PubMed

Sci Rep. 2024 Nov 28;14(1):29570. doi: 10.1038/s41598-024-80955-5.ABSTRACTMass spectrometry (MS)-based metabolomics analysis is a powerful tool, but it comes with its own set of challenges. The MS workflow involves multiple steps before its interpretation in what is denominate data mining. Data mining consists of a two-step process. First, the MS data is ordered, arranged, and presented for filtering before being analyzed. Second, the filtered and reduced data are analyzed using statistics to remove further variability. This holds true particularly for MS-based untargeted metabolomics studies, which focused on understanding fold changes in metabolic networks. Since the task of filtering and identifying changes from a large dataset is challenging, automated techniques for mining untargeted MS-based metabolomic data are needed. The traditional statistics-based approach tends to overfilter raw data, which may result in the removal of relevant data and lead to the identification of fewer metabolomic changes. This limitation of the traditional approach underscores the need for a new method. In this work, we present a novel deep learning approach using node embeddings (powered by GNNs), edge embeddings, and anomaly detection algorithm to analyze the data generated by mass spectrometry (MS)-based metabolomics called GEMNA (Graph Embedding-based Metabolomics Network Analysis), for example for an untargeted volatile study on Mentos candy, the data clusters produced by GEMNA were better than the ones used traditional tools, i.e., GEMNA has [Formula: see text], vs. the traditional approach has [Formula: see text].PMID:39609505 | DOI:10.1038/s41598-024-80955-5

Sci Rep. 2024 Nov 28;14(1):29632. doi: 10.1038/s41598-024-78537-6.NO ABSTRACTPMID:39609490 | DOI:10.1038/s41598-024-78537-6

Cell Death Discov. 2024 Nov 28;10(1):484. doi: 10.1038/s41420-024-02232-8.ABSTRACTArrhythmogenic Cardiomyopathy (ACM) is a life-threatening, genetically determined disease primarily caused by mutations in desmosomal genes, such as PKP2. Currently, there is no etiological therapy for ACM due to its complex and not fully elucidated pathogenesis. Various cardiac cell types affected by the genetic mutation, such as cardiomyocytes (CM) and cardiac mesenchymal stromal cells (cMSC), individually contribute to the ACM phenotype, driving functional abnormalities and fibro-fatty substitution, respectively. However, the relative importance of the CM and cMSC alterations, as well as their reciprocal influence in disease progression remain poorly understood. We hypothesised that ACM-dependent phenotypes are driven not only by alterations in individual cell types but also by the reciprocal interactions between CM and cMSC, which may further impact disease pathogenesis. We utilized a patient-specific, multicellular cardiac system composed of either control or PKP2-mutated CM and cMSC to assess the mutation's role in fibro-fatty phenotype by immunofluorescence, and contractile behaviour of co-cultures using cell motion detection software. Additionally, we investigated reciprocal interactions both in silico and via multi-targeted proteomics. We demonstrated that ACM CM can promote fibro-adipose differentiation of cMSC. Conversely, ACM cMSC contribute to increasing the rate of abnormal contractile events with likely arrhythmic significance. Furthermore, we showed that an ACM-causative mutation alters the CM-cMSC interaction pattern. We identified the CM-sourced DLK1 as a novel regulator of fibro-adipose remodelling in ACM. Our study challenges the paradigm of exclusive cell-specific mechanisms in ACM. A deeper understanding of the cell-cell influence is crucial for identifying novel therapeutic targets for ACM, and this concept is exploitable for other cardiomyopathies.PMID:39609399 | DOI:10.1038/s41420-024-02232-8

