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

PubMed

Untargeted Metabolomic Study of Patients with Macular Edema Secondary to Retinal Vein Occlusion in Aqueous Humor

Mon, 13/01/2025 - 12:00
Clin Ophthalmol. 2025 Jan 6;19:59-72. doi: 10.2147/OPTH.S500860. eCollection 2025.ABSTRACTPURPOSE: The aim of this study was to identify metabolic biomarkers and investigate the metabolic changes associated with aqueous humor in retinal vein occlusion macular edema (RVO-ME).METHODS: Aqueous humor (AH) samples were collected from patients, including those diagnosed with central retinal vein occlusion macular edema (CRVO-ME), branch retinal vein occlusion macular edema (BRVO-ME), and a control group undergoing cataract surgery. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was utilized to analyze the metabolomic profiles in aqueous humor.RESULTS: A total of 28 metabolites were identified as potential biomarkers capable of distinguishing RVO-ME patients from the control group. Of these, 26 metabolites were specific for distinguishing CRVO-ME patients from controls, and 24 metabolites were specific for differentiating BRVO-ME patients from controls. Additionally, 9 metabolites were identified that could differentiate CRVO-ME patients from BRVO-ME patients.CONCLUSION: This study successfully identified significant metabolic biomarkers that enhance our understanding of the pathogenesis of RVO-ME. These findings may offer new avenues for the treatment of RVO-ME and aid in differentiating between CRVO-ME and BRVO-ME patients.PMID:39801565 | PMC:PMC11721502 | DOI:10.2147/OPTH.S500860

Chronodisruption that dampens output of the central clock abolishes rhythms in metabolome profiles and elevates acylcarnitine levels in the liver of female rats

Mon, 13/01/2025 - 12:00
Acta Physiol (Oxf). 2025 Feb;241(2):e14278. doi: 10.1111/apha.14278.ABSTRACTAIM: Exposure to light at night and meal time misaligned with the light/dark (LD) cycle-typical features of daily life in modern 24/7 society-are associated with negative effects on health. To understand the mechanism, we developed a novel protocol of complex chronodisruption (CD) in which we exposed female rats to four weekly cycles consisting of 5-day intervals of constant light and 2-day intervals of food access restricted to the light phase of the 12:12 LD cycle.METHODS: We examined the effects of CD on behavior, estrous cycle, sleep patterns, glucose homeostasis and profiles of clock- and metabolism-related gene expression (using RT qPCR) and liver metabolome and lipidome (using untargeted metabolomic and lipidomic profiling).RESULTS: CD attenuated the rhythmic output of the central clock in the suprachiasmatic nucleus via Prok2 signaling, thereby disrupting locomotor activity, the estrous cycle, sleep patterns, and mutual phase relationship between the central and peripheral clocks. In the periphery, CD abolished Per1,2 expression rhythms in peripheral tissues (liver, pancreas, colon) and worsened glucose homeostasis. In the liver, it impaired the expression of NAD+, lipid, and cholesterol metabolism genes and abolished most of the high-amplitude rhythms of lipids and polar metabolites. Interestingly, CD abolished the circadian rhythm of Cpt1a expression and increased the levels of long-chain acylcarnitines (ACar 18:2, ACar 16:0), indicating enhanced fatty acid oxidation in mitochondria.CONCLUSION: Our data show the widespread effects of CD on metabolism and point to ACars as biomarkers for CD due to misaligned sleep and feeding patterns.PMID:39801395 | DOI:10.1111/apha.14278

Galactooligosaccharide-Metabolism-Related Genes of <em>Bifidobacterium pseudocatenulatum</em> Contribute to the Regulation of Glucose and Lipid Metabolism in Type 2 Diabetic Mice

Mon, 13/01/2025 - 12:00
J Agric Food Chem. 2025 Jan 12. doi: 10.1021/acs.jafc.4c05616. Online ahead of print.ABSTRACTThis study investigated whether the galactooligosaccharide (GOS)-metabolism-related genes (GOS-cluster) in Bifidobacterium pseudocatenulatum contribute to alleviating glucose and lipid metabolic disorders in type 2 diabetic mice. Genomic analysis of 69 B. pseudocatenulatum strains based on the GOS-cluster, combined with in vitro fermentation experiments, revealed that high-GOS-cluster strains (≥24 MFS, ≥39 GOS-cluster) demonstrated superior GOS utilization and bile salt tolerance. In vivo, the high-GOS-cluster strains resulted in a significant reduction of blood glucose levels by 18.52 to 32.01% compared to the model group. Mechanistic studies showed that these strains significantly activated the FXR/FGF15/GSK3β and FXR/SREBP1/FAS signaling pathways. Species-specific quantification of B. pseudocatenulatum, metabolomics, and network analysis suggested that GOS treatment increased the abundance of B. pseudocatenulatum, particularly strains rich in the GOS-cluster, with a 32.03% increase compared to strains with a low GOS-cluster. This indirectly increased choloylglycine hydrolase levels and altered the profiles of primary and secondary bile acids, resulting in an increase in FXR agonists, such as glycocholic acid, cholic acid, and deoxycholic acid. These findings suggest that the presence of the GOS-cluster is a crucial factor in determining whether a B. pseudocatenulatum strain can prevent or ameliorate type 2 diabetes.PMID:39801054 | DOI:10.1021/acs.jafc.4c05616

