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At least 289 records · Page 16Linked to original sources
PubMed1993

NMR spectroscopy as a novel approach to the monitoring of renal transplant function.

High field 1H NMR spectroscopy was used for the rapid multicomponent analysis of low molecular wt compounds in urine in order to investigate the patterns of metabolic changes associated with early renal allograft dysfunction. Urine samples were collected daily for 14 days from 33 patients who underwent primary renal allograft transplantation, and analyzed by 500 and/or 600 MHz 1H NMR spectroscopy. All patients received 20 mg prednisolone and 5 mg/kg b.d. oral cyclosporin A (CsA) solution. In this study no patient showed clinical or histopathological evidence of CsA nephrotoxicity. For each patient the NMR-generated metabolite data were correlated with the clinical observations, graft biopsy pathology, and data from conventional laboratory techniques for assessing renal function. The NMR spectra of urine from patients with immediate functioning grafts were similar with respect to their patterns of amino acids, organic acids and organic amines, whereas the patients with delayed or non-functioning grafts showed significantly different metabolite excretion patterns. In longitudinal studies on individual patients there were increased urinary levels of trimethylamine-N-oxide (TMAO), dimethylamine (DMA), lactate, acetate, succinate, glycine and alanine during episodes of graft dysfunction. However, only the urinary concentration of TMAO was statistically significantly higher (P < 0.025) in the urine collected from patients during episodes of graft dysfunction (410 +/- 102 microM TMAO/mM creatinine) than in patients with good graft function (91 +/- 18 microM TMAO/mM creatinine) or healthy control subjects (100 +/- 50 microM TMAO/mM creatinine). These findings suggest that graft dysfunction is associated with damage to the renal medulla which causes the release of TMAO into the urine from the damaged renal medullary cells. This provides a possible novel urinary marker for post-transplant graft dysfunction. This study shows that NMR spectroscopy of biofluids, when used in combination with conventional laboratory techniques, is a valuable aid to renal transplant monitoring.

Adult↗
PubMed2026

Proteo-metabolomic integration identifies stage-specific candidate biomarkers for Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder with a prolonged prodromal phase and complex motor symptoms. Despite improved clinical criteria, early diagnosis and longitudinal monitoring remain challenging. While cerebrospinal fluid (CSF) and plasma metabolites and proteins show biomarker potential, their utility in predictive models is insufficiently characterized. We employed a secondary computational approach to integrate proteometabolomic profiles from CSF and plasma samples of >1100 Parkinson's Progression Markers Initiative (PPMI) participants. Using multi-omics machine learning, we identified biofluid-specific signatures and evaluated predictive performance. Twenty-one biomarker candidates were validated across three models (SVM, GLMNET, RF); SVM and GLMNET achieved the highest recall (83-86%) and AUCs of 0.84-0.89. Longitudinal mixed-effects modeling revealed eight candidates associated with progression across diagnostic stages. We identified a three-part molecular framework characterizing neurodegeneration: a diagnostic subpanel reflecting early microbiome dysregulation (secretory granins and metabolites) and synaptic breakdown; a second subpanel monitoring phenoconversion via neurogenesis precursors and extracellular matrix proteins; and a third subpanel tracking progression through chronic neuroinflammation and immune activation. This integrated multi-omics approach provides a robust framework for stage-specific PD monitoring and potential clinical deployment.

Journal Article↗
PubMed2022

Characterizing the metabolic effects of the selective inhibition of gut microbial &#x3b2;-glucuronidases in mice.

