PubMed

STAR Protoc. 2024 Mar 13;5(2):102953. doi: 10.1016/j.xpro.2024.102953. Online ahead of print.ABSTRACTHigh mortality of ovarian cancer (OC) is primarily attributed to the lack of effective early detection methods. Uterine fluid, pooling molecules from neighboring ovaries, presents an organ-specific advantage over conventional blood samples. Here, we present a protocol for identifying metabolite biomarkers in uterine fluid for early OC detection. We describe steps for uterine fluid collection from patients, metabolite extraction, metabolomics experiments, and candidate metabolite biomarker screening. This standardized workflow holds the potential to achieve early OC diagnosis in clinical practice. For complete details on the use and execution of this protocol, please refer to Wang et al.1.PMID:38489270 | DOI:10.1016/j.xpro.2024.102953

Elife. 2024 Mar 15;12:RP90993. doi: 10.7554/eLife.90993.ABSTRACTDysregulated pre-mRNA splicing and metabolism are two hallmarks of MYC-driven cancers. Pharmacological inhibition of both processes has been extensively investigated as potential therapeutic avenues in preclinical and clinical studies. However, how pre-mRNA splicing and metabolism are orchestrated in response to oncogenic stress and therapies is poorly understood. Here, we demonstrate that jumonji domain containing 6, arginine demethylase, and lysine hydroxylase, JMJD6, acts as a hub connecting splicing and metabolism in MYC-driven human neuroblastoma. JMJD6 cooperates with MYC in cellular transformation of murine neural crest cells by physically interacting with RNA binding proteins involved in pre-mRNA splicing and protein homeostasis. Notably, JMJD6 controls the alternative splicing of two isoforms of glutaminase (GLS), namely kidney-type glutaminase (KGA) and glutaminase C (GAC), which are rate-limiting enzymes of glutaminolysis in the central carbon metabolism in neuroblastoma. Further, we show that JMJD6 is correlated with the anti-cancer activity of indisulam, a 'molecular glue' that degrades splicing factor RBM39, which complexes with JMJD6. The indisulam-mediated cancer cell killing is at least partly dependent on the glutamine-related metabolic pathway mediated by JMJD6. Our findings reveal a cancer-promoting metabolic program is associated with alternative pre-mRNA splicing through JMJD6, providing a rationale to target JMJD6 as a therapeutic avenue for treating MYC-driven cancers.PMID:38488852 | DOI:10.7554/eLife.90993

Gigascience. 2024 Jan 2;13:giae005. doi: 10.1093/gigascience/giae005.ABSTRACTIn classic semiquantitative metabolomics, metabolite intensities are affected by biological factors and other unwanted variations. A systematic evaluation of the data processing methods is crucial to identify adequate processing procedures for a given experimental setup. Current comparative studies are mostly focused on peak area data but not on absolute concentrations. In this study, we evaluated data processing methods to produce outputs that were most similar to the corresponding absolute quantified data. We examined the data distribution characteristics, fold difference patterns between 2 metabolites, and sample variance. We used 2 metabolomic datasets from a retail milk study and a lupus nephritis cohort as test cases. When studying the impact of data normalization, transformation, scaling, and combinations of these methods, we found that the cross-contribution compensating multiple standard normalization (ccmn) method, followed by square root data transformation, was most appropriate for a well-controlled study such as the milk study dataset. Regarding the lupus nephritis cohort study, only ccmn normalization could slightly improve the data quality of the noisy cohort. Since the assessment accounted for the resemblance between processed data and the corresponding absolute quantified data, our results denote a helpful guideline for processing metabolomic datasets within a similar context (food and clinical metabolomics). Finally, we introduce Metabox 2.0, which enables thorough analysis of metabolomic data, including data processing, biomarker analysis, integrative analysis, and data interpretation. It was successfully used to process and analyze the data in this study. An online web version is available at http://metsysbio.com/metabox.PMID:38488666 | DOI:10.1093/gigascience/giae005

