Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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In systemic sclerosis (SSc), a disease characterized by fibrosis of the skin and internal organs, the occurrence of interstitial lung disease is responsible for high morbidity and mortality. We previously demonstrated that proteasome inhibitors (PI) show anti-fibrotic properties in vitro by reducing collagen production and favoring collagen degradation in a c-jun N-terminal kinase (JNK)-dependent manner in human fibroblasts. Therefore, we tested whether PI could control fibrosis development in bleomycin-induced lung injury, which is preceded by massive inflammation. We extended the study to test PI in TSK-1/+ mice, where skin fibrosis develops in the absence of overt inflammation. C57Bl/6 mice received bleomycin intratracheally and were treated or not with PI. Lung inflammation and fibrosis were assessed by histology and quantification of hydroxyproline content, type I collagen mRNA, and TGF-beta at Days 7, 15, and 21, respectively. Histology was used to detect skin fibrosis in TSK-1/+mice. The chymotryptic activity of 20S proteasome was assessed in mice blood. JNK and Smad2 phosphorylation were evaluated by Western blot on lung protein extracts. PI reduced collagen mRNA levels in murine lung fibroblasts, without affecting their viability in vitro. In addition, PI inhibited the chymotryptic activity of proteasome and enhanced JNK and TGF-beta signaling in vivo. PI failed to prevent bleomycin-induced lung inflammation and fibrosis and to attenuate skin fibrosis in TSK-1/+mice. In conclusion, our results provide direct evidence that, despite promising in vitro results, proteasome blockade may not be a strategy easily applicable to control fibrosis development in diseases such as lung fibrosis and scleroderma.
Am J Respir Cell Mol Biol 2008 Oct
PMID:In vivo investigations on anti-fibrotic potential of proteasome inhibition in lung and skin fibrosis. 1845 39

Connective tissue growth factor (CTGF, CCN2) is overexpressed in lung fibroblasts isolated from patients with interstitial lung disease (ILD) and systemic sclerosis (SSc, scleroderma) and is considered to be a molecular marker of fibrosis. To understand the significance of elevated CTGF, we investigated the changes in lung fibroblast proteome in response to CTGF overexpression. Using 2-dimensional gel electrophoresis followed by in-gel proteolytic digestion and mass spectrometric analysis, we identified 13 proteins affected by CTGF. Several of the CTGF-induced proteins, such as pro-alpha (I) collagen and cytoskeletal proteins vinculin, moesin, and ezrin, are known to be elevated in pulmonary fibrosis, whereas 9 of 13 proteins have not been studied in pulmonary fibrosis and are, therefore, novel CTGF-responsive molecules that may have important roles in ILD. Our study demonstrates that 1 of the novel CTGF-induced proteins, IQ motif containing GTPase activating protein (IQGAP) 1, is elevated in lung fibroblasts isolated from scleroderma patients with ILD. IQGAP1 is a scaffold protein that plays a pivotal role in regulating migration of endothelial and epithelial cells. Scleroderma lung fibroblasts and normal lung fibroblasts treated with CTGF demonstrated increased rate of migration in a wound healing assay. Depletion of IQGAP1 expression by small interfering RNA inhibited CTGF-induced migration and MAPK ERK1/2 phosphorylation in lung fibroblasts. MAPK inhibitor U0126 decreased CTGF-induced cell migration and did not interfere with CTGF-induced IQGAP1 expression, suggesting that MAPK pathway is downstream of IQGAP1. These findings further implicate the importance of CTGF in lung tissue repair and fibrosis and propose that CTGF-induced migration of lung fibroblasts to the damaged tissue is mediated via IQGAP1 and MAPK signaling pathways.
Am J Physiol Lung Cell Mol Physiol 2008 Oct
PMID:Proteomic analysis of CTGF-activated lung fibroblasts: identification of IQGAP1 as a key player in lung fibroblast migration. 1867 75

Systemic sclerosis (SSc) is a systemic autoimmune disease that is characterized by microangiopathy with progressive loss of capillaries and tissue fibrosis. Imatinib exerts potent anti-fibrotic effects and is currently evaluated in clinical trials. The aim of the present study was to exclude that the anti-fibrotic effects of imatinib are complicated by inhibitory effects on endothelial cell functions, which might augment vascular disease in SSc. Endothelial cells and mice were treated with pharmacologically relevant concentrations of imatinib. The expression of markers of vascular activation was assessed with real-time PCR. Proliferation was analysed with the cell counting experiments and the MTT assay. Apoptosis was quantified with caspase 3 assays, annexin V in vitro and with TUNEL staining in vivo. Migration was studied with scratch and transwell assays. Tube forming was investigated with the matrigel assay. Imatinib did not alter the expression of markers of vascular activation. Imatinib did not increase the percentage of annexin V positive cells or the activity of caspase 3. No reduction in proliferation or metabolic activity of endothelial cells was observed. Imatinib did not affect migration of endothelial cells and did not reduce the formation of capillary tubes. Consistent with the in vitro data, no difference in the number of apoptotic endothelial cells was observed in vivo in mice treated with imatinib. Imatinib does not inhibit activation, viability, proliferation, migration or tube forming of endothelial cells in vitro and in vivo. Thus, treatment with imatinib might not augment further endothelial cell damage in SSc.
J Cell Mol Med 2009 Oct
PMID:Lack of inhibitory effects of the anti-fibrotic drug imatinib on endothelial cell functions in vitro and in vivo. 1877 58

