PubMed

Food Chem Toxicol. 2023 Apr 4:113765. doi: 10.1016/j.fct.2023.113765. Online ahead of print.ABSTRACTDiquat (DQ) has been confirmed to be toxic to humans and responsible for severe health impairment. While to date, very little is known about the toxicological mechanisms of DQ. Thus, investigations to discover the toxic targets and potential biomarkers of DQ poisoning are urgently needed. In this study, a metabolic profiling analysis was conducted to reveal the changes of metabolites of plasma and find out the potential biomarkers of DQ intoxication by GC-MS. First, multivariate statistical analysis demonstrated that acute DQ poisoning can lead to metabolomic changes in human plasma. Then, metabolomics studies showed that 31 of the identified metabolites were significantly altered by DQ. Pathway analysis indicated that three primarily metabolic pathways including phenylalanine, tyrosine and tryptophan biosynthesis, taurine and hypotaurine metabolism, and phenylalanine metabolism were affected by DQ, resulting in the perturbations of phenylalanine, tyrosine, taurine, and cysteine. Finally, the results of receiver operating characteristic analysis showed the above four metabolites could be used as reliable tools for the diagnosis and severity assessments of DQ intoxication. These data provided the theoretical basis for basic research to understand the potential mechanisms of DQ poisoning, and also identified the desirable biomarkers with great potential for clinical applications.PMID:37023971 | DOI:10.1016/j.fct.2023.113765

Ecotoxicol Environ Saf. 2023 Apr 4;256:114866. doi: 10.1016/j.ecoenv.2023.114866. Online ahead of print.ABSTRACTThe multifarious problems created by arsenic (As), for collective environment and human health, serve a cogent case for searching integrative agricultural approaches to attain food security. Rice (Oryza sativa L.) acts as a sponge for heavy metal(loid)s accretion, specifically As, due to anaerobic flooded growth conditions facilitating its uptake. Acclaimed for their positive impact on plant growth, development and phosphorus (P) nutrition, 'mycorrhizas' are able to promote stress tolerance. Albeit, the metabolic alterations underlying Serendipita indica (S. indica; S.i) symbiosis-mediated amelioration of As stress along with nutritional management of P are still understudied. By using biochemical, RT-qPCR and LC-MS/MS based untargeted metabolomics approach, rice roots of ZZY-1 and GD-6 colonized by S. indica, which were later treated with As (10 µM) and P (50 µM), were compared with non-colonized roots under the same treatments with a set of control plants. The responses of secondary metabolism related enzymes, especially polyphenol oxidase (PPO) activities in the foliage of ZZY-1 and GD-6 were enhanced 8.5 and 12-fold, respectively, compared to their respective control counterparts. The current study identified 360 cationic and 287 anionic metabolites in rice roots, and the commonly enriched pathway annotated by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was biosynthesis of phenylalanine, tyrosine and tryptophan, which validated the results of biochemical and gene expression analyses associated with secondary metabolic enzymes. Particularly under As+S.i+P comparison, both genotypes exhibited an upregulation of key detoxification and defense related metabolites, including fumaric acid, L-malic acid, choline, 3,4-dihydroxybenzoic acid, to name a few. The results of this study provided the novel insights into the promising role of exogenous P and S. indica in alleviating As stress.PMID:37023649 | DOI:10.1016/j.ecoenv.2023.114866