Nat Commun. 2024 Nov 28;15(1):9903. doi: 10.1038/s41467-024-54137-w.ABSTRACTLipidomics and metabolomics communities comprise various informatics tools; however, software programs handling multimodal mass spectrometry (MS) data with structural annotations guided by the Lipidomics Standards Initiative are limited. Here, we provide MS-DIAL 5 for in-depth lipidome structural elucidation through electron-activated dissociation (EAD)-based tandem MS and determining their molecular localization through MS imaging (MSI) data using a species/tissue-specific lipidome database containing the predicted collision-cross section values. With the optimized EAD settings using 14 eV kinetic energy, the program correctly delineated lipid structures for 96.4% of authentic standards, among which 78.0% had the sn-, OH-, and/or C = C positions correctly assigned at concentrations exceeding 1 μM. We showcased our workflow by annotating the sn- and double-bond positions of eye-specific phosphatidylcholines containing very-long-chain polyunsaturated fatty acids (VLC-PUFAs), characterized as PC n-3-VLC-PUFA/FA. Using MSI data from the eye and n-3-VLC-PUFA-supplemented HeLa cells, we identified glycerol 3-phosphate acyltransferase as an enzyme candidate responsible for incorporating n-3 VLC-PUFAs into the sn1 position of phospholipids in mammalian cells, which was confirmed using EAD-MS/MS and recombinant proteins in a cell-free system. Therefore, the MS-DIAL 5 environment, combined with optimized MS data acquisition methods, facilitates a better understanding of lipid structures and their localization, offering insights into lipid biology.PMID:39609386 | DOI:10.1038/s41467-024-54137-w

Phytochem Anal. 2024 Nov 28. doi: 10.1002/pca.3481. Online ahead of print.ABSTRACTINTRODUCTION: Determining the bittering profile of hops is a prerequisite for their use in beer making industry. To fully grasp the brewing potential of Corsican hops, it is therefore essential to perform a precise quantification of the molecules responsible for their bittering power.OBJECTIVE: The aim of this study is highlighting of the bittering profile of Corsican hops.METHODOLOGY: A method for the characterization and quantification of α-acids, β-acids, and phenolic compounds in Corsican hops using high performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) has been developed. In addition to the six α- and β-acids commonly quantified in hops, seven others hop acids were identified using a new methodology based on the analysis of their fragmentation pattern in full-scan detection mode. The compounds were then quantified as humulone or lupulone equivalents. Subsequently, a metabolomic analysis of hop cones was conducted using the method of molecular networking.RESULTS: A total of 28 compounds were quantified. The influence of both annual climate variations and transplantation on the chemical composition of hops extractives was highlighted. The molecular network elucidation led to the identification of 34 compounds. Among them, eight were previously undescribed in hops, including one previously unknown to the literature.CONCLUSION: The methodologies developed in this study have shed light on the "bittering" potential of Corsican hops which represents a significant economic opportunity for the local brewing industry potentially establishing a new, sustainable, and profitable hops market. This work focuses extensively on the phenolic compounds and the bittering acids of Corsican hops, aiming to highlight their unique organoleptic characteristics and the influence of the Corsican terroir on their chemical composition and abundance.PMID:39609247 | DOI:10.1002/pca.3481

ACS Nano. 2024 Nov 28. doi: 10.1021/acsnano.4c12801. Online ahead of print.ABSTRACTIntestinal dysbiosis and the associated l-tryptophan metabolic disorder are pivotal in inflammatory bowel disease progression, leading to a compromised intestinal barrier integrity. Remedying the dysfunction in tryptophan metabolism has emerged as a promising therapeutic strategy. Herein, we reprogram the tryptophan metabolism in situ by EcN-TRP@A/G, encapsulating the engineered probiotic, EcN-TRP, with enhanced tryptophan synthesis capacity, for sustained modulation, thereby restoring intestinal barrier function and microbial homeostasis. The pH-responsive dual-layered EcN-TRP@A/G microcapsule developed via high-voltage electrospraying and liquid interface self-assembly, preserved probiotic viability in the harsh gastrointestinal milieu, and facilitated targeted colon release. Bioluminescent tracking in mice reveals a 22.84-fold increase in EcN-TRP@A/G viability and distribution compared to naked EcN-TRP. Targeted metabolomics highlights EcN-TRP@A/G's modulation of the tryptophan-indole pathway. Oral administration of EcN-TRP@A/G sustained elevates indole metabolites, particularly indole-3-acetic acid and indole-3-propionic acid, in colon tissue for up to 7 days. In IBD mice, EcN-TRP@A/G improves intestinal permeability, reduces inflammation, and recovers the gut microbiome by enhancing beneficial bacteria abundance like Prevotellaceae_UCG-001 and Anaerostipes while suppressing pathogenic strains like Escherichia-Shigella. Our findings offer a cost-effective approach, harnessing the probiotic metabolic potential in situ through engineered modifications for effective IBD treatment.PMID:39609102 | DOI:10.1021/acsnano.4c12801

