PubMed

Clin Chim Acta. 2024 Jul 17:119853. doi: 10.1016/j.cca.2024.119853. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Myocardial infarction (MI) and unstable angina (UA) exhibit overlapping symptoms, yet they require distinct management approaches. Identifying the metabolic differences between MI and UA may facilitate more precise diagnosis and treatment.MATERIALS AND METHODS: Metabolomic analysis was conducted on 95 patients, comprising 33 UA patients, 38 MI patients, and 24 normal controls. Serum metabolites were profiled using tandem mass spectrometry coupled with liquid chromatography.RESULTS: Metabolic analysis revealed notable differences in several metabolites, including xylidine, hydroxycaproic acid, butylbenzenesulfonamide, octanetriol, phosphocholine, and medronic acid, between MI and UA. These metabolites displayed promising diagnostic capabilities for distinguishing between MI and UA. Pathway analysis identified connections with cardiac hypertrophy, Wnt signaling, and fatty acid oxidation.CONCLUSION: Potential metabolite biomarkers and pathways differentially altered in MI compared to UA were identified in this metabolomics study. The results provide new insights into the metabolic signatures of these ischemic heart diseases. With further confirmation, improved early diagnosis and personalized treatment approaches could be facilitated.PMID:39029647 | DOI:10.1016/j.cca.2024.119853

Anal Biochem. 2024 Jul 17:115620. doi: 10.1016/j.ab.2024.115620. Online ahead of print.ABSTRACTGC-MS/MS combines the superior chromatographic resolution of GC with the specific and sensitive detection of tandem MS. On paper, it is an ideal system for the routine analyses of organic acids, yet very few studies have used and published such methods. This is likely due to several challenges highlighted in this communication. Briefly, the combination of EI ionization with MRM detection provides arguably insufficient specificity when targeting organic acids. Moreover, the narrow peaks generally produced by GC can lead to inaccurate quantification when the mass spectrometer's cycle time is too long. Potential solutions to these problems are discussed.PMID:39029642 | DOI:10.1016/j.ab.2024.115620

J Pharm Biomed Anal. 2024 Jul 15;249:116367. doi: 10.1016/j.jpba.2024.116367. Online ahead of print.ABSTRACTAngelica sinensis (Oliv.) Diels (AS) is a commonly used herbal medicine and culinary spice known for its gastrointestinal protective properties. Angelica sinensis oil (AO) is the main bioactive component of AS. However, the therapeutic effects and mechanisms of AO on the gastrointestinal tract remain unclear. In this study, we aim to investigated the potential of AO in restoring gut microbiota disorder and metabolic disruptions associated with ulcerative colitis (UC). A systematic chemical characterization of AO was conducted using GC×GC-Q TOF-MS. A UC mouse model was established by freely drinking DSS to assess the efficacy of AO. Utilizing 16 S rRNA sequencing in combination with untargeted metabolomics analysis of serum, we identified alterations in gut microbiota, differential metabolites, and pathways influenced by AO in UC treatment, thereby elucidating the therapeutic mechanism of AO in UC management. Pharmacodynamic results indicated that AO effectively inhibited the content of inflammation mediators, such as Interleukin-1β, Interleukin-6 and tumor necrosis factor-α, and proserved colon tissue integrity in UC mice. Furthermore, AO significantly downregulated the abundance of pathogenic bacteria (Bacteroidetes, Proteobacteria, and Desulfobacteriaceae) while increasing the abundance of beneficial bacteria (Firmicutes, Blautia, Akkermansia, and Lachnospiraceae). Metabolomics analysis highlighted significant disruptions in endogenous metabolism in UC mice, with a notable restoration of SphK1 and S1P levels following AO administration. Besides, we discovered that AO regulated the balance of sphingolipid metabolism and protected the intestinal barrier, potentially through the SphK1/MAPK signaling pathway. Overall, this study indicated that AO effectively ameliorates the clinical manifestations of UC by synergistically regulating gut microbe and metabolite homeostasis. AO emerges as a potential functional and therapeutic ingredient for UC treatment.PMID:39029356 | DOI:10.1016/j.jpba.2024.116367

