PubMed

Metabolomics. 2023 Jun 25;19(7):63. doi: 10.1007/s11306-023-02019-5.ABSTRACTINTRODUCTION: Helminths are parasitic worms that infect millions of people worldwide and secrete a variety of excretory-secretory products (ESPs), including proteins, peptides, and small molecules. Despite this, there is currently no comprehensive review article on cataloging small molecules from helminths, particularly focusing on the different classes of metabolites (polar and lipid molecules) identified from the ESP and somatic tissue extracts of helminths that were studied in isolation from their hosts.OBJECTIVE: This review aims to provide a comprehensive assessment of the metabolomics and lipidomics studies of parasitic helminths using all available analytical platforms.METHOD: To achieve this objective, we conducted a meta-analysis of the identification and characterization tools, metabolomics approaches, metabolomics standard initiative (MSI) levels, software, and databases commonly applied in helminth metabolomics studies published until November 2021.RESULT: This review analyzed 29 studies reporting the metabolomic assessment of ESPs and somatic tissue extracts of 17 helminth species grown under ex vivo/in vitro culture conditions. Of these 29 studies, 19 achieved the highest level of metabolite identification (MSI level-1), while the remaining studies reported MSI level-2 identification. Only 155 small molecule metabolites, including polar and lipids, were identified using MSI level-1 characterization protocols from various helminth species. Despite the significant advances made possible by the 'omics' technology, standardized software and helminth-specific metabolomics databases remain significant challenges in this field. Overall, this review highlights the potential for future studies to better understand the diverse range of small molecules that helminths produce and leverage their unique metabolomic features to develop novel treatment options.PMID:37356029 | DOI:10.1007/s11306-023-02019-5

Commun Biol. 2023 Jun 24;6(1):673. doi: 10.1038/s42003-023-05024-5.ABSTRACTWhile heme synthesis requires the formation of a potentially lethal intermediate, protoporphyrin IX (PPIX), surprisingly little is known about the mechanism of its toxicity, aside from its phototoxicity. The cellular protein interactions of PPIX might provide insight into modulators of PPIX-induced cell death. Here we report the development of PPB, a biotin-conjugated, PPIX-probe that captures proteins capable of interacting with PPIX. Quantitative proteomics in a diverse panel of mammalian cell lines reveal a high degree of concordance for PPB-interacting proteins identified for each cell line. Most differences are quantitative, despite marked differences in PPIX formation and sensitivity. Pathway and quantitative difference analysis indicate that iron and heme metabolism proteins are prominent among PPB-bound proteins in fibroblasts, which undergo PPIX-mediated death determined to occur through ferroptosis. PPB proteomic data (available at PRIDE ProteomeXchange # PXD042631) reveal that redox proteins from PRDX family of glutathione peroxidases interact with PPIX. Targeted gene knockdown of the mitochondrial PRDX3, but not PRDX1 or 2, enhance PPIX-induced death in fibroblasts, an effect blocked by the radical-trapping antioxidant, ferrostatin-1. Increased PPIX formation and death was also observed in a T-lymphoblastoid ferrochelatase-deficient leukemia cell line, suggesting that PPIX elevation might serve as a potential strategy for killing certain leukemias.PMID:37355765 | DOI:10.1038/s42003-023-05024-5

Oncogene. 2023 Jun 24. doi: 10.1038/s41388-023-02756-w. Online ahead of print.ABSTRACTTherapy resistance to second-generation androgen receptor (AR) antagonists, such as enzalutamide, is common in patients with advanced prostate cancer (PCa). To understand the metabolic alterations involved in enzalutamide resistance, we performed metabolomic, transcriptomic, and cistromic analyses of enzalutamide-sensitive and -resistant PCa cells, xenografts, patient-derived organoids, patient-derived explants, and tumors. We noted dramatically higher basal and inducible levels of reactive oxygen species (ROS) in enzalutamide-resistant PCa and castration-resistant PCa (CRPC), in comparison to enzalutamide-sensitive PCa cells or primary therapy-naive tumors respectively. Unbiased metabolomic evaluation identified that glutamine metabolism was consistently upregulated in enzalutamide-resistant PCa cells and CRPC tumors. Stable isotope tracing studies suggest that this enhanced glutamine metabolism drives an antioxidant program that allows these cells to tolerate higher basal levels of ROS. Inhibition of glutamine metabolism with either a small-molecule glutaminase inhibitor or genetic knockout of glutaminase enhanced ROS levels, and blocked the growth of enzalutamide-resistant PCa. The critical role of compensatory antioxidant pathways in maintaining enzalutamide-resistant PCa cells was validated by targeting another antioxidant program driver, ferredoxin 1. Taken together, our data identify a metabolic need to maintain antioxidant programs and a potentially targetable metabolic vulnerability in enzalutamide-resistant PCa.PMID:37355762 | DOI:10.1038/s41388-023-02756-w

