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At least 19 recordsLinked to original sources
PubMed1998

Differential metabolite accumulation may be the cause of strain differences in sensitivity to streptozotocin-induced beta cell death in inbred mice.

Inbred strains of mice vary in their sensitivity to the diabetogenic effects of streptozotocin (STZ). To investigate the basis for this strain difference we exposed islet cells from two strains of mice that differ in sensitivity to the drug. We examined them morphologically and measured islet NAD + NADH content, streptozotocin metabolite accumulation, glucose transport capacity, Glut2 levels and medium nitrite accumulation. C57bl/6J mice were more sensitive to STZ than Balb/c mice as judged by the extent of pancreatic insulin depletion and beta cell death, in vivo and in vitro. The mode of cell death was necrosis. After a 30-min in vitro exposure to the drug the more sensitive C57bl/6J islets contained higher levels of streptozotocin metabolites and less NAD + NADH than the more resistant Balb/c islets. The lack of any strain differences in 3-O-methyl glucose transport, Glut2 levels and medium nitrite accumulation suggested that STZ transport and nitric oxide metabolism were not responsible for differences in STZ sensitivity and metabolite accumulation. Thus the strain differences in STZ sensitivity appears to be due to intracellular events within the beta cell occurring after STZ transport and before NAD + NADH depletion. STZ metabolite accumulation appears to be associated with STZ sensitivity. Further studies are warranted to determine if differential STZ metabolite accumulation is responsible for STZ sensitivity.

Animals↗
PubMed2001

2-Methoxyestradiol, an endogenous estradiol metabolite, differentially inhibits granulosa and endothelial cell mitosis: a potential follicular antiangiogenic regulator.

2-Methoxyestradiol (2-ME) is an estradiol metabolite with antiangiogenic and antitumor activity. It is formed by granulosa cell (GC) catechol-O-methyltransferase activity and is present in the normal follicle at high concentrations. In this unique microenvironment, it may regulate selected cell types via autocrine and/or paracrine action. To assess the possibility that 2-ME or estradiol might exert differential mitotic and/or apoptotic effects on endothelial cells and GCs, we compared their actions on primary cultures of hormone- and/or growth factor-stimulated porcine GCs (pGCs) as well as two types of endothelial cells, primary cultures of porcine endothelial cells (pECs), and a spontaneously transformed rabbit endothelial vascular cell (REVC) line. The 2-ME, but not estradiol, dose dependently suppressed tritiated thymidine ((3)H-T) incorporation into epidermal growth factor (EGF)-stimulated REVCs and EGF/insulin (INS)-stimulated pECs. In contrast, 2-ME did not attenuate incorporation in FSH/INS-stimulated pGCs. It reduced incorporation by approximately 50% in EGF/INS-stimulated pGCs, indicating that responsiveness to 2-ME in normal cells can be modulated by hormone and growth factor treatment. Estradiol was not antimitotic to pGCs. As indicated by 4',6-diamido-2-phenylindole hydrochloride nuclear staining, estradiol was nonapoptotic in either cell type, and 2-ME significantly increased apoptosis of REVCs, but not of pGCs. In a cell migration assay, REVC movement was attenuated by 2-ME, but not by estradiol. In summary, the results show that antimitotic as well as proapoptotic responses to 2-ME vary with cell type and, in the case of pGC antimitotic activity, with the regulatory microenvironment. Thus, they provide a rationale for autocrine and/or paracrine action of 2-ME at its site of production in vivo, and they strongly support the concept of 2-ME as a candidate ovarian angiogenesis inhibitor.

2-Methoxyestradiol↗
PubMed2000

Morphine-related metabolites differentially activate adenylyl cyclase isozymes after acute and chronic administration.