BMJ Open. 2024 Nov 27;14(11):e078660. doi: 10.1136/bmjopen-2023-078660.ABSTRACTINTRODUCTION: Dementia is one of the leading causes of disability among older people aged 60 years and above, with majority eventually being diagnosed with Alzheimer's disease (AD). Pharmacological agents approved for dementia include acetylcholinesterase enzyme (AChE) inhibitors like rivastigmine, donepezil and galantamine and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine, prescribed as monotherapy or in combination with each other, depending on the severity of disease. There is currently no available study demonstrating the clinical response to these drugs for AD in the Filipino population. Hence, this protocol aims to characterise the clinical, genetic, microbial and metabolic factors associated with drug responses to donepezil, rivastigmine and/or memantine for AD in a cohort of Filipinos with late-onset AD.METHODS AND ANALYSIS: This protocol involves a multisite descriptive study that will use two study designs: (1) a descriptive, cross-sectional study to characterise the clinical profile of Filipino dementia patients with AD and (2) an exploratory prospective cohort study to investigate drug response-related genetic, gut microbiome and metabolome signatures of a subset of the recruited AD patients. At least 153 patients with mild or moderate AD aged 65 years old and above will be recruited regardless of their treatment status. A subset of these patients (n=60) who meet inclusion and exclusion criteria will be included further in the exploratory cohort study. These patients will be grouped according to their baseline medications and will be observed for treatment response in 6 months. The cognitive, functional and behavioural domains of patients and levels of functioning will be measured using different assessment tools. Drug responses of Filipino patients will then be investigated employing multi-omics technology to characterise genetic variations via whole exome sequencing, gut microbiome profile via shotgun metagenomic sequencing and metabolome profile via liquid chromatography with mass spectrometry.ETHICS AND DISSEMINATION: The study has received ethical clearance from the Department of Health Single Joint Research Ethics Board (SJREB-2022-15). Results of psychometric scales will be made available to enrolled patients. The study results will be presented at national/international conferences and published in international peer-reviewed scientific journals, and summaries of the results will be provided to the study funders and institutional review boards of the three tertiary referral hospitals.TRIAL REGISTRATION NUMBER: Philippine Health Research Registry ID PHRR230220-0054116; ClinicalTrials.gov ID NCT05801380.PMID:39608999 | DOI:10.1136/bmjopen-2023-078660

J Biol Chem. 2024 Nov 26:108019. doi: 10.1016/j.jbc.2024.108019. Online ahead of print.ABSTRACTBenzoxazinoids (BXDs) are important defense compounds produced by a number of species from different, evolutionarily unrelated plant families. While BXD biosynthesis has been extensively studied in the grasses (monocots) and core eudicots, the mechanism of BXD synthesis in the basal eudicots is still unclear. We used an integrated metabolomics and transcriptomics approach to elucidate the BXD pathway in Consolida orientalis, a Ranunculaceae species known to produce the BXD DIBOA-Glc. Overexpression of candidate genes in Nicotiana benthamiana identified a flavin-dependent monooxygenase (CoBX2-3) and two cytochrome P450 enzymes (CoBX4 and CoBX5) that catalyze the oxidation steps that transform indole into DIBOA. Co-expression of CoBx2-3, CoBx4, and CoBx5 with the previously described indole synthase gene CoBx1 and the UDP-glucosyltransferase gene CoBx8 in N. benthamiana resulted in the reconstitution of a fully active BXD pathway. The fact that CoBX2-3, CoBX4, and CoBX5 are not phylogenetically related to their counterparts in the grasses and core eudicots suggests independent evolution of benzoxazinoids biosynthesis in these three angiosperm lineages.PMID:39608711 | DOI:10.1016/j.jbc.2024.108019