Preliminary exploration of metabolomics mechanisms in patients with patent foramen ovale and migraine

Mon, 13/01/2025 - 12:00
J Oral Facial Pain Headache. 2024 Dec;38(4):111-121. doi: 10.22514/jofph.2024.044. Epub 2024 Dec 12.ABSTRACTThis study aimed to investigate the metabolic mechanisms underlying the combination of patent foramen ovale (PFO) and migraine by assessing metabolite expression before and after interventional occlusion surgery. The study included 11 PFO patients from the Heart Center of Xinjiang Medical University Affiliated Hospital of Traditional Chinese Medicine, who underwent transcatheter PFO intervention and occlusion surgery between January 2018 and February 2023, and 11 healthy controls. Blood samples were collected pre-surgery, 3 days post-surgery, and 30 days post-surgery for metabolomics analysis. The goal was to identify differentially expressed metabolites between groups. Statistical analyses were performed to evaluate these metabolites alongside migraine disability, assessed using the Migraine Disability Assessment (MIDAS) score. Preliminary analysis of metabolic pathways was also conducted. Results showed significant differences in serum metabolites, including dopamine, L-proline, L-tyrosine, D-proline, acetylcarnitine, and dulcitol, between PFO migraine patients and healthy controls based on Liquid Chromatography-Mass Spectrometry (LC-MS) non-targeted metabolomics analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of these metabolites revealed enrichment in protein digestion, absorption, and metabolic signaling pathways, highlighting the role of metabolism in the disease process. Elevated levels of dopamine and other metabolites were found in migraine patients, with differential metabolites primarily associated with the arginine metabolic pathway, suggesting its importance in the condition's progression. Additionally, patients with PFO and migraine showed significant improvements in headache frequency, duration, and severity post-treatment (p < 0.05), though accompanying symptoms did not show statistically significant changes (p > 0.05). Overall, interventional closure surgery for PFO significantly alleviates headache symptoms in patients.PMID:39800962 | DOI:10.22514/jofph.2024.044

Microseparation of Lipophilic and Hydrophilic Metabolites for Single Oocyte Mass Spectrometry Analysis

Mon, 13/01/2025 - 12:00
Anal Chem. 2025 Jan 12. doi: 10.1021/acs.analchem.4c04900. Online ahead of print.ABSTRACTSingle-cell metabolic analysis has not yet achieved the coverage of bulk analysis due to the diversity of cellular metabolites and the ionization competition among species. Direct ionization methods without separation lead to the masking of low-intensity species. By designing a capillary column emitter and introducing reverse-phase chromatography principles, we achieved the microseparation of lipophilic and hydrophilic metabolites and lowered the limit of detection of hydrophilic metabolites to the level of a single oocyte. We identified 517 metabolite species in a single oocyte, achieving coverage and reproducibility comparable to those of bulk analysis. By comparing oocytes at different maturation stages, 76 metabolic features were identified with significant differences between the germinal vesicle and meiosis II stages. Metabolite level changes suggested the roles of lipid metabolism remodeling, increased amino acid synthesis, and a shift from pyrimidine metabolism to purine metabolism in the process of oocyte maturation. This microseparation mass spectrometry analysis is expected to promote single-cell metabolomics.PMID:39800910 | DOI:10.1021/acs.analchem.4c04900

The Use of Omics in Untangling the Effect of Lifestyle Factors in Pregnancy and Gestational Diabetes: A Systematic Review

