Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

Myocardial Metabolomics of Human Heart Failure With Preserved Ejection Fraction

Wed, 01/03/2023 - 12:00
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

Metabolomic Profiles in Serum and Urine Uncover Novel Biomarkers in Children with Nephrotic Syndrome

Wed, 01/03/2023 - 12:00
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

AUF1 recognizes 8-oxo-guanosine embedded in DNA and stimulates APE1 endoribonuclease activity

Wed, 01/03/2023 - 12:00
Antioxid Redox Signal. 2023 Mar 1. doi: 10.1089/ars.2022.0105. Online ahead of print.ABSTRACTAIMS: The existence of modified rNMPs embedded in genomic DNA, as a consequence of oxidative stress conditions, including 8-oxo-guanosine and ribose monophosphate abasic site (rAP), has been recently highlighted by several works including ours. Although the activity of APE1, a key enzyme of the base excision repair pathway, in the repair of rAP sites results as efficient as the canonical deoxyribose monophosphate abasic sites (dAP), its incision repair activity on 8-oxo-guanosine is very weak. The aims of this work were to: i) identify proteins able to specifically bind 8-oxo-guanosine embedded in DNA and promote APE1 endoribonuclease on this lesion and ii) characterize the molecular and biological relevance of this interaction using human cancer cell lines.RESULTS: By using an unbiased proteomic approach, we discovered that AUF1 actively recognizes 8-oxo-guanosine and stimulates the APE1 enzymatic activity on this DNA lesion. By using orthogonal approaches, we found that: i) the interaction between AUF1 and APE1 is modulated by H2O2-treatment; ii) depletion of APE1 and AUF1 causes the accumulation of single- and double- strand breaks; iii) both proteins are involved in modulating the formation of DNA:RNA hybrids.INNOVATION: These data establish unexpected functions of AUF1 in modulating genome stability, and improve our knowledge of APE1 biology with respect to 8-oxo-guanosine embedded in DNA.CONCLUSIONS: By showing a novel function of AUF1, our findings shed new light on the process of maintenance of genome stability in mammalian cells towards oxidative stress-related damages.PMID:36855946 | DOI:10.1089/ars.2022.0105

Progress of metabolomics in atopic dermatitis: a systematic review

Wed, 01/03/2023 - 12:00
J Dtsch Dermatol Ges. 2023 Feb 28. doi: 10.1111/ddg.14960. Online ahead of print.ABSTRACTAtopic dermatitis (AD), a chronic inflammatory skin disorder characterized by recurrent eczema and intense pruritus, is a major skin-related burden worldwide. The diagnosis and treatment of AD is often challenging due to the high heterogeneity of AD, and its exact etiology is unknown. Metabolomics offers the opportunity to follow continuous physiological and pathological changes in individuals, which allows accurate diagnosis and management as well as providing deep insights into the etiopathogenesis of AD. Several metabolomic studies of AD have been published over the past few years. The aim of this review is to summarize these findings and help researchers to understand the rapid development of metabolomics for AD. A comprehensive and systematic search was performed using the PubMed, Embase, Cochrane Library and Web of Science databases. Twenty-six papers were finally included in the review after quality assessment. Significant differences in metabolite profiles were found between patients with AD and healthy individuals. This study provides a comprehensive overview of metabolomic research in AD. A better understanding of the metabolomics of AD may offer novel diagnostic, prognostic, and therapeutic approaches.PMID:36855837 | DOI:10.1111/ddg.14960

Efficacy and Mechanism of Qianshan Huoxue Gao in Acute Coronary Syndrome via Regulation of Intestinal Flora and Metabolites

