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

Elevated levels of branched chain fatty acids in low-salt fish sauce by co-fermentation: flavor improvement and metabolism analysis

Wed, 21/08/2024 - 12:00
J Sci Food Agric. 2024 Aug 21. doi: 10.1002/jsfa.13829. Online ahead of print.ABSTRACTBACKGROUND: Traditional fish sauce products rely on relatively long fermentation time and high salt concentration, resulting in inconsistent quality and health risks. Branched-chain fatty acids (BCFAs) are associated with nutritional benefits and health-care effects, mainly derived from food fermentation. This study aimed to screen BCFAs-producing bacteria with high protease and aminotransferase activity as starter cultures for fish sauce fermentation.RESULTS: The low-salt fish sauce products were obtained by co-fermentation with three chosen strains. Trichloroacetic acid (TCA)-soluble peptides and amino acid nitrogen concentrations were higher in the co-fermentation group (FH group). The organoleptic evaluation showed co-fermentation optimized flavor composition and endured with rich taste. The levels of BCFAs and branched-chain amino acids (BCAAs) significantly increased by co-fermentation. Volatile metabolomics analysis indicated that BCFAs, branched-chain esters, and pyrazines were the key flavor compounds in the co-fermented group.CONCLUSION: The co-fermentation system with selected strains to ferment low-salt fish sauce has the potential to increase BCFA content and improve flavor and nutrition. © 2024 Society of Chemical Industry.PMID:39166735 | DOI:10.1002/jsfa.13829

Machine learning-causal inference based on multi-omics data reveals the association of altered gut bacteria and bile acid metabolism with neonatal jaundice

Wed, 21/08/2024 - 12:00
Gut Microbes. 2024 Jan-Dec;16(1):2388805. doi: 10.1080/19490976.2024.2388805. Epub 2024 Aug 21.ABSTRACTEarly identification of neonatal jaundice (NJ) appears to be essential to avoid bilirubin encephalopathy and neurological sequelae. The interaction between gut microbiota and metabolites plays an important role in early life. It is unclear whether the composition of the gut microbiota and metabolites can be used as an early indicator of NJ or to aid clinical decision-making. This study involved a total of 196 neonates and conducted two rounds of "discovery-validation" research on the gut microbiome-metabolome. It utilized methods of machine learning, causal inference, and clinical prediction model evaluation to assess the significance of gut microbiota and metabolites in classifying neonatal jaundice (NJ), as well as the potential causal relationships between corresponding clinical variables and NJ. In the discovery stage, NJ-associated gut microbiota, network modules, and metabolite composition were identified by gut microbiome-metabolome association analysis. The NJ-associated gut microbiota was closely related to bile acid metabolites. By Lasso machine learning assessment, we found that the gut bacteria were associated with abnormal bile acid metabolism. The machine learning-causal inference approach revealed that gut bacteria affected serum total bilirubin and NJ by influencing bile acid metabolism. NJ-associated gut bile acids are potential biomarkers of NJ, and clinical prediction models constructed based on these biomarkers have some clinical effects and the model may be used for disease risk prediction. In the validation stage, it was found that intestinal metabolites can predict NJ, and the machine learning-causal inference approach revealed that bile acid metabolites affected NJ itself by affecting the total bilirubin content. Intestinal bile acid metabolites are potential biomarkers of NJ. By applying machine learning-causal inference methods to gut microbiome-metabolome association studies, we found NJ-associated intestinal bacteria and their network modules and bile acid metabolite composition. The important role of intestinal bacteria and bile acid metabolites in NJ was determined, which can predict the risk of NJ.PMID:39166704 | DOI:10.1080/19490976.2024.2388805

Metabolic profiling of psoriasis vulgaris and palmoplantar pustulosis

Wed, 21/08/2024 - 12:00
Exp Dermatol. 2024 Aug;33(8):e15159. doi: 10.1111/exd.15159.ABSTRACTPsoriasis is a chronic inflammatory skin disorder with various subtypes, including psoriasis vulgaris (PV) and palmoplantar pustulosis (PPP). Metabolomics studies have provided insights into psoriasis pathogenesis. However, research on metabolomic alterations in PV and PPP patients is limited. We aimed to explore and compare the metabolic profiles of patients with PV and PPP to those of healthy volunteers (HVs). A single-centre retrospective cohort was constructed, comprising Korean patients with psoriasis and HVs matched by age and sex. Clinical information including demographics, disease severity, and comorbidities were collected. Plasma samples were subjected to targeted metabolic analysis using an Absolute IDQ®p180 kit, which quantified 188 metabolites, including amino acids and carnitines. Statistical significance was assessed using an independent t-test and chi-square test, with p-values adjusted by the Benjamini-Hochberg procedure. Pathway analyses were employed to gain a comprehensive understanding of the metabolite profile. This study included 93 patients (73 PV and 20 PPP) and an equal number of HVs. PV patients showed increased levels of sarcosine, serotonin, propionylcarnitine, proline, aspartic acid, tyrosine, taurine, spermine and ornithine, but exhibited a decreased level of acetylcarnitine than matched HVs. Notably, sarcosine levels were significantly elevated in PPP patients. Furthermore, the sarcosine/glycine ratio was significantly higher in both PV and PPP patients than in HVs. Pathway analysis showed significant increases in metabolites involved in amino acid metabolism and the urea cycle in PV patients. In conclusion, this study demonstrated distinct metabolic profiles in PV and PPP patients compared to HVs, suggesting sarcosine as a potential biomarker for psoriasis.PMID:39166459 | DOI:10.1111/exd.15159

