Individual Metabolites Research Articles

PredCMB: Predicting changes in microbial metabolites based on the gene-metabolite network analysis of shotgun metagenome data.

Microbiota-derived metabolites significantly impact host biology, prompting extensive research on metabolic shifts linked to the microbiota. Recent studies have explored both direct metabolite analyses and computational tools for inferring metabolic functions from microbial shotgun metagenome data. However, no existing tool specifically focuses on predicting changes in individual metabolite levels, as opposed to metabolic pathway activities, based on shotgun metagenome data. Understanding these changes is crucial for directly estimating the metabolic potential associated with microbial genomic content. We introduce PredCMB (Predicting Changes in Microbial metaBolites), a novel method designed to predict alterations in individual metabolites between conditions using shotgun metagenome data and enzymatic gene-metabolite networks. PredCMB evaluates differential enzymatic gene abundance between conditions and estimates its influence on metabolite changes. To validate this approach, we applied it to two publicly available datasets comprising paired shotgun metagenomics and metabolomics data from inflammatory bowel disease (IBD) cohorts and the cohort of gastrectomy for gastric cancer. Benchmark evaluations revealed that PredCMB outperformed a previous method by demonstrating higher correlations between predicted metabolite changes and experimentally measured changes. Notably, it identified metabolite classes exhibiting major alterations between conditions. By enabling the prediction of metabolite changes directly from shotgun metagenome data, PredCMB provides deeper insights into microbial metabolic dynamics than existing methods focused on pathway activity evaluation. Its potential applications include refining target metabolite selection in microbial metabolomic studies and assessing the contributions of microbial metabolites to disease pathogenesis. Freely available to non-commercial users at https://www.sysbiolab.org/predcmb. Supplementary data are available at Bioinformatics online.

The Current Applications of Metabolomics in Understanding Endometriosis: A Systematic Review

Endometriosis is a common gynecological disease that affects approximately 10–15% of reproductive-aged women worldwide. This debilitating disease has a negative impact on the quality of life of those affected. Despite this condition being very common, the pathogenesis is not well understood. Metabolomics is the study of the array of low-weight metabolites in a given sample. This emerging field of omics-based science has proved to be effective at furthering the understanding of endometriosis. In this systematic review, we seek to provide an overview of the application of metabolomics in endometriosis. We highlight the use of metabolomics in locating biomarkers for identification, understanding treatment mechanisms and symptoms, and relating external factors to endometriosis. The literature search took place in the Web of Science, Pubmed, and Google Scholar based on the keywords “metabolomics” AND “endometriosis” or “metabolome” AND “endometriosis”. We found 58 articles from 2012 to 2024 that met our search criteria. Significant alterations of lipids, amino acids, as well as other compounds were present in human and animal models. Discrepancies among studies of significantly altered metabolites make it difficult to make general conclusions on the metabolic signature of endometriosis. However, several individual metabolites were elevated in multiple studies of women with endometriosis; these include 3-hydroxybutyrate, lactate, phosphatidic acids, succinate, pyruvate, tetradecenoylcarnitine, hypoxanthine, and xanthine. Accordingly, L-isoleucine and citrate were reduced in multiple studies of women with endometriosis. Including larger cohorts, standardizing testing methods, and studying the individual phenotypes of endometriosis may lead to more separable results.

Prenatal exposure to phthalates and phthalate replacements in relation to chorionic plate surface vasculature at delivery.