Ecotoxicol Environ Saf. 2023 Apr 4;256:114852. doi: 10.1016/j.ecoenv.2023.114852. Online ahead of print.ABSTRACTAntimony (Sb) poses a significant threat to human health due to sharp increases in its exploitation and application globally, but few studies have explored the pathophysiological mechanisms of acute hepatotoxicity induced by Sb exposure. We established an in vivo model to comprehensively explore the endogenous mechanisms underlying liver injury induced by short-term Sb exposure. Adult female and male Sprague-Dawley rats were orally administrated various concentrations of potassium antimony tartrate for 28 days. After exposure, the serum Sb concentration, liver-to-body weight ratio, and serum glucose levels significantly increased in a dose-dependent manner. Body weight gain and serum concentrations of biomarkers of hepatic injury (e.g., total cholesterol, total protein, alkaline phosphatase, and the aspartate aminotransferase/alanine aminotransferase ratio) decreased with increasing Sb exposure. Through integrative non-targeted metabolome and lipidome analyses, alanine, aspartate, and glutamate metabolism; phosphatidylcholines; sphingomyelins; and phosphatidylinositols were the most significantly affected pathways in female and male rats exposed to Sb. Additionally, correlation analysis showed that the concentrations of certain metabolites and lipids (e.g., deoxycholic acid, N-methylproline, palmitoylcarnitine, glycerophospholipids, sphingomyelins, and glycerol) were significantly associated with hepatic injury biomarkers, indicating that metabolic remodeling may be involved in apical hepatotoxicity. Our study demonstrated that short-term exposure to Sb induces hepatotoxicity, possibly through a glycolipid metabolism disorder, providing an important reference for the health risks of Sb pollution.PMID:37023648 | DOI:10.1016/j.ecoenv.2023.114852

J Chromatogr A. 2023 Mar 21;1696:463923. doi: 10.1016/j.chroma.2023.463923. Online ahead of print.ABSTRACTIsotope tracing assisted metabolic analysis is becoming a unique tool to understand metabolic regulation in cell biology and biomedical research. Targeted mass spectrometry analysis based on selected reaction monitoring (SRM) has been widely applied in isotope tracing experiment with the advantages of high sensitivity and broad linearity. However, its application for new pathway discovery is largely restrained by molecular coverage. To overcome this limitation, we describe a strategy called pseudo-targeted profiling of isotopic metabolomics (PtPIM) to expand the analysis of isotope labeled metabolites beyond the limit of known pathways and chemical standards. Pseudo-targeted metabolomics was first established with ion transitions and retention times transformed from high resolution (orbitrap) mass spectrometry. Isotope labeled MRM transitions were then generated according to chemical formulas of fragments, which were derived from accurate ion masses acquired by HRMS. An in-house software "PseudoIsoMRM" was developed to simulate isotope labeled ion transitions in batch mode and correct the interference of natural isotopologues. This PtPIM strategy was successfully applied to study 13C6-glucose traced HepG2 cells. As 313 molecules determined as analysis targets, a total of 4104 ion transitions were simulated to monitor 13C labeled metabolites in positive-negative switching mode of QQQ mass spectrometer with minimum dwell time of 0.3 ms achieved. A total of 68 metabolites covering glycolysis, TCA cycle, nucleotide biosynthesis, one-carbon metabolism and related derivatives were found to be labeled (> 2%) in HepG2 cells. Active pentose phosphate pathway was observed with diverse labeling status of glycolysis intermediates. Meanwhile, our PtPIM strategy revealed that rotenone severely suppressed mitochondrial function e.g. oxidative phosphorylation and fatty acid beta-oxidation. In this case, anaerobic respiration became the major source of energy metabolism by producing abundant lactate. Conclusively, the simulation based PtPIM method demonstrates a strategy to broaden metabolite coverage in isotope tracing analysis independent of standard chemicals.PMID:37023637 | DOI:10.1016/j.chroma.2023.463923

Meat Sci. 2023 Mar 30;201:109177. doi: 10.1016/j.meatsci.2023.109177. Online ahead of print.ABSTRACTThis study aimed to determine the effects of fermented mixed feed (FMF) supplementation (0%, 5% and 10%) on the intestinal microbial community and metabolism, and the compositions of volatile flavor compounds and inosine monophosphate (IMP) contents in the longissimus thoracis. In this study, 144 finishing pigs (Duroc × Berkshire × Jiaxing Black) were randomly allocated to 3 groups with 4 replicate pens per group and 12 pigs per pen. The experiment lasted 38 days after 4 days of acclimation. The 16S rRNA gene sequences and an untargeted metabolomics analysis showed FMF altered the profiles of microbes and metabolites in the colon. Heracles flash GC e-nose analysis showed that 10% FMF (treatment 3) had a greater influence on the compositions of volatile flavor compounds than 5% FMF (treatment 2). Compared to 0% FMF (treatment 1), the contents of total aldehydes, (E,E)-2,4-nonadienal, dodecanal, nonanal and 2-decenal were significantly increased by treatment 3, and treatment 3 increased IMP concentrations and gene expressions related to its synthesis. Correlations analysis showed significantly different microbes and metabolites had strong correlations with the contents of IMP and volatile flavor compounds. In conclusion, treatment 3 regulated intestinal microbial community and metabolism, that in turn altered the compositions of volatile compounds, which contributed to improving pork flavor and umami.PMID:37023593 | DOI:10.1016/j.meatsci.2023.109177

