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

Behavioral metabolomics: how behavioral data can guide metabolomics research on neuropsychiatric disorders

Wed, 02/08/2023 - 12:00
Metabolomics. 2023 Aug 2;19(8):69. doi: 10.1007/s11306-023-02034-6.ABSTRACTINTRODUCTION: Metabolomics produces vast quantities of data but determining which metabolites are the most relevant to the disease or disorder of interest can be challenging.OBJECTIVES: This study sought to demonstrate how behavioral models of psychiatric disorders can be combined with metabolomics research to overcome this limitation.METHODS: We designed a preclinical, untargeted metabolomics procedure, that focuses on the determination of central metabolites relevant to substance use disorders that are (a) associated with changes in behavior produced by acute drug exposure and (b) impacted by repeated drug exposure. Untargeted metabolomics analysis was carried out on liquid chromatography-mass spectrometry data obtained from 336 microdialysis samples. Samples were collected from the medial striatum of male Sprague-Dawley (N = 21) rats whilst behavioral data were simultaneously collected as part of a (±)-3,4-methylenedioxymethamphetamine (MDMA)-induced behavioral sensitization experiment. Analysis was conducted by orthogonal partial least squares, where the Y variable was the behavioral data, and the X variables were the relative concentrations of the 737 detected features.RESULTS: MDMA and its derivatives, serotonin, and several dopamine/norepinephrine metabolites were the greatest predictors of acute MDMA-produced behavior. Subsequent univariate analyses showed that repeated MDMA exposure produced significant changes in MDMA metabolism, which may contribute to the increased abuse liability of the drug as a function of repeated exposure.CONCLUSION: These findings highlight how the inclusion of behavioral data can guide metabolomics data analysis and increase the relevance of the results to the phenotype of interest.PMID:37530897 | DOI:10.1007/s11306-023-02034-6

Identification of Ecdysteroid Sinapate Esters with COX-2 Inhibitory Effects from <em>Fibraurea recisa</em> Using Molecular Networking and MS2LDA

Wed, 02/08/2023 - 12:00
J Nat Prod. 2023 Aug 2. doi: 10.1021/acs.jnatprod.3c00371. Online ahead of print.ABSTRACTThe roots of Fibraurea recisa are recognized as a rich source of protoberberine and aporphine alkaloids, but the non-alkaloidal metabolites in this plant are underexplored. The present study investigated the chemical composition of the plant roots using untargeted metabolomics-based molecular networking and MS2LDA motif annotation, revealing the presence of a characteristic fragment motif related to several sinapoyl-functionalized metabolites. Guided by the targeted motif, two new sinapic acid-ecdysteroid hybrids, named 3-O-sinapoyl makisterone A (1) and 2-O-sinapoyl makisterone A (2), were isolated. The structures of these compounds, including their absolute configuration, were elucidated by HR-ESIQTOFMS, MS2 fragmentation, NMR spectroscopy, and chemical degradation coupled with optical rotation measurements. Although neither compound inhibited nitric oxide (NO) production or inducible nitric oxide synthase (iNOS) protein expression on lipopolysaccharide-induced RAW 264 cells, 2 significantly suppressed cyclooxygenase 2 (COX-2) protein expression at 1-30 μM. Additionally, decreased expression of COX-2 protein was barely observed after treatment with methyl sinapate or makisterone A, the steroid skeleton of 1 and 2. These results indicated that the presence of the sinapoyl moiety at C-2 on the C28-ecdysteroid skeleton played a key role in the selectivity for the suppression of the COX-2 protein expression.PMID:37530540 | DOI:10.1021/acs.jnatprod.3c00371

The <em>Chlamydia</em> effector CpoS modulates the inclusion microenvironment and restricts the interferon response by acting on Rab35