Neural Regen Res. 2024 Oct 1;19(10):2281-2289. doi: 10.4103/1673-5374.391310. Epub 2023 Dec 21.ABSTRACTJOURNAL/nrgr/04.03/01300535-202410000-00029/figure1/v/2024-02-06T055622Z/r/image-tiff Disturbances in the microbiota-gut-brain axis may contribute to the development of Alzheimer's disease. Magnesium-L-threonate has recently been found to have protective effects on learning and memory in aged and Alzheimer's disease model mice. However, the effects of magnesium-L-threonate on the gut microbiota in Alzheimer's disease remain unknown. Previously, we reported that magnesium-L-threonate treatment improved cognition and reduced oxidative stress and inflammation in a double-transgenic line of Alzheimer's disease model mice expressing the amyloid-β precursor protein and mutant human presenilin 1 (APP/PS1). Here, we performed 16S rRNA amplicon sequencing and liquid chromatography-mass spectrometry to analyze changes in the microbiome and serum metabolome following magnesium-L-threonate exposure in a similar mouse model. Magnesium-L-threonate modulated the abundance of three genera in the gut microbiota, decreasing Allobaculum and increasing Bifidobacterium and Turicibacter. We also found that differential metabolites in the magnesium-L-threonate-regulated serum were enriched in various pathways associated with neurodegenerative diseases. The western blotting detection on intestinal tight junction proteins (zona occludens 1, occludin, and claudin-5) showed that magnesium-L-threonate repaired the intestinal barrier dysfunction of APP/PS1 mice. These findings suggest that magnesium-L-threonate may reduce the clinical manifestations of Alzheimer's disease through the microbiota-gut-brain axis in model mice, providing an experimental basis for the clinical treatment of Alzheimer's disease.PMID:38488562 | DOI:10.4103/1673-5374.391310

Environ Sci Technol. 2024 Mar 15. doi: 10.1021/acs.est.3c10030. Online ahead of print.ABSTRACTThe anammox dynamic membrane bioreactor (DMBR) is promising in applications with enhanced anammox biomass enrichment and fouling alleviation. However, the metabolic mechanism underlying the functional features of anammox sludge and the biofilm membrane is still obscure. We investigated the metabolic networks of anammox sludge and membrane biofilm in the DMBR. The cooperation between anammox and dissimilatory nitrate reduction to ammonium processes favored the robust anammox process in the DMBR. The rapid bacterial growth occurred in the DMBR sludge with 1.33 times higher biomass yield compared to the MBR sludge, linked to the higher activities of lipid metabolism, nucleotide metabolism, and B vitamin-related metabolism of the DMBR sludge. The metabolism of the DMBR biofilm microbial community benefited the fouling alleviation that the abundant fermentative bacteria and their cooperation with the anammox sludge microbial community promoted organics degradation. The intensified degradation of foulants by the DMBR biofilm community was further evidenced by the active carbohydrate metabolism and the upregulated vitamin B intermediates in the biofilms of the DMBR. Our findings provide insights into key metabolic mechanisms for enhanced biomass enrichment and fouling control of the anammox DMBR, guiding manipulations and applications for overcoming anammox biomass loss in the treatment of wastewater under detrimental environmental conditions.PMID:38488464 | DOI:10.1021/acs.est.3c10030

CNS Neurosci Ther. 2024 Mar;30(3):e14676. doi: 10.1111/cns.14676.ABSTRACTAIM: To explore the neuroprotective effects of ARA290 and the role of β-common receptor (βCR) in a mouse model of middle cerebral artery occlusion (MCAO).METHODS: This study included male C57BL/6J mice that underwent MCAO and reperfusion. The neuroprotective effect of ARA290 on MCAO-induced brain injury was investigated using neurological function tests (Longa and modified neurological severity score). Cerebral infarction was examined by 2, 3, 5-triphenyl tetrazolium chloride staining, neuronal apoptosis was assessed by immunofluorescence staining, blood parameters were measured using a flow cytometry-based automated hematology analyzer, liquid chromatography with tandem mass spectrometry was used to identify the serum metabolomics signature, inflammatory cytokines and liver index were detected by commercially available kits, and the protein levels of the erythropoietin (EPO) receptor and βCR were measured by western blot.RESULTS: ARA290 exerted a qualitatively similar neuroprotective effect after MCAO as EPO. ARA290 significantly reduced neuronal apoptosis and the level of inflammatory cytokines in the brain tissue. However, ARA290's neuroprotective effect was significantly suppressed following the injection of siRNA against βCR.CONCLUSION: ARA290 provided a neuroprotective effect via βCR in cerebral ischemic mice without causing erythropoiesis. This study provides novel insights into the role of ARA290 in ischemic stroke intervention.PMID:38488446 | DOI:10.1111/cns.14676

