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

PubMed

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

Direct and transgenerational effects of simvastatin on the metabolism of the amphipod Gammarus locusta

Sun, 12/01/2025 - 12:00
Aquat Toxicol. 2024 Dec 26;279:107221. doi: 10.1016/j.aquatox.2024.107221. Online ahead of print.ABSTRACTIn this study, untargeted Nuclear Magnetic Resonance (NMR) metabolomics was applied for the first time, to our knowledge, to assess the metabolic impact of direct and transgenerational exposure (F0 and F3 generations, respectively) of amphipods Gammarus locusta to simvastatin (SIM), a pharmaceutical widely prescribed for the treatment of hypercholesterolemia. Results revealed the important gender-dependent nature of each of these effects. Directly exposed males showed enhanced glucose catabolism and tricarboxylic acid (TCA) cycle activity, in tandem with adaptations in osmotic regulation and glyoxylate metabolism. Exposed females exhibited only a small osmoregulatory effect. It is suggested that the response of exposed males may reflect reported high levels of methyl farnesoate hormone (low levels in females) and alterations in apical factors, namely decreased growth. Conversely, transgenerational effects were identified only in females, with impact on energy metabolism (glycolysis and TCA cycle enhancement) and osmoregulatory response. This expresses the ability of female gametes to transmit the effects of direct SIM exposure. Such effects were putatively related to reported delayed maturation and transcriptomic deviations impacting on carbohydrate and lipid metabolisms, possibly specifically engaging phenylalanine/tyrosine and choline in dopamine and choline metabolisms. These findings reflect the importance of untargeted metabolomics in addressing not only direct exposure of contaminants, but also their transgenerational effects, potentially contributing towards improving hazard and risk assessment of biologically active compounds.PMID:39799757 | DOI:10.1016/j.aquatox.2024.107221

Evaluation of a machine learning-based metabolic marker for coronary artery disease in the UK Biobank

Sun, 12/01/2025 - 12:00
Atherosclerosis. 2024 Dec 18;401:119103. doi: 10.1016/j.atherosclerosis.2024.119103. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: An in silico quantitative score of coronary artery disease (ISCAD), built using machine learning and clinical data from electronic health records, has been shown to result in gradations of risk of subclinical atherosclerosis, coronary artery disease (CAD) sequelae, and mortality. Large-scale metabolite biomarker profiling provides increased portability and objectivity in machine learning for disease prediction and gradation. However, these models have not been fully leveraged. We evaluated a quantitative score of CAD derived from probabilities of a machine learning model trained on metabolomic data.METHODS: We developed a CAD-predictive learning model using metabolic data from 93,642 individuals from the UK Biobank (median [IQR] age, 57 [14] years; 39,796 [42 %] male; 5640 [6 %] with diagnosed CAD), and assessed its probabilities as a quantitative metabolic risk score for CAD (M-CAD; range 0 [lowest probability] to 1 [highest probability]) in participants of the UK Biobank. The relationship of M-CAD with arterial stiffness index, ejection fraction, CAD sequelae, and mortality was assessed.RESULTS: The model predicted CAD with an area under the receiver-operating-characteristic curve of 0.712. Arterial Stiffness Index increased by 0.19 and ejection fraction decreased by 0.2 % per 0.1 increase in M-CAD. Both incident and recurrent myocardial infarction increased stepwise over M-CAD quartiles (odds ratio (OR) 15.3 [4.2 %] and 12.5 [0.2 %]) in top quartiles as compared to the first quartile of incident and recurrent MI respectively). Likewise, the hazard ratio and prevalence of all-cause mortality, CVD-associated mortality, and CAD-associated mortality increased stepwise over M-CAD deciles (2.98 [14 %], 9.34 [4.3 %], 26.7 [2.7 %] in the top deciles as compared to the first decile of all-cause, CVD, and CAD mortality respectively).CONCLUSIONS: Metabolic-based machine learning can be used to build a quantitative risk score for CAD that is associated with atherosclerotic burden, CAD sequelae and mortality.PMID:39799755 | DOI:10.1016/j.atherosclerosis.2024.119103