Salivary metabolomics in early detection of oral squamous cell carcinoma - a meta- analysis

Wed, 21/08/2024 - 12:00
Expert Rev Proteomics. 2024 Aug 21. doi: 10.1080/14789450.2024.2395398. Online ahead of print.ABSTRACTINTRODUCTION: Oral squamous cell carcinoma (OSCC) represents the most prevalent form of oral cancer. Potentially malignant disorders of oral mucosa exhibit an elevated propensity for malignant progression. A substantial proportion of cases are discerned during advanced stages, significantly impacting overall survival. This investigation aims to ascertain salivary metabolites with potential utility in the early detection of OSCC.METHODS: A search encompassing PubMed, EMBASE, Scopus, Ovid, Science Direct, and Web of Science databases was conducted to identify eligible articles. The search strategy employed precise terms. The quality assessment of the included studies was executed using the QUADAS 2 ROB tool. This was registered with PROSPERO CRD42021278217.RESULTS: Upon removing duplicate articles and publications that didn't satisfy the inclusion criteria, seven articles were included in the current study. The Random Effects Maximum Likelihood (REML) model adopted for quantitative synthesis identified N-acetyl glucosamine as the sole metabolite in two studies included in this meta-analysis. The pathways significantly influenced by these identified metabolites were delineated.CONCLUSION: This study highlights N-acetyl glucosamine as a distinctive metabolite with the potential to serve as an early diagnostic marker for OSCC. Nevertheless, further research is warranted to validate its clinical utility.PMID:39166387 | DOI:10.1080/14789450.2024.2395398

Urine Metabolites Changes in Acute Myocardial Infarction Rats via Metabolomic Analysis

Wed, 21/08/2024 - 12:00
Fa Yi Xue Za Zhi. 2024 Jun 25;40(3):227-236. doi: 10.12116/j.issn.1004-5619.2023.431108.ABSTRACTOBJECTIVES: To screen biomarkers for forensic identification of acute myocardial infarction (AMI) by non-targeted metabolomic studies on changes of urine metabolites in rats with AMI.METHODS: The rat models of the sham surgery group, AMI group and hyperlipidemia + acute myocardial infarction (HAMI) group were established. Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was used to analyze the changes of urine metabolic spectrometry in AMI rats. Principal component analysis, partial least squares-discriminant analysis, and orthogonal partial least squares-discriminant analysis were used to screen differential metabolites. The MetaboAnalyst database was used to analyze the metabolic pathway enrichment and access the predictive ability of differential metabolites.RESULTS: A total of 40 and 61 differential metabolites associated with AMI and HAMI were screened, respectively. Among them, 22 metabolites were common in both rat models. These small metabolites were mainly concentrated in the niacin and nicotinamide metabolic pathways. Within the 95% confidence interval, the area under the curve (AUC) values of receiver operator characteristic curve for N8-acetylspermidine, 3-methylhistamine, and thymine were greater than 0.95.CONCLUSIONS: N8-acetylspermidine, 3-methylhistamine, and thymine can be used as potential biomarkers for AMI diagnosis, and abnormal metabolism in niacin and nicotinamide may be the main causes of AMI. This study can provide reference for the mechanism and causes of AMI identification.PMID:39166303 | DOI:10.12116/j.issn.1004-5619.2023.431108

Gut metabolomic profiles in paediatric ulcerative colitis patients prior to and after receiving faecal microbiota transplants

