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Molecular & Cellular Proteomics : MCP Apr 2005Here, we describe the use of antibody-based proteomics involving the generation of protein-specific antibodies to functionally explore the human proteome. The antibodies... (Review)
Review
Here, we describe the use of antibody-based proteomics involving the generation of protein-specific antibodies to functionally explore the human proteome. The antibodies can be used for analysis of corresponding proteins in a wide range of assay platforms, including i) immunohistochemistry for detailed tissue profiling, ii) specific affinity reagents for various functional protein assays, and iii) capture ("pull-down") reagents for purification of specific proteins and their associated complexes for structural and biochemical analyses. In this review, the use of antibodies for such analysis will be discussed with focus on the possibility to create a descriptive and comprehensive protein atlas for tissue distribution and subcellular localization of human proteins in both normal and disease tissues.
Topics: Antibodies; Humans; Protein Array Analysis; Protein Processing, Post-Translational; Proteins; Proteome; Proteomics; Tissue Distribution
PubMed: 15695805
DOI: 10.1074/mcp.R500009-MCP200 -
European Journal of Drug Metabolism and... Jan 2021Cariprazine, a dopamine D-preferring D/D receptor partial agonist, is approved for the treatment of adults with schizophrenia (1.5-6 mg/day) and manic/mixed...
BACKGROUND AND OBJECTIVES
Cariprazine, a dopamine D-preferring D/D receptor partial agonist, is approved for the treatment of adults with schizophrenia (1.5-6 mg/day) and manic/mixed (3-6 mg/day) episodes associated with bipolar I disorder. This population pharmacokinetic analysis describes the concentration-time profiles of cariprazine and its two major active metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). Additionally, the potential impact of patient characteristics, creatinine clearance, and cytochrome P450 2D6 (CYP2D6) metabolizer status on the pharmacokinetics of cariprazine and its metabolites was evaluated.
METHODS
Data from three phase 1 and ten phase 2/3 studies in adult patients with schizophrenia or bipolar mania were included. Nonlinear mixed-effects pharmacokinetic modeling was performed using the NONMEM software package. Compartmental modeling was performed sequentially with the cariprazine elimination rate used as the DCAR formation rate and likewise the elimination rate of DCAR used with a delay as the DDCAR formation rate.
RESULTS
Cariprazine pharmacokinetics were described by a three-compartment model with zero-order input of the dose to a depot compartment followed by first-order absorption and first-order elimination. DCAR and DDCAR pharmacokinetics were described by two-compartment models with linear elimination. Statistically significant predictors of pharmacokinetic parameters included weight, sex, and race, though differences in exposures were not large enough to require an adjustment in dose. Creatinine clearance was not a statistically significant predictor of drug clearance, and a post hoc analysis found that CYP2D6 metabolizer status was not associated with changes in exposure levels for cariprazine, DCAR, or DDCAR. The median time to 90% of steady state was approximately 1 week for cariprazine and DCAR and 3 weeks for DDCAR.
CONCLUSIONS
Population pharmacokinetic modeling provided a quantitative description of the concentration-time profile of cariprazine and its metabolites.
Topics: Adolescent; Adult; Antipsychotic Agents; Clinical Trials as Topic; Databases, Factual; Female; Humans; Male; Middle Aged; Models, Biological; Piperazines; Schizophrenia; Young Adult
PubMed: 33141308
DOI: 10.1007/s13318-020-00650-4 -
Advances in Nutrition (Bethesda, Md.) Nov 2016Interest in the application of phenolic compounds from the diet or supplements for the prevention of chronic diseases has grown substantially, but the efficacy of such... (Review)
Review
Interest in the application of phenolic compounds from the diet or supplements for the prevention of chronic diseases has grown substantially, but the efficacy of such approaches in humans is largely dependent on the bioavailability and metabolism of these compounds. Although food and dietary factors have been the focus of intense investigation, the impact of disease states such as obesity or diabetes on their absorption, metabolism, and eventual efficacy is important to consider. These factors must be understood in order to develop effective strategies that leverage bioactive phenolic compounds for the prevention of chronic disease. The goal of this review is to discuss the inducible metabolic systems that may be influenced by disease states and how these effects impact the bioavailability and metabolism of dietary phenolic compounds. Because current studies generally report that obesity and/or diabetes alter the absorption and excretion of these compounds, this review includes a description of the absorption, conjugation, and excretion pathways for phenolic compounds and how they are potentially altered in disease states. A possible mechanism that will be discussed related to the modulation of phenolic bioavailability and metabolism may be linked to increased inflammatory status from increased amounts of adipose tissue or elevated plasma glucose concentrations. Although more studies are needed, the translation of benefits derived from dietary phenolic compounds to individuals with obesity or diabetes may require the consideration of dosing strategies or be accompanied by adjunct therapies to improve the bioavailability of these compounds.