Syst Appl Microbiol. 2024 Jul 17;47(5):126539. doi: 10.1016/j.syapm.2024.126539. Online ahead of print.ABSTRACTHistamine is an important biogenic amine known to impact a variety of patho-physiological processes ranging from allergic reactions, gut-mediated anti-inflammatory responses, and neurotransmitter activity. Histamine is found both endogenously within specialized host cells and exogenously in microbes. Exogenous histamine is produced through the decarboxylation of the amino acid L-histidine by bacterial-derived histidine decarboxylase enzymes. To investigate how widespread histamine production is across bacterial species, we examined 102,018 annotated genomes in the Integrated Microbial Genomes Database and identified 3,679 bacterial genomes (3.6 %) which possess the enzymatic machinery to generate histamine. These bacteria belonged to 10 phyla: Bacillota, Bacteroidota, Actinomycetota, Pseudomonadota, Lentisphaerota, Fusobacteriota, Armatimonadota, Cyanobacteriota, Thermodesulfobacteriota, and Verrucomicrobiota. The majority of the identified bacteria were terrestrial or aquatic in origin, although several bacteria originated in the human gut microbiota. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted metabolomics to confirm our genome discoveries correlated with L-histidine-to-histamine conversion in a chemically defined bacterial growth medium by a cohort of select environmental and human gut bacteria. We found that environmental microbes Vibrio harveyi, Pseudomonas fluorescens and Streptomyces griseus generated considerable levels of histamine (788 - 8,730 ng/mL). Interestingly, we found higher concentrations of histamine produced by gut-associated Fusobacterium varium, Clostridium perfringens, Limosilactobacillus reuteri and Morganella morganii (8,510--82,400 ng/mL). This work expands our knowledge of histamine production by diverse microbes.PMID:39029335 | DOI:10.1016/j.syapm.2024.126539

Plant Physiol Biochem. 2024 Jul 15;214:108939. doi: 10.1016/j.plaphy.2024.108939. Online ahead of print.ABSTRACTGDSL-type esterase/lipase protein (GELP) genes are crucial in the specialized lipid metabolism, in the responses to abiotic stresses, and in the regulation of plant homeostasis. R. communis is an important oilseed crop species that can sustain growth and productivity when exposed to harsh environmental conditions. Herein, we raised the question of whether the GELP gene family could be involved in the acquisition of R. communis tolerance to abiotic stresses during seed germination and seedling establishment. Thus, we used bioinformatics and transcriptomics to characterize the R. communis GELP gene family. R. communis genome possesses 96 GELP genes that were characterized by extensive bioinformatics, including phylogenetic analysis, subcellular localization, exon-intron distribution, the analysis of regulatory cis-elements, tandem duplication, and physicochemical properties. Transcriptomics indicated that numerous RcGELP genes are readily responsive to high-temperature and salt stresses and might be potential candidates for genome editing techniques to develop abiotic stress-tolerant crops.PMID:39029309 | DOI:10.1016/j.plaphy.2024.108939

Int Immunopharmacol. 2024 Jul 18;139:112669. doi: 10.1016/j.intimp.2024.112669. Online ahead of print.ABSTRACTBACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is very common worldwide, and alcohol consumption is a notable contributing factor. Researches have shown that gut microbiota can be influenced by alcohol consumption and is an important mediator in regulating Th17 cell immunity. However, it is still unclear the exact mechanism by which alcohol exacerbates the CP/CPPS and the role of gut microbiota in this process.METHOD: We first constructed the most-commonly used animal model for CP/CPPS, the experimental autoimmune prostatitis (EAP) model, through immunoassay. Based on this, mice were divided into EAP group and alcohol-consuming EAP group. By 16S rRNA sequencing and non-targeted metabolomics analysis, differential gut microbiota and their metabolites between the two groups were identified. Subsequently, metabolomics detection targeting cholesterols was carried out to identify the exact difference in cholesterol. Furthermore, multiple methods such as flow cytometry and immunohistochemistry were used to detect the differentiation status of Th17 cells and severity of prostatitis treated with 27-hydroxycholesterol (the differential cholesterol) and its upstream regulatory factor-sterol regulatory element-binding protein 2 (SREBP2). Lastly, fecal transplantation was conducted to preliminary study on whether alcohol intake exacerbates EAP in immune receptor mice.RESULTS: Alcohol intake increased the proportion of Th17 cells and levels of related inflammatory factors. It also led to an altered gut bacterial richness and increased gut permeability. Further metabolomic analysis showed that there were significant differences in a variety of metabolites between EAP and alcohol-fed EAP mice. Metabolic pathway enrichment analysis showed that the pathways related to cholesterol synthesis and metabolism were significantly enriched, which was subsequently confirmed by detecting the expression of metabolic enzymes. By targeting cholesterol synthesis, 27-hydroxycholesterol was significantly increased in alcohol-fed EAP mice. Subsequent mechanistic research showed that supplementation with 27-hydroxycholesterol could aggravate EAP and promote Th17 cell differentiation both in vivo and in vitro, which is regulated by SREBP2. In addition, we observed that fecal transplantation from mice with alcohol intake aggravated EAP in immunized recipient mice fed a normal diet.CONCLUSION: Our study is the first to show that alcohol intake promotes Th17 cell differentiation and exacerbates EAP through microbiota-derived cholesterol biosynthesis.PMID:39029231 | DOI:10.1016/j.intimp.2024.112669

