Analysis of metabolic profiles of prostaglandins in urine using a lipophilic anion exchange.
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Animals↗
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Quantitative analysis of metabolism of hepatic triglyceride in ethanol-treated rats.
An acute intraperitoneal injection of ethanol (0.7 or 2.1g/kg body wt.) causes the reversible, dose-dependent accumulation of hepatic triglyceride in rats. By using a pulse of [14C]palmitate injected into a tail vein, it was found that ethanol (2.1g/kg)had no effect on the flux of unesterified fatty acid of serum (4.3mumol/min per 100g body wt.). However, either dose increased the fraction of the total flux going to liver from 0.16 to0.27 as rapidly as could be measured (30s), and it remained elevated until all ethanol had been cleared from the blood. The fraction of the total radioactivity in lipids of liver that was in triglyceride increased linearly for 1 h from 30 to 50% and there was a simultaneous decrease in phospholipid from 60 to 40%. The rate of synthesis of hepatic triglyceride derived directly from unesterified fatty acid of serum was calculated by using the flux rate of unesterified fatty acid in serum, the fractional hepatic uptake of this flux, and the percentage of liver fatty acid esterified to triglyceride. This contribution is related to the total synthetic rate of hepatic triglyceride (rate of accumulation+rate of release) to determine quantitatively how much of the developing fatty liver is attributable to increased uptake of unesterfied fatty acid of serum. At the higher dose of ethanol, about half of the accumulating triglyceride is derived from this source, whereas with the lower dose of ethanol it can account for all of the build-up.
Animals↗
Biochemical aspects of dopamine (3,4-dihydroxyphenethylamine) in an invertebrate nervous system: uptake, metabolism and analysis of receptors [proceedings].
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Animals↗
Compartment analysis of metabolism of chromium(III) in rats of various ages.
The metabolism of chromium(III) was studied in groups of female Wistar rats of various ages (35, 60, and 120 days) after a single intravenous injection of 51CrCl3 in trace amounts. In all the animals, the plasma disappearance curve could be adequately described by a sum of three exponential terms between 0 and 265 h postinjection. A three-compartment mammillary model is proposed that permits the description of Cr(III) metabolism in quantitative terms. The model defines compartment volumes, clearances by exchange, and clearances by excretion. The total excretory clearance is the sum of three components: urinary clearance (fu), fecal clearance (fd), and a residual clearance (fs), corresponding to an apparently irreversible deposition of chromium into long term body reservoirs. The parameters of the model are reported for each age group; when their values are expressed per 100 g of body wt, all the components of the excretory clearance decrease with age. In all cases elimination takes place primarily via the urine and fs accounts for 31-41% of the total excretory clearance. Consistent with the model, 51Cr was found to accumulate with time in several organs such as bone, kidney, spleen, and liver after a single intravenous injection of 51CrCl3.
Aging↗
Quantitative analysis of metabolic compensation in respiratory acid-base disorders.
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Acidosis, Respiratory↗
Analysis of metabolic changes in revertants of antibiotic-resistant micobacteria.
In the present report evaluation of the possible metabolic changes in partially revertants of M. tuberculosis var. hominis, reisolated from strains at high levels of drug-resistance after treatment with mutagenic agents, was reported. Based on the data presented here, it must be concluded that no significant biological and biochemical differences in mycobacterial cells revertant from high mutants mono-resistant to four aminoglycosides (Sm, Kana, Vio, Neo) and p-aminonasalicylic acid (PAS) are to be found.
Aminosalicylic Acids↗
[Oscillations in the energy metabolism of the host and symbiont of a cicada. I. Analysis of possible metabolic and physiologic correlations of both systems].
