Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

C-reactive protein (CRP) contributes to the process of atherosclerosis by inducing pro-inflammatory changes in endothelial cells. However, the exact receptor involved in CRP-induced endothelial changes remains unclear. Human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs) were used for the experiments. After incubation with CRP, immunoblotting showed a significant decrease of IkappaB protein and electrophoretic mobility shift assay showed a significant increase of nuclear NF-kappaB binding capacity. These changes were associated with a significant increase of vascular cell adhesion molecule-1 (VCAM-1) expression. The mRNA level of CD32, the major binding protein for CRP in endothelial cells, increased significantly as measured by Northern blot and Western blot. When these cells were transfected with siRNA directed against CD32, the mRNA of CD32 decreased significantly. The IkappaB degradation, NF-kappaB nuclear translocation and VCAM-1 up-regulation induced by CRP were all inhibited by treatment with siRNA against CD32. SB203580, a P38 inhibitor, significantly attenuated the CRP-induced responses while SP600125 (c-jun kinase inhibitor) did not. In conclusion, CRP-induced IkappaB degradation, NF-kappaB nuclear translocation and VCAM-1 protein expression in HUVECs and HAECs. CRP also increased the expression of CD32, which might serve as the receptor for CRP in endothelial cells and mediated the effects of CRP.
J Mol Cell Cardiol 2006 Mar
PMID:C-reactive protein activates the nuclear factor-kappaB pathway and induces vascular cell adhesion molecule-1 expression through CD32 in human umbilical vein endothelial cells and aortic endothelial cells. 1643 Sep 14

Fenofibrate, a selective (1)PPAR-alpha activator, is prescribed to treat human dyslipidemia. The aim of this study was to delineate the mechanism of fenofibrate-mediated reductions in adiposity, improvements in insulin sensitivity, and lowering of triglycerides (TG) and free fatty acids (FFA) and to investigate if these favorable changes are related to the inhibition of lipid deposition in the aorta. To test this hypothesis we used male LDLr deficient mice that exhibit the clinical features of metabolic syndrome X when fed a high fat high cholesterol (HF) diet. LDLr deficient mice fed HF diet and simultaneously treated with fenofibrate (100 mg/kg body weight) prevented development of obesity, lowered serum triglycerides and cholesterol, improved insulin sensitivity, and prevented accumulation of lipids in the aorta. Lowering of circulating lipids occurred via down-regulation of lipogenic genes, including fatty acid synthase, acetyl CoA carboxylase and diacyl glycerol acyl transferase-2, concomitant with decreased liver TG and cholesterol, and TG output rate. Fenofibrate also suppressed liver apoCIII mRNA levels and markedly increased lipoprotein lipase mRNA levels, known to enhance serum TG catabolism. In addition, fenofibrate profoundly reduced epididymal fat and mesenteric fat mass to the levels seen in lean mice. The reductions in body weight were associated with elevation of hepatic uncoupling protein 2 (UCP2) mRNA, a concomitant increase in the ketone body formation, and improved insulin sensitivity associated with tumor necrosis factor-alpha reductions and phosphoenol pyruvate carboxykinase down-regulation. These results demonstrate that fenofibrate improves lipid abnormalities partly via inhibition of TG production and partly via clearance of TG-rich apoB particles by elevating LPL and reduced apoCIII. The prevention of obesity development occurred via energy expenditure. Fenofibrate-mediated hypolipidemic effects together with improved insulin sensitivity and loss of adiposity led to the reductions in the aortic lipid deposition by inhibiting early stages of atherosclerosis possibly via vascular cell adhesion molecule-1 (VCAM-1) modulation. These results suggest that potent PPAR-alpha activators may be useful in the treatment of syndrome X.
Mol Cell Biochem 2006 Apr
PMID:Peroxisome proliferator-activated receptor-alpha selective ligand reduces adiposity, improves insulin sensitivity and inhibits atherosclerosis in LDL receptor-deficient mice. 1647 80

