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PubMed1999

The characterization of macrophages and osteoclasts in tissues harvested from revised total hip prostheses.

The differentiation and maturation of macrophages and osteoclasts at the prosthetic interface in cases of implant loosening are poorly understood. Using histochemical and immunohistochemical staining methods, we compare macrophage differentiation in tissues from revised hip replacements in patients with specific clinical-radiological appearances. Periprosthetic tissues were harvested from 12 cemented acetabular and 12 cemented femoral components in 24 patients undergoing revision hip replacement. The prostheses were all radiographically and clinically loose. Six acetabular and six femoral components demonstrated radiographic ballooning osteolysis. Serial 6 microm frozen sections of the periprosthetic tissues were processed with hematoxylin and eosin for general tissue morphology, and analyzed for the presence of tartrate resistant acid phosphatase (TRAP, an osteoclast marker). Immunoperoxidase staining using monoclonal antibodies to CD68 (macrophages and osteoclasts) and CD51 (the alpha chain of the vitronectin receptor, an osteoclast marker) was also performed. Approximately 8-30% of the total cells in the tissues were positive for TRAP and the vitronectin receptor, and comprised a subset of the CD68 positive macrophages and macrophage polykaryons. However, there were no statistically significant differences between specific groups (femoral vs. acetabular, osteolysis vs. no osteolysis) for the numbers or percentages of macrophages or osteoclast-like cells. Once prosthetic loosening has occurred, few differences in the macrophage-osteoclast profile of tissues from different periprosthetic locations, with and without osteolysis, are noted. This suggests a final common biologic pathway for periprosthetic bone resorption, once implant loosening has transpired.

Acid Phosphatase↗

PubMed2026

Comprehensive Analysis of miRNAs and Predicted Protein Interaction Networks in Skeletal Muscle Development of Myostatin-Deficient Rabbits.

Myostatin (MSTN), encoded by the MSTN gene, is a critical negative regulator of skeletal muscle mass. This study aims to identify and characterize the miRNAs involved in the development of the double-muscling phenotype in MSTN-deficient rabbits. We performed high-throughput sequencing to analyze the miRNA expression profiles in gluteus maximus tissue from wild type (MSTN+/+) and MSTN-KO (MSTN+/- and MSTN-/- inclusive) rabbits. Differentially expressed miRNAs (DEmiRNAs) were identified, and their potential target genes were predicted. Functional enrichment analysis of these target mRNAs was conducted using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database to elucidate the involved biological pathways and regulatory networks. A total of 25 DEmiRNAs (13 downregulated and 12 upregulated, |log2FC| ≥ 1.0, adjusted p < 0.05) and 1178 differentially expressed mRNAs (408 upregulated and 770 downregulated, |log2FC| ≥ 2.0, adjusted p < 0.05) were identified in MSTN-KO compared to MSTN+/+ rabbits. Bioinformatics analysis revealed that the target genes of these DEmiRNAs were significantly enriched in key pathways governing muscle growth and metabolism, including the PI3K-Akt signaling pathway, MAPK signaling pathway, and pathways related to ECM-receptor interaction and insulin signaling. Notably, many predicted target mRNAs are expressed by genes that encode key inhibitors of myogenesis (e.g., HDAC4) and major extracellular matrix components (e.g., COL4A3, POSTN). Our results demonstrate that MSTN deficiency induces a distinct and widespread change in the miRNA expression landscape of skeletal muscle.

Animals↗

PubMed2006

The involvement of ErbB4 with schizophrenia: association and expression studies.

