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

L-Glyceraldehyde Inhibits Neuroblastoma Cell Growth via a Multi-Modal Mechanism on Metabolism and Signaling

Sat, 11/05/2024 - 12:00
Cancers (Basel). 2024 Apr 25;16(9):1664. doi: 10.3390/cancers16091664.ABSTRACTGlyceraldehyde (GA) is a three-carbon monosaccharide that can be present in cells as a by-product of fructose metabolism. Bruno Mendel and Otto Warburg showed that the application of GA to cancer cells inhibits glycolysis and their growth. However, the molecular mechanism by which this occurred was not clarified. We describe a novel multi-modal mechanism by which the L-isomer of GA (L-GA) inhibits neuroblastoma cell growth. L-GA induces significant changes in the metabolic profile, promotes oxidative stress and hinders nucleotide biosynthesis. GC-MS and 13C-labeling was employed to measure the flow of carbon through glycolytic intermediates under L-GA treatment. It was found that L-GA is a potent inhibitor of glycolysis due to its proposed targeting of NAD(H)-dependent reactions. This results in growth inhibition, apoptosis and a redox crisis in neuroblastoma cells. It was confirmed that the redox mechanisms were modulated via L-GA by proteomic analysis. Analysis of nucleotide pools in L-GA-treated cells depicted a previously unreported observation, in which nucleotide biosynthesis is significantly inhibited. The inhibitory action of L-GA was partially relieved with the co-application of the antioxidant N-acetyl-cysteine. We present novel evidence for a simple sugar that inhibits cancer cell proliferation via dysregulating its fragile homeostatic environment.PMID:38730615 | DOI:10.3390/cancers16091664

Lipid turnover through lipophagy in the newly identified extremophilic green microalga Chlamydomonas urium

Sat, 11/05/2024 - 12:00
New Phytol. 2024 May 10. doi: 10.1111/nph.19811. Online ahead of print.ABSTRACTAutophagy is a central degradative pathway highly conserved among eukaryotes, including microalgae, which remains unexplored in extremophilic organisms. In this study, we described and characterized autophagy in the newly identified extremophilic green microalga Chlamydomonas urium, which was isolated from an acidic environment. The nuclear genome of C. urium was sequenced, assembled and annotated in order to identify autophagy-related genes. Transmission electron microscopy, immunoblotting, metabolomic and photosynthetic analyses were performed to investigate autophagy in this extremophilic microalga. The analysis of the C. urium genome revealed the conservation of core autophagy-related genes. We investigated the role of autophagy in C. urium by blocking autophagic flux with the vacuolar ATPase inhibitor concanamycin A. Our results indicated that inhibition of autophagic flux in this microalga resulted in a pronounced accumulation of triacylglycerols and lipid droplets (LDs). Metabolomic and photosynthetic analyses indicated that C. urium cells with impaired vacuolar function maintained an active metabolism. Such effects were not observed in the neutrophilic microalga Chlamydomonas reinhardtii. Inhibition of autophagic flux in C. urium uncovered an active recycling of LDs through lipophagy, a selective autophagy pathway for lipid turnover. This study provided the metabolic basis by which extremophilic algae are able to catabolize lipids in the vacuole.PMID:38730535 | DOI:10.1111/nph.19811

Untargeted serum metabolic profiling of diabetes mellitus among Parkinson's disease patients

Fri, 10/05/2024 - 12:00
NPJ Parkinsons Dis. 2024 May 10;10(1):100. doi: 10.1038/s41531-024-00711-4.ABSTRACTType 2 diabetes mellitus (T2DM) is a common comorbidity among Parkinson's disease (PD) patients. Yet, little is known about dysregulated pathways that are unique in PD patients with T2DM. We applied high-resolution metabolomic profiling in serum samples of 636 PD and 253 non-PD participants recruited from Central California. We conducted an initial discovery metabolome-wide association and pathway enrichment analysis. After adjusting for multiple testing, in positive (or negative) ion mode, 30 (25) metabolic features were associated with T2DM in both PD and non-PD participants, 162 (108) only in PD participants, and 32 (7) only in non-PD participants. Pathway enrichment analysis identified 17 enriched pathways associated with T2DM in both the PD and non-PD participants, 26 pathways only in PD participants, and 5 pathways only in non-PD participants. Several amino acid, nucleic acids, and fatty acid metabolisms were associated with T2DM only in the PD patient group suggesting a possible link between PD and T2DM.PMID:38730245 | DOI:10.1038/s41531-024-00711-4

Integrated multi-omic approach reveals the effect of a Graminaceae-derived biostimulant and its lighter fraction on salt-stressed lettuce plants