Medicine (Baltimore). 2024 Jul 19;103(29):e39051. doi: 10.1097/MD.0000000000039051.ABSTRACTThe interwoven relationship between gut microbiota and the epigenetic landscape constitutes a pivotal axis in understanding human health and disease. Governed by a myriad of dietary, genetic, and environmental influences, the gut microbiota orchestrates a sophisticated metabolic interplay, shaping nutrient utilization, immune responses, and defenses against pathogens. Recent strides in genomics and metabolomics have shed light on the intricate connections between these microbial influencers and the host's physiological dynamics, presenting a dynamic panorama across diverse disease spectra. DNA methylation and histone modifications, as key players in epigenetics, intricately align with the dynamic orchestration of the gut microbiota. This seamless collaboration, notably evident in conditions like inflammatory bowel disease and obesity, has captured the attention of researchers, prompting an exploration of its nuanced choreography. Nevertheless, challenges abound. Analyzing data is intricate due to the multifaceted nature of the gut microbiota and the limitations of current analytical methods. This underscores the need for a multidisciplinary approach, where diverse disciplines converge to pave innovative research pathways. The integration of insights from microbiome and epigenome studies assumes paramount importance in unraveling the complexities of this intricate partnership. Deciphering the synchronized interactions within this collaboration offers a deeper understanding of these delicate interplays, potentially heralding revolutionary strides in treatment modalities and strategies for enhancing public health.PMID:39029010 | DOI:10.1097/MD.0000000000039051

Anal Chem. 2024 Jul 19. doi: 10.1021/acs.analchem.4c02219. Online ahead of print.ABSTRACTOpen mass spectral libraries (OMSLs) are critical for metabolite annotation and machine learning, especially given the rising volume of untargeted metabolomic studies and the development of annotation pipelines. Despite their importance, the practical application of OMSLs is hampered by the lack of standardized file formats, metadata fields, and supporting ontology. Current libraries, often restricted to specific topics or matrices, such as natural products, lipids, or the human metabolome, may limit the discovery potential of untargeted studies. The goal of FragHub is to provide users with the capability to integrate various OMSLs into a single unified format, thereby enhancing the annotation accuracy and reliability. FragHub addresses these challenges by integrating multiple OMSLs into a single comprehensive database, supporting various data formats, and harmonizing metadata. It also proposes some generic filters for the mass spectrum using a graphical user interface. Additionally, a workflow to generate in-house libraries compatible with FragHub is proposed. FragHub dynamically segregates libraries based on ionization modes and chromatography techniques, thereby enhancing data utility in metabolomic research. The FragHub Python code is publicly available under a MIT license, at the following repository: https://github.com/eMetaboHUB/FragHub. Generated data can be accessed at 10.5281/zenodo.11057687.PMID:39028894 | DOI:10.1021/acs.analchem.4c02219