Wed, 01/03/2023 - 12:00
Drug Des Devel Ther. 2023 Feb 22;17:579-595. doi: 10.2147/DDDT.S396649. eCollection 2023.ABSTRACTPURPOSE: To study the efficacy of Qianshan Huoxue Gao (QS) in treating acute coronary syndrome (ACS) and to explore the mechanism of action from the perspective of intestinal flora regulation.METHODS: Male Sprague-Dawley rats were divided into control, model, QS, and atorvastatin groups; except for the control group, rats underwent ligation of the left anterior descending branch of the coronary artery. Following treatment for 28 days, cardiac function was evaluated using an echocardiographic assay; ELISAs for serum creatine kinase isoenzyme (CK-MB), cardiac troponin I (cTnI), high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-2 (IL-2), IL-6, and tumor necrosis factor-α (TNF-α); assessment of cardiac enzymes and inflammatory response; hematoxylin and eosin (HE) staining for histopathological changes in the heart, skin, and viscera; 16S rRNA gene sequencing for intestinal flora diversity and structural differences analysis; and we further investigated intestinal contents using metabolomics.RESULTS: Compared with controls, CK-MB and cTnI were increased (P<0.01); ejection factor and fractional shortening were decreased (P<0.01); left ventricular internal end-diastolic dimension and left ventricular internal end-systolic dimension were increased (P<0.01); and IL-2, IL-6, TNF-α, and hs-CRP were increased in the model group. Myocardial damage and inflammation were also observed by HE staining. QS improved these indexes, similar to the atorvastatin group; therefore, QS could effectively treat ACS. QS modulates the structure and abundance of the intestinal flora in ACS model rats, among which Bacteroides, Lactobacillus, and Rikenellaceae_RC9_gut_group are associated with cardiovascular disease. Metabolomics revealed that the intestinal metabolite content changed in ACS, with ethanolamine (EA) being the most relevant metabolite for ACS treatment by QS. EA was significantly positively correlated with Eubacterium xylanophilum group, Ruminococcus, unclassified f__Oscillospiraceae, Intestinimonas, Eubacterium siraeum group, Lachnospiraceae NK4A136 group, and norank f__Desulfovibrionaceae.CONCLUSION: QS can effectively treat ACS and can restore regulation of the intestinal flora. EA may be the primary metabolite of QS, exerting a therapeutic effect in ACS.PMID:36855515 | PMC:PMC9968440 | DOI:10.2147/DDDT.S396649

Circulating amino acid levels and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition and UK Biobank cohorts

Wed, 01/03/2023 - 12:00
BMC Med. 2023 Feb 28;21(1):80. doi: 10.1186/s12916-023-02739-4.ABSTRACTBACKGROUND: Amino acid metabolism is dysregulated in colorectal cancer patients; however, it is not clear whether pre-diagnostic levels of amino acids are associated with subsequent risk of colorectal cancer. We investigated circulating levels of amino acids in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank cohorts.METHODS: Concentrations of 13-21 amino acids were determined in baseline fasting plasma or serum samples in 654 incident colorectal cancer cases and 654 matched controls in EPIC. Amino acids associated with colorectal cancer risk following adjustment for the false discovery rate (FDR) were then tested for associations in the UK Biobank, for which measurements of 9 amino acids were available in 111,323 participants, of which 1221 were incident colorectal cancer cases.RESULTS: Histidine levels were inversely associated with colorectal cancer risk in EPIC (odds ratio [OR] 0.80 per standard deviation [SD], 95% confidence interval [CI] 0.69-0.92, FDR P-value=0.03) and in UK Biobank (HR 0.93 per SD, 95% CI 0.87-0.99, P-value=0.03). Glutamine levels were borderline inversely associated with colorectal cancer risk in EPIC (OR 0.85 per SD, 95% CI 0.75-0.97, FDR P-value=0.08) and similarly in UK Biobank (HR 0.95, 95% CI 0.89-1.01, P=0.09) In both cohorts, associations changed only minimally when cases diagnosed within 2 or 5 years of follow-up were excluded.CONCLUSIONS: Higher circulating levels of histidine were associated with a lower risk of colorectal cancer in two large prospective cohorts. Further research to ascertain the role of histidine metabolism and potentially that of glutamine in colorectal cancer development is warranted.PMID:36855092 | DOI:10.1186/s12916-023-02739-4

Global Lipidome Profiling Revealed Multifaceted Role of Lipid Species in Hepatitis C Virus Replication, Assembly, and Host Antiviral Response

