes. Our results provide experimental evidence supporting further study of ouabain as a potential anti-psoriatic agent.PMID:36856826 | DOI:10.1007/s00438-023-02001-9

Metabolomics. 2023 Mar 1;19(3):15. doi: 10.1007/s11306-023-01976-1.ABSTRACTINTRODUCTION: There is still no community consensus regarding strategies for data quality review in liquid chromatography mass spectrometry (LC-MS)-based untargeted metabolomics. Assessing the analytical robustness of data, which is relevant for inter-laboratory comparisons and reproducibility, remains a challenge despite the wide variety of tools available for data processing.OBJECTIVES: The aim of this study was to provide a model to describe the sources of variation in LC-MS-based untargeted metabolomics measurements, to use it to build a comprehensive curation pipeline, and to provide quality assessment tools for data quality review.METHODS: Human serum samples (n=392) were analyzed by ultraperformance liquid chromatography coupled to high-resolution mass spectrometry (UPLC-HRMS) using an untargeted metabolomics approach. The pipeline and tools used to process this dataset were implemented as part of the open source, publicly available TidyMS Python-based package.RESULTS: The model was applied to understand data curation practices used by the metabolomics community. Sources of variation, which are often overlooked in untargeted metabolomic studies, were identified in the analysis. New tools were used to characterize certain types of variations.CONCLUSION: The developed pipeline allowed confirming data robustness by comparing the experimental results with expected values predicted by the model. New quality control practices were introduced to assess the analytical quality of data.PMID:36856823 | DOI:10.1007/s11306-023-01976-1

FASEB J. 2023 Apr;37(4):e22827. doi: 10.1096/fj.202201585R.ABSTRACTMetabolic rhythms include rapid, ultradian (hourly) dynamics, but it remains unclear what their relationship to circadian metabolic rhythms is, and what role meal timing plays in coordinating these ultradian rhythms in metabolism. Here, we characterized widespread ultradian rhythms under ad libitum feeding conditions in the plasma metabolome of the vole, the gold standard animal model for behavioral ultradian rhythms, naturally expressing ~2-h foraging rhythms throughout the day and night. These ultradian metabolite rhythms co-expressed with diurnal 24-h rhythms in the same metabolites and did not align with food intake patterns. Specifically, under light-dark entrained conditions we showed twice daily entrainment of phase and period of ultradian behavioral rhythms associated with phase adjustment of the ultradian cycle around the light-dark and dark-light transitions. These ultradian activity patterns also drove an ultradian feeding pattern. We used a unique approach to map this behavioral activity/feeding status to high temporal resolution (every 90 min) measures of plasma metabolite profiles across the 24-h light-dark cycle. A total of 148 known metabolites were detected in vole plasma. Supervised, discriminant analysis did not group metabolite concentration by feeding status, instead, unsupervised clustering of metabolite time courses revealed clusters of metabolites that exhibited significant ultradian rhythms with periods different from the feeding cycle. Two clusters with dissimilar ultradian dynamics, one lipid-enriched (period = 3.4 h) and one amino acid-enriched (period = 4.1 h), both showed co-expression with diurnal cycles. A third cluster solely comprised of glycerophospholipids (specifically ether-linked phosphatidylcholines) expressed an 11.9 h ultradian rhythm without co-expressed diurnal rhythmicity. Our findings show coordinated co-expression of diurnal metabolic rhythms with rapid dynamics in feeding and metabolism. These findings reveal that ultradian rhythms are integral to biological timing of metabolic regulation, and will be important in interpreting the impact of circadian desynchrony and meal timing on metabolic rhythms.PMID:36856610 | DOI:10.1096/fj.202201585R

