PubMed

Curr Pollut Rep. 2023 Sep;9(3):510-568. doi: 10.1007/s40726-023-00269-4. Epub 2023 Jun 29.ABSTRACTPURPOSE OF REVIEW: There is a growing interest in understanding the health effects of exposure to per- and polyfluoroalkyl substances (PFAS) through the study of the human metabolome. In this systematic review, we aimed to identify consistent findings between PFAS and metabolomic signatures. We conducted a search matching specific keywords that was independently reviewed by two authors on two databases (EMBASE and PubMed) from their inception through July 19, 2022 following PRISMA guidelines.RECENT FINDINGS: We identified a total of 28 eligible observational studies that evaluated the associations between 31 different PFAS exposures and metabolomics in humans. The most common exposure evaluated was legacy long-chain PFAS. Population sample sizes ranged from 40 to 1,105 participants at different stages across the lifespan. A total of 19 studies used a non-targeted metabolomics approach, 7 used targeted approaches, and 2 included both. The majority of studies were cross-sectional (n = 25), including four with prospective analyses of PFAS measured prior to metabolomics.SUMMARY: Most frequently reported associations across studies were observed between PFAS and amino acids, fatty acids, glycerophospholipids, glycerolipids, phosphosphingolipids, bile acids, ceramides, purines, and acylcarnitines. Corresponding metabolic pathways were also altered, including lipid, amino acid, carbohydrate, nucleotide, energy metabolism, glycan biosynthesis and metabolism, and metabolism of cofactors and vitamins. We found consistent evidence across studies indicating PFAS-induced alterations in lipid and amino acid metabolites, which may be involved in energy and cell membrane disruption.PMID:37753190 | PMC:PMC10520990 | DOI:10.1007/s40726-023-00269-4

Biophys Rep. 2023 Apr 30;9(2):82-98. doi: 10.52601/bpr.2023.230007.ABSTRACTPhosphorylation is one of the most important post-translational modifications (PTMs) of proteins, governing critical protein functions. Most human proteins have been shown to undergo phosphorylation, and phosphoproteomic studies have been widely applied due to recent advancements in high-resolution mass spectrometry technology. Although the experimental workflow for phosphoproteomics has been well-established, it would be useful to optimize and summarize a detailed, feasible protocol that combines phosphoproteomics and data-independent acquisition (DIA), along with follow-up data analysis procedures due to the recent instrumental and bioinformatic advances in measuring and understanding tens of thousands of site-specific phosphorylation events in a single experiment. Here, we describe an optimized Phos-DIA protocol, from sample preparation to bioinformatic analysis, along with practical considerations and experimental configurations for each step. The protocol is designed to be robust and applicable for both small-scale phosphoproteomic analysis and large-scale quantification of hundreds of samples for studies in systems biology and systems medicine.PMID:37753060 | PMC:PMC10518521 | DOI:10.52601/bpr.2023.230007

iScience. 2023 Aug 19;26(10):107678. doi: 10.1016/j.isci.2023.107678. eCollection 2023 Oct 20.ABSTRACTSoft tissue sarcomas (STSs) are rare malignant tumors that are difficult to prognosticate using currently available instruments. Omics sciences could provide more accurate and individualized survival predictions for patients with metastatic STS. In this pilot, hypothesis-generating study, we integrated clinicopathological variables with proton nuclear magnetic resonance (1H NMR) plasma metabolomic and lipoproteomic profiles, capturing both tumor and host characteristics, to identify novel prognostic biomarkers of 2-year survival. Forty-five metastatic STS (mSTS) patients with prevalent leiomyosarcoma and liposarcoma histotypes receiving trabectedin treatment were enrolled. A score combining acetate, triglycerides low-density lipoprotein (LDL)-2, and red blood cell count was developed, and it predicts 2-year survival with optimal results in the present cohort (84.4% sensitivity, 84.6% specificity). This score is statistically significant and independent of other prognostic factors such as age, sex, tumor grading, tumor histotype, frailty status, and therapy administered. A nomogram based on these 3 biomarkers has been developed to inform the clinical use of the present findings.PMID:37752948 | PMC:PMC10518687 | DOI:10.1016/j.isci.2023.107678