Morphine-3- and morphine-6-glucuronide are morphine's major metabolites. As morphine-6-glucuronide produces stronger analgesia than morphine, we investigated the effects of acute and chronic morphine glucuronides on adenylyl cyclase (AC) activity. Using COS-7 cells cotransfected with representatives of the nine cloned AC isozymes, we show that AC-I and V are inhibited by acute morphine and morphine-6-glucuronide, and undergo superactivation upon chronic exposure, while AC-II is stimulated by acute and inhibited by chronic treatment. Morphine-3-glucuronide had no effect. The weak opiate agonists codeine and dihydrocodeine are also addictive. These opiates, in contrast to their 3-O-demethylated metabolites morphine and dihydromorphine (formed by cytochrome P450 2D6), demonstrated neither acute inhibition nor chronic-induced superactivation. These results suggest that metabolites of morphine (morphine-6-glucuronide) and codeine/dihydrocodeine (morphine/dihydromorphine) may contribute to the development of opiate addiction.

Adenylyl Cyclase Inhibitors↗
PubMed2006

Dehydroepiandrosterone and its metabolites: differential effects on androgen receptor trafficking and transcriptional activity.

Dehydroepiandrosterone (DHEA) is a multi-functional steroid that has been implicated in a broad range of biological effects in humans and rodents. Recent studies demonstrated that DHEA acts genomically through the androgen receptor (AR) in addition to its well-known effects on cell surface receptors. However, the relative contribution of DHEA and its major metabolites, including DHEA-Sulfate (DHEA-S), 7alpha-OH-DHEA, 7beta-OH-DHEA, 7-oxo-DHEA, androstenedione (Adione), and androstenediol (Adiol), in the production of genomic effects remains controversial, in part because the metabolism of DHEA varies in different cells and tissues. In the current study, the ability of DHEA and its metabolites to promote AR intracellular trafficking and regulate AR-mediated reporter gene expression, which are characteristic effects of androgens, was determined. Intracellular trafficking of AR-GFP protein was assessed in COS-7 cells while AR transcriptional activity was tested in CV-1 cells transiently co-transfected with AR expression plasmid and an MMTV-ARE-CAT reporter. The results demonstrated that DHEA, the 3beta-HSD metabolite Adione, and the 17beta-HSD metabolite Adiol, were androgenic. Each promoted AR-GFP intracellular trafficking, the formation of nuclear clusters, and AR-dependent transcriptional activity in a dose-dependent manner. In contrast, DHEA-S, 7alpha-OH-DHEA, 7beta-OH-DHEA, and 7-oxo-DHEA were ineffective and exhibited minimal androgenic activity, even at relatively high concentrations (10(-6) M). These results provide the first systematic comparison of the (i) androgenic activity of DHEA and its sulfated and hydroxylated metabolites, (ii) relative androgenicity of DHEA itself vs. the established androgens Adione and Adiol, and (iii) ability of DHEA and its major metabolites to promote AR-GFP intracellular trafficking. In addition to partitioning DHEA and its metabolites into compounds with (DHEA, Adione, Adiol) and without (DHEA-S, 7alpha-OH-DHEA, 7beta-OH-DHEA, and 7-oxo-DHEA) androgenic activity, the findings improve our understanding of the intracellular processes mediating the genomic effects of DHEA through AR.

Animals↗
PubMed1996

Sphingolipid metabolites differentially regulate extracellular signal-regulated kinase and stress-activated protein kinase cascades.

The mitogen-activated protein kinase (MAPK) signalling pathway serves to translocate information from activated plasma-membrane receptors to initiate nuclear transcriptional events. This cascade has recently been subdivided into two analogous pathways: the extracellular signal-regulated kinase (ERK) cascade, which preferentially signals mitogenesis, and the stress-activated protein kinase (SAPK) cascade, which is linked to growth arrest and/or cellular inflammation. In concurrent experiments utilizing rat glomerular mesangial cells (MCs), we demonstrate that growth factors or sphingosine activate ERK but not SAPK. In contrast, inflammatory cytokines or cell-permeable ceramide analogues activate SAPK but not ERK. Ceramide, but not sphingosine, induces interleukin-6 secretion, a marker of an inflamed phenotype. Moreover, ceramide can suppress growth factor- or sphingosine-induced ERK activation as well as proliferation. These studies implicate sphingolipid metabolites as opposing regulators of cell proliferation and inflammation through activation of separate kinase cascades.