Fungal Biol Biotechnol. 2023 Jun 24;10(1):13. doi: 10.1186/s40694-023-00158-x.ABSTRACTBACKGROUND: Fungi are important sources for bioactive compounds that find their applications in many important sectors like in the pharma-, food- or agricultural industries. In an environmental monitoring project for fungi involved in soil nitrogen cycling we also isolated Cephalotrichum gorgonifer (strain NG_p51). In the course of strain characterisation work we found that this strain is able to naturally produce high amounts of rasfonin, a polyketide inducing autophagy, apoptosis, necroptosis in human cell lines and showing anti-tumor activity in KRAS-dependent cancer cells.RESULTS: In order to elucidate the biosynthetic pathway of rasfonin, the strain was genome sequenced, annotated, submitted to transcriptome analysis and genetic transformation was established. Biosynthetic gene cluster (BGC) prediction revealed the existence of 22 BGCs of which the majority was not expressed under our experimental conditions. In silico prediction revealed two BGCs with a suite of enzymes possibly involved in rasfonin biosynthesis. Experimental verification by gene-knock out of the key enzyme genes showed that one of the predicted BGCs is indeed responsible for rasfonin biosynthesis.CONCLUSIONS: This study identified a biosynthetic gene cluster containing a key-gene responsible for rasfonin production. Additionally, molecular tools were established for the non-model fungus Cephalotrichum gorgonifer which allows strain engineering and heterologous expression of the BGC for high rasfonin producing strains and the biosynthesis of rasfonin derivates for diverse applications.PMID:37355668 | DOI:10.1186/s40694-023-00158-x

Methods Mol Biol. 2023;2691:351-369. doi: 10.1007/978-1-0716-3331-1_25.ABSTRACTEpitope-specific immunotherapies have enabled the targeted treatment of a variety of diseases, ranging from cancer, infection, and autoimmune disorders. For CD8+ T cell-based therapies, the precise identification of immunogenic peptides presented by human leukocyte antigen (HLA) class I is essential which can be achieved by immunopeptidomics. Here, using lentivirus-mediated transduction and cell sorting approaches, we present a method to engineer a cell line that does not express its native HLA but instead expresses an HLA of interest (in this instance HLA-A*02:01). This technique can be used to elucidate the immunopeptidome of cell lines expressing different HLAs.PMID:37355557 | DOI:10.1007/978-1-0716-3331-1_25

Anal Chim Acta. 2023 Sep 1;1272:341467. doi: 10.1016/j.aca.2023.341467. Epub 2023 Jun 1.ABSTRACTLiquid chromatography mass spectrometry (LC-MS) has been increasingly used for metabolome analysis. One of the critical steps in the LC-MS metabolome analysis workflow is related to metabolite identification. Among the measured parameters, peak mass is commonly used to search against a database for potential metabolite matches. Higher accuracy mass measurement allows the use of a narrower mass tolerance window for mass search. While various types of mass analyzers can routinely measure a peak mass with an error of less than a few ppm, mass measurement accuracy is not uniform for peaks with different intensities, particularly for quadrupole time-of-flight (QTOF) MS. Herein we present a simple and convenient method to determine the relation between peak intensity and mass error in LC-QTOF-MS-based metabolome analysis, followed by intensity-dependent mass search (IDMS) of a database for metabolite matches. This method is based on running a series of sodium formate mass calibrants, as part of the standard operating procedure (SOP) in LC-MS data acquisition, and then curve-fitting the measured mass errors and peak intensities. We show that, in two different quadrupole time-of-flight (QTOF) mass analyzers, mass accuracy is generally reduced as peak intensity decreases, which is independent of m/z values in the range commonly used for metabolite detection (e.g., m/z < 1000). We demonstrate the improvement in metabolite matches using IDMS in the analyses of dansyl labeled standards and human urine samples. We have implemented the IDMS method in the freely available MCID database at www.mycompoundid.org, which is composed of 8021 known human endogenous metabolites and their predicted metabolic products (375,809 compounds from one metabolic reaction and 10,583,901 compounds from two reactions).PMID:37355326 | DOI:10.1016/j.aca.2023.341467