Untargeted LC-HRMS analyses reveal metabolomic specificities between wine yeast strains selected for their malic acid production

Sun, 12/01/2025 - 12:00
Food Chem. 2024 Dec 27;471:142686. doi: 10.1016/j.foodchem.2024.142686. Online ahead of print.ABSTRACTThe alcoholic fermentation of wine is mostly achieved by the species Saccharomyces cerevisiae that display a large variability for their ability to consume or produce malic acid. To better characterize the metabolism of such group of strains we explored their non-volatile metabolome using an untargeted LC-HRMS approach. The chemical classes and the putative structures of several hundred compounds where annotated using MS2 spectra using the SIRIUS software. By using both supervised and univariate statistical analyses, several metabolic features able to discriminate the two group of strains in several wines were listed. Quantitative enrichment analyses pointed out drastic differences in pantothenic acid metabolism between the two group of strains. In addition, the produced showed important change in their nitrogen composition that might be due to the pH difference in the resulting wines. Altogether this work paves the avenue for better characterizing the biochemical impact of yeast strains that modulate wine acidity.PMID:39799692 | DOI:10.1016/j.foodchem.2024.142686

Ultra-high performance liquid chromatography ion mobility-high-resolution mass spectrometry for the assessment of raw milk traceability

Sun, 12/01/2025 - 12:00
Food Chem. 2025 Jan 9;471:142796. doi: 10.1016/j.foodchem.2025.142796. Online ahead of print.ABSTRACTThe complexity of modern food supply chains limits the effectiveness of targeted approaches to address food traceability issues. Untargeted metabolomics provides a comprehensive profile of small molecules present within biological samples. In this study, the potential of ultra-high performance liquid chromatography-ion mobility-high resolution mass spectrometry (UHPLC-IMS-HRMS) to discriminate bovine milk samples collected at individual level was evaluated for traceability purposes. For the first time, IMS coupled with UHPLC-HRMS was applied to milk analysis, increasing confidence in metabolite annotation. Supervised Partial Least Squares-Discriminant Analysis coupled to backward elimination variable selection allowed the selection of 52 and 153 features able to discriminate samples belonging to different dairy supply chains and trace samples at herd level, respectively. Amino acids, glycerolipids, and glycerophospholipids were the most represented classes, influencing the biological/technological properties of the final product. The perfect classification of samples belonging to external test sets demonstrated the reliability of the proposed approach.PMID:39799686 | DOI:10.1016/j.foodchem.2025.142796

Ionomic and metabolomic analyses reveal association between nutritional value and aleurone layer thickness in rice

Sun, 12/01/2025 - 12:00
Food Chem. 2025 Jan 9;471:142829. doi: 10.1016/j.foodchem.2025.142829. Online ahead of print.ABSTRACTThe fortification of aleurone cells represents a promising avenue for enhancing the nutritional quality of cereal. This study investigated dorsal aleurone thickness (DAT) in a rice diversity panel comprising 180 varieties, revealing that DAT of the Geng subspecies is typically greater than that of the Xian subspecies. The minerals and primary metabolites accumulated in the brown grains of ten rice varieties exhibiting distinct DAT were subjected to analysis using spectrometry-based technologies. A positive correlation was identified between essential mineral zinc and DAT, whereas toxic mineral cadmium exhibited a negative correlation. Moreover, our findings revealed that the Xian varieties with high DAT exhibited greater lipid accumulation in the brown seeds than those with thin DAT, while the Geng varieties with high DAT predominantly influenced amino acid accumulation. The findings suggest that the natural variations in aleurone thickness may be exploited for the development of rice varieties that are enriched in nutrients.PMID:39799679 | DOI:10.1016/j.foodchem.2025.142829

Disclosure of the nature of glycosylated varietal precursors of eugenol from the hybrid, tolerant grapevine variety Baco blanc: Methodology and quantification

