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Assessment of Protein Binding of 5-Hydroxythalidomide Bioactivated in Humanized Mice with Human P450 3A-Chromosome or Hepatocytes by Two-Dimensional Electrophoresis/Accelerator Mass Spectrometry.
Yamazaki H, Suemizu H, Kazuki Y, Oofusa K, Kuribayashi S, Shimizu M, Ninomiya S, Horie T, Shibata N, Guengerich FP
(2016) Chem Res Toxicol 29: 1279-81
MeSH Terms: Animals, Cytochrome P-450 Enzyme System, Electrophoresis, Gel, Two-Dimensional, Hepatocytes, Humans, Mass Spectrometry, Mice, Protein Binding, Thalidomide
Show Abstract · Added March 14, 2018
Bioactivation of 5-hydroxy-[carbonyl-(14)C]thalidomide, a known metabolite of thalidomide, by human artificial or native cytochrome P450 3A enzymes, and nonspecific binding in livers of mice was assessed using two-dimensional electrophoresis combined with accelerator mass spectrometry. The apparent major target proteins were liver microsomal cytochrome c oxidase subunit 6B1 and ATP synthase subunit α in mice containing humanized P450 3A genes or transplanted humanized liver. Liver cytosolic retinal dehydrogenase 1 and glutathione transferase A1 were targets in humanized mice with P450 3A and hepatocytes, respectively. 5-Hydroxythalidomide is bioactivated by human P450 3A enzymes and trapped with proteins nonspecifically in humanized mice.
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9 MeSH Terms
Medically Relevant Acinetobacter Species Require a Type II Secretion System and Specific Membrane-Associated Chaperones for the Export of Multiple Substrates and Full Virulence.
Harding CM, Kinsella RL, Palmer LD, Skaar EP, Feldman MF
(2016) PLoS Pathog 12: e1005391
MeSH Terms: Acinetobacter, Acinetobacter Infections, Animals, Electrophoresis, Gel, Two-Dimensional, Electrophoresis, Polyacrylamide Gel, Humans, Mice, Mice, Inbred C57BL, Molecular Chaperones, Type II Secretion Systems, Virulence
Show Abstract · Added February 8, 2016
Acinetobacter baumannii, A. nosocomialis, and A. pittii have recently emerged as opportunistic human pathogens capable of causing severe human disease; however, the molecular mechanisms employed by Acinetobacter to cause disease remain poorly understood. Many pathogenic members of the genus Acinetobacter contain genes predicted to encode proteins required for the biogenesis of a type II secretion system (T2SS), which have been shown to mediate virulence in many Gram-negative organisms. Here we demonstrate that Acinetobacter nosocomialis strain M2 produces a functional T2SS, which is required for full virulence in both the Galleria mellonella and murine pulmonary infection models. Importantly, this is the first bona fide secretion system shown to be required for virulence in Acinetobacter. Using bioinformatics, proteomics, and mutational analyses, we show that Acinetobacter employs its T2SS to export multiple substrates, including the lipases LipA and LipH as well as the protease CpaA. Furthermore, the Acinetobacter T2SS, which is found scattered amongst five distinct loci, does not contain a dedicated pseudopilin peptidase, but instead relies on the type IV prepilin peptidase, reinforcing the common ancestry of these two systems. Lastly, two of the three secreted proteins characterized in this study require specific chaperones for secretion. These chaperones contain an N-terminal transmembrane domain, are encoded adjacently to their cognate effector, and their disruption abolishes type II secretion of their cognate effector. Bioinformatic analysis identified putative chaperones located adjacent to multiple previously known type II effectors from several Gram-negative bacteria, which suggests that T2SS chaperones constitute a separate class of membrane-associated chaperones mediating type II secretion.
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11 MeSH Terms
Comparative Proteome Profiling during Cardiac Hypertrophy and Myocardial Infarction Reveals Altered Glucose Oxidation by Differential Activation of Pyruvate Dehydrogenase E1 Component Subunit β.