Tue, 28/02/2023 - 12:00
Viruses. 2023 Feb 7;15(2):464. doi: 10.3390/v15020464.ABSTRACTHepatitis C virus (HCV) is a major human pathogen that requires a better understanding of its interaction with host cells. There is a close association of HCV life cycle with host lipid metabolism. Lipid droplets (LDs) have been found to be crucial organelles that support HCV replication and virion assembly. In addition to their role in replication, LDs also have protein-mediated antiviral properties that are activated during HCV infection. Studies have shown that HCV replicates well in cholesterol and sphingolipid-rich membranes, but the ways in which HCV alters host cell lipid dynamics are not yet known. In this study, we performed a kinetic study to check the enrichment of LDs at different time points of HCV infection. Based on the LD enrichment results, we selected early and later time points of HCV infection for global lipidomic study. Early infection represents the window period for HCV sensing and host immune response while later infection represents the establishment of viral RNA replication, virion assembly, and egress. We identified the dynamic profile of lipid species at early and later time points of HCV infection by global lipidomic study using mass spectrometry. At early HCV infection, phosphatidylinositol phospholipids (PIPs), lysophosphatidic acid (LPA), triacyl glycerols (TAG), phosphatidylcholine (PC), and trihexosylceramides (Hex3Cer) were observed to be enriched. Similarly, free fatty acids (FFA), phosphatidylethanolamine (PE), N-acylphosphatidylethanolamines (NAPE), and tri acylglycerols were enriched at later time points of HCV infection. Lipids enriched at early time of infection may have role in HCV sensing, viral attachment, and immune response as LPA and PIPs are important for immune response and viral attachment, respectively. Moreover, lipid species observed at later infection may contribute to HCV replication and virion assembly as PE, FFA, and triacylglycerols are known for the similar function. In conclusion, we identified lipid species that exhibited dynamic profile across early and later time points of HCV infection compared to mock cells, which could be therapeutically relevant in the design of more specific and effective anti-viral therapies.PMID:36851679 | PMC:PMC9965260 | DOI:10.3390/v15020464

Untargeted metabolomic analysis of metabolites related to body dysmorphic disorder (BDD)

Tue, 28/02/2023 - 12:00
Funct Integr Genomics. 2023 Feb 28;23(1):70. doi: 10.1007/s10142-023-00995-4.ABSTRACTBody dysmorphic disorder (BDD) is a disorder associated with depression and eating disorders. It often arises from minor defects in appearance or an individual imagining that he or she is defective. However, the mechanisms causing BDD remain unclear, and its pathogenesis and adjuvant treatment methods still need to be explored. Here, we employed a liquid chromatography-mass spectrometry (LC-MS)-based metabolomics approach to identify key metabolic differences in BDD versus healthy patients. We obtained plasma samples from two independent cohorts (including eight BDD patients and eight healthy control patients). Raw data were analyzed using Compound Discoverer to determine peak alignment, retention time correction, and extraction of peak areas. Metabolite structure identification was also obtained using Compound Discoverer by of accurate mass matching (< 10 ppm) and secondary spectral matching queries of compound databases. Next, multidimensional statistical analyses were performed using the ropls R package. These analyses included: unsupervised principal component analysis, supervised partial Least-Squares Discriminant Analysis, and orthogonal partial Least-Squares Discriminant Analysis. We then identified the most promising metabolic signatures associated with BDD across all metabolomic datasets. Principal component analysis showed changes in small-molecule metabolites in patients, and we also found significant differences in metabolite abundance between the BDD and normal groups. Our findings suggest that the occurrence of BDD may be related to metabolites participating in the following KEGG pathways: ABC transporters, purine metabolism, glycine, serine and threonine metabolism, pyrimidine, pyrimidine metabolism, biosynthesis of 12-, 14-, and 16-membered macrolides, microbial metabolism in diverse environments, biosynthesis of secondary metabolites, and caffeine and insect hormone biosynthesis.PMID:36854840 | DOI:10.1007/s10142-023-00995-4

Blood metabolites in preterm infants with retinopathy of prematurity based on tandem mass spectrometry: a preliminary study