Sun, 12/01/2025 - 12:00
Food Chem. 2024 Dec 24;471:142632. doi: 10.1016/j.foodchem.2024.142632. Online ahead of print.ABSTRACTA varietal origin of eugenol was previously demonstrated in Baco blanc, a major grapevine variety used to produce Armagnac wine spirits. Eugenol was found in high amount, both as the free and as unidentified glycosylated forms. To reveal their identity, a specific method was developed and applied to berry skin extracts. This EPIQ (Extraction-Purification-Identification-Quantification) procedure comprised HS-SPME GC-MS-guided LC fractionation, combined with specific enzymatic hydrolyses as well as LC-MS/MS and LC-HRMS analyses. Comparison with commercial standards allowed for the identification of geoside (eugenyl-6-O-α-L-arabinopyranosyl-b-D-glucopyranoside) as a major eugenol precursor. This is the first study to find geoside in grapevine. Three minor eugenol precursors were also putatively determined, including the monoglucoside, citrusin C. Two other diglycosides of eugenol were also hypothesised. LC-MS/MS quantifications confirmed presence of a larger amount of geoside in Baco blanc than in Vitis vinifera grapes. Geoside reach a maximum concentration in berry skins of Baco blanc at veraison.PMID:39799678 | DOI:10.1016/j.foodchem.2024.142632

Protocol for transcriptomic and epigenomic analyses of tip-like endothelial cells using scRNA-seq and ChIP-seq

Sun, 12/01/2025 - 12:00
STAR Protoc. 2025 Jan 10;6(1):103326. doi: 10.1016/j.xpro.2024.103326. Online ahead of print.ABSTRACTAngiogenesis begins as endothelial cells migrate, forming a sprouting tip and subsequent growth-rich stalk cells. Here, we present a protocol for transcriptomic and epigenomic analyses of tip-like cells in cultured endothelial cells. We describe steps for stimulating human umbilical vein endothelial cells (HUVECs) with vascular endothelial cell growth factor (VEGF) to generate tip-like cells. We then detail procedures for library preparation for single-cell RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq), and data analysis. This scalable protocol is also applicable to diverse omics studies, including proteomics and metabolomics. For complete details on the use and execution of this protocol, please refer to Miyamura et al.1.PMID:39799578 | DOI:10.1016/j.xpro.2024.103326

Metabolomic Analysis of Patients With Patent Foramen Ovale and Migraine Using Liquid Chromatography-Mass Spectrometry Technology

Sun, 12/01/2025 - 12:00
Rapid Commun Mass Spectrom. 2025 Mar 30;39(6):e9972. doi: 10.1002/rcm.9972.ABSTRACTOBJECTIVE: This study aims to examine the changes in metabolic profiles in patients with patent foramen ovale (PFO) and migraine, as well as in patients with isolated migraine, before and after surgical intervention using metabolomics.METHODS: Patients were categorized into four groups: the simple migraine (SM) group, the PFO with migraine preoperative group (PRE), the PFO with migraine postoperative Day 3 group (POST_3d), and the PFO with migraine postoperative Day 30 group (POST_30d). Untargeted metabolomics using liquid chromatography-mass spectrometry (LC-MS) were employed to identify differential metabolites across these groups. Differential metabolites were identified, their clinical diagnostic value was assessed, and a correlation analysis was conducted to examine changes in metabolic pathways before and after surgery.RESULTS: The expression levels of metabolites such as linoleic acid, quinolinic acid, homophenylalanine, and amphetamine showed significant changes in patients with PFO and migraine following surgery. Notably, linoleic acid demonstrated strong diagnostic potential for this patient population. Trend analysis revealed that the levels of 3-phenylpropionic acid and caffeine decreased on postoperative Day 3 and subsequently increased by postoperative Day 30, whereas gallic acid continuously declined. Compared to the PRE group, differential metabolites in the SM group were primarily associated with α-linolenic acid metabolism, niacin and nicotinamide metabolism, sphingolipid signaling, and tyrosine metabolism. In contrast, differential metabolites in the POST_3d group were predominantly enriched in phenylalanine metabolism, niacin and nicotinamide metabolism, protein digestion and absorption, and caffeine metabolism.CONCLUSION: Linoleic acid may serve as a potential biomarker, and the activation of inflammation and oxidative stress-related pathways could contribute significantly to the development of complicated migraine in patients with PFO.PMID:39799415 | DOI:10.1002/rcm.9972