The insect group which includes cicadas harbours intracellular bacterial symbionts which are passed on from generation to generation in the form of a 'symbiont ball' inserted between the egg membrane and the rear pole of the egg cell. Bioluminiscence methods can be used to measure the oscillations in ATP, ADP and AMP levels in egg systems which have been separated into a host and a symbiont part (Euscelidius variegatus, Euscelis incisus), and which are exposed to constant light or light-dark variations under otherwise constant conditions (26 degrees C, 70% relative humidity, 7000 lux). The energy charge can be calculated from the ATP, ADP and AMP concentrations. Comparisons of such curves suggest an 'antagonistic' relationship in the energy metabolism of the host and symbiont parts of the egg. The minima of oscilaltions in the host's energy metabolism generally occur at the same time as the maxima in the endocytobionts energy metabolism. Antagonistic correlations between the nucleus/cytoplasm and mitochondria/plastids were also observed in the eucyte system. Analogies between the two systems can be explained satisfactorily by the endosymbiont theory of the origin of eucytes. It follows that insect endocytobioses can serve as an experimental model for the biochemical analysis of the eucyte system.
Adenine Nucleotides↗
Pentaerythritol trinitrate and glyceryl trinitrate on intramyocardial oxygenation and perfusion in the dog. Krogh analysis of transmural metabolism.
1. The effect of intravenous pentaerythritol trinitrate and glyceryl trinitrate on left ventricular subepicardial (epi) and subendocardial (endo) PO2 and perfusion were compared in anaesthetized open-chest mongrel dogs. Tissue PO2 was determined simultaneously at a depth of 3 mm (epicardial) and 9 mm (endocardial) with small platinum electrodes by polarography. In a separate series of dogs tissue perfusion of those regions was measured by hydrogen (H2) clearance using similar electrodes. 2. Both nitrates increased endocardial PO2 while epicardial PO2 was not altered. Perfusion was determined at the point of the maximal rise in endocardial PO2 (4-7 min after injection of either nitrate). At that period average coronary artery inflow and epicardial perfusion were decreased but endocardial perfusion was not significantly altered. 3. Using the data on PO2, hydrogen clearance and intercapillary distance, the effect of the nitrates on transmural metabolism (oxygen consumption) was estimated by Krogh analysis. Basal endocardial metabolism was 20-30% higher than epicardial metabolism. The nitrates reduced metabolism in each region. The absolute decrease in oxygen consumption was greater in the endocardium. 4. The results show that both pentaerythritol trinitrate and glyceryl trinitrate improve endocardial oxygenation by producing a more favourable balance between perfusion and oxygen requirements in that region.
Animals↗
Metabolism of diethylstilbestrol in the C3H mouse: chromatographic systems for the quantitative analysis of DES metabolic products.
Initial excretion studies with orally administered [monoethyl-1-3H] DES demonstrated the feces to be the principal mode of elimination of DES in the C3H mouse. Metabolic studies with tritiated DES and/or [UL-14C] DES were performed with orally dosed C3H high (MTV+) and low (MTV-) titer MMTV female mice. Extraction and partitioning of the fecal radioactivity demonstrated 77 to 86% (n = 4) to be benzene soluble and the remainder H2O soluble. The principal product in the organic phase following Sephadex LH-20 and HPLC purification was DES. The aqueous phase was resolved by LH-20 into two conjugate fractions that were partially hydrolyzed by beta-glucuronidase. The principal aglycone was chromatographically identical with authentic DES. The urinary conjugates were resolved into six fractions. The four major fractions were 80% hydrolyzable with beta-glucuronidase. Two of these fractions had trans-DES as the principal aglycone, whereas the other two had a major peak similar to but not chromatographically coincident with cis-DES. In certain experiments mice were sequentially dosed with tritium (24 hr) followed by a 14C dose (24 hr). Two mice (MTV+) were also previously fed 1000 ppb DES prior to these experiments. The tritated and 14C products were combined and analyzed simultaneously. This experiment did not reveal significant differences in the metabolism due to the modes of radioactive labeling, MMTV titer, or the prior feeding of DES. The developed methodology was judged to purify quantitatively 90% or more of the DES radioactive products.
Animals↗
[Information value of the compartimental analysis of potassium metabolism for clinical medicine].