Tue, 28/02/2023 - 12:00
Zhongguo Dang Dai Er Ke Za Zhi. 2023 Feb 15;25(2):140-146. doi: 10.7499/j.issn.1008-8830.2209142.ABSTRACTOBJECTIVES: To study new biomarkers for the early diagnosis of retinopathy of prematurity (ROP) by analyzing the differences in blood metabolites based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) and metabolomics.METHODS: Dried blood spots were collected from 21 infants with ROP (ROP group) and 21 infants without ROP (non-ROP group) who were hospitalized in the Sixth Affiliated Hospital of Sun Yat-sen University from January 2013 to December 2016. LC-MS/MS was used to measure the metabolites, and orthogonal partial least squares-discriminant analysis was used to search for differentially expressed metabolites and biomarkers.RESULTS: There was a significant difference in blood metabolic profiles between the ROP and non-ROP groups. The pattern recognition analysis, Score-plot, and weight analysis obtained 10 amino acids with a relatively large difference. Further statistical analysis showed that the ROP group had significant increases in blood levels of glutamic acid, leucine, aspartic acid, ornithine, and glycine compared with the non-ROP group (P<0.05). The receiver operating characteristic curve analysis showed that glutamic acid and ornithine had the highest value in diagnosing ROP.CONCLUSIONS: Blood metabolites in preterm infants with ROP are different from those without ROP. Glutamic acid and ornithine are the metabolic markers for diagnosing ROP. LC-MS/MS combined with metabolomics analysis has a potential application value in the early identification and diagnosis of ROP.PMID:36854689 | DOI:10.7499/j.issn.1008-8830.2209142

Integrated transcriptome and metabolome analyses shed light on the defense mechanisms in tomato plants after (E)-2-hexenal fumigation

Tue, 28/02/2023 - 12:00
Genomics. 2023 Feb 26:110592. doi: 10.1016/j.ygeno.2023.110592. Online ahead of print.ABSTRACTTomato is a widely cultivated fruit and vegetable and is valued for its flavor, colour, and nutritional value. C6-aldehydes, such as (E)-2-hexenal, not only have antibacterial and antifungal properties but also function as signaling molecules that control the defense mechanisms of plants, including tomatoes. In this study, we used liquid chromatography-mass spectrometry (LC-MS) and RNA sequencing techniques to generate metabolome and transcriptome datasets that elucidate the molecular mechanisms regulating defense responses in tomato leaves exposed to (E)-2-hexenal. A total of 28.27 Gb of clean data were sequenced and assembled into 23,720 unigenes. In addition, a non-targeted metabolomics approach detected 739 metabolites. There were 233 significant differentially expressed genes (DEGs) (158 up-regulated, 75 down-regulated) and 154 differentially expressed metabolites (DEMs) (86 up-regulated, 69 down-regulated). Most nucleotides and amino acids (L-Phenylalanine, L-Asparagine, L-Histidine, L-Arginine, and L-Tyrosine) and their derivatives were enriched. The analyses revealed that mitogen-activated protein kinase (MPK), pathogenesis-related protein (PR), and endochitinase (CHIB) were primarily responsible for the adaptation of plant defense responses. Therefore, the extensive upregulation of these genes may be associated with the increased plant defense response. These findings help us comprehend the defense response of plants to (E)-2-hexenal and improve the resistance of horticultural plants.PMID:36854356 | DOI:10.1016/j.ygeno.2023.110592

The Promises of Proteomics and Metabolomics for Unravelling the Mechanism and Side Effect Landscape of Beta-Adrenoceptor Antagonists in Cardiovascular Therapeutics

Tue, 28/02/2023 - 12:00
OMICS. 2023 Feb 28. doi: 10.1089/omi.2023.0003. Online ahead of print.ABSTRACTCardiovascular medicine witnessed notable advances for the past decade. Multiomics research offers a new lens for precision/personalized medicine for existing and emerging drugs used in the cardiovascular clinic. Beta-blockers are vital in treating hypertension and chronic heart failure. However, clinical use of beta-blockers is also associated with side effects and person-to-person variations in their pharmacokinetics and pharmacodynamics. A comprehensive understanding of the mechanisms that underpin the side effect landscape of beta-blockers is imperative to optimize their therapeutic value. In addition, current research emphasizes the circadian clock's vital roles in regulating pharmacological parameters. Administration of the beta-blockers at specific dosing times could potentially improve their effectiveness and reduce their toxic effects. The rapid development of mass spectrometry technologies with chemical proteomics and thermal proteome profiling methods has also substantially advanced our understanding of underlying side effects mechanisms by unbiased deconvolution of drug targets and off-targets. Metabolomics is steadily demonstrating its utility for conducting mechanistic and toxicological analyses of pharmacological compounds. This article discusses the promises of cutting-edge proteomics and metabolomics approaches to investigate the molecular targets, mechanism of action, adverse effects, and dosing time dependency of beta-blockers.PMID:36854142 | DOI:10.1089/omi.2023.0003