MedComm (2020). 2023 Sep 24;4(5):e380. doi: 10.1002/mco2.380. eCollection 2023 Oct.ABSTRACTGenetic heterogeneity poses a challenge to research and clinical translation of autism spectrum disorder (ASD). In this study, we conducted a plasma proteomic and metabolomic study of children with ASD with and without risk genes (de novo mutation) and controls to explore the impact of genetic heterogeneity on the search for biomarkers for ASD. In terms of the proteomic and metabolomic profiles, the groups of children with ASD carrying and those not carrying de novo mutation tended to cluster and overlap, and integrating them yielded differentially expressed proteins and differential metabolites that effectively distinguished ASD from controls. The mechanisms associated with them focus on several common and previously reported mechanisms. Proteomics results highlight the role of complement, inflammation and immunity, and cell adhesion. The main pathways of metabolic perturbations include amino acid, vitamin, glycerophospholipid, tryptophan, and glutamates metabolic pathways and solute carriers-related pathways. Integrating the two omics analyses revealed that L-glutamic acid and malate dehydrogenase may play key roles in the pathogenesis of ASD. These results suggest that children with ASD may have important underlying common mechanisms. They are not only potential therapeutic targets for ASD but also important contributors to the study of biomarkers for the disease.PMID:37752942 | PMC:PMC10518435 | DOI:10.1002/mco2.380

Adv Sci (Weinh). 2023 Sep 26:e2301300. doi: 10.1002/advs.202301300. Online ahead of print.ABSTRACTBlood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism in these processes remains unclear. The present study finds that ovariectomized mice exhibit reduced blood vessel density in the bone and reduced expression of the endothelial glycolytic regulator pyruvate kinase M2 (PKM2). Endothelial cell (EC)-specific deletion of Pkm2 impairs osteogenesis and worsens osteoporosis in mice. This is attributed to the impaired ability of bone mesenchymal stem cells (BMSCs) to differentiate into osteoblasts. Mechanistically, EC-specific deletion of Pkm2 reduces serum lactate levels secreted by ECs, which affect histone lactylation in BMSCs. Using joint CUT&Tag and RNA sequencing analyses, collagen type I alpha 2 chain (COL1A2), cartilage oligomeric matrix protein (COMP), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and transcription factor 7 like 2 (TCF7L2) as osteogenic genes regulated by histone H3K18la lactylation are identified. PKM2 overexpression in ECs, lactate addition, and exercise restore the phenotype of endothelial PKM2-deficient mice. Furthermore, serum metabolomics indicate that patients with osteoporosis have relatively low lactate levels. Additionally, histone lactylation and related osteogenic genes of BMSCs are downregulated in patients with osteoporosis. In conclusion, glycolysis in ECs fuels BMSC differentiation into osteoblasts through histone lactylation, and exercise partially ameliorates osteoporosis by increasing serum lactate levels.PMID:37752768 | DOI:10.1002/advs.202301300

Adv Sci (Weinh). 2023 Sep 26:e2301939. doi: 10.1002/advs.202301939. Online ahead of print.ABSTRACTThe leading first-in-class ruthenium-complex BOLD-100 currently undergoes clinical phase-II anticancer evaluation. Recently, BOLD-100 is identified as anti-Warburg compound. The present study shows that also deregulated lipid metabolism parameters characterize acquired BOLD-100-resistant colon and pancreatic carcinoma cells. Acute BOLD-100 treatment reduces lipid droplet contents of BOLD-100-sensitive but not -resistant cells. Despite enhanced glycolysis fueling lipid accumulation, BOLD-100-resistant cells reveal diminished lactate secretion based on monocarboxylate transporter 1 (MCT1) loss mediated by a frame-shift mutation in the MCT1 chaperone basigin. Glycolysis and lipid catabolism converge in the production of protein/histone acetylation substrate acetyl-coenzymeA (CoA). Mass spectrometric and nuclear magnetic resonance analyses uncover spontaneous cell-free BOLD-100-CoA adduct formation suggesting acetyl-CoA depletion as mechanism bridging BOLD-100-induced lipid metabolism alterations and histone acetylation-mediated gene expression deregulation. Indeed, BOLD-100 treatment decreases histone acetylation selectively in sensitive cells. Pharmacological targeting confirms histone de-acetylation as central mode-of-action of BOLD-100 and metabolic programs stabilizing histone acetylation as relevant Achilles' heel of acquired BOLD-100-resistant cell and xenograft models. Accordingly, histone gene expression changes also predict intrinsic BOLD-100 responsiveness. Summarizing, BOLD-100 is identified as epigenetically active substance acting via targeting several onco-metabolic pathways. Identification of the lipid metabolism as driver of acquired BOLD-100 resistance opens novel strategies to tackle therapy failure.PMID:37752764 | DOI:10.1002/advs.202301939