Pregnant people are ubiquitously exposed to endocrine-disrupting phthalates through consumer products and food. The placenta may be particularly vulnerable to the adverse effects of phthalates, with evidence from animal models suggesting impacts on placental development and vascularization. We translate this research to humans, examining gestational exposure to phthalates and phthalate replacements in relation to novel markers of chorionic plate surface vascularization. Phthalate and phthalate replacement metabolites were measured in first trimester urine from pregnant participants in the Understanding Pregnancy Signals and Infant Development (UPSIDE) cohort (n=154). At delivery, placentae underwent specialized 2D and 3D digital imaging to quantify chorionic plate surface vasculature. Using weighted quantile g-computation mixtures methods as well as multivariable linear regression models examining individual metabolites, we evaluated associations with overall chorionic plate surface area and five chorionic plate surface vascular measures, adjusting for covariates. We additionally examined interactions with placental sex. Exposure to a phthalate mixture was associated with longer total arterial arc length (β=9.64cm; 95%CI: 1.68, 17.59), shorter mean arterial arc length (β=-0.07cm; 95%CI: -0.14, -0.01), and more arterial branch points (β=5.77; 95%CI: 1.56, 9.98), but not chorionic plate surface area. In models considering individual metabolites and their molar sums, results were strongest for the metabolites of Di-isobutyl phthalate (DiBP), Di-isononyl phthalate (DiNP), and Di(2-ethylhexyl) phthalate (DEHP). Associations with metabolites of phthalate replacements tended to be in the same direction but weaker. Few sex differences were observed. Gestational phthalate exposure may be associated with alterations in placental chorionic plate surface vasculature characterized by more branching and shorter segments. These alterations may have implications for placental perfusion and suggest a placental mechanism by which phthalates may impact fetal development.

Multi-Omics Analysis in Mouse Primary Cortical Neurons Reveals Complex Positive and Negative Biological Interactions Between Constituent Compounds of Centella asiatica

Background: A water extract of the Ayurvedic plant Centella asiatica (L.) Urban, family Apiaceae (CAW), improves cognitive function in mouse models of aging and Alzheimer’s disease and affects dendritic arborization, mitochondrial activity, and oxidative stress in mouse primary neurons. Triterpenes (TT) and caffeoylquinic acids (CQA) are constituents associated with these bioactivities of CAW, although little is known about how interactions between these compounds contribute to the plant’s therapeutic benefit. Methods: Mouse primary cortical neurons were treated with CAW or equivalent concentrations of four TT combined, eight CQA combined, or these twelve compounds combined (TTCQA). Treatment effects on the cell transcriptome (18,491 genes) and metabolome (192 metabolites) relative to vehicle control were evaluated using RNAseq and metabolomic analyses, respectively. Results: Extensive differentially expressed genes (DEGs) were seen with all treatments, as well as evidence of interactions between compounds. Notably, many DEGs seen with TT treatment were not observed in the TTCQA condition, possibly suggesting CQA reduced the effects of TT. Moreover, additional gene activity seen with CAW as compared to TTCQA indicates the presence of additional compounds in CAW that further modulate TTCQA interactions. Weighted Gene Correlation Network Analysis (WGCNA) identified 4 gene co-expression modules altered by treatments that were associated with extracellular matrix organization, fatty acid metabolism, cellular response to stress and stimuli, and immune function. Compound interaction patterns were seen at the eigengene level in these modules. Interestingly, in metabolomics analysis, the TTCQA treatment saw the highest number of changes in individual metabolites (20), followed by CQA (15), then TT (8), and finally CAW (3). WGCNA analysis found two metabolomics modules with significant eigenmetabolite differences for TT and CQA and possible compound interactions at this level. Conclusions: Four gene expression modules and two metabolite modules were altered by the four treatment types applied. This methodology demonstrated the existence of both negative and positive interactions between TT, CQA, and additional compounds found in CAW on the transcriptome and metabolome of mouse primary cortical neurons.

Association between volatile organic compounds and circadian syndrome among pre- and postmenopausal women: A population-based study.

Air pollution is closely associated with the development of multiple metabolic diseases. Circadian syndrome (CircS), as an extended concept of metabolic syndrome (MetS), has been proven to be a better predictor of metabolic diseases than MetS. However, the relationship between volatile organic compounds (VOCs) and CircS in pre- and postmenopausal remains unclear. This study used data from the National Health and Nutrition Examination Survey (NHANES) 2011-2020, including 520 premenopausal women and 531 postmenopausal women. Generalized linear model (GLM), restricted cubic splines (RCS) model, subgroup analyses, and weighted quantile sum (WQS) model was used to assess the relationship between VOCs and CircS. In addition, sensitivity analyses were performed to evaluate the robustness of the results. Our findings showed that seven VOC metabolites were positively associated with the risk of CircS in postmenopausal women. In premenopausal women, only two VOC metabolites were positively associated with the risk of CircS. The WQS analysis further confirmed that VOC mixtures selected by least absolute shrinkage and selection operator (LASSO) were significantly associated with an increased risk of CircS in postmenopausal women, with HPMMA identified as the primary contributor to the combined effect. This association was not evident in premenopausal women. Meanwhile, in postmenopausal women, individual urinary VOC metabolites and VOC mixtures were observed to be positively associated with elevated glucose and short sleep. Our results highlighted that VOCs exposure was strongly associated with the occurrence of CircS in postmenopausal women. Further research is needed to confirm this conclusion.

