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At least 127 records · Page 7Linked to original sources
PubMed2006

The in vitro stability of air-filled polybutylcyanoacrylate microparticles.

Different methods of manufacturing permitted the production of air-filled PBCA microparticles (af-pbca-mp) with different physical properties such as size and wall thickness. These differences led to distinctions with respect to mechanical stability and, at the same time, to different levels of biochemical stability when incubated in biofluids. Microparticles, designed as they are to be mechanically more stable (composed of larger nanoparticles resulting in thicker shell wall, no surface hydrolysis), persist longer under in vitro conditions in biofluids such as serum, plasma and whole blood than do the more fragile ones. It was possible when using the measurement of ultrasound attenuation to characterize af-pbca-mp degradation with respect to the disappearance of the ultrasound properties of the particles and therefore to find out how long different formulations can be expected to be active as contrast agents under simulated in vivo conditions. The present examination showed that using either serum, plasma or whole blood leads to results with the same tendencies in terms of the stability and durability of af-pbca-mp in the media, mimicking in vivo conditions. It was thus possible to validate successfully the use of either serum or plasma as substitutes for whole blood. Further studies dealing with the in vitro in vivo correlation will be needed to find out if the situation in this in vitro assay corresponds to the situation in the body.

Air↗
PubMed2026

Effects of apple phenolics on the human metabolome: modulation of key metabolic pathways.

Apples are widely recognized for their potential health benefits, partly attributed to their phenolic compounds. However, their impact on human metabolism remains incompletely understood. This study investigated metabolic effects of apple-derived phenolic compounds using untargeted metabolomics approach across multiple biofluids. In a crossover intervention study, 30 healthy men consumed a phenolic-rich apple juice or a placebo for two weeks. Blood, urine and saliva samples were collected before and after each intervention and analyzed by direct infusion ultra-high resolution mass spectrometry. Consumption of apple phenolic compounds resulted in significant alterations of the human metabolome, including increased levels of phenolic-derived degradation products and microbial-associated metabolites across all biofluids. Pathway enrichment analysis revealed pronounced effects on phenylalanine and tyrosine metabolism, as well as linoleic and arachidonic acid metabolism, Overall, these findings demonstrate that apple phenolic compounds induce measurable, microbiota-associated and systemic metabolic changes, providing new insights into their metabolic fate and biological relevance.

Humans↗
PubMed2005

Quantitative analysis of the low molecular weight serum proteome using 18O stable isotope labeling in a lung tumor xenograft mouse model.

With advancements in the analytical technologies and methodologies in proteomics, there is great interest in biomarker discovery in biofluids such as serum and plasma. Current hypotheses suggest that the low molecular weight (LMW) serum proteome possesses an archive of clipped and cleaved protein fragments that may provide insight into disease development. Though these biofluids represent attractive samples from which new and more accurate disease biomarkers may be found, the intrinsic person-to-person variability in these samples complicates their discovery. Mice are one of the most extensively used animal models for studying human disease because they represent a highly controllable experimental model system. In this study, the LMW serum proteome was compared between xenografted tumor-bearing mice and control mice by differential labeling utilizing trypsin-mediated incorporation of the stable isotope of oxygen, 18O. The digestates were combined, fractionated by strong cation exchange chromatography, and analyzed by nanoflow reversed-phase liquid chromatography coupled online with tandem mass spectrometry, resulting in the identification of 6003 proteins identified by at least a single, fully tryptic peptide. Almost 1650 proteins were identified and quantitated by two or more fully tryptic peptides. The methodology adopted in this work provides the means for future quantitative measurements in comparative animal models of disease and in human disease cohorts.

Animals↗
PubMed2005

Fluorine-19 or phosphorus-31 NMR spectroscopy: a suitable analytical technique for quantitative in vitro metabolic studies of fluorinated or phosphorylated drugs.