J Ethnopharmacol. 2024 Nov 26:119160. doi: 10.1016/j.jep.2024.119160. Online ahead of print.ABSTRACTBACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation, bone and cartilage damage, musculoskeletal pain, swelling, and stiffness. Inflammation is one of the key factors that induce RA. Jingfang Granule (JFG) is a traditional Chinese medicine (TCM) with significant anti-inflammatory effects. Clinical studies have confirmed that JFG can be used to treat RA, but the mechanism is still vague.PURPOSE: This study was designed to evaluate the protective function and the mechanism of JFG on rats with RA.STUDY DESIGN AND METHODS: Complete Freud's Adjuvant (CFA) was used to establish a rat RA model, and JFG or Diclofenac Sodium (Dic) was orally administered. Foot swelling and hematoxylin eosin (H&E) staining were used to test the therapeutic effect of JFG on RA treatment, while ELISA kits were used to detect serum cytokines. Malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), and reactive oxygen species (ROS) were used to evaluate oxidative stress levels. The integration of label free proteomics, fecal short chain fatty acid (SCFA) targeted metabolomics, peripheral blood SCFA, medium and long chain fatty acid targeted metabolomics, and 16S rDNA sequencing of gut microbiota were used to screen the mechanism. Western blot technology was used to validate the results of multiple omics studies. Serum D-Lactic acid, lipopolysaccharide specific IgA antibody (LPS IgA), diamine oxidase (DAO), and colon Claudin 5 and ZO-1 were used to evaluate the intestinal barrier.RESULTS: The results confirmed that JFG effectively protected rats from RA injury, which was confirmed by improved foot swelling and synovial pathology. At the same time, JFG reduced the levels of TNF-α, IL-1β, and IL-6 in serum by inhibiting the NLRP3 inflammasome signaling pathway and TLR4/NF-κB signaling pathway in synovial tissue. Multiple omics studies indicated that JFG increased the abundance of gut microbiota and regulated the number of gut bacteria, thereby increased the levels of Acetic acid, Propionic acid, and Butyric acid in the gut and serum of RA rats, which activated AMPK to regulate fatty acid metabolism and fatty acid biosynthesis, thereby inhibited lipid oxidative stress induced ferroptosis to improve tissue damage caused by RA. Meanwhile, JFG improved the intestinal barrier by upregulating the expresses of Claudin 5 and ZO-1, which was confirmed by low concentrations of D-Lactic acid, LPS-SIgA and DAO in serum.CONCLUSIONS: This study confirmed that JFG improved the disturbance of fatty acid metabolism by modulating gut microbiota and the production of fecal SCFAs to activate AMPK, and then inhibited ferroptosis caused by lipid oxidative stress in synovium tissue and prevented AR injury. This study proposes for the first time to investigate the mechanism of JFG treatment for RA from the perspective of the "Gut-joint" axis, and provides a promising approach for the treatment of RA.PMID:39608616 | DOI:10.1016/j.jep.2024.119160

Mol Cell Proteomics. 2024 Nov 26:100887. doi: 10.1016/j.mcpro.2024.100887. Online ahead of print.ABSTRACTThe foundation of all biological processes is the network of diverse and dynamic protein interactions with other molecules in cells known as the interactome. Understanding the interactome is crucial for elucidating molecular mechanisms but has been a longstanding challenge. Recent developments in mass spectrometry (MS)-based techniques, including affinity purification, proximity labeling, cross-linking, and co-fractionation mass spectrometry (MS), have significantly enhanced our abilities to study the interactome. They do so by identifying and quantifying protein interactions, yielding profound insights into protein organizations and functions. This review summarizes recent advances in MS-based interactomics, focusing on the development of techniques that capture protein-protein, protein-metabolite, and protein-nucleic acid interactions. Additionally, we discuss how integrated MS-based approaches have been applied to diverse biological samples, focusing on significant discoveries that have leveraged our understanding of cellular functions. Finally, we highlight state-of-the-art bioinformatic approaches for predictions of interactome and complex modeling, as well as strategies for combining experimental interactome data with computation methods, thereby enhancing the ability of MS-based techniques to identify protein interactomes. Indeed, advances in MS technologies and their integrations with computational biology provide new directions and avenues for interactome research, leveraging new insights into mechanisms that govern the molecular architecture of living cells and, thereby, our comprehension of biological processes.PMID:39608603 | DOI:10.1016/j.mcpro.2024.100887