Microbiome. 2023 Sep 27;11(1):212. doi: 10.1186/s40168-023-01659-y.ABSTRACTBACKGROUND: Aging-related fertility decline is a prevalent concern globally. Male reproductive system aging is mainly characterized by a decrease in sperm quality and fertility. While it is known that intestinal physiology changes with age and that microbiota is shaped by physiology, the underlying mechanism of how the microbiota affects male reproductive aging is still largely unexplored.RESULTS: Here, we utilized fecal microbiota transplantation (FMT) to exchange the fecal microbiota between young and old mice. Cecal shotgun metagenomics and metabolomics were used to identify differences in gut microbiota composition and metabolic regulation during aging. Our results demonstrated that FMT from young to old mice alleviated aging-associated spermatogenic dysfunction through an unexpected mechanism mediated by a gut bacteria-derived metabolite, 3-hydroxyphenylacetic acid (3-HPAA). 3-HPAA treatment resulted in an improvement of spermatogenesis in old mice. RNA sequencing analysis, qRT-PCR and Western blot revealed that 3-HPAA induced an upregulation of GPX4, thereby restraining ferroptosis and restoring spermatogenesis. These findings were further confirmed by in vitro induction of ferroptosis and inhibition of GPX4 expression.CONCLUSIONS: Our results demonstrate that the microbiome-derived metabolite, 3-HPAA, facilitates spermatogenesis of old mice through a ferroptosis-mediated mechanism. Overall, these findings provide a novel mechanism of dysregulated spermatogenesis of old mice, and suggest that 3-HPAA could be a potential therapy for fertility decline of aging males in clinical practice. Video Abstract.PMID:37752615 | DOI:10.1186/s40168-023-01659-y

BMC Med Genomics. 2023 Sep 26;16(1):224. doi: 10.1186/s12920-023-01666-w.ABSTRACTBACKGROUND: Individuals with sepsis exhibited a higher likelihood of benefiting from early initiation of specialized treatment to enhance the prognosis of the condition. The objective of this study is to identify potential biomarkers of sepsis by means of serum metabolomics.MATERIALS AND METHODS: The screening of putative biomarkers of sepsis was conducted using serum samples from patients with sepsis and a control group of healthy individuals. The pathogenesis of sepsis was determined through the utilization of liquid chromatography-mass spectrometry-based metabolic profiles and bioinformatic techniques, which in turn provided a foundation for timely diagnosis and intervention.RESULTS: Individuals with sepsis had significantly different metabolic characteristics compared to those with normal health. The concentrations of phosphatidylcholines (PCs), phosphatidylserine (PS), lysophosphatidylethanolamine (LysoPEs), and lysophosphatidylcholine (LysoPCs) exhibited a decrease, while the levels of creatinine, C17-Sphinganine, and PS(22:0/22:1(11Z)) demonstrated an increase in the serum of sepsis patients when compared to the control group. Additionally, ROC curves were generated to assess the discriminatory ability of the differentially expressed metabolites. The area under the ROC curve for PS (22:0/22:1(11Z)) and C17-Sphinganine were determined to be 0.976 and 0.913, respectively. These metabolites may potentially serve as diagnostic markers for sepsis. Additionally, the pathogenesis of sepsis is associated with mTOR signaling, NF-κB signaling pathway, calcium signaling, calcium transport, and tRNA charging pathway.CONCLUSION: The identification of differential expression of these metabolites in sepsis serum samples could aid in the timely diagnosis and intervention of sepsis, as well as enhance our understanding of its pathogenesis.PMID:37752563 | DOI:10.1186/s12920-023-01666-w

