PubMed

Plant J. 2023 Jun 7. doi: 10.1111/tpj.16329. Online ahead of print.ABSTRACTLegumes represent an important component of human and livestock diets; they are rich in macro- and micronutrients such as proteins, dietary fibers and polyunsaturated fatty acids. Whilst, several health-promoting and anti-nutritious properties have been associated with grain content, in-depth metabolomics characterization of major legume species remains elusive. In this article, we used both gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) to assess the metabolic diversity in the five legume species commonly grown in Europe, including common bean, chickpea, lentil, white and pearl lupin at the tissue-specific level. We were able to detect and quantify over 3,430 metabolites covering major nutritional and anti-nutritional compounds. Specifically, the metabolomics atlas includes 224 derivatized metabolites, 2283 specialized metabolites, and 923 lipids. The data generated here will serve the community as a basis for future integration to metabolomics-assisted crop breeding and facilitate the metabolite-based genome-wide association study (mGWAS) to dissect the genetic and biochemical bases of metabolism in legume species.PMID:37285370 | DOI:10.1111/tpj.16329

Environ Sci Technol. 2023 Jun 7. doi: 10.1021/acs.est.3c02071. Online ahead of print.ABSTRACTThe effects and mechanisms of zinc oxide nanoparticles (ZnO NPs) and their aging products, sulfidized (s-) ZnO NPs, on the carbon cycling in the legume rhizosphere are still unclear. We observed that, after 30 days of cultivation, in the rhizosphere soil of Medicago truncatula, under ZnO NP and s-ZnO NP treatments, the dissolved organic carbon (DOC) concentrations were significantly increased by 1.8- to 2.4-fold compared to Zn2+ treatments, although the soil organic matter (SOM) contents did not change significantly. Compared to Zn2+ additions, the additions of NPs significantly induced the production of root metabolites such as carboxylic acids and amino acids and also stimulated the growth of microbes involved in the degradations of plant-derived and recalcitrant SOM, such as bacteria genera RB41 and Bryobacter, and fungi genus Conocybe. The bacterial co-occurrence networks indicated that microbes associated with SOM formation and decomposition were significantly increased under NP treatments. The adsorption of NPs by roots, the generation of root metabolites (e.g., carboxylic acid and amino acid), and enrichment of key taxa (e.g., RB41 and Gaiella) were the major mechanisms by which ZnO NPs and s-ZnO NPs drove DOC release and SOM decomposition in the rhizosphere. These results provide new perspectives on the effect of ZnO NPs on agroecosystem functions in soil-plant systems.PMID:37285309 | DOI:10.1021/acs.est.3c02071

Cell Rep. 2023 Jun 6;42(6):112620. doi: 10.1016/j.celrep.2023.112620. Online ahead of print.ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer that typically demonstrates resistance to chemotherapy. Tumor-associated macrophages (TAMs) are essential in tumor microenvironment (TME) regulation, including promoting chemoresistance. However, the specific TAM subset and mechanisms behind this promotion remain unclear. We employ multi-omics strategies, including single-cell RNA sequencing (scRNA-seq), transcriptomics, multicolor immunohistochemistry (mIHC), flow cytometry, and metabolomics, to analyze chemotherapy-treated samples from both humans and mice. We identify four major TAM subsets within PDAC, among which proliferating resident macrophages (proliferating rMφs) are strongly associated with poor clinical outcomes. These macrophages are able to survive chemotherapy by producing more deoxycytidine (dC) and fewer dC kinases (dCKs) to decrease the absorption of gemcitabine. Moreover, proliferating rMφs promote fibrosis and immunosuppression in PDAC. Eliminating them in the transgenic mouse model alleviates fibrosis and immunosuppression, thereby re-sensitizing PDAC to chemotherapy. Consequently, targeting proliferating rMφs may become a potential treatment strategy for PDAC to enhance chemotherapy.PMID:37285267 | DOI:10.1016/j.celrep.2023.112620

