PubMed

Comput Struct Biotechnol J. 2023 Nov 28;23:96-105. doi: 10.1016/j.csbj.2023.11.045. eCollection 2024 Dec.ABSTRACTImmune-mediated inflammatory diseases (IMIDs) comprise a complex group of pathologies with diverse etiologies and clinical manifestations. In particular, omics technologies have remodeled our understanding of a set of IMIDs such as systemic autoimmune rheumatic diseases (SARDs), generating vast amounts of data on the genome, epigenome, transcriptome, proteome and metabolome of immune cells and SARDs patients. However, the integration of omics data to advance our knowledge of these diseases is challenging, requiring advanced bioinformatic tools. This review explores different multi-omic integrative tools for refining previous research, exploring the biological relevance of datasets within different contexts, or translating omics results into clinical advances. We also discuss relevant multi-omic studies in SARDs research and the potential of omics data from available repositories to complement ongoing investigation in this field.PMID:38089468 | PMC:PMC10714331 | DOI:10.1016/j.csbj.2023.11.045

Diabetes Metab Syndr Obes. 2023 Dec 7;16:4013-4024. doi: 10.2147/DMSO.S428864. eCollection 2023.ABSTRACTOBJECTIVE: Previous studies have shown that oxymatrine (OMT) can improve high-fat-high-fructose-diet-induced non-alcoholic fatty liver disease (NAFLD), and our study aimed to explore its possible metabolic potential mechanisms.METHODS: Wistar rats were fed a high-fat-high-fructose diet for 8 weeks and treated with oxymatrine by gavage for the last 4 weeks. We measured biochemical indicators and pathological changes in each group and used liquid chromatography-mass spectrometry (LC-MS) to analyze changes in metabolites in the serum and liver of the rats.RESULTS: The results showed that OMT can alleviate the high-fat-high-fructose-induced weight gain and hepatic lipid deposition in rats. Metabolomic analysis showed that the level of eicosapentaenoic acid (EPA) was downregulated and levels of desmosterol and d-galactose were upregulated in livers fed with HFDHFr. The levels of L-isoleucine, L-valine, arachidonic acid (AA), taurocholic acid (TCA), chenodeoxycholyltaurine (TDCA), isocitrate, and glutathione (GSH) were downregulated in the liver, whereas those of linoleic acid (LA), phosphocholine (PC), glycerophosphocholine (GPC), and oxidized glutathione (GSSG) were upregulated in the serum treated with OMT.CONCLUSION: In summary, OMT can improve HFDHFr-induced NAFLD, and metabolomic analysis can provide an early warning for the development of NAFLD as well as provide a rationale for therapeutic targets.PMID:38089430 | PMC:PMC10712261 | DOI:10.2147/DMSO.S428864

Front Pharmacol. 2023 Nov 27;14:1243505. doi: 10.3389/fphar.2023.1243505. eCollection 2023.ABSTRACTBackground: We hypothesize that the poor survival outcomes of end-stage kidney disease (ESKD) patients undergoing hemodialysis are associated with a low filtering efficiency and selectivity. The current gold standard criteria using single or several markers show an inability to predict or disclose the treatment effect and disease progression accurately. Methods: We performed an integrated mass spectrometry-based metabolomic and proteomic workflow capable of detecting and quantifying circulating small molecules and proteins in the serum of ESKD patients. Markers linked to cardiovascular disease (CVD) were validated on human induced pluripotent stem cell (iPSC)-derived cardiomyocytes. Results: We identified dozens of elevated molecules in the serum of patients compared with healthy controls. Surprisingly, many metabolites, including lipids, remained at an elevated blood concentration despite dialysis. These molecules and their associated physical interaction networks are correlated with clinical complications in chronic kidney disease. This study confirmed two uremic toxins associated with CVD, a major risk for patients with ESKD. Conclusion: The retained molecules and metabolite-protein interaction network address a knowledge gap of candidate uremic toxins associated with clinical complications in patients undergoing dialysis, providing mechanistic insights and potential drug discovery strategies for ESKD.PMID:38089059 | PMC:PMC10715419 | DOI:10.3389/fphar.2023.1243505