Fluorine-19 or phosphorus-31 NMR (19F NMR or 31P NMR) spectroscopy provides a highly specific tool for identification of fluorine- or phosphorus-containing drugs and their metabolites in biological media as well as a suitable analytical technique for their absolute quantification. This article focuses on the application of in vitro 19F or 31P NMR to the quantitative metabolic studies of some fluoropyrimidine or oxazaphosphorine drugs in clinical use. The first part presents an overview of the advantages (non-destructive and non-selective direct quantitative study of the biological matrices) and limitations (expensive cost of the spectrometers, limited mass or concentration sensitivity) of NMR spectroscopy. The second part deals with the criteria to be considered for successful quantification by NMR (uniform excitation over the entire spectral width of the spectrum, resonance signals properly characterised by taking into account T1 values and avoiding NOE enhancements, optimisation of the data processing, choice of a suitable standard reference). The third and fourth parts report some examples of quantification of 5-fluorouracil, its prodrug capecitabine, 5-fluorocytosine and their metabolites in bulk solutions (biofluids, tissue extracts, perfusates and culture media) and heterogeneous media (excised tissues and packed intact cells) as well as cyclophosphamide and ifosfamide in biofluids. These two parts emphasise the high potential of in vitro 19F or 31P NMR for absolute quantification, in a single run, of all the fluorine- or phosphorus-containing species in the matrices analysed. The limit of quantification in bulk solutions is 1-3 microM for 19F NMR and approximately 10 microM for 31P NMR. In heterogeneous media analysed with 19F NMR, it is 2-5 nmol in excised tissues and cell pellets.

Animals↗
PubMed2006

The application of NMR-based metabonomics in neurological disorders.

Advances in postgenomic technologies have radically changed the information output from complex biological systems, generating vast amounts of high complexity data that can be interpreted by means of chemometric and bioinformatic methods to achieve disease diagnosis and prognosis. High-resolution nuclear magnetic resonance (NMR) spectroscopy of biofluids such as plasma, cerebrospinal fluid (CSF), and urine can generate robust, interpretable metabolic fingerprints that contain latent information relating to physiological or pathological status. This technology has been successfully applied to both preclinical and clinical studies of neurodegenerative diseases such as Huntington's disease, muscular dystrophy, and cerebellar ataxia. An extension of this technology, (1)H magic-angle-spinning (HRMAS) NMR spectroscopy, can be used to generate metabolic information on small intact tissue samples, providing a metabolic link between metabolic profiling of biofluids and histology. In this review we provide a summary of high-resolution NMR studies in neurodegenerative disease and explore the potential of metabonomics in evaluating disease progression with respect to therapeutic intervention.

Animals↗
PubMed2003

DISCO--a general computer program for the computation of acid dissociation constants of polyprotic molecules in water and biological fluids, from nuclear magnetic resonance data: application to polyamines.

A new computer program, DISCO, running under Windows, has been developed under the project CSA98P22 falling within the Competitive Support Activities initiative launched within the EU 4th Framework Programme. DISCO allows the calculation of the stepwise acid dissociation constants of polyprotic molecules in water and in complex media (i.e., biofluids, etc.) from nuclear magnetic resonance (NMR) data (chemical shifts) by means of two derivative-free methods: Pit-mapping and Simplex. DISCO performances were tested using simulated-unaffected by experimental error-data sets, for systems having up to seven equilibrium constants and experimental NMR data of spermine, 6-monofluorospermine, and 6,6-difluorospermine, dissolved in D(2)O and in physiological solution (D(2)O/NaCl). Results demonstrated that (i) DISCO enables the determination of pK(A) values with high precision even when small-sized raw data sets are employed, when chemical shifts are measured with low precision (the usual condition in biofluids due to the impossibility to obtain narrow line shape), and when the guess solution, necessary as an initial step of the mathematical iterative process, is fixed within a large interval of variation; (ii) DISCO always converges to the root; (iii) DISCO permits the calculation of pK(A) values which lie within the observed pH range, independent of the narrowness of the pH range.

Algorithms↗
PubMed1998

High performance liquid chromatographic analysis of a novel aminoalkylpyridine anticonvulsant 2-(4-chlorophenyl)amino-2-(4-pyridyl)ethane.

A simple, rapid and specific high performance liquid chromatographic (HPLC) method for the quantitation of 2-(4-chlorophenyl)amino-2-(4-pyridyl)ethane (AAP-Cl) and identification of its putative metabolite, 2-(4-chlorophenyl)amino-2-(4-pyridyl)ethanol (beta-AA) in rat blood and urine has been developed. AAP-Cl, beta-AA and an appropriate internal standard were extracted from rat biofluids by a solid phase extraction technique using C18 cartridges prior to the HPLC analysis. The extractibility was 92% for AAP-Cl and 98% for beta-AA. The HPLC analysis employed a symmetrical or standard reversed-phase HPLC column (Apex ODS, 5 microm, 25 cm x 0.46 cm) for blood or urine analysis, a mobile phase of water methanol acetonitrile (40:30:30) containing 20 microl 100 ml(-1) diethylamine at a flow rate of 1 ml min(-1), and UV detection at 254 nm. The limit of detection was 100 ng ml(-1) for both analytes in both blood and urine. The calibration curves for AAP-Cl in rat biofluids were shown to be linear in both low and high concentration ranges (blood: 0-1 and 1-10 microg ml(-1); urine: 0-10 and 10-100 microg ml(-1)) with intra- and inter-day coefficients of variation of no more than 18% for blood and 14% for urine. The method developed was successfully applied to a preliminary analysis of intact AAP-Cl in both blood and urine obtained from rats dosed with AAP-Cl.