1. The special information value of the dynamic compartment analysis consists in functional evidence concerning the potassium metabolism. 2. Basis of the dynamic compartment analysis is an open central 3 compartment model. 3. The rate of metabolism which is determined by size of the pool and constant of speed is the most important parameter. 4. The mathematical modelling of the tracer course renders visible the compartmental effects of inflow and outflow of the speed constant. 5. Disturbances of the very quickly and quickly exchanging constituents of the potassium metabolism reflect themselves perhaps directly as a functional loss of the permanent and latent functional capacity of the organism.
Extracellular Space↗
Neonatal mononuclear cell metabolism: further evidence for diminished monocyte function in the neonate.
The metabolic capacity of neonatal monocytes was compared to the metabolic capacity of adult monocytes by two entirely different methods: the selective diminution of monocyte contamination of whole mononuclear cells and the isolation of relatively purified populations of monocytes. Monocyte removal from whole mononuclear cells produced a diminution in the pyruvate kinase (PK) activity (from 28.6 +/- 1.1 to 15.6 +/- 1.2 nmoles/min/10(7) cells) and an increase in adenosine triphosphate (ATP) content (from 7.9 +/- 1.0 to 9.5 +/- 0.8 nmoles/10(7) cells) in adult cells. No change in PK activity (from 13.5 +/- 1.3 to 14.0 +/- 1.3) was observed in cord cells, but the ATP content of cord cells was higher after monocytes depletion (from 4.7 +/- 0.5 to 6.2 +- 0.7). The suggestion of metabolic vulnerability was confirmed by metabolic analysis of isolated adult and cord monocytes. The PK activity of adult monocytes was greater than that of cord monocytes (57 +/- 9 and 25 +/- 0.3, respectively) and the ATP content of adult monocytes (5.7 +/- 0.2) was greater than that of cord monocytes (2.3 +/- 0.1). The data confirm prior observations of diminished energy metabolism in neonatal mononucler cells and suggest that the metabolic perturbations may, in part, correlate with functional immaturity of the neonatal monocyte.
Adenosine Triphosphate↗
Light regulates capsaicinoid biosynthesis via the CaHY5-CaBBX2-CaACS8 module in pepper.
Capsaicinoids are a class of unique alkaloids that confer the pungent taste to pepper fruits. However, it remains largely unknown how light regulates the biosynthesis of capsaicinoids. We conducted a metabolic analysis on light- and dark-adapted pepper fruits. The results showed that dark-adapted pepper fruits had lower capsaicinoid contents and correspondingly downregulated transcription of capsaicinoid biosynthetic genes (CBGs), indicating that light plays a crucial role in capsaicinoid biosynthesis. Furthermore, silencing of CaHY5, a pivotal transcription factor gene in the light signaling pathway, decreased the content of capsaicinoid and suppressed the expression of CBGs, whereas transient overexpression of CaHY5 generated exactly opposite results. CaHY5 can bind to the G-box motif in the promoters of CaBBX2 and CaACS8, thereby enhancing their transcriptional levels. The activated CaBBX2 then binds to the T/G-box in the CaACS8 promoter to stimulate its expression. CaBBX2 or CaACS8 silencing led to decreased levels of capsaicinoids, while their transient overexpression produced increased capsaicinoid contents. Collectively, our results indicated that the light-activated CaHY5-CaBBX2-CaACS8 regulatory module plays a pivotal role in capsaicinoid biosynthesis. These findings provide new insights into the influence of light on capsaicinoid biosynthesis and potential targets for activation of this biosynthetic pathway in pepper.
Capsicum↗
Integrative multi-omics analysis proposes a metabolic classification of gliomas: distinct metabolic states, immune infiltration, and prognosis.