Neurosci Lett. 2023 Jun 22:137357. doi: 10.1016/j.neulet.2023.137357. Online ahead of print.ABSTRACTThe relationship between the gut microbiota and neurocognitive outcomes is becoming increasingly recognized; however, findings in humans are inconsistent. In addition, few studies have investigated the gut microbial metabolites that may mediate this relationship. The objective of this study was to investigate associations between full-scale intelligence (FSIQ) and the composition of the gut microbiota and metabolome in preschool children. Stool samples were collected from a community sample of 245 typically developing children (3-5 years) from the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort. The faecal microbiome was assessed using 16S rRNA sequencing and the metabolome using LC-MS/MS. FSIQ and scores on the Verbal Comprehension, Visual Spatial, Working Memory indices of the Wechsler Preschool and Primary Scale of Intelligence-IV were used to assess neurocognition. Associations between the gut microbiota and FSIQ were determined using Pearson and Spearman correlations, which were corrected for multiple testing and relevant covariates. Verbal Comprehension negatively correlated with both Shannon alpha diversity (r=-0.14, p=0.032) and the caffeine-derived metabolite paraxanthine (r=-0.22, p<0.001). No other significant correlations were observed. Overall, the weak to modest correlations between Verbal Comprehension with alpha diversity and paraxanthine provide limited evidence of an association between the gut microbiota and neurocognitive outcomes in typically developing preschool children.PMID:37355156 | DOI:10.1016/j.neulet.2023.137357

J Ethnopharmacol. 2023 Jun 22:116835. doi: 10.1016/j.jep.2023.116835. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: The genus Hedychium of family Zingiberaceae comprises several perennial rhizomatous species widely used in perfumery and traditional folk medicine to treat diseases related to asthma, diarrhoea, nausea, stomach disorders, inflammation and tumours. Several species of Hedychium have remained under-explored with respect to their chemical composition and biological activities.AIM OF THE STUDY: The current research aimed to explore the chemical composition and evaluate the antiproliferative and anti-inflammatory activities of rhizome essential oil from four Hedychium species (H. coccineum, H. gardnerianum, H. greenii and H. griffithianum).MATERIALS AND METHODS: Compound identification was accomplished using a Clarus 580 Gas Chromatography system in conjunction with mass spectrometry (GC-MS). The multivariate data statistics using chemometrics (PCA, PLS-DA, sPLS-DA) and cluster analysis (Dendrogram, Heat maps, K-means) were used to compare the similarity and relationship among Hedychium metabolomes. MTT assay was employed to visualize the antiproliferative property against MCF7, HepG2 and PC3 cancerous cell lines. The toxicity of essential oils was determined using 3T3-L1 non-tumorigenic/normal cells. Lipopolysaccharide (LPS)-induced RAW 264.7 cells were used to investigate the anti-inflammatory properties of Hedychium essential oils by measuring the production of nitric oxide (NO) using the Griess reagent method. Furthermore, the levels of prostaglandin (PGE2) and pro-inflammatory cytokines was assessed using the ELISA technique.RESULTS: In total, 82 compounds were identified in four targeted species of Hedychium from which 1,8-cineole (52.71%), β-pinene (32.83%), α-pinene (19.62%), humulene epoxide II (19.86%) and humulene epoxide I (19.10%) were the major constituents. Monoterpenes (8.5-59.9%) and sesquiterpenes (2.87-54.11%) were the two class of compounds that revealed as the most prevalent in the extracted essential oils. The multivariate analysis classified the four Hedychium species into three different clusters. Hedychium essential oils exhibited potent antiproliferative activity against MCF7, HepG2 and PC3 cancer cell lines with IC50 values less than 150 μg/mL where H. gardnerianum exhibited highest selective cytotoxicity against human breast and prostate adenocarcinoma cells with an IC50 value of 44.04 ± 1.07 μg/mL and 56.11 ± 1.44 μg/mL, respectively. The essential oils on normal (3T3-L1) cells displayed no toxicity with higher IC50 values thereby concluding as safe to use for normal human health without causing any side effects. Besides, the essential oils at 100 μg/mL concentration revealed remarkable anti-inflammatory activity in LPS-activated RAW 264.7 murine macrophages by inhibiting the production of inflammatory mediators, with H. greenii exhibiting the maximum anti-inflammation response by significantly suppressing the levels of NO (84%), PGE2 (87%), TNF-α (94.3%), IL-6 (95%) and IL-1β (85%) as compared to LPS treated group.CONCLUSION: The present findings showed that the Hedychium species traditionally used in therapeutics could be potential source of active compounds with antiproliferative and anti-inflammatory properties.PMID:37355085 | DOI:10.1016/j.jep.2023.116835