Neuregulin 1 (NRG1) has been found to be associated with schizophrenia in several populations. Consistently, mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. These observations raised the hypothesis that impaired NRG1-ErbB4 signaling may contribute to schizophrenia susceptibility. Nineteen SNPs encompassing the ErbB4 gene were selected from the HapMap database and genotyped in genomic DNA isolated from 59 Ashkenazi schizophrenia patients and 130 matched controls. Expression analysis of ErbB4 splice variants was performed on postmortem DLPFC samples obtained from Caucasian patients and controls by real-time PCR. We found a highly significant difference between patient and control groups in three SNPs from one linkage disequilibrium (LD) block both in allele (P = 0.013, 0.0045, 0.0049) and genotype frequencies (P = 0.00013, 0.000021, 0.00018), as well as a risk haplotype (P = 0.00044). Expression analysis indicated that the CYT-1 isoform is overexpressed in patients (P = 0.047) and that juxtamembrane (JM)-a displays a similar trend (P = 0.081). This study provides a direct link between ErbB4 and the disease. We propose that NRG1 and its receptor ErbB4 are components of a biological pathway, involved in the pathophysiology of schizophrenia.

Adolescent↗

PubMed2026

Assessment of Genetic Correlations Between Tobacco or Alcohol Use and Neurodegenerative Diseases Using East Asian Genetic Ancestry Genome-Wide Association Study Results.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent late-onset neurodegenerative diseases worldwide. Both are influenced in part by genetic factors and are currently incurable. Tobacco and alcohol, the two most common substances used among the general adult population, are potential AD/PD risk factors and are also heritable. Although important progress has been made, most existing research on the genetics of AD and PD has been carried out in individuals of European genetic ancestry. Investigations in a broad range of groups are crucial to understand disease mechanisms. Given the current availability of ancestry-specific tobacco and alcohol use as well as AD and PD genome-wide association study summary statistics, we performed global and local genetic correlation analyses using East Asian datasets. Genes within the correlated genetic regions were subsequently used to identify potentially enriched biological pathways between substance use and neurodegenerative diseases. We identified a global genetic correlation between smoking cessation and PD, which we confirmed in complementary European genetic ancestry data. Gene set enrichment analyses highlighted potentially shared genetic mechanisms between breast cancer and AD, which warrants further exploration. This work aims to promote further analyses across genetic ancestry groups.

Female↗

PubMed1994

Using inhibitors of metalloproteinases to treat arthritis. Easier said than done?

Collagenase and stromelysin have a premier role in the irreversible degradation of the extracellular matrix seen in rheumatic disease. It is therefore no surprise that considerable attention has been devoted to developing strategies to reduce their levels in diseased joints. Most efforts have focused on inhibiting the activity of the enzymes, either by increasing the concentration of natural inhibitors such as the TIMPs or by introducing into the joint synthetic compounds that will complex with the enzymes and inactivate them. There have also been studies directed at inhibiting enzyme synthesis. These preclinical studies have been carried out in cell-free and/or cell culture systems and in animal models. Despite promising preclinical data, there have been no stunning successes in the clinical arena. The reasons for this are several. In part, they are rooted in the technical difficulties associated with designing inhibitors of enzyme activity that are of high affinity, and then delivering them to the affected joints while still maintaining specificity and efficacy. The complicated structure of the proteoglycan and collagen that comprise articular cartilage, along with the biochemistry of inflamed synovial tissue, only compound the difficulties. In addition to these technical problems, the lack of fundamental knowledge about the biochemistry and molecular biology of the enzymes has handicapped our efforts. We are just resolving the crystal structure of the metalloproteinases (108) and beginning to understand the mechanisms controlling gene expression (67, 68, 70-72). These advances represent significant achievements in metalloproteinase enzymology and biology and should form the scientific basis for a new generation of effective therapies. For example, knowledge of the active site as derived from the crystal structure of the enzymes may facilitate the development of tightly-binding specific inhibitors which function well in vivo. Similarly, based on our current understanding of mechanisms controlling the regulation of both the TIMP genes and the MMP genes, we are beginning to elucidate how to turn these genes on or off, and hopefully, to modulate disease accordingly. Indeed, although some studies are still at a preclinical level, these possible approaches are becoming a reality (109). Arthritic diseases in general, and rheumatoid arthritis in particular, represent a complicated multifaceted set of clinical disorders. The clinical symptoms and pathologic features result from a cascade of biologic pathways that involve acute and chronic inflammation, the immune response, and metalloproteinase biochemistry.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2004

Work above shoulder level and degenerative alterations of the rotator cuff tendons: a magnetic resonance imaging study.