BACKGROUND: The tumor microenvironment (TME) of glioma harbors diverse cell types; however, cell metabolic heterogeneity remains to be explored. This study aims to characterize the metabolic features of different cell types in the TME by integrating multiple datasets, including genomics, bulk and single-cell transcriptomics, and metabolomics. METHODS: Unsupervised machine learning was used to construct an energy metabolic classifier based on the metabolic pathways identified from bulk RNA-seq of gliomas in the TCGA dataset. The classifier was externally validated using multiple datasets, including genomics, bulk RNA-seq, snRNA-seq, and the metabolomics data. Furthermore, metabolic heterogeneity associated with the classifier was further characterized at single-cell resolution. RESULTS: The energy metabolism-based classifier stratified patients into two prognostic clusters: patients in cluster 1 were characterized by high pathway activity of glycolysis, the pentose phosphate pathway (PPP), and fatty acid oxidation (FAO), whereas patients in cluster 2 exhibited higher activity in glutaminolysis. This metabolic classifier revealed both intratumoral and intertumoral metabolic heterogeneity, and the complexity was further validated by the metabolomics profiling and snRNA-seq data from the CPTAC dataset. Notably, OSMR, highly expressed in cluster 1, showed significant co-expression with key glycolytic enzyme genes. The OSM/OSMR/JAK1/STAT3 axis potently drives malignant progression of glioma cells, specially enhancing their invasive and migratory capabilities. Single-cell resolution analyses demonstrated that tumor metabolic heterogeneity is primarily driven by malignant cells rather than non-malignant components, while tumor microenvironment (TME) factors were also found to modulate malignant cell metabolism. Significantly, glycolytic activity in glioma cells increased during the phenotypic transition from PN (proneural) to MES (mesenchymal), with cluster 1 metabolic phenotypes predominating in the tumor core. Compared to cluster 2, cluster 1 patients exhibited higher mRNA expression of immunosuppressive checkpoint genes, which correlated with pronounced immunosuppression in the TME. Furthermore, various immune cells demonstrated distinct metabolic preferences at single-cell resolution. CONCLUSIONS: This study developed an energy metabolic-based classifier for gliomas with prognostic and therapeutic potential. Metabolic reprogramming was linked with the PN-to-MES transition of glioma cells and immunosuppression in the tumor microenvironment. Multi-omics data, especially snRNA-seq, offered insights into metabolism heterogeneity at single-cell resolution, enabling personalized treatment strategies.
Humans↗
Integrative multi-omics analysis unravels the metabolic landscape and reveals serum biomarkers for early diagnosis of hyperuricemia.
BACKGROUND: Hyperuricemia (HUA) is a major risk factor for gout and multiple metabolic disorders. Although serum uric acid (UA) is the gold standard for HUA diagnosis, it fails to reflect early metabolic disturbances and shows limited predictive value for asymptomatic HUA. This study sought to elucidate the pathological mechanisms underlying HUA and identify novel diagnostic biomarkers beyond UA. METHODS: This study enrolled 195 patients with HUA and 98 healthy controls. Global metabolomics and proteomics profiling were performed to characterize molecular alterations underlying HUA. Based on the biological relevance of the shared dysregulated pathways, a pathway correlation network was constructed to elucidate the pathological mechanisms driving HUA initiation and progression. Furthermore, diagnostic biomarkers for HUA were identified using machine learning algorithms, and were validated with an external cohort. RESULTS: HUA patients exhibited distinct metabolic and proteomic profiles compared with healthy controls. Integrated multi-omics pathway analysis revealed that peroxisome proliferators-activated receptor signaling pathway, arachidonic acid metabolism, purine metabolism, pyrimidine metabolism and sphingolipid signaling pathway were significantly dysregulated in HUA. Among them, arachidonic acid metabolism was identified as a hub pathway involved in HUA progression. Furthermore, a metabolite panel consisting of cysteine-S-sulfate, glycerophosphocholine and 4-hydroxyphenylpyruvic acid was screened by machine learning and validated in an independent cohort, which showed slightly higher diagnostic performance for HUA than UA. CONCLUSIONS: This study reveals the core metabolic and protein regulatory networks of HUA, and identifies a novel serum metabolite panel for the diagnosis of HUA. These findings provide new insights for improved clinical diagnosis and management.
Humans↗
Kinetic analysis of lead metabolism in healthy humans.