Topics: Biological Availability; Diabetes Mellitus; Diet; Dietary Supplements; Functional Food; Humans; Inflammation; Obesity; Phenols
PubMed: 28140326
DOI: 10.3945/an.116.013029 -
Veterinary Journal (London, England :... May 2011Determination of glomerular filtration rate (GFR) is a valuable, yet underused, diagnostic tool for evaluating renal function in dogs and cats. This article first... (Review)
Review
Determination of glomerular filtration rate (GFR) is a valuable, yet underused, diagnostic tool for evaluating renal function in dogs and cats. This article first reviews the hormonal and hemodynamic factors which contribute to GFR, followed by a description of considerations when selecting a pharmacokinetic model and methods of animal-to-animal standardization. The best-characterized existing GFR markers, including creatinine, radiolabeled markers, and iohexol, are reviewed in depth, as well as alternative but lesser used techniques. A weighted means analysis of reported GFR measurements in healthy dogs and cats and a review of selected studies that have examined GFR alterations in animals with naturally occurring and experimental diseases provide the reader with preliminary guidelines on expected GFR results in these species and disease conditions.
Topics: Animals; Biomarkers; Cat Diseases; Cats; Creatinine; Dog Diseases; Dogs; Glomerular Filtration Rate; Iohexol; Metabolic Clearance Rate
PubMed: 20541957
DOI: 10.1016/j.tvjl.2010.05.006 -
Springer Seminars in Immunopathology 1983To map the multiple interactive sites on the C3 polypeptide, it is advantageous to combine the approaches of protein chemistry, nucleic acid technology, and molecular... (Review)
Review
To map the multiple interactive sites on the C3 polypeptide, it is advantageous to combine the approaches of protein chemistry, nucleic acid technology, and molecular biology. This review summarizes the currently known molecular properties of mouse liver C3 mRNA, cloned C3 cDNA, and genomic DNA. Original data communicated have specified the amino acid sequence of the 215 amino-terminal residues of mature mouse C3 beta. Southern blot analysis of liver DNA indicated that the mouse genome contains only one type of C3 gene, that murine and human C3 sequences strongly cross-hybridize, and that the human C3 gene is not somatically rearranged. Included are descriptions of the first human C3 genomic DNA clones, their preparation, and their use to map the human C3 gene to chromosome 19 in linkage with the myotonic dystrophy (DM) locus. After a brief survey of reports describing inherited human C3 deficiencies, we discuss a Dutch family and their three members with total homozygous C3 deficiency who were the subjects of a recent publication. The restricted synthesis of C3 in major and minor producer tissues is discussed and it is proposed that the C3 gene provides a good model system for studying the molecular basis of tissue-specific gene expression. Data are presented documenting the production of C3 in two established mouse macrophage-like cell lines and two rat hepatoma cell lines in tissue cultures. A short account covers the extensive literature on regulation of C3 serum concentrations in acute and chronic inflammation and the very incomplete picture that presently depicts hormonal regulation of C3 synthesis. The final experiment reported demonstrates that nucleic acid hybridization with cloned cDNA probes is a sensitive assay for quantitative determinations of C3 mRNA. With the help of cloned cDNA and genomic DNA, researchers can address questions concerning the functional topography of the C3 polypeptide, the gene's structure, and the molecular nature of inherited C3 deficiencies in humans.