Application of 1H NMR Metabolic Profiling of Serum in Canine Multicentric Lymphoma.

Canine lymphoma represents a biologically and metabolically heterogeneous group of neoplasms that arise from malignant transformation of lymphoid cells. An accurate diagnosis is crucial because of its impact on survival. Current diagnostic methods include clinical laboratory tests and imaging, most of which are invasive and lack sensitivity and specificity. Interestingly, recent work in cancer patients focuses on the search for biomarkers for diagnosis, investigation of treatment response mechanisms, treatment efficacy and prognosis and the discovery of tumour metabolic pathways using metabolomic analysis. In this study, we compare the metabolite profiles in serum from 37 dogs with multicentric lymphoma (22 B-cell lymphomas/LB, 9 CD45+ T-cell lymphomas/LTCD45+, 6 CD45- T-cell lymphomas/LTCD45-) and 25 healthy dogs using 1H nuclear magnetic resonance spectroscopy (NMR). 1H NMR-based metabolite profiling analysis recognised lipids and 22 metabolites, with 16 of them altered, and was shown to be an effective approach for differentiating samples from dogs with lymphoma and healthy controls based on principal component analysis of the NMR data. We also investigated variations in the serum metabolome between immunophenotypes and the control group through pairwise comparisons of the healthy against the LB, LTCD45+ and LTCD45- groups, respectively which showed similar metabolomic profiles. In addition, there were significant differences in the levels of five individual metabolites based on the univariate statistical analysis. Our results showed alterations in energy, protein and lipid metabolism, suggesting glucose, lactate, N-acetyl glycoproteins (NAGs), scyllo-inositol and choline as possible new candidate biomarkers in canine multicentric lymphoma.

Impact of Drying on Phytonutritional Compounds, In Vitro Antioxidant Activity and Cytotoxicity of Spiny Saltbush (Rhagodia spinescens).

The Spiny saltbush (Rhagodia spinscens) is a halophyte species with the potential to provide natural ingredients used in food and pharmaceutical industries. In food and pharmaceutical applications, drying is necessary to maintain shelf-life, which reduces phytonutrient content. In this study, changes in the nutritional composition, phenolic and carotenoid profiles of radical antioxidant scavenging activity [(2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)(ABTS)], antioxidant power [ferric reducing antioxidant ability assay (FRAP)], and cytotoxicity of freeze- and oven-dried (55 °C for 24 h) spiny saltbush were determined. Sodium (4.72 g/100 g dry weight (DW), potassium (6.86 g/100 g DW), calcium (4.06 g/100 g DW), zinc (372 mg/kg DW) and protein content were higher in oven-dried samples than freeze-dried samples. Ultra-performance liquid chromatography-mass spectrometry analysis detected 18 metabolites in saltbush extracts. Partial Least-Squares Discriminant Analysis, Hierarchical Cluster Analysis, and Variable Importance in Projection discriminated between freeze-dried and oven-dried samples. Freeze-dried samples retained more individual metabolites than oven-dried samples, while oven-dried samples had higher antioxidant activity (ABTS and FRAP), lutein, trans-β carotene, and cis-β-carotene. Correlation analysis identified potential antioxidant candidates between phenolic and carotenoid compounds. Neither freeze-dried nor oven-dried spiny saltbush samples showed cytotoxicity. The study uncovered changes in phytonutritional compounds after the oven and freeze-drying spiny saltbush, a potential salt alternative and functional ingredient for the food industry.