Anal Chem. 2023 Dec 13. doi: 10.1021/acs.analchem.3c03765. Online ahead of print.ABSTRACTSpatially resolved lipidomics is pivotal for detecting and interpreting lipidomes within spatial contexts using the mass spectrometry imaging (MSI) technique. However, comprehensive and efficient lipid identification in MSI remains challenging. Herein, we introduce a high-coverage, database-driven approach combined with air-flow-assisted desorption electrospray ionization (AFADESI)-MSI to generate spatial lipid profiles across whole-body mice. Using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), we identified 2868 unique lipids in the serum and various organs of mice. Subsequently, we systematically evaluated the distinct ionization properties of the lipids between LC-MS and MSI and created a detailed MSI database containing 14 123 ions. This method enabled the visualization of aberrant fatty acid and phospholipid metabolism across organs in a diabetic mouse model. As a powerful extension incorporated into the MSIannotator tool, our strategy facilitates the rapid and accurate annotation of lipids, providing new research avenues for probing spatially resolved heterogeneous metabolic changes in response to diseases.PMID:38088904 | DOI:10.1021/acs.analchem.3c03765

Clin Cancer Res. 2023 Dec 13. doi: 10.1158/1078-0432.CCR-23-2025. Online ahead of print.ABSTRACTPURPOSE: Thyroid cancer (TC) metabolic characteristics vary depending on the molecular subtype determined by mutational status. We aimed to investigate the molecular subtype-specific metabolic characteristics of TCs.EXPERIMENTAL DESIGN: An integrative multi-omics analysis was conducted, incorporating transcriptomics, metabolomics, and proteomics data obtained from human tissues representing distinct molecular characteristics of TCs; BRAF-like (papillary TC with BRAFV600E mutation; PTC-B), RAS-like (follicular TC with RAS mutation; FTC-R), and ATC-like (anaplastic TC with BRAFV600E or RAS mutation; ATC-B or ATC-R). To validate our findings, we employed tissue microarray of human TC tissues and performed in vitro analyses of cancer cell phenotypes and metabolomic assays after inducing genetic knockdown.RESULTS: Metabolic properties differed between differentiated TCs of PTC-B and FTC-R, but were similar in de-differentiated TCs of ATC-B/R, regardless of their mutational status. Tricarboxylic acid (TCA) intermediates and branched-chain amino acids (BCAA) were enriched with the activation of TCA cycle only in FTC-R, whereas one-carbon metabolism and pyrimidine metabolism increased in both PTC-B and FTC-R and to a great extent in ATC-B/R. However, the protein expression levels of the BCAA transporter (SLC7A5) and a key enzyme in one-carbon metabolism (SHMT2) increased in all TCs and were particularly high in ATC-B/R. Knockdown of SLC7A5 or SHMT2 inhibited the migration and proliferation of TC cell lines differently, depending on the mutational status.CONCLUSIONS: These findings define the metabolic properties of each molecular subtype of TCs and identify metabolic vulnerabilities, providing a rationale for therapies targeting its altered metabolic pathways in advanced TC.PMID:38088902 | DOI:10.1158/1078-0432.CCR-23-2025

Biophys Chem. 2023 Dec 7;305:107153. doi: 10.1016/j.bpc.2023.107153. Online ahead of print.ABSTRACTThe classical approach restricts the detection of metabolites in serum samples by using nuclear magnetic resonance (NMR) spectroscopy; however, the presence of copious proteins and lipoproteins emphasize and necessitate the development of a contemporary, high-throughput tactic. To eliminate the lipoproteins and proteins from sera to engender filtered sera (FS), the study was executed with 50 μl serum obtained from five healthy individuals with 5 years of age difference from 25 to 45 years old and the application of a unique mechanical filter with molecular weight cut-off value of 2KDa. The 10 μl FS from each individual was pooled to make 50 μl final volume filled in a co-axial tube for acquisition of a battery of 1D/2D investigations at 800 MHz NMR spectrometer and the assigned metabolites was confirmed through mass spectrometry as well as by comparing 1H NMR spectra of individual metabolites. This innovative tactic is commissioning to reveal more than 100 metabolites. In contrast to the protein precipitation method, 24 new metabolites were recognized in the present study. The present innovative approach characterizes nucleosides, nitrogenous bases, and volatile metabolites that possibly produce a landmark for the delineation of a comprehensive metabolic profile applicable for detection of the molecular cause of pathogenicity, early-stage disease detection and prognosis, inborn error of metabolism, and forensic investigations exerting the least volume of FS and NMR spectroscopy. The assignment of 100 metabolites using 1H NMR-based FS is described for the first time in the present report.PMID:38088005 | DOI:10.1016/j.bpc.2023.107153