The hydrolysis of xenobiotic glucuronides by gut bacterial glucuronidases reactivates previously detoxified compounds resulting in severe gut toxicity for the host. Selective bacterial &#x3b2;-glucuronidase inhibitors can mitigate this toxicity but their impact on wider host metabolic processes has not been studied. To investigate this the inhibitor 4-(8-(piperazin-1-yl)-1,2,3,4-tetrahydro-[1,2,3]triazino[4',5':4,5]thieno[2,3-c]isoquinolin-5-yl)morpholine (UNC10201652, Inh 9) was administered to mice to selectively inhibit a narrow range of bacterial &#x3b2;-glucuronidases in the gut. The metabolomic profiles of the intestinal contents, biofluids, and several tissues involved in the enterohepatic circulation were measured and compared to control animals. No biochemical perturbations were observed in the plasma, liver or gall bladder. In contrast, the metabolite profiles of urine, colon contents, feces and gut wall were altered compared to the controls. Changes were largely restricted to compounds derived from gut microbial metabolism. This work establishes that inhibitors targeted towards bacterial &#x3b2;-glucuronidases modulate the functionality of the intestinal microbiota without adversely impacting the host metabolic system.

Mice↗
PubMed2002

Chemometric contributions to the evolution of metabonomics: mathematical solutions to characterising and interpreting complex biological NMR spectra.

The pharmaceutical industry has embraced emerging technologies such as genomics, proteomics and metabonomics over the past decade with a view to minimizing attrition and expanding drug development pipelines. Metabonomic technology, based on the multivariate analysis of complex biological profiles generated from spectroscopic instruments, has enabled the construction of successful expert systems for toxicity screening and disease diagnosis. Here we describe the evolution of chemometric and bioinformatic methodologies to accommodate the multi- and megavariate data generated by high resolution NMR spectroscopy of biofluids, tissues and cell cultures and explore their potential role in mining, modeling and predicting metabolic data.

Animals↗
PubMed2003

A metabonomic investigation of hepatotoxicity using diffusion-edited 1H NMR spectroscopy of blood serum.

It has been shown extensively, that chemometric investigations of 1H NMR spectra of rat urine taken from animals dosed with model toxins produce characteristic patterns of metabolic responses and that this permits the identification of biomarkers of toxic response and regeneration. To date, metabonomic methods have been mainly optimised for urine which contains mainly low molecular weight moieties, and thus a conventional 1-dimensional 1H NMR pulse sequence is an efficient means of obtaining information-rich data. In the case of biofluids such as blood plasma or serum, which contain a wide range of macromolecules the resonances of which can overlap with peaks from small molecule metabolites, the information giving rise to sample classification can be concealed in a conventional NMR spectrum andthis presents a different analytical challenge in terms of chemometric analysis of spectral profiles. Here, the use of other types of NMR data have been investigated and it is shown that by using spectra where the peak intensities are edited according to their molecular diffusion coefficients, it is possible to improve differentiation of control animals and those treated with the model hepatotoxin, alpha-naphthylisothiocyanate (ANIT). By using diffusion-edited spectroscopy, plasma lipid moieties are less attenuated than those from small endogenous metabolites and thus the toxin-induced changes to the lipoprotein profiles are more easily detectable.

1-Naphthylisothiocyanate↗
PubMed2004

G-factor analysis of protein secondary structure in solutions and thin films.

The biological activity of proteins is structure dependent. In this discussion, we describe development of g-factor analysis for characterizing the secondary structure of proteins in solutions and films. In g-factor analysis, experimental circular dichroism (CD) and UV absorbance spectra are converted to dimensionless g-factor spectra by dividing the differential absorbance of circularly polarized light (AL - AR) by the UV absorbance (A) at each wavelength. The spectra can be deconvolved and the secondary structure estimated without information on the protein molecular weight, sample concentration, or sample path length. We have refined g-factor spectral acquisition and deconvolution parameters to improve the precision and accuracy of experimental g-factor spectra and the subsequent secondary structure estimations. In general, slower scan rates and longer response times are required to obtain high quality g-factor spectra than to obtain ordinary CD spectra, particularly for data at wavelengths longer than 230 nm. The spectral acquisition and deconvolution procedures have been validated for aqueous bovine serum albumin (BSA) and poly(L-proline). The secondary structures of fibronectin and laminin in buffer solutions are predicted. When BSA and poly(L-proline) form films on quartz, their secondary structures change significantly: 13% for BSA and 32% for poly(L-proline). By contrast, the secondary structure of fibronectin is the same in solution and films. The g-factor method is an easy, rapid, accurate and precise method for determining secondary structure and structural changes in protein solutions and films. Potential applications range from proteomics and structure-based drug discovery, to the design and fabrication of biosensors, biomaterials and biofluidic devices.