Abstract 4134707: Metabolomics Discovery and Epicardial Adipose Tissue : a PROMISE Clinical Trial Substudy

Introduction: Epicardial adipose tissue (EAT) is a metabolically active tissue associated with cardiometabolic disease. EAT likely has local paracrine inflammatory and atherogenic effects on coronary vessels, but the metabolic underpinnings related to systemic metabolic pathways has not been evaluated. Hypothesis: We hypothesized that metabolic markers of lipid and fatty acid oxidation will be positively associated with volume of EAT. Methods: In a biomarker substudy of the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) clinical trial which randomized participants to computed tomography angiography (CTA) vs. stress testing, we analyzed 1542 participants randomized to the CTA arm with available plasma at baseline. CTA phenotyping of EAT volume indexed to body surface area (cm 3 /m 2 ) was determined using a validated deep-learning algorithm. Comprehensive metabolomic profiling was performed on plasma samples using mass spectrometry. Principal components analysis (PCA) was used for dimensionality reduction of 571 named metabolites. Linear regression tested the association of metabolomic factors with EAT. Univariate models were adjusted for multiple comparisons and multivariate models were adjusted for age, race and ethnicity, sex, diabetes, BMI, LDL-C, HDL-C and metabolic syndrome. Results: Of 82 PCA-derived metabolomic factors, 16 were associated with EAT in univariate models and nine were associated with EAT in multivariate models (p=0.001-0.046); 116 individual metabolites heavily loaded within these factors were significantly associated with EAT volume in multivariate models ( Figure 1 ). This included three linoleic acid derivatives, six cholesterol esters, and glycine that were inversely associated with EAT volume (p<0.04) and 106 metabolites positively associated with EAT volume including di- and triacylcerols, glycerophospholipids, fatty acyls and dimethylguanidino valeric acid (p<0.05). Conclusions: Leveraging a large clinical trial of CTA to study metabolomics of EAT, we have identified circulating lipid species associated with EAT independent of BMI and conventional lipids. These findings highlight biomarkers of systemic metabolic dysregulation as risk modifiers and therapeutic targets in cardiometabolic disease prevention and treatment.

A Phase 1 Randomized, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Enteric-Coated Stabilized Sulforaphane (SFX-01) in Male Participants.

Sulforaphane (SFN) is a naturally occurring isothiocyanate associated with various health benefits, including reduced cancer risk, and has been extensively explored as a potential therapeutic. However, its inherent instability presents challenges in formulation, storage, and administration as a medicinal product. SFX-01 (Sulforadex®) is a patented synthetic form of d,l-SFN stabilized within a biologically inert alpha-cyclodextrin complex. The safety, tolerability, and pharmacokinetics of an enteric-coated tablet formulation of SFX-01 were evaluated in a randomized, double-blind, placebo-controlled, dose-escalation study [300mg once daily (46.2mg SFN), 300mg twice daily or 600mg once daily (92.4mg SFN)] over 7days in healthy male participants. Treatment-emergent adverse events (TEAEs) occurred in 94% of participants who received SFX-01 and were most commonly gastrointestinal events, which were mild in severity and related to treatment. Following ingestion of SFX-01 tablets, SFN was rapidly absorbed, with a timescale consistent with the enteric coating, and subsequently metabolized. The observed peak blood concentration (Cmax) for the sum of SFN and metabolites (total thiol) across all treatment cohorts ranged from 0.43 to 2.12µmol/L in 3-6h. Cmax data were considered inconclusive with respect to dose-proportionality and there was minimal evidence of accumulation of SFN and metabolites. Urinary excretion of SFN and individual metabolites ranged from<1 to 41%, and the proportion excreted did not appear to be influenced by the dose. This study demonstrated the safety and tolerability of SFX-01 over 7days and indicated that the pharmacokinetic behavior of SFX-01 enteric-coated tablets was in line with expectations. European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) number: 2022-001601-43; ISRCTN Study Registration number: ISRCTN9628565.

The Effects of Anthropogenic Stressors on Above- and Belowground Phytochemical Diversity of the Wetland Grass, Phragmites australis.

