PubMed

bioRxiv. 2023 May 22:2023.05.20.541585. doi: 10.1101/2023.05.20.541585. Preprint.ABSTRACTAIMS: Mitochondria play a vital role in cellular metabolism and energetics and support normal cardiac function. Disrupted mitochondrial function and homeostasis cause a variety of heart diseases. Fam210a (family with sequence similarity 210 member A), a novel mitochondrial gene, is identified as a hub gene in mouse cardiac remodeling by multi-omics studies. Human FAM210A mutations are associated with sarcopenia. However, the physiological role and molecular function of FAM210A remain elusive in the heart. We aim to determine the biological role and molecular mechanism of FAM210A in regulating mitochondrial function and cardiac health in vivo .METHODS AND RESULTS: Tamoxifen-induced αMHC MCM -driven conditional knockout of Fam210a in the mouse cardiomyocytes induced progressive dilated cardiomyopathy and heart failure, ultimately causing mortality. Fam210a deficient cardiomyocytes exhibit severe mitochondrial morphological disruption and functional decline accompanied by myofilament disarray at the late stage of cardiomyopathy. Furthermore, we observed increased mitochondrial reactive oxygen species production, disturbed mitochondrial membrane potential, and reduced respiratory activity in cardiomyocytes at the early stage before contractile dysfunction and heart failure. Multi-omics analyses indicate that FAM210A deficiency persistently activates integrated stress response (ISR), resulting in transcriptomic, translatomic, proteomic, and metabolomic reprogramming, ultimately leading to pathogenic progression of heart failure. Mechanistically, mitochondrial polysome profiling analysis shows that FAM210A loss of function compromises mitochondrial mRNA translation and leads to reduced mitochondrial encoded proteins, followed by disrupted proteostasis. We observed decreased FAM210A protein expression in human ischemic heart failure and mouse myocardial infarction tissue samples. To further corroborate FAM210A function in the heart, AAV9-mediated overexpression of FAM210A promotes mitochondrial-encoded protein expression, improves cardiac mitochondrial function, and partially rescues murine hearts from cardiac remodeling and damage in ischemia-induced heart failure.CONCLUSION: These results suggest that FAM210A is a mitochondrial translation regulator to maintain mitochondrial homeostasis and normal cardiomyocyte contractile function. This study also offers a new therapeutic target for treating ischemic heart disease.TRANSLATIONAL PERSPECTIVE: Mitochondrial homeostasis is critical for maintaining healthy cardiac function. Disruption of mitochondrial function causes severe cardiomyopathy and heart failure. In the present study, we show that FAM210A is a mitochondrial translation regulator required for maintaining cardiac mitochondrial homeostasis in vivo . Cardiomyocyte-specific FAM210A deficiency leads to mitochondrial dysfunction and spontaneous cardiomyopathy. Moreover, our results indicate that FAM210A is downregulated in human and mouse ischemic heart failure samples and overexpression of FAM210A protects hearts from myocardial infarction induced heart failure, suggesting that FAM210A mediated mitochondrial translation regulatory pathway can be a potential therapeutic target for ischemic heart disease.PMID:37293097 | PMC:PMC10245825 | DOI:10.1101/2023.05.20.541585

bioRxiv. 2023 May 24:2023.05.23.541633. doi: 10.1101/2023.05.23.541633. Preprint.ABSTRACTBioactive metabolites produced by symbiotic microbiota causally impact host health and disease, nonetheless, incomplete functional annotation of genes as well as complexities and dynamic nature of microbiota make understanding species-level contribution in production and actions difficult. Alpha-galactosylceramides produced by Bacteroides fragilis (BfaGC) are one of the first modulators of colonic immune development, but biosynthetic pathways and the significance of the single species in the symbiont community still remained elusive. To address these questions at the microbiota level, we have investigated the lipidomic profiles of prominent gut symbionts and the metagenome-level landscape of responsible gene signatures in the human gut. We first elucidated the chemical diversity of sphingolipid biosynthesis pathways of major bacterial species. In addition to commonly shared ceramide backbone synthases showing two distinct intermediates, alpha-galactosyltransferase (agcT), the necessary and sufficient component for BfaGC production and host colonic type I natural killer T (NKT) cell regulation by B. fragilis, was characterized by forward-genetics based targeted metabolomic screenings. Phylogenetic analysis of agcT in human gut symbionts revealed that only a few ceramide producers have agcT and hence can produce aGCs, on the other hand, structurally conserved homologues of agcT are widely distributed among species lacking ceramides. Among them, alpha-glucosyl-diacylglycerol(aGlcDAG)-producing glycosyltransferases with conserved GT4-GT1 domains are one of the most prominent homologs in gut microbiota, represented by Enterococcus bgsB . Of interest, aGlcDAGs produced by bgsB can antagonize BfaGC-mediated activation of NKT cells, showing the opposite, lipid structure-specific actions to regulate host immune responses. Further metagenomic analysis of multiple human cohorts uncovered that the agcT gene signature is almost exclusively contributed by B. fragilis , regardless of age, geographical and health status, where the bgsB signature is contributed by >100 species, of which abundance of individual microbes is highly variable. Our results collectively showcase the diversities of gut microbiota producing biologically relevant metabolites in multiple layers-biosynthetic pathways, host immunomodulatory functions and microbiome-level landscapes in the host.PMID:37293019 | PMC:PMC10245877 | DOI:10.1101/2023.05.23.541633