Mitra A, Basak T, Ahmad S, Datta K, Datta R, Sengupta S, Sarkar S
(2015) J Mol Biol 427: 2104-20
MeSH Terms: Adenosine Triphosphate, Animals, Cardiomegaly, Case-Control Studies, Disease Models, Animal, Electrophoresis, Gel, Two-Dimensional, Energy Metabolism, Enzyme Activation, Glucose, Male, Myocardial Infarction, Oxidation-Reduction, Phosphorylation, Protein-Serine-Threonine Kinases, Proteomics, Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase, Pyruvate Dehydrogenase (Lipoamide), Rats, Wistar, Reproducibility of Results, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Show Abstract · Added November 3, 2017
Cardiac hypertrophy and myocardial infarction (MI) are two etiologically different disease forms with varied pathological characteristics. However, the precise molecular mechanisms and specific causal proteins associated with these diseases are obscure to date. In this study, a comparative cardiac proteome profiling was performed in Wistar rat models for diseased and control (sham) groups using two-dimensional difference gel electrophoresis followed by matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry. Proteins were identified using Protein Pilot™ software (version 4.0) and were subjected to stringent statistical analysis. Alteration of key proteins was validated by Western blot analysis. The differentially expressed protein sets identified in this study were associated with different functional groups, involving various metabolic pathways, stress responses, cytoskeletal organization, apoptotic signaling and other miscellaneous functions. It was further deciphered that altered energy metabolism during hypertrophy in comparison to MI may be predominantly attributed to induced glucose oxidation level, via reduced phosphorylation of pyruvate dehydrogenase E1 component subunit β (PDHE1-B) protein during hypertrophy. This study reports for the first time the global changes in rat cardiac proteome during two etiologically different cardiac diseases and identifies key signaling regulators modulating ontogeny of these two diseases culminating in heart failure. This study also pointed toward differential activation of PDHE1-B that accounts for upregulation of glucose oxidation during hypertrophy. Downstream analysis of altered proteome and the associated modulators would enhance our present knowledge regarding altered pathophysiology of these two etiologically different cardiac disease forms.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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20 MeSH Terms
Discovery of new membrane-associated proteins overexpressed in small-cell lung cancer.
Ocak S, Friedman DB, Chen H, Ausborn JA, Hassanein M, Detry B, Weynand B, Aboubakar F, Pilette C, Sibille Y, Massion PP
(2014) J Thorac Oncol 9: 324-36
MeSH Terms: Adenocarcinoma, Aged, Biomarkers, Tumor, Blotting, Western, Bronchi, Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Cells, Cultured, Electrophoresis, Gel, Two-Dimensional, Female, Humans, Immunoenzyme Techniques, Lung Neoplasms, Male, Membrane Proteins, Middle Aged, Neoplasm Staging, Prognosis, Small Cell Lung Carcinoma, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Survival Rate
Show Abstract · Added March 10, 2014
INTRODUCTION - Small-cell lung cancer (SCLC) is the most aggressive subtype of lung cancer, with no early detection strategy or targeted therapy currently available. We hypothesized that difference gel electrophoresis (DIGE) may identify membrane-associated proteins (MAPs) specific to SCLC, advance our understanding of SCLC biology, and discover new biomarkers of SCLC.
METHODS - MAP lysates were prepared from three SCLCs, three non-small-cell lung cancers, and three immortalized normal bronchial epithelial cell lines and coanalyzed by DIGE. Subsequent protein identification was performed by mass spectrometry. Proteins were submitted to Ingenuity Pathway Analysis. Candidate biomarkers were validated by Western blotting (WB) and immunohistochemistry (IHC).
RESULTS - Principal component analysis on the global DIGE data set demonstrated that the four replicates derived from each of the nine cell lines clustered closely, as did samples within the same histological group. One hundred thirty-seven proteins were differentially expressed in SCLC compared with non-small-cell lung cancer and immortalized normal bronchial epithelial cells. These proteins were overrepresented in cellular/tissue morphology networks. Dihydropyrimidinase-related protein 2, guanine nucleotide-binding protein alpha-q, laminin receptor 1, pontin, and stathmin 1 were selected as candidate biomarkers among MAPs overexpressed in SCLC. Overexpression of all candidates but RSSA in SCLC was verified by WB and/or IHC on tissue microarrays. These proteins were significantly associated with SCLC histology and survival in univariables analyses.
CONCLUSION - DIGE analysis of a membrane-associated subproteome discovered overexpression of dihydropyrimidinase-related protein 2, guanine nucleotide-binding protein alpha-q, RUVB1, and stathmin 1 in SCLC. Results were verified by WB and/or IHC in primary tumors, suggesting that investigating their functional relevance in SCLC progression is warranted. Association with survival requires further validation in larger clinical data sets.