BMC Pulm Med. 2023 Sep 26;23(1):361. doi: 10.1186/s12890-023-02654-7.ABSTRACTBACKGROUND: To study the role of microecology and metabolism in iatrogenic tracheal injury and cicatricial stenosis, we investigated the tracheal microbiome and metabolome in patients with tracheal stenosis after endotracheal intubation.METHODS: We collected 16 protected specimen brush (PSB) and 8 broncho-alveolar lavage (BAL) samples from 8 iatrogenic subglottic tracheal stenosis patients, including 8 PSB samples from tracheal scar sites, 8 PSB samples from scar-free sites and 8 BAL samples, by lavaging the subsegmental bronchi of the right-middle lobe. Metagenomic sequencing was performed to characterize the microbiome profiling of 16 PSB and 8 BAL samples. Untargeted metabolomics was performed in 6 PSB samples (3 from tracheal scar PSB and 3 from tracheal scar-free PSB) using high-performance liquid chromatography‒mass spectrometry (LC‒MS).RESULTS: At the species level, the top four bacterial species were Neisseria subflava, Streptococcus oralis, Capnocytophaga gingivals, and Haemophilus aegyptius. The alpha and beta diversity among tracheal scar PSB, scar-free PSB and BAL samples were compared, and no significant differences were found. Untargeted metabolomics was performed in 6 PSB samples using LC‒MS, and only one statistically significant metabolite, carnitine, was identified. Pathway enrichment analysis of carnitine revealed significant enrichment in fatty acid oxidation.CONCLUSION: Our study found that carnitine levels in tracheal scar tissue were significantly lower than those in scar-free tissue, which might be a new target for the prevention and treatment of iatrogenic tracheal stenosis in the future.PMID:37752498 | DOI:10.1186/s12890-023-02654-7

BMC Plant Biol. 2023 Sep 27;23(1):453. doi: 10.1186/s12870-023-04457-8.ABSTRACTBACKGROUND: Color-leaved O. fragrans is a variety of Osmanthus fragrans, which has both the fragrance of Osmanthus and the color of color-leaved plants. However, the molecular mechanism of color change of color-leaved O. fragrans is not clear. In this study, we analyzed the regulatory mechanism of four different color leaves of 'Ziyan Gongzhu' through physiological, transcriptome and metabolome levels.RESULTS: Firstly, we measured the leaf pigments content and leaf chromatic parameters for correlation analysis, indicating a significant correlation between them. Overall, the content of chlorophyll a + b is low and the content of anthocyanin is high in T1 and T2 leaves, along with low expression of chlorophyll synthesis genes (HEMA, CHLG, and CAO, etc.) and high expression of anthocyanin synthesis genes (F3H, F3'H, DFR and ANS, etc.), resulting purple red and light purple in T1 and T2 leaves, respectively. It was also found that the pigment closely related to the color leaves of 'Ziyan Gongzhu' was cyanidin. The content anthocyanins, may be regulated by two putative MYB activators (OfMYB3 and OfMYB4) and two putative MYB repressors (OfMYB1 and OfMYB2). In contrast, the content of chlorophyll a + b is high and the content of anthocyanin is low in T3 and T4 leaves, along with high expression of chlorophyll synthesis genes and low expression of anthocyanin synthesis genes, resulting yellow green and dark green in T3 and T4 leaves, respectively. And abnormal chloroplast development affects chlorophyll content in T1, T2, and T3 leaves. Although the content of carotenoids first dropped in T2 leaves, it then rapidly accumulated in T4 leaves, in sync with the increase in the expression of genes related to carotenoid biosynthesis (ZDS, LHYB, and ZEP, for example). Analysis of photosynthetic, carbohydrate and hormone-related differentially abundant metabolites (DAMs) and DEGs found that they may participate in the regulation of leaf color change of 'Ziyan Gongzhu' by affecting pigment synthesis.CONCLUSION: Our results pave the way for a comprehensive knowledge of the regulatory processes governing leaf color in 'Ziyan Gongzhu' and identify possible genes for application regarding molecular colored-leaf cultivar breeding.PMID:37752431 | DOI:10.1186/s12870-023-04457-8

BMC Mol Cell Biol. 2023 Sep 26;24(1):30. doi: 10.1186/s12860-023-00491-4.ABSTRACTBACKGROUND: Hydrogen-rich water (HRW) has been shown to prevent cognitive impairment caused by ionizing radiation. This study aimed to investigate the pharmacological effects and mechanisms of HRW on ionizing radiation by coupling the brain metabolomics and biological target network methods.METHODS AND RESULTS: HRW significantly improves the cognitive impairment in rats exposed to ionizing radiation. Based on metabolomics and biological network results, we identified 54 differential metabolites and 93 target genes. The KEGG pathway indicates that glutathione metabolism, ascorbic acid and aldehyde acid metabolism, pentose and glucuronic acid interconversion, and glycerophospholipid metabolism play important roles in ionizing radiation therapy.CONCLUSION: Our study has systematically elucidated the molecular mechanism of HRW against ionizing radiation, which can be mediated by modulating targets, pathways and metabolite levels. This provides a new perspective for identifying the underlying pharmacological mechanism of HRW.PMID:37752412 | DOI:10.1186/s12860-023-00491-4