Sun, 12/01/2025 - 12:00
Diabetes Metab Res Rev. 2025 Jan;41(1):e70026. doi: 10.1002/dmrr.70026.ABSTRACTAIM: To synthesise the evidence from clinical trials and observational studies using omics techniques to investigate the impact of diet and lifestyle factors on metabolite profile in pregnancy, and in the prevention and management of gestational diabetes mellitus (GDM).MATERIALS AND METHODS: A systematic literature search was performed using PubMed, Ovid, CINAHL, and Web of Science databases in October 2023 and updated in September 2024. Inclusion criteria were randomised controlled trials (RCT) or non-RCTs in pregnant women with or without GDM, that measured diet and lifestyle factors, and which applied post-transcriptional omics approaches. Risk of bias was assessed using the ROBINS-I for non-RCTs and ROB-2 tool for RCTs. The results of all studies are narratively synthesised.RESULTS: Of 6293 studies identified, eight observational studies and three RCTs comprising 2639 pregnant women were included. Three studies reported on changes in diet-related metabolic phenotypes during pregnancy; however, the impact of certain foods on the metabolome and risk for GDM was less clear. Compared with women without GDM, women with GDM had a worse deterioration in metabolites, including saturated fatty acids, branched chain amino acids and purine degradation metabolites. There is limited evidence that conventional dietary treatment for GDM may modify the metabolome in women with GDM.CONCLUSIONS: Metabolome profiles in pregnancy may be altered by certain dietary choices; however, it is inconclusive whether improved diet related metabolite profiles have a beneficial impact in the prevention or management of GDM. High quality studies with larger sample sizes are needed to better understand the role that maternal nutrition plays in modulating the maternal metabolome, not only for a healthy pregnancy but also for the prevention and management of GDM.PMID:39800861 | DOI:10.1002/dmrr.70026

Life stage impact on the human skin ecosystem: lipids and the microbial community

Sun, 12/01/2025 - 12:00
NPJ Biofilms Microbiomes. 2025 Jan 13;11(1):13. doi: 10.1038/s41522-025-00652-7.ABSTRACTSebaceous free fatty acids are metabolized by multiple skin microbes into bioactive lipid mediators termed oxylipins. This study investigated correlations between skin oxylipins and microbes on the superficial skin of pre-pubescent children (N = 36) and adults (N = 100), including pre- (N = 25) and post-menopausal females (N = 25). Lipidomics and metagenomics revealed that Malassezia restricta positively correlated with the oxylipin 9,10-DiHOME on adult skin and negatively correlated with its precursor, 9,10-EpOME, on pre-pubescent skin. Co-culturing Malassezia with keratinocytes demonstrated a link between 9,10-DiHOME and pro-inflammatory cytokines IL-1β and IL-6 production. We also observed strong correlations between other skin oxylipins and microbial taxa, highlighting life stage differences in sebum production and microbial community composition. Our findings imply a complex host-microbe communication system mediated by lipid metabolism occurring on human skin, warranting further research into its role in skin health and disease and paving the way towards novel therapeutic targets and treatments.PMID:39800795 | DOI:10.1038/s41522-025-00652-7

Moderate-intensity interval exercise exacerbates cardiac lipotoxicity in high-fat, high-calories diet-fed mice

Sun, 12/01/2025 - 12:00
Nat Commun. 2025 Jan 12;16(1):613. doi: 10.1038/s41467-025-55917-8.ABSTRACTPhysical exercise is a cornerstone for preventing diet-induced obesity, while it is unclear whether physical exercise could offset high-fat, high-calories diet (HFCD)-induced cardiac dysfunction. Here, mice were fed with HFCD and simultaneously subjected to physical exercise. As expected, physical exercise prevented HFCD-induced whole-body fat deposition. However, physical exercise exacerbated HFCD-induced cardiac damage. Further metabolomic analysis results showed that physical exercise induced circulating lipid redistribution, leading to excessive cardiac lipid uptake and lipotoxicity. Our study provides valuable insights into the cardiac effects of exercise in mice fed with HFCD, suggesting that counteracting the negative effect of HFCD by simultaneous physical exercise might be detrimental. Moreover, inappropriate physical exercise may damage certain organs even though it leads to weight loss and overall metabolic benefits. Of note, the current findings are based on animal experiments, the generalizability of these findings beyond this specific diet and mouse strain remains to be further explored.PMID:39800728 | DOI:10.1038/s41467-025-55917-8

Sputum Microbiota Correlates With Metabolome and Clinical Outcomes in Asthma-Bronchiectasis Overlap