Wed, 21/08/2024 - 12:00
Gut Microbiome (Camb). 2023;4:e19. doi: 10.1017/gmb.2023.15. Epub 2023 Oct 6.ABSTRACTUlcerative colitis (UC) is an immune-mediated inflammation of the colonic mucosa. Gut microbiota dysbiosis may play a significant role in disease pathogenesis by causing shifts in metabolomic profiles within the gut. To identify differences and trends in the metabolomic profile of paediatric UC patients pre- and post-faecal microbiota transplants (FMT). Forty-six paediatric patients with mild-to-moderate UC and 30 healthy paediatric patients were enrolled in this study. Baseline stool samples were collected prior to FMT initiation and at months 1, 3, 6, and 12 post-FMT. Pediatric Ulcerative Colitis Activity Index (PUCAI) scores were calculated at baseline and months 1, 3, 6, and 12 after FMT. The average Bray-Curtis dissimilarities to healthy subjects decreased after FMT. In principal coordinate analysis plots, UC patients' centroids drew nearer to healthy individuals. The variance explained by phenotype (Healthy versus UC) reduced and remained significant. From 1 to 3 months after FMT, PUCAI trends were statistically significant and decreasing. PUCAI scores remain flat starting 6 months after FMT. This study concludes that paediatric UC patients have a significantly different baseline metabolite profile than healthy controls. Although being time limited, FMT significantly altered these metabolite profiles and shifted them towards that of healthy controls.PMID:39165756 | PMC:PMC11334712 | DOI:10.1017/gmb.2023.15

Protein Phosphatase 1 Regulatory Subunit 3 Beta rs4240624 Genotype Is Associated With Gallstones and With Significant Changes in Bile Lipidome

Wed, 21/08/2024 - 12:00
Gastro Hep Adv. 2024 Mar 12;3(5):594-601. doi: 10.1016/j.gastha.2024.03.005. eCollection 2024.ABSTRACTBACKGROUND AND AIMS: Gallstone disease (GSD) associates with significant morbidity and mortality. Decreased secretion of bile acids has been suggested as a driving factor for GSD. Recently, we linked the protein phosphatase 1 regulatory subunit 3 beta (PPP1R3B) rs4240624 genotype to decreased bile acid levels in bile. In this study, we investigated whether these individuals had an increased risk for GSD as well as the differences in the lipid composition of the gallbladder bile of these individuals compared to controls and patients with GSD.METHODS: Bile acids, cholesterol, and phospholipid levels in gallbladder bile samples were enzymatically measured in 46 patients (34 female, age 45.7 ± 9.8 years, BMI 41.3 ± 4.4 kg/m2) who underwent elective laparoscopic Roux-en-Y gastric bypass. The lipidome of gallbladder bile was analyzed using high-performance liquid chromatography-mass spectrometry. Gallstone status was evaluated using abdominal ultrasonography before the surgery.RESULTS: The G allele of PPP1R3B rs4240624 was significantly associated with GSD in patients with obesity. We validated this association in the UK Biobank. Bile lipidomics demonstrated that 13 of the 17 minor lipid classes measured were higher in individuals with the G allele. The concentrations of bile acids, cholesterol, and phospholipids, as well as the cholesterol saturation index, were lower in patients with GSD than in those without gallstones. GSD had an effect similar to that of PPP1R3B genotype on minor lipids.CONCLUSION: The PPP1R3B rs4240624 genotype is associated with gallstones and with changes in gallbladder bile similar to those observed in patients with gallstones, suggesting that the PPP1R3B genotype contributes to the risk of gallstones by altering the bile lipidome.PMID:39165418 | PMC:PMC11330930 | DOI:10.1016/j.gastha.2024.03.005

HerbMet: Enhancing metabolomics data analysis for accurate identification of Chinese herbal medicines using deep learning

Wed, 21/08/2024 - 12:00
Phytochem Anal. 2024 Aug 21. doi: 10.1002/pca.3437. Online ahead of print.ABSTRACTINTRODUCTION: Chinese herbal medicines have been utilized for thousands of years to prevent and treat diseases. Accurate identification is crucial since their medicinal effects vary between species and varieties. Metabolomics is a promising approach to distinguish herbs. However, current metabolomics data analysis and modeling in Chinese herbal medicines are limited by small sample sizes, high dimensionality, and overfitting.OBJECTIVES: This study aims to use metabolomics data to develop HerbMet, a high-performance artificial intelligence system for accurately identifying Chinese herbal medicines, particularly those from different species of the same genus.METHODS: We propose HerbMet, an AI-based system for accurately identifying Chinese herbal medicines. HerbMet employs a 1D-ResNet architecture to extract discriminative features from input samples and uses a multilayer perceptron for classification. Additionally, we design the double dropout regularization module to alleviate overfitting and improve model's performance.RESULTS: Compared to 10 commonly used machine learning and deep learning methods, HerbMet achieves superior accuracy and robustness, with an accuracy of 0.9571 and an F1-score of 0.9542 for distinguishing seven similar Panax ginseng species. After feature selection by 25 different feature ranking techniques in combination with prior knowledge, we obtained 100% accuracy and an F1-score for discriminating P. ginseng species. Furthermore, HerbMet exhibits acceptable inference speed and computational costs compared to existing approaches on both CPU and GPU.CONCLUSIONS: HerbMet surpasses existing solutions for identifying Chinese herbal medicines species. It is simple to use in real-world scenarios, eliminating the need for feature ranking and selection in classical machine learning-based methods.PMID:39165116 | DOI:10.1002/pca.3437