Animals↗
PubMed2004

MRS shows syndrome differentiated metabolite changes in human-generalized epilepsies.

OBJECTIVE: While it is generally accepted that the thalamo-cortical loop is abnormal in idiopathic generalized epilepsy (IGE), it is uncertain whether this loop is similarly affected among different IGE syndromes. We recently demonstrated reduced frontal lobe levels of N-acetyl aspartate (NAA) in patients with juvenile myoclonic epilepsy (JME). The present follow-up study investigates if similar or other types of changes exist in subjects with pure primarily generalized tonic clonic epilepsy (GTCS). METHOD: Twenty patients with GTCS, 26 patients with JME, and 10 matched healthy controls were investigated with quantitative single voxel MR spectroscopy (MRS) measurements of NAA, choline (Cho), creatine (Cr), and myo-inositol (mI) at 1.5 T scanner. The voxels were placed over the right cerebellum, right thalamus, prefrontal, occipital cortex, and over a spherical phantom above the subject's head. RESULTS: Patients with JME had reduced frontal lobe NAA (mmol/l) in relation to controls (9.8 +/- 1.1 vs. 10.8 +/- 0.7, P = 0.01), as well as GTCS patients (9.8 +/- 1.1 vs. 10.6 +/- 0.7, P = 0.007), whose values were normal. Patients with GTCS, on the other hand, showed significantly lower thalamic NAA than controls (9.7 +/- 1.0 vs. 10.8 +/- 0.9, P = 0.002), and both groups of patients had reduced thalamic Cho, and mI; [CHO: 2.0 +/- 0.4 (control) vs. 1.61 +/- 0.3 (JME) P = 0.001, and vs. 1.57 +/- 0.3 (GTCS) P = 0.0005; MI: 4.8 +/- 1.5 (control) vs. 3.3 +/- 1.4 (JME) P = 0.003, and vs. 3.2 +/- 1.5 (GTCS), P = 0.002]. No other regional changes were observed. CONCLUSION: The present MRS data emphasize the involvement of thalamus in IGE. They also show partly differentiated alterations within the thalamo-cortical loop in JME vs. GTCS. The various clinical expressions of IGE may, thus, be associated with more localized neuroanatomical substrates than generally believed.

Adolescent↗
PubMed1993

Metabolic activation of tris(2,3-dibromopropyl)phosphate to reactive intermediates. II. Covalent binding, reactive metabolite formation, and differential metabolite-specific DNA damage in vivo.