J Ethnopharmacol. 2023 Jun 22:116805. doi: 10.1016/j.jep.2023.116805. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Growing evidence indicates that hyperuricemia is closely associated with gut microbiota dysbiosis. Orthosiphon aristatus (Blume) Miq. (O. aristatus), as a traditional Chinese medicine, has been widely used to treat hyperuricemia in China. However, the mechanism by which O. aristatus treats hyperuricemia has not been clarified.AIM OF THE STUDY: In this study, we investigated whether the molecular mechanism underlying the anti-hyperuricemia effect of O. aristatus is related to the regulation of gut microbiota by 16S rDNA gene sequencing combined with widely targeted metabolomics.MATERIALS AND METHODS: Hyperuricemia was induced in rats by administration of 10% fructose and 20% yeast, and the uricosuric effect was assessed by measuring the uric acid (UA) levels in serum and cecal contents. Intestinal morphology was observed by hematoxylin and eosin (HE) staining. To explore the effects of O. aristatus on the gut microbiota and its metabolites, we utilized 16S rDNA gene sequencing combined with widely targeted metabolomics. Furthermore, metabolic pathway enrichment analysis was performed on the screened differential metabolites. The real time quantitative polymerase chain reaction (RT-PCR) and western blotting (WB) were used to detect the expression of relevant proteins in the key pathway.RESULTS: Our results indicated that O. aristatus intervention decreased serum UA levels and increased the UA levels in cecal contents in hyperuricemic rats. Additionally, O. aristatus improved intestinal morphology and altered the composition of the gut microbiota and its metabolites. Specifically, 16S rDNA revealed that O. aristatus treatment significantly reduced the abundance of unidentified-Ruminococcaceae and Lachnospiraceae-NK4A136-group. Meanwhile, widely targeted metabolomics showed that 17 metabolites, including lactose, 4-oxopentanoate and butyrate, were elevated, while 55 metabolites, such as flavin adenine dinucleotide and xanthine, were reduced. Metabolic pathway enrichment analysis found that O. aristatus was mainly involved in purine metabolism. Moreover, RT-PCR and WB suggested that O. aristatus could significantly up-regulate the expression of UA excretion transporter ATP-binding cassette subfamily G member 2 (ABCG2) in the intestine.CONCLUSION: O. aristatus exerts UA-lowering effect by regulating the gut microbiota and ABCG2 expression, indicating that this herb holds great promise in the treatment of hyperuricemia.PMID:37355082 | DOI:10.1016/j.jep.2023.116805

Int J Biol Macromol. 2023 Jun 22:125542. doi: 10.1016/j.ijbiomac.2023.125542. Online ahead of print.ABSTRACTPolysaccharides are one of the active components of Cistanche deserticola. Cistanche deserticola polysaccharides (CDPs) significantly regulated gut microbiota, immune activity and neuroprotective functions. However, it merely scratches the surface that the anti-depression effects of CDPs. We aimed to demonstrate the anti-depression effects of CDPs and the underlying mechanisms from the perspectives of gut homeostasis by behavioral evaluations and applying integrally microbiome, metabolome and molecular biology. CDPs showed significant effects on improving abnormal behaviors of depressed rats. Additionally, CDPs maintained Th17/Treg balance and modulated gut immunity of depressed rats. Comprehensive microbiome and metabolome analysis showed that CDPs significantly ameliorated abundances of beneficial bacteria, and increased the contents of SCFAs, consequently maintaining gut homeostasis. Besides, the anti-depression effects of CDPs involved in amino acids metabolism including BCAAs, glutamine, etc., maintaining metabolic balance. The current findings provide not only deeper understanding of depression focusing on gut, but also evidence about anti-depression effects of CDPs, broadening clinic applications of CDPs. Of note, the present study is of significance in a long run, in terms of providing novel strategies and protocols for revealing mechanisms of anti-depression drugs, and for the discovery of new antidepressants and functional foods from natural products.PMID:37355069 | DOI:10.1016/j.ijbiomac.2023.125542