Proteinase-activated receptors (PARs) are a novel family of G-protein-coupled receptors. PAR2 has been implicated in inflammatory airways disease. Although fibroblasts are pathologically important in the airways, the proinflammatory role of PAR2 in these cells remains unknown. We assessed PAR expression and functionality in human primary bronchial fibroblasts (HPBFs) before assessing PAR2-mediated HPBF proliferation, cytokine production, and adhesion molecule expression. RT-PCR and flow cytometry demonstrated that HPBFs express hPAR1, hPAR2, and hPAR3, but not hPAR4. Intracellular calcium signaling in HPBFs in response to PAR agonists showed that only hPAR1 and hPAR2 were functional receptors. We used the MTT assay to assess HPBF proliferation. Of the PAR2 agonist proteinases or selective PAR2-activating peptides (PAR2-APs) tested, none stimulated HPBF proliferation, whereas thrombin was a HPBF growth factor. mRNA for IL-8 and granulocyte colony-stimulating factor (G-CSF) was upregulated after addition of SLIGKV-NH2 when assessed by RT-PCR. No significant increase in G-CSF or IL-8 protein was detected. Trypsin stimulated IL-8 and G-CSF release from HPBF in a time- and dose-dependent manner. Leupeptin and soya trypsin inhibitor abrogated trypsin-stimulated cytokine release, indicating a requirement for trypsin's proteolytic activity. Trypsin and SLIGKV-NH2 stimulated an increase in VCAM-1 expression at 12 h after treatment, which declined thereafter. PAR2-driven upregulation of VCAM-1 cell surface expression and the release of IL-8 and G-CSF from bronchial fibroblasts may be important in promoting neutrophilic airways inflammation.
Am J Respir Cell Mol Biol 2006 Jul
PMID:Proteinase-activated receptor2 agonists upregulate granulocyte colony-stimulating factor, IL-8, and VCAM-1 expression in human bronchial fibroblasts. 1649 82

Allogeneic transplantation with human umbilical cord blood (hUCB) in adult recipients is mainly limited by a low CD34+ cell dose. To break the limit, hUCB as a novel source of hUCB-derived stromal cells was incorporated in an attempt to expand CD34+ cells from hUCB in vitro. Cord blood CD34 cells were separated by MACS system. HUCB-derived stromal cells were cultured by the Dexter system and characterized by morphologic, immunophenotypical, and functional analysis. We studied the effects of hUCB-derived stromal cells, cytokines, and hUCB-derived stromal cells combined with cytokines on expansion of hUCB CD34 cells. The CD34+ cells were assessed for the degree of expansion and the number of colony-forming units in semisolid culture. Our research found that hUCB-derived stromal cells were mainly composed of three kinds of cell components, with CD106, CD29, CD44, CD45, CD50, CD68, CD31, Fn, Lm, and collagen IV positive, but CD34 negative immunophenotype. Functionally, it was discovered by cell cycle and growth curve analyses that the capability of colony and parietal layer formation of hUCB-derived stromal cells was poorer than that of BM stromal cells, and the doubling time of hUCB-derived stromal cells was longer than that of BM stromal cells. It was indicated by ELISA and RT-PCR that hUCB-derived stromal cells express higher level of TPO and less GM-CSF and SCF than BM stromal cell. Adherent layer of hUCB-derived stromal cells alone or combining with cytokines, increased CD34+ cell expansion. In vitro formation of CFUs by expanded CCD34 cells was significantly higher than that of unexpanded CD34+ cells (P < 0.05). When cocultured with hUCB-derived stromal cells in the presence of cytokines, cell growth was significantly enhanced: CD34 cells by 8.02 +/- 0.96-fold, CFU-GM by 217.60 +/- 6.72-fold, CFU-E by 1940.80 +/- 52.78-fold, and CFU-Mg by 142.60 +/- 4.39-fold. HUCB-derived stromal cells have significant superiority on the expansion of CFU-Mg (P < 0.05). The results indicate that human umbilical cord blood-derived stromal cells may be a suitable feeder layer for expansion of hematopoietic progenitors from hUCB in vitro.
Blood Cells Mol Dis
PMID:Human umbilical cord blood-derived stromal cell, a new resource of feeder layer to expand human umbilical cord blood CD34+ cells in vitro. 1650 Jan 23