J Sci Food Agric. 2023 Dec 12. doi: 10.1002/jsfa.13215. Online ahead of print.ABSTRACTBACKGROUND: Mulberry leaves (MLs) are widely used in food because of their nutritional and functional characteristics. However, plant cell walls and natural bitterness influence nutrient release and flavor properties of MLs. Liquid-state fermentation using Monascus purpureus (LFMP) is a common processing method used to improve food properties. This study used headspace solid-phase micro extraction gas chromatography-mass spectrometry (HS-SPME-GC-MS) and non-targeted metabolomics to examine changes in volatile and non-volatile metabolites in MLs. The transformation mechanism of LFMP was investigated by microscopic observation and dynamic analysis of enzyme activity, and changes in the biological activity of MLs were analyzed.RESULTS: LFMP significantly increased total phenolics, total flavonoids, free amino acids, and soluble sugars in MLs, while decreasing phytic acid levels. A total of 92 volatile organic compounds (VOCs) were identified and quantified in this study. VOCs such as (2R,3R)-(-)-2,3-butanediol, terpineol, and eugenol showed some improvement in the flavour characteristics of MLs. By using non-targeted metabolomics, 124 unique metabolites in total were examined. LFMP altered the metabolic profile of MLs, mainly in plant secondary metabolism, lipid metabolism and amino acid metabolism. Microscopic observation and dynamic analysis of enzyme activity indicated that LFMP promoted MLs' cell wall degradation and biotransformation. In addition, LFMP significantly increased the ACE, α-glucosidase inhibitory activity of MLs.CONCLUSION: LFMP altered the flavour characteristics, metabolite profile and biological activity of MLs. These findings will provide ideas for the processing of MLs into functional foods. In addition, they also provide useful information for biochemical studies of fermented MLs. This article is protected by copyright. All rights reserved.PMID:38087418 | DOI:10.1002/jsfa.13215

J Sci Food Agric. 2023 Dec 12. doi: 10.1002/jsfa.13213. Online ahead of print.ABSTRACTBACKGROUND: Qizha Shuangye granules (QSG) comprise six traditional Chinese herbal medicines (TCHMs), and these six herbs have a long history of treating hyperlipidemia (HLP) in China. This study aimed to evaluate the potential lipid-lowering effects of QSG in an HLP rat model and investigate possible mechanisms. The HLP rat model was induced by a high-fat diet. The lipid-related indicators in serum were detected. The serum and liver metabolites were investigated using a liquid chromatography-mass spectrometry (LC-MS)-based metabolomics approach. The herb-compound-target-metabolite (H-C-T-M) network was further constructed to reveal the possible molecular mechanism of QSG to alleviate HLP.RESULTS: The administration of QSG inhibited the HLP-induced changes in the total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and non-esterified fatty acid (NEFA) levels. Additionally, QSG significantly attenuated the liver histopathological changes induced by HLP. Metabolomic analysis showed the serum and liver metabolic disorders presented in HLP rats. QSG can reverse the abnormal metabolism caused by HLP. Through network pharmacology analysis, key proteins such as AR, HMGCR, and PPARα were screened out, and they were speculated to be possible therapeutic targets for QSG to treat HLP.CONCLUSION: The present study integrated metabolomics and network pharmacology analysis to reveal the efficacy and possible mechanism of QSG in treating HLP, which provides a new reference for the research and development of QSG as a functional food. This article is protected by copyright. All rights reserved.PMID:38087399 | DOI:10.1002/jsfa.13213