HR LC-MS/MS metabolomic profiling of Yucca aloifolia fruit and the potential neuroprotective effect on rotenone-induced Parkinson's disease in rats

Tue, 28/02/2023 - 12:00
PLoS One. 2023 Feb 28;18(2):e0282246. doi: 10.1371/journal.pone.0282246. eCollection 2023.ABSTRACTYucca aloifolia L. fruit (Yucca or Spanish bayonet, family Asparagaceae) is recognized for its purplish red color reflecting its anthocyanin content, which has a powerful antioxidant activity. This study aimed to investigate yucca (YA) fruit extract's protective effect on Parkinson's disease (PD). In vitro study, the anti-inflammatory activity of yucca fruit extracts was explored by measuring tumor necrosis factor receptor 2 (TNF-R2) and nuclear factor kappa B (NF-KB) to choose the most effective extract. Afterward, a detailed in vivo investigation of the protective effect of the most active extract on rotenone-induced PD was performed on male albino Wister rats. First, the safety of the extract in two different doses (50 and 100 mg/kg in 0.9% saline orally) was confirmed by a toxicological study. The rats were divided into four groups: 1) normal control (NC); 2) rotenone group; and third and fourth groups received 50 and 100 mg/kg yucca extract, respectively. The neurobehavioral and locomotor activities of the rats were tested by rotarod, open field, and forced swim tests. Striatal dopamine, renal and liver functions, and oxidative stress markers were assessed. Western blot analysis of brain tissue samples was performed for p-AMPK, Wnt3a, and β-catenin. Histopathological examination of striatal tissue samples was performed by light and electron microscopy (EM). The metabolites of the active extract were characterized using high-resolution LC-MS/MS, and the results showed the prevalence of anthocyanins, saponins, phenolics, and choline. Biochemical and histopathological tests revealed a dose-dependent improvement with oral Yucca extract. The current study suggests a possible neuroprotective effect of the acidified 50% ethanol extract (YA-C) of the edible Yucca fruit, making it a promising therapeutic target for PD.PMID:36854038 | DOI:10.1371/journal.pone.0282246

Isotope-guided metabolomics reveals divergent incorporation of valine into different flavor precursor classes in chives

Tue, 28/02/2023 - 12:00
Chembiochem. 2023 Feb 28:e202300056. doi: 10.1002/cbic.202300056. Online ahead of print.ABSTRACTPlants of the genus Allium such as chives, onions or garlic produce S-alk(en)yl cysteine sulfoxides as flavor precursors. Two major representatives are S-propenyl cysteine sulfoxide (isoalliin) and S-propyl cysteine sulfoxide (propiin), which only differ by a double bond in the C3 side chain. The propenyl group of isoalliin is derived from the amino acid valine, but the source of the propyl group of propiin remains unclear. Here, we present an untargeted metabolomics approach in seedlings of chives (Allium schoenoprasum) to track mass features containing sulfur and/or 13C from labeling experiments with valine-13C5 guided by their isotope signatures. Our data show that propiin and related propyl-bearing metabolites incorporate carbon derived from valine-13C5, but to a much lower extent than isoalliin and related propenyl compounds. Our findings provide new insights into the biosynthetic pathways of flavor precursors in Allium species and open new avenues for future untargeted labeling experiments.PMID:36853993 | DOI:10.1002/cbic.202300056

Identifying Plasma and Urinary Biomarkers of Fermented Food Intake and Their Associations with Cardiometabolic Health in a Dutch Observational Cohort

Tue, 28/02/2023 - 12:00
J Agric Food Chem. 2023 Feb 28. doi: 10.1021/acs.jafc.2c05669. Online ahead of print.ABSTRACTIdentification of food intake biomarkers (FIBs) for fermented foods could help improve their dietary assessment and clarify their associations with cardiometabolic health. We aimed to identify novel FIBs for fermented foods in the plasma and urine metabolomes of 246 free-living Dutch adults using nontargeted LC-MS and GC-MS. Furthermore, associations between identified metabolites and several cardiometabolic risk factors were explored. In total, 37 metabolites were identified corresponding to the intakes of coffee, wine, and beer (none were identified for cocoa, bread, cheese, or yoghurt intake). While some of these metabolites appeared to originate from raw food (e.g., niacin and trigonelline for coffee), others overlapped different fermented foods (e.g., 4-hydroxybenzeneacetic acid for both wine and beer). In addition, several fermentation-dependent metabolites were identified (erythritol and citramalate). Associations between these identified metabolites with cardiometabolic parameters were weak and inconclusive. Further evaluation is warranted to confirm their relationships with cardiometabolic disease risk.PMID:36853956 | DOI:10.1021/acs.jafc.2c05669