bioRxiv. 2023 May 22:2023.05.20.541602. doi: 10.1101/2023.05.20.541602. Preprint.ABSTRACTThe Sorting and Assembly Machinery (SAM) Complex functions in the assembly of β-barrel in the mitochondrial membrane. The SAM complex is made up of three subunits, Sam35, Sam37, and Sam50. While both Sam35 and Sam37 are peripheral membrane proteins that are not required for survival, Sam50 interacts with the MICOS complex to connect the inner and outer mitochondrial membranes and forms the mitochondrial intermembrane space bridging (MIB) complex. Specifically, Sam50 stabilizes the MIB complex for protein transport, respiratory chain complex assembly, and cristae integrity regulation. To structurally form and sustain the cristae, the MICOS complex assembles at the cristae junction and binds directly to Sam50. However, the role of Sam50 in overall mitochondrial structure and metabolism in skeletal muscle remains unclear. Here, we use SBF-SEM and Amira software perform 3D renderings of mitochondria and autophagosomes in human myotubes. Beyond this, Gas Chromatography-Mass Spectrometry-based metabolomics was utilized to interrogate differential changes of the metabolites in wild-type (WT) and Sam50 deficient myotubes. Ablation of Sam50 , revealed increases in ß-Alanine, propanoate, and phenylalanine, and tyrosine metabolism. Additionally, we observed that mitochondrial fragmentation and autophagosome formation was increased in Sam50 -deficient myotubes compared to control myotubes. Beyond this, the metabolomic analysis revealed an increase in amino acid metabolism and fatty acid metabolism. XF24 Seahorse Analyzer shows that oxidative capacity is further impaired upon ablation of Sam50 in both murine and human myotubes. Together, these data suggest Sam50 is critical for establishing and maintaining mitochondria, mitochondrial cristae structure, and mitochondrial metabolism.PMID:37292887 | PMC:PMC10245823 | DOI:10.1101/2023.05.20.541602

medRxiv. 2023 May 24:2023.05.17.23289772. doi: 10.1101/2023.05.17.23289772. Preprint.ABSTRACTPulmonary hypertension (PH) is a severe hemodynamic, progressive condition associated with high morbidity and mortality where early and less invasive diagnostics could crucially improve management. There is a need for biomarkers in PH that are functional, diagnostic, and prognostic. We used a broad metabolomics approach with machine learning analysis and specific free fatty acid (FFA)/lipid-ratios to develop diagnostic and prognostic PH biomarkers. In a training cohort of 74 PH patients, 30 disease controls without PH, and 65 healthy controls, we identified diagnostic and prognostic markers that were validated in an independent cohort of 64 subjects. Markers based on lipophilic metabolites were more robust than those based on hydrophilic metabolites. FFA/lipid-ratios provided excellent diagnostic accuracy for PH with an AUC of up to 0.89 and 0.90 in the training and the validation cohorts, respectively. The ratios provided age-independent prognostic information and a combination of a ratio with established clinical scores increased the hazard ratio (HR) for FPHR4p and COMPERA2 from 2.5 to 4.3 and from 3.3 to 5.6, respectively. Pulmonary arteries (PA) of idiopathic PAH (IPAH) lungs show lipid accumulation and altered expression of lipid homeostasis-related genes that may explain this accumulation. Our functional studies in PA endothelial and smooth muscle cells have shown that increased FFA levels caused excessive proliferation and PA endothelial barrier dysfunction, both hallmarks of pulmonary artery hypertension (PAH). In conclusion, lipidomic changes in PH provide novel diagnostic and prognostic biomarkers and may point to new metabolic therapy targets.PMID:37292870 | PMC:PMC10246148 | DOI:10.1101/2023.05.17.23289772