Anal Bioanal Chem. 2023 Sep 27. doi: 10.1007/s00216-023-04926-x. Online ahead of print.ABSTRACTEnd-stage renal disease (ESRD) is a rapidly increasing health problem, and every year, about 2 million ESRD cases are reported worldwide. Hemodialysis (HD) is the vital renal reinstatement therapy for ESRD, and HD patterns play a crucial role in patients' health. Plasma metabolomics is the potential approach to understanding the HD process, effectiveness, and patterns. The lack of protein vitality is a primary problem for HD patients, and the quantities of amino acids intracellularly and in the blood are considered to be a symbolic index of protein metabolism and nutrition conditions. In the current study, LC/MS/MS and GC/MS methods were developed for 29 targeted plasma metabolites and validated as per ICH bioanalytical method validation M10 guidelines. The 29 metabolites included 20 proteinogenic amino acids and nine other related metabolites. The methods were employed to measure the absolute quantities (µM) of the targeted metabolites in HD patients (n=60) before and after dialysis (PRE-HD and POST-HD), and compared with the healthy control (HC) group (n=60). Phenylacetylglutamine was found to be higher in both PRE-HD (72.88±14.5 µM) and POST-HD (26.62±7.9 µM), when compared to HC (1.61±0.6 µM). On the other hand, glutamic acid was lower in PRE-HD (14.90±6.5 µM), and POST-HD (13.6±6.1 µM) than that of HC (245.4±37.8 µM). The dialytic loss was found to be 52-45% for arginine, lysine, and histidine, while it was 38-26% for glycine, cysteine, proline, alanine, threonine, glutamine, valine, and methionine. The dialytic loss was low (≤12%) for aspartic acid, glutamic acid, asparagine, leucine, tyrosine, tryptophan, and isoleucine. Graphical abstract adapted from mass spectrometry templates by Biorender.com retrieved from https://app.biorender.com/biorender-templates .PMID:37752301 | DOI:10.1007/s00216-023-04926-x

Br J Cancer. 2023 Sep 26. doi: 10.1038/s41416-023-02446-0. Online ahead of print.ABSTRACTIn recent years, liquid biopsy has emerged as an alternative method to diagnose and monitor tumors. Compared to classical tissue biopsy procedures, liquid biopsy facilitates the repetitive collection of diverse cellular and acellular analytes from various biofluids in a non/minimally invasive manner. This strategy is of greater significance for high-grade brain malignancies such as glioblastoma as the quantity and accessibility of tumors are limited, and there are collateral risks of compromised life quality coupled with surgical interventions. Currently, blood and cerebrospinal fluid (CSF) are the most common biofluids used to collect circulating cells and biomolecules of tumor origin. These liquid biopsy analytes have created opportunities for real-time investigations of distinct genetic, epigenetic, transcriptomics, proteomics, and metabolomics alterations associated with brain tumors. This review describes different classes of liquid biopsy biomarkers present in the biofluids of brain tumor patients. Moreover, an overview of the liquid biopsy applications, challenges, recent technological advances, and clinical trials in the brain have also been provided.PMID:37752289 | DOI:10.1038/s41416-023-02446-0

NPJ Biofilms Microbiomes. 2023 Sep 26;9(1):71. doi: 10.1038/s41522-023-00431-2.ABSTRACTLacticaseibacillus rhamnosus GG (LGG) is a Gram-positive beneficial bacterium that resides in the human intestinal tract and belongs to the family of lactic acid bacteria (LAB). This bacterium is a widely used probiotic and was suggested to provide numerous benefits for human health. However, as in most LAB strains, the molecular mechanisms that mediate the competitiveness of probiotics under different diets remain unknown. Fermentation is a fundamental process in LAB, allowing the oxidation of simple carbohydrates (e.g., glucose, mannose) for energy production under oxygen limitation, as in the human gut. Our results indicate that fermentation reshapes the metabolome, volatilome, and proteome architecture of LGG. Furthermore, fermentation alters cell envelope remodeling and peptidoglycan biosynthesis, which leads to altered cell wall thickness, aggregation properties, and cell wall composition. In addition, fermentable sugars induced the secretion of known and novel metabolites and proteins targeting the enteric pathogens Enterococcus faecalis and Salmonella enterica Serovar Typhimurium. Overall, our results link simple carbohydrates with cell wall remodeling, aggregation to host tissues, and biofilm formation in probiotic strains and connect them with the production of broad-spectrum antimicrobial effectors.PMID:37752249 | DOI:10.1038/s41522-023-00431-2