Am J Physiol Heart Circ Physiol. 2024 Jul 19. doi: 10.1152/ajpheart.00193.2024. Online ahead of print.ABSTRACTHigh altitude (HA) hypoxia lowers uterine artery (UtA) blood flow during pregnancy and birth weight. Adenosine monophosphate kinase (AMPK) activation has selective, uteroplacental vasodilator effects which lessen hypoxia-associated birth weight reductions. In this study, we determined the relationship between AMPK-pathway gene expression and metabolites in the maternal circulation during HA pregnancy as well as with the maintenance of UtA blood flow and birth weight at HA. HA (2793 m) vs low altitude (LA; 1640 m) residents had smaller UtA diameters at weeks 20 and 34, lower UtA blood flow at week 20, and lower birth weight babies. At week 34, HA vs LA women had decreased expression of up- and down-stream AMPK-pathway genes. Expression of the a-1 AMPK catalytic subunit, PRKAA1, correlated positively with UtA diameter and blood flow at week 20 (HA) and 34 (LA). Downstream AMPK-pathway gene expression positively correlated with week 20 fetal biometry at both altitudes and with UtA diameter and birth weight at LA. Reduced gene expression of AMPK activators and downstream targets in HA versus LA women, together with positive correlations between PRKAA1 gene expression, UtA diameter, and blood flow suggest that greater sensitivity to AMPK activation at mid-gestation at HA may help offset later depressant effects of hypoxia on fetal growth.PMID:39028630 | DOI:10.1152/ajpheart.00193.2024

Environ Health Perspect. 2024 Jul;132(7):77005. doi: 10.1289/EHP13865. Epub 2024 Jul 19.ABSTRACTBACKGROUND: Evidence suggested that abiotic airborne exposures may be associated with changes in body composition. However, more evidence is needed to identify key pollutants linked to adverse health effects and their underlying biomolecular mechanisms, particularly in sensitive older adults.OBJECTIVES: Our research aimed to systematically assess the relationship between abiotic airborne exposures and changes in body composition among healthy older adults, as well as the potential mediating mechanisms through the serum lipidome.METHODS: From September 2018 to January 2019, we conducted a monthly survey among 76 healthy adults (60-69 years old) in the China Biomarkers of Air Pollutant Exposure (BAPE) study, measuring their personal exposures to 632 abiotic airborne pollutions using MicroPEM and the Fresh Air wristband, 18 body composition indicators from the InBody 770 device, and lipidomics from venous blood samples. We used an exposome-wide association study (ExWAS) and deletion/substitution/addition (DSA) model to unravel complex associations between exposure to contaminant mixtures and body composition, a Bayesian kernel machine regression (BKMR) model to assess the overall effect of key exposures on body composition, and mediation analysis to identify lipid intermediators.RESULTS: The ExWAS and DSA model identified that 2,4,5-T methyl ester (2,4,5-TME), 9,10-Anthracenedione (ATQ), 4b,8-dimethyl-2-isopropylphenanthrene, and 4b,5,6,7,8,8a,9,10-octahydro-(DMIP) were associated with increased body fat mass (BFM), fat mass indicators (FMI), percent body fat (PBF), and visceral fat area (VFA) in healthy older adults [Bonferroni-Hochberg false discovery rate (FDRBH)<0.05]. The BKMR model demonstrated a positive correlation between contaminants (anthracene, ATQ, copaene, di-epi-α-cedrene, and DMIP) with VFA. Mediation analysis revealed that phosphatidylcholine [PC, PC(16:1e/18:1), PC(16:2e/18:0)] and sphingolipid [SM, SM(d18:2/24:1)] mediated a significant portion, ranging from 12.27% to 26.03% (p-value <0.05), of the observed increase in VFA.DISCUSSION: Based on the evidence from multiple model results, ATQ and DMIP were statistically significantly associated with the increased VFA levels of healthy older adults, potentially regulated through lipid intermediators. These findings may have important implications for identifying potentially harmful environmental chemicals and developing targeted strategies for the control and prevention of chronic diseases in the future, particularly as the global population is rapidly aging. https://doi.org/10.1289/EHP13865.PMID:39028628 | DOI:10.1289/EHP13865