OBJECTIVE: To determine whether work performed with the arms in a highly elevated position is associated with alterations in the rotator cuff tendons as assessed by magnetic resonance imaging (MRI). METHODS: A cross-sectional study was performed in a historical cohort of male machinists, car mechanics, and house painters. The participants were right-handed, ages 40-50 years, and had been employed in their trades for not less than 10 years. Seventy-one percent of invited subjects participated (136 of 192). Lifetime upper arm elevation was assessed by direct measurements combined with individual work histories obtained by questionnaire and from registry data. Supraspinatus tendinopathy was evidenced by MRI signal intensity changes and morphologic alterations. Infraspinatus and subscapularis tendinopathy were also assessed. Additional outcomes were acromioclavicular joint degeneration and humeral head cysts. The MRI findings were evaluated by radiologists who were blinded to exposure status and symptoms. RESULTS: An exposure-response relationship was found between lifetime upper arm elevation and supraspinatus tendinopathy, with an age-adjusted odds ratio of 1.27 (95% confidence interval 1.02-1.60) for a 5-month increase in the total number of full-time working months spent with the arm elevated >90 degrees . CONCLUSION: Work with the arms in a highly elevated position is associated with MRI-diagnosed alterations in the supraspinatus tendon. By demonstrating the first part of a possible biologic pathway, the study corroborates the work-relatedness of rotator cuff disorders.

Adult↗

PubMed2005

Interaction of pyrin with 14.3.3 in an isoform-specific and phosphorylation-dependent manner regulates its translocation to the nucleus.

OBJECTIVE: Pyrin, the familial Mediterranean fever gene product, exists in several isoforms of unknown functions. The recombinant full-length isoform (pyrin.fl) is cytoplasmic, whereas an alternatively spliced isoform lacking exon 2 (pyrin.DeltaEx2) concentrates in the nucleus. Native pyrin, mainly consisting of pyrin.fl, is also cytoplasmic in monocytes but is predominantly nuclear in other cell types. To understand pyrin-dependent biologic pathways and to decipher the mechanisms accounting for such different patterns of subcellular compartmentalization, binding partners and posttranslational modifications of pyrin were assessed. METHODS: A yeast 2-hybrid screen was performed with pyrin.fl as the bait. The interaction identified between pyrin.fl and 14.3.3 proteins was confirmed by immunoprecipitation of (35)S-radiolabeled protein complexes; similar experiments were performed with pyrin.DeltaEx2, pyrin.fl after alkaline phosphatase treatment, and pyrin.fl mutants in which several exon 2-encoded serine residues were replaced by nonphosphorylatable alanines. The subcellular localization of the different wild-type and mutated pyrin proteins was assessed by immunofluorescence. RESULTS: Two members of the 14.3.3 protein family were identified as pyrin partners. Whereas pyrin.fl interacted with 14.3.3tau and 14.3.3epsilon, these interactions did not occur with pyrin.DeltaEx2. Pyrin.fl was phosphorylated, and this modification mediated 14.3.3 binding. Serines 208, 209, and 242, within exon 2, acted as critical residues in the interaction between pyrin.fl and 14.3.3. When an S208-S209-S242A pyrin.fl triple mutant or wild-type pyrin.fl in the presence of an inhibitor of 14.3.3-ligand interactions was used, promotion of nuclear translocation of pyrin was observed. CONCLUSION: These results disclose the role played by 14.3.3 in the regulation of the subcellular compartmentalization of pyrin in a phosphorylation- and isoform-dependent manner. They also reconcile the observations made in vitro with those made in vivo, while providing a direct link between 14.3.3-dependent pathways and pyrin.

Cell Nucleus↗

PubMed2006

The compound 13-D selectively induces apoptosis in white blood cancers versus other cancer cell types.