Triglyceride-rich lipoproteins (TGRLs) are a cardiovascular risk factor and induce endothelial dysfunction. In the present study we investigated the effects of TGRLs from type IV hyperlipidemic and normolipidemic subjects on endothelial activation focusing on the effects on intracellular pathways and gene expression. A total of 54 subjects, 30 hypertriglyceridemic (triglyceride (TG) levels 284+/-101 mg/dl) and 23 normotriglyceridemic (TG levels 109+/-40 mg/dl) were enrolled as lipoprotein donors. TGRLs were isolated from hypertriglyceridemic (H-TGRL) and normotriglyceridemic (N-TGRL) subjects. RNA from human endothelial cells incubated with N-TGRL or H-TGRL was prepared for cDNA microarray analyses. Western blotting was used to study intracellular signaling pathways. Regulated genes were further studied with real-time PCR, immunofluorescence and FACS. Furthermore, a protein/DNA array and chromatin-immunoprecipitation were used to identify transcription factors involved in the observed effects. Both N-TGRL and H-TGRL activated ERK1/2 and p38 MAPK. However, there were differences in the pattern of upregulated target genes between the two types of lipoproteins in HUVECs and/or HAECs: PAI-1, VCAM-1, ELAM-1 and MCP-1 were upregulated by both N-TGRL and H-TGRL, while PECAM-1, IL-6 and ADAMTs1 were selectively upregulated by H-TGRL. Chromatin immunoprecipitation analysis demonstrated the involvement of transcription factors NF-kB and CREB in the activation of these genes. These results support the possible involvement of hypertriglyceridemic TGRLs in endothelial dysfunction via induction of a pro-inflammatory and pro-thrombotic state.
J Mol Cell Cardiol 2006 Apr
PMID:Triglyceride-rich lipoproteins from hypertriglyceridemic subjects induce a pro-inflammatory response in the endothelium: Molecular mechanisms and gene expression studies. 1651 17

Asthma is characterized by appearance of eosinophils in the airway. Eosinophils purified from the airway 48 h after segmental antigen challenge are described as exhibiting greater adhesion to albumin-coated surfaces via an unidentified beta2 integrin and increased expression of alphaMbeta2 (CD11b/18) compared with purified blood eosinophils. We have investigated the determinants of this hyperadhesive phenotype. Airway eosinophils exhibited increased reactivity with the CBRM1/5 anti-alphaM activation-sensitive antibody as well as enhanced adhesion to VCAM-1 (CD106) and diverse ligands, including albumin, ICAM-1 (CD54), fibrinogen, and vitronectin. Purified blood eosinophils did not adhere to the latter diverse ligands. Enhanced adhesion of airway eosinophils was blocked by anti-alphaMbeta2. Podosomes, structures implicated in cell movement and proteolysis of matrix proteins, were larger and more common on airway eosinophils adherent to VCAM-1 when compared with blood eosinophils. Incubation of blood eosinophils with IL-5 replicated the phenotype of airway eosinophils. That is, IL-5 enhanced recognition of alphaM by CBRM1/5; stimulated alphaMbeta2-mediated adhesion to VCAM-1, albumin, ICAM-1, fibrinogen, and vitronectin; and increased podosome formation on VCAM-1. Thus, the hyperadhesion of airway eosinophils after antigen challenge is mediated by upregulated and activated alphaMbeta2.
Am J Respir Cell Mol Biol 2006 Sep
PMID:Dissection of the hyperadhesive phenotype of airway eosinophils in asthma. 1660 Dec 40