Environ Sci Pollut Res Int. 2023 Jun 7. doi: 10.1007/s11356-023-27990-3. Online ahead of print.ABSTRACTNowadays, people are interested to use plants, especially air-purifying plants, in residential and other indoor settings to purify indoor air and increase the green area in the building. In this study, we investigated the effect of water deficit and low light intensity on the physiology and biochemistry of popular ornamental plants, including Sansevieria trifasciata, Episcia cupreata and Epipremnum aureum. Plants were grown under low light intensity in the range of 10-15 μmol quantum m-2 s-1 and 3 days of water deficit. The results showed that these three ornamental plants responded to water deficit with different pathways. Metabolomic analysis indicated that water deficit affected Episcia cupreata and Epipremnum aureum by inducing a 1.5- to 3-fold increase of proline and a 1.1- to 1.6-fold increase in abscisic acid compared to well-watered conditions, which led to hydrogen peroxide accumulation. This resulted in a reduction of stomatal conductance, photosynthesis rate and transpiration. Sansevieria trifasciata responded to water deficit by significantly increasing gibberellin by around 2.8-fold compared to well-watered plants and proline contents by around 4-fold, while stomatal conductance, photosynthesis rate and transpiration were maintained. Notably, proline accumulation under water deficit stress could be attributed to both gibberellic acid and abscisic acid, depending on plant species. Therefore, the enhancement of proline accumulation in ornamental plants under water deficit could be detected early from day 3 after water deficit conditions, and this compound can be used as a key compound for real-time biosensor development in detecting plant stress under water deficit in a future study.PMID:37284956 | DOI:10.1007/s11356-023-27990-3

Metabolomics. 2023 Jun 7;19(6):55. doi: 10.1007/s11306-023-02017-7.ABSTRACTINTRODUCTION: Various studies have identified TB-induced metabolome variations. However, in most of these studies, a large degree of variation exists between individual patients.OBJECTIVES: To identify differential metabolites for TB, independent of patients' sex or HIV status.METHODS: Untargeted GCxGC/TOF-MS analyses were applied to the sputum of 31 TB + and 197 TB- individuals. Univariate statistics were used to identify metabolites which are significantly different between TB + and TB- individuals (a) irrespective of HIV status, and (b) with a HIV + status. Comparisons a and b were repeated for (i) all participants, (ii) males only and (iii) females only.RESULTS: Twenty-one compounds were significantly different between the TB + and TB- individuals within the female subgroup (11% lipids; 10% carbohydrates; 1% amino acids, 5% other and 73% unannotated), and 6 within the male subgroup (20% lipids; 40% carbohydrates; 6% amino acids, 7% other and 27% unannotated). For the HIV + patients (TB + vs. TB-), a total of 125 compounds were significant within the female subgroup (16% lipids; 8% carbohydrates; 12% amino acids, 6% organic acids, 8% other and 50% unannotated), and 44 within the male subgroup (17% lipids; 2% carbohydrates; 14% amino acids related, 8% organic acids, 9% other and 50% unannotated). Only one annotated compound, 1-oleoyl lysophosphaditic acid, was consistently identified as a differential metabolite for TB, irrespective of sex or HIV status. The potential clinical application of this compound should be evaluated further.CONCLUSIONS: Our findings highlight the importance of considering confounders in metabolomics studies in order to identify unambiguous disease biomarkers.PMID:37284915 | DOI:10.1007/s11306-023-02017-7

Front Plant Sci. 2023 May 22;14:1122621. doi: 10.3389/fpls.2023.1122621. eCollection 2023.ABSTRACTINTRODUCTION: Humic substances (HSs), components of plant biostimulants, are known to influence plant physiological processes, nutrient uptake and plant growth, thereby increasing crop yield. However, few studies have focused on the impact of HS on overall plant metabolism, and there is still debate over the connection between HS' structural characteristics and their stimulatory actions.METHODS: In this study, two different HSs (AHA, Aojia humic acid and SHA, Shandong humic acid) screened in a previous experiment were chosen for foliar spraying, and plant samples were collected on the tenth day after spraying (62 days after germination) to investigate the effects of different HSs on photosynthesis, dry matter accumulation, carbon and nitrogen metabolism and overall metabolism in maize leaf.RESULTS AND DISCUSSION: The results showed different molecular compositions for AHA and SHA and a total of 510 small molecules with significant differences were screened using an ESI-OPLC-MS techno. AHA and SHA exerted different effects on maize growth, with the AHA inducing more effective stimulation than the SHA doing. Untargeted metabolomic analysis revealed that the phospholipid components of maize leaves treated by SHA generally increased significantly than that in the AHA and control treatments. Additionally, both HS-treated maize leaves exhibited different levels of accumulation of trans-zeatin, but SHA treatment significantly decreased the accumulation of zeatin riboside. Compared to CK treatment, AHA treatment resulted in the reorganization of four metabolic pathways: starch and sucrose metabolism, TCA cycle, stilbenes, diarylheptanes, and curcumin biosynthesis, and ABC transport, SHA treatment modified starch and sucrose metabolism and unsaturated fatty acid biosynthesis. These results demonstrate that HSs exert their function through a multifaceted mechanism of action, partially connected to their hormone-like activity but also involving hormoneindependent signaling pathways.PMID:37284724 | PMC:PMC10239833 | DOI:10.3389/fpls.2023.1122621