Sun, 12/01/2025 - 12:00
Arch Bronconeumol. 2025 Jan 6:S0300-2896(25)00006-7. doi: 10.1016/j.arbres.2025.01.002. Online ahead of print.ABSTRACTOBJECTIVES: To investigate the microbiota and metabolome of patients with ABO compared with bronchiectasis and asthma, and determine the relevance with clinical characteristics, inflammatory endotype and exacerbation risks.METHODS: In this prospective cohort study, patients underwent comprehensive assessments, including sputum differential cell count, and sputum collection at baseline. Sputum microbiota was profiled via 16S rRNA gene sequencing and metabolome via liquid chromatography/mass spectrometry. Shannon-Wiener Diversity Index (SWDI) was used to reflect dysbiosis. Patients were followed-up to record exacerbations. ABO patients were stratified by the SWDI and sputum eosinophilia to determine the exacerbation risks.RESULTS: Two hundred forty-seven patients were recruited, including 99 ABO (median age: 53.2 years, 65.7% female), 61 asthma (median age: 39.5 years, 50.8% female) and 87 bronchiectasis patients (median age: 52.3 years, 55.2% female). Both microbiota compositions and metabolites differed among asthma, ABO and bronchiectasis, and between eosinophilic and non-eosinophilic ABO at steady-state. Baseline SWDI of microbiota was highest in asthma, followed by ABO. Both Pseudomonadaceae and Rothia most effectively discriminated ABO from asthma and bronchiectasis. Pseudomonas exhibited a more pronounced negative correlation with other taxa in nonEos-ABO. ABO patients with low SWDI with sputum eosinophilia, or those with high SWDI without sputum eosinophilia, had a shorter time to the first exacerbation. Metabolomic compositions in Eos-ABO separated from nonEos-ABO. The relative abundance of Enterobacteriaceae correlated negatively with 15-hydroxylated eicosatetraenoic acid, whose concentrations were higher in Eos-ABO.CONCLUSIONS: Integrating microbiota and metabolome profiles, together with eosinophilic inflammatory endotyping, can inform exacerbation risk and personalized management of ABO.PMID:39800636 | DOI:10.1016/j.arbres.2025.01.002

Enhanced nano-LC-MS for analyzing dansylated oral cancer tissue metabolome dissolved in solvents with high elution strength

Sun, 12/01/2025 - 12:00
Anal Chim Acta. 2025 Feb 1;1337:343514. doi: 10.1016/j.aca.2024.343514. Epub 2024 Dec 11.ABSTRACTBACKGROUND: Tissue metabolomics analysis, alongside genomics and proteomics, offers crucial insights into the regulatory mechanisms of tumorigenesis. To enhance metabolite detection sensitivity, chemical isotope labeling (CIL) techniques, such as dansylation, have been developed to improve metabolite separation and ionization in mass spectrometry (MS). However, the dissolution of hydrophobic derivatized metabolites in solvents with high acetonitrile content limits the use of liquid chromatography (LC) systems with small-volume reversed-phase (RP) columns. In this study, we established a nano-LC-MS system with an online dilution design to address this issue, enabling sensitive analysis of oral cancer tissue metabolomes.RESULTS: Our nano-LC system features a flow path design with online sample dilution before an RP trap column and backflushing of the trap column before entering the analytical column. Compared to other nano-LC systems, both with and without online dilution designs, our system demonstrates the superiority of the T-connector-based dilution method. Using only 1/20th of the sample required for popular micro-LC systems, our nano-LC detects a larger number of peak pairs with similar recovery rates for both hydrophilic and hydrophobic metabolites, ensuring unbiased results. Thirty-two matched pairs of oral squamous cell carcinoma (OSCC) tissue samples and adjacent noncancerous tissues (ANTs) underwent high-throughput CIL-metabolome analysis using our nano-LC system. Compared to our previous micro-LC methods, the nano-LC-MS system exhibits enhanced detection sensitivity, significantly reducing sample requirements.SIGNIFICANCE: Our findings highlight the efficacy of our platform for metabolomic analysis with limited sample amounts. The nano-LC system's ability to analyze samples dissolved in strong eluents suggests potential applications for handling other hydrophobic compounds using RPLC or other separation methods facing similar solvent incompatibility issues. This approach holds promise for identifying novel metabolite biomarkers for oral cancers, advancing our understanding of tumorigenesis, and enhancing clinical applications.PMID:39800537 | DOI:10.1016/j.aca.2024.343514

A sensitive post-column derivatization approach for enhancing hydroxyl metabolites detection