Plant Physiol Biochem. 2023 Jun 20;201:107856. doi: 10.1016/j.plaphy.2023.107856. Online ahead of print.ABSTRACTCyclocarya paliurus (Batal.) Iljinskaja is a multiple function tree species used for functional food and valued timber production. Carbohydrates, especially water-soluble carbohydrates, play an important role in osmotic protection, signal transduction and carbon storage. Under the circumstance of global climate change the abiotic stress would restrict the development of C. paliurus plantation, whereas there is few knowledge on the regulatory mechanisms of sugar metabolism under drought stress in C. paliurus. To investigate the drought response of C. paliurus at molecular level, we conducted an integrated analysis of transcriptomic and metabolomic of C. paliurus at three PEG-induced drought stress levels (0%: control; 15%: moderate drought; 25%: severe drought) in short term. Both moderate and severe drought treatments activated the chemical defense with lowering relative water content, and enhancing the contents of soluble protein, proline and malondialdehyde in the leaves. Meanwhile, alterations in the expression of differentially expressed genes and carbohydrate metabolism profiles were observed among the treatments. Weighted gene co-expression network analysis (WGCNA) showed 3 key modules, 8 structural genes (such as genes encoding beta-fructofuranosidase (INV), sucrose synthase (SUS), raffinose synthase (RS)) and 14 regulatory transcription factors were closely linked to sugar metabolism. Our results provided the foundation to understand the response mechanism of sugar metabolism in C. paliurus under drought stress, and would drive progress in breeding of drought-tolerant varieties and plantation development of the species.PMID:37354727 | DOI:10.1016/j.plaphy.2023.107856

J Sep Sci. 2023 Jun 23:e2300264. doi: 10.1002/jssc.202300264. Online ahead of print.ABSTRACTThe fruits of Rubus chingii Hu have high medicinal and nutritional values. However, the metabolite profiles of R. chingii, especially the alterations during different development stages of fruit, have not been comprehensively analyzed, hindering the effective utilization of the unique species. In this study, we comprehensively analyzed the metabolites of R. chingii fruit at four developmental stages using systematic untargeted and targeted liquid chromatography-mass spectrometry metabolomics analysis and identified 682 metabolites. Significant changes were observed in metabolite accumulation and composition in fruits during the different developmental stages. The contents of the index components, kaempferol-3-O-rutinoside and ellagic acid, were the highest in immature fruit. The analysis identified 64 differentially expressed flavonoids and 39 differentially expressed phenolic acids; the accumulation of most of these differentially expressed metabolites decreased with the developmental stages of fruit from immaturity to maturity. These results confirmed that the developmental stages of fruit are a critical factor in determining its secondary metabolite compositions. This study elucidated the metabolic profile of R. chingii fruit at different stages of development to understand the dynamic changes in metabolites.PMID:37353914 | DOI:10.1002/jssc.202300264

BMC Plant Biol. 2023 Jun 24;23(1):337. doi: 10.1186/s12870-023-04358-w.ABSTRACTSoil salinization is a growing issue that limits agriculture globally. Understanding the mechanism underlying salt tolerance in halophytic grasses can provide new insights into engineering plant salinity tolerance in glycophytic plants. Seashore paspalum (Paspalum vaginatum Sw.) is a halophytic turfgrass and genomic model system for salt tolerance research in cereals and other grasses. However, the salt tolerance mechanism of this grass largely unknown. To explore the correlation between Na+ accumulation and salt tolerance in different tissues, we utilized two P. vaginatum accessions that exhibit contrasting tolerance to salinity. To accomplish this, we employed various analytical techniques including ICP-MS-based ion analysis, lipidomic profiling analysis, enzyme assays, and integrated transcriptomic and metabolomic analysis. Under high salinity, salt-tolerant P. vaginatum plants exhibited better growth and Na+ uptake compared to salt-sensitive plants. Salt-tolerant plants accumulated heightened Na+ accumulation in their roots, leading to increased production of root-sourced H2O2, which in turn activated the antioxidant systems. In salt-tolerant plants, metabolome profiling revealed tissue-specific metabolic changes, with increased amino acids, phenolic acids, and polyols in roots, and increased amino acids, flavonoids, and alkaloids in leaves. High salinity induced lipidome adaptation in roots, enhancing lipid metabolism in salt-tolerant plants. Moreover, through integrated analysis, the importance of amino acid metabolism in conferring salt tolerance was highlighted. This study significantly enhances our current understanding of salt-tolerant mechanisms in halophyte grass, thereby offering valuable insights for breeding and genetically engineering salt tolerance in glycophytic plants.PMID:37353755 | DOI:10.1186/s12870-023-04358-w