Physiol Plant. 2024 Mar-Apr;176(2):e14248. doi: 10.1111/ppl.14248.ABSTRACTThe Chinese tallow tree (Triadica sebifera) is an economically important plant on account of its ornamental value and oil-producing seeds. Leaf colour is a key characteristic of T. sebifera, with yellow-, red- and purple-leaved varieties providing visually impressive displays during autumn. In this study, we performed metabolomic and transcriptomic analyses to gain a better understanding of the mechanisms underlying leaf colour development in purple-leaved T. sebifera at three stages during the autumnal colour transition, namely, green, hemi-purple, and purple leaves. We accordingly detected 370 flavonoid metabolites and 10 anthocyanins, among the latter of which, cyanidin-3-xyloside and peonidin-3-O-glucoside were identified as the predominant compounds in hemi-purple and purple leaves. Transcriptomic analysis revealed that structural genes associated with the anthocyanin biosynthetic pathway, chlorophyll synthesis pathway and carotenoid synthesis pathway were significantly differential expressed at the three assessed colour stages. Additionally, transcription factors associated with the MYB-bHLH-WD40 complex, including 22 R2R3-MYBs, 79 bHLHs and 44 WD40 genes, were identified as candidate regulators of the anthocyanin biosynthetic pathway. Moreover, on the basis of the identified differentially accumulated anthocyanins and key genes, we generated genetic and metabolic regulatory networks for anthocyanin biosynthesis in T. sebifera. These findings provide comprehensive information on the leaf transcriptome and three pigments of T. sebifera, thereby shedding new light on the mechanisms underlying the autumnal colouring of the leaves of this tree.PMID:38488424 | DOI:10.1111/ppl.14248

Microbiol Spectr. 2024 Mar 15:e0257423. doi: 10.1128/spectrum.02574-23. Online ahead of print.ABSTRACTThe clavicipitaceous fungus Epichloë gansuensis forms symbiotic associations with drunken horse grass (Achnatherum inebrians), providing biotic and abiotic stress protection to its host. However, it is unclear how E. gansuensis affects the assembly of host plant-associated bacterial communities after ammonium nitrogen (NH4+-N) treatment. We examined the shoot- and root-associated bacterial microbiota and root metabolites of A. inebrians when infected (I) or uninfected (F) with E. gansuensis endophyte. The results showed more pronounced NH4+-N-induced microbial and metabolic changes in the endophyte-infected plants compared to the endophyte-free plants. E. gansuensis significantly altered bacterial community composition and β-diversity in shoots and roots and increased bacterial α-diversity under NH4+-N treatment. The relative abundance of 117 and 157 root metabolites significantly changed with E. gansuensis infection under water and NH4+-N treatment compared to endophyte-free plants. Root bacterial community composition was significantly related to the abundance of the top 30 metabolites [variable importance in the projection (VIP) > 2 and VIP > 3] contributing to differences between I and F plants, especially alkaloids. The correlation network between root microbiome and metabolites was complex. Microorganisms in the Proteobacteria and Firmicutes phyla were significantly associated with the R00693 metabolic reaction of cysteine and methionine metabolism. Co-metabolism network analysis revealed common metabolites between host plants and microorganisms.IMPORTANCEOur results suggest that the effect of endophyte infection is sensitive to nitrogen availability. Endophyte symbiosis altered the composition of shoot and root bacterial communities, increasing bacterial diversity. There was also a change in the class and relative abundance of metabolites. We found a complex co-occurrence network between root microorganisms and metabolites, with some metabolites shared between the host plant and its microbiome. The precise ecological function of the metabolites produced in response to endophyte infection remains unknown. However, some of these compounds may facilitate plant-microbe symbiosis by increasing the uptake of beneficial soil bacteria into plant tissues. Overall, these findings advance our understanding of the interactions between the microbiome, metabolome, and endophyte symbiosis in grasses. The results provide critical insight into the mechanisms by which the plant microbiome responds to nutrient stress in the presence of fungal endophytes.PMID:38488391 | DOI:10.1128/spectrum.02574-23