Front Plant Sci. 2023 May 22;14:1101994. doi: 10.3389/fpls.2023.1101994. eCollection 2023.ABSTRACTPeanut growth, development, and eventual production are constrained by biotic and abiotic stresses resulting in serious economic losses. To understand the response and tolerance mechanism of peanut to biotic and abiotic stresses, high-throughput Omics approaches have been applied in peanut research. Integrated Omics approaches are essential for elucidating the temporal and spatial changes that occur in peanut facing different stresses. The integration of functional genomics with other Omics highlights the relationships between peanut genomes and phenotypes under specific stress conditions. In this review, we focus on research on peanut biotic stresses. Here we review the primary types of biotic stresses that threaten sustainable peanut production, the multi-Omics technologies for peanut research and breeding, and the recent advances in various peanut Omics under biotic stresses, including genomics, transcriptomics, proteomics, metabolomics, miRNAomics, epigenomics and phenomics, for identification of biotic stress-related genes, proteins, metabolites and their networks as well as the development of potential traits. We also discuss the challenges, opportunities, and future directions for peanut Omics under biotic stresses, aiming sustainable food production. The Omics knowledge is instrumental for improving peanut tolerance to cope with various biotic stresses and for meeting the food demands of the exponentially growing global population.PMID:37284721 | PMC:PMC10239885 | DOI:10.3389/fpls.2023.1101994

Oncoimmunology. 2023 Jun 3;12(1):2219591. doi: 10.1080/2162402X.2023.2219591. eCollection 2023.ABSTRACTImmunogenic cell death (ICD) refers to an immunologically distinct process of regulated cell death that activates, rather than suppresses, innate and adaptive immune responses. Such responses culminate into T cell-driven immunity against antigens derived from dying cancer cells. The potency of ICD is dependent on the immunogenicity of dying cells as defined by the antigenicity of these cells and their ability to expose immunostimulatory molecules like damage-associated molecular patterns (DAMPs) and cytokines like type I interferons (IFNs). Moreover, it is crucial that the host's immune system can adequately detect the antigenicity and adjuvanticity of these dying cells. Over the years, several well-known chemotherapies have been validated as potent ICD inducers, including (but not limited to) anthracyclines, paclitaxels, and oxaliplatin. Such ICD-inducing chemotherapeutic drugs can serve as important combinatorial partners for anti-cancer immunotherapies against highly immuno-resistant tumors. In this Trial Watch, we describe current trends in the preclinical and clinical integration of ICD-inducing chemotherapy in the existing immuno-oncological paradigms.PMID:37284695 | PMC:PMC10240992 | DOI:10.1080/2162402X.2023.2219591

Kidney Int Rep. 2023 Mar 23;8(6):1239-1254. doi: 10.1016/j.ekir.2023.03.015. eCollection 2023 Jun.ABSTRACTINTRODUCTION: Nephrotic syndrome (NS) occurs commonly in children with glomerular disease and glucocorticoids (GCs) are the mainstay treatment. Steroid resistant NS (SRNS) develops in 15% to 20% of children, increasing the risk of chronic kidney disease compared to steroid sensitive NS (SSNS). NS pathogenesis is unclear in most children, and no biomarkers exist that predict the development of pediatric SRNS.METHODS: We studied a unique patient cohort with plasma specimens collected before GC treatment, yielding a disease-only sample not confounded by steroid-induced gene expression changes (SSNS n = 8; SRNS n = 7). A novel "patient-specific" bioinformatic approach merged paired pretreatment and posttreatment proteomic and metabolomic data and identified candidate SRNS biomarkers and altered molecular pathways in SRNS versus SSNS.RESULTS: Joint pathway analyses revealed perturbations in nicotinate or nicotinamide and butanoate metabolic pathways in patients with SRNS. Patients with SSNS had perturbations of lysine degradation, mucin type O-glycan biosynthesis, and glycolysis or gluconeogenesis pathways. Molecular analyses revealed frequent alteration of molecules within these pathways that had not been observed by separate proteomic and metabolomic studies. We observed upregulation of NAMPT, NMNAT1, and SETMAR in patients with SRNS, in contrast to upregulation of ALDH1B1, ACAT1, AASS, ENPP1, and pyruvate in patients with SSNS. Pyruvate regulation was the change seen in our previous analysis; all other targets were novel. Immunoblotting confirmed increased NAMPT expression in SRNS and increased ALDH1B1 and ACAT1 expression in SSNS, following GC treatment.CONCLUSION: These studies confirmed that a novel "patient-specific" bioinformatic approach can integrate disparate omics datasets and identify candidate SRNS biomarkers not observed by separate proteomic or metabolomic analysis.PMID:37284673 | PMC:PMC10239920 | DOI:10.1016/j.ekir.2023.03.015