bioRxiv. 2023 May 26:2023.05.26.542501. doi: 10.1101/2023.05.26.542501. Preprint.ABSTRACTArthropod-borne microbes rely on the metabolic state of a host to cycle between evolutionarily distant species. For instance, arthropod tolerance to infection may be due to redistribution of metabolic resources, often leading to microbial transmission to mammals. Conversely, metabolic alterations aids in pathogen elimination in humans, who do not ordinarily harbor arthropod-borne microbes. To ascertain the effect of metabolism on interspecies relationships, we engineered a system to evaluate glycolysis and oxidative phosphorylation in the tick Ixodes scapularis . Using a metabolic flux assay, we determined that the rickettsial bacterium Anaplasma phagocytophilum and the Lyme disease spirochete Borrelia burgdorferi , which are transstadially transmitted in nature, induced glycolysis in ticks. On the other hand, the endosymbiont Rickettsia buchneri, which is transovarially maintained, had a minimal effect on I. scapularis bioenergetics. Importantly, the metabolite β-aminoisobutyric acid (BAIBA) was elevated during A. phagocytophilum infection of tick cells following an unbiased metabolomics approach. Thus, we manipulated the expression of genes associated with the catabolism and anabolism of BAIBA in I. scapularis and detected impaired feeding on mammals, reduced bacterial acquisition, and decreased tick survival. Collectively, we reveal the importance of metabolism for tick-microbe relationships and unveil a valuable metabolite for I. scapularis fitness.PMID:37292783 | PMC:PMC10245996 | DOI:10.1101/2023.05.26.542501

Front Immunol. 2023 May 24;14:1203015. doi: 10.3389/fimmu.2023.1203015. eCollection 2023.ABSTRACTBACKGROUND: Postpartum depression has a crucial impact on the physical and psychological comfort and the work of postnatal women, the growth and development of infants and mental health in adulthood. Finding a safe and effective anti-postnatal depression drug is currently an important research goal in this field.METHODS: In this study, the forced swimming test (FST) and tail suspension test (TST) were used to evaluated the depressive behaviors of mice, and the changes of metabolites and intestinal microflora in mice with postpartum depression were examined through non-target metabolomics and 16S RNA sequencing respectively.RESULTS: We found that traditional Chinese medicine compound 919 Syrup could alleviate postpartum depression in mice and inhibit the elevated erucamide level in depressive hippocampus. However, mice treated with antibiotics were not sensitive to the anti-postnatal depression effect of 919 Syrup, and the level of 5-aminovaleric acid betaine (5-AVAB) in their hippocampus was significantly decreased. Transplanting fecal microflora treated with 919 Syrup could effectively improve the depressive behaviors of mice, upregulate the level of gut-derived 5-AVAB in the hippocampus, and downregulate the level of erucamide. Erucamide was significantly negatively correlated with increased Bacteroides in intestine after 919 Syrup treatment or fecal transplantation, and significantly positively correlated with Ruminococcaceae UCG-014 which was increased in feces of mice with postpartum depression. The increase of Bacteroides, Lactobacillus, and Ruminiclostridium in intestine after fecal transplantation had a clearly positive correlation with 5-AVAB.CONCLUSION: In brief, 919 Syrup may downregulate the ratio of hippocampal metabolites erucamide to 5-AVAB by regulating intestinal flora to alleviate postpartum depression, laying a scientific foundation for future pathological research and development of therapeutic drugs for postpartum depression.PMID:37292211 | PMC:PMC10244653 | DOI:10.3389/fimmu.2023.1203015

Front Immunol. 2023 May 23;14:1159112. doi: 10.3389/fimmu.2023.1159112. eCollection 2023.ABSTRACTPURPOSE: Olfactory dysfunction (OD) is a debilitating symptom frequently reported by patients with chronic rhinosinusitis (CRS) and it is associated with a dysregulated sinonasal inflammation. However, little information is available about the effect of the inflammation-related nasal microbiota and related metabolites on the olfactory function in these patients. Therefore, the current study aimed to investigate the nasal microbiota-metabolites-immune interactions and their role in the pathogenesis of OD in CRS patients.METHODS: 23 and 19 CRS patients with and without OD, respectively, were enrolled in the present study. The "Sniffin' Sticks" was used to measure the olfactory function, while the metagenomic shotgun sequencing and the untargeted metabolite profiling were performed to assess the differences in terms of the nasal microbiome and metabolome between the two groups. The levels of nasal mucus inflammatory mediators were investigated by a multiplex flow Cytometric Bead Array (CBA).RESULTS: A decreased diversity in the nasal microbiome from the OD group compared to the NOD group was evidenced. The metagenomic analysis revealed a significant enrichment of Acinetobacter johnsonii in the OD group, while Mycoplasma arginini, Aeromonas dhakensis, and Salmonella enterica were significantly less represented (LDA value > 3, p < 0.05). The nasal metabolome profiles were significantly different between the OD and NOD groups (P < 0.05). The purine metabolism was the most significantly enriched metabolic subpathway in OD patients compared with NOD patients (P < 0.001). The expressions of IL-5, IL-8, MIP-1α, MCP-1, and TNF were statistically and significantly increased in the OD group (P < 0.05). All these data, including the dysregulation of the nasal microbiota, differential metabolites, and elevated inflammatory mediators in OD patients demonstrated a clear interaction relationship.CONCLUSION: The disturbed nasal microbiota-metabolite-immune interaction networks may be implicated in the pathogenesis of OD in CRS patients and the underlying pathophysiological mechanisms need to be further investigated in future studies.PMID:37292198 | PMC:PMC10245275 | DOI:10.3389/fimmu.2023.1159112