Anal Chem. 2023 Apr 6. doi: 10.1021/acs.analchem.2c04603. Online ahead of print.ABSTRACTDrug combinations are commonly used to treat various diseases to achieve synergistic therapeutic effects or to alleviate drug resistance. Nevertheless, some drug combinations might lead to adverse effects, and thus, it is crucial to explore the mechanisms of drug interactions before clinical treatment. Generally, drug interactions have been studied using nonclinical pharmacokinetics, toxicology, and pharmacology. Here, we propose a complementary strategy based on metabolomics, which we call interaction metabolite set enrichment analysis, or iMSEA, to decipher drug interactions. First, a digraph-based heterogeneous network model was constructed to model the biological metabolic network based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Second, treatment-specific influences on all detected metabolites were calculated and propagated across the whole network model. Third, pathway activity was defined and enriched to quantify the influence of each treatment on the predefined functional metabolite sets, i.e., metabolic pathways. Finally, drug interactions were identified by comparing the pathway activity enriched by the drug combination treatments and the single drug treatments. A data set consisting of hepatocellular carcinoma (HCC) cells that were treated with oxaliplatin (OXA) and/or vitamin C (VC) was used to illustrate the effectiveness of the iMSEA strategy for evaluation of drug interactions. Performance evaluation using synthetic noise data was also performed to evaluate sensitivities and parameter settings for the iMSEA strategy. The iMSEA strategy highlighted synergistic effects of combined OXA and VC treatments including the alterations in the glycerophospholipid metabolism pathway and glycine, serine, and threonine metabolism pathway. This work provides an alternative method to reveal the mechanisms of drug combinations from the viewpoint of metabolomics.PMID:37023366 | DOI:10.1021/acs.analchem.2c04603

Mov Disord. 2023 Apr 6. doi: 10.1002/mds.29395. Online ahead of print.ABSTRACTBACKGROUND: Severe reduced synaptic density was observed in spinocerebellar ataxia (SCA) in postmortem neuropathology, but in vivo assessment of synaptic loss remains challenging. OBJECTIVE SPINOCEREBELLAR ATAXIA TYPE 3: The objective of this study was to assess in vivo synaptic loss and its clinical correlates in spinocerebellar ataxia type 3 (SCA3) patients by synaptic vesicle glycoprotein 2A (SV2A)-positron emission tomography (PET) imaging.METHODS: We recruited 74 SCA3 individuals including preataxic and ataxic stages and divided into two cohorts. All participants received SV2A-PET imaging using 18 F-SynVesT-1 for synaptic density assessment. Specifically, cohort 1 received standard PET procedure and quantified neurofilament light chain (NfL), and cohort 2 received simplified PET procedure for exploratory purpose. Bivariate correlation was performed between synaptic loss and clinical as well as genetic assessments.RESULTS: In cohort 1, significant reductions of synaptic density were observed in cerebellum and brainstem in SCA3 ataxia stage compared to preataxic stage and controls. Vermis was found significantly involved in preataxic stage compared to controls. Receiver operating characteristic (ROC) curves highlighted SV2A of vermis, pons, and medulla differentiating preataxic stage from ataxic stage, and SV2A combined with NfL improved the performance. Synaptic density was significantly negatively correlated with disease severity in cerebellum and brainstem (International Co-operative Ataxia Rating Scale: ρ ranging from -0.467 to -0.667, P ≤ 0.002; Scale of Assessment and Rating of Ataxia: ρ ranging from -0.465 to -0.586, P ≤ 0.002). SV2A reduction tendency of cerebellum and brainstem identified in cohort 1 was observed in cohort 2 with simplified PET procedure.CONCLUSIONS: We first identified in vivo synaptic loss was related to disease severity of SCA3, suggesting SV2A PET could be a promising clinical biomarker for disease progression of SCA3. © 2023 International Parkinson and Movement Disorder Society.PMID:37023261 | DOI:10.1002/mds.29395