Plant Environ Interact. 2023 Feb 9;4(1):36-54. doi: 10.1002/pei3.10101. eCollection 2023 Feb.ABSTRACTThrough crosstalk, FLAGELLIN SENSITIVE 2 (FLS2) and RESPIRATORY BURST OXIDASE HOMOLOG D (RBOHD) are involved in regulating the homeostasis of cellular reactive oxygen species (ROS) and are linked to the metabolic response of plants toward both biotic and abiotic stress. In the present study, we examined the metabolome of Arabidopsis seedlings under drought and salt conditions to better understand the potential role of FLS2 and RBOHD-dependent signaling in the regulation of abiotic stress response. We identified common metabolites and genes that are regulated by FLS2 and RBOHD, and are involved in the response to drought and salt stress. Under drought conditions, D-aspartic acid and the expression of associated genes, such as ASPARAGINE SYNTHASE 2 (ASN2), increased in both fls2 and robed/f double mutants. The accumulation of amino acids, carbohydrates, and hormones, such as L-proline, D-ribose, and indoleacetaldehyde increased in both fls2 and rbohd/f double mutants under salt conditions, as did the expression of related genes, such as PROLINE IMINOPEPTIDASE, PHOSPHORIBOSYL PYROPHOSPHATE SYNTHASE 5, and NITRILASE 3. Collectively, these results indicate that the FLS2-RBOHD module regulates plant response to drought and salt stress through ROS signaling by adjusting the accumulation of metabolites and expression of genes related to metabolite synthesis.PMID:37284598 | PMC:PMC10168046 | DOI:10.1002/pei3.10101

Theranostics. 2023 May 21;13(9):3103-3116. doi: 10.7150/thno.81893. eCollection 2023.ABSTRACTObesity is a chronic metabolic disease, affecting individuals throughout the world. Bariatric surgery such as vertical sleeve gastrectomy (VSG) provides sustained weight loss and improves glucose homeostasis in obese mice and humans. However, the precise underlying mechanisms remain elusive. In this study, we investigated the potential roles and the mechanisms of action of gut metabolites in VSG-induced anti-obesity effect and metabolic improvement. Methods: High-fat diet (HFD)-fed C57BL/6J mice were subjected to VSG. Energy dissipation in mice was monitored using metabolic cage experiments. The effects of VSG on gut microbiota and metabolites were determined by 16S rRNA sequencing and metabolomics, respectively. The metabolic beneficial effects of the identified gut metabolites were examined in mice by both oral administration and fat pad injection of the metabolites. Results: VSG in mice greatly increased thermogenic gene expression in beige fat, which was correlated with increased energy expenditure. VSG reshaped gut microbiota composition, resulting in elevated levels of gut metabolites including licoricidin. Licoricidin treatment promoted thermogenic gene expression in beige fat by activating the Adrb3-cAMP-PKA signaling pathway, leading to reduced body weight gain in HFD-fed mice. Conclusions: We identify licoricidin, which mediates the crosstalk between gut and adipose tissue in mice, as a VSG-provoked anti-obesity metabolite. Identification of anti-obesity small molecules should provide new insights into treatment options for obesity and its associated metabolic diseases.PMID:37284437 | PMC:PMC10240825 | DOI:10.7150/thno.81893