Cadmium translocation combined with metabolomics analysis revealed potential mechanisms of MT@MSN-CS and GSH@MSN-CS in reducing cadmium accumulation in rice (Oryza sativa L.) grains

Sat, 11/01/2025 - 12:00
Environ Sci Pollut Res Int. 2025 Jan 11. doi: 10.1007/s11356-025-35888-5. Online ahead of print.ABSTRACTApplying nano-delivery systems for phytohormones via foliar application has proven effective in reducing grain cadmium (Cd) levels in crops. However, the mechanisms underlying this reduction remain inadequately understood. This study integrated the determination of leaf photosynthetic parameters, Cd translocation analysis, and metabolomics to elucidate the effects of reduced glutathione (GSH) and melatonin (MT), delivered with or without chitosan-encapsulated mesoporous silica nanoparticles (MSN-CS), on grain Cd levels in rice. Our findings revealed that the foliar application of MT@MSN-CS significantly outperformed MT alone in reducing grain Cd levels and enhancing leaf photosynthesis under Cd stress. Conversely, GSH@MSN-CS showed comparable effects to GSH alone. Foliar-applied GSH@MSN-CS and MT@MSN-CS both decreased the Cd transport coefficients from panicle nodes to brown rice by 26.2-53.3%, with MT@MSN-CS demonstrating superior efficiency in reducing Cd concentrations across roots, stems, leaves, panicle nodes, and grains. Metabolomic analysis revealed substantial shifts in rice metabolite profiles following GSH@MSN-CS and MT@MSN-CS treatments. Foliar application of MT@MSN-CS or GSH@MSN-CS may rapidly and effectively activate the primary antioxidant defense system and alleviate membrane lipid peroxidation in rice grown on low-to-moderately Cd-contaminated soils by upregulating amino acid metabolism. The secondary defense mechanism, phenylpropanoid biosynthesis, was reprogrammed to reduce energy expenditure and decrease Cd translocation.PMID:39799254 | DOI:10.1007/s11356-025-35888-5

Circulating serum metabolites as biomarkers and predictors of residual feed intake in lactating dairy cows

Sat, 11/01/2025 - 12:00
Sci Rep. 2025 Jan 11;15(1):1709. doi: 10.1038/s41598-025-85610-1.ABSTRACTThis study explored the potential of circulatory serum metabolite profiles to increase understanding of the physiology of feed efficiency and identify biomarkers to predict residual feed intake (RFI) in lactating Holsteins. Serum metabolite profiles were compared in high (n = 20) and low RFI (n = 20) cows at early, mid, and late lactation stages. The low RFI cows had decreased (P < 0.05) concentrations of dodecanoylcarnitine, dodecenoylcarnitine, dodecanedioylcarnitine, tetradecanoylcarnitine, succinic acid, trimethylamine N-oxide, betaine, and increased concentrations of p-Hydroxyhippuric acid, hydroxysphingomyeline C16:1, phosphatidylcholine diacyl C40:6, and glutarylcarnitine at early lactation. A similar comparison at mid lactation stage showed altered serum concentrations of 26 metabolites that fall into the categories of acyl carnitines, glycerophospholipids, biogenic amines, amino acids, and organic acids. At late lactation, fewer sets of metabolites were significantly affected by RFI grouping. Receiver operator curve analyses identified p-Hydroxyhippuric acid as the top biomarker at early lactation and acetylornithine at mid and late lactation. Models based on sets of serum metabolites in early, mid, and late lactation stages predicted RFI with a validation coefficient of determination of 0.54, 0.68, and 0.64, respectively. This study demonstrated the potential of circulatory serum metabolites as biomarkers and predictors of RFI in lactating dairy cows.PMID:39799245 | DOI:10.1038/s41598-025-85610-1