Microbiome. 2023 Dec 12;11(1):273. doi: 10.1186/s40168-023-01681-0.ABSTRACTBACKGROUND: Oral infection with cysts is the main transmission route of Toxoplasma gondii (T. gondii), which leads to lethal intestinal inflammation. It has been widely recognized that T. gondii infection alters the composition and metabolism of the gut microbiota, thereby affecting the progression of toxoplasmosis. However, the potential mechanisms remain unclear. In our previous study, there was a decrease in the severity of toxoplasmosis after T. gondii α-amylase (α-AMY) was knocked out. Here, we established mouse models of ME49 and Δα-amy cyst infection and then took advantage of 16S rRNA gene sequencing and metabolomics analysis to identify specific gut microbiota-related metabolites that mitigate T. gondii-induced intestinal inflammation and analyzed the underlying mechanism.RESULTS: There were significant differences in the intestinal inflammation between ME49 cyst- and Δα-amy cyst-infected mice, and transferring feces from mice infected with Δα-amy cysts into antibiotic-treated mice mitigated colitis caused by T. gondii infection. 16S rRNA gene sequencing showed that the relative abundances of gut bacteria, such as Lactobacillus and Bacteroides, Bifidobacterium, [Prevotella], Paraprevotella and Macellibacteroides, were enriched in mice challenged with Δα-amy cysts. Spearman correlation analysis between gut microbiota and metabolites indicated that some fatty acids, including azelaic acid, suberic acid, alpha-linolenic acid (ALA), and citramalic acid, were highly positively correlated with the identified bacterial genera. Both oral administration of ALA and fecal microbiota transplantation (FMT) decreased the expression of pro-inflammatory cytokines and restrained the MyD88/NF-κB pathway, which mitigated colitis and ultimately improved host survival. Furthermore, transferring feces from mice treated with ALA reshaped the colonization of beneficial bacteria, such as Enterobacteriaceae, Proteobacteria, Shigella, Lactobacillus, and Enterococcus.CONCLUSIONS: The present findings demonstrate that the host gut microbiota is closely associated with the severity of T. gondii infection. We provide the first evidence that ALA can alleviate T. gondii-induced colitis by improving the dysregulation of the host gut microbiota and suppressing the production of pro-inflammatory cytokines via the MyD88/NF-κB pathway. Our study provides new insight into the medical application of ALA for the treatment of lethal intestinal inflammation caused by Toxoplasma infection. Video Abstract.PMID:38087373 | DOI:10.1186/s40168-023-01681-0

BMC Complement Med Ther. 2023 Dec 12;23(1):449. doi: 10.1186/s12906-023-04286-0.ABSTRACTBACKGROUND: Respiratory Syncytial Virus (RSV) stands out as a primary contributor to lower respiratory tract infections and hospitalizations, particularly in infants. Lonicerae japonicae flos (LJF), a traditional Chinese medicine renowned for its efficacy against various viral infections, including RSV, has been widely employed. Despite its common use, the precise therapeutic mechanism of LJF against RSV remains elusive. This study aimed to investigate the underlying mechanism of LJF against RSV through network pharmacology and metabolomics.METHODS: In this study, based on network pharmacology, potential targets related to LJF and RSV were obtained from PubChem and Swiss Target Prediction. The core targets and pathways were established and verified by enrichment analysis and molecular docking. The anti-RSV efficacy of LJF was determined by in vitro experiments. Additionally, metabolomics analysis was integrated, allowing for the identification of differential metabolites and their correlation with targets following LJF treatment in the context of RSV infection.RESULTS: A total of 23 active ingredients and 780 targets were obtained, of which 102 targets were associated with LJF anti-RSV. The construction of the corresponding Protein-Protein Interaction (PPI) network unveiled potential core targets, including STAT3, TNF, and AKT1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that LJF's anti-RSV effects primarily involve key pathways such as the PI3K-Akt signaling pathway, EGFR tyrosine kinase inhibitor resistance, and FoxO signaling pathway. Molecular docking showed that ZINC03978781, 4,5'-Retro-.beta.,.beta.-Carotene -3,3'-dione, 4',5'-didehydro and 7-epi-Vogeloside had better binding ability. The cellular assay showed that the therapeutic index of LJF against RSV was 4.79. Furthermore, 18 metabolites were screened as potential biomarkers of LJF against RSV, and these metabolites were mainly involved in the pathways of purine metabolism, linoleic acid metabolism, alpha-linolenic acid metabolism, and other related pathways.CONCLUSIONS: The intergration of network pharmacology and metabolomics can clarify the active targets and related pathways of LJF against RSV, which could provide a valuable reference for further research and clinical application of LJF.PMID:38087272 | DOI:10.1186/s12906-023-04286-0