Wed, 02/08/2023 - 12:00
mBio. 2023 Aug 2:e0319022. doi: 10.1128/mbio.03190-22. Online ahead of print.ABSTRACTThe obligate intracellular bacterium Chlamydia trachomatis inserts a family of inclusion membrane (Inc) proteins into the membrane of its vacuole (the inclusion). The Inc CpoS is a critical suppressor of host cellular immune surveillance, but the underlying mechanism remained elusive. By complementing a cpoS mutant with various natural orthologs and variants of CpoS, we linked distinct molecular interactions of CpoS to distinct functions. Unexpectedly, we found CpoS to be essential for the formation of inclusion membrane microdomains that control the spatial organization of multiple Incs involved in signaling and modulation of the host cellular cytoskeleton. While the function of CpoS in microdomains was uncoupled from its role in the suppression of host cellular defenses, we found the ability of CpoS to interact with Rab GTPases to be required not only for the manipulation of membrane trafficking, such as to mediate transport of ceramide-derived lipids (sphingolipids) to the inclusion, but also for the inhibition of Stimulator of interferon genes (STING)-dependent type I interferon responses. Indeed, depletion of Rab35 phenocopied the exacerbated interferon responses observed during infection with CpoS-deficient mutants. Overall, our findings highlight the role of Inc-Inc interactions in shaping the inclusion microenvironment and the modulation of membrane trafficking as a pathogenic immune evasion strategy. IMPORTANCE Chlamydia trachomatis is a prevalent bacterial pathogen that causes blinding ocular scarring and urogenital infections that can lead to infertility and pregnancy complications. Because Chlamydia can only grow within its host cell, boosting the intrinsic defenses of human cells may represent a novel strategy to fight pathogen replication and survival. Hence, CpoS, a Chlamydia protein known to block host cellular defenses, or processes regulated by CpoS, could provide new opportunities for therapeutic intervention. By revealing CpoS as a multifunctional virulence factor and by linking its ability to block host cellular immune signaling to the modulation of membrane trafficking, the present work may provide a foundation for such rationale targeting and advances our understanding of how intracellular bacteria can shape and protect their growth niche.PMID:37530528 | DOI:10.1128/mbio.03190-22

<em>Coptis chinensis</em>-Induced Changes in Metabolomics and Gut Microbiota in Rats

Wed, 02/08/2023 - 12:00
Am J Chin Med. 2023 Aug 2:1-30. doi: 10.1142/S0192415X23500702. Online ahead of print.ABSTRACTRhizoma coptidis (CR) is traditionally used for treating gastrointestinal diseases. Wine-processed CR (wCR), zingiber-processed CR (zCR), and evodia-processed CR (eCR) are its major processed products. However, the related study of their specific mechanisms is very limited, and they need to be further clarified. The aim of this study is to compare the intervening mechanism of wCR/zCR/eCR on rats via faecal metabolomics and 16S rDNA gene sequencing analysis. First, faecal samples were collected from the control and CR/wCR/zCR/eCR groups. Then, a metabolomics analysis was performed using UHPLC-Q/TOF-MS to obtain the metabolic profile and significantly altered metabolites. The 16S rDNA gene sequencing analysis was carried out to analyze the composition of gut microbiota and screen out the significantly altered microbiota at the genus level. Finally, a pathway enrichment analysis of the significantly altered metabolites via the KEGG database and a functional prediction of relevant gut microbes based on PICRUSt2 software were performed in combination. Together with the correlation analysis between metabolites and gut microbiota, the potential intervening mechanism of wCR/zCR/eCR was explored. The results suggested that wCR played a good role in maintaining immune homeostasis, promoting glycolysis, and reducing cholesterol; zCR had a better effect on protecting the integrity of the intestinal mucus barrier, preventing gastric ulcers, and reducing body cholesterol; eCR was good at protecting the integrity of the intestinal mucus barrier and promoting glycolysis. This study scientifically elucidated the intervening mechanism of wCR/zCR/eCR from the perspective of faecal metabolites and gut microbiota, providing a new insight into the processing mechanism research of Chinese herbs.PMID:37530506 | DOI:10.1142/S0192415X23500702

Muscle characteristics comparison and targeted metabolome analysis reveal differences in carcass traits and meat quality of three pig breeds