Commun Biol. 2023 Sep 26;6(1):984. doi: 10.1038/s42003-023-05342-8.ABSTRACTAll biology happens in space, and spatial structuring plays an important role in mediating biological processes at all scales from cells to ecosystems. However, the metabolomic structuring of the coral holobiont has yet to be fully explored. Here, we present a method to detect high-quality metabolomic data from individual coral polyps and apply this method to study the patterning of biochemicals across multiple spatial (~1 mm - ~100 m) and organizational scales (polyp to population). The data show a strong signature for individual coral colonies, a weaker signature of branches within colonies, and variation at the polyp level related to the polyps' location along a branch. Mapping metabolites to either the coral or algal components of the holobiont reveals that polyp-level variation along the length of a branch was largely driven by molecules associated with the cnidarian host as opposed to the algal symbiont, predominantly putative sulfur-containing metabolites. This work yields insights on the spatial structuring of biochemicals in the coral holobiont, which is critical for design, analysis, and interpretation of studies on coral reef biochemistry.PMID:37752236 | DOI:10.1038/s42003-023-05342-8

Am J Obstet Gynecol MFM. 2023 Sep 20:101110. doi: 10.1016/j.ajogmf.2023.101110. Online ahead of print.ABSTRACTBACKGROUND: Preeclampsia screening is a critical component of antenatal care worldwide. Currently, the most developed screening test for preeclampsia at 11 to 13 weeks' gestation integrates maternal demographic characteristics and medical history with 3 biomarkers-serum placental growth factor, mean arterial pressure, and uterine artery pulsatility index-to identify approximately 75% of women who develop preterm preeclampsia with delivery before 37 weeks of gestation. It is generally accepted that further improvements to preeclampsia screening require the use of additional biomarkers. We recently reported that the levels of specific metabolites and metabolite ratios are associated with preterm preeclampsia. Notably, for several of these markers, preterm preeclampsia prediction varied according to maternal body mass index class. These findings motivated us to study whether patient classification allowed for combining metabolites with the current biomarkers more effectively to improve prediction of preterm preeclampsia.OBJECTIVE: This study aimed to investigate whether metabolite biomarkers can improve biomarker-based preterm preeclampsia prediction in 3 screening resource scenarios according to the availability of: (1) placental growth factor, (2) placental growth factor+mean arterial pressure, and (3) placental growth factor+mean arterial pressure+uterine artery pulsatility index.STUDY DESIGN: This was an observational case-control study, drawn from a large prospective screening study at 11 to 13 weeks' gestation on the prediction of pregnancy complications, conducted at King's College Hospital, London, United Kingdom. Maternal blood samples were also collected for subsequent research studies. We used liquid chromatography-mass spectrometry to quantify levels of 50 metabolites previously associated with pregnancy complications in plasma samples from singleton pregnancies. Biomarker data, normalized using multiples of medians, on 1635 control and 106 preterm preeclampsia pregnancies were available for model development. Modeling was performed using a methodology that generated a prediction model for preterm preeclampsia in 4 consecutive steps: (1) z-normalization of predictors, (2) combinatorial modeling of so-called (weak) classifiers in the unstratified patient set and in discrete patient strata based on body mass index and/or race, (3) selection of classifiers, and (4) aggregation of the selected classifiers (ie, bagging) into the final prediction model. The prediction performance of models was evaluated using the area under the receiver operating characteristic curve, and detection rate at 10% false-positive rate.RESULTS: First, the predictor development methodology itself was evaluated. The patient set was split into a training set (2/3) and a test set (1/3) for predictor model development and internal validation. A prediction model was developed for each of the 3 different predictor panels, that is, placental growth factor+metabolites, placental growth factor+mean arterial pressure+metabolites, and placental growth factor+mean arterial pressure+uterine artery pulsatility index+metabolites. For all 3 models, the area under the receiver operating characteristic curve in the test set did not differ significantly from that of the training set. Next, a prediction model was developed using the complete data set for the 3 predictor panels. Among the 50 metabolites available for modeling, 26 were selected across the 3 prediction models; 21 contributed to at least 2 out of the 3 prediction models developed. Each time, area under the receiver operating characteristic curve and detection rate were significantly higher with the new prediction model than with the reference model. Markedly, the estimated detection rate with the placental growth factor+mean arterial pressure+metabolites prediction model in all patients was 0.58 (95% confidence interval, 0.49-0.70), a 15% increase (P<.001) over the detection rate of 0.43 (95% confidence interval, 0.33-0.55) estimated for the reference placental growth factor+mean arterial pressure. The same prediction model significantly improved detection in Black (14%) and White (19%) patients, and in the normal-weight group (18.5≤body mass index<25) and the obese group (body mass index≥30), with respectively 19% and 20% more cases detected, but not in the overweight group, when compared with the reference model. Similar improvement patterns in detection rates were found in the other 2 scenarios, but with smaller improvement amplitudes.CONCLUSION: Metabolite biomarkers can be combined with the established biomarkers of placental growth factor, mean arterial pressure, and uterine artery pulsatility index to improve the biomarker component of early-pregnancy preterm preeclampsia prediction tests. Classification of the pregnant women according to the maternal characteristics of body mass index and/or race proved instrumental in achieving improved prediction. This suggests that maternal phenotyping can have a role in improving the prediction of obstetrical syndromes such as preeclampsia.PMID:37752025 | DOI:10.1016/j.ajogmf.2023.101110