Analogs of tris(2,3-dibromopropyl)phosphate (Tris-BP) either labeled at specific positions with carbon-14 and phosphorus-32 or dual-labeled with both deuterium and tritium were administered to male Wistar rats at a nephrotoxic dose of 360 mumol/kg. The covalent binding of Tris-BP metabolites to hepatic, renal, and testicular proteins was determined after 9 and 24 hr, and plasma concentrations of bis(2,3-dibromopropyl)-phosphate (Bis-BP) formed metabolically from Tris-BP were measured at intervals throughout the initial 9-hr postdosing period. The covalent binding of 14C-Tris-BP metabolites in the kidney (2495 +/- 404 pmol/mg protein) was greater than that in the liver (476 +/- 123 pmol/mg protein) or testes (94 +/- 11 pmol/mg protein); the extent of renal covalent protein binding of Tris-BP metabolites was decreased by 82 and 84% when deuterium was substituted at carbon-2 and carbon-3, respectively. Substitution of Tris-BP with deuterium at carbon-2 or carbon-3 also decreased the mean area under the curve for Bis-BP plasma concentration by 48 and 57%, respectively. The mechanism of Tris-BP-induced renal and hepatic DNA damage was evaluated in Wistar rats by an automated alkaline elution procedure after the administration of analogs of Tris-BP or Bis-BP labeled at specific positions with deuterium. Renal DNA damage was decreased when Tris-BP was substituted with deuterium at either carbon-2 or carbon-3; the magnitude of the change correlated with both a decrease in the area under the Bis-BP plasma curve and a decrease in renal covalent binding of Tris-BP metabolites for each of the deuterated analogs. In marked contrast, analogs of Bis-BP labeled with deuterium at carbon-2 or carbon-3 did not show a decrease in the severity of renal DNA damage compared to unlabeled Bis-BP. On the basis of these observations a metabolic scheme for hepatic P-450-mediated oxidation at either carbon-2 or carbon-3 of Tris-BP affording Bis-BP by two alternate pathways that are susceptible to primary deuterium kinetic isotope effects is proposed. The Tris-BP metabolite, Bis-BP, is subsequently metabolized to reactive intermediates that cause DNA damage and bind to kidney proteins in a mechanism independent of cytochrome P-450.

Animals↗
PubMed2026

Metabolomics Reveals Metabolic Characteristics of Functional Cure in Chronic Hepatitis B Treated With Entecavir Combined With Pegylated Interferon Alpha.

BACKGROUND: Entecavir (ETV) combined with pegylated interferon alpha (PEG-IFNα) improves chronic hepatitis B (CHB) functional cure rates, but therapeutic heterogeneity and underlying metabolic mechanisms remain unclear. This study used untargeted metabolomics to identify metabolic signatures, mechanisms, and predictive biomarkers of functional cure with ETV-PEG-IFNα. METHODS: Thirty-eight CHB patients were grouped into ETV monotherapy (Group E, n = 12) and ETV-PEG-IFNα combination therapy (Group Z, n = 26); Group Z was subdivided into cured (Group A, n = 13) and noncured (Group B, n = 13). Serum metabolomic profiling, multivariate statistics, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified differential metabolites. A random forest model was built using key metabolites. RESULTS: Three hundred eighty-eight metabolites were identified. Four differential metabolites distinguished Group A and B (upregulated guanidinoacetic acid, uracil 5-carboxylate; downregulated L-methionine S-oxide, oleamide), enriching amino acid metabolism pathways. Nine differential metabolites between Group E and Z implicated amino acid, immune, and fatty acid pathways. The random forest model based on the four Group A/B metabolites showed 88.5% cross-validation accuracy (AUC = 0.920), with L-methionine S-oxide and oleamide as key predictors. CONCLUSIONS: This study reveals metabolic rewiring in CHB functional cure via ETV-PEG-IFNα therapy, involving energy metabolism, oxidative stress, and immunomodulation, based on which we propose a tentative metabolism-immunity synergy model to guide future research. Key metabolites, especially L-methionine S-oxide and oleamide, show exploratory predictive potential for functional cure that warrants further validation in independent cohorts.

Humans↗
PubMed2002

Membrane mediated signaling mechanisms are used differentially by metabolites of vitamin D(3) in musculoskeletal cells.