Application of ultrasound-mediated destruction of microbubbles (US + Bubble) to skeletal muscle creates capillary ruptures leading to leakage of the cell components. We studied whether US + Bubble combined with bone-marrow-derived mononuclear cells (BM-MNCs) infusion enables the targeted delivery of endothelial-lineage cells into the myocardium and improves cardiac function of the cardiomyopathy model due to the paucity of neocapillary formation. Pulsed US was applied to the anterior chest of BIOTO2 cardiomyopathy hamsters for 90 s after the intravenous injection of microbubble (Optison) followed by infusion of BM-MNCs. Cardiac samples from US + microbubble + BM-MNCs (US + Bubble + BM), US + Bubble, US + BM without Bubble, and saline infusion control groups were analyzed 12 weeks after treatment. Labeled BM-MNCs transplanted by US + Bubble were found to be mainly localized in the microvessels, but not by US stimulation without microbubble (121.2 +/- 24.5 vs. 2.80 +/- 1.30 cells/mm2, P < 0.001). Capillary densities in US + Bubble + BM group were increased 1.7-fold (P < 0.05) over the control, and neither US + Bubble nor US + BM enhanced neocapillary formation. 99mTc-Tetrofosmin scintigraphy revealed that blood perfusion area in the US + Bubble + BM group was 48% greater than the control (P < 0.01). US + Bubble stimulation induces the expression of adhesion molecules (VCAM-1 and ICAM-1) in capillaries, and the US + Bubble-mediated supply of BM-MNCs increased the myocardial content of VEGF and bFGF. The left ventricular wt/body wt, area of cardiac fibrosis, and apoptotic cell numbers in the US + Bubble + BM group significantly (P < 0.05) decreased by 82%, 73%, and 64% relative to the control, respectively. The cardiac function in myopathic hamsters (assessed by fractional shortening) was markedly improved 36% (P < 0.05) by US + Bubble + BM treatment. Targeted delivery of BM-MNCs by US + Bubble to the myocardium of the cardiomyopathic hamster increased the capillary densities and regional blood flow and inhibited cardiac remodeling, resulting in the prevention of heart failure. This non-invasive cell delivery system may be useful as a novel efficient approach for angiogenic cell therapy to the myocardium.
J Mol Cell Cardiol 2006 Jun
PMID:Myocardium-targeted delivery of endothelial progenitor cells by ultrasound-mediated microbubble destruction improves cardiac function via an angiogenic response. 1667

Aims-To analyse the topographical distribution of adhesion molecules involved in lymphocyte recirculation in human lymph nodes and tonsils. The study focused on the expression of LECAM-1 (CD62L), VLA-alpha4 (CD49d), VLA-beta1 (CD29), LFA-1 alphaL (CD11a), LFA-beta2 (CD18), VCAM-1 (CD106), ICAM-1 (CD54), and H-CAM (CD44).Methods-Reactive lymph nodes and palatine tonsils were studied using immunofluorescence methods with fluorescein isothiocyanate (FITC) labelled monoclonal antibodies directed against cell adhesion molecules. To investigate the expression patterns of these molecules in the T and B cell populations, double labelling experiments were performed using Texas Red labelled antibodies against CD2 or CD19, respectively. The images from each fluorochrome were then simultaneously analysed using a laser scanning confocal microscope.Results-LECAM-1, VLA-alpha4 and H-CAM were predominantly expressed by mantle zone B cells, VCAM-1 and ICAM-1 by germinal centre cells, most of which exhibited a reticular staining pattern suggestive of follicular dendritic cells, whereas LFA-1 alphaL and LFA-beta2 were mainly found in extrafollicular and germinal centre T cells. All high endothelial venules expressed VLA-beta1 and ICAM-1, whereas VCAM-1 was present in only a few, with variable intensity.Conclusions-The data show that all of these adhesion molecules are differentially distributed within the distinct functional microenvironments of both organs. The differences observed in the expression patterns among the B and T cells belonging to different compartments probably depend on the momentum of cell traffic, the stage of maturation/activation, as well as on their functional role in the immune response.
Clin Mol Pathol 1995 Apr
PMID:Differential expression of cell adhesion molecules in the functional compartments of lymph nodes and tonsils. 1669 89