Aniline Compounds↗
PubMed2001

Determination of molecular self-diffusion coefficient using multiple spin-echo NMR spectroscopy with removal of convection and background gradient artifacts.

A new approach is presented for the measurement of the self-diffusion coefficients of molecules in solution. It has been applied to metabolites in biofluids such as seminal and blood plasma at physiological temperature. The method is based on the double-gradient-spin-echo pulse sequence in which CPMG and bipolar gradient pulses have been implemented. The double-gradient spin-echo is shown to be useful in reducing the thermal convection that can cause over-estimation of the diffusion coefficients. The multiple spin-echoes in association with the CPMG approach is also insensitive to background gradient artifacts. In addition, the CPMG sequence enables longer diffusion periods (up to seconds) to be used without phase distortion; therefore, the proposed method is suitable for determining the diffusion coefficients of small metabolites in biofluids, where the resonances of large molecules, such as proteins, are suppressed during the spin-echo period as a result of their fast relaxation.

Amino Acids↗
PubMed2005

Evaluation of the orthogonal projection on latent structure model limitations caused by chemical shift variability and improved visualization of biomarker changes in 1H NMR spectroscopic metabonomic studies.

In general, applications of metabonomics using biofluid NMR spectroscopic analysis for probing abnormal biochemical profiles in disease or due to toxicity have all relied on the use of chemometric techniques for sample classification. However, the well-known variability of some chemical shifts in 1H NMR spectra of biofluids due to environmental differences such as pH variation, when coupled with the large number of variables in such spectra, has led to the situation where it is necessary to reduce the size of the spectra or to attempt to align the shifting peaks, to get more robust and interpretable chemometric models. Here, a new approach that avoids this problem is demonstrated and shows that, moreover, inclusion of variable peak position data can be beneficial and can lead to useful biochemical information. The interpretation of chemometric models using combined back-scaled loading plots and variable weights demonstrates that this peak position variation can be handled successfully and also often provides additional information on the physicochemical variations in metabonomic data sets.

3-Hydroxybutyric Acid↗
PubMed2004

Impact of nano- and mesoscale particles on the performance of microcantilever-based sensors.

Microcantilever-based sensors comprise an emerging class of chemomechanical sensors. The crucial challenge for every new and promising sensing platform lies in its performance in complex mixtures. Since most biofluids are rich in particulates, we assessed the impact of particles in the liquid stream on the performance of microcantilever sensors operated in both deflection and resonance modes. For both detection modes, sensor response depends on the particle diameter, concentration, and velocity as well as the composition of a thin-film coating. The presence of particles in the fluid stream produce substantial scattering of the laser beam used to measure cantilever deflection. Thus, prior removal of particulate matter from biofluids is required for optimal performance of microcantilever-based biosensors.

Artifacts↗
PubMed2006

Metabolite projection analysis for fast identification of metabolites in metabonomics. Application in an amiodarone study.

The assignment of significantly changed NMR signals, which were identified with the help of multivariate models, to individual metabolites in biofluids is a manual and tedious task requiring knowledge in chemometrics and NMR spectroscopy. Metabolite projection analysis, introduced in this work, allows automatic linking of multivariate models with metabolites by skipping the level of manual NMR signal identification. The method depends on the projection of sets of metabolite NMR spectra from a database into PCA or PLS models of NMR spectra of biofluid samples. Metabolites that are significantly changed can be identified graphically in metabolite projection plots or numerically as projected virtual concentration. The method is demonstrated together with a newly introduced algorithm for refined nonequidistant binning using a metabonomics study with amiodarone as administered drug. Amiodarone can induce phospholipidosis in the lung and liver, which is accompanied by associated organ toxicity in these organs. It is shown how metabolite projection analysis allows easy and fast tentative assignment of all structures of metabolites whose concentrations in the urine samples significantly changed upon dosage. These metabolites had also been identified previously by manually interpreting the multivariate models and spectra. Among these metabolites, phenylacetylglycine was also identified as being significantly increased. This metabolite has recently been proposed as urinary biomarker for phospholipidosis.

Amiodarone↗
PubMed2026

Proteins as Regulators of Metabolic Changes in Sepsis: Alterations in Body Fluids, Immune Cells, and Organs through the Eyes of Proteomics.

Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection and profound metabolic alterations that contribute to immune dysfunction and organ failure. This Review synthesizes proteomic evidence on sepsis-associated alterations in proteins involved in metabolic pathways across circulating biofluids, immune cells, and organs. Across plasma and urine, proteomic studies identify disturbances in lipoprotein-associated pathways, redox homeostasis, mitochondrial function, and substrate metabolism, indicating that protein signatures of metabolic dysregulation are systemic and detectable across biofluids. In immune cells, monocytes and neutrophils, proteomic analyses reveal a shift toward glycolysis with concurrent impairment of mitochondrial pathways alongside phenotype-dependent differences in lipid and redox-related programs. Organ-level studies further show that metabolic responses are heterogeneous, with distinct trajectories in the kidney, heart, liver, lung, skeletal muscle, and brain. These observations support the concept that sepsis involves compartment-specific remodeling of metabolism-associated protein networks rather than a single convergent metabolic state. Proteomics also highlights potential translational opportunities by identifying metabolism-associated proteins linked to disease severity, clinical phenotypes, and biologically distinct patient subgroups, although the current evidence remains largely exploratory and context-dependent. Overall, proteomics provides a complementary framework for understanding the molecular regulation of sepsis-associated metabolic dysfunction and may refine biological stratification and therapeutic targeting, particularly when integrated with longitudinal sampling and multiomic data.

Humans↗
PubMed2007

Photografted poly(ethylene glycol) matrix for affinity interaction studies.

A poly(ethylene glycol) (PEG)-based matrix for studies of affinity interactions is developed and demonstrated. The PEG matrix, less than 0.1 microm thick, is graft copolymerized onto a cycloolefin polymer from a mixture of PEG methacrylates using a free radical reaction initiated by UV light at 254 nm. The grafting process is monitored in real time, and characteristics such as thickness, homogeneity, relative composition, photostability, and performance in terms of protein resistance in complex biofluids and sensor qualities are investigated with null ellipsometry, infrared spectroscopy, and surface plasmon resonance. The matrix is subsequently modified to contain carboxyl groups, thereby making it possible to immobilize ligands in a controlled and functional manner. Human serum albumin and fibrinogen are immobilized and successfully detected by antibody recognition using surface plasmon resonance. The results are encouraging and suggest that the PEG matrix is suitable for biochip and biosensor applications in demanding biofluids.

Adsorption↗
PubMed2006

Predictive metabolite profiling applying hierarchical multivariate curve resolution to GC-MS data--a potential tool for multi-parametric diagnosis.

A method for predictive metabolite profiling based on resolution of GC-MS data followed by multivariate data analysis is presented and applied to three different biofluid data sets (rat urine, aspen leaf extracts, and human blood plasma). Hierarchical multivariate curve resolution (H-MCR) was used to simultaneously resolve the GC-MS data into pure profiles, describing the relative metabolite concentrations between samples, for multivariate analysis. Here, we present an extension of the H-MCR method allowing treatment of independent samples according to processing parameters estimated from a set of training samples. Predictions or inclusion of the new samples, based on their metabolite profiles, into an existing model could then be carried out, which is a requirement for a working application within, e.g., clinical diagnosis. Apart from allowing treatment and prediction of independent samples the proposed method also reduces the time for the curve resolution process since only a subset of representative samples have to be processed while the remaining samples can be treated according to the obtained processing parameters. The time required for resolving the 30 training samples in the rat urine example was approximately 13 h, while the treatment of the 30 test samples according to the training parameters required only approximately 30 s per sample (approximately 15 min in total). In addition, the presented results show that the suggested approach works for describing metabolic changes in different biofluids, indicating that this is a general approach for high-throughput predictive metabolite profiling, which could have important applications in areas such as plant functional genomics, drug toxicity, treatment efficacy and early disease diagnosis.

Animals↗
PubMed2001

Metabonomic investigations into hydrazine toxicity in the rat.