Front Immunol. 2023 May 24;14:1151728. doi: 10.3389/fimmu.2023.1151728. eCollection 2023.ABSTRACTINTRODUCTION: Sepsis is intricately linked to intestinal damage and barrier dysfunction. At present times, there is a growing interest in a metabolite-based therapy for multiple diseases.METHODS: Serum samples from septic patients and healthy individuals were collected and their metabonomics profiling assessed using Ultra-Performance Liquid Chromatography-Time of Flight Mass Spectrometry (UPLC-TOFMS). The eXtreme Gradient Boosting algorithms (XGBOOST) method was used to screen essential metabolites associated with sepsis, and five machine learning models, including Logistic Regression, XGBoost, GaussianNB(GNB), upport vector machines(SVM) and RandomForest were constructed to distinguish sepsis including a training set (75%) and validation set(25%). The area under the receiver-operating characteristic curve (AUROC) and Brier scores were used to compare the prediction performances of different models. Pearson analysis was used to analysis the relationship between the metabolites and the severity of sepsis. Both cellular and animal models were used to HYPERLINK "javascript:;" assess the function of the metabolites.RESULTS: The occurrence of sepsis involve metabolite dysregulation. The metabolites mannose-6-phosphate and sphinganine as the optimal sepsis-related variables screened by XGBOOST algorithm. The XGBoost model (AUROC=0.956) has the most stable performance to establish diagnostic model among the five machine learning methods. The SHapley Additive exPlanations (SHAP) package was used to interpret the XGBOOST model. Pearson analysis reinforced the expression of Sphinganine, Mannose 6-phosphate were positively associated with the APACHE-II, PCT, WBC, CRP, and IL-6. We also demonstrated that sphinganine strongly diminished the LDH content in LPS-treated Caco-2 cells. In addition, using both in vitro and in vivo examination, we revealed that sphinganine strongly protects against sepsis-induced intestinal barrier injury.DISCUSSION: These findings highlighted the potential diagnostic value of the ML, and also provided new insight into enhanced therapy and/or preventative measures against sepsis.PMID:37292192 | PMC:PMC10245321 | DOI:10.3389/fimmu.2023.1151728

Front Pharmacol. 2023 May 24;14:1205323. doi: 10.3389/fphar.2023.1205323. eCollection 2023.ABSTRACTBackground: The relationships among intestinal dysbiosis, bile acid (BA) metabolism disorders, and ulcerative colitis pathogenesis are now recognized. However, how specific strains regulate BA metabolism to alleviate colitis is still unclear. This study investigated the effects of Bacteroides dorei on the development of acute colitis and elucidated the underlying mechanisms. Methods: The safety of BDX-01 was evaluated in vitro and in vivo. 2.5% dextran sulfate sodium (DSS) induced colitis in C57BL/6 mice, Caco-2, and J774A.1 cells were used to evaluate the anti-inflammatory effect of BDX-01. qPCR and Western blotting were used to detect the expression of inflammatory pathways. Microbiota composition was analyzed by 16S rRNA gene sequencing. Enzyme activity analysis and targeted metabolomics were used to analyze fecal bile salt hydrolase (BSH) and BA levels. Antibiotic-induced pseudo-germ-free mice were used to investigate the role of gut microbiota in the alleviation of colitis by BDX-01. Results: We confirmed the safety of novel strain Bacteroides dorei BDX-01 in vitro and in vivo. Oral BDX-01 administration significantly ameliorated the symptoms and pathological damage of DSS-induced acute colitis. Moreoever, 16S rRNA sequencing and enzyme activity analysis showed that BDX-01 treatment increased intestinal BSH activity and the abundance of bacteria harboring this enzyme. Targeted metabolomics revealed that BDX-01 significantly increased intestinal BA excretion and deconjugation. Certain BAs act as FXR agonists. The β-muricholic acid (βMCA): taurine β-muricholic acid (T-βMCA) and cholic acid (CA): taurocholic acid (TCA) ratios and the deoxycholic acid (DCA) level decreased markedly in the colitis models but increased substantially in BDX-01-treated mice. The colonic farnesoid X receptor (FXR) and fibroblast growth factor 15 (FGF15) were upregulated in mice treated with BDX-01. BDX-01 downregulated the expression of colonic proinflammatory cytokines pyrin domain-containing 3 (NLRP3), ASC, cleaved caspase-1, and IL-1β. Antibiotic treatment didn't abolish the protective effect of BDX-01 on colitis. In vitro studies showed TβMCA abolished the effects of BDX-01 on FXR activation and inhibition of the NLRP3 inflammasome activation. Conclusion: BDX-01 improved DSS-induced acute colitis by regulating intestinal BSH activity and the FXR-NLRP3 signaling pathway. Our findings indicate that BDX-01 is a promising probiotic to improve the management of ulcerative colitis.PMID:37292154 | PMC:PMC10244678 | DOI:10.3389/fphar.2023.1205323