Coastal wetlands face threats from climate change-induced flooding and biological invasions. Plants respond to these stressors through changes in their phytochemical metabolome, but it is unclear whether stressors affecting one tissue compartment (e.g., leaves) create vulnerabilities in others (e.g., roots) or elicit similar responses across tissues. Additionally, responses to multiple simultaneous stressors remain poorly understood due to the focus on individual metabolites in past studies. This study aims to elucidate how the phytochemical metabolome of three Phragmites australis (Cav.) lineages, common in the Mississippi River Delta, responds to flooding and infestation by the non-native scale insect Nipponaclerda biwakoensis (Kuwana). Among these lineages, one is non-native and poses a threat to North American wetlands. Results indicate that metabolomic responses are highly specific, varying with lineage, tissue type, stressor type, and the presence of multiple stressors. Notably, the non-native lineage displayed high chemical evenness, while the other two showed stressor-dependent responses. The 10 most informative features identified by a machine learning model showed less than 1% overlap with known metabolites linked to water and herbivory stress, underscoring gaps in our understanding of plant responses to environmental stressors. Our metabolomic approach offers a valuable tool for identifying candidate plant genotypes for wetland restoration.

Sources of variation in the serum metabolome of female participants of the HUNT2 study.

The aim of this study was to explore the intricate relationship between serum metabolomics and lifestyle factors, shedding light on their impact on health in the context of breast cancer risk. Detailed metabolic profiles of 2283 female participants in the Trøndelag Health Study (HUNT study) were obtained through nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS).We show that lifestyle-related variables can explain up to 30% of the variance in individual metabolites. Age and obesity were the primary factors affecting the serum metabolic profile, both associated with increased levels of triglyceride-rich very low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL), amino acids and glycolysis-related metabolites, and decreased levels of high-density lipoproteins (HDL). Moreover, factors like hormonal changes associated with menstruation and contraceptive use or education level influence the metabolite levels.Participants were clustered into three distinct clusters based on lifestyle-related factors, revealing metabolic similarities between obese and older individuals, despite diverse lifestyle factors, suggesting accelerated metabolic aging with obesity. Our results show that metabolic associations to cancer risk may partly be explained by modifiable lifestyle factors.

Multi-omics analysis in mouse primary cortical neurons reveals complex positive and negative biological interactions between constituent compounds in Centella asiatica.

A water extract of the Ayurvedic plant Centella asiatica (CAW) improves cognitive function in mouse models of aging and Alzheimer's disease, and affects dendritic arborization, mitochondrial activity and oxidative stress in mouse primary neurons. Triterpenes (TT) and caffeoylquinic acids (CQA) are constituents associated with these bioactivities of CAW although little is known about how interactions between these compounds contribute to the plant's therapeutic benefit. Mouse primary cortical neurons were treated with CAW, or equivalent concentrations of four TT combined, eight CQA combined, or these twelve compounds combined (TTCQA). Treatment effects on the cell transcriptome (18,491 genes) and metabolome (192 metabolites) relative to vehicle control were evaluated using RNAseq and metabolomic analyses respectively. Extensive differentially expressed genes (DEGs) were seen with all treatments, as well as evidence of interactions between compounds. Notably many DEGs seen with TT treatment were not observed in the TTCQA condition, possibly suggesting CQA reduced the effects of TT. Moreover, additional gene activity seen with CAW as compared to TTCQA indicate the presence of additional compounds in CAW that further modulate TTCQA interactions. Weighted Gene Correlation Network Analysis (WGCNA) identified 4 gene co-expression modules altered by treatments that were associated with extracellular matrix organization, fatty acid metabolism, cellular response to stress and stimuli, and immune function. Compound interaction patterns were seen at the eigengene level in these modules. Interestingly, in metabolomics analysis, the TTCQA treatment saw the highest number of changes in individual metabolites (20), followed by CQA (15), then TT (8) and finally CAW (3). WGCNA analysis found two metabolomics modules with significant eigenmetabolite differences for TT and CQA, and possible compound interactions at this level. Four gene expression modules and two metabolite modules were altered by the four types of treatments applied. This methodology demonstrated the existence of both negative and positive interactions between TT, CQA and additional compounds found in CAW on the transcriptome and metabolome of mouse primary cortical neurons.

Association between metabolomics-based biomarker scores and 10-year cognitive decline in men and women. The Doetinchem Cohort Study.