Plant Environ Interact. 2022 Dec 26;3(6):264-289. doi: 10.1002/pei3.10096. eCollection 2022 Dec.ABSTRACTTo prevent yield losses caused by climate change, it is important to identify naturally tolerant genotypes with traits and related pathways that can be targeted for crop improvement. Here we report on the characterization of contrasting vegetative heat tolerance in two UK bread wheat varieties. Under chronic heat stress, the heat-tolerant cultivar Cadenza produced an excessive number of tillers which translated into more spikes and higher grain yield compared to heat-sensitive Paragon. RNAseq and metabolomics analyses revealed that over 5000 genotype-specific genes were differentially expressed, including photosynthesis-related genes, which might explain the observed ability of Cadenza to maintain photosynthetic rate under heat stress. Around 400 genes showed a similar heat-response in both genotypes. Only 71 genes showed a genotype × temperature interaction. As well as known heat-responsive genes such as heat shock proteins (HSPs), several genes that have not been previously linked to the heat response, particularly in wheat, have been identified, including dehydrins, ankyrin-repeat protein-encoding genes, and lipases. Contrary to primary metabolites, secondary metabolites showed a highly differentiated heat response and genotypic differences. These included benzoxazinoid (DIBOA, DIMBOA), and phenylpropanoids and flavonoids with known radical scavenging capacity, which was assessed via the DPPH assay. The most highly heat-induced metabolite was (glycosylated) propanediol, which is widely used in industry as an anti-freeze. To our knowledge, this is the first report on its response to stress in plants. The identified metabolites and candidate genes provide novel targets for the development of heat-tolerant wheat.PMID:37284432 | PMC:PMC10168084 | DOI:10.1002/pei3.10096

Front Pharmacol. 2023 May 22;14:1197847. doi: 10.3389/fphar.2023.1197847. eCollection 2023.ABSTRACTBackground: Farnesoid X receptor (FXR) is a key metabolic target of bile acids (BAs) and is also a target for drugs against several liver diseases. However, the contribution of FXR in the pathogenesis of cholestasis is still not fully understood. The purpose of this study is to provide a comprehensive insight into the metabolic properties of FXR-involved cholestasis in mice. Materials and methods: In this study, an alpha-naphthylisothiocyanate (ANIT)-induced cholestasis mouse model and FXR-/- mice were established to investigate the effect of FXR on cholestasis. The effect of FXR on liver and ileal pathology was evaluated. Simultaneously, Untargeted metabolomics combined with 16s rRNA gene sequencing analysis was applied to reveal the involvement of FXR in the pathogenesis of cholestasis. Results: The results showed that ANIT (75 mg/kg) induced marked cholestasis in WT and FXR -/- mice. It is noteworthy that FXR-/- mice developed spontaneous cholestasis. Compared with WT mice, significant liver and ileal tissue damage were found. In addition, 16s rRNA gene sequencing analysis revealed gut microbiota dysbiosis in FXR-/- mice and ANIT-induced cholestasis mice. Differential biomarkers associated with the pathogenesis of cholestasis caused by FXR knockout were screened using untargeted metabolomics. Notably, Lactobacillus_ johnsonii_FI9785 has a high correlation with the differential biomarkers associated with the pathogenesis and progression of cholestasis caused by FXR knockout. Conclusion: Our results implied that the disorder of the intestinal flora caused by FXR knockout can also interfere with the metabolism. This study provides novel insights into the FXR-related mechanisms of cholestasis.PMID:37284301 | PMC:PMC10239812 | DOI:10.3389/fphar.2023.1197847

Plant Environ Interact. 2021 Nov 22;2(6):277-289. doi: 10.1002/pei3.10066. eCollection 2021 Dec.ABSTRACTTall fescue (Festuca arundinacea) is an important cool-season perennial forage grass that forms mutualistic symbioses with fungal endophytes. Physiological, biochemical and transcriptional comparisons were made between two tall fescue genotypes with contrasting drought tolerance (tolerant, T400, and sensitive, S279), either with or without endophyte (Epichloë coenophiala). Drought stress was applied by withholding watering until plants reached mild, moderate and severe stresses. Physiological characterization showed that T400 had narrower, thicker leaves, and lower leaf conductance under well-watered conditions, compared to S279. After severe drought and recovery, endophytic T400 had greater shoot and root biomass than other plant types. Under drought, leaf osmotic pressure increased much more in T400 than S279, consistent with accumulation of metabolites/osmolytes, especially proline. Gene Ontology enrichment analysis indicated that T400 had more active organic acid metabolism than S279 under drought, and implicated the role of endophyte in stimulating protein metabolism in both genotypes. Overall T400 and S279 responded to endophyte differently in aspects of physiology, gene transcription and metabolites, indicating plant genotype-specific reactions to endophyte infection.PMID:37284176 | PMC:PMC10168078 | DOI:10.1002/pei3.10066