Nicotine Tob Res. 2024 Jul 19:ntae179. doi: 10.1093/ntr/ntae179. Online ahead of print.ABSTRACTINTRODUCTION: Smoking is one of the most important predisposing factors of intestinal inflammatory diseases. Heated tobacco product (HTP) is a novel tobacco category that is claimed to deliver reduced chemicals to human those reported in combustible cigarette smoke (CS). However, the effect of HTP on intestine is still unknown.METHODS: In the framework of Organization for Economic Co-operation and Development guidelines 413 guidelines, Sprague-Dawley rats were exposed to HTP aerosol and CS for 13 weeks. The atmosphere was characterized and oxidative stress and inflammation of intestine were investigated after exposure. Furthermore, the faeces we performed with 16S sequencing and metabolomics analysis.RESULTS: HTP aerosol and CS led to obvious intestinal damage evidenced by increased intestinal pro-inflammatory cytokines and oxidative stress in male and female rats After HTP and CS exposure, the abundance that obviously changed were Lactobacillus and Turiciacter in male rats and Lactobacillus and Prevotella in female rats. HTP mainly induced the metabolism of amino acids and fatty acyls such as short-chain fatty acids and tryptophan, while CS involved into the main metabolism of bile acids, especially indole and derivatives. Although different metabolic pathways in the gut mediated by HTP and CS, both to inflammation and oxidative stress were ultimately induced.CONCLUSIONS: HTP aerosol and CS induced intestinal damage mediated by different gut microbiota and metabolites, while both lead to inflammation and oxidative stress.IMPLICATIONS: The concentration of various harmful components in heated tobacco product aerosol is reported lower than that of traditional cigarette smoke, however, its health risk impact on consumers remains to be studied. Our research findings indicate that heated tobacco product and cigarette smoke inhalation induced intestinal damage through different metabolic pathways mediated by gut microbiome, indicating the health risk of heated tobacco product in intestine.PMID:39028556 | DOI:10.1093/ntr/ntae179

Mycotoxin Res. 2024 Jul 19. doi: 10.1007/s12550-024-00541-6. Online ahead of print.ABSTRACTEnvironmental factors influence fungal growth and mycotoxin production in stored grains. However, the concentrations of free mycotoxins and their conjugates and how they are impacted by different interacting environment conditions have not been previously examined. The objectives of this study were to examine the impact of storage conditions (0.93-0.98 aw) and temperature (20-25 °C) on (a) the concentrations of deoxynivalenol and zearalenone and their respective glucosides/conjugates and (b) the concentrations of emerging mycotoxins in both naturally contaminated and irradiated wheat grains inoculated with Fusarium graminearum. Contaminated samples were analysed for multiple mycotoxins using Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS). Method validation was performed according to the acceptable performance criteria set and updated by the European Commission regulations No. 2021/808/EC. As an important conjugate of deoxynivalenol, the concentrations of deoxynivalenol-3-glucoside were significantly different from its precursor deoxynivalenol at 0.93 aw (22% moisture content- MC) at 25 °C in the naturally contaminated wheat with a ratio proportion of 56:44% respectively. The high concentrations of deoxynivalenol-3-glucoside could be influenced by the wheat's variety and/or harvested season/fungal strain type/location. Zeralenone-14-sulfate concentrations were surprisingly three times higher than Zearalenone in the naturally contaminated wheat at 0.98 aw (26% MC) at both temperatures. Emerging mycotoxins such as moniliformin increased with temperature rise with the highest concentrations at 0.95 aw and 25 °C. These findings highlight the influence and importance of storage aw x temperature conditions on the relative presence of free vs conjugated mycotoxins which can have implications for food safety.PMID:39028531 | DOI:10.1007/s12550-024-00541-6

Cell Biochem Biophys. 2024 Jul 19. doi: 10.1007/s12013-024-01408-4. Online ahead of print.ABSTRACTCratoxylum formosum ssp. pruniflorum (CF), a traditional medicinal plant in Southern China, is widely recognized as a popular medicinal and tea plant traditionally utilized by diverse linguistic groups in the region for the treatment of gastrointestinal ailments. The objective of this study was to explore the active components and mechanisms of CF against gastric cancer (GC). The chemical ingredients of CF were obtained by using UPLC-MS/MS-based metabolomics. MGC-803 and HGC-27 cells were employed to investigate the direct anti-GC effect. The potential targets and signaling pathway of CF were identified through network pharmacology and proteomics, followed by subsequent experimental validation. Through UPLC-MS/MS metabolomics analysis, a total of 197 chemical ingredients were identified in CF leaves. Network pharmacology and proteomics techniques revealed 25 potential targets for GC, with a protein-protein interaction (PPI) network highlighting 12 cores targets, including CTNNB1, CDK2, et al. Furthermore, seven key CF ingredients - vismione B, feruloylcholine, α-amyrin, vanillic acid, galangin, cinnamic acid, and caffeic acid - were found to mediate anti-GC effects through pathways such as reactive oxygen species (ROS) and cell cycle signaling pathway. In vitro experiments demonstrated that CF significantly inhibited the proliferation and migration of GC cells, increased intracellular reactive oxygen species (ROS), malondialdehyde (MDA) and lactate dehydrogenase (LDH) levels, arrested the cell cycle at the S-phase, induced apoptosis and pyroptosis, and upregulated expression of apoptosis proteins (Bax, Bax/Bcl-2, cleaved-Caspase-3/Caspase-3), and pyroptosis proteins (GSDMD-N/GSDMD and GSDME-N/GSDME), while downregulating expression of cell cycle proteins (CDK2 and cyclin A1) as well as necroptosis proteins (RIP1 and MLKL). Collectively, these findings reveal CF's therapeutic potential against GC by the augmentation of ROS production, cell cycle arrest, promotion of apoptosis, and pyroptosis, offering valuable evidence for the development and utilization of CF in clinical settings.PMID:39028496 | DOI:10.1007/s12013-024-01408-4