Patterns of variations in lipid molecular profile during larval development of red king crab, Paralithodes camtschaticus, and Japanese mitten crab, Eriocheir Japonica

Sat, 11/01/2025 - 12:00
Sci Rep. 2025 Jan 11;15(1):1737. doi: 10.1038/s41598-025-85901-7.ABSTRACTThe red king crab, Paralithodes camtschaticus, and the Japanese mitten crab, Eriocheir japonica, are the major commercially valuable species. In addition to their high nutritional value, these crabs are used as objects of ecological research. To extend our knowledge of crustacean biochemistry and provide a more comprehensive model of lipidomic patterns during embryonic and larval development of these crab species, we studied the dynamics of molecular species profiles of reserve lipids such as triacylglycerols (TG) and membrane lipids such as glycerophospholipids (PL). A complete disappearance of TG was observed in zoea IV larvae of E. japonica and zoea III larvae of P. camtschaticus. The appearance of TG at older stages of larval development was accompanied by considerable changes in TG composition. The dynamics of PL with major polyunsaturated fatty acids (PUFA) (20:5n-3, 22:6n-3, and 20:4n-3) during the larval development was species-specific. The obtained results indicate different demands for PUFA in P. camtschaticus and E. japonica, which can be taken into account when selecting optimum diets. The lipidomic approach allows identifying new patterns of lipid changes during crab embryonic development, which may be useful for improvement of aquaculture techniques.PMID:39799183 | DOI:10.1038/s41598-025-85901-7

Limosilactobacillus reuteri fermented brown rice alleviates anxiety improves cognition and modulates gut microbiota in stressed mice

Sat, 11/01/2025 - 12:00
NPJ Sci Food. 2025 Jan 11;9(1):5. doi: 10.1038/s41538-025-00369-z.ABSTRACTChronic stress disrupts gut microbiota homeostasis, contributing to anxiety and depression. This study explored the effects of Limosilactobacillus reuteri fermented brown rice (FBR) on anxiety using an ICR mouse chronic mild stress (CMS) model. Anxiety was assessed through body weight, corticosterone levels, neurotransmitter profiles, and behavioral tests. A four-week FBR regimen reduced corticosterone, restored neurotransmitters like gamma-aminobutyric acid (GABA) and serotonin, and improved anxiety-related behaviors. Metagenomic (16S rRNA) and metabolomic analyses revealed enhanced amino acid metabolism, energy metabolism, and short-chain fatty acid (SCFA) production in FBR-treated mice. FBR-enriched beneficial gut bacteria, aligning the microbiota profile with that of non-stressed mice. FBR also modulated GABA receptor-related gene expression, promoting relaxation. Network pharmacology identified quercetin, GABA, glutamic acid, phenylalanine, and ferulic acid as bioactive compounds with neuroprotective potential. These findings highlight FBR's potential as a gut-brain axis-targeted therapeutic for anxiety and stress-related disorders.PMID:39799113 | DOI:10.1038/s41538-025-00369-z

Screening of Leuconostoc mesenteroides strains suitable for kimoto-style brewing of sake with high antioxidant capacity