Metabolomics. 2023 Apr 6;19(4):37. doi: 10.1007/s11306-023-02004-y.ABSTRACTBACKGROUND: Seronegative elderly-onset rheumatoid arthritis (EORA)neg and polymyalgia rheumatica (PMR) have similar clinical characteristics making them difficult to distinguish based on clinical features. We hypothesized that the study of serum metabolome could identify potential biomarkers of PMR vs. EORAneg.METHODS: Arthritis in older adults (ARTIEL) is an observational prospective cohort with patients older than 60 years of age with newly diagnosed arthritis. Patients' blood samples were compared at baseline with 18 controls. A thorough clinical examination was conducted. A Bruker Avance 600 MHz spectrometer was used to acquire Nuclear Magnetic Resonance (NMR) spectra of serum samples. Chenomx NMR suite 8.5 was used for metabolite identification and quantification.Student t-test, one-way ANOVA, binary linear regression and ROC curve, Pearson's correlation along with pathway analyses were conducted.RESULTS: Twenty-eight patients were diagnosed with EORAneg and 20 with PMR. EORAneg patients had a mean disease activity score (DAS)-Erythrocyte Sedimentation Rate (ESR) of 6.21 ± 1.00. All PMR patients reported shoulder pain, and 90% reported pelvic pain. Fifty-eight polar metabolites were identified. Of these, 3-hydroxybutyrate, acetate, glucose, glycine, lactate, and o-acetylcholine (o-ACh), were significantly different between groups. Of interest, IL-6 correlated with different metabolites in PMR and EORAneg suggesting different inflammatory activated pathways. Finally, lactate, o-ACh, taurine, and sex (female) were identified as distinguishable factors of PMR from EORAneg with a sensitivity of 90%, specificity of 92.3%, and an AUC of 0.925 (p < 0.001).CONCLUSION: These results suggest that EORAneg and PMR have different serum metabolomic profiles that might be related to their pathobiology and can be used as biomarker to discriminate between both diseases.PMID:37022535 | DOI:10.1007/s11306-023-02004-y

Arch Toxicol. 2023 Apr 6. doi: 10.1007/s00204-023-03474-8. Online ahead of print.ABSTRACTToxicity studies, among them hepatotoxicity, are key throughout preclinical stages of drug development to minimise undesired toxic effects that might eventually appear in the course of the clinical use of the new drug. Understanding the mechanism of injury of hepatotoxins is essential to efficiently anticipate their potential risk of toxicity in humans. The use of in vitro models and particularly cultured hepatocytes represents an easy and robust alternative to animal drug hepatotoxicity testing for predicting human risk. Here, we envisage an innovative strategy to identify potential hepatotoxic drugs, quantify the magnitude of the alterations caused, and uncover the mechanisms of toxicity. This strategy is based on the comparative analysis of metabolome changes induced by hepatotoxic and non-hepatotoxic compounds on HepG2 cells, assessed by untargeted mass spectrometry. As a training set, we used 25 hepatotoxic and 4 non-hepatotoxic compounds and incubated HepG2 cells for 24 h at a low and a high concentration (IC10 and IC50) to identify mechanism-related and cytotoxicity related metabolomic biomarkers and to elaborate prediction models accounting for global hepatotoxicity and mechanisms-related toxicity. Thereafter, a second set of 69 chemicals with known predominant mechanisms of toxicity and 18 non-hepatotoxic compounds were analysed at 1, 10, 100 and 1000 µM concentrations from which and based on the magnitude of the alterations caused as compared with non-toxic compounds, we defined a "toxicity index" for each compound. In addition, we extracted from the metabolome data the characteristic signatures for each mechanism of hepatotoxicity. The integration of all this information allowed us to identify specific metabolic patterns and, based on the occurrence of that specific metabolome changes, the models predicted the likeliness of a compound to behave as hepatotoxic and to act through a given toxicity mechanism (i.e., oxidative stress, mitochondrial disruption, apoptosis and steatosis) for each compound and concentration.PMID:37022445 | DOI:10.1007/s00204-023-03474-8