Artif Cells Nanomed Biotechnol. 2024 Dec;52(1):201-217. doi: 10.1080/21691401.2024.2326616. Epub 2024 Mar 15.ABSTRACTThe main purpose of this study was to explore the changes of biomarkers in different developmental stages of bleomycin-induced pulmonary fibrosis (PF) in rats via comprehensive pathophysiology, UPLC-QTOF/MS metabonomic technology, and 16S rRNA gene sequencing of intestinal microbiota. The rats were randomly divided into normal control and 1-, 2- and 4-week model group. The rat model of PF was established by one-time intratracheal instillation of bleomycin. The levels of inflammatory and fibrosis-related factors such as hydroxyproline (HYP), type III procollagen (COL-III), type IV collagen (COL-IV), hyaluronidase (HA), laminin (LN), interleukin (IL)-1β, IL-6, malondialdehyde (MDA) increased and superoxide dismutase (SOD) decreased as the PF cycle progressed. In the 1-, 2- and 4-week model group, 2, 19 and 18 potential metabolic biomarkers and 3, 16 and 12 potential microbial biomarkers were detected, respectively, which were significantly correlated. Glycerophospholipid metabolism pathway was observed to be an important pathway affecting PF at 1, 2 and 4 weeks; arginine and proline metabolism pathways significantly affected PF at 2 weeks. Linoleic acid metabolism pathway exhibited clear metabolic abnormalities at 2 and 4 weeks of PF, and alpha-linolenic acid metabolism pathway significantly affected PF at 4 weeks.PMID:38488151 | DOI:10.1080/21691401.2024.2326616

Food Funct. 2024 Mar 15. doi: 10.1039/d4fo90023e. Online ahead of print.ABSTRACTCorrection for 'Mechanisms of the ethanol extract of Gelidium amansii for slow aging in high-fat male Drosophila by metabolomic analysis' by Yushi Chen et al., Food Funct., 2022, 13, 10110-10120, https://doi.org/10.1039/D2FO02116A.PMID:38488026 | DOI:10.1039/d4fo90023e

Brief Bioinform. 2024 Jan 22;25(2):bbae087. doi: 10.1093/bib/bbae087.ABSTRACTThe major histocompatibility complex (MHC) encodes a range of immune response genes, including the human leukocyte antigens (HLAs) in humans. These molecules bind peptide antigens and present them on the cell surface for T cell recognition. The repertoires of peptides presented by HLA molecules are termed immunopeptidomes. The highly polymorphic nature of the genres that encode the HLA molecules confers allotype-specific differences in the sequences of bound ligands. Allotype-specific ligand preferences are often defined by peptide-binding motifs. Individuals express up to six classical class I HLA allotypes, which likely present peptides displaying different binding motifs. Such complex datasets make the deconvolution of immunopeptidomic data into allotype-specific contributions and further dissection of binding-specificities challenging. Herein, we developed MHCpLogics as an interactive machine learning-based tool for mining peptide-binding sequence motifs and visualization of immunopeptidome data across complex datasets. We showcase the functionalities of MHCpLogics by analyzing both in-house and published mono- and multi-allelic immunopeptidomics data. The visualization modalities of MHCpLogics allow users to inspect clustered sequences down to individual peptide components and to examine broader sequence patterns within multiple immunopeptidome datasets. MHCpLogics can deconvolute large immunopeptidome datasets enabling the interrogation of clusters for the segregation of allotype-specific peptide sequence motifs, identification of sub-peptidome motifs, and the exportation of clustered peptide sequence lists. The tool facilitates rapid inspection of immunopeptidomes as a resource for the immunology and vaccine communities. MHCpLogics is a standalone application available via an executable installation at: https://github.com/PurcellLab/MHCpLogics.PMID:38487848 | DOI:10.1093/bib/bbae087