Fri, 10/05/2024 - 12:00
Sci Rep. 2024 May 10;14(1):10710. doi: 10.1038/s41598-024-61576-4.ABSTRACTPlant biostimulants are widely applied in agriculture for their ability to improve plant fitness. In the present work, the impact of Graminaceae-derived protein hydrolysate (P) and its lighter molecular fraction F3 (< 1 kDa) on lettuce plants, subjected to either no salt or high salt conditions, was investigated through the combination of metabolomics and transcriptomics. The results showed that both treatments significantly modulated the transcriptome and metabolome of plants under salinity stress, highlighting an induction of the hormonal response. Nevertheless, P and F3 also displayed several peculiarities. F3 specifically modulated the response to ethylene and MAPK signaling pathway, whereas P treatment induced a down-accumulation of secondary metabolites, albeit genes controlling the biosynthesis of osmoprotectants and antioxidants were up-regulated. Moreover, according with the auxin response modulation, P promoted cell wall biogenesis and plasticity in salt-stressed plants. Notably, our data also outlined an epigenetic control of gene expression induced by P treatment. Contrarily, experimental data are just partially in agreement when not stressed plants, treated with P or F3, were considered. Indeed, the reduced accumulation of secondary metabolites and the analyses of hormone pathways modulation would suggest a preferential allocation of resources towards growth, that is not coherent with the down-regulation of the photosynthetic machinery, the CO2 assimilation rate and leaves biomass. In conclusion, our data demonstrate that, although they might activate different mechanisms, both the P and F3 can result in similar benefits, as far as the accumulation of protective osmolytes and the enhanced tolerance to oxidative stress are concerned. Notably, the F3 fraction exhibits slightly greater growth promotion effects under high salt conditions. Most importantly, this research further corroborates that biostimulants' mode of action is dependent on plants' physiological status and their composition, underscoring the importance of investigating the bioactivity of the different molecular components to design tailored applications for the agricultural practice.PMID:38729985 | DOI:10.1038/s41598-024-61576-4

Metabolomic insights into the profile, bioaccessibility, and transepithelial transport of polyphenols from germinated quinoa during in vitro gastrointestinal digestion/Caco-2 cell transport, and their prebiotic effects during colonic fermentation

Fri, 10/05/2024 - 12:00
Food Res Int. 2024 Jun;186:114339. doi: 10.1016/j.foodres.2024.114339. Epub 2024 Apr 19.ABSTRACTThe health-promoting activities of polyphenols and their metabolites originating from germinated quinoa (GQ) are closely related to their digestive behavior, absorption, and colonic fermentation; however, limited knowledge regarding these properties hinder further development. The aim of this study was to provide metabolomic insights into the profile, bioaccessibility, and transepithelial transport of polyphenols from germinated quinoa during in vitro gastrointestinal digestion and Caco-2 cell transport, whilst also investigating the changes in the major polyphenol metabolites and the effects of prebiotics during colonic fermentation. It was found that germination treatment increased the polyphenol content of quinoa by 21.91%. Compared with RQ group, 23 phenolic differential metabolites were upregulated and 47 phenolic differential metabolites were downregulated in GQ group. Compared with RQ group after simulated digestion, 7 kinds of phenolic differential metabolites were upregulated and 17 kinds of phenolic differential metabolites were downregulated in GQ group. Compared with RQ group after cell transport, 7 kinds of phenolic differential metabolites were upregulated and 9 kinds of phenolic differential metabolites were downregulated in GQ group. In addition, GQ improved the bioaccessibilities and transport rates of various polyphenol metabolites. During colonic fermentation, GQ group can also increase the content of SCFAs, reduce pH value, and adjust gut microbial populations by increasing the abundance of Actinobacteria, Bacteroidetes, Verrucomicrobiota, and Spirochaeota at the phylum level, as well as Bifidobacterium, Megamonas, Bifidobacterium, Brevundimonas, and Bacteroides at the genus level. Furthermore, the GQ have significantly inhibited the activity of α-amylase and α-glucosidase. Based on these results, it was possible to elucidate the underlying mechanisms of polyphenol metabolism in GQ and highlight its beneficial effects on the gut microbiota.PMID:38729694 | DOI:10.1016/j.foodres.2024.114339

Association of Circulating Long-Chain Free Fatty Acids and Incident Diabetes Risk Among Normoglycemic Chinese Adults: A Prospective Nested Case-Control Study