Phytopathology. 2023 Mar 1. doi: 10.1094/PHYTO-11-22-0415-FI. Online ahead of print.ABSTRACTPlants produce a high diversity of secondary metabolites that are involved in a wide range of different functions, including stress tolerance, signaling molecule for interactions with other species (allelopathy) and protecting plants against herbivores and pathogens. With the rise of more accessible, high-throughput mass spectrometry and new analytical tools it becomes feasible to identify and validate new secondary metabolites involved in pathogen resistance or assign new roles to previously detected compounds. In this review, we provide a brief overview of the major pathogen defence-associated classes of secondary metabolites, with a focus on those with direct anti-pathogen function. For each class we highlight one or more typical examples representing the class to give a comprehensive summary of some of the work done to date. In the second part of this review, we highlight how new technological advances and high throughput experiments in combination with other sources of -omics data, like genomics and transcriptomics can accelerate the studies on secondary metabolites and help to link these compounds to genotypes. Employing such approaches will improve our understanding of chemical defences against plant pathogens and allow rapid development of markers for resistance breeding.PMID:36856491 | DOI:10.1094/PHYTO-11-22-0415-FI

New Phytol. 2023 Mar 1. doi: 10.1111/nph.18844. Online ahead of print.ABSTRACTThe greater duckweed (Spirodela polyrhiza 7498) exhibits trophic diversity (photoautotrophic, heterotrophic, photoheterotrophic, and mixotrophic growth) depending on the availability of exogenous organic carbon sources and light. Here, we show that the ability to transition between various trophic growth conditions is an advantageous trait, providing great phenotypic plasticity and metabolic flexibility in S. polyrhiza 7498. By comparing S. polyrhiza 7498 growth characteristics, metabolic acclimation, and cellular ultrastructure across these trophic modes, we show that mixotrophy decreases photosynthetic performance and relieves the CO2 limitation of photosynthesis by enhancing the CO2 supply through the active respiration pathway. Proteomic and metabolomic analyses corroborated that S. polyrhiza 7498 increases its intracellular CO2 and decreases reactive oxygen species under mixotrophic and heterotrophic conditions, which substantially suppressed the wasteful photorespiration and oxidative-damage pathways. As a consequence, mixotrophy resulted in a higher biomass yield than the sum of photoautotrophy and heterotrophy. Our work provides a basis for using trophic transitions in S. polyrhiza 7498 for the enhanced accumulation of value-added products.PMID:36856336 | DOI:10.1111/nph.18844

Am J Physiol Endocrinol Metab. 2023 Mar 1. doi: 10.1152/ajpendo.00159.2022. Online ahead of print.ABSTRACTLactate, which is an end product of glycolysis, has traditionally been considered as a metabolic waste. However, numerous studies have demonstrated that lactate serves metabolic and nonmetabolic functions in physiological processes and multiple diseases. Cancer and pulmonary arterial hypertension have been shown to undergo metabolic reprogramming, which is accompanied by increased lactate production. Metabolic reprogramming and epigenetic modifications have been extensively linked; furthermore, posttranslational modifications of histones caused by metabolites play a vital role in epigenetic alterations. In this paper, we reviewed recent research on lactate-induced histone modifications and provided a new vision about the metabolic effect of glycolysis. Based on our review, the crosstalk between the metabolome and epigenome induced by glycolysis may indicate novel epigenetic regulatory and therapeutic opportunities. There is a magnificent progress of the interaction between metabolomics and epigenomics in recent decades, but many questions still remained to be investigated. Lactylation is found in different pathophysiological states and leads to diverse biological effects, however, only a few mechanisms of lactylation have been illustrated. Further research on lactylation would provide us with a better understanding of the crosstalk between the metabolomics and epigenomics.PMID:36856188 | DOI:10.1152/ajpendo.00159.2022