Sat, 11/01/2025 - 12:00
J Biosci Bioeng. 2025 Jan 10:S1389-1723(24)00338-4. doi: 10.1016/j.jbiosc.2024.12.005. Online ahead of print.ABSTRACTSake brewed using the kimoto-style exhibits high antioxidant capacity and is expected to inhibit the deterioration of sake quality due to oxidation. However, the antioxidant capacity of the added lactic acid bacteria has not been explored. We aimed to screen the lactic acid bacterium, Leuconostoc mesenteroides, with excellent brewing and antioxidant capacity, to develop sake with high antioxidant capacity. Three Le. mesenteroides strains (19-2, 19-5, and 19-23) were selected from eight screened strains based on their alcohol intolerance, growth performance in koji extract, aroma compound, and low biogenic amine production. Among these, Le. mesenteroides 19-23 exhibited a significantly higher hydrophilic-oxygen radical absorbance capacity (H-ORAC) in the culture medium than the control strain, Le. mesenteroides NBRC102481. In a medium-scale sake brewing test, sake prepared with Le. mesenteroides 19-23 had a significantly higher H-ORAC value than that prepared using the sokujo-style (without Le. mesenteroides). Additionally, metabolome analysis using capillary electrophoresis time-of-flight mass spectrometry identified ferulic acid, p-coumaric acid, 3-hydroxyanthranilic acid (3-HAA), and 6,8-thioctic acid in the main mash. High-performance liquid chromatography-based quantification revealed that antioxidants in the unrefined filtrates of the main mash prepared using the kimoto-style tended to be more abundant than in those prepared using the sokujo-style. Specifically, 3-HAA and ferulic acid were more concentrated in some unrefined filtrates of the kimoto-style than sokujo-style. In conclusion, the screened Le. mesenteroides strain demonstrated potential for brewing sake with high antioxidant capacity using the kimoto-style, offering a promising method for antioxidant-rich sake production.PMID:39799009 | DOI:10.1016/j.jbiosc.2024.12.005

Mitochondrial HMG-CoA synthase deficiency

Sat, 11/01/2025 - 12:00
Mol Genet Metab. 2025 Jan;144(1):109007. doi: 10.1016/j.ymgme.2024.109007. Epub 2024 Dec 26.ABSTRACTMitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) deficiency is a rare, potentially life-threatening autosomal recessive disorder resulting from mutations in the HMGCS2 gene, leading to impaired ketogenesis. We systematically reviewed the clinical presentations, biochemical and genetic abnormalities in 93 reported cases and 2 new patients diagnosed based on biochemical findings. Reported onset ages ranged from 3 months to 6 years, mostly before the age of 3. Children younger than one year old are more prone to a severe clinical course. In most patients, the initial metabolic decompensation occurs after an episode of gastroenteritis or gastroenteritis-like symptoms. Other commonly observed symptoms during the first clinical episode included poor intake, altered consciousness, dyspnea, seizures and hepatomegaly. Severity was correlated with the number of truncating mutations. Most patients presented with acute metabolic decompensation with hypoglycemia, dicarboxyluria and inadequate ketonuria. Dicarboxylic acid levels were elevated in 54/56 cases. The organic acid 4-hydroxy-6-methyl-2-pyrone (4HMP) was detected in 33/35 urine samples taken during the acute episodes, but typically only retrospectively. The plasma C2/C0 acylcarnitine ratio was abnormal in 16/18 (88.9 %) of acute plasma samples, but only in 2/6 (33 %) of DBS samples. Other metabolites that have been reported are hydroxyhexenoic acid, 3,5-dihydroxyhexanoic (1,5 lactone), glutaric acidand 3-OH-isovaleric acid. Laboratories should look for 4HMP in urinary organic acid analysis and an increased plasma C2/C0 acylcarnitine ratio to facilitate the diagnosis of HMGCS2 deficiency, especially in cases of metabolic decompensation with dicarboxyluria without adequate ketonuria.PMID:39798988 | DOI:10.1016/j.ymgme.2024.109007

Sequential Versus Continuous Feeding and Its Effect on the Gut Microbiota in Critically Ill Patients: A Randomized Controlled Trial