iScience. 2024 Feb 23;27(4):109315. doi: 10.1016/j.isci.2024.109315. eCollection 2024 Apr 19.ABSTRACTAs the only cell type responsible for oxygen delivery, erythrocytes play a crucial role in supplying oxygen to hypoxic tissues, ensuring their normal functions. Hypoxia commonly occurs under physiological or pathological conditions, and understanding how erythrocytes adapt to hypoxia is fundamental for exploring the mechanisms of hypoxic diseases. Additionally, investigating acute and chronic mountain sickness caused by plateaus, which are naturally hypoxic environments, will aid in the study of hypoxic diseases. In recent years, increasingly developed proteomics and metabolomics technologies have become powerful tools for studying mature enucleated erythrocytes, which has significantly contributed to clarifying how hypoxia affects erythrocytes. The aim of this article is to summarize the composition of the cytoskeleton and cytoplasmic proteins of hypoxia-altered erythrocytes and explore the impact of hypoxia on their essential functions. Furthermore, we discuss the role of microRNAs in the adaptation of erythrocytes to hypoxia, providing new perspectives on hypoxia-related diseases.PMID:38487547 | PMC:PMC10937114 | DOI:10.1016/j.isci.2024.109315

Front Immunol. 2024 Feb 29;15:1342837. doi: 10.3389/fimmu.2024.1342837. eCollection 2024.ABSTRACTDiabetic kidney disease (DKD) is becoming the leading cause of chronic kidney disease, especially in the industrialized world. Despite mounting evidence has demonstrated that immunity and inflammation are highly involved in the pathogenesis and progression of DKD, the underlying mechanisms remain incompletely understood. Substantial molecules, signaling pathways, and cell types participate in DKD inflammation, by integrating into a complex regulatory network. Most of the studies have focused on individual components, without presenting their importance in the global or system-based processes, which largely hinders clinical translation. Besides, conventional technologies failed to monitor the different behaviors of resident renal cells and immune cells, making it difficult to understand their contributions to inflammation in DKD. Recently, the advancement of omics technologies including genomics, epigenomics, transcriptomics, proteomics, and metabolomics has revolutionized biomedical research, which allows an unbiased global analysis of changes in DNA, RNA, proteins, and metabolites in disease settings, even at single-cell and spatial resolutions. They help us to identify critical regulators of inflammation processes and provide an overview of cell heterogeneity in DKD. This review aims to summarize the application of multiple omics in the field of DKD and emphasize the latest evidence on the interplay of inflammation and DKD revealed by these technologies, which will provide new insights into the role of inflammation in the pathogenesis of DKD and lead to the development of novel therapeutic approaches and diagnostic biomarkers.PMID:38487541 | PMC:PMC10937589 | DOI:10.3389/fimmu.2024.1342837

Front Endocrinol (Lausanne). 2024 Feb 29;15:1285666. doi: 10.3389/fendo.2024.1285666. eCollection 2024.ABSTRACTOBJECTIVE: Precocious puberty (PP) is a prevalent endocrine disorder affecting the physical and mental wellbeing of children. Identifying the triggering factors of PP has become a central issue. This study seeks to investigate the metabolomic and transcriptomic alterations in PP.MATERIAL AND METHODS: First, 37 school-aged girls diagnosed with PP and 25 age-matched prepubertal control girls were recruited, and the fecal samples were collected for non-targeted metabolomic analysis to screen for differentially expressed metabolites (DEMs). Subsequently, an animal model of PP was constructed by danazol administration to neonatal female rats, and both fecal non-targeted metabolomics and serum next-generation transcriptomic sequencing were performed to screen DEMs and differentially expressed genes (DEGs) in PP. Moreover, the DEM co-existing in clinical and animal models was administrated to PP rats to explore the role of the target metabolite in PP.RESULTS: A total of 24 DEMs in PP clinical samples and 180 DEMs and 425 DEGs in PP animal samples were identified. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that these DEMs and DEGs were enriched in disease-associated pathways, including fatty acid synthesis, glycerolipid metabolism, pyrimidine metabolism, steroid hormone biosynthesis, progesterone-mediated oocyte maturation, and gonadotropin-releasing hormone (GnRH) signaling pathway, forming a tight DEM-DEG pathway regulatory network. Further DEM validation demonstrated that thymine supplementation delayed the opening of the vagina and development of PP in model rats.CONCLUSION: This study reveals that the metabolomic and transcriptomic changes, along with enriched pathways, are implicated in PP based on clinical and animal analyses. The findings may provide new strategies and research avenues for PP treatment.PMID:38487340 | PMC:PMC10937432 | DOI:10.3389/fendo.2024.1285666