Algorithms↗
PubMed2006

A pragmatic and readily implemented quality control strategy for HPLC-MS and GC-MS-based metabonomic analysis.

Metabonomic/metabolomic studies can involve the analysis of large numbers of samples for the detection of biomarkers and confidence in the analytical data, generated by methods such as GC and HPLC-MS, requires active measures on the part of the analyst. However, quality control for complex multi-component samples such as biofluids, where many of the components of interest in the sample are unknown prior to analysis, poses significant problems. Here the repeat analysis of a pooled sample throughout the run, thereby enabling the analysis to be monitored and controlled using targeted inspection of the data and pattern recognition, is advocated as a pragmatic solution to this problem.

Biomarkers↗
PubMed2026

Body mass index-specific nanoparticle protein corona signatures in late pregnancy.

The protein corona (PC) formed on the surface of nanoparticles (NPs) upon exposure to human biofluids is a dynamic interface that reflects the physiological and pathological status of the host. In this study, we investigated how the maternal body mass index (BMI) influences the composition of the NPs' PC during late pregnancy. Polystyrene NPs were incubated with plasma samples collected from third-trimester pregnant individuals across normal weight, overweight, and obese BMI categories. Comprehensive characterization using dynamic light scattering (DLS), zeta potential measurements, and transmission electron microscopy (TEM) confirmed BMI-dependent differences in PC thickness and colloidal stability. SDS-PAGE and label-free quantitative proteomics revealed distinct molecular compositions: PCs from obese individuals were enriched in inflammatory and lipid metabolism-associated proteins (e.g., APOE and CRP), while normal weight-derived PCs showed higher levels of complementary regulators and extracellular matrix proteins. Principal component analysis (PCA) demonstrated clear clustering of proteomic profiles by the BMI group, suggesting BMI-specific PC fingerprints. These findings indicate that the maternal metabolic phenotype shapes nano-bio interactions at the proteomic level and highlight the potential of PC profiling as a non-invasive approach for assessing maternal health and metabolic status. This work lays the foundation for integrating NP-based proteomics into precision nanomedicine for maternal-fetal health monitoring.

Female↗
PubMed2000

Interaction of antimony tartrate with the tripeptide glutathione implication for its mode of action.

The tripeptide glutathione (gamma-L-Glu-L-Cys-Gly, GSH) is thought to play an important role in the biological processing of antimony drugs. We have studied the complexation of the antileishmanial drug potassium antimony(III) tartrate to GSH in both aqueous solution and intact red blood cells by NMR spectroscopy and electrospray ionization mass spectrometry. The deprotonated thiol group of the cysteine residue is shown to be the only binding site for Sb(III), and a complex with the stoichiometry [Sb(GS)3] is formed. The stability constant for [Sb(GS)3] was determined to be log K 25 (I = 0.1 M, 298 K) based on a competition reaction between tartrate and GSH at different pH* values. In spite of being highly thermodynamically stable, the complex is kinetically labile. The rate of exchange of GSH between its free and Sb-bound form is pH-dependent, ranging from slow exchange on the 1H-NMR timescale at low pH (2 s-1 at pH 3.2) to relatively rapid exchange at biological pH (> 440 s-1). Such facile exchange may be important in the transport of Sb(III) in various biofluids and tissues in vivo. Our spin-echo 1H-NMR data show that Sb(III) rapidly entered red blood cell walls and was complexed by intracellular glutathione.

Antimony Potassium Tartrate↗
PubMed2001

Iron(III)-mediated intra-articular crystal deposition in arthritis: a therapeutic role for iron chelators.