Fri, 10/05/2024 - 12:00
Am J Clin Nutr. 2024 May 8:S0002-9165(24)00465-9. doi: 10.1016/j.ajcnut.2024.05.003. Online ahead of print.ABSTRACTBACKGROUND: Long-chain free fatty acids (FFAs) are associated with risk of incident diabetes. However, comprehensive assessment of the associations in normoglycemic populations is lacking.OBJECTIVE: Our study aims to comprehensively investigate the prospective associations and patterns of FFA profiles with diabetes risk among normoglycemic Chinese adults.METHODS: This is a prospective nested case-control study from the China Cardiometabolic Disease and Cancer Cohort (4C) study. We quantitatively measured 53 serum FFAs using targeted metabolomics approach in 1707 incident diabetes subjects and 1707 propensity score-matched normoglycemic controls. Conditional logistic regression models were employed to estimate odds ratios (ORs) for associations. Least Absolute Shrinkage and Selection Operator (LASSO) penalty regression and quantile g-computation (qg-comp) analyses were implemented to estimate the association between multi-FFA exposures and incident diabetes.RESULTS: The majority of odd-chain FFAs exhibited an inverse association with incident diabetes, wherein the ORs per SD increment of all 7 saturated fatty acids (SFAs), monounsaturated fatty acid (MUFA) 15:1 and polyunsaturated fatty acid (PUFA) 25:2 were ranging from 0.79 to 0.88 (95%CIs ranging between 0.71 and 0.97). Even-chain FFAs comprised 99.3% of total FFAs and displayed heterogeneity with incident diabetes. SFAs with 18 to 26 carbon atoms are inversely linked to incident diabetes, with ORs ranging from 0.81 to 0.86 (95%CIs ranging between 0.73 and 0.94). MUFAs 26:1 (OR[95%CI]: 0.85[0.76-0.94]), PUFAs 20:4 (0.84[0.75-0.94]) and 24:2 (0.87[0.78-0.97]) demonstrated significant associations. In multi-FFA exposure model, 24 FFAs were significantly associated with incident diabetes, most of which were consistent with univariate results. The mixture OR was 0.78 [0.61-0.99] (P= 0.04159). Differential correlation network analysis revealed pre-existing perturbations in intraclass and interclass FFA coregulation before diabetes onset.CONCLUSIONS: These findings underscore the variations in diabetes risk associated with FFAs across chain length and unsaturation degree, highlighting the importance of recognizing FFA subtypes in the pathogenesis of diabetes.PMID:38729573 | DOI:10.1016/j.ajcnut.2024.05.003

β-hydroxybutyrate Restrains Colitis-Associated Tumorigenesis by Inhibiting HIF-1α-Mediated Angiogenesis

Fri, 10/05/2024 - 12:00
Cancer Lett. 2024 May 8:216940. doi: 10.1016/j.canlet.2024.216940. Online ahead of print.ABSTRACTDecreased levels of β-hydroxybutyrate (BHB), a lipid metabolic intermediate known to slow the progression of colorectal cancer (CRC), have been observed in the colon mucosa of patients with inflammatory bowel diseases (IBD). In particular, patients with recurrent IBD present an increased risk of developing colitis-associated colorectal cancer (CAC). The role and molecular mechanism of BHB in the inflammatory and carcinogenic process of CAC remains unclear. Here, the anti-tumor effect of BHB was investigated in the (Azoxymethane) AOM /(Dextran Sulfate Sodium) DSS-induced CAC model and tumor organoids derivatives. The underlying mechanisms were studied using transcriptome and non-target metabolomic assay and further validated in colon tumor cell lineage CT26 in vitro. The tumor tissues and the nearby non-malignant tissues from colon cancer patients were collected to measure the expression levels of ketogenic enzymes. The exogenous BHB supplement lightened tumor burden and angiogenesis in the CAC model. Notably, transcriptome analysis revealed that BHB effectively decreased the expression of VEGFA in the CAC tumor mucosa. In vitro, BHB directly reduced VEGFA expression in hypoxic-treated CT26 cells by targeting transcriptional factor HIF-1α. Conversely, the deletion of HIF-1α largely reversed the inhibitory effect of BHB on CAC tumorigenesis. Additionally, decreased expression of ketogenesis-related enzymes in tumor tissues were associated with poor survival outcomes in patients with colon cancer. In summary, BHB carries out anti-angiogenic activity in CAC by regulating HIF-1α/VEGFA signaling. These findings emphasize the role of BHB in CAC and may provide novel perspectives for the prevention and treatment of colonic tumors.PMID:38729554 | DOI:10.1016/j.canlet.2024.216940

Study on the mechanisms by which pumpkin polysaccharides regulate abnormal glucose and lipid metabolism in diabetic mice under oxidative stress