Sun, 12/01/2025 - 12:00
Anal Chim Acta. 2025 Feb 1;1337:343559. doi: 10.1016/j.aca.2024.343559. Epub 2024 Dec 18.ABSTRACTBACKGROUND: Chemical derivatization is a common technique in liquid chromatography-mass spectrometry (LC-MS) metabolomics used to improve the ionizability and chromatographic properties of metabolites in complex biological samples. This process facilitates better detection and separation of a wide array of compounds. The reagent 2-(4-boronobenzyl) isoquinolin-2-ium bromide (BBII), developed as a glucose labeling reagent for matrix-assisted laser desorption/ionization MS, enhances ionization for glucose and other hydroxyl metabolites. Its quaternary ammonium group increases ionization efficiency, and its rapid reaction time simplifies pretreatment procedures.RESULTS: We developed a novel post-column derivatization (PCD) method using BBII to boost the detection sensitivity of hydroxyl metabolites in LC-MS. By optimizing this BBII PCD approach with 14 hydroxyl-containing compounds, we were able to detect previously undetectable metabolites such as glucose, ribose, and long-chain alcohols. Sensitivity enhancements for these metabolites ranged from 1.1 to 42.9-fold. Applying this method to metabolic profiling of hydroxyl metabolites in the DBTRG-05MG glioblastoma cell line, with and without treatment with the new drug MFB [1-(4-chlorobenzyl)-2-(5-methyl-2-furfurylideneamino)benzimidazole], revealed several hydroxyl metabolites with significantly reduced levels post-treatment.SIGNIFICANCE AND NOVELTY: This study presents a new BBII PCD method that substantially improves the detection sensitivity of hydroxyl metabolites in LC-MS. This innovative approach is highly valuable for untargeted metabolomics studies in biological and clinical research, offering a robust tool for identifying metabolite changes and advancing our understanding of metabolic processes in disease and therapeutic contexts.PMID:39800515 | DOI:10.1016/j.aca.2024.343559

Characterization of Quality Marker for Mume Fructus Pulp by Ultra-Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry-Based Untargeted Metabolomics Combined With Biological Activities

Sun, 12/01/2025 - 12:00
Phytochem Anal. 2025 Jan 12. doi: 10.1002/pca.3502. Online ahead of print.ABSTRACTINTRODUCTION: As a widely used Chinese herbal medicine, Mume Fructus pulp (MFP) has rich nutritional value and biological activity, but its quality control research is relatively scarce.OBJECTIVES: The objective of the study was to evaluate the quality difference between MFPs from different origins and its adulterant apricot pulp (APP), and to identify potential quality markers.METHODS: The chemical compositions were identified by untargeted metabolomics analysis based on ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry combined with feature-based molecular networking. The effect of the test samples on the gene expression of the pro-inflammatory cytokines was investigated by RT-qPCR and ELISA analyses to determine their anti-inflammatory potential. Antioxidant activity was assessed by a free radical scavenging assay. Subsequently, the relationship between biological activity and chemical composition was analyzed by chemometrics, and the quality index of MFP was preliminarily determined. Based on network pharmacology and molecular docking, quality markers of MFP and their possible molecular mechanisms were further determined.RESULTS: There were significant differences in the contents of flavonoids and organic acids, as well as the anti-inflammatory and antioxidant activities of MFPs from different habitats. Its adulterant APP was not only different from MFP in composition, but also had significantly weaker biological activity. Sixteen compounds were positively correlated with the antioxidant or anti-inflammatory effects of MFP. Combined with network pharmacology and molecular docking, citric acid, maleic acid, rutin, quercetin, isoquercetin, spiraeoside, and hesperidin were identified as potential quality markers of MFP.CONCLUSION: This study showed the potential of untargeted metabolomic analysis combined with bioactivity assays in the identification of herbal quality markers.PMID:39800487 | DOI:10.1002/pca.3502

The associations between prenatal plastic phthalate exposure and lipid acylcarnitine levels in humans and mice