Sat, 11/01/2025 - 12:00
Clin Nutr ESPEN. 2025 Jan 9:S2405-4577(25)00019-1. doi: 10.1016/j.clnesp.2025.01.019. Online ahead of print.ABSTRACTBACKGROUND: Gut microbiota disturbance may worsen critical illnesses and is responsible for the progression of multiple organ dysfunction syndrome. In our previous study, there was a trend towards a higher α-diversity of the gut microbiota in sequential feeding (SF) than in continuous feeding (CF) for critically ill patients. We designed this non-blinded, randomized controlled study to confirm these results.METHODS: All the enrolled patients received continuous feeding in the beginning. After achieving ≥80% of the nutrition target calories (25-30 kcal/kg/d), the patients were randomized into the SF group or the CF group. In the SF group, continuous feeding was changed into intermittent feeding. The total daily dosage of enteral nutrition was equally distributed during three periods at 7-9:00, 11-13:00 and 17-19:00. After 7 days of randomization, fresh stool and serum were collected for 16S rRNA gene sequencing and untargeted metabolomics analysis respectively. Meanwhile, routine blood test indicators and metabolic indicators were recorded.RESULTS: Finally, data from 65 patients in the SF group and 69 patients in the CF group were used for intention-to-treat analysis. There was no difference in the Shannon index between the SF group and CF group [2.5 (1.7-3.4) vs. 2.6 (1.5-3.5), P =0.934]. However, at the genus level, the abundances of Erysipelotrichaceae_UCG-003 and Howardella increased in the SF group. Some metabolic indicators (the albumin level, total cholesterol level and total bile acid level) and the increases in lymphocyte counts in the SF group were different from those in the CF group (P <0.05). In untargeted metabolomic analysis, 58 differentially abundant metabolites between the two groups were found. The pathway with the highest enrichment factors was primary bile acid biosynthesis according to the Kyoto Encyclopedia of Genes and Genomes Database classification. Regarding adverse events, the gut tolerance, average glucose and incidence of hyperglycemia and hypoglycemia were similar between the SF group and CF group. The mortality rate in the SF group was lower than that in the CF group, but there was no statistical difference (9.2% vs. 13.0%, P=0.484).CONCLUSION: SF did not increase the diversity of gut microbiota in critically ill patients. However, it did alter the abundances of some gut microbes and affect some metabolites. Its clinical significance requires further exploration. In addition, the gut tolerance and safety of SF were similar to that of CF.TRIAL REGISTRATION: www.CLINICALTRIALS: gov, registration number NCT04443335. Registered 21 June, 2020.PMID:39798866 | DOI:10.1016/j.clnesp.2025.01.019

Multi-omics analyses of early-onset familial Alzheimer's disease and Sanfilippo syndrome zebrafish models reveal commonalities in disease mechanisms

Sat, 11/01/2025 - 12:00
Biochim Biophys Acta Mol Basis Dis. 2025 Jan 9:167651. doi: 10.1016/j.bbadis.2024.167651. Online ahead of print.ABSTRACTSanfilippo syndrome (mucopolysaccharidosis type III, MPSIII) causes childhood dementia, while Alzheimer's disease is the most common type of adult-onset dementia. There is no cure for either of these diseases, and therapeutic options are extremely limited. Increasing evidence suggests commonalities in the pathogenesis of these diseases. However, a direct molecular-level comparison of these diseases has never been performed. Here, we exploited the power of zebrafish reproduction (large families of siblings from single mating events raised together in consistent environments) to conduct sensitive, internally controlled, comparative transcriptome and proteome analyses of zebrafish models of early-onset familial Alzheimer's disease (EOfAD, psen1Q96_K97del/+) and MPSIIIB (nagluA603fs/A603fs) within single families. We examined larval zebrafish (7 days post fertilisation), representing early disease stages. We also examined the brains of 6-month-old zebrafish, which are approximately equivalent to young adults in humans. We identified substantially more differentially expressed genes and pathways in MPS III zebrafish than in EOfAD-like zebrafish. This is consistent with MPS III being a rapidly progressing and earlier onset form of dementia. Similar changes in expression were detected between the two disease models in gene sets representing extracellular matrix receptor interactions in larvae, and the ribosome and lysosome pathways in 6-month-old adult brains. Cell type-specific changes were detected in MPSIIIB brains at 6 months of age, likely reflecting significant disturbances of oligodendrocyte, neural stem cell, and inflammatory cell functions and/or numbers. Our 'omics analyses have illuminated similar disease pathways between EOfAD and MPS III indicating where efforts to find mutually effective therapeutic strategies can be targeted.PMID:39798820 | DOI:10.1016/j.bbadis.2024.167651