Sci Rep. 2023 Jun 23;13(1):10213. doi: 10.1038/s41598-023-36895-7.ABSTRACTNovel small RNAs derived from tRNAs are continuously identified, however, their biological functions are rarely reported. Here, we accidentally found the reads peak at 32nt during statistical analysis on the miRNA-seq data of lamb skin tissue, and found that it was related to the wool type of lambs. This 32nt peak was composed of small tRNA fragments. The main component sequence of this peak was a novel small tRNA derived from Glycyl tRNA (tRNAGly), the expression level of tRNAGly-derived tRNA fragments (tRFGly) was 5.77 folds higher in the coarse wool lambs than that in the fine wool lambs. However, in contrast, the expression of tRNAGly in the skin of fine wool lambs is 6.28 folds more than that in coarse wool lambs. tRNAGly promoted the synthesis of high glycine protein including KAP6 in fine wool lamb skin. These proteins were reported as the major genes for fine curly wool. Integrative analysis of target gene prediction, proteomics and metabolomics results revealed that tRFGly reduced the level of reactive oxygen species (ROS) in the skin of coarse wool lambs by targeted inhibition of the Metabolic signal and the corresponding Glutathione metabolic pathway, on the contrary, the level of oxidative stress in the skin of fine wool lambs was significantly higher. This study revealed for the first time the relationship between tRNAGly and its derived tRFGly and animal traits. tRFGly has the function of targeting and regulating protein synthesis. At the same time, tRFGly can reduce the expression of its resource complete tRNA, thereby reducing its ability to transport specific amino acid and affecting the expression of corresponding proteins.PMID:37353550 | DOI:10.1038/s41598-023-36895-7

Sci Rep. 2023 Jun 23;13(1):10233. doi: 10.1038/s41598-023-36779-w.ABSTRACTTransportation stress is one of the most serious issues in the management of yak. Previous studies have demonstrated that transport stress is caused by a pro-oxidant state in the animal resulting from an imbalance between pro-oxidant and antioxidant status. In this context, vitamin C has the ability to regulate reactive oxygen species (ROS) synthesis and alleviate oxidative stress. Although this effect of vitamin C is useful in pigs, goats and cattle, the effect of vitamin C on the mitigation of transport stress in yaks is still unclear. The purpose of this study was to better assess the metabolic changes induced by the action of vitamin C in yaks under transportation stress, and whether these changes can influence antioxidant status. After the yaks arrived at the farm, control or baseline blood samples were collected immediately through the jugular vein (VC_CON). Then, 100 mg/kg VC was injected intramuscularly, and blood samples were collected on the 10th day before feeding in the morning (VC). Relative to the control group, the VC injection group had higher levels of VC. Compared with VC_CON, VC injection significantly (P < 0.05) decreased the blood concentrations of ALT, AST, T-Bil, D-Bil, IDBIL, UREA, CRP and LDH. However, VC injection led to greater (P < 0.05) AST/ALT and CREA-S relative to VC_CON. There was no difference (P > 0.05) in GGT, ALP, TBA, TP, ALBII, GLO, A/G, TC, TG, HDL-C, LDL-C, GLU and L-lactate between VC_CON and VC. The injection of VC led to greater (P < 0.05) concentration of MDA, but did not alter (P > 0.05) the serum concentrations of LPO and ROS. The injection of VC led to greater (P < 0.05) serum concentrations of POD, CAT and GSH-PX. In contrast, lower (P < 0.05) serum concentrations of SOD, POD and TPX were observed in VC relative to VC_CON. No difference (P > 0.05) in GSH, GSH-ST and GR was observed between VC_CON and VC. Compared with the control group, metabolomics using liquid chromatography tandem-mass spectrometry identified 156 differential metabolites with P < 0.05 and a variable importance in projection (VIP) score > 1.5 in the VC injection group. The injection of VC resulted in significant changes to the intracellular amino acid metabolism of glutathione, glutamate, cysteine, methionine, glycine, phenylalanine, tyrosine, tryptophan, alanine and aspartate. Overall, our study indicated that VC injections were able to modulate antioxidant levels by affecting metabolism to resist oxidative stress generated during transport.PMID:37353533 | DOI:10.1038/s41598-023-36779-w