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21 MeSH Terms
Quantitative proteomic analysis of Niemann-Pick disease, type C1 cerebellum identifies protein biomarkers and provides pathological insight.
Cologna SM, Jiang XS, Backlund PS, Cluzeau CV, Dail MK, Yanjanin NM, Siebel S, Toth CL, Jun HS, Wassif CA, Yergey AL, Porter FD
(2012) PLoS One 7: e47845
MeSH Terms: Alzheimer Disease, Animals, Biomarkers, Blotting, Western, Cerebellum, Child, Electrophoresis, Gel, Two-Dimensional, Female, Gene Expression Profiling, Humans, Intracellular Signaling Peptides and Proteins, Mass Spectrometry, Mice, Mice, Inbred BALB C, Mice, Knockout, Middle Aged, Niemann-Pick Disease, Type C, Oligonucleotide Array Sequence Analysis, Prefrontal Cortex, Proteins, Proteome, Proteomics, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added March 13, 2014
Niemann-Pick disease, type C1 (NPC1) is a fatal, neurodegenerative disorder for which there is no definitive therapy. In NPC1, a pathological cascade including neuroinflammation, oxidative stress and neuronal apoptosis likely contribute to the clinical phenotype. While the genetic cause of NPC1 is known, we sought to gain a further understanding into the pathophysiology by identifying differentially expressed proteins in Npc1 mutant mouse cerebella. Using two-dimensional gel electrophoresis and mass spectrometry, 77 differentially expressed proteins were identified in Npc1 mutant mice cerebella compared to controls. These include proteins involved in glucose metabolism, detoxification/oxidative stress and Alzheimer disease-related proteins. Furthermore, members of the fatty acid binding protein family, including FABP3, FABP5 and FABP7, were found to have altered expression in the Npc1 mutant cerebellum relative to control. Translating our findings from the murine model to patients, we confirm altered expression of glutathione s-transferase α, superoxide dismutase, and FABP3 in cerebrospinal fluid of NPC1 patients relative to pediatric controls. A subset of NPC1 patients on miglustat, a glycosphingolipid synthesis inhibitor, showed significantly decreased levels of FABP3 compared to patients not on miglustat therapy. This study provides an initial report of dysregulated proteins in NPC1 which will assist with further investigation of NPC1 pathology and facilitate implementation of therapeutic trials.
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23 MeSH Terms
Changes in the striatal proteome of YAC128Q mice exhibit gene-environment interactions between mutant huntingtin and manganese.
Wegrzynowicz M, Holt HK, Friedman DB, Bowman AB
(2012) J Proteome Res 11: 1118-32
MeSH Terms: Analysis of Variance, Animals, Blotting, Western, Electrophoresis, Gel, Two-Dimensional, Gene-Environment Interaction, Huntingtin Protein, Male, Manganese, Mice, Mice, Transgenic, Neostriatum, Nerve Tissue Proteins, Nuclear Proteins, Principal Component Analysis, Proteome, Proteomics
Show Abstract · Added May 19, 2014
Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of a CAG repeat within the Huntingtin (HTT) gene, though the clinical presentation of disease and age-of-onset are strongly influenced by ill-defined environmental factors. We recently reported a gene-environment interaction wherein expression of mutant HTT is associated with neuroprotection against manganese (Mn) toxicity. Here, we are testing the hypothesis that this interaction may be manifested by altered protein expression patterns in striatum, a primary target of both neurodegeneration in HD and neurotoxicity of Mn. To this end, we compared striatal proteomes of wild-type and HD (YAC128Q) mice exposed to vehicle or Mn. Principal component analysis of proteomic data revealed that Mn exposure disrupted a segregation of WT versus mutant proteomes by the major principal component observed in vehicle-exposed mice. Identification of altered proteins revealed novel markers of Mn toxicity, particularly proteins involved in glycolysis, excitotoxicity, and cytoskeletal dynamics. In addition, YAC128Q-dependent changes suggest that axonal pathology may be an early feature in HD pathogenesis. Finally, for several proteins, genotype-specific responses to Mn were observed. These differences include increased sensitivity to exposure in YAC128Q mice (UBQLN1) and amelioration of some mutant HTT-induced alterations (SAE1, ENO1). We conclude that the interaction of Mn and mutant HTT may suppress proteomic phenotypes of YAC128Q mice, which could reveal potential targets in novel treatment strategies for HD.