1 alpha,25(OH)(2)D(3) and 24R,25(OH)(2)D(3) mediate their effects on chondrocytes and osteoblasts in part through increased activity of protein kinase C (PKC). For both cell types, 1 alpha,25(OH)(2)D(3) exerts its effects primarily on more mature cells within the lineage, whereas 24R,25(OH)(2)D(3) exerts its effects primarily on relatively immature cells. Studies using the rat costochondral cartilage growth plate as a model indicate that the two metabolites increase PKC activity by different mechanisms. In growth zone cells (prehypertrophic/upper hypertrophic cell zones), 1 alpha,25(OH)(2)D(3) causes a rapid increase in PKC that does not involve new gene expression. 1 alpha,25(OH)(2)D(3) binds its membrane receptor (1,25-mVDR), resulting in activation of phospholipase A(2) and the rapid release of arachidonic acid, as well as activation of phosphatidylinositol-specific phospholipase C, resulting in formation of diacylglycerol and inositol-1,4,5-tris phosphate (IP(3)). IP(3) leads to release of intracellular Ca(2+) from the rough endoplasmic reticulum, and together with diacylglycerol, the increased Ca(2+) activates PKC. PKC is then translocated to the plasma membrane, where it initiates a phosphorylation cascade, ultimately phosphorylating the extracellular signal-regulated kinase-1 and -2 (ERK1/2) family of MAP kinases (MAPK). PKC increases are maximal at 9 min, and MAPK increases are maximal at 90 min in these cells. By contrast, 24R,25(OH)(2)D(3) increases PKC through activation of phospholipase D in resting zone cells. Peak production of diacylglycerol via phospholipase D2 is at 90 min, as are peak increases in PKC. Some of the effect is direct on existing plasma membrane PKC, but most is due to new PKC expression; translocation is not involved. Arachidonic acid and its metabolites also play differential roles in the mechanisms, stimulating PKC in growth zone cells and inhibiting PKC in resting zone cells. 24R,25(OH)(2)D(3) decreases phospholipase A(2) activity and prostaglandin production, thereby overcoming this potential inhibitory component, which may account for the delay in the PKC response. Ultimately, ERK1/2 is phosphorylated. PKC-dependent MAPK activity transduces some, but not all, of the physiological responses of each cell type to its respective vitamin D metabolite, suggesting that the membrane receptor(s) and nuclear receptor(s) may function interdependently to regulate proliferation and differentiation of musculoskeletal cells, but different pathways are involved at different stages of phenotypic maturation.

24,25-Dihydroxyvitamin D 3↗
PubMed2006

Redox reactions of dehydroepiandrosterone and its metabolites in differentiating 3T3-L1 adipocytes: A liquid chromatographic-mass spectrometric study.

Dehydroepiandrosterone is known to depress fatty acid formation in differentiating 3T3-L1 adipocytes. The metabolism of dehydroepiandrosterone and four of its natural metabolites in differentiating adipocytes was studied by liquid chromatography-mass spectrometry. Adipocytes rapidly converted dehydroepiandrosterone to androst-5-ene-3beta,17beta-diol. 7alpha-Hydroxy-DHEA was interconverted with 7-oxo-DHEA and 7beta-hydroxy-DHEA and the corresponding 17beta reduced products. Dehydroepiandrosterone and its derivatives were detected only in the culture medium suggesting that dehydroepiandrosterone is metabolized via enzymes located in close proximity to, or that are integral parts of the cell membrane. Alternatively, there may be efficient mechanisms at play for extrusion of the steroids to the aqueous media rather than being retained in the lipid-rich cell. An interesting aspect of the study was finding androstenediol as the major metabolite of dehydroepiandrosterone. Androst-5-ene-3beta,17beta-diol has been implicated in prostate cancer. The contribution of adipose cells to the circulating supply of androst-5-ene-3beta,17beta-diol may therefore be considered in managing prostate cancer.

3T3-L1 Cells↗
PubMed2026

Untargeted-targeted metabolomics: energy metabolism characteristics in heart failure staging and discovery of novel biomarkers.