Int J Biol Macromol. 2024 Nov 26:138122. doi: 10.1016/j.ijbiomac.2024.138122. Online ahead of print.ABSTRACTOral intake of probiotics is a promising approach to alleviate colitis. However, environmental sensitivity of the gastrointestinal tract and poor adhesion of probiotics to the intestine hamper the remedial effects. In this study, a simple yet effective novel probiotic multilayer coating consisting of Fe3+-protocatechuic acid (PCA) crosslinked network and Ca2+-induced sodium alginate (SA) for arming Lactiplantibacillus plantarum (LP) was developed. In the dextran sulfate sodium-induced colitis mouse model, SA-PCA-LP effectively alleviated colitis by regulating the expression of inflammatory cytokines, and repairing gut barriers. In addition, SA-PCA-LP regulated the gut microbiota and promoted the production of short-chain fatty acids, which further promoted the remission of colitis. Untargeted metabolomics also revealed that the scymnol, adenosine 5'-monophosphat, guanidylic acid, and 9H-purine-9-ol were significantly up-regulated in SA-PCA-LP group. In general, the novel coating strategies developed in the present study will motivate researchers to arm probiotics with various prebiotics to effectively alleviate colitis.PMID:39608540 | DOI:10.1016/j.ijbiomac.2024.138122

Microb Pathog. 2024 Nov 26:107162. doi: 10.1016/j.micpath.2024.107162. Online ahead of print.ABSTRACTXanthomonas campestris pathovar campestris (Xcc) is the pathogen responsible for causing black rot in cruciferous plants. In this study, we show that mutation of AAW18_RS04175 (pacR, encodes a hypothetical protein containing a domain of unknown function, DUF1631) of Xcc strain Xc17 had decreased bacterial attachment, exopolysaccharide production, hypersensitive response and virulence. Furthermore, the pacR mutant exhibited reduced cell membrane integrity and outer membrane vesicle production. Transcriptomic analysis indicated that 225 genes were differentially expressed following pacR mutation. These genes can be classified into various functional categories, such as the type three secretion system and membrane component. Among them, genes associated with attachment, exopolysaccharide synthesis, the type three secretion system, and nucleotide metabolism were further verified by quantitative RT-PCR. Metabolomic analysis showed that 81 and 132 metabolites in positive and negative modes, respectively, were altered after pacR mutation. Among the identified metabolites, some are known to belong to different pathways, such as biosynthesis of secondary metabolites, microbial metabolism in diverse environments, and nucleotide and purine metabolism, while others have not been previously documented in microbial systems. Additionally, the transcription initiation point of pacR was mapped, and promoter analysis indicated that pacR expression is influenced by different conditions. Taken together, our findings advance the understanding of PacR function and expression in Xcc and offer new insights into the role of the DUF1631-containing hypothetical protein in bacterial physiology.PMID:39608507 | DOI:10.1016/j.micpath.2024.107162