PNAS Nexus. 2024 Mar 4;3(3):pgae097. doi: 10.1093/pnasnexus/pgae097. eCollection 2024 Mar.ABSTRACTCytosolic sulfotransferases (SULTs) are cytosolic enzymes that catalyze the transfer of sulfonate group to key endogenous compounds, altering the physiological functions of their substrates. SULT enzymes catalyze the O-sulfonation of hydroxy groups or N-sulfonation of amino groups of substrate compounds. In this study, we report the discovery of C-sulfonation of α,β-unsaturated carbonyl groups mediated by a new SULT enzyme, SULT7A1, and human SULT1C4. Enzymatic assays revealed that SULT7A1 is capable of transferring the sulfonate group from 3'-phosphoadenosine 5'-phosphosulfate to the α-carbon of α,β-unsaturated carbonyl-containing compounds, including cyclopentenone prostaglandins as representative endogenous substrates. Structural analyses of SULT7A1 suggest that the C-sulfonation reaction is catalyzed by a novel mechanism mediated by His and Cys residues in the active site. Ligand-activity assays demonstrated that sulfonated 15-deoxy prostaglandin J2 exhibits antagonist activity against the prostaglandin receptor EP2 and the prostacyclin receptor IP. Modification of α,β-unsaturated carbonyl groups via the new prostaglandin-sulfonating enzyme, SULT7A1, may regulate the physiological function of prostaglandins in the gut. Discovery of C-sulfonation of α,β-unsaturated carbonyl groups will broaden the spectrum of potential substrates and physiological functions of SULTs.PMID:38487162 | PMC:PMC10939482 | DOI:10.1093/pnasnexus/pgae097

EXCLI J. 2024 Feb 13;23:264-282. doi: 10.17179/excli2023-6785. eCollection 2024.ABSTRACTSpontaneous preterm delivery presents one of the most complex challenges in obstetrics and is a leading cause of perinatal morbidity and mortality. Although it is a common endpoint for multiple pathological processes, the mechanisms governing the etiological complexity of spontaneous preterm birth and the placental responses are poorly understood. This study examined placental tissues collected between May 2019 and May 2022 from a well-defined cohort of women who experienced spontaneous preterm birth (n = 72) and healthy full-term deliveries (n = 30). Placental metabolomic profiling of polar metabolites was performed using Ultra-High Performance Liquid Chromatography/Mass Spectrometry (UHPLC/MS) analysis. The resulting data were analyzed using multi- and univariate statistical methods followed by unsupervised clustering. A comprehensive metabolomic evaluation of the placenta revealed that spontaneous preterm birth was associated with significant changes in the levels of 34 polar metabolites involved in intracellular energy metabolism and biochemical activity, including amino acids, purine metabolites, and small organic acids. We found that neither the preterm delivery phenotype nor the inflammatory response explain the reported differential placental metabolome. However, unsupervised clustering revealed two molecular subtypes of placentas from spontaneous preterm pregnancies exhibiting differential enrichment of clinical parameters. We also identified differences between early and late preterm samples, suggesting distinct placental functions in early spontaneous preterm delivery. Altogether, we present evidence that spontaneous preterm birth is associated with significant changes in the level of placental polar metabolites. Dysregulation of the placental metabolome may underpin important (patho)physiological mechanisms involved in preterm birth etiology and long-term neonatal outcomes.PMID:38487084 | PMC:PMC10938235 | DOI:10.17179/excli2023-6785