BACKGROUND: Heart Failure represents the severe stage of various heart diseases. Its global morbidity and mortality are on the rise, making it a serious public health issue that imposes a heavy burden on patients' families and society. Currently, there are relatively few systematic studies on the changes in specific metabolites and pathways in different stages of heart failure, such as Stage A, Stage B and Stage C. AIMS: Using untargeted-targeted metabolomics to explore the metabolic characteristics of Heart Failure, and screen out serum metabolic markers with potential diagnostic and prognostic value. METHODS: This study is a cross-sectional study. A total of 210 heart failure patients from Xiyuan Hospital of China Academy of Chinese Medical Sciences were enrolled between October 2023 and October 2024. Among them, 60 patients were selected for targeted metabolomics analysis via stratified sampling. Serum samples of the patients were collected and pretreated with methanol, then metabolites were detected using untargeted and targeted LC-MS respectively. After the raw data were processed with MSDIAL, pattern recognition was performed using principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA). Differential metabolites with variable importance in projection (VIP)&#x2009;>&#x2009;1 and P&#x2009;<&#x2009;0.05 were screened, and relevant pathways were analyzed via enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Untargeted metabolomics revealed that, compared with patients in Stages A and B, those with heart failure in Stage C had decreased serum levels of alanine, creatine, and branched-chain amino acids, along with increased levels of citric acid, fumaric acid, and malic acid. The differential metabolites were primarily enriched in pathways including the citric acid cycle, central carbon metabolism, and amino acid metabolism, indicating that energy metabolism plays a crucial role in the occurrence and progression of HF. Targeted metabolomics validated the findings from untargeted metabolomics: compared with Stage A, the level of phosphoenolpyruvate in Stage B was reduced; and in comparison with patients in Stage A or B, patients in Stage C showed decreased serum levels of multiple energy metabolites (e.g., glucose-6-phosphate, fructose-6-phosphate, 3-phosphoglyceric acid, AMP, ADP and ATP) as well as increased levels of malic acid, which is consistent with the characteristics of the "hypermetabolism-energy starvation" paradox. CONCLUSION: Stage C of heart failure is characterized by energy metabolism collapse (decreased ATP and TCA compensation), and differential metabolites (such as malic acid) may serve as potential candidate biomarkers pending longitudinal validation.

Humans↗
PubMed2026

Plasma Exosome Metabolomics Reveal Stage-Specific Alterations in Elderly Women With Premetabolic and Metabolic Syndrome.

BACKGROUND: Metabolic syndrome (MetS) is a chronic disorder that poses a major threat to global health. Exosomes have emerged as promising biomarkers for diagnosing and monitoring chronic diseases. However, stage-specific alterations in the exosomal metabolome during MetS development remain poorly understood. This study aimed to characterize the plasma exosomal metabolome and explore candidate exosomal biomarkers in individuals with MetS. METHODS: This study included 20 patients with MetS, 23 individuals with pre-MetS, and 45 healthy controls. Plasma exosomes were isolated and analyzed using untargeted liquid chromatography-mass spectrometry-based metabolomics. Differential metabolites were defined by a dual-threshold, that is, p&#x2009;<&#x2009;0.05 from t-test and variable importance in projection >&#x2009;1 from partial least squares discriminant analysis, with fold change indicating their expression changes. Further, we employed machine learning algorithms to predict MetS status. RESULTS: We identified 27 differential metabolites between the pre-MetS and control groups, mainly enriched in histidine metabolism and the tricarboxylic acid cycle. Of these, 12 metabolites were upregulated, and 15 were downregulated, with 1-methylhistidine and isocitrate playing central regulatory roles. Comparison between the MetS and control groups revealed 45 differentially expressed metabolites, mainly enriched in thiamine metabolism, including 13 upregulated and 32 downregulated. In the pre-MetS group, cladribine showed the highest area under the curve (AUC) (0.743, p&#x2009;<&#x2009;0.05), whereas 3-methylxanthine yielded the largest AUC (0.714, p&#x2009;<&#x2009;0.05) in the MetS group. CONCLUSION: Our study characterized stage-dependent alterations in the plasma exosome-derived metabolome in MetS and suggests that exosomal metabolomics may provide complementary molecular information on early MetS metabolic perturbations.

exosomal features↗
PubMed2026

Integrated landscape of salivary metagenome and multi-biofluid metabolome characterizes a microbial-metabolic axis in upper gastrointestinal cancer progression.