Fri, 10/05/2024 - 12:00
Int J Biol Macromol. 2024 May 8:132249. doi: 10.1016/j.ijbiomac.2024.132249. Online ahead of print.ABSTRACTPumpkin polysaccharide (PPe-H) can perform physiological functions through its antioxidative and hypoglycemic effects; however, the mechanisms through which PPe-H regulates abnormal glucose and lipid metabolism caused by oxidative stress injury remain unclear. In the present study, streptozotocin was used to generate an acute diabetic mouse model, and the effects of PPe-H on glucose and lipid metabolism impaired by oxidative stress in diabetic mice were studied. PPe-H significantly reduced blood glucose levels and enhanced the oral glucose tolerance of diabetic mice under stress injury (p < 0.05). The analysis of liver antioxidant enzymes showed that PPe-H significantly enhanced the activities of SOD and CAT (p < 0.05), increased the GSH level, and decreased the level of MDA (p < 0.05). Transcriptomic and metabolomic analyses of the liver tissues of mice revealed characteristic differences in the genetic and metabolic levels of the samples, which showed that PPe-H treatment may play a positive role in regulating the metabolism of methionine, cysteine, glycerol phospholipid, and linoleic acid. These results indicated that PPe-H alleviated the symptoms of hyperglycemia by regulating metabolites related to oxidative stress and glycolipid metabolism in diabetic mice.PMID:38729500 | DOI:10.1016/j.ijbiomac.2024.132249

A comprehensive review of the molecular and genetic mechanisms underlying gum and resin synthesis in Ferula species

Fri, 10/05/2024 - 12:00
Int J Biol Macromol. 2024 May 8:132168. doi: 10.1016/j.ijbiomac.2024.132168. Online ahead of print.ABSTRACTFerula spp. are plants that produce oleo-gum-resins (OGRs), which are plant exudates with various colors. These OGRs have various industrial applications in pharmacology, perfumery, and food. The main constituents of these OGRs are terpenoids, a diverse group of organic compounds with different structures and functions. The biosynthesis of OGRs in Ferula spp., particularly galbanum, holds considerable economic and ecological importance. However, the molecular and genetic underpinnings of this biosynthetic pathway remain largely enigmatic. This review provides an overview of the current state of knowledge on the biosynthesis of OGRs in Ferula spp., highlighting the major enzymes, genes, and pathways involved in the synthesis of different terpenoid classes, such as monoterpenes, sesquiterpenes, and triterpenes. It also examines the potential of using omics techniques, such as transcriptomics and metabolomics, and genome editing tools, such as CRISPR/Cas, to increase the yield and quality of Ferula OGRs, as well as to create novel bioactive compounds with enhanced properties. Moreover, this review addresses the current challenges and opportunities of applying gene editing in Ferula spp., and suggests some directions for future research and development.PMID:38729496 | DOI:10.1016/j.ijbiomac.2024.132168

Living under natural conditions of ocean acidification entails energy expenditure and oxidative stress in a mussel species

Fri, 10/05/2024 - 12:00
Mar Pollut Bull. 2024 May 9;203:116470. doi: 10.1016/j.marpolbul.2024.116470. Online ahead of print.ABSTRACTWe investigated the health conditions of the Mediterranean mussel Mytilus galloprovincialis recruited in the CO2 vents system of Castello Aragonese at Ischia Island (Mediterranean Sea). Individuals of M. galloprovincialis were sampled in three sites along the pH gradient (8.10, 7.7 and up to <7.4). Untargeted metabolomics and biochemical endpoints related to energetic metabolism, oxidative stress/damage, neurotoxicity and immune defense were analyzed. Corrosion of the valves occurred at low pH. A separation of the metabolome was observed along the pH gradient. Metabolites belonging to amino acids, nucleosides, lipids and organic osmolytes were significantly reduced in the organisms from the most acidified sites. The content of reactive oxygen species and the activity of glutathione peroxidase were reduced in organisms from the acidified sites compared to ambient pH, and no oxidative damage was induced. Overall results suggested the presence of an energy cost underpinning long-term survival in acidified conditions for this species.PMID:38728956 | DOI:10.1016/j.marpolbul.2024.116470

Multi-omics reveal disturbance of glucose homeostasis in pregnant rats exposed to short-chain perfluorobutanesulfonic acid