Central Nervous System Disturbances by Thiamethoxam in Japanese Quail (Coturnix japonica): In Vivo, ex Vivo, and in Silico Study

Tue, 20/08/2024 - 12:00
Environ Pollut. 2024 Aug 18:124768. doi: 10.1016/j.envpol.2024.124768. Online ahead of print.ABSTRACTThe neurotoxic effects of neonicotinoids (NEOs) have been widely reported in relation to the poisoning of wild birds, yet the underlying molecular mechanism has remained elusive. This study employed Japanese quails (Coturnix japonica) and primary quail embryonic neurons as in vivo and ex vivo models, respectively, to investigate the neurotoxic effects and mechanism of thiamethoxam (TMX), a representative neonicotinoid insecticide, at environmentally relevant concentrations. Following a 28-day exposure to TMX, metabolomic analysis of quail brain revealed TMX-induced changes in glutamatergic, GABA-ergic, and dopaminergic function. Subsequent ex vivo and in silico experimentation revealed that the activation of nicotinic acetylcholine receptors and calcium signaling, induced by clothianidin (CLO), the primary metabolite of TMX, served as upstream events for the alterations in neurotransmitter synthesis, metabolism, release, and uptake. Our findings propose that the disruption of the central nervous system, caused by environmentally significant concentrations of NEOs, may account for the avian poisoning events induced by NEOs.PMID:39163946 | DOI:10.1016/j.envpol.2024.124768

Biological effects of Bougainvillea glabra, Delonix regia, Lantana camara, and Platycladus orientalis extracts and their possible metabolomics therapeutics against the West Nile virus vector, Culex pipiens (Diptera: Culicidae)

Tue, 20/08/2024 - 12:00
Microb Pathog. 2024 Aug 18:106870. doi: 10.1016/j.micpath.2024.106870. Online ahead of print.ABSTRACTPlants are a treasure trove of biological materials containing a wide range of potential phytochemicals that are target-specific, rapidly biodegradable, and environmentally friendly, with multiple medicinal effects. Unfortunately, the development of resistance to synthetic pesticides and antibiotics led to the discovery of new antibiotics, antioxidants, and biopesticides. This has also led to the creation of new medications that work very well. The current study aimed to prove that ornamental plants contain specialized active substances that are used in several biological processes. Mosquitoes, one of the deadliest animals on the planet, cause millions of fatalities each year by transmitting several human illnesses. Phytochemicals are possible biological agents for controlling pests that are harmful. The potential of leaf extracts of Bougainvillea glabra, Delonix regia, Lantana camara, and Platycladus orientalis against Culex pipiens and microbial agents was evaluated. Acetone extracts had more toxic effects against Cx. pipiens larvae (99.0-100%, 72 h post-treatment), and the LC50 values were 142.8, 189.5, 95.4, and 71.1 ppm for B. glabra, D. regia, L. camara, and P. orientalis, respectively. Plant extracts tested in this study showed high insecticidal, antimicrobial, and antioxidant potential. GC-MS and HPLC analyses showed a higher number of terpenes, flavonoids, and phenolic compounds. The ADME analysis of element, caryophyllene oxide, caryophyllene, and copaene showed that they were similar to drugs and that they were better absorbed by the body and able to pass through the blood-brain barrier. Our results confirm the ability of ornamental plants to have promising larvicidal and antimicrobial activity and biotechnology.PMID:39163920 | DOI:10.1016/j.micpath.2024.106870

Socioeconomic adversity, maternal nutrition, and the prenatal programming of offspring cognition and language at two years of age through maternal inflammation