Effects of colloids with different compositions on benzophenone-3 biotoxicity in zebrafish embryos

Sat, 11/01/2025 - 12:00
Environ Pollut. 2025 Jan 9:125670. doi: 10.1016/j.envpol.2025.125670. Online ahead of print.ABSTRACTThe fate of the pollutants in aquatic environment is closely related to colloids, and the carrier effect of colloids on pollutants not only affects their bioaccumulation, but may also affect their toxicity. In this study, the effects of natural colloid with different components on the biological toxicity of benzophenone-3 (BP3) to zebrafish larvae (Diano rerio) were studied. BP3 caused oxidative stress damage, thyroid system disorders and neurotoxicity in zebrafish larvae. And in the co-exposure groups, the organic and black carbon mineral (BCM) colloids enhanced the organism's antioxidant system by regulating the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx), reducing the lipid peroxidation damage in larvae. BCM colloids caused the thyroid system disorders in organisms, while organic colloids exacerbated the thyroid toxicity by transporting more BP3 into organisms, inducing severe abnormal heartbeats. The BCM and organic colloids regulated the acetylcholinesterase (AChE) activity and/or 5-hydroxytryptamine (5-ht) contents by affecting the neuroactive ligand receptor interaction pathway in zebrafish larvae, significantly increasing their swimming speed in co-exposure groups under the light condition. In addition, the effects of colloid-bound and freely dissolved BP3 absorbed by organisms on their physiological and biochemical activities were different. By analyzing the relative expression of the significant differential metabolites affected by BP3 in all experimental groups, it was found that colloid-bound and freely dissolved BP3 had a synergistic effect on most of these metabolites and pathways. However, the freely dissolved BP3 interfered with the purine metabolic pathway by mediating 2-(amidino)-n1-(5-phospho-d-ribosyl)acetamidine, and the tyrosine metabolic pathway by mediating choline and uranylacetic acid, while the colloid-bound BP3 has no or inverse regulatory effects on these three metabolites. This study provided a new perspective for the biotoxicity study of the pollutants in aquatic environment, necessitating a reconsideration of the real ecological risks of emerging pollutants in the presence of natural colloids.PMID:39798796 | DOI:10.1016/j.envpol.2025.125670

Omics approaches: Role in acute myeloid leukemia biomarker discovery and therapy

Sat, 11/01/2025 - 12:00
Cancer Genet. 2025 Jan 3;292-293:14-26. doi: 10.1016/j.cancergen.2024.12.006. Online ahead of print.ABSTRACTAcute myeloid leukemia (AML) is the most common acute leukemia in adults and has the highest fatality rate. Patients aged 65 and above exhibit the poorest prognosis, with a mere 30 % survival rate within one year. One important issue in optimizing outcomes for AML patients is their limited ability to predict responses to specific therapies, response duration, and likelihood of relapse. Despite rigorous therapeutic interventions, a significant proportion of patients experience relapse. Consequently, there is a pressing need to introduce new targets for therapy. Sequencing and biotechnology have come a long way in the last ten years. This has made it easier for many omics technologies, like genomics, transcriptomics, proteomics, and metabolomics, to study molecular mechanisms of AML. An integrative approach is necessary to understand a complex biological process fully and offers an important opportunity to understand the information underlying diseases. In this review, we studied papers published between 2010 and 2024 employing omics approaches encompassing diagnosis, prognosis, and risk stratification of AML. Finally, we discuss prospects and challenges in applying -omics technologies to the discovery of novel biomarkers and therapy targets. Our review may be helpful for omics researchers who want to study AML from different molecular aspects.PMID:39798496 | DOI:10.1016/j.cancergen.2024.12.006

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