Microbiol Spectr. 2023 Apr 6:e0444022. doi: 10.1128/spectrum.04440-22. Online ahead of print.ABSTRACTHyperlipidemia is a key risk factor for cardiovascular disease, and it is associated with lipid metabolic disorders and gut microbiota dysbiosis. Here, we aimed to investigate the beneficial effects of 3-month intake of a mixed probiotic formulation in hyperlipidemic patients (n = 27 and 29 in placebo and probiotic groups, respectively). The blood lipid indexes, lipid metabolome, and fecal microbiome before and after the intervention were monitored. Our results showed that probiotic intervention could significantly decrease the serum levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol (P < 0.05), while increasing the levels of high-density lipoprotein cholesterol (P < 0.05) in patients with hyperlipidemia. Probiotic recipients showing improved blood lipid profile also exhibited significant differences in their lifestyle habits after the 3-month intervention, with an increase in daily intake of vegetable and dairy products, as well as weekly exercise time (P < 0.05). Moreover, two blood lipid metabolites (namely, acetyl-carnitine and free carnitine) significantly increased after probiotic supplementation cholesterol (P < 0.05). In addition, probiotic-driven mitigation of hyperlipidemic symptoms were accompanied by increases in beneficial bacteria like Bifidobacterium animalis subsp. lactis and Lactiplantibacillus plantarum in patients' fecal microbiota. These results supported that mixed probiotic application could regulate host gut microbiota balance, lipid metabolism, and lifestyle habits, through which hyperlipidemic symptoms could be alleviated. The findings of this study urge further research and development of probiotics into nutraceuticals for managing hyperlipidemia. IMPORTANCE The human gut microbiota have a potential effect on the lipid metabolism and are closely related to the disease hyperlipidemia. Our trial has demonstrated that 3-month intake of a mixed probiotic formulation alleviates hyperlipidemic symptoms, possibly by modulation of gut microbes and host lipid metabolism. The findings of the present study provide new insights into the treatment of hyperlipidemia, mechanisms of novel therapeutic strategies, and application of probiotics-based therapy.PMID:37022264 | DOI:10.1128/spectrum.04440-22

J Agric Food Chem. 2023 Apr 6. doi: 10.1021/acs.jafc.3c00427. Online ahead of print.ABSTRACTGerms associated with insect eggs can profoundly mediate interactions between host plants and herbivores, with the potential to coordinate plant physiological reactions with cascading effects on insect fitness. An experimental system was established including the oriental fruit fly (OFF, Bactrocera dorsalis) and tomato to examine the functions of egg-associated germs in mediating plant-herbivore interactions. OFF feeding resulted in significantly increased tannins, flavonoids, amino acids, and salicylic acid in the host tomato. These defensive responses of tomato were induced by the egg-associated germs, including Lactococcus sp., Brevundimonas sp., and Vagococcus sp. Tannins and flavonoids had no significant feedback effects on the pupal weight of OFF, while pupal biomass was significantly decreased by tannins and flavonoids in the germ-free treatment. Metabolome analysis showed that OFF mainly induced metabolic changes in carboxylic acid derivatives. Phenylalanine significantly induced downstream metabolic changes associated with phenylpropanoid accumulation. Finally, we conclude that the effects of egg-associated germs played an important role in facilitating OFF population adaptation and growth by mediating plant defenses, which provides a new paradigm for exploring the interaction of plant-pest and implementing effective pest biocontrol.PMID:37021960 | DOI:10.1021/acs.jafc.3c00427