Topics: Animals; Base Sequence; Chromosome Mapping; Cloning, Molecular; Complement C3; Dexamethasone; Gene Expression Regulation; Genes; Humans; Inflammation; Mice; RNA, Messenger; Tissue Distribution
PubMed: 6356427
DOI: 10.1007/BF00205869 -
Toxins Apr 2016Ochratoxin A (OTA) is a widely-spread mycotoxin all over the world causing major health risks. The focus of the present review is on the molecular and cellular... (Review)
Review
Ochratoxin A (OTA) is a widely-spread mycotoxin all over the world causing major health risks. The focus of the present review is on the molecular and cellular interactions of OTA. In order to get better insight into the mechanism of its toxicity and on the several attempts made for prevention or attenuation of its toxic action, a detailed description is given on chemistry and toxicokinetics of this mycotoxin. The mode of action of OTA is not clearly understood yet, and seems to be very complex. Inhibition of protein synthesis and energy production, induction of oxidative stress, DNA adduct formation, as well as apoptosis/necrosis and cell cycle arrest are possibly involved in its toxic action. Since OTA binds very strongly to human and animal albumin, a major emphasis is done regarding OTA-albumin interaction. Displacement of OTA from albumin by drugs and by natural flavonoids are discussed in detail, hypothesizing their potentially beneficial effect in order to prevent or attenuate the OTA-induced toxic consequences.
Topics: Albumins; Animals; Diet; Food Contamination; Humans; Ochratoxins; Protective Agents
PubMed: 27092524
DOI: 10.3390/toxins8040111 -
Nutrition (Burbank, Los Angeles County,... Oct 2022Heart failure and preserved ejection fraction (HFpEF) in patients is often complicated by abdominal obesity and arteriosclerosis. The aim of this study was to determine...
OBJECTIVES
Heart failure and preserved ejection fraction (HFpEF) in patients is often complicated by abdominal obesity and arteriosclerosis. The aim of this study was to determine the relationship between adipose tissue distribution and arterial stiffness in patients with HFpEF.
METHODS
This was a cross-sectional descriptive study involving 93 patients with HFpEF. Several anthropometric measurements were measured, including height, weight, waist circumference, body fat mass, percent body fat, body fat rate, and visceral fat area (VFA). We calculated body mass index. Arterial stiffness was assessed by measurement of brachial-ankle pulse wave velocity (baPWV). The association between VFA and baPWV was investigated by linear regression analysis.
RESULTS
In univariate analysis, VFA showed strong relations with bilateral baPWV in Spearman correlation analysis (P = 0.003 and P = 0.002, respectively). After adjusting for VFA, age, systolic blood pressure, diastolic blood pressure, and heart rate, VFA and age were significantly and positively associated with bilateral baPWV (P = 0.024 and P = 0.032, respectively). After adjusting for VFA, age, left ventricular posterior wall, and interventricular septal thickness, VFA and age were still significantly correlated with bilateral baPWV (P = 0.028 and P = 0.008, respectively).
CONCLUSIONS
In patients with HFpEF, adipose tissue distribution was correlated with arterial stiffness. VFA was independently associated with baPWV.
Topics: Ankle Brachial Index; Cross-Sectional Studies; Heart Failure; Humans; Pulse Wave Analysis; Risk Factors; Stroke Volume; Tissue Distribution; Vascular Stiffness
PubMed: 35843103
DOI: 10.1016/j.nut.2022.111726 -
Drug Metabolism and Pharmacokinetics 2009Pharmacokinetic-Pharmacodynamic (PK-PD) modeling helps to better understand drug efficacy and safety and has, therefore, become a powerful tool in the... (Review)
Review
Pharmacokinetic-Pharmacodynamic (PK-PD) modeling helps to better understand drug efficacy and safety and has, therefore, become a powerful tool in the learning-confirming cycles of drug-development. In translational drug research, mechanism-based PK-PD modeling has been recognized as a tool for bringing forward early insights in drug efficacy and safety into the clinical development. These models differ from descriptive PK-PD models in that they quantitatively characterize specific processes in the causal chain between drug administration and effect. This includes target site distribution, binding and activation, pharmacodynamic interactions, transduction and homeostatic feedback mechanisms. Compared to descriptive models mechanism-based PK-PD models that utilize receptor theory concepts for characterization of target binding and target activation processes have improved properties for extrapolation and prediction. In this respect, receptor theory constitutes the basis for 1) prediction of in vivo drug concentration-effect relationships and 2) characterization of target association-dissociation kinetics as determinants of hysteresis in the time course of the drug effect. This approach intrinsically distinguishes drug- and system specific parameters explicitly, allowing accurate extrapolation from in vitro to in vivo and across species. This review provides an overview of recent developments in incorporating receptor theory in PK-PD modeling with a specific focus on the identifiability of these models.