Wed, 02/08/2023 - 12:00
Food Funct. 2023 Aug 2. doi: 10.1039/d2fo03709b. Online ahead of print.ABSTRACTThis study investigated the molecular basis for differences in meat yield and quality between Duroc, Taoyuan black (TB), and Xiangcun black (XB) pigs. The results show that TB pigs have lower carcass weight, lean percentage, pH decline, and glycolytic potential but have higher fat percentage, water- holding capacity, intramuscular fat content, antioxidant capacity, and percentage of slow-twitch fibers than the Duroc pigs. Moreover, muscles of TB pigs have lower protein synthesis and lipolysis gene expression than the muscles of Duroc pigs. Targeted metabolome analysis indicates that 24 metabolites significantly differ among these three pig breeds. Correlation analysis suggests that L-malic acid and β-alanine contents in muscle are closely related to meat quality. These findings suggest that the excellent meat quality of TB pigs is closely related to muscle metabolism and fiber characteristics, while lower protein synthesis and lipolysis may contribute to less meat yield.PMID:37530176 | DOI:10.1039/d2fo03709b

Metabolomic profiles and pathogenesis of nephrolithiasis

Wed, 02/08/2023 - 12:00
Curr Opin Nephrol Hypertens. 2023 Sep 1;32(5):490-495. doi: 10.1097/MNH.0000000000000903. Epub 2023 Jul 21.ABSTRACTPURPOSE OF REVIEW: Kidney stone disease is caused by supersaturation of urine with certain metabolites and minerals. The urine composition of stone formers has been measured to prevent stone recurrence, specifically calcium, uric acid, oxalate, ammonia, citrate. However, these minerals and metabolites have proven to be unreliable in predicting stone recurrence. Metabolomics using high throughput technologies in well defined patient cohorts can identify metabolites that may provide insight into the pathogenesis of stones as well as offer possibilities in therapeutics.RECENT FINDINGS: Techniques including 1H-NMR, and liquid chromatography paired with tandem mass spectroscopy have identified multiple possible metabolites involved in stone formation. Compared to formers of calcium oxalate stones, healthy controls had higher levels of hippuric acid as well as metabolites involved in caffeine metabolism. Both the gut and urine microbiome may contribute to the altered metabolome of stone formers.SUMMARY: Although metabolomics has offered several potential metabolites that may be protective against or promote stone formation, the mechanisms behind these metabolomic profiles and their clinical significance requires further investigation.PMID:37530089 | DOI:10.1097/MNH.0000000000000903

Classification and severity progression measure of COVID-19 patients using pairs of multi-omic factors

Wed, 02/08/2023 - 12:00
J Appl Stat. 2022 May 4;50(11-12):2473-2503. doi: 10.1080/02664763.2022.2064975. eCollection 2023.ABSTRACTEarly detection and effective treatment of severe COVID-19 patients remain two major challenges during the current pandemic. Analysis of molecular changes in blood samples of severe patients is one of the promising approaches to this problem. From thousands of proteomic, metabolomic, lipidomic, and transcriptomic biomarkers selected in other research, we identify several pairs of biomarkers that after additional nonlinear spline transformation are highly effective in classifying and predicting severe COVID-19 cases. The performance of these pairs is evaluated in-sample, in a cross-validation exercise, and in an out-of-sample analysis on two independent datasets. We further improve our classifier by identifying complementary pairs using hierarchical clustering. In a result, we achieve 96-98% AUC on the validation data. Our findings can help medical experts to identify small groups of biomarkers that after nonlinear transformation can be used to construct a cost-effective test for patient screening and prediction of severity progression.PMID:37529561 | PMC:PMC10388828 | DOI:10.1080/02664763.2022.2064975

Untargeted metabolomics on first trimester serum implicates metabolic perturbations associated with BMI in development of hypertensive disorders: a discovery study