As general cytotoxins are still the backbone of anticancer chemotherapy, the identification of selective inducers of cell death in defined cancer types and subtypes is one of the major goals of modern oncology research. Thus, compounds identified with such selectivity have utility as probes of cancer-type-specific biological pathways, and optimized versions have potential in targeted anticancer therapy. Described herein is the discovery that compound 13-D selectively induces apoptotic cell death in white blood cancer cell lines but not in other cancer cell lines. Further experiments indicate that this selectivity is not simply due to selective cell permeability. The compound localizes to both the nucleus and cytoplasm and arrests cells in the prophase/prometaphase of the cell cycle, and there is a very sharp dependence of activity on compound structure, with the trans-alpha,beta-unsaturated amide of 13-D being critical for inducing cell death. The macromolecular target of 13-D could be involved in white blood cell-specific oncogenic pathways.

Antineoplastic Agents↗

PubMed2006

1,3,5-Triazepane-2,6-diones as structurally diverse and conformationally constrained dipeptide mimetics: identification of malaria liver stage inhibitors from a small pilot library.

The development of the 1,3,5-triazepane-2,6-dione system as a novel, conformationally restricted, and readily accessible class of dipeptidomimetics is reported. The synthesis of the densely functionalized 1,3,5-triazepane-2,6-dione skeleton was achieved in only four steps from a variety of simple linear dipeptide precursors. To extend the practical value of 1,3,5-triazepane-2,6-diones, a general polymer-assisted solution-phase synthesis approach amenable to library production in a multiparallel format was developed. The conformational preferences of the 1,3,5-triazepane-2,6-dione skeleton were investigated in detail by NMR spectroscopy and X-ray diffraction. The ring exhibits a characteristic folded conformation which was compared to that of related dipeptide-derived scaffolds including the more planar 2,5-diketopiperazine (DKP). Molecular and structural diversity was increased further through post-cyclization appending operations at urea nitrogens. Preliminary biological screens of a small collection of 1,3,5-triazepane-2,6-diones revealed inhibitors of the underexplored malaria liver stage and suggest strong potential for this dipeptide-derived scaffold to interfere with and to modulate biological pathways.

Combinatorial Chemistry Techniques↗

PubMed2004

Regio- and diastereocontrolled preparative oxidation of methyloctalones by a biomimetic porphyrin catalyst.

Both enantiomers of methyloctalone were oxidized by a biomimetic manganese/porphyrin/imidazole catalytic system in order to obtain sufficient amounts of various model metabolites. The double bond proved to be less sensitive than the ring methylenes. Hydroxylation occurred mainly in the allylic position (position 8) and also at positions 7 and 6. In position 8, two diastereomers were obtained while in positions 7 and 6 the reaction was diastereospecific. In the case of position 8 only the oxidation yielded a keto compound. The efficiency of this method for the preparation of functionalized chiral synthons was better than it was for biological pathways.

Biomimetics↗

PubMed2003

The mitochondrial proteins of the neuroblastoma cell line IMR-32.

Mitochondrial proteins exert important functions in biological pathways, particularly they are involved in apoptotic processes. We applied proteomics technologies to analyze the mitochondrial proteins of the neuroblastoma cell line IMR-32, which is often used in apoptosis studies. The proteins were analyzed by two-dimensional (2-D) electrophoresis followed by matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS). 185 different gene products were identified, of which approximately 55% were enzymes with a broad spectrum of catalytic activities. Sixteen proteins were detected only in this preparation, the others have been detected in two or more protein samples analyzed by MS in our laboratory. The 16 unique gene products were represented by one spot each, whereas most of the frequently detected proteins were represented by multiple spots. In average, approximately 5-10 spots corresponded to one gene product. For two thirds of the proteins identified, an annotation exists in the SWISS-PROT database about their subcellular location. They are mainly described as mitochondrial, 8 as endoplasmic reticulum, 3 as peroxisomal and only 12 low-abundance proteins are described as cytosolic proteins. The list includes about 30 unknown, hypothetical or poorly described gene products. Some of them are represented by strong spots and the present study shows that they are indeed expressed and are localized in the mitochondria.