Fri, 10/05/2024 - 12:00
Ecotoxicol Environ Saf. 2024 May 9;278:116402. doi: 10.1016/j.ecoenv.2024.116402. Online ahead of print.ABSTRACTPerfluorobutanesulfonic acid (PFBS), a short-chain alternative to perfluorooctanesulfonic acid (PFOS), is widely used in various products and is increasingly present in environmental media and human bodies. Recent epidemiological findings have raised concerns about its potential adverse health effects, although the specific toxic mechanism remains unclear. This study aimed to investigate the metabolic toxicity of gestational PFBS exposure in maternal rats. Pregnant Sprague Dawley (SD) rats were randomly assigned to three groups and administered either 3% starch gel (control), 5, or 50 mg/kg bw·d PFBS. Oral glucose tolerance tests (OGTT) and lipid profiles were measured, and integrated omics analysis (transcriptomics and non-targeted metabolomics) was employed to identify changes in genes and metabolites and their relationships with metabolic phenotypes. The results revealed that rats exposed to 50 mg/kg bw·d PFBS exhibited a significant decrease in 1-h glucose levels and the area under the curve (AUC) of OGTT compared with the starch group. Transcriptomics analysis indicated significant alterations in gene expression related to cytochrome P450 exogenous metabolism, glutathione metabolism, bile acid secretion, tumor pathways, and retinol metabolism. Differentially expressed metabolites (DEMs) were enriched in pathways such as pyruvate metabolism, the glucagon signaling pathway, central carbon metabolism in cancer, and the citric acid cycle. Co-enrichment analysis and pairwise correlation analysis among genes, metabolites, and outcomes identified several differentially expressed genes (DEGs), including Gstm1, Kit, Adcy1, Gck, Ppp1r3c, Ppp1r3d, and DEMs such as fumaric acid, L-lactic acid, 4-hydroxynonenal, and acetylvalerenolic acid. These DEGs and DEMs may play a role in the modulation of glucolipid metabolic pathways. In conclusion, our results suggest that gestational exposure to PFBS may induce molecular perturbations in glucose homeostasis. These findings provide insights into the potential mechanisms contributing to the heightened risk of abnormal glucose tolerance associated with PFBS exposure.PMID:38728940 | DOI:10.1016/j.ecoenv.2024.116402

Atractylenolide-I Alleviates Hyperglycemia-Induced Heart Developmental Malformations through Direct and Indirect Modulation of the STAT3 Pathway

Fri, 10/05/2024 - 12:00
Phytomedicine. 2024 May 1;129:155698. doi: 10.1016/j.phymed.2024.155698. Online ahead of print.ABSTRACTBACKGROUND: Gestational diabetes could elevate the risk of congenital heart defects (CHD) in infants, and effective preventive and therapeutic medications are currently lacking. Atractylenolide-I (AT-I) is the active ingredient of Atractylodes Macrocephala Koidz (known as Baizhu in China), which is a traditional pregnancy-supporting Chinese herb.PURPOSE: In this study, we investigated the protective effect of AT-I on the development of CHD in embryos exposed to high glucose (HG).STUDY DESIGN AND METHODS: First, systematic review search results revealed associations between gestational diabetes mellitus (GDM) and cardiovascular malformations. Subsequently, a second systematic review indicated that heart malformations were consistently associated with oxidative stress and cell apoptosis. We assessed the cytotoxic impacts of Atractylenolide compounds (AT-I, AT-II, and AT-III) on H9c2 cells and chick embryos, determining an optimal concentration of AT-I for further investigation. Second, immunofluorescence, western blot, Polymerase Chain Reaction (PCR), and flow cytometry were utilized to delve into the mechanisms through which AT-I mitigates oxidative stress and apoptosis in cardiac cells. Molecular docking was employed to investigate whether AT-I exerts cardioprotective effects via the STAT3 pathway. Then, we developed a streptozotocin-induced diabetes mellitus (PGDM) mouse model to evaluate AT-I's protective efficacy in mammals. Finally, we explored how AT-I protects hyperglycemia-induced abnormal fetal heart development through microbiota analysis and untargeted metabolomics analysis.RESULTS: The study showed the protective effect of AT-I on embryonic development using a chick embryo model which rescued the increase in the reactive oxygen species (ROS) and decrease in cell survival induced by HG. We also provided evidence suggesting that AT-I might directly interact with STAT3, inhibiting its phosphorylation. Further, in the PGDM mouse model, we observed that AT-I not only partially alleviated PGDM-related blood glucose issues and complications but also mitigated hyperglycemia-induced abnormal fetal heart development in pregnant mice. This effect is hypothesized to be mediated through alterations in gut microbiota composition. We proposed that dysregulation in microbiota metabolism could influence the downstream STAT3 signaling pathway via EGFR, consequently impacting cardiac development and formation.CONCLUSIONS: This study marks the first documented instance of AT-I's effectiveness in reducing the risk of early cardiac developmental anomalies in fetuses affected by gestational diabetes. AT-I achieves this by inhibiting the STAT3 pathway activated by ROS during gestational diabetes, significantly reducing the risk of fetal cardiac abnormalities. Notably, AT-I also indirectly safeguards normal fetal cardiac development by influencing the maternal gut microbiota and suppressing the EGFR/STAT3 pathway.PMID:38728919 | DOI:10.1016/j.phymed.2024.155698