Aims-To determine which inflammatory and immune pathways are implicated in the development of chronic graft versus host disease (GvHD) and whether differences between these pathways are responsible for the different presentations of chronic GvHD.Methods-Biopsy specimens of diseased and normal skin were obtained from patients presenting with lichen planus-like and sclerodermatous type chronic GvHD. Expression of epidermal cytokines, adhesion molecules and lymphoid surface markers was analysed by means of immunohistochemistry. Apoptosis was detected using the in situ nick endlabelling method.Results-In both GvHD lesion types, CD8+ cells predominated in the epidermis, whereas CD4+ cells were the most prevalentin the dermis. Apoptotickeratinocytes were found in diseased skin only and Fas antibodies labelled a considerable number of keratinocytes. The epidermis in both types of lesions expressed interleukin (IL) 1alpha, tumour necrosis factor (TNF) alpha and intercellular adhesion molecule (ICAM)-1, but dermal vascular cell adhesion molecule (VCAM)-1 expression was restricted to specimens of lichen planus-like GvHD. IL1alpha and E-selectin were expressed in normal looking skin of 55% and 80%, respectively, of patients with lichen planus-like GvHD.Conclusion-The similarity between expression of epidermal cytokines and adhesion molecules (with the exception of VCAM-1) and lymphocyte phenotype in lichen planus-like and sclerodermatous GvHD strongly suggests that the latter occurs as a consequence of the healing process. VCAM-1 distinguishes between lichen planus-like and sclerodermatous lesions. IL1alpha and E-selectin are potential early markers of chronic GvHD.
Clin Mol Pathol 1996 Aug
PMID:Lymphocytes, cytokines and adhesion molecules in chronic graft versus host disease. 1669 80

Hypoxia-induced mitogenic factor (HIMF), also known as FIZZ1 (found in inflammatory zone 1), is an important player in lung inflammation. However, the effects of HIMF on cell adhesion molecules involved in lung inflammation remain largely unknown. In the present work, we tested whether HIMF modulates vascular adhesion molecule (VCAM)-1 expression, and dissected the possible signaling pathways that link HIMF to VCAM-1 upregulation. Recombinant HIMF protein, instilled intratracheally into adult mouse lungs, results in a significant increase of VCAM-1 production in vascular endothelial, alveolar type II, and airway epithelial cells. In cultured mouse endothelial SVEC 4-10 and lung epithelial MLE-12 cells, we demonstrated that HIMF induces VCAM-1 expression via the phosphatidylinositol-3 kinase (PI-3K)/Akt-nuclear factor (NF)-kappaB signaling pathway. Knockdown of HIMF expression by small interference RNA attenuated LPS-induced VCAM-1 expression in vitro. We showed that HIMF induced phosphorylation of the IkappaB kinase signalsome and, subsequently, IkappaBalpha, leading to activation of NF-kappaB. Meanwhile, VCAM-1 production was correspondingly upregulated. Blocking NF-kappaB signaling pathway by expression of dominant-negative mutants of IkappaB kinase and IkappaBalpha suppressed HIMF-induced VCAM-1 upregulation. HIMF also strongly induced phosphorylation of Akt. A dominant-negative mutant of PI-3K, Deltap85, as well as PI-3K inhibitor, LY294002, also blocked HIMF-induced NF-kappaB activation and attenuated VCAM-1 production. Furthermore, LY294002 pretreatment abolished HIMF-enhanced mononuclear cells adhesion to endothelial and epithelial cells. Our findings connect HIMF to signaling pathways that regulate inflammation, and thus reveal the critical roles that HIMF plays in lung inflammation.
Am J Respir Cell Mol Biol 2006 Oct
PMID:Hypoxia-induced mitogenic factor promotes vascular adhesion molecule-1 expression via the PI-3K/Akt-NF-kappaB signaling pathway. 1670 59


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