J Cell Physiol. 2023 Apr 6. doi: 10.1002/jcp.31009. Online ahead of print.ABSTRACTThe present study employed microRNA (miRNA) sequencing and metabolome profiling of Trichoderma parental strains and fusants during normal growth and interaction with the phytopathogen Sclerotium rolfsii Sacc. In-vitro antagonism indicated that abiotic stress-tolerant Tricho-fusant FU21 was examined as a potent biocontroller with mycoparasitic action after 10 days. During interaction with the test pathogen, the most abundant uprising intracellular metabolite was recognized as l-proline, which corresponds to held-down l-alanine, associated with arginine and proline metabolism, biosynthesis of secondary metabolites, and nitrogen metabolism linked to predicted genes controlled by miRNAs viz., cel-miR-8210-3p, hsa-miR-3613-5p, and mml-miR-7174-3p. The miRNAs- mml-miR-320c and mmu-miR-6980-5p were found to be associated with phenylpropanoid biosynthesis, transcription factors, and signal transduction pathways, respectively, and were ascertained downregulated in potent FU21_IB compared with FU21_CB. The amino benzoate degradation and T cell receptor signaling pathways were regulated by miRNAs cel-miR-8210 and tca-miR-3824 as stress tolerance mechanisms of FU21. The intracellular metabolites l-proline, maleic acid, d-fructose, Myo-inositol, arabinitol, d-xylose, mannitol, and butane were significantly elevated as potential biocontrol and stress-tolerant constituents associated with miRNA regulatory pathways in potent FU21_IB. A network analysis between regulatory miRNA-predicted genes and intracellular metabolomics acknowledged possible biocontrol pathways/mechanisms in potent FU21_IB to restrain phytopathogen.PMID:37021806 | DOI:10.1002/jcp.31009

Plant Physiol. 2023 Apr 6:kiad212. doi: 10.1093/plphys/kiad212. Online ahead of print.ABSTRACTPhosphorus is an essential nutrient acquired from soil as phosphate (Pi), and its deficiency severely reduces plant growth and crop yield. Here, we show that single nucleotide polymorphisms (SNPs) at the PHOSPHATIDYLINOSITOL TRANSFER PROTEIN7 (AtPITP7) locus, which encodes a chloroplastic Sec14-like protein, are associated with genetic diversity regarding Pi uptake activity in Arabidopsis (Arabidopsis thaliana). Inactivation of AtPITP7 and its rice (Oryza sativa) homolog (OsPITP6) through T-DNA insertion and CRISPR/Cas9-mediated gene editing, respectively, decreased Pi uptake and plant growth, regardless of Pi availability. By contrast, overexpression of AtPITP7 and OsPITP6 enhanced Pi uptake and plant growth, especially under limited Pi supply. Importantly, overexpression of OsPITP6 increased tiller number and grain yield in rice. Targeted metabolome analysis of glycerolipids in leaves and chloroplasts revealed that inactivation of OsPITP6 alters phospholipid contents, independent of Pi availability, diminishing the reduction in phospholipid content and increase in glycolipid content induced by Pi deficiency; meanwhile, overexpression of OsPITP6 enhanced Pi deficiency induced metabolic alterations. Together with transcriptome analysis of ospitp6 rice plants and phenotypic analysis of grafted Arabidopsis chimeras, these results suggest that chloroplastic Sec14-like proteins play an essential role in growth modulations in response to changes in Pi availability, although their function is critical for plant growth under any Pi condition. The superior traits of OsPITP6-overexpressing rice plants also highlight the potential of OsPITP6 and its homologs in other crops as additional tools for improving Pi uptake and plant growth in low Pi environments.PMID:37021761 | DOI:10.1093/plphys/kiad212

Nucleic Acids Res. 2023 Apr 6:gkad230. doi: 10.1093/nar/gkad230. Online ahead of print.ABSTRACTFacioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent neuromuscular disorders. The disease is linked to copy number reduction and/or epigenetic alterations of the D4Z4 macrosatellite on chromosome 4q35 and associated with aberrant gain of expression of the transcription factor DUX4, which triggers a pro-apoptotic transcriptional program leading to muscle wasting. As today, no cure or therapeutic option is available to FSHD patients. Given its centrality in FSHD, blocking DUX4 expression with small molecule drugs is an attractive option. We previously showed that the long non protein-coding RNA DBE-T is required for aberrant DUX4 expression in FSHD. Using affinity purification followed by proteomics, here we identified the chromatin remodeling protein WDR5 as a novel DBE-T interactor and a key player required for the biological activity of the lncRNA. We found that WDR5 is required for the expression of DUX4 and its targets in primary FSHD muscle cells. Moreover, targeting WDR5 rescues both cell viability and myogenic differentiation of FSHD patient cells. Notably, comparable results were obtained by pharmacological inhibition of WDR5. Importantly, WDR5 targeting was safe to healthy donor muscle cells. Our results support a pivotal role of WDR5 in the activation of DUX4 expression identifying a druggable target for an innovative therapeutic approach for FSHD.PMID:37021550 | DOI:10.1093/nar/gkad230

