Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute lung injury (ALI) is characterized by an early inflammatory response followed by a late fibroproliferative phase, and by an increase in the bronchoalveolar lavage fluid (BALF) concentrations of bioactive soluble FasL (sFasL). Activation of Fas (CD95) has been associated with the development of lung fibrosis in mice. The goal of this study was to determine the mechanisms that link Fas activation with the development of fibrosis in the lungs. We treated mice with three daily intratracheal instillations of a Fas-activating monoclonal antibody (Jo2) or a control IgG, and studied the animals at sequential times. Mice treated with Jo2 had increased caspase-3 activation in alveolar wall cells on Days 2, 4, and 7; an inflammatory response peaking on Day 7, and increased total lung collagen on Day 21. Gene expression profiling performed on Days 2, 4, and 7 showed sequential activation of co-regulated profibrotic genes, including marked up-regulation of matrix metalloproteinase 12 (MMP-12). Targeted deletion of MMP-12 protected mice from Fas-induced pulmonary fibrosis, even though the inflammatory responses in the lungs were similar to those of wild-type mice. Compared with wild-type mice, the mmp12(-/-) mice showed decreased expression of the profibrotic genes egr1 and cyr61. We conclude that Fas activation in the lungs induces a complex response that includes apoptosis, inflammation, and eventually fibrosis, and that MMP-12 is essential for the fibrotic phenotype. We speculate that MMP-12 activity is required for activation of the profibrotic genes egr1 and cyr61.
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PMID:Essential role of MMP-12 in Fas-induced lung fibrosis. 1819 46

The complement inhibitor, Crry, which blocks both the classical and alternative pathways, alleviates CNS disease in the lupus model, MRL/MpJ-Tnfrsf6lpr (MRL/lpr) mice. To understand the role of the alternative pathway, we studied mice deficient in a key alternative pathway protein, complement factor B (fB). Immune deposits (IgG and C3) were reduced in the brains of MRL/lpr fB-deficient (fB-/-MRL/lpr) compared to fB-sufficient (MRL/lpr) mice, indicating reduced complement activation. Reduced neutrophil infiltration (22% of MRL/lpr mice) and apoptosis (caspase-3 activity was reduced to 33% of MRL/lpr mice) in these mice indicates that the absence of the alternative pathway was neuroprotective. Furthermore, expression of phospho (p)-Akt (0.16+/-0.02 vs. 0.35+/-0.13, p<0.03) was increased, while expression of p-PTEN (0.40+/-0.06 vs. 0.11+/-0.07, p<0.05) was decreased in fB-/-MRL/lpr mice compared to their MRL/lpr counterparts. The expression of fibronectin, laminin and collagen IV was significantly decreased in fB-/-MRL/lpr mice compared to MRL/lpr mice, indicating that in the lupus setting, tissue integrity was maintained in the absence of the alternative pathway. Absence of fB reduced behavioral alterations in MRL/lpr mice. Our results suggest that in lupus, the alternative pathway may be the key mechanism through which complement activation occurs in brain, and therefore it might serve as a therapeutic target for lupus cerebritis.
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PMID:Absence of functional alternative complement pathway alleviates lupus cerebritis. 1752 12

This study, using tissue microarrays, aimed at the immunomorphologic profiling of nonsmall cell lung cancer (NSCLC) cases to reveal clinically relevant disease groups and biomarkers associated with patients' survival and tumor progression including brain metastatic potential. Donor tissue blocks were form 59 patients, including 33 primary tumors without distant metastasis and 26 brain metastatic primary tumors as well as the brain metastases. Sections were immunostained for 29 markers targeting molecules of cell adhesion, cell growth, cell cycle, and apoptosis regulation. beta-Catenin expression was the only independent prognostic marker associated with better outcome. Elevated expression of collagen XVII, CD44v6, and caspase-9, and the reduced production of beta-catenin and cellular apoptosis susceptibility protein were significantly associated with the metastatic potential of primary NSCLC. Expression of positive cell cycle regulators cyclin D1 and cyclin D3 was also increased in metastatic primary tumors. Metastatic tumor progression into the brain was accompanied by prominent p16, syndecan-1, p53 (DO7), and caspase-3 protein levels. Hierarchical clustering of complex immunoprofiles based on the differentially expressed markers grouped NSCLCs of the poorest outcome with high correlation including 2/3 of brain metastases of mixed histology. The brain metastatic potential of NSCLCs may be linked to the elevated levels of cyclinD1, cyclinD3, p16, p53, caspase-3, caspase-9, CD44v6, and collagen XVII and the down-regulation of beta-catenin and cellular apoptosis susceptibility protein. Unsupervised immunoprofiles based on differentially expressed biomarkers may help selecting lung cancers with aggressive behavior.
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PMID:Immunophenotypic profiling of nonsmall cell lung cancer progression using the tissue microarray approach. 1753 3