Food Funct. 2023 Dec 12. doi: 10.1039/d3fo03259k. Online ahead of print.ABSTRACTConstipation is a prevalent gastrointestinal (GI) problem affecting a large number of individuals. This study aimed to investigate peristalsis-promoting potential characteristics of Ligilactobacillus acidipiscis YJ5 and the underlying molecular mechanism. The study demonstrated the relieving effect of L. acidipiscis YJ5 on constipation in both zebrafish and mouse models. L. acidipiscis YJ5 intervention significantly increased intestinal peristalsis by reducing the peak time and increasing the fluorescence disappearance rate in the zebrafish model. In the mouse model, the symptoms of constipation relief induced by L. acidipiscis YJ5 included a shortened first black stool time, an increased number of defecation particles, an accelerated propulsion rate of the small intestine, and an increase in fecal water content. L. acidipiscis YJ5 was found to reduce the expression of colonic aquaporins to normalize the colonic water transport system of constipated mice. Additionally, L. acidipiscis YJ5 reversed loperamide-induced morphological damage in the ileum and colon and increased the colonic mucosal barrier. The results of the 16S rRNA gene analysis indicated that L. acidipiscis YJ5 could reverse the structure of gut microbiota to a near-normal group, including levels of β-diversity, phylum, family, and genus. Furthermore, the fermentation supernatant of L. acidipiscis YJ5 was shown to relieve constipation, and metabolomics analysis revealed that these positive effects were related to its metabolites like malic acid and heliangin.PMID:38086666 | DOI:10.1039/d3fo03259k

Curr Opin Chem Biol. 2023 Dec 11;78:102407. doi: 10.1016/j.cbpa.2023.102407. Online ahead of print.ABSTRACTThe aetiology of every human disease lies in a combination of genetic and environmental factors, each contributing in varying proportions. While genomics investigates the former, a comparable holistic paradigm was proposed for environmental exposures in 2005, marking the onset of exposome research. Since then, the exposome definition has broadened to include a wide array of physical, chemical, and psychosocial factors that interact with the human body and potentially alter the epigenome, the transcriptome, the proteome, and the metabolome. The chemical exposome, deeply intertwined with the metabolome, includes all small molecules originating from diet as well as pharmaceuticals, personal care and consumer products, or pollutants in air and water. The set of techniques to interrogate these exposures, primarily mass spectrometry and nuclear magnetic resonance spectroscopy, are also extensively used in metabolomics. Recent advances in untargeted metabolomics using high resolution mass spectrometry have paved the way for the development of methods able to provide in depth characterisation of both the internal chemical exposome and the endogenous metabolome simultaneously. Herein we review the available tools, databases, and workflows currently available for such work, and discuss how these can bridge the gap between the study of the metabolome and the exposome.PMID:38086287 | DOI:10.1016/j.cbpa.2023.102407