Metabolomic scores based on age (MetaboAge) and mortality (MetaboHealth) are considered indicators of overall health, but their association with cognition in the general population is unknown. Therefore, the association between MetaboAge/MetaboHealth and level and decline in cognition was studied, as were differences between men and women. Data of 2821 participants (50% women, age range 45-75) from the Doetinchem Cohort Study was used. MetaboAge and MetaboHealth were calculated from 1H-NMR metabolomics data at baseline. Cognitive domain scores (memory, flexibility and processing speed) and global cognitive functioning were available over a 10-year period. The association between MetaboAge/MetaboHealth and level of cognitive functioning was studied using linear regressions while for the association between MetaboAge/MetaboHealth and cognitive decline longitudinal linear mixed models were used. Analyses were adjusted for demographics and lifestyle factors. Higher MetaboAge, indicating poorer metabolomic ageing, was only associated with lower levels of processing speed in men. Higher MetaboHealth, indicating poorer immune-metabolic health, was associated with lower levels of cognitive functioning for all three domains and global cognitive functioning in both men and women. Only in men, MetaboHealth was also associated with 10-year decline in flexibility, processing speed and global cognition. Metabolites that contributed to the observed associations were in men mainly markers of protein metabolism, and in women mainly markers of lipid metabolism and inflammatory metabolites. MetaboHealth, not MetaboAge, was associated with cognitive functioning independent of conventional risk factors. Individual metabolites affect cognitive functioning differently in men and women, suggesting sex-specific pathophysiological pathways underlying cognitive functioning.

Serum metabolomics improve risk stratification for incident heart failure

Abstract Background The prediction and early detection of heart failure (HF) is vital to reduce its substantial impact on quality of life, survival and healthcare expenditure. Current incident HF risk stratification strategies achieve only modest performance. Moreover, state-of-the-art risk scores focus on commonly acknowledged clinical risk factors, thus necessitating the integration of heterogenous data sources and prioritizing individuals with obvious risk constellations. Purpose Here, we explored the predictive value of serum metabolomics (168 metabolites detected by proton nuclear magnetic resonance (1H-NMR) spectroscopy) for incident HF. Methods Leveraging data of n = 68,311 individuals and &amp;gt; 0.8 million person-years of follow-up from the UK Biobank (UKB) cohort, we (I) evaluated the association of individual metabolites with incident HF via fitting of per-metabolite COX proportional hazards models and (II) trained and validated elastic net (EN) models to predict incident HF using the serum metabolome. Discriminative performance was benchmarked against a comprehensive, well-validated clinical risk score (Pooled Cohort Equations to Prevent HF, PCP-HF). External validation was conducted in the independent FINRISK study. Results Several metabolites were independently associated with incident HF (90/168 adjusting for age and sex, 48/168 adjusting for PCP-HF). Performance-optimized risk models effectively retained key predictors representing highly correlated clusters (≈ 80 % feature reduction). The addition of metabolomics to PCP-HF improved predictive performance (Harrel’s C: 0.768 vs. 0.755, ΔC = 0.013 (95% confidence interval (CI) 0.004 – 0.022), continuous net reclassification improvement (NRI) = 0.287 (95% CI 0.200 – 0.367), relative integrated discrimination improvement (IDI): 17.47 % (95% CI 9.463 - 27.825)). Simplified models only including age, sex and metabolomics performed almost as well as the PCP-HF model (Harrel’s C: 0.745 vs. 0.755, ΔC = 0.010 (95% CI -0.004 - 0.027), continuous NRI: 0.097 (95% CI -0.025 - 0.217), relative IDI: 13.445 % (95% CI -10.608 - 41.454)). Risk and survival stratification was improved by integrating metabolomics. External validation within FINRISK revealed similar patterns using the original model coefficients. Conclusions Serum metabolomics improve the prediction of incident HF risk. Scores obtained from the combination of age, sex and metabolomics exhibit similar predictive power as clinical risk models. Offering serum metabolomics to a middle-aged cohort might significantly improve HF risk stratification, thus facilitating preventive efforts. Via a single blood draw, serum metabolomics displays a highly cost- and time-effective, standardizable, and scalable alternative to clinical risk scores involving physical measurements and history taking in addition to clinical chemistry.Relative performance (test split)ROC &amp; DCA plots (test split)

Potential of pre-diagnostic metabolomics for colorectal cancer risk assessment or early detection