Tue, 20/08/2024 - 12:00
Brain Behav Immun. 2024 Aug 18:S0889-1591(24)00556-7. doi: 10.1016/j.bbi.2024.08.033. Online ahead of print.ABSTRACTIncreasing rates of child neurodevelopmental vulnerability are a significant public health challenge. The adverse effect of socioeconomic adversity on offspring cognition may be mediated through elevated prenatal maternal systemic inflammation, but the role of modifiable antecedents such as maternal nutrition has not yet been clarified. This study aimed to examine (1) whether prenatal factors, with an emphasis on maternal nutrition, were associated with prenatal maternal systemic inflammation at 28 weeks' gestation, including the metabolomic marker glycoprotein acetyls (GlycA); (2) the extent to which the association between prenatal maternal nutrition and child cognition and language at age two years was mediated by elevated maternal inflammation in pregnancy; (3) the extent to which the associations between prenatal socioeconomic adversity and child neurodevelopment were mediated through prenatal maternal nutrition and GlycA levels. We used a prospective population-derived pre-birth longitudinal cohort study, the Barwon Infant Study (Barwon region of Victoria, Australia), where 1074 mother-child pairs were recruited by 28 weeks' gestation using an unselected sampling frame. Exposures included prenatal factors such as maternal diet measured by a validated food frequency questionnaire at 28 weeks' gestation and dietary patterns determined by principal component analysis. The main outcome measures were maternal inflammatory biomarkers (GlycA and hsCRP levels) at 28 weeks' gestation, and offspring Bayley-III cognition and language scores at age two years. Results showed that the 'modern wholefoods' and 'processed' maternal dietary patterns were independently associated with reduced and elevated maternal inflammation respectively (GlycA or hsCRP p < 0.001), and also with higher and reduced offspring Bayley-III scores respectively (cognition p ≤ 0.004, language p ≤ 0.009). Associations between dietary patterns and offspring cognition and language were partially mediated by higher maternal GlycA (indirect effect: cognition p ≤ 0.036, language p ≤ 0.05), but were less evident for hsCRP. The maternal dietary patterns mediated 22 % of the association between socioeconomic adversity (lower maternal education and/or lower household income vs otherwise) and poorer offspring cognition (indirect effect p = 0.001). Variation in prenatal GlycA levels that were independent of these dietary measures appeared less important. In conclusion, modifiable prenatal maternal dietary patterns were associated with adverse child neurocognitive outcomes through their effect on maternal inflammation (GlycA). Maternal diet may partially explain the association between socioeconomic adversity and child neurocognitive vulnerability. Maternal diet-by-inflammation pathways are an attractive target for future intervention studies.PMID:39163911 | DOI:10.1016/j.bbi.2024.08.033

Metabolomics and serum pharmacochemistry combined with network pharmacology uncover the potential effective ingredients and mechanisms of Yin-Chen-Si-Ni Decoction treating ANIT-induced cholestatic liver injury

Tue, 20/08/2024 - 12:00
J Ethnopharmacol. 2024 Aug 18:118713. doi: 10.1016/j.jep.2024.118713. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Yin-Chen-Si-Ni Decoction is a classical traditional Chinese medicine (TCM) prescription that is used clinically for treating cholestatic liver injury (CLI) and other hepatic diseases. However, the material basis and underlying mechanisms of YCSND are not clear.AIM OF THE STUDY: To investigate effective components and mechanisms of YCSND in the treatment of CLI using serum pharmacochemistry, metabolomics, and network pharmacology.MATERIALS AND METHODS: Biochemical indicators, liver index, and histopathology analysis were adopted to evaluate the protective effect of YCSND on ANIT-induced CLI rats. Then, a UPLC-Q-Exactive Orbitrap MS/MS analysis of the migrant components in serum and liver including prototype and metabolic components was performed in YCSND. In addition, a study of the endogenous metabolites using serum and liver metabolomics was performed to discover potential biomarkers, metabolic pathways, and associated mechanisms. Further, the network pharmacology oriented by in vivo migrant components was also used to pinpoint the active ingredients, core targets, and signaling pathways of YCSND. Finally, molecular docking and molecular dynamics simulation (MDS) were used to predict the binding ability between components and core targets, and a real-time qPCR (RT-qPCR) experiment was used to measure the mRNA expression of the core target genes.RESULTS: Pharmacodynamic studies suggest that YCSND could exert obvious hepatoprotective effects on CLI rats. Furthermore, 68 compounds, comprising 32 prototype components and 36 metabolic components from YCSND, were found by serum pharmacochemistry analysis. Network pharmacology combining molecular docking and MDS showed that apigenin, naringenin, 18β-glycyrrhetinic acid, and isoformononetin have better binding ability to 6 core targets (EGFR, AKT1, IL6, MMP9, CASP3, PPARG). Additionally, PI3K, TNF-α, MAPK3, and six core target genes in liver tissues were validated with RT-qPCR. Metabolomics revealed the anti-CLI effects of YCSND by regulating four metabolic pathways of primary bile acid and biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis, taurine and hypotaurine metabolism, and arachidonic acid metabolism. Integrating metabolomics and network pharmacology identified four pathways related to CLI, including the PI3K-Akt, HIF-1, MAPK, and TNF signaling pathway, which revealed multiple mechanisms of YCSND against CLI that might involve anti-inflammatory and apoptosis.CONCLUSION: The research based on serum pharmacochemistry, network pharmacology, and metabolomics demonstrates the beneficial hepatoprotective effects of YCSND on CLI rats by regulating multiple components, multiple targets, and multiple pathways, and provides a potent means of illuminating the material basis and mechanisms of TCM prescriptions.PMID:39163894 | DOI:10.1016/j.jep.2024.118713