Integrated Metabolic and Inflammatory Signatures Associated with Severity of, Fatality of, and Recovery from COVID-19

Tue, 28/02/2023 - 12:00
Microbiol Spectr. 2023 Feb 28:e0219422. doi: 10.1128/spectrum.02194-22. Online ahead of print.ABSTRACTSevere manifestations of coronavirus disease 2019 (COVID-19) and mortality have been associated with physiological alterations that provide insights into the pathogenesis of the disease. Moreover, factors that drive recovery from COVID-19 can be explored to identify correlates of protection. The cellular metabolism represents a potential target to improve survival upon severe disease, but the associations between the metabolism and the inflammatory response during COVID-19 are not well defined. We analyzed blood laboratorial parameters, cytokines, and metabolomes of 150 individuals with mild to severe disease, of which 33 progressed to a fatal outcome. A subset of 20 individuals was followed up after hospital discharge and recovery from acute disease. We used hierarchical community networks to integrate metabolomics profiles with cytokines and markers of inflammation, coagulation, and tissue damage. Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) promotes significant alterations in the plasma metabolome, whose activity varies according to disease severity and correlates with oxygen saturation. Differential metabolism underlying death was marked by amino acids and related metabolites, such as glutamate, glutamyl-glutamate, and oxoproline, and lipids, including progesterone, phosphocholine, and lysophosphatidylcholines (lysoPCs). Individuals who recovered from severe disease displayed persistent alterations enriched for metabolism of purines and phosphatidylinositol phosphate and glycolysis. Recovery of mild disease was associated with vitamin E metabolism. Data integration shows that the metabolic response is a hub connecting other biological features during disease and recovery. Infection by SARS-CoV-2 induces concerted activity of metabolic and inflammatory responses that depend on disease severity and collectively predict clinical outcomes of COVID-19. IMPORTANCE COVID-19 is characterized by diverse clinical outcomes that include asymptomatic to mild manifestations or severe disease and death. Infection by SARS-CoV-2 activates inflammatory and metabolic responses that drive protection or pathology. How inflammation and metabolism communicate during COVID-19 is not well defined. We used high-resolution mass spectrometry to investigate small biochemical compounds (<1,500 Da) in plasma of individuals with COVID-19 and controls. Age, sex, and comorbidities have a profound effect on the plasma metabolites of individuals with COVID-19, but we identified significant activity of pathways and metabolites related to amino acids, lipids, nucleotides, and vitamins determined by disease severity, survival outcome, and recovery. Furthermore, we identified metabolites associated with acute-phase proteins and coagulation factors, which collectively identify individuals with severe disease or individuals who died of severe COVID-19. Our study suggests that manipulating specific metabolic pathways can be explored to prevent hyperinflammation, organ dysfunction, and death.PMID:36852984 | DOI:10.1128/spectrum.02194-22

Identification of a secondary Q-marker in high-quality ecotypes of <em>Carthamus tinctorius</em> L. and exploration of the target preference

Tue, 28/02/2023 - 12:00
Food Funct. 2023 Feb 28. doi: 10.1039/d2fo02596e. Online ahead of print.ABSTRACTSafflower (Carthamus tinctorius) has the efficacy for promoting blood circulation and preventing cardiovascular and Alzheimer's diseases and is thus a valuable medicinal and functional food plant. However, how to evaluate high-quality safflower is still a problem. To differentiate intraspecies ecotypes and illustrate the mechanisms of differential metabolites of C. tinctorius from different regions, this study combined the widely targeted metabolome, weighted network pharmacology, and molecular docking to filter bioactive compounds and predict the target preference. The results indicated that kaempferol is suitable as a secondary Q-marker to differentiate intraspecies ecotypes. In secondary metabolites, the average content of kaempferol and its derivates in C. tinctorius from Sichuan is three times that of other areas, which have the potential for the targeted medicine of CA2 and TNF. In volatile metabolites, isoaromadendrene epoxide has the potential as a specifically targeted medicine of RXRA. The change of the target preference could be the reason for the difference in drug efficacy among different varieties of C. tinctorius. It is reasonable that Sichuan was recognized as a high-quality ecotype producing region of C. tinctorius in China, which promotes blood circulation and removes blood stasis. This study provides an innovative method to differentiate intraspecies ecotypes and explore their target preference.PMID:36852499 | DOI:10.1039/d2fo02596e