Anal Chem. 2023 Apr 6. doi: 10.1021/acs.analchem.2c01723. Online ahead of print.ABSTRACTMetabolic perturbation score-based mass spectrometry imaging (MPS-MSI) is proposed to reveal the spatially resolved functional metabolic response associated with disease progression or drug action including metabolism pathways, species, biofunction, or biotransformation. The MPS-MSI enables the exploration of therapeutic or adverse effects, regional heterogeneous responses to drug treatment, possible molecular mechanisms, and even drug potential targets. MPS-MSI was demonstrated to be a promising molecular imaging tool not only for efficacy and safety evaluation but also for molecular mechanism investigation at the early stage of drug research and development.PMID:37021399 | DOI:10.1021/acs.analchem.2c01723

Front Plant Sci. 2023 Mar 20;14:1142840. doi: 10.3389/fpls.2023.1142840. eCollection 2023.ABSTRACTToon buds, a popular woody vegetable, contain large amounts of nutrients. However, toon buds have strong respiratory metabolism after harvest and are highly prone to decay, resulting in quality deterioration. Low temperature can effectively inhibit postharvest senescence of toon buds. GC-TOF-MS combined with quantitative real-time PCR was used to elucidate the toon bud deterioration mechanism after harvest by analyzing the difference in the relative contents of primary metabolites and their derivatives, and the expression of key genes associated with metabolic pathways in toon buds between low temperature and room temperature storages for 72 h. Results showed that the ethylene synthesis in toon buds accelerated under room temperature storage, along with significant changes in the primary metabolic pathway. The catabolism of amino acids, fatty acids, and cell membrane phospholipids was accelerated, and the gluconeogenesis synthesis was strengthened. Moreover, the sucrose synthesis was increased, the glycolysis and TCA cycle were broken down, and the pentose phosphate pathway was vigorous. As metabolic intermediates, organic acids were considerably accumulated. Moreover, varieties of toxic compounds were produced in parallel with the activation of aromatic compounds. This work provided a comprehensive understanding of the metabolic regulation, thereby revealing how low and room temperatures differentially influenced the quality deterioration of postharvest toon buds.PMID:37021311 | PMC:PMC10067724 | DOI:10.3389/fpls.2023.1142840

Diabetes Metab Syndr Obes. 2023 Mar 30;16:901-912. doi: 10.2147/DMSO.S401863. eCollection 2023.ABSTRACTOBJECTIVE: This study is aimed to determine the metabolomic effects of the hybrid medicine formula Yi-Qi-Bu-Shen (YQBS) on the neurotransmitter aspects of cognitive impairment in diabetic rats.METHODS: In the current study, streptozotocin (STZ) was used to induce diabetic animal model in male Sprague Dawley (SD) rats. After successful establishment of diabetic SD rats' model, age-matched healthy SD rats and diabetic SD rats were treated with low and high doses of YQBS, and then tested for learning memory ability and analyzed for pathological changes. In addition, neurotransmitter metabolic changes in hippocampal subdivisions of rats from different treated groups were analyzed using liquid chromatography-mass spectrometry (LC-MS) technique.RESULTS: YQBS could significantly improve memory-cognitive impairment in diabetic rats as evidenced by the shortening of latency to target and the reduction of latency first entrance to target. Moreover, YQBS also improved the pathological alterations in the hippocampal region in the brains of diabetic rats. Metabolomic analysis showed that the expression of noradrenaline hydrochloride was down-regulated and the expressions of levodopa and 5-hydroxytryptophan were up-regulated in the hippocampal tissues of diabetic rats treated with YQBS.CONCLUSION: These findings demonstrate that YQBS has protective effects against diabetic cognitive dysfunction, which might act through alteration in tyrosine and tryptophan metabolism.PMID:37021127 | PMC:PMC10069430 | DOI:10.2147/DMSO.S401863