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16 MeSH Terms
HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events.
Rosenson RS, Brewer HB, Chapman MJ, Fazio S, Hussain MM, Kontush A, Krauss RM, Otvos JD, Remaley AT, Schaefer EJ
(2011) Clin Chem 57: 392-410
MeSH Terms: Apolipoprotein A-I, Apolipoprotein A-II, Apolipoproteins B, Atherosclerosis, Blood Chemical Analysis, Cardiovascular Diseases, Centrifugation, Density Gradient, Electrophoresis, Gel, Two-Dimensional, Humans, Immunoblotting, Lipoproteins, HDL, Magnetic Resonance Spectroscopy, Predictive Value of Tests, Risk Factors, Sensitivity and Specificity, Terminology as Topic
Show Abstract · Added December 10, 2013
BACKGROUND - A growing body of evidence from epidemiological data, animal studies, and clinical trials supports HDL as the next target to reduce residual cardiovascular risk in statin-treated, high-risk patients. For more than 3 decades, HDL cholesterol has been employed as the principal clinical measure of HDL and cardiovascular risk associated with low HDL-cholesterol concentrations. The physicochemical and functional heterogeneity of HDL present important challenges to investigators in the cardiovascular field who are seeking to identify more effective laboratory and clinical methods to develop a measurement method to quantify HDL that has predictive value in assessing cardiovascular risk.
CONTENT - In this report, we critically evaluate the diverse physical and chemical methods that have been employed to characterize plasma HDL. To facilitate future characterization of HDL subfractions, we propose the development of a new nomenclature based on physical properties for the subfractions of HDL that includes very large HDL particles (VL-HDL), large HDL particles (L-HDL), medium HDL particles (M-HDL), small HDL particles (S-HDL), and very-small HDL particles (VS-HDL). This nomenclature also includes an entry for the pre-β-1 HDL subclass that participates in macrophage cholesterol efflux.
SUMMARY - We anticipate that adoption of a uniform nomenclature system for HDL subfractions that integrates terminology from several methods will enhance our ability not only to compare findings with different approaches for HDL fractionation, but also to assess the clinical effects of different agents that modulate HDL particle structure, metabolism, and function, and in turn, cardiovascular risk prediction within these HDL subfractions.
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16 MeSH Terms
Deciphering the iron response in Acinetobacter baumannii: A proteomics approach.
Nwugo CC, Gaddy JA, Zimbler DL, Actis LA
(2011) J Proteomics 74: 44-58
MeSH Terms: Acinetobacter baumannii, Bacterial Outer Membrane Proteins, Cells, Cultured, Electrophoresis, Gel, Two-Dimensional, Iron, Iron Chelating Agents, Mass Spectrometry, Proteomics, RNA, Small Interfering
Show Abstract · Added January 13, 2014
Iron is an essential nutrient that plays a role in bacterial differential gene expression and protein production. Accordingly, the comparative analysis of total lysate and outer membrane fractions isolated from A. baumannii ATCC 19606(T) cells cultured under iron-rich and -chelated conditions using 2-D gel electrophoresis-mass spectrometry resulted in the identification of 58 protein spots differentially produced. While 19 and 35 of them represent iron-repressed and iron-induced protein spots, respectively, four other spots represent a metal chelation response unrelated to iron. Most of the iron-repressed protein spots represent outer membrane siderophore receptors, some of which could be involved in the utilization of siderophores produced by other bacteria. The iron-induced protein spots represent a wide range of proteins including those involved in iron storage, such as Bfr, metabolic and energy processes, such as AcnA, AcnB, GlyA, SdhA, and SodB, as well as lipid biosynthesis. The detection of an iron-regulated Hfq ortholog indicates that iron regulation in this bacterium could be mediated by Fur and small RNAs as described in other bacteria. The iron-induced production of OmpA suggests this protein plays a role in iron metabolism as shown by the diminished ability of an isogenic OmpA deficient derivative to grow under iron-chelated conditions.
Copyright © 2010 Elsevier B.V. All rights reserved.
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9 MeSH Terms
Proteomic analysis of osteogenic sarcoma: association of tumour necrosis factor with poor prognosis.