Allergol Int. 2023 Sep 24:S1323-8930(23)00103-X. doi: 10.1016/j.alit.2023.09.005. Online ahead of print.ABSTRACTThe ongoing COhort for Childhood Origin of Asthma and allergic diseases (COCOA) study is a prospective birth cohort investigating the origin and natural courses of childhood allergic diseases, including atopic dermatitis, food allergy, allergic rhinitis and asthma, with long-term prognosis. Initiated under the premise that allergic diseases result from a complex interplay of immune development alterations, environmental exposures, and host susceptibility, the COCOA study explores these dynamic interactions during prenatal and postnatal periods, framed within the hygiene and microbial hypotheses alongside the developmental origins of health and disease (DOHaD) hypothesis. The scope of the COCOA study extends to genetic predispositions, indoor and outdoor environmental variables affecting mothers and their offsprings such as outdoor and indoor air pollution, psychological factors, diets, and the microbiomes of skin, gut, and airway. We have embarked on in-depth investigations of diverse risk factors and the pathophysiological underpinnings of allergic diseases. By employing multi-omics approaches-proteomics, transcriptomics, and metabolomics-we gain deeper insights into the distinct pathophysiological processes across various endotypes of childhood allergic diseases, incorporating the exposome using extensive resources within the COCOA study. Integration with large-scale datasets, such as national health insurance records, enhances robustness and mitigates potential limitations inherent to birth cohort studies. As part of global networks focused on childhood allergic diseases, the COCOA study fosters collaborative research across multiple cohorts. The findings from the COCOA study are instrumental in informing precision medicine strategies for childhood allergic diseases, underpinning the establishment of disease trajectories.PMID:37752021 | DOI:10.1016/j.alit.2023.09.005

Photochem Photobiol Sci. 2023 Sep 26. doi: 10.1007/s43630-023-00478-2. Online ahead of print.ABSTRACTChlamydomonas (C.) reinhardtii metabolomic changes in cyclic electron flow-dependent mutants are still unknown. Here, we used mass spectrometric analysis to monitor the changes in metabolite levels in wild-type, cyclic electron-deficient mutants pgrl1 and pgr5 grown under high-light stress. A total of 55 metabolites were detected using GC-MS analysis. High-light stress-induced selective anaplerotic amino acids in pgr5. In addition, pgr5 showed enhancement in carbohydrate, polyamine, and polyol metabolism by 2.5-fold under high light. In response to high light, pgr5 triggers an increase in several metabolites involved in regulating osmotic pressure. Among these metabolites are glycerol pathway compounds such as glycerol-3-phosphate and glyceryl-glycoside, which increase significantly by 1.55 and 3.07 times, respectively. In addition, pgr5 also enhanced proline and putrescine levels by 2.6- and 1.36-fold under high light. On the other hand, pgrl1-induced metabolites, such as alanine and serine, are crucial for photorespiration when subjected to high-light stress. We also observed a significant increase in levels of polyols and glycerol by 1.37- and 2.97-fold in pgrl1 under high-light stress. Both correlation network studies and KEGG pathway enrichment analysis revealed that metabolites related to several biological pathways, such as amino acid, carbohydrate, TCA cycle, and fatty acid metabolism, were positively correlated in pgrl1 and pgr5 under high-light stress conditions. The relative mRNA expression levels of genes related to the TCA cycle, including PDC3, ACH1, OGD2, OGD3, IDH3, and MDH4, were significantly upregulated in pgrl1 and pgr5 under HL. In pgr5, the MDH1 level was significantly increased, while ACS1, ACS3, IDH2, and IDH3 levels were reduced considerably in pgrl1 under high-light stress. The current study demonstrates both pgr5 and prgl1 showed a differential defense response to high-light stress at the primary metabolites and mRNA expression level, which can be added to the existing knowledge to explore molecular regulatory responses of prg5 and pgrl1 to high-light stress.PMID:37751074 | DOI:10.1007/s43630-023-00478-2