Front Mol Biosci. 2023 Mar 20;10:1178115. doi: 10.3389/fmolb.2023.1178115. eCollection 2023.NO ABSTRACTPMID:37021112 | PMC:PMC10067906 | DOI:10.3389/fmolb.2023.1178115

Cell Stress. 2023 Mar 21;7(4):20-33. doi: 10.15698/cst2023.04.278. eCollection 2023 Apr.ABSTRACTMacrolide antibiotics are widely used antibacterial agents that are associated with autophagy inhibition. This study aimed to investigate the association between macrolide antibiotics and malignant tumors, as well as the effect on autophagy, reactive oxygen species (ROS) accumulation and integrated stress response (ISR). The meta-analysis indicated a modestly higher risk of cancer in macrolide antibiotic ever-users compared to non-users. Further experiments showed that macrolides block autophagic flux by inhibiting lysosomal acidification. Additionally, azithromycin, a representative macrolide antibiotic, induced the accumulation of ROS, and stimulated the ISR and the activation of transcription factor EB (TFEB) and TFE3 in a ROS-dependent manner. Finally, animal experiments confirmed that azithromycin promoted tumor progression in vivo, which could be receded by N-acetylcysteine, an inhibitor of ROS and ISR. Overall, this study reveals the potential role of macrolide antibiotics in malignant progression and highlights the need for further investigation into their effects.PMID:37021084 | PMC:PMC10069438 | DOI:10.15698/cst2023.04.278

Heliyon. 2023 Mar 13;9(3):e14491. doi: 10.1016/j.heliyon.2023.e14491. eCollection 2023 Mar.ABSTRACTThe pigeon breeding industry employs a high-rearing pattern to achieve economic benefits. However, too many squabs consume more energy of the breeding pigeons causing adverse effects on their breeding performance. To determine the optimal rearing patterns and the effects of different numbers of squabs on reproductive performance, oxidative stress, and glucolipid metabolism of lactating breeding pigeons in winter, three rearing patterns consisting of "2 + 2″, "2 + 3″ and "2 + 4" (a pair of breeding pigeons feeding two, three and four squabs, respectively) were adopted using European Mimas white pigeons breed. The feed intake, bodyweight loss, feed-to-meat ratio, and squab mortality were linearly increased with the number of squabs during lactation, while the bodyweight recovery rate and squab growth performance were significantly slowed down after lactation. Similarly, the laying rate was linearly decreased on days 16, 17, and 18 of lactation, with a similar pattern on the re-laying rate on days 11, 12, and 13 after first laying. In addition, the number of non-laying pigeons in the second batch was significantly increased, implying that the number of squabs significantly affected the reproductive performance of female pigeons. The eggshell weight and thickness in the "2 + 3″ group were significantly increased. However, the number of squabs in the "2 + 3″ group had no significant effect on plasma calcium (Ca) and phosphorus (P) levels. Analysis of the glucolipid metabolism index and oxidative stress level of pigeons further revealed that the contents of triglyceride (TG), total cholesterol (T-CHO), and low-density lipoprotein cholesterol (LDL-C) in the plasma of male pigeons were significantly decreased with the increase in the number of squabs, but there was no obvious oxidative stress. On the contrary, glucose (GLU), TG, malondialdehyde (MDA) in the plasma of female pigeons were significantly increased, total antioxidant capacity (T-AOC) were significantly decreased, implying that the female pigeons suffered more oxidative stress and more dramatic changes in glucolipid metabolism. Metabolomics revealed that the differential metabolites in the plasma of female pigeons in "2 + 2″, "2 + 3″, and "2 + 4″ groups were significantly enriched in the fatty acid, phospholipid, sphingolipid metabolism, and the Krebs cycle pathways, especially under "2 + 4″ rearing pattern. Overall, in female pigeons, the available lipids were reduced; hence, their body turned to sugar dysplasia and protein utilization mode, increasing the oxidative stress level and decreasing their reproductive performance. Therefore, an increased number of squabs significantly affects the body condition and reproductive performance of breeding pigeons. The "2 + 3″ rearing pattern is the most suitable for winter breeding pigeon production under the current nutrition level.PMID:37020945 | PMC:PMC10068127 | DOI:10.1016/j.heliyon.2023.e14491