Scleroderma is a systemic, mixed connective tissue disease that can impact the lungs through pulmonary fibrosis, vascular remodeling, and the development of pulmonary hypertension and right heart failure. Currently, little is known about the molecular mechanisms that drive this condition, but we have recently identified a novel gene product that is up-regulated in a murine model of hypoxia-induced pulmonary hypertension. This molecule, known as hypoxia-induced mitogenic factor (HIMF), is a member of the newly described resistin gene family. We have demonstrated that HIMF has mitogenic, angiogenic, vasoconstrictive, inflammatory, and chemokine-like properties, all of which are associated with vascular remodeling in the lung. Here, we demonstrate that the human homolog of HIMF, resistin-like molecule (RELM)-beta, is expressed in the lung tissue of patients with scleroderma-associated pulmonary hypertension and is up-regulated compared with normal control subjects. Immunofluorescence colocalization revealed that RELM-beta is expressed in the endothelium and vascular smooth muscle of remodeled vessels, as well as in plexiform lesions, macrophages, T cells, and myofibroblast-like cells. We also show that addition of recombinant RELM-beta induces proliferation and activation of ERK1/2 in primary cultured human pulmonary endothelial and smooth muscle cells. These results suggest that RELM-beta may be involved in the development of scleroderma-associated pulmonary hypertension.
Am J Respir Cell Mol Biol 2009 Nov
PMID:Resistin-like molecule-beta in scleroderma-associated pulmonary hypertension. 1925 45

The aim of this study was to investigate the possible role of STAT4 gene in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. A total of 1317 SSc patients [896 with limited cutaneous SSc (lcSSc) and 421 with diffuse cutaneous SSc (dcSSc)] and 3113 healthy controls, from an initial case-control set of Spanish Caucasian ancestry and five independent cohorts of European ancestry (The Netherlands, Germany, Sweden, Italy and USA), were included in the study. The rs7574865 polymorphism was selected as STAT4 genetic marker. We observed that the rs7574865 T allele was significantly associated with susceptibility to lcSSc in the Spanish population [P = 1.9 x 10(-5) odds ratio (OR) 1.61 95% confidence intervals (CI) 1.29-1.99], but not with dcSSc (P = 0.41 OR 0.84 95% CI 0.59-1.21). Additionally, a dosage effect was observed showing individuals with rs7574865 TT genotype higher risk for lcSSc (OR 3.34, P = 1.02 x 10(-7) 95% CI 2.11-5.31). The association of the rs7574865 T allele with lcSSc was confirmed in all the replication cohorts with different effect sizes (OR ranging between 1.15 and 1.86), as well as the lack of association of STAT4 with dcSSc. A meta-analysis to test the overall effect of the rs7574865 polymorphism showed a strong risk effect of the T allele for lcSSc susceptibility (pooled OR 1.54 95% CI 1.36-1.74; P < 0.0001). Our data show a strong and reproducible association of the STAT4 gene with the genetic predisposition to lcSSc suggesting that this gene seems to be one of the genetic markers influencing SSc phenotype.
Hum Mol Genet 2009 Jun 01
PMID:The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype. 1928 70

Interleukin 17 (IL-17) is a Th17 cytokine associated with inflammation, autoimmunity and defense against some bacteria, it has been implicated in many chronic autoimmune diseases including psoriasis, multiple sclerosis and systemic sclerosis. However, whether IL-17 plays a role in the pathogenesis of systemic lupus erythematosus (SLE) remains unclear. In the present study, we aimed to investigate the serum IL-17 level in patients with SLE and it's associations with disease manifestations and activity. Fifty-seven patients with SLE and 30 healthy volunteers were recruited. Serum IL-17 levels were examined by enzyme linked immunosorbent assay (ELISA). Statistic analyzes were performed by SPSS 10.01. Results show that serum IL-17 levels were significantly elevated in SLE patients as compared with normal controls. Nevertheless, no associations of serum IL-17 level with clinical and laboratory parameters were found; no significant difference regarding serum IL-17 level between SLE patients with nephritis and those without nephritis was found; no significant difference was found between Less active SLE and More active SLE; Correlation analysis between serum IL-17 levels and SLEDAI showed no association. Taken together, our results indicate increased serum IL-17 levels in SLE patients, suggesting that this cytokine may trigger the inflammatory process in SLE. However, no associations of serum IL-17 level with disease manifestations were found. Therefore, further studies are required to confirm this preliminary data.
Mol Biol Rep 2010 Jan
PMID:Increased serum interleukin 17 in patients with systemic lupus erythematosus. 1934 4