Wed, 02/08/2023 - 12:00
Front Nutr. 2023 Jul 17;10:1144131. doi: 10.3389/fnut.2023.1144131. eCollection 2023.ABSTRACTGOAL: Body mass index (BMI) in early pregnancy is a critical risk factor for hypertensive disorders of pregnancy (HDP). The pathobiology of the interplay between BMI and HDP is not fully understood and represents the focus of this investigation.METHODS: BMI and 1st-trimester serum samples were obtained from the Global Alliance to Prevent Prematurity and Stillbirth repository for 154 women (105 without HDP and 49 with HDP). Metabotyping was conducted using ultra-high-performance liquid-chromatography high-resolution mass spectrometry (UHPLC HR-MS). Multivariable linear regression and logistic models were used to determine metabolites and pathway perturbations associated with BMI in women with and without HDP, and to determine metabolites and pathway perturbations associated with HDP for women in categories of obese, overweight, and normal weight based on the 1st trimester BMI. These outcome-associated signals were identified or annotated by matching against an in-house physical standards library and public database. Pathway analysis was conducted by the Mummichog algorithm in MetaboAnalyst.RESULT: Vitamin D3 and lysine metabolism were enriched to associate with BMI for women with and without HDP. Tryptophan metabolism enrichment was associated with HDP in all the BMI categories. Pregnant women who developed HDP showed more metabolic perturbations with BMI (continuous) than those without HDP in their 1st-trimester serum. The HDP-associated pathways for women with normal weight indicated inflammation and immune responses. In contrast, the HDP-associated pathways for women of overweight and obese BMI indicated metabolic syndromes with disorders in glucose, protein, and amino acid, lipid and bile acid metabolism, and oxidative and inflammatory stress.CONCLUSION: High first-trimester BMI indicates underlying metabolic syndromes, which play critical roles in HDP development. Vitamin D3 and tryptophan metabolism may be the targets to guide nutritional interventions to mitigate metabolic and inflammatory stress in pregnancy and reduce the onset of HDP.PMID:37528997 | PMC:PMC10388370 | DOI:10.3389/fnut.2023.1144131

Study on semi-bionic extraction of Astragalus polysaccharide and its anti-aging activity <em>in vivo</em>

Wed, 02/08/2023 - 12:00
Front Nutr. 2023 Jul 17;10:1201919. doi: 10.3389/fnut.2023.1201919. eCollection 2023.ABSTRACTAstragalus membranaceus (A. membranaceus) is a homologous plant with high medicinal and edible value. Therefore, the extraction methods of Astragalus polysaccharide (APS) have attracted the attention of many research groups, but the yield of the active components is still not high. The aim of this study was to extract APS by a semi-bionic extraction method, optimize the extraction process, and evaluate the anti-aging activities of APS in vivo. The results showed that the APS yield was 18.23% when extracted by the semi-bionic extraction method. Anti-aging evaluation in rats showed that APS extracted by this method significantly decreased the malondialdehyde (MDA) content and increased superoxide dismutase (SOD) activity to cope with D-galactose-induced aging. Serum metabolomic analysis indicated that a total of 48 potential biomarkers showed significant differences, mainly involving 5 metabolic pathways. These altered metabolic pathways were mainly related to energy metabolism, amino acid metabolism, and lipid metabolism. These results indicated that the semi-bionic extraction method can effectively improve the yield of APS, and the extracted APS exhibited anti-aging activity in rats. Our study provided a novel and effective method to extract APS and indicated that APS can be used as functional food and natural medicine to delay aging and prevent its complications.PMID:37528992 | PMC:PMC10389262 | DOI:10.3389/fnut.2023.1201919

Quality variation and biosynthesis of anti-inflammatory compounds for <em>Capparis spinosa</em> based on the metabolome and transcriptome analysis

Wed, 02/08/2023 - 12:00
Front Plant Sci. 2023 Jul 17;14:1224073. doi: 10.3389/fpls.2023.1224073. eCollection 2023.ABSTRACTINTRODUCTION: Capparis spinosa L. fruits as edible and medicinal plant, has anti-inflammatory activities. The different morphological characteristics of C. spinosa fruits from Ili, Turpan, and Karamay may affect their anti-inflammatory components and functions.METHODS: The anti-inflammatory activity of C. spinosa fruit was assessed using an LPS-induced inflammatory cell model. Furthermore, the differences in anti-inflammatory compounds were analyzed by metabolome and RNA-seq. Additionally, the anti-inflammatory mechanism was elucidated using network pharmacology.RESULTS: In the study, we found that the 95% ethanol extracts (CSE) obtained from the three kinds of fruits showed remarkable anti-inflammatory effects both in vivo and in vitro. However, the CSE derived from Ili fruits significantly reduced CD86 levels on DCs. As a result of metabolomic analysis, the metabolic profiles of Ili fruits differed significantly from those of the other two habitats, which were consistent with transcriptome analysis. A total of 15 compounds exhibiting anti-inflammatory activity were subjected to screening, revealing a greater accumulation of flavonoids in the Turpan and Karamay districts. Notably, phenolic compounds were identified as the principal anti-inflammatory components in C. spinosa.CONCLUSION: There were significant differences in the morphology, metabolites, transcriptional levels, and anti-inflammatory activity of C. spinosa from the three districts.PMID:37528974 | PMC:PMC10388242 | DOI:10.3389/fpls.2023.1224073