EMBO Rep. 2023 Jun 9:e56352. doi: 10.15252/embr.202256352. Online ahead of print.ABSTRACTFetal development and parturition are precisely regulated processes that involve continuous crosstalk between the mother and the fetus. Our previous discovery that wild-type mice carrying steroid receptor coactivator (Src)-1 and Src-2 double-deficient fetuses exhibit impaired lung development and delayed labor, which indicates that the signals for parturition emanate from the fetus. In this study, we perform RNA sequencing and targeted metabolomics analyses of the lungs from fetal Src-1/-2 double-knockout mice and find that expression of arginase 1 (Arg1) is significantly decreased, accompanied by increased levels of the Arg1 substrate L-arginine. Knockdown of Arg1 in the lungs of fetal mice induces apoptosis of epithelial cells and dramatically delays initiation of labor. Moreover, treatment of human myometrial smooth muscle cells with L-arginine significantly inhibits spontaneous contractions by attenuating activation of NF-κB and downregulating expression of contraction-associated protein genes. Transcription factors GR and C/EBPβ increase transcription of Arg1 in an Src-1/Src-2-dependent manner. These findings provide new evidence that fetus-derived factors may play dual roles in coordinating fetal lung development and the initiation of labor.PMID:37291976 | DOI:10.15252/embr.202256352

J Obstet Gynaecol Res. 2023 Jun 9. doi: 10.1111/jog.15709. Online ahead of print.ABSTRACTAIM: Uterine cervical cancer (UCC) is the fourth most common cancer in women, responsible for more than 300 000 deaths worldwide. Its early detection, by cervical cytology, and prevention, by vaccinating against human papilloma virus, greatly contribute to reducing cervical cancer mortality in women. However, penetration of the effective prevention of UCC in Japan remains low. Plasma metabolome analysis is widely used for biomarker discovery and the identification of cancer-specific metabolic pathways. Here, we aimed to identify predictive biomarkers for the diagnosis and radiation sensitivity of UCC using wide-targeted plasma metabolomics.METHODS: We analyzed 628 metabolites in plasma samples obtained from 45 patients with UCC using ultra-high-performance liquid chromatography with tandem mass spectrometry.RESULTS: The levels of 47 metabolites were significantly increased and those of 75 metabolites were significantly decreased in patients with UCC relative to healthy controls. Increased levels of arginine and ceramides, and decreased levels of tryptophan, ornithine, glycosylceramides, lysophosphatidylcholine, and phosphatidylcholine were characteristic of patients with UCC. Comparison of metabolite profiles in groups susceptible and non-susceptible to radiation therapy, a treatment for UCC, revealed marked variations in polyunsaturated fatty acid, nucleic acid, and arginine metabolism in the group not susceptible to treatment.CONCLUSIONS: Our findings suggest that the metabolite profile of patients with UCC may be an important indicator for distinguishing these patients from healthy cohorts, and may also be useful for predicting sensitivity to radiotherapy.PMID:37291943 | DOI:10.1111/jog.15709