Sun, 12/01/2025 - 12:00
Reprod Toxicol. 2025 Jan 10:108835. doi: 10.1016/j.reprotox.2025.108835. Online ahead of print.ABSTRACTPhthalates are ubiquitous environmental pollutants known for their endocrine-disrupting properties, particularly during critical periods such as pregnancy and early childhood. Phthalates alter lipid metabolism, but the role of prenatal exposure on the offspring lipidome is less understood. In particular, we focused on long chain acylcarnitines - intermediates of fatty acid oxidation that serve as potential biomarkers of mitochondrial function and energy metabolism. This study aimed (i) to investigate the association between prenatal phthalate exposure and the child's blood acylcarnitine concentrations and, (ii) to evaluate the impact of prenatal administration of di-(2-ethylhexyl) phthalate (DEHP) on acylcarnitine levels in mouse offspring blood, brain and liver. We conducted analyses of both a prospective birth cohort study and an experimental study in mice. From the Barwon Infant Study cohort (1074 mother-child pairs), prenatal phthalate exposure was assessed at 36 weeks' gestation and its association with acylcarnitine levels was examined in cord blood, and child's blood at 6 months, 12 months and 4 years. In mice, pregnant C57BL/6J mouse dams were exposed to 20μg/kg DEHP for 5 days mid-gestation, and offspring tissues were analyzed at 1 month of age postnatally for acylcarnitine profiles. Our findings demonstrate that prenatal phthalate levels (specifically butyl benzyl phthalate (BBzP) and diisobutyl phthalate (DiBP)) are inversely associated with total long chain acylcarnitine levels in human cord blood at birth. In contrast, BBzP was positively associated with the long chain acylcarnitines at 12 months of age. In mice, prenatal DEHP exposure for only 5 days led to decreased palmitoylcarnitine (AC16:0) levels in the brain and liver, but not in blood. Taken together, our findings highlight that prenatal phthalate exposure can alter acylcarnitine profiles, indicating disruptions in fatty acid metabolism that may have long-term effects on metabolic health.PMID:39800279 | DOI:10.1016/j.reprotox.2025.108835

Right ventricular remodeling in complex congenital heart disease

Sun, 12/01/2025 - 12:00
Can J Cardiol. 2025 Jan 10:S0828-282X(25)00012-1. doi: 10.1016/j.cjca.2025.01.005. Online ahead of print.ABSTRACTIn congenital heart diseases (CHD) of moderate to great complexity involving the right ventricle (RV), the morphologic RV can be exposed to significant stressors across the lifespan either in a biventricular circulation in a sub-pulmonary or sub-aortic position, or as part of a univentricular circulation. These include pressure and/or volume overload, hypoxia, ischemia, and periprocedural surgical stress leading to remodeling, maladaptation, dilation hypertrophy and dysfunction. This review examines the macroscopic remodeling of the RV in various forms of CHD and explores remodeling trajectories, along with the effects of surgeries and residual lesion repair, in tetralogy of Fallot, Ebstein anomaly, congenitally corrected transposition of the great arteries, transposition of the great arteries with atrial switch surgery, and single ventricle palliated by Fontan. Additionally, the role of metabolism, genetic markers and imaging criteria of RV remodeling are explored. Finally, the optimal timing for addressing residual lesions in CHD through surgery or percutaneous interventions is discussed, along with advanced heart failure management strategies and medical therapy aimed at preventing further RV dilation and/or systolic deterioration or promoting reverse remodeling.PMID:39800187 | DOI:10.1016/j.cjca.2025.01.005

Metabolic pathway and genetically causal links of 1,400 circulating metabolites on the risk of intracranial aneurysms and aneurysmal subarachnoid hemorrhage

Sun, 12/01/2025 - 12:00
Neuroscience. 2025 Jan 10:S0306-4522(25)00019-3. doi: 10.1016/j.neuroscience.2025.01.017. Online ahead of print.ABSTRACTBACKGROUND: The rupture of intracranial aneurysms (IAs) leads to aneurysmal subarachnoid hemorrhage (aSAH), which is associated with significant disability and mortality rates. This study aims to identify metabolic markers causally linked to the occurrence of IAs and aSAH through Mendelian randomization (MR), thereby offering novel predictive and therapeutic targets.METHODS: We conducted a genome-wide association study (GWAS) on IAs and aSAH, analyzing 1,400 metabolomic indices from the Canadian Longitudinal Study on Aging (CLSA) cohort (n = 8,299). Subsequently, we employed two-sample Mendelian randomization to ascertain potential causal relationships between each metabolite and the conditions IAs and aSAH by various MR methodologies, including MR Egger, Weighted median, Inverse variance weighted (IVW), MR-PRESSO, Simple mode, and Weighted mode. The heterogeneity of instrumental variables was assessed using Cochran's Q statistics, and metabolic pathway analyses were performed via the Metaconflict 5.0 platform.RESULTS: Our analysis found that 87 metabolites/metabolic ratios were associated with IAs, and 85 metabolites/metabolic ratios were associated with aSAH. After false discovery rate (FDR) correction and sensitivity analyses, nine metabolites/metabolic ratios were significantly causally associated with aSAH. Conversely, while 87 metabolites and their ratios initially showed potential causal links with IA, none demonstrated significant causal associations post-FDR correction. The study also pinpointed eight significant metabolic pathways implicated in both IAs and aSAH.CONCLUSION: This study found that nine circulating metabolites and their ratios with significant causal associations to aSAH, while no metabolites and their ratios were causally linked to IAs. These results suggest possible mechanisms and predictive molecular targets for IAs and aSAH.PMID:39800046 | DOI:10.1016/j.neuroscience.2025.01.017