Front Cardiovasc Med. 2024 Feb 29;11:1346443. doi: 10.3389/fcvm.2024.1346443. eCollection 2024.ABSTRACTBACKGROUND: Pulmonary artery (PA) strain is associated with structural and functional alterations of the vessel and is an independent predictor of cardiovascular events. The relationship of PA strain to metabolomics in participants without cardiovascular disease is unknown.METHODS: In the current study, community-based older adults, without known cardiovascular disease, underwent simultaneous cine cardiovascular magnetic resonance (CMR) imaging, clinical examination, and serum sampling. PA global longitudinal strain (GLS) analysis was performed by tracking the change in distance from the PA bifurcation to the pulmonary annular centroid, using standard cine CMR images. Circulating metabolites were measured by cross-sectional targeted metabolomics analysis.RESULTS: Among n = 170 adults (mean age 71 ± 6.3 years old; 79 women), mean values of PA GLS were 16.2 ± 4.4%. PA GLS was significantly associated with age (β = -0.13, P = 0.017), heart rate (β = -0.08, P = 0.001), dyslipidemia (β = -2.37, P = 0.005), and cardiovascular risk factors (β = -2.49, P = 0.001). Alanine (β = -0.007, P = 0.01) and proline (β = -0.0009, P = 0.042) were significantly associated with PA GLS after adjustment for clinical risk factors. Medium and long-chain acylcarnitines were significantly associated with PA GLS (C12, P = 0.027; C12-OH/C10-DC, P = 0.018; C14:2, P = 0.036; C14:1, P = 0.006; C14, P = 0.006; C14-OH/C12-DC, P = 0.027; C16:3, P = 0.019; C16:2, P = 0.006; C16:1, P = 0.001; C16:2-OH, P = 0.016; C16:1-OH/C14:1-DC, P = 0.028; C18:1-OH/C16:1-DC, P = 0.032).CONCLUSION: By conventional CMR, PA GLS was associated with aging and vascular risk factors among a contemporary cohort of older adults. Metabolic pathways involved in PA stiffness may include gluconeogenesis, collagen synthesis, and fatty acid oxidation.PMID:38486706 | PMC:PMC10937542 | DOI:10.3389/fcvm.2024.1346443

Biomed Chromatogr. 2024 Mar 14:e5853. doi: 10.1002/bmc.5853. Online ahead of print.ABSTRACTQingxuan Zhike granules (QXZKG), a traditional Chinese patent medication, has shown therapeutic potential against acute lung injury (ALI). However, the precise mechanism underlying its lung-protective effects requires further investigation. In this study, integrated network pharmacology, molecular docking, and lipidomics were used to elucidate QXZKG's regulatory effect on lipid metabolism in lipopolysaccharide-induced ALI. Animal experiments were conducted to substantiate the efficacy of QXZKG in reducing pro-inflammatory cytokines and mitigating pulmonary pathology. Network pharmacology analysis identified 145 active compounds that directly targeted 119 primary targets of QXZKG against ALI. Gene Ontology function analysis emphasized the roles of lipid metabolism and mitogen-activated protein kinase (MAPK) cascade as crucial biological processes. The MAPK1 protein exhibited promising affinities for naringenin, luteolin, and kaempferol. Lipidomic analysis revealed that 12 lipids showed significant restoration following QXZKG treatment (p < 0.05, FC >1.2 or <0.83). Specifically, DG 38:4, DG 40:7, PC O-40:8, TG 18:1_18:3_22:6, PI 18:2_20:4, FA 16:3, FA 20:3, FA 20:4, FA 22:5, and FA 24:5 were downregulated, while Cer 18:0;2O/24:0 and SM 36:1;2O/34:5 were upregulated in the QXZKG versus model groups. This study enhances our understanding of the active compounds and targets of QXZKG, as well as the potential of lipid metabolism in the treatment of ALI.PMID:38486466 | DOI:10.1002/bmc.5853