Physiol Plant. 2023 Jun 8. doi: 10.1111/ppl.13950. Online ahead of print.ABSTRACTPlant acclimation to salt and alkali stress is closely linked to the ability of the antioxidant system to mediate the scavenging of reactive oxygen species (ROS). In this study, we investigated the effects of salt stress and alkali stress on ROS, antioxidant enzymes, transcriptome, and metabolome. The results showed that the levels of superoxide anions, hydrogen peroxide, malondialdehyde, and electrolyte leakage increased under salt and alkali stress, with higher concentrations observed under alkali stress than salt stress. The activities of superoxide dismutase (EC 1.15.1.1), peroxidase (EC 1.11.1.7), catalase (EC 1.11.1.6), ascorbate peroxidase (EC 1.11.1.11), glutathione reductase (EC 1.6.4.2), dehydroascorbate reductase (EC 1.8.5.1), and monodehydroascorbate reductase (EC 1.6.5.4) varied under salt and alkali stress. The transcriptome analysis revealed the induction of signal transduction and metabolic processes and differential expression of genes encoding antioxidant enzymes in response to salt and alkali stress. The metabolome analysis demonstrated increased ascorbic acid and glutathione under salt stress, while most phenolic acids, flavonoids, and alkaloids increased under salt and alkali stress. Integrative analysis of the metabolome and transcriptome data revealed that the flavonoid biosynthesis pathway played a key role in the grapevine's response to salt stress. The total flavonoid content increased under salt and alkali stress, but the accumulation of flavonoids was higher under salt stress than alkali stress. In conclusion, our findings indicate significant differences in the antioxidant defense of grapevines under these two stresses, providing insight into distinct acclimation mechanisms in grapevine under salt and alkali stress. This article is protected by copyright. All rights reserved.PMID:37291799 | DOI:10.1111/ppl.13950

Kidney360. 2023 Jun 9. doi: 10.34067/KID.0000000000000158. Online ahead of print.ABSTRACTBACKGROUND: Since chronic kidney disease (CKD) is caused by genetic and environmental factors, biomarker development through metabolomic analysis, which reflects gene-derived downstream effects and host adaptation to the environment, is warranted.METHODS: We measured the metabolites in urine samples collected from 789 patients at the time of kidney biopsy and from urine samples from 147 healthy subjects using nuclear magnetic resonance (NMR). The composite outcome was defined as a 30% decline in estimated glomerular filtration rate (eGFR), doubling of serum creatinine levels, or end-stage kidney disease.RESULTS: Among the 28 candidate metabolites, we identified 7 metabolites showing 1) good discrimination between healthy controls and patients with stage 1 CKD and 2) a consistent change in pattern from controls to patients with advanced-stage CKD. Among the 7 metabolites, betaine, choline, glucose, fumarate, and citrate showed significant associations with the composite outcome after adjustment for age, sex, eGFR, the urine protein-creatinine ratio, and diabetes. Furthermore, adding choline, glucose, or fumarate to traditional biomarkers, including eGFR and proteinuria, significantly improved the ability of the net reclassification improvement (P<0.05) and integrated discrimination improvement (P<0.05) to predict the composite outcome.CONCLUSION: Urinary metabolites, including betaine, choline, fumarate, citrate, and glucose, were found to be significant predictors of the progression of CKD. As a signature of kidney injury-related metabolites, it would be warranted to monitor to predict the renal outcome.PMID:37291728 | DOI:10.34067/KID.0000000000000158

BMC Pregnancy Childbirth. 2023 Jun 8;23(1):425. doi: 10.1186/s12884-023-05666-7.ABSTRACTBACKGROUND: Metabolites in spent embryo culture medium correlate with the embryo's viability. However, there is no widely accepted method using metabolite dada to predict successful implantation. We sought to combine metabolomic profiling of spent embryo culture medium and clinical variables to create an implantation prediction model as an adjunct to morphological screening of day 3 embryos.METHODS: This investigation was a prospective, nested case-control study. Forty-two day 3 embryos from 34 patients were transferred, and the spent embryo culture medium was collected. Twenty-two embryos implanted successfully, and the others failed. Metabolites in the medium relevant to implantation were detected and measured by Liquid Chromatography-Mass Spectrometry. Clinical signatures relevant to embryo implantation were subjected to univariate analysis to select candidates for a prediction model. Multivariate logistical regression of the clinical and metabolomic candidates was used to construct a prediction model for embryo implantation potential.RESULTS: The levels of 13 metabolites were significantly different between the successful and failed groups, among which five were most relevant and interpretable selected by Least Absolute Shrinkage and Selection Operator regression analysis. None of the clinical variables significantly affected day 3 embryo implantation. The most relevant and interpretable set of metabolites was used to construct a prediction model for day 3 embryo implantation potential with an accuracy of 0.88.CONCLUSIONS: Day 3 embryos'implantation potential could be noninvasively predicted by the spent embryo culture medium's metabolites measured by LC-MS. This approach may become a useful adjunct to morphological evaluation of day 3 embryos.PMID:37291503 | DOI:10.1186/s12884-023-05666-7

Nat Commun. 2023 Jun 8;14(1):3309. doi: 10.1038/s41467-023-38382-z.ABSTRACTA mid-level data fusion coupled with multivariate analysis approach is applied to dual-platform mass spectrometry data sets using Rapid Evaporative Ionization Mass Spectrometry and Inductively Coupled Plasma Mass Spectrometry to determine the correct classification of salmon origin and production methods. Salmon (n = 522) from five different regions and two production methods are used in the study. The method achieves a cross-validation classification accuracy of 100% and all test samples (n = 17) have their origins correctly determined, which is not possible with single-platform methods. Eighteen robust lipid markers and nine elemental markers are found, which provide robust evidence of the provenance of the salmon. Thus, we demonstrate that our mid-level data fusion - multivariate analysis strategy greatly improves the ability to correctly identify the geographical origin and production method of salmon, and this innovative approach can be applied to many other food authenticity applications.PMID:37291121 | DOI:10.1038/s41467-023-38382-z