Functional and structural abnormalities in the renal microvasculature are important processes contributing to the pathophysiology of ischemic acute kidney injury (AKI). In this study, we examine the contribution of endothelial cell loss via apoptosis on microvascular permeability and rarefaction in a mouse model of ischemic AKI. Three-dimensional reconstructions of microvascular networks obtained 24 h following acute ischemic injury demonstrate an intact endothelial monolayer in areas of increased microvascular permeability. A 45% decrease in microvascular density was observed 4 wk after acute ischemic injury. Examination of microvascular endothelial cells following acute ischemic injury did not reveal evidence of positive terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling staining at 1, 2, 8, and 16 days following ischemia; however, activation of caspase-3 was evident in endothelial cells following acute ischemic injury. Examination of angiopoietin (Ang) protein expression in the kidney 24 h after ischemic injury revealed an eightfold increase in Ang-1 but no significant change in Ang-2. No significant difference in the expression of vascular endothelial growth factor or Ang-2 was observed 4 wk after ischemic injury, although an almost twofold elevation in Ang-1 was observed. An increase in angiostatic breakdown products of collagen IV was observed at both 24 h and 4 wk after ischemic injury. Taken together, these findings indicate that the loss of endothelial cells following ischemic injury is not a major contributor to altered microvascular permeability, although renal microvascular endothelial cells are vulnerable to the initiation of apoptotic mechanisms following ischemic injury that can ultimately impact microvascular density.
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PMID:Acute and chronic microvascular alterations in a mouse model of ischemic acute kidney injury. 1762 53

A growing problem in cardiac drug toxicity has been blamed on the lack of adequate testing prior to authorization for prescription use. This study offers an effective alternative to the current method of in vivo pharmaceutical testing, which is time and cost prohibitive. We have accomplished this by developing the novel three-dimensional heart tube model. At the "heart" of our model lies our patented collagen scaffold that enables the cardiac myocytes to display an in vivo-like architecture. The cardiac myocytes were cocultured with the collagen tube for a period of 5 weeks, resulting in the heart tubes. Our heart tubes were treated with specific drugs (nifedipine, isoproterenol, and lidocaine) at varying concentrations. The percent of apoptotic cells was calculated based on observing the number of cells that labeled positive for caspase-3 via confocal microscopy. All three drugs exhibited negative effects at high concentrations in that the number of living cells decreased. Lidocaine showed an increase in apoptosis at concentrations of 75 microM and above. This may indicate that certain drugs have a minimum concentration level that must be reached before the cells experience apoptosis from the toxic levels.
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PMID:Novel tissue engineered tubular heart tissue for in vitro pharmaceutical toxicity testing. 1763 75

We attempted to repair full-thickness defects in the articular cartilage of the trochlear groove of the femur in 30 rabbit knee joints using allogenic cultured chondrocytes embedded in a collagen gel. The repaired tissues were examined at 2, 4, 8, 12 and 24 weeks after operation using histological and histochemical methods. The articular defect filling index measurement was derived from safranin-O stained sections. Apoptotic cellular fractions were derived from analysis of apoptosis in situ using TUNEL staining, and was confirmed using caspase-3 staining along with quantification of the total cellularity. The mean articular defect filling index decreased with time. After 24 weeks it was 0.7 (SD 0.10), which was significantly lower than the measurements obtained earlier (p < 0.01). The highest mean percentage of apoptotic cells were observed at 12 weeks, although the total cellularity decreased with time. Because apoptotic cell death may play a role in delamination after chondrocyte transplantation, anti-apoptotic gene therapy may protect transplanted chondrocytes from apoptosis.
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PMID:Chondrocyte apoptosis in the regenerated articular cartilage after allogenic chondrocyte transplantation in the rabbit knee. 1767 98

Vitamin K(2) (menaquinone-4, MK-4) has been reported to induce apoptosis in hepatocellular carcinoma, leukemia and myelodysplastic syndrome cell lines. The effects of MK-4 on the development of arthritis have never been addressed thus far. In the present study, we investigated the effect of MK-4 upon the proliferation of rheumatoid synovial cells and the development of arthritis in collagen-induced arthritis. We analyzed the effect of MK-4 on the proliferation of fibroblast-like synoviocytes using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The pro-apoptotic effect of MK-4 upon fibroblast-like synoviocytes was investigated with annexin V staining and DNA fragmentation and caspase 3/7 assays. Moreover, we analyzed the effect of MK-4 on the development of collagen-induced arthritis in female dark agouti rats. Our results indicated that MK-4 inhibited the proliferation of fibroblast-like synoviocytes and the development of collagen-induced arthritis in a dose-dependent manner. We conclude that MK-4 may represent a new agent for the treatment of rheumatoid arthritis in the setting of combination therapy with other disease-modifying antirheumatic drugs.
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PMID:Anti-arthritis effects of vitamin K(2) (menaquinone-4)--a new potential therapeutic strategy for rheumatoid arthritis. 1768 Oct 15