Front Immunol. 2023 May 22;14:1177580. doi: 10.3389/fimmu.2023.1177580. eCollection 2023.ABSTRACTBACKGROUND: Recent observational studies and meta-analyses have shown that vitamin C reduces cancer incidence and mortality, but the underlying mechanisms remain unclear. We conducted a comprehensive pan-cancer analysis and biological validation in clinical samples and animal tumor xenografts to understand its prognostic value and association with immune characteristics in various cancers.METHODS: We used the Cancer Genome Atlas gene expression data involving 5769 patients and 20 cancer types. Vitamin C index (VCI) was calculated using the expression of 11 genes known to genetically predict vitamin C levels, which were classified into high and low subgroups. The correlation between VCI and patient overall survival (OS), tumor mutational burden (TMB), microsatellite instability (MSI), and immune microenvironment was evaluated, using Kaplan-Meier analysis method and ESTIMATE (https://bioinformatics.mdanderson.org/estimate/). Clinical samples of breast cancer and normal tissues were used to validate the expression of VCI-related genes, and animal experiments were conducted to test the impact of vitamin C on colon cancer growth and immune cell infiltration.RESULTS: Significant changes in expression of VCI-predicted genes were observed in multiple cancer types, especially in breast cancer. There was a correlation of VCI with prognosis in all samples (adjusted hazard ratio [AHR] = 0.87; 95% confidence interval [CI] = 0.78-0.98; P = 0.02). The specific cancer types that exhibited significant correlation between VCI and OS included breast cancer (AHR = 0.14; 95% CI = 0.05-0.40; P < 0.01), head and neck squamous cell carcinoma (AHR = 0.20; 95% CI = 0.07-0.59; P < 0.01), kidney clear cell carcinoma (AHR = 0.66; 95% CI = 0.48-0.92; P = 0.01), and rectum adenocarcinoma (AHR = 0.01; 95% CI = 0.001-0.38; P = 0.02). Interestingly, VCI was correlated with altered immunotypes and associated with TMB and MSI negatively in colon and rectal adenocarcinoma (P < 0.001) but positively in lung squamous cell carcinoma (P < 0.05). In vivo study using mice bearing colon cancer xenografts demonstrated that vitamin C could inhibit tumor growth with significant impact on immune cell infiltration.CONCLUSION: VCI is significantly correlated with OS and immunotypes in multiple cancers, and vitamin C might have therapeutic potential in colon cancer.PMID:37283769 | PMC:PMC10239825 | DOI:10.3389/fimmu.2023.1177580

Neurosurg Focus. 2023 Jun;54(6):E4. doi: 10.3171/2023.3.FOCUS2379.ABSTRACTOBJECTIVE: Gliomas exhibit high intratumor and interpatient heterogeneity. Recently, it has been shown that the microenvironment and phenotype differ significantly between the glioma core (inner) and edge (infiltrating) regions. This proof-of-concept study differentiates metabolic signatures associated with these regions, with the potential for prognosis and targeted therapy that could improve surgical outcomes.METHODS: Paired glioma core and infiltrating edge samples were obtained from 27 patients after craniotomy. Liquid-liquid metabolite extraction was performed on the samples and metabolomic data were obtained via 2D liquid chromatography-mass spectrometry/mass spectrometry. To gauge the potential of metabolomics to identify clinically relevant predictors of survival from tumor core versus edge tissues, a boosted generalized linear machine learning model was used to predict metabolomic profiles associated with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation.RESULTS: A panel of 66 (of 168) metabolites was found to significantly differ between glioma core and edge regions (p ≤ 0.05). Top metabolites with significantly different relative abundances included DL-alanine, creatine, cystathionine, nicotinamide, and D-pantothenic acid. Significant metabolic pathways identified by quantitative enrichment analysis included glycerophospholipid metabolism; butanoate metabolism; cysteine and methionine metabolism; glycine, serine, alanine, and threonine metabolism; purine metabolism; nicotinate and nicotinamide metabolism; and pantothenate and coenzyme A biosynthesis. The machine learning model using 4 key metabolites each within core and edge tissue specimens predicted MGMT promoter methylation status, with AUROCEdge = 0.960 and AUROCCore = 0.941. Top metabolites associated with MGMT status in the core samples included hydroxyhexanoycarnitine, spermine, succinic anhydride, and pantothenic acid, and in the edge samples metabolites included 5-cytidine monophosphate, pantothenic acid, itaconic acid, and uridine.CONCLUSIONS: Key metabolic differences are identified between core and edge tissue in glioma and, furthermore, demonstrate the potential for machine learning to provide insight into potential prognostic and therapeutic targets.PMID:37283447 | DOI:10.3171/2023.3.FOCUS2379