Human AKR1C3 binds agonists of GPR84 and participates in an expanded polyamine pathway

Tue, 20/08/2024 - 12:00
Cell Chem Biol. 2024 Aug 9:S2451-9456(24)00313-1. doi: 10.1016/j.chembiol.2024.07.011. Online ahead of print.ABSTRACTAltered human aldo-keto reductase family 1 member C3 (AKR1C3) expression has been associated with poor prognosis in diverse cancers, ferroptosis resistance, and metabolic diseases. Despite its clinical significance, the endogenous biochemical roles of AKR1C3 remain incompletely defined. Using untargeted metabolomics, we identified a major transformation mediated by AKR1C3, in which a spermine oxidation product "sperminal" is reduced to "sperminol." Sperminal causes DNA damage and activates the DNA double-strand break response, whereas sperminol induces autophagy in vitro. AKR1C3 also pulls down acyl-pyrones and pyrone-211 inhibits AKR1C3 activity. Through G protein-coupled receptor ligand screening, we determined that pyrone-211 is also a potent agonist of the semi-orphan receptor GPR84. Strikingly, mammalian fatty acid synthase produces acyl-pyrones in vitro, and this production is modulated by NADPH. Taken together, our studies support a regulatory role of AKR1C3 in an expanded polyamine pathway and a model linking fatty acid synthesis and NADPH levels to GPR84 signaling.PMID:39163853 | DOI:10.1016/j.chembiol.2024.07.011

Untargeted metabolomics and mendelian randomization analysis identify alpha-linolenic acid and linoleic acid as novel biomarkers of perioperative neurocognitive dysfunction

Tue, 20/08/2024 - 12:00
Clin Nutr. 2024 Aug 12;43(9):2198-2210. doi: 10.1016/j.clnu.2024.07.039. Online ahead of print.ABSTRACTPerioperative neurocognitive dysfunction (PND) occurs in elderly individuals undergoing anesthesia and surgery. To explore the potential molecular mechanisms, we performed right-sided cervical exploratory surgery under sevoflurane anesthesia in 18-month-old male Sprague-Dawley rats. Anxiety-depression-like behaviors and learning memory abilities were assessed using the Open Field Test (OFT) and Novel Object Recognition (NOR). Additionally, the hippocampus was collected one day after surgery for inflammatory factor detection, TUNEL staining, and metabolomics analysis. Mendelian randomization (MR) analyses were subsequently conducted to validate the causal relationships by using a series of GWAS datasets related to representative differential metabolites as exposures and cognitive impairment as endpoints. The results indicated that rats exposed to anesthesia and surgery exhibited poorer cognitive performance, significant elevations in hippocampal inflammatory factors such as IL-1β and TNF-α, and extensive neuronal apoptosis. LC-MS/MS-based untargeted metabolomics identified 19 up-regulated and 32 down-regulated metabolites in the test group, with 6 differential metabolites involved in metabolic pathways enriched according to the KEGG database. ROC analysis revealed a correlation between α-linolenic acid (ALA) and linoleic acid (LA) and the development of PND. Further MR analysis confirmed that ALA was significantly associated with cognitive performance and the risk of depression, while LA was significantly associated with the risk of memory loss. Taken together, our results identified ALA and LA as potentially powerful biomarkers for PND.PMID:39163761 | DOI:10.1016/j.clnu.2024.07.039

Ultrasound-assisted improvement of thawing quality of Tibetan pork by inhibiting oxidation

Tue, 20/08/2024 - 12:00
Ultrason Sonochem. 2024 Aug 17;110:107029. doi: 10.1016/j.ultsonch.2024.107029. Online ahead of print.ABSTRACTThe challenge of meat quality degradation due to transportation difficulties in high-altitude plateaus underscores the importance of an efficient thawing process for Tibetan pork to ensure its quality. This study compared four thawing methods ultrasound thawing (UT), refrigerator thawing (RT), hydrostatic thawing (HT), and microwave thawing (MT) to assess their impact on the quality of Tibetan pork, focusing on thawing loss, tenderness, color variation, and alterations in protein secondary structure and moisture content. Additionally, the study examined the impact of thawing on the metabolites of Tibetan pork using metabolomics techniques. The results indicated that UT yielded the highest quality samples. UT significantly accelerated the thawing rate and had minimal impact on tenderness compared to traditional thawing methods. Moreover, protein and lipid oxidation levels were reduced by UT treatment. Furthermore, it enhanced the binding capacity of protein and water molecules, reduced drip loss, and maintained meat color stability. What's more, amino acid metabolites such as l-glutamic acid, l-proline, oxidized glutathione, and 1-methylhistidine played a significant role in thawing oxidation in Tibetan pork, exhibiting a positive correlation with protein oxidation. UT resulted in a notable decrease in the levels of hypoxanthine and 2-aminomethylpyrimidine, contributing to the reduction of bitterness in the thawed meat and consequently enhancing the freshness of Tibetan pork. This study offers novel insights into understanding the biological changes occurring during the thawing process, while also furnishing a theoretical framework and technical assistance to improve the quality of Tibetan pork and propel advancements in food processing technology.PMID:39163693 | DOI:10.1016/j.ultsonch.2024.107029