Neurology. 2023 Jun 8:10.1212/WNL.0000000000207459. doi: 10.1212/WNL.0000000000207459. Online ahead of print.ABSTRACTBACKGROUND AND OBJECTIVES: Excessive activation of certain lipid mediator (LM) pathways play a role in the complex pathogenesis of multiple sclerosis (MS). However, the relation between bioactive LMs and different aspects of CNS-related pathophysiological processes remains largely unknown. Therefore, we here assessed the association of bioactive LMs belonging to the ω-3 / ω-6 lipid classes with clinical, biochemical (serum neurofilament light (sNfL) and serum glial fibrillary acidic protein (sGFAP)) parameters and MRI-based brain volumes in patients with MS (PwMS) and healthy controls (HC).METHODS: A targeted high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) approach was used on plasma samples of PwMS and HC of the Project Y cohort, a cross-sectional population based cohort that contains PwMS all born in 1966 in the Netherlands and age-matched HCs. LMs were compared between PwMS and HC and were correlated with levels of sNfL, sGFAP, disability (EDSS) and brain volumes. Finally, significant correlates were included in a backward multivariate regression model to identify which LMs best related to disability.RESULTS: The study sample consisted of 170 patients with relapsing remitting MS (RRMS), 115 patients with progressive MS (PMS) and 125 HC. LM profiles of patients with PMS significantly differed from RRMS and HC, in particular, patients with PMS showed elevated levels of several arachidonic acid (AA) derivatives. In particular 15-HETE (r = 0.24, p < 0.001), positively correlated (average r = 0.2, p < 0.05) with clinical and biochemical parameters such as EDSS and sNfL. In addition, higher 15-HETE levels were related to lower total brain (r = -0.24, p = 0.04) and deep gray matter volumes (r = -0.27, p = 0.02) in patients with PMS and higher lesion volume (r = 0.15, p = 0.03) in all PwMS.DISCUSSION: In PwMS of the same birth year, we show that ω-3 and -6 LMs are associated with disability, biochemical (sNfL, GFAP) and MRI measures. Furthermore, our findings indicate that particularly in patients with PMS, elevated levels of specific products of the AA pathway, such as 15-HETE, associate with neurodegenerative processes. Our findings highlight the potential relevance of ω-6 LMs in the pathogenesis of MS.PMID:37290971 | DOI:10.1212/WNL.0000000000207459

Neurology. 2023 Jun 8:10.1212/WNL.0000000000207458. doi: 10.1212/WNL.0000000000207458. Online ahead of print.ABSTRACTBACKGROUND AND OBJECTIVES: Cerebral small vessel disease is a major cause of stroke and dementia. Metabolomics can help identify novel risk factors to better understand pathogenesis and predict disease progression and severity.METHODS: We analysed baseline metabolomics profiles from 118,021 UK Biobank participants. We examined cross-sectional associations of 325 metabolites with MRI markers of small vessel disease, evaluated longitudinal associations with incident stroke and dementia, and ascertained causal relationships using Mendelian randomization.RESULTS: In cross-sectional analyses, lower levels of apolipoproteins, free cholesterol, cholesteryl esters, fatty acids, lipoprotein particle concentrations, phospholipids, and triglycerides were associated with increased white matter microstructural damage on diffusion tensor MRI. In longitudinal analyses, lipoprotein subclasses of very large HDL were associated with increased risk of stroke, and acetate and 3-hydroxybutyrate were associated with increased risk of dementia. Mendelian randomization analyses identified strong evidence supporting causal relationships for many findings. A few metabolites had consistent associations across multiple analysis types. Increased total lipids in very large HDL and increased HDL particle size were associated with increased white matter damage (Lower FA: OR: 1.44, 95% CI: 1.07-1.95, and OR: 1.19, 95% CI: 1.06-1.34, respectively; MD: OR: 1.49, 95% CI: 1.11-2.01, and OR: 1.24, 95% CI: 1.11-1.40, respectively) and increased risk of incident all stroke (HR: 4.04, 95% CI: 2.13-7.64, and HR: 1.54, 95% CI: 1.20-1.98, respectively) and ischaemic stroke (HR: 3.12, 95% CI: 1.53-6.38; HR: 1.37, 95% CI: 1.04-1.81). Valine was associated with decreased MD (OR: 0.51, 95% CI: 0.30-0.88) and had a protective association with all-cause dementia (HR: 0.008, 95% CI: 0.002-0.035). Cholesterol in small HDL had an inverse association with incident all stroke (HR: 0.17, 95% CI: 0.08-0.39) and ischaemic stroke (HR: 0.19, 95% CI: 0.08-0.46) that was supported by evidence of a causal association with MRI-confirmed lacunar stroke (OR: 0.96, 95% CI: 0.93-0.99).DISCUSSION: In this large-scale metabolomics study, we found multiple metabolites associated with stroke, dementia, and MRI markers of small vessel disease. Further studies may help inform development of personalised prediction models and provide insights into mechanistic pathways and future treatment approaches.PMID:37290969 | DOI:10.1212/WNL.0000000000207458