Alzheimers Dement. 2023 Jun 7. doi: 10.1002/alz.13076. Online ahead of print.ABSTRACTMicrobial infections of the brain can lead to dementia, and for many decades microbial infections have been implicated in Alzheimer's disease (AD) pathology. However, a causal role for infection in AD remains contentious, and the lack of standardized detection methodologies has led to inconsistent detection/identification of microbes in AD brains. There is a need for a consensus methodology; the Alzheimer's Pathobiome Initiative aims to perform comparative molecular analyses of microbes in post mortem brains versus cerebrospinal fluid, blood, olfactory neuroepithelium, oral/nasopharyngeal tissue, bronchoalveolar, urinary, and gut/stool samples. Diverse extraction methodologies, polymerase chain reaction and sequencing techniques, and bioinformatic tools will be evaluated, in addition to direct microbial culture and metabolomic techniques. The goal is to provide a roadmap for detecting infectious agents in patients with mild cognitive impairment or AD. Positive findings would then prompt tailoring of antimicrobial treatments that might attenuate or remit mounting clinical deficits in a subset of patients.PMID:37283269 | DOI:10.1002/alz.13076

Crit Rev Food Sci Nutr. 2023 Jun 7:1-25. doi: 10.1080/10408398.2023.2217451. Online ahead of print.ABSTRACTExposure to mycotoxins through the dietary route occurs on a daily basis while their deleterious effects are exhibited in the form of ailments, such as inflammation, cancer, and hormonal imbalance. The negative impact of mycotoxins can be attributed to their interaction with various biomolecules and their interference in metabolic pathways. The activity of biomolecules, such as enzymes/receptors, which engage the intricate mechanism of endogenous metabolism, is more susceptible to disruption by metabolites of high toxicity, which gives rise to adverse health effects. Metabolomics is a useful analytical approach that can assist in unraveling such information. It can simultaneously and comprehensively analyze a large number of endogenous and exogenous molecules present in biofluids and can, thus, reveal biologically relevant perturbations following mycotoxin exposure. Information provided by genome, transcriptome and proteome analyses, which have been utilized for the elucidation of biological mechanisms so far, are further complemented by the addition of metabolomics in the available bioanalytics toolbox. Metabolomics can offer insight into complex biological processes and their respective response to several (co-)exposures. This review focuses on the most extensively studied mycotoxins reported in literature and their respective impact on the metabolome upon exposure.PMID:37283072 | DOI:10.1080/10408398.2023.2217451