Crystal deposition in arthritic diseases has attracted much interest. Many reports have established the presence of calcium pyrophosphate (CPPD), hydroxyapatite (HAP) and urate crystals throughout the range of arthritic diseases. In particular, HAP crystals have been detected in 30-60% of synovial fluid (SF) samples from patients suffering from osteoarthritis (OA) and 33% of those suffering from rheumatoid arthritis (RA). In OA, crystal deposition has been linked to greater joint deterioration. The mechanism of intra-articular calcification is unknown. Nucleation is required to transform a 'metastable' phosphate- and calcium-rich biofluid into one that generates crystals. Ferric ions have been demonstrated to induce crystallization of these stable supersaturated solutions via the process of nucleation. The inflamed arthritic joint is prone to iron loading. Microbleeding from compromised vasculature contributes to intra-articular iron loading in arthritic conditions. Low-molecular-mass redox-active iron complexes have been detected in SF in inflammatory joint diseases. These species are credited with mediating oxidative stress via interaction with peroxides and superoxide. In addition, adventitious low-molecular-mass iron complexes can cause nucleation leading to crystal growth within the joint. Decorporating agents capable of removing this misplaced iron from the arthritic joint would have the joint benefit of relieving oxidative stress and preventing crystal nucleation. Systemic side effects could be overcome by the targeting suitable chelators using bioreductive delivery systems that are activated in hypoxic inflamed synovial tissue.

Arthritis, Rheumatoid↗
PubMed2004

Convergence of excitatory and inhibitory hair cell transmitters shapes vestibular afferent responses.

The vestibular semicircular canals respond to angular acceleration that is integrated to angular velocity by the biofluid mechanics of the canals and is the primary origin of afferent responses encoding velocity. Surprisingly, some afferents actually report angular acceleration. Our data indicate that hair-cell/afferent synapses introduce a mathematical derivative in these afferents that partially cancels the biomechanical integration and results in discharge rates encoding angular acceleration. We examined the role of convergent synaptic inputs from hair cells to this mathematical differentiation. A significant reduction in the order of the differentiation was observed for low-frequency stimuli after gamma-aminobutyric acid type B receptor antagonist administration. Results demonstrate that gamma-aminobutyric acid participates in shaping the temporal dynamics of afferent responses.

Acceleration↗
PubMed2006

Compensatory mechanism for homeostatic blood pressure regulation in Ephx2 gene-disrupted mice.

Arachidonic acid-derived epoxides, epoxyeicosatrienoic acids, are important regulators of vascular homeostasis and inflammation, and therefore manipulation of their levels is a potentially useful pharmacological strategy. Soluble epoxide hydrolase converts epoxyeicosatrienoic acids to their corresponding diols, dihydroxyeicosatrienoic acids, modifying or eliminating the function of these oxylipins. To better understand the phenotypic impact of Ephx2 disruption, two independently derived colonies of soluble epoxide hydrolase-null mice were compared. We examined this genotype evaluating protein expression, biofluid oxylipin profile, tissue oxylipin production capacity, and blood pressure. Ephx2 gene disruption eliminated soluble epoxide hydrolase protein expression and activity in liver, kidney, and heart from each colony. Plasma levels of epoxy fatty acids were increased, and fatty acid diols levels were decreased, while measured levels of lipoxygenase- and cyclooxygenase-dependent oxylipins were unchanged. Liver and kidney homogenates also show elevated epoxide fatty acids. However, in whole kidney homogenate a 4-fold increase in the formation of 20-hydroxyeicosatetraenoic acid was measured along with a 3-fold increase in lipoxygenase-derived hydroxylation and prostanoid production. Unlike previous reports, however, neither Ephx2-null colony showed alterations in basal blood pressure. Finally, the soluble epoxide hydrolase-null mice show a survival advantage following acute systemic inflammation. The data suggest that blood pressure homeostasis may be achieved by increasing production of the vasoconstrictor, 20-hydroxyeicosatetraenoic acid in the kidney of the Ephx2-null mice. This shift in renal metabolism is likely a metabolic compensation for the loss of the soluble epoxide hydrolase gene.

Animals↗
PubMed2005

Development of an internally controlled antibody microarray.