Metabolism. 2024 Nov 26:156085. doi: 10.1016/j.metabol.2024.156085. Online ahead of print.ABSTRACTBACKGROUND: Evidence is limited regarding the association of circulating metabolites with decline of kidney function, letting alone their value in prediction of development of chronic kidney disease (CKD).METHODS: This study included 3802 participants aged 64.1 ± 7.4 years from the Dongfeng-Tongji cohort, among whom 3327 were CKD-free at baseline (estimated glomerular filtration rate [eGFR] > 60 ml/min per 1.73 m2). We measured baseline levels of 211 metabolites with liquid chromatography coupled with mass spectrometry, including 25 amino acids, 12 acyl-carnitines, 161 lipids, and 13 other metabolites.RESULTS: The mean (SD) absolute annual change in eGFR was -0.14 ± 4.11 ml/min per 1.73 m2 per year, and a total of 472 participants who were free of CKD at baseline developed incident CKD during follow-up of 4.6 ± 0.2 years (14.2 %). We identified a total of 22 metabolites associated with annual eGFR change and survived Bonferroni correction for multiple testing, including seven metabolites associated with eGFR increase (six being docosahexaenoic acid [DHA]-containing lipids) and 15 associated with eGFR decline (nine being phosphatidylcholines [PCs]). Among them, eight metabolites obtained non-zero coefficients in least absolute shrinkage and selection operator (LASSO) regression on incident CKD, indicating predictive potential, including one amino acid (arginine), one acyl-carnitine (C2), one lysophosphatidylcholine (LPC 22:6), two PCs (32:1 and 34:3), one triacylglycerol (TAG 56:8 [22:6]) and two other metabolites (inosine, niacinamide), and the composite score of these eight metabolites showed an odds ratio (OR) of 8.79 (95 % confidence interval [CI]: 7.49, 10.32; P < 0.001) per SD increase in association with incident CKD. The addition of the metabolite score increased the c-statistic of the reference model of traditional risk factors (including baseline eGFR) by 0.065 (95 % CI: 0.046 to 0.084; P = 3.39 × 10-11) to 0.765 (0.742 to 0.788) in 1000 repetitions of 10-fold cross-validation, while the application of two advanced machine learning algorithms, random forest (RF), and extreme gradient boosting (XGBoost) models produced similar c-statistics, to 0.753 (0.729 to 0.777) and 0.778 (0.733 to 0.824) with increases of 0.074 (0.055 to 0.093; P = 4.11 × 10-14) and 0.073 (0.032 to 0.114; P = 4.00 × 10-4), respectively.CONCLUSIONS: In this study, we identified 22 metabolites associated with longitudinal eGFR change, nine of which were PCs and six were DHA-containing lipids. We screened out a panel of eight metabolites which improved prediction for the development of CKD by 9 % beyond traditional risk factors including baseline eGFR. Our findings highlighted involvement of lipid metabolism in kidney function impairment, and provided novel predictors for CKD risk.PMID:39608488 | DOI:10.1016/j.metabol.2024.156085

Plant Physiol Biochem. 2024 Nov 23;218:109327. doi: 10.1016/j.plaphy.2024.109327. Online ahead of print.ABSTRACTPhotosynthesis is a source of energy for various types of plant life activities and is essential for plant growth and development. Consequently, the study of photosynthetic mechanisms has been a hot spot. Leaf color mutants has always been ideal materials for exploring the mechanisms of chlorophyll metabolism and photosynthesis. In this study, we identified a leaf color mutant of 'Benihoppe' strawberry in the field, which exhibited a darker green leaf color compared with the wild type. The content of total chlorophyll and carotenoid in the mutant leaves was elevated by 7.44-20.23% and 8.9-21.92%, respectively, compared with that of the wild type. Additionally, net photosynthetic rate in the mutant increased by 20.13%. Further transcriptome analysis showed that significant upregulation of genes such as GLK1, PPR, and MORF9 in the mutant leaves, which promoted chloroplast development. The expression levels of UROD, PPOC, PORA, CHLG, and CPOX were significantly upregulated during chlorophyll synthesis, while the expression levels of HCAR and CYP89A9 were significantly downregulated during chlorophyll degradation, thus leading to the accumulation of chlorophyll in mutant leaves. The upregulation of gene expression levels such as PetM, AtpD, PGK, and RPI4 during photosynthesis promoted multiple stages of light and dark reaction, thereby enhancing the photosynthetic capacity of the mutant. And the changes in metabolites such as monogalactosyl monoacylglycerol (MGMG), glucuronosyldiacylglycerol (GlcADG), raffinose, etc. also indicate that the mutant has metabolic differences in chloroplast composition and photosynthesis compared to 'Benihoppe'. The above results not only deepen our understanding of the mechanism behind the dark-green leaf color in strawberry mutants but also provide potential genetic resources for cultivating strawberry varieties with enhanced photosynthetic capacity.PMID:39608287 | DOI:10.1016/j.plaphy.2024.109327