Gut microbial metabolism is linked to variations in circulating non-high density lipoprotein cholesterol

Fri, 10/05/2024 - 12:00
EBioMedicine. 2024 May 9;104:105150. doi: 10.1016/j.ebiom.2024.105150. Online ahead of print.ABSTRACTBACKGROUND: Non-high-density lipoprotein cholesterol (non-HDL-c) was a strong risk factor for incident cardiovascular diseases and proved to be a better target of lipid-lowering therapies. Recently, gut microbiota has been implicated in the regulation of host metabolism. However, its causal role in the variation of non-HDL-c remains unclear.METHODS: Microbial species and metabolic capacities were assessed with fecal metagenomics, and their associations with non-HDL-c were evaluated by Spearman correlation, followed by LASSO and linear regression adjusted for established cardiovascular risk factors. Moreover, integrative analysis with plasma metabolomics were performed to determine the key molecules linking microbial metabolism and variation of non-HDL-c. Furthermore, bi-directional mendelian randomization analysis was performed to determine the potential causal associations of selected species and metabolites with non-HDL-c.FINDINGS: Decreased Eubacterium rectale but increased Clostridium sp CAG_299 were causally linked to a higher level of non-HDL-c. A total of 16 microbial capacities were found to be independently associated with non-HDL-c after correcting for age, sex, demographics, lifestyles and comorbidities, with the strongest association observed for tricarboxylic acid (TCA) cycle. Furthermore, decreased 3-indolepropionic acid and N-methyltryptamine, resulting from suppressed capacities for microbial reductive TCA cycle, functioned as major microbial effectors to the elevation of circulating non-HDL-c.INTERPRETATION: Overall, our findings provided insight into the causal effects of gut microbes on non-HDL-c and uncovered a novel link between non-HDL-c and microbial metabolism, highlighting the possibility of regulating non-HDL-c by microbiota-modifying interventions.FUNDING: A full list of funding bodies can be found in the Sources of funding section.PMID:38728837 | DOI:10.1016/j.ebiom.2024.105150

Metabolic network analysis of pre-ASD newborns and 5-year-old children with autism spectrum disorder

Fri, 10/05/2024 - 12:00
Commun Biol. 2024 May 10;7(1):536. doi: 10.1038/s42003-024-06102-y.ABSTRACTClassical metabolomic and new metabolic network methods were used to study the developmental features of autism spectrum disorder (ASD) in newborns (n = 205) and 5-year-old children (n = 53). Eighty percent of the metabolic impact in ASD was caused by 14 shared biochemical pathways that led to decreased anti-inflammatory and antioxidant defenses, and to increased physiologic stress molecules like lactate, glycerol, cholesterol, and ceramides. CIRCOS plots and a new metabolic network parameter, V ° net, revealed differences in both the kind and degree of network connectivity. Of 50 biochemical pathways and 450 polar and lipid metabolites examined, the developmental regulation of the purine network was most changed. Purine network hub analysis revealed a 17-fold reversal in typically developing children. This purine network reversal did not occur in ASD. These results revealed previously unknown metabolic phenotypes, identified new developmental states of the metabolic correlation network, and underscored the role of mitochondrial functional changes, purine metabolism, and purinergic signaling in autism spectrum disorder.PMID:38729981 | DOI:10.1038/s42003-024-06102-y

In vitro batch fermentation demonstrates variations in the regulation of gut microbiota and metabolic functions by β-glucans of differing structures