Cates JM, Friedman DB, Seeley EH, Dupont WD, Schwartz HS, Holt GE, Caprioli RM, Young PP
(2010) Int J Exp Pathol 91: 335-49
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Animals, Biomarkers, Tumor, Blotting, Western, Bone Neoplasms, Cell Line, Tumor, Child, Child, Preschool, Electrophoresis, Gel, Two-Dimensional, Female, Humans, Immunohistochemistry, Intramolecular Oxidoreductases, Kaplan-Meier Estimate, Macrophage Migration-Inhibitory Factors, Male, Mice, Middle Aged, Neoplasm Staging, Osteosarcoma, Proportional Hazards Models, Proteomics, Risk Assessment, Risk Factors, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Time Factors, Tissue Array Analysis, Treatment Outcome, Tumor Necrosis Factor-alpha, Young Adult
Show Abstract · Added March 15, 2013
A significant proportion of patients with osteogenic sarcoma die from lung metastasis within 5 years of diagnosis. Molecular signatures that predict pulmonary metastasis from primary osteogenic sarcoma and identify those patients at risk would be clinically useful as prognostic markers. Protein expression profiles of two clonally related murine osteogenic sarcoma cell lines with low (K12) and high (K7M2) metastatic potential were compared using two different proteomic technologies, two-dimensional difference gel electrophoresis and cell profiling by matrix-assisted laser desorption/ionization mass spectrometry. Interrogation of a molecular pathways network database suggested several additional candidate molecules that potentially predict metastatic potential of primary osteogenic sarcoma. Two such proteins, macrophage migration inhibitory factor and tumour necrosis factor were selected for further validation studies. Western blots confirmed increased expression of both cytokines in K7M2 cells compared to K12 cells. Levels of migration inhibitory factor and tumour necrosis factor were semi-quantitatively measured in human osteogenic sarcoma samples by immunohistochemistry and were correlated with clinicopathologic parameters and patient outcomes. Multivariate survival analysis demonstrated that tumour necrosis factor expression in chemotherapy naïve osteogenic sarcoma is an independent prognostic factor for overall and metastasis-free survival. No significant differences in adverse outcomes were observed based on macrophage migration inhibitory factor expression.
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33 MeSH Terms
Staphylococcus aureus fur regulates the expression of virulence factors that contribute to the pathogenesis of pneumonia.
Torres VJ, Attia AS, Mason WJ, Hood MI, Corbin BD, Beasley FC, Anderson KL, Stauff DL, McDonald WH, Zimmerman LJ, Friedman DB, Heinrichs DE, Dunman PM, Skaar EP
(2010) Infect Immun 78: 1618-28
MeSH Terms: Animals, Bacterial Proteins, Chromatography, Liquid, Disease Models, Animal, Electrophoresis, Gel, Two-Dimensional, Female, Gene Expression Profiling, Gene Expression Regulation, Bacterial, Gene Knockout Techniques, Mass Spectrometry, Mice, Mice, Inbred C57BL, Pneumonia, Staphylococcal, Proteome, Repressor Proteins, Staphylococcus aureus, Virulence Factors
Show Abstract · Added March 20, 2014
The tremendous success of Staphylococcus aureus as a pathogen is due to the controlled expression of a diverse array of virulence factors. The effects of host environments on the expression of virulence factors and the mechanisms by which S. aureus adapts to colonize distinct host tissues are largely unknown. Vertebrates have evolved to sequester nutrient iron from invading bacteria, and iron availability is a signal that alerts pathogenic microorganisms when they enter the hostile host environment. Consistent with this, we report here that S. aureus senses alterations in the iron status via the ferric uptake regulator (Fur) and alters the abundance of a large number of virulence factors. These Fur-mediated changes protect S. aureus against killing by neutrophils, and Fur is required for full staphylococcal virulence in a murine model of infection. A potential mechanistic explanation for the impact of Fur on virulence is provided by the observation that Fur coordinates the reciprocal expression of cytolysins and a subset of immunomodulatory proteins. More specifically, S. aureus lacking fur exhibits decreased expression of immunomodulatory proteins and increased expression of cytolysins. These findings reveal that Fur is involved in initiating a regulatory program that organizes the expression of virulence factors during the pathogenesis of S. aureus pneumonia.
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17 MeSH Terms