Zhongguo Zhong Yao Za Zhi. 2023 May;48(10):2792-2802. doi: 10.19540/j.cnki.cjcmm.20230111.401.ABSTRACTGenkwa Fols, Kansui Radix, and Euphorbiae Pekinensis Radix in Shizao Decoction(SZD) are toxic to intestinal tract. Jujubae Fructus in this prescription can alleviate the toxicity, but the mechanism is still unclear. Therefore, this study aims to explore the mechanism. To be specific, 40 normal Sprague-Dawley(SD) rats were classified into the normal group, high-dose and low-dose SZD groups, and high-dose and low-dose SZD without Jujubae Fructus(SZD-JF) groups. The SZD groups were given(ig) SZD, while SZD-JF groups received the decoction without Jujubae Fructus. The variation of body weight and spleen index were recorded. The patho-logical changes of intestinal tissue were observed based on hematoxylin and eosin(HE) staining. The content of malondialdehyde(MDA) and glutathione(GSH) and activity of superoxide dismutase(SOD) in intestinal tissue were measured to evaluate the intestinal injury. Fresh feces of rats were collected to detect intestinal flora structure by 16S ribosomal RNA gene(16S rDNA) sequencing technology. The content of fecal short chain fatty acids and fecal metabolites was determined by gas chromatography-mass spectrometer(GC-MS) and liquid chromatography-mass spectrometer ultra-fast liquid chromatography-quadrupole-time-of-flight mass spectrometer(UFLC-Q-TOF-MS), separately. Spearman's correlation analysis was employed to analyze the differential bacteria genera and differential metabolites. RESULTS:: showed that high-dose and low-dose SZD-JF groups had high content of MDA in intestinal tissue, low GSH content and SOD activity, short intestinal villi(P&lt;0.05), low diversity and abundance of intestinal flora, variation in the intestinal flora structure, and low content of short chain fatty acids(P&lt;0.05) compared with the normal group. Compared with high-dose and low-dose SZD-JF groups, high-dose and low-dose SZD groups displayed low content of MDA in intestinal tissue, high GSH content and SOD activity, recovery of the length of intestinal villi, increased abundance and diversity of intestinal flora, alleviation of dysbacteria, and recovery of the content of short chain fatty acids(P&lt;0.05). According to the variation of intestinal flora and fecal metabolites after the addition of Jujubae Fructus, 6 differential bacterial genera(Lactobacillus, Butyricimonas, Clostridia＿UCG-014, Prevotella, Escherichia-Shigella, Alistipes),4 differential short chain fatty acids(such as acetic acid, propionic acid, butyric acid, valeric acid) and 18 differential metabolites(such as urolithin A, lithocholic acid, and creatinine) were screened out. Beneficial bacteria such as Lactobacillus were in positive correlation with butyric acid and urolithin A(P&lt;0.05). The pathogenic bacteria such as Escherichia-Shigella were in negative correlation with propionic acid and urolithin A(P&lt;0.05). In summary, SZD-JF caused obvious intestinal injury to normal rats, which could lead to intestinal flora disorder. The addition of Jujubae Fructus can alleviate the disorder and relieve the injury by regulating intestinal flora and the metabolites. This study discusses the effect of Jujubae Fructus in relieving the intestinal injury caused by SZD and the mechanism from the perspective of intestinal flora-host metabolism, which is expected to serve as a reference for clinical application of this prescription.PMID:37282939 | DOI:10.19540/j.cnki.cjcmm.20230111.401

Zhongguo Zhong Yao Za Zhi. 2023 Apr;48(8):2193-2202. doi: 10.19540/j.cnki.cjcmm.20221213.401.ABSTRACTThis study aims to explore the effect of tryptanthrin on potential metabolic biomarkers in the serum of mice with ulcerative colitis(UC) induced by dextran sulfate sodium(DSS) based on liquid chromatography-mass spectrometry(LC-MS) and predict the related metabolic pathways. C57BL/6 mice were randomly assigned into a tryptanthrin group, a sulfasalazine group, a control group, and a model group. The mouse model of UC was established by free drinking of 3% DSS solution for 11 days, and corresponding drugs were adminsitrated at the same time. The signs of mice were observed and the disease activity index(DAI) score was recorded from the first day. Colon tissue samples were collected after the experiment and observed by hematoxylin-eosin(HE) staining. The levels of interleukin-4(IL-4), interleukin-10(IL-10), tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), and interleukin-8(IL-8) in the serum were measured by enzyme linked immunosorbent assay(ELISA). The serum samples were collected from 6 mice in each group for widely targeted metabolomics. The metabolic pathways were enriched by MetaboAnalyst 5.0. The results showed that compared with the model group, tryptanthrin treatment decreased the DAI score(P&lt;0.05), alleviated the injury of the colon tissue and the infiltration of inflammatory cells, lowered the levels of proinflammatory cytokines, and elevated the levels of anti-inflammatory cytokines in the serum. The metabolomic analysis revealed 28 differential metabolites which were involved in 3 metabolic pathways including purine metabolism, arachidonic acid metabolism, and tryptophan metabolism. Tryptanthrin may restore the metabolism of the mice with UC induced by DSS to the normal level by regulating the purine metabolism, arachidonic acid metabolism, and tryptophan metabolism. This study employed metabolomics to analyze the mechanism of tryptanthrin in the treatment of UC, providing an experimental basis for the utilization and development of tryptanthrin.PMID:37282907 | DOI:10.19540/j.cnki.cjcmm.20221213.401