Antibody microarrays are a high throughput technology used to concurrently screen for protein expression. Most antibody arrays currently used are based on the ELISA sandwich approach that uses two antibodies to screen for the expression of a limited number of proteins. Also because antigen-antibody interactions are concentration-dependent, antibody microarrays need to normalize the amount of antibody that is used. In response to the limitations with the currently existing technology we have developed a single antibody-based microarray where the quantity of antibody spotted is used to standardize the antigen concentration. In addition, this new array utilizes an internally controlled system where one color represents the amount of antibody spotted, and the other color represents the amount of the antigen that is used to quantify the level of protein expression. When compared with median fluorescence intensity alone, normalization for antibody spot intensity decreased variability and lowered the limits of detection. This new antibody array was tested using standard cytokine proteins and also cell lysates obtained from mouse macrophages stimulated in vitro and evaluated for the expression of the cytokine proteins interleukin (IL)-1beta, IL-5, IL-6, and macrophage inflammatory proteins 1alpha and 1beta. The levels of protein expression seen with the antibody microarray was compared with that obtained with Western blot analysis, and the magnitude of protein expression observed was similar with both technologies with the antibody array actually showing a greater degree of sensitivity. In summary, we have developed a new type of antibody microarray to screen for protein expression that utilizes a single antibody and controls for the amount of antibody spotted. This type of array appears at least as sensitive as Western blot analysis, and the technology can be scaled up for high throughput screening for hundreds of proteins in complex biofluids such as blood.

Animals↗
PubMed2006

Advances and challenges in liquid chromatography-mass spectrometry-based proteomics profiling for clinical applications.

Recent advances in proteomics technologies provide tremendous opportunities for biomarker-related clinical applications; however, the distinctive characteristics of human biofluids such as the high dynamic range in protein abundances and extreme complexity of the proteomes present tremendous challenges. In this review we summarize recent advances in LC-MS-based proteomics profiling and its applications in clinical proteomics as well as discuss the major challenges associated with implementing these technologies for more effective candidate biomarker discovery. Developments in immunoaffinity depletion and various fractionation approaches in combination with substantial improvements in LC-MS platforms have enabled the plasma proteome to be profiled with considerably greater dynamic range of coverage, allowing many proteins at low ng/ml levels to be confidently identified. Despite these significant advances and efforts, major challenges associated with the dynamic range of measurements and extent of proteome coverage, confidence of peptide/protein identifications, quantitation accuracy, analysis throughput, and the robustness of present instrumentation must be addressed before a proteomics profiling platform suitable for efficient clinical applications can be routinely implemented.

Biomarkers↗
PubMed2002

Pharmacokinetics, toxicokinetics, distribution, metabolism and excretion of linezolid in mouse, rat and dog.

1. Linezolid (ZYVOX), the first of a new class of antibiotics, the oxazolidinones, is approved for treatment of Gram-positive bacterial infections. 2. The aim was to determine the absorption, distribution, metabolism and excretion (ADME) of linezolid in mouse, rat and dog in support of preclinical safety studies and clinical development. 3. Conventional replicate study designs were employed in animal experiments, and biofluids were assayed by HPLC or HPLC-MS. 4. Linezolid was rapidly absorbed after p.o. dosing with an p.o. bioavailability of > 95% in rat and dog, and > 70% in mouse. Twenty-eight-day i.v./p.o. toxicokinetic studies in rat (20-200mg kg(-1) day(-1)) and dog (10-80 mg kg(-1) day(-1)) revealed neither a meaningful increase in clearance nor accumulation upon multiple dosing. 5. Linezolid had limited protein binding (<35%) and was very well distributed to most extravascular sites, with a volume of distribution at steady-state (V(ss)) approximately equal to total body water. 6. Linezolid circulated mainly as parent drug and was excreted mainly as parent drug and two inactive carboxylic acids, PNU-142586 and PNU-142300. Minor secondary metabolites were also characterized. In all species, the clearance rate was determined by metabolism. 7. Radioactivity recovery was essentially complete within 24-48 h. Renal excretion of parent drug and metabolites was a major elimination route. Parent drug underwent renal tubular reabsorption, significantly slowing parent drug excretion and allowing a slow metabolic process to become rate-limiting in overall clearance. 8. It is concluded that ADME data were relatively consistent across species and supported the rat and dog as the principal non-clinical safety species.