Integrated morphological, metabolome, and transcriptome analyses revealed the mechanism of exogenous gibberellin promoting petiole elongation in <em>Oenanthe javanica</em>

Wed, 02/08/2023 - 12:00
Front Plant Sci. 2023 Jul 17;14:1225635. doi: 10.3389/fpls.2023.1225635. eCollection 2023.ABSTRACTOenanthe javanica (Blume) DC. is a popular vegetable with unique flavor and its leaf is the main product organ. Gibberellin (GA) is an important plant hormone that plays vital roles in regulating the growth of plants. In this study, the plants of water dropwort were treated with different concentrations of GA3. The plant height of water dropwort was significantly increased after GA3 treatment. Anatomical structure analysis indicated that the cell length of water dropwort was elongated under exogenous application of GA3. The metabolome analysis showed flavonoids were the most abundant metabolites and the biosynthesis of secondary metabolites were also regulated by GA3. The exogenous application of GA3 altered the gene expressions of plant hormone signal transduction (GID and DELLA) and metabolites biosynthesis pathways to regulate the growth of water dropwort. The GA contents were modulated by up-regulating the expression of GA metabolism gene GA2ox. The differentially expressed genes related to cell wall formation were significantly enriched. A total of 22 cellulose synthase involved in cellulose biosynthesis were identified from the genome of water dropwort. Our results indicated that GA treatment promoted the cell elongation by inducing the expression of cellulose synthase and cell wall formation in water dropwort. These results revealed the molecular mechanism of GA-mediated cell elongation, which will provide valuable reference for using GA to regulate the growth of water dropwort.PMID:37528973 | PMC:PMC10389089 | DOI:10.3389/fpls.2023.1225635

Faecal bacteriome and metabolome profiles associated with decreased mucosal inflammatory activity upon anti-TNF therapy in paediatric Crohn's disease

Tue, 01/08/2023 - 12:00
J Crohns Colitis. 2023 Aug 1:jjad126. doi: 10.1093/ecco-jcc/jjad126. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Treatment by anti-TNFα antibodies (anti-TNF) changes the dysbiotic faecal bacteriome in Crohn's disease (CD). However, it is not known whether these changes are due to decreasing mucosal inflammatory activity or whether similar bacteriome reactions might be observed in gut-healthy subjects. Therefore, we explored changes in faecal bacteriome and metabolome upon anti-TNF administration (and therapeutic response) in children with CD and contrasted those to anti-TNF-treated children with juvenile idiopathic arthritis (JIA).METHODS: Faecal samples collected longitudinally before and during anti-TNF therapy were analysed for bacteriome by massively parallel sequencing of the 16S rDNA (V4 region) and for faecal metabolome by 1H nuclear magnetic resonance. The response to treatment by mucosal healing was assessed by MINI index at three months after the treatment started. We also tested several representative gut bacterial strains for in-vitro growth inhibition by infliximab.RESULTS: We analysed 530 stool samples from 121 children (CD 54, JIA 18, healthy 49). Bacterial community composition reacted on anti-TNF in CD: three members of class Clostridia increased on anti-TNF, whereas class Bacteroidia decreased. Among faecal metabolites, glucose and glycerol increased, whereas isoleucine and uracil decreased. Some of these changes differed by treatment response (mucosal healing) after anti-TNF. No significant changes in bacteriome or metabolome were noted upon anti-TNF in JIA. Bacterial growth was not affected by infliximab in a disc diffusion test.CONCLUSIONS: Our findings suggest that gut mucosal healing is responsible for the bacteriome and metabolome changes observed in CD, rather than any general effect of anti-TNF.PMID:37527838 | DOI:10.1093/ecco-jcc/jjad126