The steady state kinetics of lead metabolism were studied in five healthy men with stable isotope tracers. Subjects lived in a metabolic unit and ate constant low lead diets. Their intake was supplemented each day with 79--204 mug of enriched lead-204 as nitrate which was ingested with meals for 1--124 days. The concentration and isotopic composition of lead was determined serially in blood, urine, feces, and diet and less commonly in hair, nails, sweat, bone, and alimentary tract secretions by isotopic dilution, mass spectrometric analysis. The data suggest a three compartmental model for lead metabolism. The first compartment encompasses blood and is 1.5--2.2 times larger than the blood mass. It contains approximately 1.7--2.0 mg of lead and has a mean life of 35 days. This pool is in direct communication with ingested lead, urinary lead, and pools two and three. The second compartment is largely composed of soft tissue, contains about 0.3--0.9 mg of lead, and has a mean life of approximately 40 days. This pool gives rise to lead in hair, nails, sweat, and salivary, gastric, pancreatic, and biliary secretions. Pool three resides primarily in the skeleton, contains the vast quantity of body lead, and has a very slow mean life. Bones appear to differ in their rates of lead turnover. Within the relatively small changes in blood lead observed in the present study, the transfer coefficients between the pools remained constant.
Adult↗
Quantitative analysis of intermediary metabolism in Tetrahymena. Cells grown in proteose-peptone and resuspended in a defined nutrient-rich medium.
Tetrahymena pyriformis were grown to early-stationary phase and resuspended in a defined mixture containing glucose, fructose, ribose, glycerol, acetate, pyruvate, bicarbonate, glutamate, and hexanoate, with only one substrate labeled with 14C in any flask. Incorporation of label into CO2, glycogen, RNA, alanine, glutamate, glycine, lipid glycerol, and lipid fatty acids was measured 20, 40, and 60 min after the start of the incubation. To develop a model suitable for quantitative analysis of the data, it was necessary to join two preceding models, one for carbohydrate-metabolizing cells and one for acetate-metabolizing cells, eliminating the over-simplified sections of each. Equations were written and programmed for a digital computer to allow computation of the amount of label expected to be incorporated into any of the products measured for any given set of steady state flux values in the metabolic network. The model formed by simply joining the two preceding models did not yield satisfactory agreement with the complete data obtained in the present study, although each partial set of data could be fit well by the appropriate partial model. Analysis of the ways in which the model failed to yield good fits to the data indicated that another pool of P-enolpyruvate, of pyruvate, and of acetyl-CoA had to be added at the junction of the two models. The presence of such poolte into fatty acids as compared to the incorporation of label from glucose into fatty acids. A new model was therefore constructed which differed from the preceding model only in its structural organization at the level of P-enolpyruvate, pyruvate, and acetyl-CoA. The model is consistent with all known information on the compartmental structure of metabolism in Tetrahymena, on enzyme localization, and on the enzyme complement of this cell. Over 70 measurements of label incorporation into products were made at each time. These, plus a large number of "limit" measurements which constrain any possible solutions, were in sufficient excess of the 39 independent flux values to permit a stringent assessment of the model. A set of flux values was found which yielded a good fit to the data. These flux values therefore provide a quantitative description of metabolite flux in the intact cell during the slow adaptation to the nine-substrate mixture. The rates of utilization of glucose, fructose, glycerol, and ribose were in the ratio of about 10:1:0.33:0.16, i.e. fairly similar to the ratio observed with carbohydrate-metabolizing cells. Initial flux through phosphofructokinase is about 160 nmol/10(6) cells.h, increasing over 3-fold during tje jpir incubation. Initial flux through fructose-1,6-diphosphatase is about 110 nmol/10(6) cells.h and also increases almost 3-fold during the incubation. Thus net flux is glycolytic and increases 4-fold during the hour with a large amount of futile cycling at this step...
Acetates↗
NAViFluX: a visualization‑centric platform for interactive analysis, refinement and design of genome‑scale metabolic networks.