Ecotoxicol Environ Saf. 2023 Dec 11;269:115811. doi: 10.1016/j.ecoenv.2023.115811. Online ahead of print.ABSTRACTOur previous study reveals that maternal exposure to 4-vinylcyclohexene diepoxide (VCD) during pregnancy causes insufficient ovarian follicle reserve and decreased fertility in offspring. The present study aims to further explore the reasons for the significant decline of fecundity in mice caused by VCD, and to clarify the changes of gut microbiota and microbial metabolites in F1 mice. The ovarian metabolomics, gut microbiota and microbial metabolites were analyzed. The results of ovarian metabolomics analysis showed that maternal VCD exposure during pregnancy significantly reduced the concentration of carnitine in the ovaries of F1 mice, while supplementation with carnitine (isovalerylcarnitine and valerylcarnitine) significantly increased the number of ovulation. The results of 16 S rDNA-seq and microbial metabolites analysis showed that maternal VCD exposure during pregnancy caused disordered gut microbiota, increased abundance of Parabacteroides and Flexispira bacteria that are involved in secondary bile acid synthesis. The concentrations of NorDCA, LCA-3S, DCA and other secondary bile acids increased significantly. Our results indicate that maternal exposure to VCD during pregnancy leads to disorder in gut microbiota and bile acid metabolism in F1 mice, accompanying with decreased ovarian function, providing further evidence that maternal exposure to VCD during pregnancy has intergenerational deleterious effects on offspring.PMID:38086265 | DOI:10.1016/j.ecoenv.2023.115811

Poult Sci. 2023 Nov 17;103(2):103283. doi: 10.1016/j.psj.2023.103283. Online ahead of print.ABSTRACTThe adverse effects of exposure to fine particulate matter (PM2.5) on body health have attracted global public attention. However, there is limited research on PM2.5 in animal houses. Numerous studies have indicated that long-term exposure to high levels of PM2.5 can cause damage to multiple systems in animals. Poultry houses are one of the primary sources of PM2.5 emissions. However, there is limited research on the effects of PM2.5 exposure on poultry organisms. This study analyzed the histopathological changes in the lung tissue of poultry under PM2.5 exposure conditions. It used the LC-MS method to analyze the alterations in the serum metabolomic profile of poultry. This study confirmed that long-term exposure to high levels of PM2.5 had significantly reduced the growth performance of poultry. Histopathological slides of the lung tissue in chickens exposed to long-term retention of PM2.5 clearly showed significant damage. Furthermore, the serum metabolome analysis revealed significant changes in the serum metabolic profile of chickens exposed to long-term PM2.5 exposure. Specifically, there were notable alterations in the Glycerophospholipid metabolism, Steroid hormone biosynthesis, and Phenylalanine, tyrosine, and tryptophan biosynthesis pathways.PMID:38086244 | DOI:10.1016/j.psj.2023.103283

Aquat Toxicol. 2023 Dec 6;266:106792. doi: 10.1016/j.aquatox.2023.106792. Online ahead of print.ABSTRACTThis study attempted to explore the metabolome profile of Azolla filiculoides subjected to two different concentrations of BPA (1 and 30 mg L-1) in congruence with two different durations (3 and 9 days) of treatment. Bisphenol A (BPA) is a ubiquitously occurring environmental pollutant that imparts acute toxicity in aquatic plants. Therefore, studying the variations in the fern metabolome profile and identifying stress-responsive metabolites can help develop criteria for assessing the aquatic ecosystem. In recent times, metabolomics has drawn attention for its ability to detect biochemical processes and help link plant responses with environmental stresses. However, the studies concerning the metabolome profile of A. filiculoides exposed to environmental contaminants are limited. In the present study, the untargeted metabolomics study allowed the detection of a large array of metabolites, with 767 shared metabolites representing 41 crucial pathways. Exposure to 30 mg L-1 BPA seemingly disrupted the primary metabolism of the fern and induced a shift toward defense-related pathways. Additionally, BPA stress triggered the expression of metabolites like 3,4-dihydroxyphenylglycol, perillic acid, and perillaldehyde in BPA_L3 (1 mg L-1 for 3 days) and BPA_L9 (1 mg L-1 for 9 days) samples indicating protective mechanism of the plants. Conversely, the BPA_H3 (30 mg L-1 for 3 days) and BPA_H9 (30 mg L-1 for 9 days) samples expressed a distinct set of markers like luteolin, 3-hydroxyanthranilic acid, cinnamaldehyde, and l-DOPA indicating the onset of senescence and apoptosis related pathways can help in the health assessment of freshwater ecosystems and also appraisal of ecotoxicological risks imposed by BPA.PMID:38086201 | DOI:10.1016/j.aquatox.2023.106792