Mol Neurobiol. 2023 Sep 26. doi: 10.1007/s12035-023-03615-1. Online ahead of print.ABSTRACTIn this study, we used Chaihu Shugan San (CSS), a traditional Chinese herbal formula, as a probe to investigate the involvement of brain functional network connectivity and hippocampus energy metabolism in perimenopausal depression. A network pharmacology approach was performed to discover the underlying mechanisms of CSS in improving perimenopausal depression, which were verified in perimenopausal depression rat models. Network pharmacology analysis indicated that complex mechanisms of energy metabolism, neurotransmitter metabolism, inflammation, and hormone metabolic processes were closely associated with the anti-depressive effects of CSS. Thus, the serum concentrations of estradiol (E2), glutamate (Glu), and 5-hydroxytryptamine (5-HT) were detected by ELISA. The brain functional network connectivity between the hippocampus and adjacent brain regions was evaluated using resting-state functional magnetic resonance imaging (fMRI). A targeted metabolomic analysis of the hippocampal tricarboxylic acid cycle was also performed to measure the changes in hippocampal energy metabolism using liquid chromatography-tandem mass spectrometry (LC-MS/MS). CSS treatment significantly improved the behavioral performance, decreased the serum Glu levels, and increased the serum 5-HT levels of PMS + CUMS rats. The brain functional connectivity between the hippocampus and other brain regions was significantly changed by PMS + CUMS processes but improved by CSS treatment. Moreover, among the metabolites in the hippocampal tricarboxylic acid cycle, the concentrations of citrate and the upregulation of isocitrate and downregulation of guanosine triphosphate (GTP) in PMS + CUMS rats could be significantly improved by CSS treatment. A brain functional network connectivity mechanism may be involved in perimenopausal depression, wherein the hippocampal tricarboxylic acid cycle plays a vital role.PMID:37751044 | DOI:10.1007/s12035-023-03615-1

Phytopathology. 2023 Sep 26. doi: 10.1094/PHYTO-07-23-0261-LE. Online ahead of print.ABSTRACTThe strains in Lysobacter have the potential to control plant parasitic nematodes. In our experiment, Lysobacter gummosus YMF3.00690 showed antagonistic effects against plant root-knot nematode. Nine metabolites were isolated and identified from cultures of L. gummosus YMF3.00690, of which compound 1 was identified as a new metabolite tetrahydro-4,4,6-trimethyl-6-[(tetrahydro-6,6-dimethyl-2-oxo-4(1H)-pyrimidinylidene) methyl]-2(1H)-pyrimidinone. The activity assay showed that two compounds, 5-(hydroxymethyl)-1H-pyrrole-2-carbaldehyde (2) and 1H-pyrrole-2-carboxylic acid (3), had nematicidal activities against Meloidogyne javanica with mortalities of 69.93% and 90.54% at 400 ppm for 96 h, respectively. These two compounds were further tested for the inhibition activity of eggs hatching, and compound 3 showed significant inhibition rate of 63.36% at 50 ppm for 48 h. In the chemotactic activity assay, three compounds (1-3) were found to have concentration-dependent chemotactic activity, of which compound 1 showed attractive activity. This experiment explored the active metabolites of L. gummosus YMF3.00690 against M. javanica, and laid the foundation for biopesticide development.PMID:37750871 | DOI:10.1094/PHYTO-07-23-0261-LE