BACKGROUND: Upper gastrointestinal cancer (UGIC) imposes a major global health burden, yet the stage-specific molecular changes along the microbial-metabolic axis remain limited understood. We aimed to delineate this molecular landscape across UGIC progression and evaluate its potential as non-invasive methods for precision screening. RESULTS: Derived from a multi-center population-based UGIC screening program, we enrolled 420 individuals, stratified into normal, low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and UGIC (n&#x2009;=&#x2009;105 per group). Integrated salivary metagenomics and paired salivary/plasma metabolomics were performed to capture local and systemic dysregulation. We uncovered distinct stage-specific divergence during UGIC progression: profound remodeling of the salivary microbiota (104 differential species) and salivary metabolomics (80 differential metabolites) initiated early at the LGIN stage, whereas plasma metabolic dysregulation (40 differential metabolites) peaked significantly later at the HGIN stage. Integrative analysis revealed salivary microbiota related more closely with salivary metabolome than plasma metabolome. Moreover, statistical evidence suggested that dysbiotic salivary microbiota was associated with altered lysine- and tryptophan-related catabolic pathways converging on Acetyl-CoA-related metabolic nodes, supporting a potential metabolic mechanism in precancerous lesions. Finally, the discriminative model integrating metagenomic and metabolomic markers demonstrated promising diagnostic performance in distinguishing these precancerous lesions (LGIN: area under the curve [AUC]&#x2009;=&#x2009;0.83; HGIN: AUC&#x2009;=&#x2009;0.77) and UGIC (AUC&#x2009;=&#x2009;0.76) from normal. CONCLUSION: This study characterizes a stage-specific microbial-metabolic axis that facilitates the comprehensive understanding of UGIC pathogenesis. These multi-biofluid signatures offer a promising non-invasive triage strategy for detecting precancerous lesions and optimizing endoscopic resource allocation. Video Abstract.

Female↗
PubMed2005

High-throughput metabolic state analysis: the missing link in integrated functional genomics of yeasts.

The lack of comparable metabolic state assays severely limits understanding the metabolic changes caused by genetic or environmental perturbations. The present study reports the application of a novel derivatization method for metabolome analysis of yeast, coupled to data-mining software that achieve comparable throughput, effort and cost compared with DNA arrays. Our sample workup method enables simultaneous metabolite measurements throughout central carbon metabolism and amino acid biosynthesis, using a standard GC-MS platform that was optimized for this purpose. As an implementation proof-of-concept, we assayed metabolite levels in two yeast strains and two different environmental conditions in the context of metabolic pathway reconstruction. We demonstrate that these differential metabolite level data distinguish among sample types, such as typical metabolic fingerprinting or footprinting. More importantly, we demonstrate that this differential metabolite level data provides insight into specific metabolic pathways and lays the groundwork for integrated transcription-metabolism studies of yeasts.

Aerobiosis↗
PubMed1987

Analysis of morphine and its major metabolites by differential radioimmunoassay.

The analysis of morphine, morphine-3-glucuronide (M-3-G) morphine-6-glucuronide (M-6-G) by differential radioimmunoassay using iodinated label and three different antisera is described. These methods were used to measure concentrations of morphine and its conjugated metabolites in human plasma, over a 3-h period, following a single 10 mg intravenous dose. In 13 patients peak concentrations of M-3-G (739 nmol/L +/- 73.7 SEM) were approximately 10 times greater than those of M-6-G (71.3 nmol/L +/- 8.6 SEM). Times to reach these peaks were similar for both metabolites. Decay of morphine from plasma followed a biexponential pattern with a mean terminal half-life of 59.3 min (+/- 8.1 SEM, n = 11). Accurate determination of the half-lives of the glucuronides was not possible due to the short sampling period, but M-6-G seemed to have a similar half-life to morphine, while M-3-G was eliminated more slowly.