Ital J Pediatr. 2024 Mar 14;50(1):52. doi: 10.1186/s13052-024-01601-4.ABSTRACTBACKGROUND: Orthostatic intolerance, which includes vasovagal syncope and postural orthostatic tachycardia syndrome, is common in children and adolescents. Elevated plasma homocysteine levels might participate in the pathogenesis of orthostatic intolerance. This study was designed to analyze the plasma metabolomic profile in orthostatic intolerance children with high levels of plasma homocysteine.METHODS: Plasma samples from 34 orthostatic intolerance children with a plasma homocysteine concentration > 9 µmol/L and 10 healthy children were subjected to ultra-high-pressure liquid chromatography and quadrupole-time-of-flight mass spectrometry analysis.RESULTS: A total of 875 metabolites were identified, 105 of which were significantly differential metabolites. Choline, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine, 1-(1Z-octadecenyl)-2-(4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoyl)-sn-glycero-3-phosphocholine, histidine, isocitric acid, and DL-glutamic acid and its downstream metabolites were upregulated, whereas 1-palmitoyl-sn-glycero-3-phosphocholine, 1-stearoyl-sn-glycerol 3-phosphocholine, sphingomyelin (d18:1/18:0), betaine aldehyde, hydroxyproline, and gamma-aminobutyric acid were downregulated in the orthostatic intolerance group compared with the control group. All these metabolites were related to choline and glutamate. Heatmap analysis demonstrated a common metabolic pattern of higher choline, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine, and DL-glutamic acid, and lower sphingomyelin (d18:1/18:0), 1-stearoyl-sn-glycerol 3-phosphocholine, and 1-palmitoyl-sn-glycero-3-phosphocholine in patients with certain notable metabolic changes (the special group) than in the other patients (the common group). The maximum upright heart rate, the change in heart rate from the supine to the upright position, and the rate of change in heart rate from the supine to the upright position of vasovagal syncope patients were significantly higher in the special group than in the common group (P < 0.05). Choline, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine, and DL-glutamic acid were positively correlated with the rate of change in heart rate from the supine to the upright position in vasovagal syncope patients (P < 0.05).CONCLUSIONS: The levels of choline-related metabolites and glutamate-related metabolites changed significantly in orthostatic intolerance children with high levels of plasma homocysteine, and these changes were associated with the severity of illness. These results provided new light on the pathogenesis of orthostatic intolerance.PMID:38486257 | DOI:10.1186/s13052-024-01601-4

Genome Biol. 2024 Mar 14;25(1):70. doi: 10.1186/s13059-024-03200-2.ABSTRACTBACKGROUND: Extensive research has been conducted on fruit development in crops, but the metabolic regulatory networks underlying perennial fruit trees remain poorly understood. To address this knowledge gap, we conduct a comprehensive analysis of the metabolome, proteome, transcriptome, DNA methylome, and small RNAome profiles of pear fruit flesh at 11 developing stages, spanning from fruitlet to ripening. Here, we systematically investigate the metabolic landscape and regulatory network involved.RESULTS: We generate an association database consisting of 439 metabolites and 14,399 genes to elucidate the gene regulatory network of pear flesh metabolism. Interestingly, we detect increased DNA methylation in the promoters of most genes within the database during pear flesh development. Application of a DNA methylation inhibitor to the developing fruit represses chlorophyll degradation in the pericarp and promotes xanthophyll, β-carotene, and abscisic acid (ABA) accumulation in the flesh. We find the gradual increase in ABA production during pear flesh development is correlated with the expression of several carotenoid pathway genes and multiple transcription factors. Of these transcription factors, the zinc finger protein PbZFP1 is identified as a positive mediator of ABA biosynthesis in pear flesh. Most ABA pathway genes and transcription factors are modified by DNA methylation in the promoters, although some are induced by the DNA methylation inhibitor. These results suggest that DNA methylation inhibits ABA accumulation, which may delay fruit ripening.CONCLUSION: Our findings provide insights into epigenetic regulation of metabolic regulatory networks during pear flesh development, particularly with regard to DNA methylation.PMID:38486226 | DOI:10.1186/s13059-024-03200-2