Fri, 10/05/2024 - 12:00
Food Res Int. 2024 Jun;186:114287. doi: 10.1016/j.foodres.2024.114287. Epub 2024 Mar 29.ABSTRACTThe gut microbiota is widely acknowledged as a crucial factor in regulating host health. The structure of dietary fibers determines changes in the gut microbiota and metabolic differences resulting from their fermentation, which in turn affect gut microbe-related health effects. β-Glucan (BG) is a widely accessible dietary fiber to humans, and its structural characteristics vary depending on the source. However, the interactions between different structural BGs and gut microbiota remain unclear. This study used an in vitro fermentation model to investigate the effects of BG on gut microbiota, and microbiomics and metabolomics techniques to explore the relationship between the structure of BG, bacterial communities, and metabolic profiles. The four sources of BG (barley, yeast, algae, and microbial fermentation) contained different types and proportions of glycosidic bonds, which differentially altered the bacterial community. The BG from algal sources, which contained only β(1 → 4) glycosidic bonds, was the least metabolized by the gut microbiota and caused limited metabolic changes. The other three BGs contain more diverse glycosidic bonds and can be degraded by bacteria from multiple genera, causing a wider range of metabolic changes. This work also suggested potential synergistic degradation relationships between gut bacteria based on BG. Overall, this study deepens the structural characterization-microbial-functional understanding of BGs and provides theoretical support for the development of gut microbiota-targeted foods.PMID:38729740 | DOI:10.1016/j.foodres.2024.114287

Identification and quality evaluation of Lushan Yunwu tea from different geographical origins based on metabolomics

Fri, 10/05/2024 - 12:00
Food Res Int. 2024 Jun;186:114379. doi: 10.1016/j.foodres.2024.114379. Epub 2024 Apr 18.ABSTRACTThe relationship between the chemical composition and quality of Lushan Yunwu tea (LYT) from different geographical origins is not clear. Sensory evaluation, metabolomics analyses combined with chemometrics were conducted on LYT from 8 different geographical origins, and altitude was identified as the main factor responsible for the differences among LYT. A total of 32 non-volatile and 27 volatile compounds were identified as marker metabolites to distinguish the origins of high altitudes from those of low altitudes. LYT samples from higher altitude areas contained more free amino acids, sugars, and organic acids, and less catechins, which may contribute to the reduction of bitterness and astringency and the enhancement of umami. The contents of geranylacetone, ethyl hexanoate, ethyl caprylate, 3-carene, d-cadinene, linalool, nerol, and nerolidol in high altitude areas were higher than those in low altitude areas, indicating that LYT from high altitude had strong floral and fruity aroma. The altitudes were positively correlated with pH value, total flavonoids, soluble protein, total free amino acids, and the antioxidant capacities of the LYT. This study provided a theoretical basis for the study of the effect of altitude on tea quality.PMID:38729702 | DOI:10.1016/j.foodres.2024.114379

GC/MS-based untargeted metabolomics reveals the differential metabolites for discriminating vintage of Chenxiang-type baijiu

Fri, 10/05/2024 - 12:00
Food Res Int. 2024 Jun;186:114319. doi: 10.1016/j.foodres.2024.114319. Epub 2024 Apr 18.ABSTRACTThe "outstanding and unique aged aroma" of Chinese Chenxiang-type baijiu (CXB)-Daoguang 25 (DG25) mainly originates from a "extraordinary storage technology" of Mujiuhai (a wooden container), so it is mysterious and interesting. In this study, an untargeted GC/MS-based metabolomics was used to reveals the volatile differential metabolites for discriminating six different vintages of DG25 combing with chemometrics. A total of 100 volatile metabolites (including unknowns) were extracted and identified, including esters (41%), alcohols (10%) and acids (7%) so on. Finally, 33 differential metabolites were identified as aging-markers. Among them, 25 aging-markers showed a downtrend, including 17 esters such as ethyl acetate, ethyl hexanoate and ethyl palmitate so on. Moreover, it was interesting and to further study that furans showed a significant downtrend. Statistically speaking, ethyl benzoate played an important role in discriminating vintage of 1Y and 3Y, and the other 24 differential metabolites with downtrend discriminating the unstored (0Y-aged) DG25. Eight differential metabolites, such as ethyl octanoate, benzaldehyde, 3-methylbutanol and 1,1-diethoxyaccetal so on increased during aging of DG25, and they played a statistical role in discriminating the 5Y-, 10Y- and 20Y-aged DG25. This study provides a theoretical basis way for the formation mechanism of aging aroma for CXB.PMID:38729690 | DOI:10.1016/j.foodres.2024.114319

Metabolite Correlation Permutation after Mice Acute Exposure to PM<sub>2.5</sub>: Holistic Exploration of Toxicometabolomics by Network Analysis