Exposure-associated DNA methylation among people exposed to multiple industrial pollutants

Tue, 20/08/2024 - 12:00
Clin Epigenetics. 2024 Aug 20;16(1):111. doi: 10.1186/s13148-024-01705-y.ABSTRACTBACKGROUND: Current research on the epigenetic repercussions of exposure to a combination of pollutants is limited. This study aims to discern DNA methylation probes associated with exposure to multiple pollutants, serving as early effect markers, and single-nucleotide polymorphisms (SNPs) as surrogate indicators for population susceptibility. The investigation involved the analysis of urine exposure biomarkers for 11 heavy metals (vanadium, arsenic, mercury, cadmium, chromium, nickel, lead, manganese, copper, strontium, thallium), polycyclic aromatic hydrocarbon (PAHs) (1-hydroxypyrene), genome-wide DNA methylation sequencing, and SNPs array on all study participants. The data were integrated with metabolomics information and analyzed both at a community level based on proximity to home addresses relative to the complex and at an individual level based on exposure biomarker concentrations.RESULTS: On a community level, 67 exposure-related CpG probes were identified, while 70 CpG probes were associated with urine arsenic concentration, 2 with mercury, and 46 with vanadium on an individual level. These probes were annotated to genes implicated in cancers and chronic kidney disease. Weighted quantile sum regression analysis revealed that vanadium, mercury, and 1-hydroxypyrene contributed the most to cg08238319 hypomethylation. cg08238319 is annotated to the aryl hydrocarbon receptor repressor (AHRR) gene, and AHRR hypomethylation was correlated with an elevated risk of lung cancer. AHRR was further linked to deregulations in phenylalanine metabolism, alanine, aspartate, and glutamate metabolism, along with heightened oxidative stress. Additionally, three SNPs (rs11085020, rs199442, and rs10947050) corresponding to exposure-related CpG probes exhibited significant interaction effects with multiple heavy metals and PAHs exposure, and have been implicated in cancer progression and respiratory diseases.CONCLUSION: Our findings underscore the pivotal role of AHRR methylation in gene-environment interactions and highlight SNPs that could potentially serve as indicators of population susceptibility in regions exposed to multiple heavy metals and PAHs.PMID:39164771 | DOI:10.1186/s13148-024-01705-y

Metabolomics analysis of patients with Schistosoma japonicum infection based on UPLC-MS method

Tue, 20/08/2024 - 12:00
Parasit Vectors. 2024 Aug 20;17(1):350. doi: 10.1186/s13071-024-06429-9.ABSTRACTBACKGROUND: Schistosomiasis is still one of the most serious parasitic diseases. Evidence showed that the metabolite profile in serum can potentially act as a marker for parasitic disease diagnosis and evaluate disease progression and prognosis. However, the serum metabolome in patients with Schistosoma japonicum infection is not well defined. In this study, we investigated the metabolite profiles of patients with chronic and with advanced S. japonicum infection.METHODS: The sera of 33 chronic S. japonicum patients, 15 patients with advanced schistosomiasis and 17 healthy volunteers were collected. Samples were extracted for metabolites and analyzed with ultra-performance liquid chromatography-mass spectrometry (UPLC-MS).RESULTS: We observed significant differences in metabolite profiles in positive and negative ion modes between patients with advanced and chronic S. japonicum infection. In patients with chronic S. japonicum infection, 199 metabolites were significantly upregulated while 207 metabolites were downregulated in advanced infection. These differential metabolites were mainly concentrated in steroid hormone biosynthesis, cholesterol metabolism and bile secretion pathways. We also found that certain bile acid levels were significantly upregulated in the progression from chronic to advanced S. japonicum infection. In receiver operator characteristic (ROC) analysis, we identified three metabolites with area under the curve (AUC) > 0.8, including glycocholic (GCA), glycochenodeoxycholate (GCDCA) and taurochenodeoxycholic acid (TCDCA) concentrated in cholesterol metabolism, biliary secretion and primary bile acid biosynthesis.CONCLUSIONS: This study provides evidence that GCA, GCDCA and TCDCA can potentially act as novel metabolite biomarkers to distinguish patients in different stages of S. japonicum infection. This study will contribute to the understanding of the metabolite mechanisms of the transition from chronic to advanced S. japonicum infection, although more studies are needed to validate this potential role and explore the underlying mechanisms.PMID:39164750 | DOI:10.1186/s13071-024-06429-9