Circulation. 2023 Mar 1. doi: 10.1161/CIRCULATIONAHA.122.061846. Online ahead of print.ABSTRACTBACKGROUND: The human heart primarily metabolizes fatty acids, and this decreases as alternative fuel use rises in heart failure with reduced ejection fraction (HFrEF). Patients with severe obesity and diabetes are thought to have increased myocardial fatty acid metabolism, but whether this is found in those who also have heart failure with preserved ejection fraction (HFpEF) is unknown.METHODS: Plasma and endomyocardial biopsies were randomly selected from a 2-center derived biobank of HFpEF (n=38), HFrEF (n=30), and nonfailing donor control (n=20) tissue. Quantitative targeted metabolomics measured organic acids, amino acids, and acylcarnitines in myocardium (72 metabolites) and plasma (69 metabolites). The results were integrated with reported RNA sequencing data. Metabolomics were analyzed using agnostic clustering tools, Kruskal-Wallis test with Dunn test, and machine learning.RESULTS: Agnostic clustering of myocardial but not plasma metabolites separated disease groups. Despite more obesity and diabetes in HFpEF versus HFrEF (body mass index, 39.8 kg/m2 versus 26.1 kg/m2; diabetes, 70% versus 30%; both P<0.0001), medium- and long-chain acylcarnitines (mostly metabolites of fatty acid oxidation) were markedly lower in myocardium from both heart failure groups versus control. In contrast, plasma levels were no different or higher than control. Gene expression linked to fatty acid metabolism was generally lower in HFpEF versus control. Myocardial pyruvate was higher in HFpEF whereas the tricarboxylic acid cycle intermediates succinate and fumarate were lower, as were several genes controlling glucose metabolism. Non-branched-chain and branched-chain amino acids (BCAA) were highest in HFpEF myocardium, yet downstream BCAA metabolites and genes controlling BCAA metabolism were lower. Ketone levels were higher in myocardium and plasma of patients with HFrEF but not HFpEF. HFpEF metabolomic-derived subgroups showed few differences in BCAA metabolites but little else.CONCLUSIONS: Despite marked obesity and diabetes, HFpEF myocardium exhibited lower fatty acid metabolites compared with HFrEF. Ketones and metabolites of the tricarboxylic acid cycle and BCAA were also lower in HFpEF, suggesting insufficient use of alternative fuels. These differences were not detectable in plasma and challenge conventional views of myocardial fuel use in HFpEF with marked diabetes and obesity and suggest substantial fuel inflexibility in this syndrome.PMID:36856044 | DOI:10.1161/CIRCULATIONAHA.122.061846

Eur J Clin Invest. 2023 Mar 1:e13978. doi: 10.1111/eci.13978. Online ahead of print.ABSTRACTBACKGROUND: Nephrotic syndrome is common in children and adults worldwide, and steroid-sensitive nephrotic syndrome (SSNS) accounts for 80%. Aberrant metabolism involvement in early SSNS is sparsely studied, and its pathogenesis remains unclear. Therefore, the goal of this study was to investigate the changes in initiated SSNS patients-related metabolites through serum and urine metabolomics and discover the novel potential metabolites and metabolic pathways.METHODS: Serum samples (27 SSNS and 56 controls) and urine samples (17 SSNS and 24 controls) were collected. Meanwhile, the non-targeted analyses were performed by ultra-high performance liquid chromatography-quadrupole time of flight-mass spectrometry (UHPLC-QTOF-MS) to determine the changes in SSNS. We applied the causal inference model, the DoWhy model, to assess the causal effects of several selected metabolites. An ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to validate hits (D-mannitol, dulcitol, D-sorbitol, XMP, NADPH, NAD, bilirubin, and α-KG-like) in 41 SSNS and 43 controls. In addition, the metabolic pathways were explored.RESULTS: Compared to urine, the metabolism analysis of serum samples was more clearly discriminated at SSNS. 194 differential serum metabolites and five metabolic pathways were obtained in the SSNS group. Eight differential metabolites were identified by establishing the diagnostic model for SSNS, and four variables had a positive causal effect. After validation by targeted MS, except XMP, others have similar trends like the untargeted metabolic analysis.CONCLUSION: With untargeted metabolomics analysis and further targeted quantitative analysis, we found seven metabolites may be new biomarkers for risk prediction and early diagnosis for SSNS.PMID:36856027 | DOI:10.1111/eci.13978