Anal Methods. 2024 Jul 19. doi: 10.1039/d4ay01225a. Online ahead of print.ABSTRACTThis study investigates the potential and complementarity of high-throughput multipulse and multidimensional NMR methods for metabolomics. Through a chemical ecology case study, three methods are investigated, offering a continuum of methods with complementary features in terms of resolution, sensitivity and experiment time. Ultrafast 2D COSY, adiabatic INEPT and SYMAPS HSQC are shown to provide a very good classification ability, comparable to the reference 1D 1H NMR method. Moreover, a detailed analysis of discriminant buckets upon supervised statistical analysis shows that all methods are highly complementary, since they are able to highlight discriminant signals that could not be detected by 1D 1H NMR. In particular, fast 2D methods appear very efficient to discriminate signals located in highly crowded regions of the 1H spectrum. Overall, the combination of these recent methods within a single NMR metabolomics workflow allows to maximize the accessible metabolic information, and also raises exciting challenges in terms of NMR data analysis for chemical ecology.PMID:39028155 | DOI:10.1039/d4ay01225a

Bioinform Adv. 2024 Apr 24;4(1):vbae060. doi: 10.1093/bioadv/vbae060. eCollection 2024.ABSTRACTMOTIVATION: Many diseases are complex heterogeneous conditions that affect multiple organs in the body and depend on the interplay between several factors that include molecular and environmental factors, requiring a holistic approach to better understand disease pathobiology. Most existing methods for integrating data from multiple sources and classifying individuals into one of multiple classes or disease groups have mainly focused on linear relationships despite the complexity of these relationships. On the other hand, methods for nonlinear association and classification studies are limited in their ability to identify variables to aid in our understanding of the complexity of the disease or can be applied to only two data types.RESULTS: We propose Deep Integrative Discriminant Analysis (IDA), a deep learning method to learn complex nonlinear transformations of two or more views such that resulting projections have maximum association and maximum separation. Further, we propose a feature ranking approach based on ensemble learning for interpretable results. We test Deep IDA on both simulated data and two large real-world datasets, including RNA sequencing, metabolomics, and proteomics data pertaining to COVID-19 severity. We identified signatures that better discriminated COVID-19 patient groups, and related to neurological conditions, cancer, and metabolic diseases, corroborating current research findings and heightening the need to study the post sequelae effects of COVID-19 to devise effective treatments and to improve patient care.AVAILABILITY AND IMPLEMENTATION: Our algorithms are implemented in PyTorch and available at: https://github.com/JiuzhouW/DeepIDA.PMID:39027641 | PMC:PMC11256945 | DOI:10.1093/bioadv/vbae060