Biomarkers for congenital ventricular outflow tract malformations based on maternal serum lipid metabolomics analysis

Tue, 20/08/2024 - 12:00
BMC Pregnancy Childbirth. 2024 Aug 20;24(1):547. doi: 10.1186/s12884-024-06738-y.ABSTRACTBACKGROUND: The congenital ventricular outflow tract malformations (CVOTMs) is a major congenital heart diseases (CHDs) subtype, and its pathogenesis is complex and unclear. Lipid metabolic plays a crucial role in embryonic cardiovascular development. However, due to the limited types of detectable metabolites in previous studies, findings on lipid metabolic and CHDs are still inconsistent, and the possible mechanism of CHDs remains unclear.METHODS: The nest case-control study obtained subjects from the multicenter China Teratology Birth Cohort (CTBC), and maternal serum from the pregnant women enrolled during the first trimester was utilized. The subjects were divided into a discovery set and a validation set. The metabolomics of CVOTMs and normal fetuses were analyzed by targeted lipid metabolomics. Differential comparison, random forest and lasso regression were used to screen metabolic biomarkers.RESULTS: The lipid metabolites were distributed differentially between the cases and controls. Setting the selection criteria of P value < 0.05, and fold change (FC) > 1.2 or < 0.833, we screened 70 differential metabolites. Within the prediction model by random forest and lasso regression, DG (14:0_18:0), DG (20:0_18:0), Cer (d18:2/20:0), Cer (d18:1/20:0) and LPC (0:0/18:1) showed good prediction effects in discovery and validation sets. Differential metabolites were mainly concentrated in glycerolipid and glycerophospholipids metabolism, insulin resistance and lipid & atherosclerosis pathways, which may be related to the occurrence and development of CVOTMs.CONCLUSION: Findings in this study provide a new metabolite data source for the research on CHDs. The differential metabolites and involved metabolic pathways may suggest new ideas for further mechanistic exploration of CHDs, and the selected biomarkers may provide some new clues for detection of COVTMs.PMID:39164614 | DOI:10.1186/s12884-024-06738-y

Amino acid profiles associated with plant-rich protein diets may contribute to lower blood pressure

Tue, 20/08/2024 - 12:00
Hypertens Res. 2024 Aug 9. doi: 10.1038/s41440-024-01849-7. Online ahead of print.NO ABSTRACTPMID:39164419 | DOI:10.1038/s41440-024-01849-7

Chlorophyll deficiency in Agave angustifolia Haw.: unveiling the impact on secondary metabolite production

Tue, 20/08/2024 - 12:00
Planta. 2024 Aug 20;260(4):77. doi: 10.1007/s00425-024-04506-y.ABSTRACTThe albino phenotype of Agave angustifolia Haw. accumulates higher levels of phenylalanine and phenylpropanoids, while the green phenotype has a greater concentration of phenolic compounds. The metabolic consequences of chlorophyll deficiency in plants continue to be a captivating field of research, especially in relation to production of metabolic compounds. This study conducts a thorough analysis of the metabolome in green (G), variegated (V), and albino (A) phenotypes of Agave angustifolia Haw. Specifically, it examines the differences in the accumulation of compounds related to the phenylpropanoid and flavonoid biosynthesis pathways. Methanol extracts of leaf and meristem tissues from the three phenotypes grown in vitro were analyzed using liquid chromatography coupled with quadrupole time-of-flight high-resolution mass spectrometry (UPLC-MS-QTOF) for untargeted metabolomics and triple quadrupole (QqQ) mass spectrometry for targeted metabolomic analyses. By employing these methods, we discovered notable differences in the levels of important metabolites such as L-phenylalanine, 4-hydroxyphenylpyruvic acid, and various flavonoids among the different phenotypes. The results of our study indicate that the A phenotype shows a significant increase in the levels of phenylalanine and phenylpropanoids in both leaf and meristem tissues. This is in contrast to a decrease in flavonoids, suggesting a metabolic reprogramming to compensate for the lack of chlorophyll. Significantly, compounds such as kaempferol-3-O-glucoside and rutin exhibited significant quantitative reduction in the A leaves, suggesting a subtle modification in the production of flavonols and potentially a changed mechanism for antioxidant protection. This study emphasizes the complex metabolic changes in A. angustifolia´s chlorophyll-deficient phenotypes, providing insight into the complex interplay between primary and secondary metabolism in response to chlorophyll deficiency. Our research not only enhances the comprehension of plant metabolism in albino phenotypes but also opens new avenues for exploring the biochemical and genetic basis of such adaptations, with potential biotechnological applications of these distinct plant variants.PMID:39164400 | DOI:10.1007/s00425-024-04506-y

Pages