J Reprod Immunol. 2024 Nov 20;167:104398. doi: 10.1016/j.jri.2024.104398. Online ahead of print.ABSTRACTOBJECTIVE: This study aimed to delineate the metabolic differences and identify enriched pathways in the decidual tissue of patients with recurrent spontaneous abortion (RSA) compared to normal pregnant women.METHODS: A cohort of 25 RSA patients and 25 normal pregnant women was recruited for the study. Non-targeted metabolomic analysis of decidual tissue was conducted using high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS). Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were employed to identify differential metabolites. Pathway enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database to elucidate associated metabolic pathways. Quantitative polymerase chain reaction (qPCR) was utilized to assess the expression levels of key proteins related to these pathways, including acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), and indoleamine 2,3-dioxygenase (IDO).RESULTS: A total of 54 metabolites were identified with significant differences between the decidual tissues of RSA patients and normal controls, corresponding to 29 significantly enriched metabolic pathways (P<0.05). The expression of ACSL4 was markedly upregulated, while the expression of GPX4 and IDO were significantly downregulated in RSA patients (P<0.05).CONCLUSIONS: This study elucidates substantial metabolic disruptions in the decidual tissue of RSA patients, identifying 54 differential metabolites and 29 enriched pathways. The altered expression of ACSL4, GPX4, and IDO underscores their potential involvement in the pathogenesis of RSA. These findings provide critical insights into the metabolic mechanisms underlying RSA and suggest promising targets for diagnostic and therapeutic interventions.PMID:39608278 | DOI:10.1016/j.jri.2024.104398

Int Immunopharmacol. 2024 Nov 27;144:113685. doi: 10.1016/j.intimp.2024.113685. Online ahead of print.ABSTRACTChronic prostatitis and Pelvic Pain syndrome (CP/CPPS) is an autoimmune inflammatory disease characterized by pelvic or perineal pain and infiltration of inflammatory cells in the prostate. C-X-C chemokine receptor type 7 (CXCR7) is an atypical chemokine receptor that has been shown to play a key role in inflammatory processes in prostate cancer. However, the role of CXCR7 in autoimmune prostate and immune regulation in CP/CPPS along with the mechanism of action for CXCR7 remains unclear. In this study, a mouse model of experimental autoimmune prostatitis (EAP) was constructed by subcutaneous injection of antigen, and CXCR7 agonist was administered to investigate the effects of CXCR7 on the proportion of immune cells and fibrosis in CP/CPPS. Western blotting, immunohistochemical staining and immunofluorescence, flow cytometry, and masson's trichrome staining were used to study the regulatory mechanisms of CXCR7 in immune regulation. CXCR7 agonists can significantly reduce pain and prostatic inflammation, and in vivo flow cytometry studies showed that the antagonists restored the imbalance of the Th17/Treg cell ratio. To elucidate the potential mechanisms by which CXCR7 influences the pathogenesis of CP/CPPS, we conducted simultaneous RNA-seq and non-targeted metabolome sequencing. Our findings suggest that CXCR7 agonists alleviate fibrosis in autoimmune prostatitis by inhibiting the TGFβ/SMAD pathway. This study provides the foundation to target the immunological function of CXCR7 as a novel therapy for CP/CPPS.PMID:39608177 | DOI:10.1016/j.intimp.2024.113685

Int Immunopharmacol. 2024 Nov 27;144:113704. doi: 10.1016/j.intimp.2024.113704. Online ahead of print.ABSTRACTBACKGROUND: Clinically, hepatoma patients are more frequently encountered in the intermediate and advanced stages. Consequently, the majority of patients miss out on the chance to undergo liver transplantation or radical surgery. Radiotherapy and chemotherapy often fall short of delivering satisfactory outcomes. The incidence and mortality rates for liver cancer approach nearly 100%. In recent years, both exosomes (Exos) and natural chemical compounds have demonstrated robust anti-cancer properties; however, the synergistic effect of their combination remains unexplored.METHODS: Exos were extracted from human umbilical cord mesenchymal stem cells (hUC-MSCs). The impact of gallic acid (GA), hUC-MSCs-Exos, and their combined administration on the proliferation inhibition rate and apoptosis of SMMC-7721 hepatoma cells was assessed to ascertain the efficacy differences before and after the combined treatment. A combination of cells metabolomics and network pharmacology techniques was employed to investigate the underlying mechanisms of action. The pivotal targets associated with glycolysis, inflammation, and oxidative stress pathways were confirmed through ELISA assays.RESULTS: The findings elucidate that GA profoundly impedes the proliferation of SMMC-7721 hepatoma cells and instigates apoptotic processes therein. While the impact of hUC-MSCs-Exos alone was inconspicuous, a notable augmentation in effect ensued upon their combined application. Concomitantly, a marked reduction was observed in the expressionlevels of key enzymes including HK, PFK, PK, LDH, TNF-α, IL-1β, CAT, SOD and GSH-Px in the malignant hepatocytes, while IL-6 and MDA exhibited heightened expression. Pathway enrichment analysis underscored selenocompound metabolism and cysteine and methionine metabolism as pivotal pathways.CONCLUSION: The potentiated efficacy of GA conjunction with hUC-MSCs-Exos may be attributed to their synergistic modulation of anti-inflammatory, antioxidant, and glycolytic functions, thereby influencing selenocompound metabolism and cysteine and methionine metabolism. This study reveals the efficacy and mechanism of Exos and GA combined therapy for hepatoma, providing new methods and ideas for the clinical treatment of hepatoma.PMID:39608175 | DOI:10.1016/j.intimp.2024.113704