Apoptosis↗

PubMed2004

Comparison of gene expression changes induced in mouse and human cells treated with direct-acting mutagens.

Exposure to DNA-damaging agents can elicit a variety of stress-related responses that may alter the gene expression of numerous biological pathways. We used Affymetrix microarrays to detect gene expression changes in mouse lymphoma (L5178Y) and human lymphoblastoid (TK6) cells in response to methyl methanesulfonate (MMS; a prototypical alkylating agent) and bleomycin (a prototypical oxidative mutagen). Cells were treated for 4 hr, and RNA was isolated either at the end of the treatment or after a 20-hr recovery period. Two concentrations of each agent were used based on cytotoxicity levels and Tk mutant frequencies. Our microarray data analysis indicated that MMS and bleomycin gene expression responses were considerably different in mouse cells versus human cells. The results also suggested that more comprehensive cellular responses to MMS and bleomycin occurred in TK6 cells than in L5178Y cells. In contrast to L5178Y cells, the response of TK6 cells to MMS and bleomycin was characterized by the induction of p53-dependent genes that are involved in DNA repair, cell cycle regulation, and apoptosis. It appears that the induction of DNA damage by MMS in human TK6 cells mediated cytotoxicity and led to decreased cell survival. This may explain the greater sensitivity of TK6 cells to cytotoxic effects of MMS compared to L5178Y cells. Bleomycin exerted comparable cytotoxic effects in the two cell lines. Overall, these studies were unable to identify distinctive gene expression changes that differentiated bleomycin from MMS in either TK6 cells or mouse lymphoma cells.

Alkylating Agents↗

PubMed2007

Ala394Thr polymorphism in the clock gene NPAS2: a circadian modifier for the risk of non-Hodgkin's lymphoma.

Circadian disruption is theorized to cause immune dysregulation, which is the only established risk factor for non-Hodgkin's lymphoma (NHL). Genes responsible for circadian rhythm are also involved in cancer-related biological pathways as potential tumor suppressors. However, no previous studies have examined associations between circadian genes and NHL risk. In this population-based case control study (n = 455 cases; 527 controls), we examined the only identified nonsynonymous polymorphism (Ala394Thr; rs2305160) in the largest circadian gene, neuronal PAS domain protein 2 (NPAS2), in order to examine its impact on NHL risk. Our results demonstrate a robust association of the variant Thr genotypes (Ala/Thr and Thr/Thr) with reduced risk of NHL (OR = 0.66, 95% CI: 0.51-0.85, p = 0.001), especially B-cell lymphoma (OR = 0.61, 95% CI: 0.47-0.80, p <or= 0.0001). These findings provide the first molecular epidemiologic evidence supporting a role of circadian genes in lymphomagenesis, which suggests that genetic variations in circadian genes might be a novel panel of promising biomarkers for NHL and warrants further investigation.

Aged↗

PubMed2003

The yeast two-hybrid system for identifying protein-protein interactions.

The yeast two-hybrid assay is a system for identifying and analysing protein-protein interactions. Since the original description in 1989, the technique has provided insight into many biological pathways. A variety of adaptations to the technique have been developed that allow analysis of protein-DNA, protein-RNA, or small molecule-protein interactions. Recent developments now allow the use of these technologies to perform global analyses of all such interactions that occur in cells. The information gained from these approaches is uncovering many aspects of the complex networks that underlie normal cellular processes and how they are perturbed in disease states.

Animals↗

PubMed2007

The future of pediatric cancer and complex diseases: aren't they all?

Over the past decade, the investigation of human genetics and disease has pursued both common and uncommon germ-line variation and shown that both can be associated with altered risk for cancer and its outcomes. This line of investigation has not only begun to generate markers for disease but also insights into the biological pathways that are altered in cancer. Already, there is emerging evidence that germ-line genetic variation can alter susceptibility to different types of cancers, including pediatric cancers. It is evident that common genetic variation has emerged as a key component of a comprehensive understanding of pediatric cancer and its outcome. Future studies should unravel the complex interaction between genes and the environment.