Metabolomic profiles of human glioma inform patient survival

Tue, 28/02/2023 - 12:00
Antioxid Redox Signal. 2023 Feb 27. doi: 10.1089/ars.2022.0085. Online ahead of print.ABSTRACTAIMS: Targeting tumor metabolism may improve the outcomes for patients with glioblastoma (GBM). To further preclinical efforts targeting metabolism in GBM, we tested the hypothesis that brain tumors can be stratified into distinct metabolic groups with different patient outcomes. Therefore, to determine if tumor metabolites relate to patient survival, we profiled the metabolomes of human gliomas and correlated metabolic information with clinical data.RESULTS: We found that isocitrate dehydrogenase-wildtype (IDHwt) GBMs are metabolically distinguishable from IDH mutated (IDHmut) astrocytomas and oligodendrogliomas. Survival of patients with IDHmut gliomas was expectedly more favorable than those with IDHwt GBM, and metabolic signatures can stratify IDHwt GBMs subtypes with varying prognoses. Patients whose GBMs were enriched in amino acids had improved survival while those whose tumors were enriched for nucleotides, redox molecules and lipid metabolites fared more poorly. These findings were recapitulated in validation cohorts using both metabolomic and transcriptomic data.INNOVATION: Our results suggest the existence of metabolic subtypes of GBM with differing prognoses and further support the concept that metabolism may drive the aggressiveness of human gliomas.CONCLUSIONS: Our data show that metabolic signatures of human gliomas can inform patient survival. These findings may be used clinically to tailor novel metabolically targeted agents for GBM patients with different metabolic phenotypes.PMID:36852494 | DOI:10.1089/ars.2022.0085

Microhabitat-specific diurnal metabolomic responses of the intertidal limpet <em>Cellana toreuma</em> to winter low temperature

Tue, 28/02/2023 - 12:00
iScience. 2023 Feb 3;26(3):106128. doi: 10.1016/j.isci.2023.106128. eCollection 2023 Mar 17.ABSTRACTHigh-throughput determination of circadian rhythms in metabolic response and their divergent patterns in various microhabitats are crucial for understanding how organisms respond to environmental stresses. A mid-intertidal limpet Cellana toreuma was collected at various time points across both daytime and nighttime in winter during low tide for investigating the diurnal metabolomic responses to cold stress and elucidating the divergent metabolic responses to temperature variations across microhabitats. Temperatures of emergent rock microhabitats were lower than the tidal pool and even aggravated at night. A series of metabolomic responses exhibited coordinated diurnal changes in winter. Metabolic responses which were associated with cellular stress responses and energy metabolism of emergent rock microhabitat individuals were highly induced compared to the tidal pool ones. This study shed light on the diurnal patterns of metabolomic responses of intertidal molluscs in the field and emphasized the variations in metabolic responses between microhabitats.PMID:36852273 | PMC:PMC9958412 | DOI:10.1016/j.isci.2023.106128

Vitamin B<sub>6,</sub> B<sub>12</sub> and folate modulate deregulated pathways and protein aggregation in yeast model of Huntington disease