Int J Biol Macromol. 2023 Jun 21:125459. doi: 10.1016/j.ijbiomac.2023.125459. Online ahead of print.ABSTRACTAquaporin 9 (AQP9) is the main channel by which blood glycerol enters the liver, where it plays key roles in osmotic pressure regulation and energy metabolism. Previous studies have shown that AQP9 is involved in the pathogenesis of many liver diseases. In this study, we aimed to clarify the role of AQP9 in maintaining the physiological environment of the liver using Aqp9-/- mice. We constructed Aqp9 knockout mice and used comprehensive multiomics analysis to elucidate the potential molecular effects of AQP9 expression on liver tissue. Knockout of Aqp9 reduced mouse body weight by affecting glycerol metabolism and led to hepatocyte death and inflammatory cell infiltration, which was confirmed by transcriptomics, proteomics and metabolomics. Moreover, knockout of Aqp9 triggered immune and inflammatory responses, leading to scattered and mild liver cell pyroptosis and compensatory liver cell proliferation.PMID:37353119 | DOI:10.1016/j.ijbiomac.2023.125459

Sci Total Environ. 2023 Jun 21:165009. doi: 10.1016/j.scitotenv.2023.165009. Online ahead of print.ABSTRACTThe heavy metals lead (Pb), cadmium (Cd), and mercury (Hg) that cause neurocognitive impairment have been extensively studied. These elements typically do not exist alone in the environment; they are often found with other heavy metals and can enter the body through various routes, thereby impacting health. Our previous research showed that low Pb, Cd, and Hg levels cause neurobehavioral impairments in weaning and adult rats. However, little is known about the biomarkers and mechanisms underlying Pb, Cd, and Hg mixture-induced neurological impairments. A combined analysis of metabolomic and proteomic data may reveal heavy metal-induced alterations in metabolic and protein profiles, thereby improving our understanding of the molecular mechanisms underlying heavy metal-induced neurological impairments. Therefore, brain tissue and serum samples were collected from rats exposed to a Pb, Cd, and Hg mixture for proteomic and metabolomic analyses, respectively. The analysis revealed 363 differential proteins in the brain and 206 metabolites in serum uniquely altered in the Pb, Cd, and Hg mixture exposure group, compared to those of the control group. The main metabolic impacted pathways were unsaturated fatty acids biosynthesis, linoleic acid metabolism, phenylalanine metabolism, and tryptophan metabolism. We further identified that the levels of arachidonic acid (C20:4 n-3) and, adrenic acid (C22:4 n-3) were elevated and that kynurenic acid (KA) and quinolinic acid (QA) levels and the KA/QA ratio, were decreased in the group exposed to the Pb, Cd, and Hg mixture. A joint analysis of the proteome and metabolome showed that significantly altered proteins such as LPCAT3, SLC7A11, ASCL4, and KYAT1 may participate in the neurological impairments induced by the heavy metal mixture. Overall, we hypothesize that the dysregulation of ferroptosis and kynurenine pathways is associated with neurological damage due to chronic exposure to a heavy metal mixture.PMID:37353033 | DOI:10.1016/j.scitotenv.2023.165009