Comprehensive multi-omics, behavioral and morphological analysis of the hazards of nano-plastics in mice with internal carotid artery occlusion

Sun, 12/01/2025 - 12:00
Ecotoxicol Environ Saf. 2025 Jan 11;289:117711. doi: 10.1016/j.ecoenv.2025.117711. Online ahead of print.ABSTRACTAccumulation of nanoplastics (NPs) poses a severe threat to the homeostasis of the internal environment in patients with chronic diseases. The effects of NP contamination on health in chronically ill populations must urgently be elucidated. In this study, NPs injected via the tail vein were distributed in the brain and internal organs in a mouse model of chronic internal carotid occlusion. Mice with chronic internal carotid artery occlusion exposed to NPs showed behavioral abnormalities, such as depression and anxiety, thus indicating detrimental effects of NPs on the brain. Subsequently, we used proteomics and metabolomics to analyze the specific mechanisms underlying the damaging effects of NP deposition in the brain. The findings helped explain the differences in the underlying biochemical responses at the microscopic level in mice after NP exposure. The NPs not only accumulated in the brain and caused pathologic damage, but also contributed to accelerating atherosclerosis in the mouse model of internal carotid artery occlusion. This work confirms the risk of NPs in a model of internal carotid artery occlusion and elucidates the mechanism underlying this harm; moreover, it provides theoretical support for developing strategies to decrease microplastic intake in patients with internal carotid artery occlusion.PMID:39799923 | DOI:10.1016/j.ecoenv.2025.117711

Thiacloprid exposure disrupts the gut-liver axis and induces liver dysfunction in the Reeves' turtles (Mauremys reevesii)

Sun, 12/01/2025 - 12:00
Ecotoxicol Environ Saf. 2025 Jan 11;289:117710. doi: 10.1016/j.ecoenv.2025.117710. Online ahead of print.ABSTRACTAs one of the neonicotinoid insecticides, thiacloprid (THI) is extensively used in agriculture and frequently detected in various aquatic environments, posing a potential threat to aquatic organisms. However, the effects of THI exposure on aquatic turtles remain unknown. In this study, we focused on investigating whether THI has a toxic effect on the gut-liver axis in aquatic turtles. The Reeves' turtles (Mauremys reevesii) were exposed to 0.0178 μM, 6 μM, and 60 μM THI for 5 consecutive weeks. The results revealed that THI altered the composition of intestinal flora, with a decrease in the relative abundance of Romboutsia, and an increase in Clostridium_sensu_stricto_1, Cetobacterium, Enterococcus. This disruption of the intestinal barrier led to an increase in lipopolysaccharide (LPS), THI, and other harmful substances entering the liver. Metabolomic and transcriptomic analyses indicated that metabolic dysregulation and differences in gene expression were concentrated in amino acid metabolism and lipid metabolism, ultimately resulting in severe liver damage and steatosis. Furthermore, elevated levels of liver function indicators, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bile acid (TBA), and triglyceride (TG), were positively correlated with increased THI concentrations. Our findings demonstrate that THI impairs the intestinal barrier and causes liver dysfunction and damage in turtles, providing new insights into evaluating the toxic effects of thiacloprid on aquatic organisms.PMID:39799922 | DOI:10.1016/j.ecoenv.2025.117710

Interspecific differences in the response of autotrophic microorganisms to atrazine and S-metolachlor exposure

Sun, 12/01/2025 - 12:00
Ecotoxicol Environ Saf. 2025 Jan 11;289:117616. doi: 10.1016/j.ecoenv.2024.117616. Online ahead of print.ABSTRACTAtrazine and S-metolachlor are herbicides widely used on corn and soybean crops where they are sometimes found in concentrations of concern in nearby aquatic ecosystems, potentially affecting autotrophic organisms. The aim of this study was to investigate the response of the green algae Enallax costatus, the diatom Gomphonema parvulum and a culture of the cyanobacteria Phormidium sp. and Microcystis aeruginosa, to atrazine and S-metolachlor alone and in mixture (0, 10, 100 and 1000 µg.L-1, for 7 days). For each culture, chlorophyll fluorescence and effective quantum yield of photosynthesis were determined and compared with lipid and methyl-ester fatty acid profiles. In general, the green algae was most strongly affected by atrazine and S-metolachlor. In particular, atrazine led to a total inhibition of photosynthesis and a sharp decrease in triacylglycerols (TAGs), while S-metolachlor caused a partial decrease in photosynthesis in the green algae and a sharp increase in reserve lipids in the diatom when the herbicide was in mixture. The effect of the mixture of compounds depended on the descriptor considered. Indeed, atrazine seemed to explain the toxicity of the mixture for photosynthetic parameters, while certain lipid classes showed intermediate responses between compounds. The results suggest mechanisms of shade adaptation, algal population increase and lipid remodeling in response to compound exposure. The results reveal differences in sensitivity between species after 7 days exposure to the two compounds alone and in mixture. These results support the value of using the study of lipid and fatty acid profiles as complementary information to traditional descriptors for the assessment of pesticide exposure on photoautotrophic organisms.PMID:39799914 | DOI:10.1016/j.ecoenv.2024.117616