Heliyon. 2024 Jun 23;10(13):e33370. doi: 10.1016/j.heliyon.2024.e33370. eCollection 2024 Jul 15.ABSTRACTBACKGROUND: Dihydroartemisinin (DHA), a derivative of Artemisia annua, has been shown to possess anti-inflammatory properties. Besides, Yes-associated protein 1 (YAP1) plays a crucial role in maintaining liver homeostasis.METHODS: This study used Yap1 Flox/Flox, Albumin-Cre mice with hepatocyte-specific Yap1 knockout (referred to as Yap1 LKO) and their control mice (Yap1 Flox/Flox, referred to as Yap1 Flox). The effect of Yap1 on lipid metabolism homeostasis was investigated through non-targeted metabolomic analysis of mouse liver. Subsequently, DHA was administered to Yap1 LKO mice to assess its potential as a treatment. Liver pathology was evaluated via H&E staining, and the levels of AST, ALT, and TG were quantified using biochemical assays. The contents of arachidonic acid (AA), prostaglandin E1 (PGE1), and leukotrienes (LT) in the liver were measured using ELISA, while the protein expressions of PLIN2, 5-lipoxygenase (5-LOX), and cyclooxygenase-2 (COX-2) were analyzed through IHC staining.RESULTS: Hepatocyte-specific Yap1 knockout activated the AA metabolic pathway, resulting in increased elevated levels of AA, PGE1, and LT levels, along with inflammatory cytokine infiltration. DHA mitigated the elevation of metabolites such as PGE1 and LT caused by the AA metabolic pathway activation by down-regulating the levels of COX-2 and 5-LOX in the liver of Yap1 LKO mice. Moreover, it alleviated the accumulation of lipid vacuoles and reduced triglyceride (TG) and perilipin-2 (PLIN2) levels in the liver of Yap1 LKO mice.CONCLUSIONS: Excessively low YAP1 expression induces liver inflammation and disturbances in lipid metabolism, whereas DHA modulated AA metabolism and mitigated liver inflammation by inhibiting the activation of 5-LOX and COX-2.PMID:39027511 | PMC:PMC11255665 | DOI:10.1016/j.heliyon.2024.e33370

Front Endocrinol (Lausanne). 2024 Jul 4;15:1406690. doi: 10.3389/fendo.2024.1406690. eCollection 2024.ABSTRACTINTRODUCTION: Secondary hyperparathyroidism (SHPT) is a common and serious complication of chronic kidney disease (CKD). Elucidating the metabolic characteristics of SHPT may provide a new theoretical basis for its prevention and treatment. This study aimed to perform a metabolomic analysis of SHPT in patients with CKD stages 3-5 not receiving dialysis.METHODS: A total of 76 patients with CKD, 85 patients with CKD-SHPT, and 67 healthy controls were enrolled in this study. CKD was diagnosed according to the criteria specified in the Kidney Disease Improving Global Outcomes 2012 guidelines. SHPT was diagnosed by experienced clinicians according to the Renal Disease Outcomes Quality Initiative Clinical Practice Guidelines. Serum renal function markers and the lipid profile were analyzed. Untargeted ultra performance liquid chromatography-tandem mass spectrometry was used to analyze the serum metabolites of patients with CKD and SHPT. Multivariate analysis of the data was performed using principal component analysis and partial least square discriminant analysis. Serum differential metabolites were identified and further characterized using databases. Pathway enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes database. Correlations between differential metabolites and clinical parameters were determined using the Spearman correlation.RESULTS: The serum metabolomic profiles of patients with CKD with and without SHPT differed significantly. Differential metabolites were mainly enriched in the top four Kyoto Encyclopedia of Genes and Genomes pathways: phenylalanine, tyrosine, and tryptophan biosynthesis; sphingolipid metabolism; glycerophospholipid metabolism; and phenylalanine metabolism. In total, 31 differential metabolites were identified; of these, L-tryptophan and (R)-(+)-1-phenylethylamine were decreased, while other amino acids and their derivatives, uremia toxins, carnitine, and lipids, were increased significantly in patients with SHPT compared to those without. The 14 lipid metabolites were positively correlated with levels of Urea, serum creatinine, cystatin C, and triglycerides and negatively correlated with the estimated glomerular filtration rate and levels of total and high- and low-density lipoprotein cholesterol.DISCUSSION: Disturbed amino acid and lipid metabolism were more apparent in patients with SHPT than in those without. This metabolomic profile of SHPT may provide a therapeutic foundation for its future clinical management.PMID:39027473 | PMC:PMC11254665 | DOI:10.3389/fendo.2024.1406690