Self-assembly methods for the immobilisation or encapsulation of the positively charged redox protein, cytochrome c (cyt c), in layered organoclays or silica nanoparticles, respectively, are described and contrasted. Protein-polymer-organoclay nanocomposites are produced by spontaneous restacking of delaminated aminopropyl-functionalised magnesium phyllosilicate sheets in the presence of an aqueous solution of poly(sodium 4-styrene sulfonate) (PSS) and cyt c. In contrast, single molecules of cyt c are encapsulated in silica nanoparticles by sol-gel reactions at the oil-water interface of microemulsion water droplets. In both cases, the protein molecules remain structurally intact after entrapment, are accessible to small molecule redox agents, exhibit excellent peroxidase activity in the presence of hydrogen peroxide, and show enhanced stability and catalytic properties under adverse conditions of pH. The ability to prepare functional protein-inorganic conjugates in general could significantly extend the technological scope of biological products and processes, and should therefore be an important adjunct in the translation of synthetic biology to real-life applications.
Mol Biosyst 2009 Jul
PMID:Immobilisation and encapsulation of functional protein-inorganic constructs. 1956 13

Rheumatoid arthritis (RA) patients are characterized by increased arterial stiffness, an independent predictor of cardiovascular risk. It has been suggested that osteopontin (OPN), a cytokine involved in RA pathogenesis, might have vascular effects. To study a possible relationship between OPN and arterial stiffness, aortic pulse wave velocity (PWV) was measured by tonometry in 69 patients (41 with RA, 28 with systemic sclerosis [SSc]) and 18 healthy controls. Plasma OPN levels, oxidative stress markers, and endothelin 1 (ET-1) were assessed. OPN levels were significantly (P < 0.05) higher in RA (median 9.93, range 4.36-47.80 ng/mL) than in SSc (4.3, 2.1-19.7 ng/mL) or controls (5.2, 4.1-9.4 ng/mL). In RA patients, log-OPN was related to log-C-reactive protein (log-CRP) (r = 0.30, P < 0.05), age (r = 0.38, P < 0.01), Health Assessment Questionnaire (HAQ) (r = 0.58, P < 0.0001), and inversely related to total cholesterol (r = -0.33, P < 0.05) and apolipoprotein A (apoA) (r = -0.58, P < 0.001), but not to oxidative stress markers and ET-1. PWV was similar in RA (median 8.1, range 4.7-16.4 m/s) and SSc (median 8.7, range 7.1-13.1 m/s), but significantly greater (P < 0.01) than controls (median 7.5, range 4.1-10.4 m/s). Aortic PWV was related to log-OPN (r = 0.40, P < 0.01) only in RA patients. It also was related to age (r = 0.34, P < 0.05), mean blood pressure (r = 0.44, P < 0.001), and HAQ (r = 0.48, P < 0.001). In multiple regression analysis (r(2) = 0.36), including confounders, log-OPN remained a significant predictor (P < 0.05) of PWV in RA. Elevated plasma OPN levels are associated with increased arterial stiffness in RA patients, suggesting that this protein might represent a bridge protein between inflammation and the consequent joint damage and cardiovascular risk in RA patients.
Mol Med
PMID:Osteopontin is associated with increased arterial stiffness in rheumatoid arthritis. 1960 4

Scleroderma is a rare multisystemic disease of unknown etiology presumed to develop in genetically predisposed patients. Since patients affected with scleroderma develop clinical features similar to those observed in some laminopathies, we decided to screen at the genomic level a cohort of 27 patients affected with either localized or systemic scleroderma for mutations in three lamin-related genes: LMNA, encoding A-type lamins; ZMPSTE24, encoding a protease involved in lamin A processing; and LBR, encoding the lamin B receptor. No mutation was retrieved, whereas 25 polymorphic sequence variations were identified, 7 of which were unreported. Functional analyses performed for three of these allowed exclusion of an impact on splicing. Multiplex ligation-dependent probe amplification analysis showed no LMNA deletion or duplication. Altogether our results suggest that LMNA, ZMPSTE24, and LBR sequence variations are not major genetic determinants involved in scleroderma pathogenesis.
Genet Test Mol Biomarkers 2009 Oct
PMID:LMNA, ZMPSTE24, and LBR are not mutated in scleroderma. 1964 29

We describe a novel approach to genetic association analyses with proteins sub-divided into biologically relevant smaller sequence features (SFs), and their variant types (VTs). SFVT analyses are particularly informative for study of highly polymorphic proteins such as the human leukocyte antigen (HLA), given the nature of its genetic variation: the high level of polymorphism, the pattern of amino acid variability, and that most HLA variation occurs at functionally important sites, as well as its known role in organ transplant rejection, autoimmune disease development and response to infection. Further, combinations of variable amino acid sites shared by several HLA alleles (shared epitopes) are most likely better descriptors of the actual causative genetic variants. In a cohort of systemic sclerosis patients/controls, SFVT analysis shows that a combination of SFs implicating specific amino acid residues in peptide binding pockets 4 and 7 of HLA-DRB1 explains much of the molecular determinant of risk.
Hum Mol Genet 2010 Feb 15
PMID:Novel sequence feature variant type analysis of the HLA genetic association in systemic sclerosis. 1993 68


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