Exploring the metabolic patterns and response mechanisms of bile acids during fasting: A study with poultry as an example

Sun, 12/01/2025 - 12:00
Poult Sci. 2024 Dec 31;104(2):104746. doi: 10.1016/j.psj.2024.104746. Online ahead of print.ABSTRACTFasting is beneficial to alleviate fatty liver, lose weight and improve reproductive function. However, previous studies have shown that, during fasting, disorders of bile acid metabolism were strongly associated with intestinal inflammation. The physiological and biochemical parameters and gene expression of multiple tissues of chickens at every critical time node were measured by ELISA and qPCR. In addition, association analysis was performed based on liver transcriptome sequencing and cecum metabolome data. At the cellular level, the regulatory effects of cecal metabolites on host bile acid metabolism were verified. During fasting, hepatic FXR-SHP-CYP7A1 and ileum-hepatic FXR-SHP-FGF15/19-FGFR4-CYP7A1 negative feedback pathways were activated to inhibit hepatic bile acid synthesis. The ileum FXR-SHP-ASBT pathways are activated, hindered the ileal bile reflux. At the same time, it promotes the secretion of bile acids and cholesterol in the liver, accelerates the utilization of H2O and CO2, to maintain liver homeostasis during fasting. In addition, enhanced gallbladder contraction and increased hunger were observed in laying hens during fasting. At the cellular level, the correlation between CYP7A1 and L-valine was verified, revealing that cecal metabolites of laying hens was enabled to regulate host bile acid metabolism. This study explored the metabolic patterns of bile acids during fasting and identified the main reasons for the accumulation of bile acids in the cecum, which provides a basis for fasting research and offers a reference for the formulation of fasting protocols.PMID:39799857 | DOI:10.1016/j.psj.2024.104746

Integrating genetics, metabolites, and clinical characteristics in predicting cardiometabolic health outcomes using machine learning algorithms - A systematic review

Sun, 12/01/2025 - 12:00
Comput Biol Med. 2025 Jan 11;186:109661. doi: 10.1016/j.compbiomed.2025.109661. Online ahead of print.ABSTRACTBACKGROUND: Machine learning (ML) integration of clinical, metabolite, and genetic data reveals variable results in predicting cardiometabolic health (CMH) outcomes. Therefore, we aim to (1) evaluate whether a multi-modal approach incorporating all three data types using ML algorithms can improve CMH outcome prediction compared to single-modal or paired-modal models, and (2) compare the methodologies used in existing prediction models.METHODS: We systematically searched five databases from 1998 to 2024 for ML predictive modelling studies using the multi-modal approach for CMH outcomes. Risk-of-bias assessment tools were used to assess methodological quality. Study characteristics, ML algorithms, data preprocessing, evaluation methods and metrics, feature selections, and feature importance parameters were synthesized narratively to show methodological heterogeneity.RESULTS: Of the four included studies (3 ML algorithms), three were at low risk of bias, and one was at high risk. The multi-modal approach consistently improved T2D and BP prediction compared to single-modal or paired-modal models. Genetics showed the lowest predictive performance in three studies. Logistic regression (n = 2 studies) and random forest (n = 1) were used in T2D studies, while XGBoost was used in one BP study. One study with missing data and variations in feature selection across all studies hindered a comprehensive comparison of feature importance.CONCLUSIONS: Our review emphasizes the potential improvement in T2D and BP prediction using ML algorithms with the multi-modal approach. However, further studies using diverse ML algorithms with optimized methodologies on single-modal, paired-modal, and multi-modal models are needed to gain insights into biomarker selection for predicting CMH outcomes.PMID:39799831 | DOI:10.1016/j.compbiomed.2025.109661

Pages