iScience. 2024 Jun 13;27(7):110265. doi: 10.1016/j.isci.2024.110265. eCollection 2024 Jul 19.ABSTRACTPatients with tuberous sclerosis complex (TSC) develop multi-organ disease manifestations, with kidney angiomyolipomas (AML) and cysts being one of the most common and deadly. Early and regular AML/cyst detection and monitoring are vital to lower TSC patient morbidity and mortality. However, the current standard of care involves imaging-based methods that are not designed for rapid screening, posing challenges for early detection. To identify potential diagnostic screening biomarkers of AML/cysts, we performed global untargeted metabolomics in blood samples from 283 kidney AML/cyst-positive or -negative TSC patients using mass spectrometry. We identified 7 highly sensitive chemical features, including octanoic acid, that predict kidney AML/cysts in TSC patients. Patients with elevated octanoic acid have lower levels of very long-chain fatty acids (VLCFAs), suggesting that dysregulated peroxisome activity leads to overproduction of octanoic acid via VLCFA oxidation. These data highlight AML/cysts blood biomarkers for TSC patients and offers valuable metabolic insights into the disease.PMID:39027368 | PMC:PMC11255849 | DOI:10.1016/j.isci.2024.110265

Front Pharmacol. 2024 Jul 4;15:1426944. doi: 10.3389/fphar.2024.1426944. eCollection 2024.ABSTRACTWolfberry, esteemed as a traditional Chinese medicinal material and functional food, is replete with nutrients and boasts a diverse array of health benefits, including hypoglycemic, antitumor, antioxidant, anti-inflammatory, and immune-enhancing properties. Notably, inflammation is a pivotal factor in the onset and progression of numerous diseases. Despite this, there is a paucity of research on the comprehensive evaluation of the components found in different wolfberries, and the exploration of their primary active components is limited. To address this issue, we conducted a comprehensive targeted metabolomics analysis, employing statistical methods such as principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA), KEGG pathway analysis, and volcano plots to delineate the compositional differences among red, black, and yellow wolfberries. Furthermore, we investigated the anti-inflammatory effects of their primary components through in vitro experiments. Our analysis revealed a total of 1,104 chemical compositions in the three wolfberries, with alkaloids, phenolic acids, flavonoids, and lipids being the predominant nutritional components. KEGG enrichment analysis indicated that these compositions were primarily involved in the biosynthesis of secondary metabolites, ABC transport, and galactose metabolism pathway. Moreover, our study demonstrated that quercetin exhibited dose-dependent anti-inflammatory activity in LPS-stimulated HUVECs. It effectively inhibited the production of inflammatory factors such as TNF-α, MCP-1, and IL-1β, while also down-regulating the gene and protein expression levels of ICAM-1 and VCAM-1. In conclusion, our findings indicate that there are variations in compositions among the three wolfberries, with flavonoids being the most abundant, and in vitro studies also confirmed the anti-inflammatory potential of quercetin. It is worth noting that Lycium ruthenicum contains higher levels of antioxidant components and possesses greater nutritional value, providing valuable insights for the future development and utilization of the three wolfberries.PMID:39027334 | PMC:PMC11255399 | DOI:10.3389/fphar.2024.1426944

Acta Pharm Sin B. 2024 Jul;14(7):3068-3085. doi: 10.1016/j.apsb.2024.03.025. Epub 2024 Mar 22.ABSTRACTSepsis progression is significantly associated with the disruption of gut eubiosis. However, the modulatory mechanisms of gut microbiota operating during sepsis are still unclear. Herein, we investigated how gut commensals impact sepsis development in a pre-clinical model. Cecal ligation and puncture (CLP) surgery was used to establish polymicrobial sepsis in mice. Mice depleted of gut microbiota by an antibiotic cocktail (ABX) exhibited a significantly higher level of mortality than controls. As determined by metabolomics analysis, ABX treatment has depleted many metabolites, and subsequent supplementation with l-rhamnose (rhamnose, Rha), a bacterial carbohydrate metabolite, exerted profound immunomodulatory properties with a significant enhancement in macrophage phagocytosis, which in turn improved organ damage and mortality. Mechanistically, rhamnose binds directly to and activates the solute carrier family 12 (potassium-chloride symporter), member 4 (SLC12A4) in macrophages and promotes phagocytosis by activating the small G-proteins, Ras-related C3 botulinum toxin substrate1 (Rac1) and cell division control protein 42 homolog (Cdc42). Interestingly, rhamnose has enhanced the phagocytosis capacity of macrophages from sepsis patients. In conclusion, by identifying SLC12A4 as the host interacting protein, we disclosed that the gut commensal metabolite rhamnose is a functional molecular that could promote the phagocytosis capacity of macrophages and protect the host against sepsis.PMID:39027244 | PMC:PMC11252530 | DOI:10.1016/j.apsb.2024.03.025