Topics: Animals; Drug Design; Drug-Related Side Effects and Adverse Reactions; Humans; Models, Biological; Pharmaceutical Preparations; Pharmacokinetics; Pharmacological Phenomena; Protein Binding; Receptors, Cell Surface
PubMed: 19252332
DOI: 10.2133/dmpk.24.3 -
Journal of the Science of Food and... Aug 2022The health benefits associated with (poly)phenols need to be supported by robust and insightful information on their biological effects. The use of in vitro, ex vivo,... (Review)
Review
The health benefits associated with (poly)phenols need to be supported by robust and insightful information on their biological effects. The use of in vitro, ex vivo, and in vivo models is crucial to demonstrate functionalities in specific targets. In this regard, bioaccessibility, bioavailability, and tissue/organ distribution need to be fully understood and established. In addition, the structure-function relationships, concerning both descriptive and mechanistic information, between specific compounds and therapeutic objectives, need to be supported by results obtained from in vivo studies. Nevertheless, these studies are not always possible or have some limitations, particularly concerning the mechanistic information explaining the health benefits provided that should be covered with complementary experimental models. Based on these premises, this review aims to overview the contribution of the separate experimental approaches to gain insights into the bioaccessibility, bioavailability, and bioactivity of (poly)phenols. To achieve this objective, recent evidence available on the linkage of healthy/functional foods with the incidence of non-communicable pathologies is presented. The different experimental approaches provide complementary information that allows advances to be applied to the knowledge gained on the functional properties and mechanistic facts responsible for the health attributions of polyphenols. © 2022 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
Topics: Biological Availability; Diet; Functional Food; Models, Theoretical; Phenols; Polyphenols
PubMed: 35285937
DOI: 10.1002/jsfa.11865 -
BMC Bioinformatics Feb 2013Drug pharmacokinetics parameters, drug interaction parameters, and pharmacogenetics data have been unevenly collected in different databases and published extensively in...
BACKGROUND
Drug pharmacokinetics parameters, drug interaction parameters, and pharmacogenetics data have been unevenly collected in different databases and published extensively in the literature. Without appropriate pharmacokinetics ontology and a well annotated pharmacokinetics corpus, it will be difficult to develop text mining tools for pharmacokinetics data collection from the literature and pharmacokinetics data integration from multiple databases.
DESCRIPTION
A comprehensive pharmacokinetics ontology was constructed. It can annotate all aspects of in vitro pharmacokinetics experiments and in vivo pharmacokinetics studies. It covers all drug metabolism and transportation enzymes. Using our pharmacokinetics ontology, a PK-corpus was constructed to present four classes of pharmacokinetics abstracts: in vivo pharmacokinetics studies, in vivo pharmacogenetic studies, in vivo drug interaction studies, and in vitro drug interaction studies. A novel hierarchical three level annotation scheme was proposed and implemented to tag key terms, drug interaction sentences, and drug interaction pairs. The utility of the pharmacokinetics ontology was demonstrated by annotating three pharmacokinetics studies; and the utility of the PK-corpus was demonstrated by a drug interaction extraction text mining analysis.
CONCLUSIONS
The pharmacokinetics ontology annotates both in vitro pharmacokinetics experiments and in vivo pharmacokinetics studies. The PK-corpus is a highly valuable resource for the text mining of pharmacokinetics parameters and drug interactions.
Topics: Cytochrome P-450 Enzyme System; Data Mining; Databases, Factual; Drug Interactions; Ketoconazole; Midazolam; Pharmacokinetics; Tamoxifen
PubMed: 23374886
DOI: 10.1186/1471-2105-14-35