Food Chem. 2024 Nov 26;466:142263. doi: 10.1016/j.foodchem.2024.142263. Online ahead of print.ABSTRACTThis study analyzed human, goat, sheep, and pig milks using metabolomics, lipidomics, and proteomics, specifically untargeted LC-MS/MS metabolomics, untargeted LC-MS/MS lipidomics, and 4D-label-free proteomics. The aim was to determine differences among these milks and identify components with similar functions to human milk, providing a reference for the research and development of infant formulae. In goat milk, expression of lactoperoxidase, inosine, and allantoin were relatively high, while in sheep milk, concentrations of ceruloplasmin and alpha-ketoglutarate were higher. The content of linoleic acid (LA) was relatively high in both goat and sheep milks. A relatively high content of milk fat globule EGF factor 8 protein was found in pig milk.PMID:39608118 | DOI:10.1016/j.foodchem.2024.142263

Food Chem. 2024 Nov 15;466:142078. doi: 10.1016/j.foodchem.2024.142078. Online ahead of print.ABSTRACTLactic acid bacteria (LAB) fermentation can modify the antioxidant capacity of food. This study investigates the impact and mechanisms of various LAB strains (Lactobacillus plantarum NCU116, Lactobacillus acidophilus NCU402, and Lactobacillus casei NCU215) fermentation on the antioxidant properties of mango juice. LAB strains inoculation enhanced the antioxidant activity of mango juice, with metabolomics showing increased in polyphenols and decreased in vitamins and carotenoids, indicating polyphenols as the main contributors. Quantification of polyphenols (free and bound forms) revealed that fermentation decreased bound gallic acid levels while increasing free pyrogallol and 1,2,3,4,6-O-pentagalloylglucose, which mainly contributed to the rise in antioxidant capacity in mango juice. L. acidophilus NCU402 had the highest increase in 1,2,3,4,6-O-pentagalloylglucose (from 918.07 to 1750 μg/10 g), whereas L. casei NCU215 facilitated the greatest release of bound gallic acid (49.29 to 11.77 μg/10 g). Bound polyphenol release may be linked to pectin degradation, with lower galacturonic acid and increased pectinase activity.PMID:39608110 | DOI:10.1016/j.foodchem.2024.142078

ACS Chem Neurosci. 2024 Nov 28. doi: 10.1021/acschemneuro.4c00297. Online ahead of print.ABSTRACTImpulsive and compulsive behaviors are associated with inhibitory control deficits. Diet plays a pivotal role in normal development, impacting both physiology and behavior. However, the specific effects of a high-fat diet (HFD) on inhibitory control have not received adequate attention. This study aimed to explore how exposure to a HFD from postnatal day (PND) 33 to PND77 affects impulsive and compulsive behaviors. The experiment involved 40 Wistar rats subjected to HFD or chow diets. Several tasks were employed to assess behavior, including variable delay to signal (VDS), five choice serial reaction time task (5-CSRTT), delay discounting task (DDT), and rodent gambling task (rGT). Genetic analyses were performed on the frontal cortex, and metabolomics and fatty acid profiles were examined by using stool samples collected on PND298. Our results showed that the HFD group exhibited increased motor impulsive behaviors while not affecting cognitive impulsivity. Surprisingly, reduced impulsive decision-making was shown in the HFD group. Furthermore, abnormal brain plasticity and dopamine gene regulation were shown in the frontal cortex, while metabolomics revealed abnormal fatty acid levels.PMID:39607956 | DOI:10.1021/acschemneuro.4c00297