Sci Total Environ. 2023 Jun 21:165018. doi: 10.1016/j.scitotenv.2023.165018. Online ahead of print.ABSTRACTThe increasing demand for rare earth elements (REEs) in modern applications has drawn significant attention. REEs can be introduced into the environment through REE-containing fertilizers, abandoned REE-rich equipment, and mining, persisting and impacting soil quality, nutrient cycles, and plant growth. Scientists have raised concerns about REEs entering the food chain from the environment and eventually accumulating in organisms. Decades of experimental evidence have shown that these effects include inhibited growth, impaired liver function, and alterations in children's intelligence quotients. However, there exists a paucity of research that has elucidated the metabolic-level biological impacts of REEs. In our study, Caenorhabditis elegans (C. elegans) was used as a model organism to investigate physiological and inherent metabolic changes under exposure to different concentrations of REEs. The diet bacteria of nematodes play a key role in their life and development. Therefore, we investigated the influence of bacterial activity on the nematodes' response to REE exposure. We observed a concentration-dependent accumulation of REEs in nematodes, which consequently led to a reduction in lifespan and alterations in body length. Exposure to a mixed solution of REEs, in comparison to a single REE solution, resulted in greater toxicity toward nematodes. The metabolic results showed that the above changes were closely related to REE-induced amino acid metabolism disorder, membrane disturbance, DNA damage, and oxidative stress. Of note, the presence of living bacteria elicits REE effects in C. elegans. These findings highlight the potential intrinsic metabolic changes occurring in nematodes under REE exposure. Our study raises awareness of the exposure risks associated with REEs, provides valuable insight into the metabolic-level biological impacts of REEs and contributes to the development of effective mitigation strategies to reduce potential risks to human health.PMID:37353023 | DOI:10.1016/j.scitotenv.2023.165018

J Adv Res. 2023 Jun 21:S2090-1232(23)00171-6. doi: 10.1016/j.jare.2023.06.008. Online ahead of print.ABSTRACTINTRODUCTION: Epidemiological evidences reveal that populations with psychological stress have an increased likelihood of respiratory viral infection involving influenza A virus (IAV) and SARS-CoV-2.OBJECTIVES: This study aims to explore the potential correlation between psychological stress and increased susceptibility to respiratory viral infections and how this may contribute to a more severe disease progression.METHODS: A chronic restraint stress (CRS) mouse model was used to infect IAV and estimate lung inflammation. Alveolar macrophages (AMs) were observed in the numbers, function and metabolic-epigenetic properties. To confirm the central importance of the gut microbiome in stress-exacerbated viral pneumonia, mice were conducted through microbiome depletion and gut microbiome transplantation.RESULTS: Stress exposure induced a decline in Lactobacillaceae abundance and hence γ-aminobutyric acid (GABA) level in mice. Microbial-derived GABA was released in the peripheral and sensed by AMs via GABAAR, leading to enhanced mitochondrial metabolism and α-ketoglutarate (αKG) generation. The metabolic intermediator in turn served as the cofactor for the epigenetic regulator Tet2 to catalyze DNA hydroxymethylation and promoted the PPARγ-centered gene program underpinning survival, self-renewing, and immunoregulation of AMs. Thus, we uncover an unappreciated GABA/Tet2/PPARγ regulatory circuitry initiated by the gut microbiome to instruct distant immune cells through a metabolic-epigenetic program. Accordingly, reconstitution with GABA-producing probiotics, adoptive transferring of GABA-conditioned AMs, or resumption of pulmonary αKG level remarkably improved AMs homeostasis and alleviated severe pneumonia in stressed mice.CONCLUSION: Together, our study identifies microbiome-derived tonic signaling tuned by psychological stress to imprint resident immune cells and defensive response in the lungs. Further studies are warranted to translate these findings, basically from murine models, into the individuals with psychiatric stress during respiratory viral infection.PMID:37353002 | DOI:10.1016/j.jare.2023.06.008

Neurobiol Dis. 2023 Jun 21:106211. doi: 10.1016/j.nbd.2023.106211. Online ahead of print.ABSTRACTBrain tissue metabolism is distributed across several cell types and subcellular compartments, which activate at different times and with different temporal patterns. The introduction of genetically-encoded fluorescent indicators that are imaged using time-lapse microscopy has opened the possibility of studying brain metabolism at cellular and sub-cellular levels. There are indicators for sugars, monocarboxylates, Krebs cycle intermediates, amino acids, cofactors, and energy nucleotides, which inform about relative levels, concentrations and fluxes. This review offers a brief survey of the metabolic indicators that have been validated in brain cells, with some illustrative examples from the literature. Whereas only a small fraction of the metabolome is currently accessible to fluorescent probes, there are grounds to be optimistic about coming developments and the application of these tools to the study of brain disease.PMID:37352985 | DOI:10.1016/j.nbd.2023.106211