Hepatic levels of S-adenosylmethionine regulate the adaptive response to fasting

Tue, 01/08/2023 - 12:00
Cell Metab. 2023 Jul 26:S1550-4131(23)00261-9. doi: 10.1016/j.cmet.2023.07.002. Online ahead of print.ABSTRACTThere has been an intense focus to uncover the molecular mechanisms by which fasting triggers the adaptive cellular responses in the major organs of the body. Here, we show that in mice, hepatic S-adenosylmethionine (SAMe)-the principal methyl donor-acts as a metabolic sensor of nutrition to fine-tune the catabolic-fasting response by modulating phosphatidylethanolamine N-methyltransferase (PEMT) activity, endoplasmic reticulum-mitochondria contacts, β-oxidation, and ATP production in the liver, together with FGF21-mediated lipolysis and thermogenesis in adipose tissues. Notably, we show that glucagon induces the expression of the hepatic SAMe-synthesizing enzyme methionine adenosyltransferase α1 (MAT1A), which translocates to mitochondria-associated membranes. This leads to the production of this metabolite at these sites, which acts as a brake to prevent excessive β-oxidation and mitochondrial ATP synthesis and thereby endoplasmic reticulum stress and liver injury. This work provides important insights into the previously undescribed function of SAMe as a new arm of the metabolic adaptation to fasting.PMID:37527658 | DOI:10.1016/j.cmet.2023.07.002

LC-MS/MS based metabolomic analysis of serum from patients with cerebrovascular stenosis

Tue, 01/08/2023 - 12:00
J Pharm Biomed Anal. 2023 Jul 28;235:115608. doi: 10.1016/j.jpba.2023.115608. Online ahead of print.ABSTRACTCerebrovascular stenosis (CVS) is the main cause of ischemic stroke, which greatly threatens human life. Hence, it's important to perform early screenings for CVS. Metabolomics is an emerging omics approach that has great advantages in disease screening and diagnosis. Therefore, we aim to elucidate the correlation between CVS and metabolomics, which can aid in conducting CVS screening at an early stage. Patients with CVS in Beijing Hospital were included in the study. A total of 36 participants, including 18 patients diagnosed with CVS and 18 healthy individuals, were recruited at Beijing Hospital between May 2022 and October 2021. The serum samples were analyzed for liquid chromatography-tandem mass spectrometry (LC-MS/MS). Then, multivariate statistical methods, including principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were performed. Differential metabolites were obtained and demonstrated by volcano plot and heatmap. The study recruited 36 participants, including 18 patients with CVS and 18 healthy participants. A total of 150 metabolites were identified. Multivariate statistical analysis revealed significant differences between patients and healthy participants. Furthermore, 30 serum metabolites levels differed significantly between two groups. Differential metabolites were enriched in phenylalanine, tyrosine, and tryptophan biosynthesis; primary bile acid biosynthesis, and other pathways. This study identified differential metabolites in patients with CVS and elucidated the relevant metabolic pathways. Thus, these findings aid in the study of the pathogenesis of CVS and its early diagnosis. DATA AVAILABILITY STATEMENT: The datasets generated for this study are available on request to the corresponding author.PMID:37527609 | DOI:10.1016/j.jpba.2023.115608

Sex-Gender-Based Differences in Metabolic Diseases

Tue, 01/08/2023 - 12:00
Handb Exp Pharmacol. 2023 Aug 2. doi: 10.1007/164_2023_683. Online ahead of print.ABSTRACTSexual dimorphism creates different biological and cellular activities and selective regulation mechanisms in males and females, thus generating differential responses in health and disease. In this scenario, the sex itself is a source of physiologic metabolic disparities that depend on constitutive genetic and epigenetic features that characterize in a specific manner one sex or the other. This has as a direct consequence a huge impact on the metabolic routes that drive the phenotype of an individual. The impact of sex is being clearly recognized also in disease, whereas male and females are more prone to the development of some disorders, or have selective responses to drugs and therapeutic treatments. Actually, very less is known regarding the probable differences guided by sex in the context of inherited metabolic disorders, owing to the scarce consideration of sex in such restricted field, accompanied by an intrinsic bias connected with the rarity of such diseases. Metabolomics technologies have been ultimately developed and adopted for being excellent tools for the investigation of metabolic mechanisms, for marker discovery or monitoring, and for supporting diagnostic procedures of metabolic disorders. Hence, metabolomic approaches can excellently embrace the discovery of sex differences, especially when associated to the outcome or the management of certain inborn errors of the metabolism.PMID:37528324 | DOI:10.1007/164_2023_683