Anal Chim Acta. 2023 Aug 15;1269:341429. doi: 10.1016/j.aca.2023.341429. Epub 2023 May 25.ABSTRACTIn this study, the use of thermal desorption in on-line solid phase extraction coupled with reversed phase liquid chromatography (on-line SPE-LC) was for the first time proposed and demonstrated for the desorption of analytes strongly retained by multiple interaction polymeric sorbents. In detail, this analytical strategy was applied to the on-line SPE-LC targeted analysis of a model set of 34 human gut metabolites characterized by heterogeneous physicochemical properties (i.e., octanol-water partition coefficient in the range -0.3 - 3.4). The novel thermally assisted on-line SPE approach was investigated in comparison to conventional room temperature desorption strategies based on the use of (i) an optimized elution gradient or (ii) organic desorption followed by post-cartridge dilution. The thermally assisted desorption strategy has been shown to be better performing and suitable for the development of a reliable and sensitive method for the analysis of the model group of analytes in urine and serum. In more detail, under the optimized experimental conditions, the proposed method provided negligible matrix effects in both biofluids for almost all target analytes. Moreover, method quantification limits were in the ranges 0.026-7.2 μg L-1 and 0.033-23 μg L-1 for urine and serum, respectively, i.e., comparable to or lower than those reported in methods previously published.PMID:37290855 | DOI:10.1016/j.aca.2023.341429

Talanta. 2023 Jun 2;264:124745. doi: 10.1016/j.talanta.2023.124745. Online ahead of print.ABSTRACTLiquid chromatography-mass spectrometry (LC-MS) is a platform for urine and blood sample analysis. However, the high variability in the urine sample reduced the confidence of metabolite identification. Therefore, pre and post-calibration operations are inevitable to ensure an accurate urine biomarker analysis. In this study, the phenomenon of a higher creatinine concentration variable in ureteropelvic junction obstruction (UPJO) patient urine samples than in healthy people was revealed, indicating the urine biomarker discovery of UPJO patients is not adapted to the creatinine calibrate strategy. Therefore, we proposed a pipeline "OSCA-Finder" to reshape the urine biomarker analysis. First, to ensure a more stable peak shape and total ion chromatography, we applied the product of osmotic pressure and injection volume as a calibration principle and integrated it with an online mixer dilution. Therefore, we obtained the most peaks and identified more metabolites in a urine sample with peak area group CV<30%. A data-enhanced strategy was applied to reduce the overfit while training a neural network binary classifier with an accuracy of 99.9%. Finally, seven accurate urine biomarkers combined with a binary classifier were applied to distinguish UPJO patients from healthy people. The results show that the UPJO diagnostic strategy based on urine osmotic pressure calibration has more potential than ordinary strategies.PMID:37290332 | DOI:10.1016/j.talanta.2023.124745

Science. 2023 Jun 9;380(6649):eabo2296. doi: 10.1126/science.abo2296. Epub 2023 Jun 9.ABSTRACTAntibiotics (ABX) compromise the efficacy of programmed cell death protein 1 (PD-1) blockade in cancer patients, but the mechanisms underlying their immunosuppressive effects remain unknown. By inducing the down-regulation of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the ileum, post-ABX gut recolonization by Enterocloster species drove the emigration of enterotropic α4β7+CD4+ regulatory T 17 cells into the tumor. These deleterious ABX effects were mimicked by oral gavage of Enterocloster species, by genetic deficiency, or by antibody-mediated neutralization of MAdCAM-1 and its receptor, α4β7 integrin. By contrast, fecal microbiota transplantation or interleukin-17A neutralization prevented ABX-induced immunosuppression. In independent lung, kidney, and bladder cancer patient cohorts, low serum levels of soluble MAdCAM-1 had a negative prognostic impact. Thus, the MAdCAM-1-α4β7 axis constitutes an actionable gut immune checkpoint in cancer immunosurveillance.PMID:37289890 | DOI:10.1126/science.abo2296