Acetamides↗
PubMedDate not supplied

Numerical study of unsteady stenosis flow: parametric evaluation of power-law model.

Currently the best indicator for surgical treatment of arterio-sclerosis is the degree of stenosis. Although X-ray angiography is currently the standard, cost and morbidity are distinct disadvantages. By modelling stenosis and studying its biofluid mechanics, one can apply its results in the field of arterial disease research. This formed the motivation for this work. A non-Newtonian (power law) incompressible Navier-Stokes (N-S) solver was developed using the method of operator splitting and artificial compressibility. The vehicle used is the computational fluid dynamics (CFD) numerical library FASTFLO. The power-law model developed is then used to do a parametric study of the effect of 'n' on blood flow mechanics where 'n' is the power index that determines the haematocrit of blood. A pulsatile pressure wave over a cardiac cycle of a second was used to simulate transient flow over a hypothetical two-dimensional stenotic geometry. By comparing the different velocity pressure, wall shear stress and viscosity profiles, it has been found when 'n' increases, the vortex formation and peak wall shear stress decreases (magnitudes of < 1.5 Pa). Since the formation of vortices and low oscillatory wall shear stress on the stenotic wall is detrimental to the well-being of the arterial tract, it can therefore be inferred that there might be a relationship between the diseased state of blood (power law) and early genesis of atherosclerosis. However, the conclusion of this paper marks the advent of new research directions in this field of study.

Arteriosclerosis↗
PubMed1999

The role of N-acetylcysteine in protecting synovial fluid biomolecules against radiolytically-mediated oxidative damage: a high field proton NMR study.

High field proton (1H) NMR spectroscopy has been employed to evaluate the abilities of the antioxidant thiol drug N-acetylcysteine and exogenous cysteine to protect metabolites present in intact inflammatory synovial fluid samples against oxidative damage arising from gamma-radiolysis (5.00 kGy) in the presence of atmospheric O2. Although oxidation of urate to allantoin by radiolytically-generated *OH radical was readily circumventable by pre-treatment of synovial fluids with N-acetylcysteine (1.00 or 3.00 x 10(-3) mol x dm(-3)) or cysteine (1.00, 2.00 or 5.00 x 10(-3) mol x dm(-3)), both thiols offered only a limited protective capacity with respect to hyaluronate depolymerisation and the production of formate from carbohydrates in general. Radiolytic products generated from the added thiols (predominantly their corresponding disulphides) were simultaneously detectable in 1H Hahn spin-echo spectra of gamma-irradiated synovial fluids, permitting a quantitative evaluation of the radioprotective capacity of these agents. It is concluded that the multicomponent analytical ability of high field 1H NMR spectroscopy provides much useful molecular information regarding mechanisms associated with the radioprotectant actions of thiols in intact biofluids.

Acetylcysteine↗
PubMedDate not supplied

Metabonomics technologies and their applications in physiological monitoring, drug safety assessment and disease diagnosis.

In this review, metabonomics, a combination of data-rich analytical chemical measurements and chemometrics for profiling metabolism in complex systems, is described and its applications are reviewed. Metabonomics is typically carried out using biofluids or tissue samples. The relevance of the technique is reviewed in relation to other '-omics', and it is shown how the methods can be applied to physiological evaluation, drug safety assessment, characterization of genetically modified animal models of disease, diagnosis of human disease, and drug therapy monitoring. The different types of analytical data, mainly from nuclear magnetic resonance spectroscopy and mass spectrometry, are summarized. The outputs from a metabonomics study allow sample classification, for example according to phenotype, drug safety or disease diagnosis, and interpretation of the reasons for classification yields information on combination biomarkers of effect. Transcriptomic and metabonomic data is currently being further integrated into a holistic understanding of systems biology. An assessment of the possible future role and impact of metabonomics is presented.

Age Factors↗