The plasma metabolome of long COVID patients two years after infection

Tue, 01/08/2023 - 12:00
Sci Rep. 2023 Aug 1;13(1):12420. doi: 10.1038/s41598-023-39049-x.ABSTRACTOne of the major challenges currently faced by global health systems is the prolonged COVID-19 syndrome (also known as "long COVID") which has emerged as a consequence of the SARS-CoV-2 epidemic. It is estimated that at least 30% of patients who have had COVID-19 will develop long COVID. In this study, our goal was to assess the plasma metabolome in a total of 100 samples collected from healthy controls, COVID-19 patients, and long COVID patients recruited in Mexico between 2020 and 2022. A targeted metabolomics approach using a combination of LC-MS/MS and FIA MS/MS was performed to quantify 108 metabolites. IL-17 and leptin were measured in long COVID patients by immunoenzymatic assay. The comparison of paired COVID-19/long COVID-19 samples revealed 53 metabolites that were statistically different. Compared to controls, 27 metabolites remained dysregulated even after two years. Post-COVID-19 patients displayed a heterogeneous metabolic profile. Lactic acid, lactate/pyruvate ratio, ornithine/citrulline ratio, and arginine were identified as the most relevant metabolites for distinguishing patients with more complicated long COVID evolution. Additionally, IL-17 levels were significantly increased in these patients. Mitochondrial dysfunction, redox state imbalance, impaired energy metabolism, and chronic immune dysregulation are likely to be the main hallmarks of long COVID even two years after acute COVID-19 infection.PMID:37528111 | DOI:10.1038/s41598-023-39049-x

Understanding quality differences between kiwifruit varieties during softening

Tue, 01/08/2023 - 12:00
Food Chem. 2023 Jul 24;430:136983. doi: 10.1016/j.foodchem.2023.136983. Online ahead of print.ABSTRACTResearch into variations between kiwifruit varieties particularly their softening quality during storage is important in improving kiwifruit quality. The potential reasons for ripening quality differences between 'Cuixiang' (CX) and 'Hayward' (HWD) kiwifruit were analyzed by physiology and metabolomic data combined with the random forests learning algorithm. The results showed that the storability difference between the two varieties mainly resulted from differences in polygalacturonase (PG) and β-galactosidase activities. The 1 °C slowed the fruit softening process of both varieties by decreasing their PG activities. A total of 368 metabolites were identified and amino acid, carbohydrate, cofactors and vitamins, as well as nucleotide metabolism are key metabolic modules that affect the ripening differences of CX and HWD kiwifruit. A total of 30 metabolites showed remarkable ability in distinguish the ripening quality of CX and HWD kiwifruit, in which d-glucose, d-maltose, 2-hydroxybutyric acid, phenyllactate, and vitamin B2 were noteworthy for their potential application on the evaluation of kiwifruit taste and nutritional value. These findings provide positive insights into the underlying mechanism of ripening quality differences between CX and HWD kiwifruit and new ideas for identifying key metabolic markers in kiwifruit.PMID:37527582 | DOI:10.1016/j.foodchem.2023.136983

Evolutionary signatures of a trade-off in direct and indirect defenses across the wild grape genus Vitis

Tue, 01/08/2023 - 12:00
Evolution. 2023 Aug 1:qpad140. doi: 10.1093/evolut/qpad140. Online ahead of print.ABSTRACTEvolutionary correlations between chemical defense and protection by mutualist bodyguards have been long predicted, but tests of these pattern remain rare. We use a phylogenetic framework to test for evolutionary correlations indicative of trade-offs or synergisms between direct defense in the form of plant secondary metabolism, and indirect defense in the form of leaf domatia, across 33 species in the wild grape genus, Vitis. We also performed a bioassay with a generalist herbivore to associate our chemical phenotypes with herbivore palatability. Finally, we tested whether defensive traits correlate with the average abiotic characteristics of each species' contemporary range and whether these correlations were consistent with plant defense theory. We found a negative evolutionary correlation between domatia size and the diversity of secondary metabolites in Vitis leaf tissue across the genus, and also that leaves with a higher diversity and richness of secondary metabolites were less palatable to a generalist herbivore, consistent with a trade-off in chemical and mutualistic defense investment. Predictions from plant defense theory were not supported by associations between investment in defense phenotypes and abiotic variables. Our work demonstrates an evolutionary pattern indicative of a trade-off between indirect and direct defense strategies across the Vitis genus.PMID:37527551 | DOI:10.1093/evolut/qpad140