This systematic review investigates the efficacy of metabolite biomarkers for risk assessment or early detection of colorectal cancer (CRC) and its precursors, focusing on pre-diagnostic biospecimens. Searches in PubMed, Web of Science, and SCOPUS through December 2023 identified relevant prospective studies. Relevant data were extracted, and the risk of bias was assessed with the QUADAS-2 tool. Among the 26 studies included, significant heterogeneity existed for case numbers, metabolite identification, and validation approaches. Thirteen studies evaluated individual metabolites, mainly lipids, while eleven studies derived metabolite panels, and two studies did both. Nine panels were internally validated, resulting in an area under the curve (AUC) ranging from 0.69 to 0.95 for CRC precursors and 0.72 to 1.0 for CRC. External validation was limited to one panel (AUC = 0.72). Metabolite panels and lipid-based biomarkers show promise for CRC risk assessment and early detection but require standardization and extensive validation for clinical use.

Behavioral Responses of Chironomus aprilinus Larvae as Proxies for Cyanobacterial Metabolite Interactions: Insights from Ternary Combinations.

This study aimed to assess the behavioral responses (immobilization, horizontal and vertical motility, and response to light) of Chironomus aprilinus larvae exposed to individual cyanobacterial metabolites aeruginosin 98B (AER-B), anabaenopeptin-B (ANA-B), and cylindrospermopsin (CYL), and their binary and ternary mixtures. The investigation revealed that single metabolites ANA-B and CYL exhibited the highest potency in immobilizing the larvae. Notably, the binary mixture AER-B+CYL induced a remarkably strong synergistic interaction, while other tested binary and ternary mixtures demonstrated antagonistic effects. Both individual metabolites and their mixtures led to a decrease in larval movement speed, with the AER-B+CYL combination showing a very synergistic effect, and strong antagonistic interactions between the oligopeptides in the ternary mixture. Conversely, while AER-B and the binary mixture ANA-B+CYL stimulated vertical movement, other single metabolites and binary and ternary mixtures decreased this parameter. Antagonistic interactions were observed in all mixtures. ANA-B emerged as the most potent inhibitor, yet all tested metabolites and their mixtures decreased larval response to light, displaying synergistic interactions, except for the AER-B+ANA-B mixture at 250 μg L-1 + 250 μg L-1. These findings underscore the sensitivity of Chironomus larvae behavioral parameters as indicators of environmental stressors and mixtures. Consequently, they are recommended for assessing toxic effects induced by cyanobacterial products and other bioactive chemicals.

Optimization of microwave parameters to enhance phytochemicals, antioxidants and metabolite profile of de-oiled rice bran

The current study explores the effects of microwave treatment at varying wattage and durations on the phytoconstituents, antioxidant status, anti-nutritional factors (ANFs), and metabolite profiles of de-oiled rice bran. The total phenolics and flavonoids showed both increases and decreases depending on specific microwave parameters, while flavonol content consistently increased across all treated groups compared to the control. The DPPH and ABTS free radical scavenging activity, total antioxidant capacity, FRAP, CUPRAC, metal chelating activity, and ascorbic acid content were enhanced in most of the microwaved samples; however, longer microwave exposure at higher wattage led to their reduction. A treatment-specific decrease in ANFs, including condensed tannins, oxalates, and phytates, was observed. HRMS-based untargeted metabolomics identified a diverse range of primary and secondary metabolites, which clustered in a group-specific manner, indicating notable group-wise metabolite variations. Analysis of discriminating metabolites revealed no significant differences in the overall levels of phenolics, flavonoids, vitamins and cofactors, sugars, amino acids, terpenoids, fatty acids, and their derivatives among the treated groups compared to the control; however, several individual metabolites within these metabolite classes differed significantly. These findings suggest that optimized microwaving of de-oiled rice bran can enhance phytochemicals and antioxidants while improving the metabolite profile.

Acylsugars, Nicotine and a Protease Inhibitor Provide Variable Protection for Nicotiana benthamiana in a Natural Setting.