Pancreatic cancer is one of the most aggressive malignant diseases. We recently reported that N-cadherin plays a key role in tumor progression and metastasis in pancreatic cancer. For this study, we sought to determine if an N-cadherin-blocking peptide (ADH-1) could prevent N-cadherin-mediated tumor progression in a mouse model for pancreatic cancer. The effect of ADH-1 on N-cadherin-mediated cell scattering and migration on collagen I was examined using pancreatic cancer cells. We also examined the influence of ADH-1 on cell apoptosis. Furthermore, in vivo animal studies were performed using orthotopic injection of N-cadherin overexpressing BxPC-3 cells with or without ADH-1 treatment. BxPC-3 and Capan-1 cells exhibited increased expression of N-cadherin in response to collagen I. This increase in N-cadherin promoted cell scattering and migration in response to collagen I. ADH-1 prevented these changes, but did not inhibit upregulation of N-cadherin. TUNEL assays and immunoblots for caspase-3 showed that ADH-1 induced apoptosis in a concentration dependent and N-cadherin dependent manner in pancreatic cancer cells. ADH-1 treatment resulted in significant reductions in tumor growth and lung metastasis in a mouse model for pancreatic cancer. The N-cadherin antagonist, ADH-1 has significant antitumor activity against N-cadherin-expressing cells using in vitro assays and in an orthotopic mouse model for pancreatic cancer, raising the possibility that N-cadherin antagonists have therapeutic potential for the treatment of pancreatic cancer in humans.
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PMID:ADH-1 suppresses N-cadherin-dependent pancreatic cancer progression. 1772 21

Low-molecular-weight colloidal crystals with enhanced biocompatibility and ordered porous structure are used in drug-delivery systems. The objective of our study is to demonstrate the use of silica nanoscale colloid particles for localized recombinant DNA release. The colloids were coated with collagen-containing viral vector constructs of lentiviral green fluorescent protein (GFP), and solidified at 37 degrees C. The colloid-collagen-viral vector platform (CCP) was transferred to cell monolayer cultures of human lung fibroblasts. Results show specific infection of cells directly beneath the platform, as evidenced by positive GFP in their cytoplasm, while neighboring cells show no cytoplasmic GFP The infection of specific cells is probably due to the gradual release of viral particles from the collagen matrix by cell-secreted collagenase, which avoids overdosing the cells with viral particles, resulting from the cytopathic effect often seen with high-titer viral infection. Cells infected with the lentiviral-GFP or lentivirus alone, not incorporated into the colloid-collagen device, show caspase 3-associated apoptotic cell death. This suggests that colloidal crystal-coated collagen may be used as a powerful platform to deliver genes of choice to localized subgroups of specific cells of interest. This specificity in the delivery mode is beneficial for functional studies of gene-directed impact on a particular cell population of interest in a heterogeneous cell culture.
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PMID:Localized delivery of DNA to the cells by viral collagen-loaded silica colloidal crystals. 1782 89

Obstructive sleep apnea (OSA) increases cardiovascular morbidity and mortality. We have reported that chronic intermittent hypoxia (CIH), a direct consequence during OSA, leads to left ventricular (LV) remodeling and dysfunction in rats. The present study is to determine LV myocardial cellular injury that is possibly associated with LV global dysfunction. Fifty-six rats were exposed either to CIH (nadir O(2) 4-5%) or sham (handled normoxic controls, HC), 8 h/day for 6 wk. At the end of the exposure, we studied LV global function by cardiac catheterization, and LV myocardial cellular injury by in vitro analyses. Compared with HC, CIH animals demonstrated elevations in mean arterial pressure and LV end-diastolic pressure, but reductions in cardiac output (CIH 141.3 +/- 33.1 vs. HC 184.4 +/- 21.2 ml x min(-1) x kg(-1), P < 0.01), maximal rate of LV pressure rise in systole (+dP/dt), and maximal rate of LV pressure fall in diastole (-dP/dt). CIH led to significant cell injury in the left myocardium, including elevated LV myocyte size, measured by cell surface area (CIH 3,564 +/- 354 vs. HC 2,628 +/- 242 microm(2), P < 0.05) and cell length (CIH 148 +/- 23 vs. HC 115 +/- 16 microm, P < 0.05), elevated terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-stained positive cell number (CIH 98 +/- 45 vs. HC 15 +/- 13, P < 0.01), elevated caspase-3 activity (906 +/- 249 vs. 2,275 +/- 1,169 pmol x min(-1) x mg(-1), P < 0.05), and elevated expression of several remodeling gene markers, including c-fos, atrial natriuretic peptide, beta-myosin heavy chain, and myosin light chain-2. However, there was no difference between groups in sarcomere contractility of isolated LV myocytes, or in LV collagen deposition on trichrome-stained slices. In conclusion, CIH-mediated LV global dysfunction is associated with myocyte hypertrophy and apoptosis at the cellular level.
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PMID:Left ventricular dysfunction and associated cellular injury in rats exposed to chronic intermittent hypoxia. 1800 71


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