Child↗

PubMed2003

Proteomic study of human umbilical vein endothelial cells in culture.

The endothelium is a single layer of cells lining the inside face of all blood vessels. It constitutes a major metabolic organ which is critically involved in the generation and the regulation of multiple physiological and pathological processes such as coagulation, hemostasis, inflammation, atherosclerosis, angiogenesis and cancerous metastasis dissemination. In order to increase our knowledge about the protein content and the main biological pathways of human vascular endothelial cells, we have undertaken the proteomic analysis of the most explored present endothelial cell model, i.e. primocultures of human umbilical vein endothelial cells (HUVECs). Using low levels of protein loads (~ 30 nug), the association of two-dimensional electrophoresis with matrix-assisted laser desorption/ionization-time of flight mass spectrometry, liquid chromatography-tandem mass spectrometry and database interrogations allowed us to identify 53 proteins of suspected endothelial origin in quiescent HUVECs. Beside cytoskeletal proteins such as actin, tubulin, tropomyosin and vimentin, we identified various proteins more especially implicated in cellular motility and plasticity (e.g. cofilin, F-actin capping protein and prefoldin), in regulation of apoptosis and senescence (protease inhibitor 9, glucose related proteins, heat shock proteins, thioredoxin peroxidase, nucleophosmin) as well as other proteins implicated in coagulation (annexin V, high mobility group protein), antigen presentation (valosin containing protein and ubiquitin carboxyl terminal hydrolase isozyme L1) and enzymatic capabilities (glutathione-S-transferase, protein disulfide isomerases, lactate deshydrogenase). The presented annotated 2-D maps of HUVECs will be soon available on the web at http://www. huvec.com.

Cells, Cultured↗

PubMed1993

Yeast mutants affected in viability upon starvation have a modified phospholipid composition.

Selection of mutations, based on the suppression of rvs161 delta defects, was performed. Ten mutants were obtained, ranged amongst four complementation groups, named SUR1, SUR2, SUR3 and SUR4. All sur mutations also suppress a mutation in another gene, RVS167, indicating that all six genes are involved in the same biological pathway. The sur mutant cells have abnormal morphologies in stationary phase, i.e. dumbbell-like in sur1, sur2 or sur3 strains and multi-budded in sur4 strains. Several phenotypic characteristics of the physiological suppressors as well as the rvs161 delta strain itself led us to analyse the phospholipid composition of the mutants. The assays show an overall decrease of the phospholipid amounts and modifications in the relative contents of some phospholipid classes in sur mutant cells.

Cell Division↗

PubMed2000

Implementation of a continuous, enzyme-coupled fluorescence assay for high-throughput analysis of glutamate-producing enzymes.

Enzymatic formation of glutamate is critical to numerous biological pathways. However, current methods for assaying the activities of glutamate-forming enzymes are not particularly suitable for high-throughput screening in drug discovery. We present a continuous-read, fluorometric assay for high-throughput analysis of glutaminases. This assay is adapted to a microplate format and employs glutamate oxidase and horseradish peroxidase to couple glutamate formation to production of the fluorescent reporter molecule, resorufin, for enhancement of sensitivity (M. Zhou, Z. Diwu, N. Panchuk-Voloshina, and R. P. Haughland, 1997, Anal. Biochem. 253, 162-168). Described herein is the selection of suitable levels of coupling enzymes for optimal kinetic response and lag time of the reporter system, based on the kinetic characteristics of the individual coupling enzymes. Finally, implementation of the assay in a format for high-throughput kinetic analysis of glutaminases is demonstrated for Escherichia coli carbamoyl phosphate synthase. Derived kinetic constants are comparable to literature values determined using a variety of assay techniques.

Glutamic Acid↗