Biochemical phenotyping of paroxysmal nocturnal hemoglobinuria reveals solute carriers and β-oxidation deficiencies

Tue, 01/08/2023 - 12:00
PLoS One. 2023 Aug 1;18(8):e0289285. doi: 10.1371/journal.pone.0289285. eCollection 2023.ABSTRACTINTRODUCTION: Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal disease of hematopoietic cells with a variable clinical spectrum characterized by intravascular hemolysis, high risk of thrombosis, and cytopenias. To understand the biochemical shifts underlying PNH, this study aimed to search for the dysfunctional pathways involved in PNH physiopathology by comparing the systemic metabolic profiles of affected patients to healthy controls and the metabolomic profiles before and after the administration of eculizumab in PNH patients undergoing treatment.METHODS: Plasma metabolic profiles, comprising 186 specific annotated metabolites, were quantified using targeted quantitative electrospray ionization tandem mass spectrometry in 23 PNH patients and 166 population-based controls. In addition, samples from 12 PNH patients on regular eculizumab maintenance therapy collected before and 24 hours after eculizumab infusion were also analyzed.RESULTS: In the PNH group, levels of the long-chain acylcarnitines metabolites were significantly higher as compared to the controls, while levels of histidine, taurine, glutamate, glutamine, aspartate and phosphatidylcholines were significantly lower in the PNH group. These differences suggest altered acylcarnitine balance, reduction in the amino acids participating in the glycogenesis pathway and impaired glutaminolysis. In 12 PNH patients who were receiving regular eculizumab therapy, the concentrations of acylcarnitine C6:1, the C14:1/C6 ratio (reflecting the impaired action of the medium-chain acyl-Co A dehydrogenase), and the C4/C6 ratio (reflecting the impaired action of short-chain acyl-Co A dehydrogenase) were significantly reduced immediately before eculizumab infusion, revealing impairments in the Acyl CoA metabolism, and reached levels similar to those in the healthy controls 24 hours after infusion.CONCLUSIONS: We demonstrated significant differences in the metabolomes of the PNH patients compared to healthy controls. Eculizumab infusion seemed to improve deficiencies in the acyl CoA metabolism and may have a role in the mitochondrial oxidative process of long and medium-chain fatty acids, reducing oxidative stress, and inflammation.PMID:37527257 | DOI:10.1371/journal.pone.0289285

GWAS reveals genomic associations with swine inflammation and necrosis syndrome

Tue, 01/08/2023 - 12:00
Mamm Genome. 2023 Aug 1. doi: 10.1007/s00335-023-10011-6. Online ahead of print.ABSTRACTThe recently identified swine inflammation and necrosis syndrome (SINS) occurs in high prevalence from newborn piglets to fattening pigs and resembles an important concern for animal welfare. The primary endogenous syndrome affects the tail, ears, teats, coronary bands, claws and heels. The basis of clinical inflammation and necrosis has been substantiated by histopathology, metabolomic and liver transcriptomic. Considerable variation in SINS scores is evident in offspring of different boars under the same husbandry conditions. The high complexity of metabolic alterations and the influence of the boar led to the hypothesis of a polygenic architecture of SINS. This should be investigated by a genome-wide association study. For this purpose, 27 sows were simultaneously inseminated with mixed semen from two extreme boars. The mixed semen always contained ejaculate from a Pietrain boar classified as extremely SINS susceptible and additionally either the ejaculate from a Pietrain boar classified as SINS stable or from a Duroc boar classified as SINS stable. The 234 piglets were phenotyped on day 3 of life, sampled and genetically assigned to the respective boar. The piglets showed the expected genetic differentiation with respect to SINS susceptibility. The suspected genetic complexity was confirmed both in the number and genome-wide distribution of 221 significantly associated SNPs, and led to 49 candidate genes. As the SNPs were almost exclusively located in noncoding regions, functional nucleotides have not yet been identified. The results suggest that the susceptibility of piglets to SINS depends not only on environmental conditions but also on genomic variation.PMID:37526658 | DOI:10.1007/s00335-023-10011-6

Pages