Fri, 10/05/2024 - 12:00
Environ Pollut. 2024 May 8:124128. doi: 10.1016/j.envpol.2024.124128. Online ahead of print.ABSTRACTMany environmental toxicants can cause systemic effects, such as fine particulate matter (PM2.5), which can penetrate the respiratory barrier and induce effects in multiple tissues. Although metabolomics has been used to identify biomarkers for PM2.5, its multi-tissue toxicology has not yet been explored holistically. Our objective is to explore PM2.5 induced metabolic alterations and unveil the intra-tissue responses along with inter-tissue communicational effects. In this study, following a single intratracheal instillation of multiple doses (0, 25, and 150 μg as the control, low, and high dose), non-targeted metabolomics was employed to evaluate the metabolic impact of PM2.5 across multiple tissues. PM2.5 induced tissue-specific and dose-dependent disturbances of metabolites and their pathways. The remarkable increase of both intra- and inter-tissue correlations was observed, with emphasis on the metabolism connectivity among lung, spleen, and heart; the tissues' functional specificity has marked their toxic modes. Beyond the inter-status comparison of the metabolite fold-changes, the current correlation network built on intra-status can offer additional insights into how the multiple tissues and their metabolites coordinately change in response to external stimuli such as PM2.5 exposure.PMID:38729510 | DOI:10.1016/j.envpol.2024.124128

A conjoint analysis of renal structure and omics characteristics reveal new insight to yak high-altitude hypoxia adaptation

Fri, 10/05/2024 - 12:00
Genomics. 2024 May 8:110857. doi: 10.1016/j.ygeno.2024.110857. Online ahead of print.ABSTRACTBACKGROUND: Yaks have unique adaptive mechanisms to the hypoxic environment, in which the kidney plays an important role. The aim of this study was to explore the histological changes of yak kidney at different altitudes and the metabolites and genes associated with adaptation to the hypoxic environment.METHODS: We analyzed the tissue structure and transcriptomic metabolomic data of yak kidney tissue at two altitudes, 2600 and 4400 m. We compared and identified the morphological adaptations of the kidney and the metabolites and genes associated with hypoxia adaptation in yaks. Changes in renal morphological adaptations, differential metabolites and genes were compared and identified, combining the two in a joint analysis.RESULTS: High-altitude yak kidneys showed significant adaptive changes: increased mitochondria, increased glomerular thylakoid area, and decreased localized ribosomes. Transcriptomics and metabolomics identified 69 DAMs (Differential metabolites) and 594 DEGs (differential genes). Functional enrichment analysis showed that the DAMs were associated with protein digestion and absorption, ABC transporter, and MTOR signaling pathway; the DEGs were significantly enriched in Cholesterol metabolism and P53 signaling pathway. The joint analysis indicated that metabolites such as lysine and arginine, as well as key genes such as ABCB5 and COL1A2, were particularly affected under hypoxic conditions, whereas changes in mitochondria in the tissue structure may be related to the expression of MFN1 and OPA1, and changes in glomerular thylakoid membranes are related to VEGFA and TGFB3.CONCLUSION: The kidney regulates metabolites and gene expression related to hormone synthesis, protein metabolism, and angiogenesis by adjusting the mitochondrial and glomerular thylakoid membrane structure to support the survival of yaks in high-altitude environments.PMID:38729453 | DOI:10.1016/j.ygeno.2024.110857

Non-target metabolomics approach for the investigation of the hidden effects induced by atrazine and its degradation products on plant metabolism

Fri, 10/05/2024 - 12:00
Chemosphere. 2024 May 8:142298. doi: 10.1016/j.chemosphere.2024.142298. Online ahead of print.ABSTRACTJapanese radish (Raphanus sativus var. longipinnatus) plants grown under laboratory conditions were individually exposed to the same doses of atrazine (2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine, ATR) or its main degradation products: either 2-amino-4-chloro-6-isopropylamino-1,3,5-triazine (DEA) or 2-amino-4-chloro-6-ethylamino-1,3,5-triazine (DIA) or desethyl-desisopropyl-atrazine (DEDIA) or 4-(ethylamino)-2-hydroxy-6-(isopropylamino)-1,3,5-triazine (HA), respectively. One week after treatment in plants exposed to ATR, DIA, and DEA, their concentrations were 7.8 μg/g, 9.7 μg/g, and 14.5 μg/g, respectively, while those treated with DEDIA and HA did not contain these compounds. These results were correlated with plant amino acid profile obtained by suspect screening analysis and metabolomic "fingerprint" based on non-target analysis, obtained by liquid chromatography coupled with QTRAP triple quadrupole mass spectrometer . In all cases, both ATR and its by-products were found to interfere with the plant's amino acid profile and modify its metabolic "fingerprint". Therefore, we proved that the non-target metabolomics approach is an effective tool for investigating the hidden effects of pesticides and their transformation products, which is particularly important as these compounds may reduce the quality of edible plants.PMID:38729438 | DOI:10.1016/j.chemosphere.2024.142298

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