Tue, 28/02/2023 - 12:00
3 Biotech. 2023 Mar;13(3):96. doi: 10.1007/s13205-023-03525-y. Epub 2023 Feb 24.ABSTRACTHuntington's disease (HD) is an incurable and progressive neurodegenerative disease affecting the basal ganglia of the brain. HD is caused due to expansion of the polyglutamine tract in the protein Huntingtin resulting in aggregates. The increased PolyQ length results in aggregation of protein Huntingtin leading to neuronal cell death. Vitamin B6, B12 and folate are deficient in many neurodegenerative diseases. We performed an integrated analysis of transcriptomic, metabolomic and cofactor-protein network of vitamin B6, B12 and folate was performed. Our results show considerable overlap of pathways modulated by Vitamin B6, B12 and folate with those obtained from transcriptomic and metabolomic data of HD patients and model systems. Further, in yeast model of HD we showed treatment of B6, B12 or folate either alone or in combination showed impaired aggregate formation. Transcriptomic analysis of yeast model treated with B6, B12 and folate showed upregulation of pathways like ubiquitin mediated proteolysis, autophagy, peroxisome, fatty acid, lipid and nitrogen metabolism. Metabolomic analysis of yeast model shows deregulation of pathways like aminoacyl-tRNA biosynthesis, metabolism of various amino acids, nitrogen metabolism and glutathione metabolism. Integrated transcriptomic and metabolomic analysis of yeast model showed concordance in the pathways obtained. Knockout of Peroxisomal (PXP1 and PEX7) and Autophagy (ATG5) genes in yeast increased aggregates which is mitigated by vitamin B6, B12 and folate treatment. Taken together our results show a role for Vitamin B6, B12 and folate mediated modulation of pathways important for preventing protein aggregation with potential implications for HD.SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-023-03525-y.PMID:36852176 | PMC:PMC9958225 | DOI:10.1007/s13205-023-03525-y

Cystathionine-γ-lyase overexpression modulates oxidized nicotinamide adenine dinucleotide biosynthesis and enhances neovascularization

Tue, 28/02/2023 - 12:00
JVS Vasc Sci. 2023 Jan 13;4:100095. doi: 10.1016/j.jvssci.2022.11.003. eCollection 2023.ABSTRACTOBJECTIVE: Hydrogen sulfide is a proangiogenic gas produced primarily by the transsulfuration enzyme cystathionine-γ-lyase (CGL). CGL-dependent hydrogen sulfide production is required for neovascularization in models of peripheral arterial disease. However, the benefits of increasing endogenous CGL and its mechanism of action have not yet been elucidated.METHODS: Male whole body CGL-overexpressing transgenic (CGLTg) mice and wild-type (WT) littermates (C57BL/6J) were subjected to the hindlimb ischemia model (age, 10-12 weeks). Functional recovery was assessed via the treadmill exercise endurance test. Leg perfusion was measured by laser Doppler imaging and vascular endothelial-cadherin immunostaining. To examine the angiogenic potential, aortic ring sprouting assay and postnatal mouse retinal vasculature development studies were performed. Finally, comparative metabolomics analysis, oxidized/reduced nicotinamide adenine dinucleotide (NAD+/NADH) analysis, and quantitative real-time polymerase chain reaction were performed on CGLWT and CGLTg gastrocnemius muscle.RESULTS: The restoration of blood flow occurred more rapidly in CGLTg mice. Compared with the CGLWT mice, the median ± standard deviation running distance and time were increased for the CGLTg mice after femoral artery ligation (159 ± 53 m vs 291 ± 74 m [P < .005] and 17 ± 4 minutes vs 27 ± 5 minutes [P < .05], respectively). Consistently, in the CGLTg ischemic gastrocnemius muscle, the capillary density was increased fourfold (0.05 ± 0.02 vs 0.20 ± 0.12; P < .005). Ex vivo, the endothelial cell (EC) sprouting length was increased in aorta isolated from CGLTg mice, especially when cultured in VEGFA (vascular endothelial growth factor A)-only media (63 ± 2 pixels vs 146 ± 52 pixels; P < .05). Metabolomics analysis demonstrated a higher level of niacinamide, a precursor of NAD+/NADH in the muscle of CGLTg mice (61.4 × 106 ± 5.9 × 106 vs 72.4 ± 7.7 × 106 area under the curve; P < .05). Similarly, the NAD+ salvage pathway gene expression was increased in CGLTg gastrocnemius muscle. Finally, CGL overexpression or supplementation with the NAD+ precursor nicotinamide mononucleotide improved EC migration in vitro (wound closure: control, 35% ± 9%; CGL, 55% ± 11%; nicotinamide mononucleotide, 42% ± 13%; P < .05).CONCLUSIONS: Our results have demonstrated that CGL overexpression improves the neovascularization of skeletal muscle on hindlimb ischemia. These effects correlated with changes in the NAD pathway, which improved EC migration.PMID:36852171 | PMC:PMC9958478 | DOI:10.1016/j.jvssci.2022.11.003

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