MOTIVATION: Genome-scale metabolic network (GSMN) models enable flux-based metabolite fate discovery, metabolic engineering, drug target identification, and multi-omics integration. However, programming requirements, architectural complexity, and limited visualization support impede its adoption by the broader scientific community. Existing tools exclusively specialize in GSMN analyses or visualization while lacking important features such as pathway-specific views, database-integrated refinement, and comprehensive enrichment and perturbation analyses. RESULTS: Here, we present NAViFluX (metabolic Network Analysis and Visualization of Flux), a visualization-centric, web browser-based tool that unifies native pathway/subsystem map generation, interactive model refinement via KEGG/BiGG, pathway merging and modules for flux computations, topology, and functional enrichment all within network views. Using three independent case studies on Escherichia coli, the utility of NAViFluX for characterization of nutrient-specific metabolic adaptations, enhancing gene essentiality predictions and interpretability, and rational design of an optimized carbon-fixing metabolic state is demonstrated. AVAILABILITY AND IMPLEMENTATION: All source code and supplementary files associated with the case studies are publicly available via Zenodo at https://zenodo.org/records/19107831. NAViFluX can be easily installed as a standalone software through https://github.com/bnsb-lab-iith/NAViFluX.
Metabolic Networks and Pathways↗
Multicompartmental analysis of cholesterol metabolism in man. Characterization of the hepatic bile acid and biliary cholesterol precursor sites.
The present report has presented the first clear evidence in man for the existence of specific hepatic cholesterol precursor sites associated with the formation and secretion of bile acids and biliary cholesterol. These hepatic compartments derive virtually all their cholesterol from newly synthesized and lipoprotein free cholesterol. The model which is presented was formulated on current concepts of cholesterol metabolism in man and is concerned, at this initial stage, with the elucidation of the bile acid and biliary cholesterol compartments. The complexity of cholesterol metabolism in man necessitated an initial approach that would minimize the number of inputs of cholesterol into the system, allow for the sampling of several cholesterol compartments, and permit the simultaneous labeling of newly synthesized cholesterol and preformed cholesterol. To achieve these objectives, we studied the patient with a total bile fistula. Six patients were administered simultaneously pulse injections of labeled mevalonic acid and [(14)C]cholesterol. The qualitative features of the specific activity time course curves after labeled mevalonic acid revealed no precursor-product relationship between bile acid, biliary cholesterol, and plasma free cholesterol. The peak specific activity of the bile acids was reached in approximately 100 min and was higher than the biliary cholesterol, which was higher than the plasma free cholesterol. The plasma free cholesterol specific activity became higher than the other lipids after 12 h and remained higher throughout the period of study. Similar related observations were made with [(14)C]cholesterol. The data were then subjected to simulation analysis and modeling using the SAAM-27 computer program. Computer least-square fits of the data were obtained after the model was evolved. During the model development, the least number of compartments and transport pathways were introduced consistent with a good fit of the data. Of particular importance was the constraint that the model fit the data obtained from both [(14)C]cholesterol and labeled mevalonic acid. The same parameter values were used to fit the data from both tracers. The fluxes arrived at in the model indicate that 31% and 20%, respectively, of the cholesterol input into the bile acid and biliary cholesterol precursor sites were derived directly from the newly synthesized hepatic cholesterol. The remainder had its origin predominantly from lipoprotein free cholesterol. Plasma esterified cholesterol (as free) made a small contribution (11%) to the bile acid compartment. Similarly, 10% of the biliary cholesterol arose from an unknown hepatic site. The present report has provided the basis for a new procedure for studying in vivo cholesterol metabolism in man. Examination of the derived cholesterol flux rates between the compartments suggests the presence of an important mechanism regulating the partitioning of lipoprotein free cholesterol between the bile acid and biliary cholesterol precursor sites. Aberrations in the proportioning of precursor cholesterol between these sites could be a causative factor precipitating the excessive secretion of biliary cholesterol and the production of lithogenic bile.
Aged↗