Aged↗
PubMed2026

Free polyphenols and multi-omics traits underlying antioxidant variation across Paeonia lactiflora leaf cultivars.

Leaves of Paeonia lactiflora are underutilized by-products with potential as natural antioxidant sources. In this study, 18 cultivars were evaluated for phytochemical composition and in vitro antioxidant capacity. Total phenolic content correlated strongly with DPPH and ABTS activities, and the comprehensive antioxidant index identified 'Coral Charm' and 'Hangshao' as representative high- and low-antioxidant cultivars, respectively. Untargeted metabolomics detected 2677 metabolites and identified 908 differential metabolites between the two cultivars. Targeted phenolic profiling quantified 27 compounds, among which 11 differed significantly between the two cultivars. Catechin and epicatechin were enriched in 'Coral Charm', with contents of 6.62 and 0.397&#xa0;ng/mg, respectively, compared with 0.012 and 0.002&#xa0;ng/mg in 'Hangshao'. (+)-Dihydroquercetin was also more abundant in 'Coral Charm', while caffeic acid showed an upward trend. Proteomic analysis identified 423 differentially expressed proteins, mainly associated with secondary metabolite biosynthesis, redox homeostasis, and central carbon metabolism. Integrated analysis identified pyruvate metabolism as the only pathway significantly enriched in both metabolomic and proteomic datasets. Molecular docking predicted favorable binding between representative phenolics and selected proteins. These findings link cultivar-dependent antioxidant variation in peony leaves with free-phenolic accumulation and pathway-level metabolic differences, supporting the selection and utilization of antioxidant-rich peony leaf resources.

Antioxidants↗
PubMed2026

Mechanic evaluation of Jisheng Shenqi Wan on calcium oxalate kidney stones: an integrated network pharmacology and metabolomics.

OBJECTIVE: To understand the efficacy of Jisheng Shenqi Wan (JSSQW, ) in treating calcium oxalate kidney stones (KS) and to investigate the mechanism of JSSQW action by combining network pharmacology with metabolomics analysis based on ultra-high performance liquid chromatography combined with tandem electrostatic field orbital trap high-resolution mass spectrometry (UHPLC-Q/Orbitrap HRMS). METHODS: The chemical components of JSSQW absorbed into rat blood were identified by UHPLC-Q/Orbitrap HRMS. The identified components were introduced into the Bioinformatics Analysis Tool for Molecular mechanism of Traditional Chinese Medicine platform to screen for target genes, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and disease enrichment analysis. A KS rat model was generated using the oxalic acid precursor method to examine the efficacy of JSSQW for treating KS. Serum metabolomics was used to monitor changes in endogenous substances in KS rats after JSSQW intervention. RESULTS: Twenty-three chemicals from JSSQW were identified in the blood of JSSQW gavage-administered rats. KEGG enrichment analysis predicted the top 20 signaling pathways affected by these 23 chemicals. Disease enrichment analysis showed that the target genes of these 23 chemicals were enriched in diseases of the urinary system and endocrine system, including kidney stones. In a KS rat model, JSSQW inhibited the aggregation of calcium oxalate crystals, reduced renal tubular injury, lowered the renal index, and improved biochemical indicators (blood creatinine, blood urea nitrogen). Serum metabolomics identified 25 differential metabolites that responded to JSSQW treatment. They were mainly lipids, with phosphatidylethanolamine and phosphorylcholine and their derivatives accounting for the highest proportion. Metabolic pathway analysis showed that the changes in differential metabolites were related to multiple metabolic pathways, especially sphingolipid metabolism and sphingolipid signaling pathways. CONCLUSIONS: JSSQW can inhibit the aggregation of calcium oxalate crystals in the kidneys, reduce tubular injury, and improve kidney function in KS rats. Its mechanism of action may be related to regulating disordered metabolites and metabolic pathways, especially glycerol phospholipid metabolism, sphingolipid metabolism, and sphingolipid signaling.

Drugs, Chinese Herbal↗