Plants produce an immense diversity of defensive specialized metabolites. However, despite extensive functional characterization, the relative importance of different defensive compounds is rarely examined in natural settings. Here, we compare the efficacy of three Nicotiana benthamiana defensive compounds, nicotine, acylsugars and a serine protease inhibitor, by growing plants with combinations of knockout mutations in a natural setting, quantifying invertebrate interactions and comparing relative plant performance. Among the three tested compounds, acylsugars had the greatest defensive capacity, affecting aphids, leafhoppers, spiders and flies. Nicotine mutants displayed increased leafhopper feeding and aphid colonization. Plants lacking both nicotine and acylsugars were more susceptible to flea beetles and thrips. By contrast, knockout of the serine protease inhibitor did not affect insect herbivory in the field. Complementary experiments under controlled laboratory conditions with caterpillars, grasshoppers and aphids confirmed results obtained in a natural setting. We conclude that the three metabolite groups collectively provide broad-spectrum protection to N. benthamiana. However, there is a gradient in their effects on the interacting invertebrates present in the field. Furthermore, we demonstrate that, even if individual metabolites do not have a measurable defensive benefit on their own, they can have an additive effect when combined with other defensive compounds.

Effects of single and combined urinary polycyclic aromatic hydrocarbon effects on lung function in the U.S. adult population

BackgroundThe impact of polycyclic aromatic hydrocarbons (PAHs) on lung function has garnered attention, but studies mostly focus on individual effect. This study investigates urinary PAH metabolites as biomarkers of exposure and assesses the relationships between single and combined exposures to nine urinary PAH metabolites and lung function in adults.MethodsData from 4040 adults in the 2007–2012 National Health and Nutrition Examination Survey (NHANES) were analyzed. Weighted generalized linear models estimated the effects of individual PAH metabolites on lung function. Additionally, weighted quantile sum (WQS) regression, quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR) were employed to evaluate the combined impacts of multiple PAH metabolites.ResultsAnalyses of individual PAH metabolites revealed negative associations with lung function, excluding forced vital capacity (FVC). The WQS, qgcomp, and BKMR models consistently showed that exposure to multiple PAH metabolites was associated with lung function decrease. WQS indicated that 2-hydroxynaphthalene (2-NAP) was the largest contributor to the reductions in forced expiratory volume in 1 s (FEV1), FVC, peak expiratory flow (PEF), and forced expiratory flow from 25 to 75% of FVC (PEF25-75%). Additionally, 1-hydroxypyrene (1-PYR) was the primary PAH metabolite contributing to the decreases in FEV1/FVC and fractional exhaled nitric oxide (FeNO). The combined effect of urinary PAH metabolites did not affect FVC in the current smokers or FeNO in nonsmokers, but decreased FEV1/FVC in current smokers.ConclusionThis study strengthens the negative relationships between multiple PAH metabolites exposure and lung function in adults. Given the limitations of this study, including the lack of knowledge of other exposure pathways and the uncertainty of urinary metabolites, further research is necessary to explore the mechanisms underlying these associations and to address the limitations in exposure assessment.

Cruciferous Plant Extracts, Their Isothyocianate or Indol Derivatives, and Their Effect on Cellular Viability of Breast Cancer Cell Lines.

Brassicaceaes are rich in glucosinolates (GSL), whose derivatives, the isothyocianates sulforaphane (SFN), iberine (IB), or indole derivatives as indole-3-carbinol (I3C), have anticancer activities. We evaluated the effects of a broccoli sprout (Brassica oleracea var italica) and red cabbage (B. oleracea L. var capitata f. rubra) extracts and their GSL derivatives on breast cancer cells. Broccoli sprout aqueous extract (BSE) and red cabbage aqueous (RCA) or ethanolic (RCE) extracts were high in SFN, IB, and/or I3C. BSE and RCA decreased proliferation at doses of 2.5-5 mg/mL but induced proliferation at lower doses. RCE decreased proliferation starting at 10 µg/mL with selectivity toward cancer cells. SFN, IB, or I3C alone or in combination did not decrease proliferation similarly, suggesting synergistic effects with other phytochemicals in the extract. RCE showed selectivity toward breast cancer cells, but the effect of the individual metabolites or their combination did not reduce proliferation to the same extent. It will be important to determine the combination responsible for this effect to characterize their use for breast cancer treatment.