The systemic biochemical effects of oral hydrazine administration (dosed at 75, 90, and 120 mg/kg) have been investigated in male Han Wistar rats using metabonomic analysis of (1)H NMR spectra of urine and plasma, conventional clinical chemistry, and liver histopathology. Plasma samples were collected both pre- and 24 h postdose, while urine was collected predose and daily over a 7 day postdose period. (1)H NMR spectra of the biofluids were analyzed visually and via pattern recognition using principal component analysis. The latter showed that there was a dose-dependent biochemical effect of hydrazine treatment on the levels of a range of low molecular weight compounds in urine and plasma, which was correlated with the severity of the hydrazine induced liver lesions. In plasma, increases in the levels of free glycine, alanine, isoleucine, valine, lysine, arginine, tyrosine, citrulline, 3-D-hydroxybutyrate, creatine, histidine, and threonine were observed. Urinary excretion of hippurate, citrate, succinate, 2-oxoglutarate, trimethylamine-N-oxide, fumarate and creatinine were decreased following hydrazine dosing, whereas taurine, creatine, threonine, N-methylnicotinic acid, tyrosine, beta-alanine, citrulline, Nalpha-acetylcitrulline and argininosuccinate excretion was increased. Moreover, the most notable effect was the appearance in urine and plasma of 2-aminoadipate, which has previously been shown to lead to neurological effects in rats. High urinary levels of 2-aminoadipate may explain the hitherto poorly understood neurological effects of hydrazine. Metabonomic analysis of high-resolution (1)H NMR spectra of biofluids has provided a means of monitoring the progression of toxicity and recovery, while also allowing the identification of novel biomarkers of development and regression of the lesion.

Administration, Oral↗
PubMed2005

Metabonomic deconvolution of embedded toxicity: application to thioacetamide hepato- and nephrotoxicity.

We present here the potential of an integrated metabonomic strategy to deconvolute the biofluid metabolic signatures in experimental animals following multiple organ toxicities, using the well-known hepato- and nephrotoxin, thioacetamide. Male Han-Wistar rats were dosed with thioacetamide (150 mg/kg, n = 25), and urine, plasma, liver, and kidney samples were collected postdose for conventional NMR and magic angle spinning (MAS) NMR spectroscopy. These data were correlated with histopathology and plasma clinical chemistry collected at all time points. 1H MAS NMR data from liver and kidney were related to sequential 1H NMR measurements in urine and plasma using pattern recognition methods. One-dimensional 1H NMR spectra were data-reduced and analyzed using principal components analysis (PCA) to show the time-dependent biochemical variations induced by thioacetamide toxicity. From the eigenvector loadings of the PCA, those regions of the 1H NMR spectra, and hence the combinations of endogenous metabolites marking the main phase of the toxic episode, were identified. The thioacetamide-induced biochemical manifestations included a renal and hepatic lipidosis accompanied by hypolipidaemia; increased urinary excretion of taurine and creatine concomitant with elevated creatine in liver, kidney, and plasma; a shift in energy metabolism characterized by depleted liver glucose and glycogen; reduced urinary excretion of tricarboxylic acid cycle intermediates and raised plasma ketone bodies; increased levels of tissue and plasma amino acids leading to amino aciduria verifying necrosis-enhanced protein degradation and renal dysfunction; and elevated hepatic and urinary bile acids indicating secondary damage to the biliary system. This integrated metabonomic approach has been able to identify the tissue of origin for biomarkers present in the metabolic profiles of biofluids, following the onset and progression of a multiorgan pathology, and as such highlights its potential in the evaluation of embedded toxicity in novel drug candidates.

Amino Acids↗
PubMed2002

Metabolic profiling of rodent biological fluids via 1H NMR spectroscopy using a 1 mm microlitre probe.

The application of a 1 mm TXI (1H/13C/15N) microlitre NMR probe with z-gradient for metabolic profiling of biofluids is described. The probe was used to provide spectral profiles for rat blood plasma using only approximately 2 microl of fluid with a range of solvent suppression techniques. Using a similar amount of fluid, spectra were obtained from rat and mouse cerebrospinal fluid, demonstrating that the probe could be used to profile rodents metabolically via biofluids previously inaccessible to NMR analysis without the need for termination.

Animals↗
PubMedDate not supplied

Toxicoproteomics: proteomics applied to toxicology and pathology.

Global measurement of proteins and their many attributes in tissues and biofluids defines the field of proteomics. Toxicoproteomics, as part of the larger field of toxicogenomics. seeks to identify critical proteins and pathways in biological systems that are affected by and respond to adverse chemical and environmental exposures using global protein expression technologies. Toxicoproteomics integrates 3 disciplinary areas: traditional toxicology and pathology, differential protein and gene expression analysis, and systems biology. Key topics to be reviewed are the evolution of proteomics, proteomic technology platforms and their capabilities with exemplary studies from biology and medicine, a review of over 50 recent studies applying proteomic analysis to toxicological research, and the recent development of databases designed to integrate -Omics technologies with toxicology and pathology. Proteomics is examined for its potential in discovery of new biomarkers and toxicity signatures, in mapping serum,plasma. and other biofluid proteomes, and in parallel proteomic and transcriptomic studies. The new field of toxicoproteomics is uniquely positioned toward an expanded understanding of protein expression during toxicity and environmental disease for the advancement of public health.

Animals↗