BMC Microbiol. 2023 Dec 12;23(1):396. doi: 10.1186/s12866-023-03094-3.ABSTRACTMalaria is a persistent illness that is still a public health issue. On the other hand, marine organisms are considered a rich source of anti‑infective drugs and other medically significant compounds. Herein, we reported the isolation of the actinomycete associated with the Red Sea sponge Callyspongia siphonella. Using "one strain many compounds" (OSMAC) approach, a suitable strain was identified and then sub-cultured in three different media (M1, ISP2 and OLIGO). The extracts were evaluated for their in-vitro antimalarial activity against Plasmodium falciparum strain and subsequently analyzed by Liquid chromatography coupled with high-resolution mass spectrometry (LC-HR-MS). In addition, MetaboAnalyst 5.0 was used to statistically analyze the LC-MS data. Finally, Molecular docking was carried out for the dereplicated metabolites against lysyl-tRNA synthetase (PfKRS1). The phylogenetic study of the 16S rRNA sequence of the actinomycete isolate revealed its affiliation to Streptomyces genus. Antimalarial screening revealed that ISP2 media is the most active against Plasmodium falciparum strain. Based on LC-HR-MS based metabolomics and multivariate analyses, the static cultures of the media, ISP2 (ISP2-S) and M1 (M1-S), are the optimal media for metabolites production. OPLS-DA suggested that quinone derivatives are abundant in the extracts with the highest antimalarial activity. Fifteen compounds were identified where eight of these metabolites were correlated to the observed antimalarial activity of the active extracts. According to molecular docking experiments, saframycin Y3 and juglomycin E showed the greatest binding energy scores (-6.2 and -5.13) to lysyl-tRNA synthetase (PfKRS1), respectively. Using metabolomics and molecular docking investigation, the quinones, saframycin Y3 (5) and juglomycin E (1) were identified as promising antimalarial therapeutic candidates. Our approach can be used as a first evaluation stage in natural product drug development, facilitating the separation of chosen metabolites, particularly biologically active ones.PMID:38087203 | DOI:10.1186/s12866-023-03094-3

Sci Rep. 2023 Dec 12;13(1):22013. doi: 10.1038/s41598-023-49443-0.ABSTRACTAdverse drug reactions (ADRs) are considered an inherent risk of medication use, and some ADRs have been associated with off-target drug interactions with mitochondria. Metabolites that reflect mitochondrial function may help identify patients at risk of mitochondrial toxicity. We employed a database strategy to identify candidate mitochondrial metabolites that could be clinically useful to identify individuals at increased risk of mitochondrial-related ADRs. This led to L-carnitine being identified as the candidate mitochondrial metabolite. L-carnitine, its acetylated metabolite, acetylcarnitine and other acylcarnitines are mitochondrial biomarkers used to detect inborn errors of metabolism. We hypothesized that changes in L-carnitine disposition, induced by a "challenge test" of intravenous L-carnitine, could identify mitochondrial-related ADRs by provoking variation in L-carnitine and/or acetylcarnitine blood levels. To test this hypothesis, we induced mitochondrial drug toxicity with clofazimine (CFZ) in a mouse model. Following CFZ treatment, mice received an L-carnitine "challenge test". CFZ-induced changes in weight were consistent with previous work and reflect CFZ-induced catabolism. L-carnitine induced differences in whole blood acetylcarnitine concentrations in a manner that was dependent on CFZ treatment. This supports the usefulness of a database strategy for the discovery of candidate metabolite biomarkers of drug toxicity and substantiates the potential of the L-carnitine "challenge test" as a "probe" to identify drug-related toxicological manifestations.PMID:38086883 | DOI:10.1038/s41598-023-49443-0

Nat Commun. 2023 Dec 13;14(1):8260. doi: 10.1038/s41467-023-43917-5.ABSTRACTMetabolic reprogramming in cancer and immune cells occurs to support their increasing energy needs in biological tissues. Here we propose Single Cell Spatially resolved Metabolic (scSpaMet) framework for joint protein-metabolite profiling of single immune and cancer cells in male human tissues by incorporating untargeted spatial metabolomics and targeted multiplexed protein imaging in a single pipeline. We utilized the scSpaMet to profile cell types and spatial metabolomic maps of 19507, 31156, and 8215 single cells in human lung cancer, tonsil, and endometrium tissues, respectively. The scSpaMet analysis revealed cell type-dependent metabolite profiles and local metabolite competition of neighboring single cells in human tissues. Deep learning-based joint embedding revealed unique metabolite states within cell types. Trajectory inference showed metabolic patterns along cell differentiation paths. Here we show scSpaMet's ability to quantify and visualize the cell-type specific and spatially resolved metabolic-protein mapping as an emerging tool for systems-level understanding of tissue biology.PMID:38086839 | DOI:10.1038/s41467-023-43917-5

Nat Commun. 2023 Dec 12;14(1):8040. doi: 10.1038/s41467-023-43719-9.ABSTRACTEpigenetic dysregulation may influence disease progression. Here we explore whether epigenetic alterations in human pancreatic islets impact insulin secretion and type 2 diabetes (T2D). In islets, 5,584 DNA methylation sites exhibit alterations in T2D cases versus controls and are associated with HbA1c in individuals not diagnosed with T2D. T2D-associated methylation changes are found in enhancers and regions bound by β-cell-specific transcription factors and associated with reduced expression of e.g. CABLES1, FOXP1, GABRA2, GLR1A, RHOT1, and TBC1D4. We find RHOT1 (MIRO1) to be a key regulator of insulin secretion in human islets. Rhot1-deficiency in β-cells leads to reduced insulin secretion, ATP/ADP ratio, mitochondrial mass, Ca2+, and respiration. Regulators of mitochondrial dynamics and metabolites, including L-proline, glycine, GABA, and carnitines, are altered in Rhot1-deficient β-cells. Islets from diabetic GK rats present Rhot1-deficiency. Finally, RHOT1methylation in blood is associated with future T2D. Together, individuals with T2D exhibit epigenetic alterations linked to mitochondrial dysfunction in pancreatic islets.PMID:38086799 | DOI:10.1038/s41467-023-43719-9

Talanta. 2023 Dec 7;269:125519. doi: 10.1016/j.talanta.2023.125519. Online ahead of print.ABSTRACTAlzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive decline and the accumulation of beta-amyloid plaques and tau tangles in the brain. Current therapies have limited efficacy, prompting the search for novel treatments. Selenium nanoparticles (SeNPs) have emerged as promising candidates for AD therapy due to their unique physicochemical properties and potential therapeutic effects. This review provides an overview of SeNPs and their potential application in AD treatment, as well as the main bioanalytical techniques applied in this field. SeNPs possess antioxidant and anti-inflammatory properties, making them potential candidates to combat the oxidative stress and neuroinflammation associated with AD. Moreover, SeNPs have shown the ability to cross the blood-brain barrier (BBB), allowing them to target brain regions affected by AD pathology. Various methods for synthesizing SeNPs are explored, including chemical, physical and biological synthesis approaches. Based on the employment of algae, yeast, fungi, and plants, green methods offer a promising and biocompatible alternative for SeNPs production. In vitro studies have demonstrated the potential of SeNPs in reducing beta-amyloid aggregation and inhibiting tau hyperphosphorylation, providing evidence of their neuroprotective effects on neuronal cells. In vivo studies using transgenic mouse models and AD-induced symptoms have shown promising results, with SeNPs treatment leading to cognitive improvements and reduced amyloid plaque burden in the hippocampus. Looking ahead, future trends in SeNPs research involve developing innovative brain delivery strategies to enhance their therapeutic potential, exploring alternative animal models to complement traditional mouse studies, and investigating multi-targeted SeNPs formulations to address multiple aspects of AD pathology. Overall, SeNPs represent a promising avenue for AD treatment, and further research in this field may pave the way for effective and much-needed therapeutic interventions for individuals affected by this debilitating disease.PMID:38086100 | DOI:10.1016/j.talanta.2023.125519