Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

At the end of a nonconception estrous cycle, the sheep corpus luteum undergoes involution (luteolysis), a process thought to involve apoptotic deletion of cells. It is not yet clear which of the heterogeneous luteal cell types is involved or what mechanisms drive the apoptotic progression. We examined intact paraffin-embedded corpora lutea (in situ terminal dUTP nick end-labeling method) and found direct evidence for apoptotic deletion of cells during luteolysis, but not in healthy, nonregressing corpora lutea. We then sought to implement in vitro models to dissect apoptotic mechanisms in the constituent cells of the corpus luteum. Cells prepared using standard collagenase dispersion of corpus luteum were evaluated for evidence of apoptosis (DNA laddering) by direct agarose gel electrophoresis, a method that obviates the need for DNA extraction, so allowing examination of relatively few cells (< or = 0.5 x 10(6)). When cells were prepared from nonregressing corpus luteum for in vitro manipulation, a population(s) of cells undergoing spontaneous apoptosis was detected. Apoptosis was inhibited by Zn2+ (5 mM), by the tyrosine phosphatase inhibitor sodium orthovanadate (100 microM), or by maintenance at 4 degrees C. It appears that simple collagenase digestion of intact corpus luteum removes a subset of constituent cells from their survival signal, leading to rapid initiation of endonuclease activity and apoptotic cell death. Identification of the required survival factors and their actions is being pursued to facilitate development of appropriate in vitro models for this endocrine system.
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PMID:Spontaneous apoptosis of cells prepared from the nonregressing corpus luteum. 765 26

Mice carrying a targeted mutation (r) in Col1a1, encoding a collagenase-resistant form of type I collagen, have altered skeletal remodeling. In hematoxylin and eosin-stained paraffin sections, we detect empty lacunae in osteocytes in calvariae from Col1a1(r/r) mice at age 2 weeks, increasing through age 10-12 months. Empty lacunae appear to result from osteocyte apoptosis, since staining of osteocytes/periosteal osteoblasts with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling is increased in Col1a1(r/r) relative to wild-type bones. Osteocyte perilacunar matrices stained with Ab that recognizes collagenase collagen alpha1(I) chain cleavage ends in wild-type but not Col1a1(r/r) calvariae. Increased calvarial periosteal and tibial/femoral endosteal bone deposition was found in Col1a1(r/r) mice from ages 3-12 months. Calcein labeling of calvarial surfaces was increased in Col1a1(r/r) relative to wild-type mice. Daily injections of synthetic parathyroid hormone for 30 days increased calcein-surface labeling in wild-type but caused no further increase in the already high calcein staining of Col1a1(r/r) bones. Thus, failure of collagenase cleavage of type I collagen in Col1a1(r/r) mice is associated with osteocyte/osteoblast death but increases bone deposition in a manner that mimics the parathyroid hormone-induced bone surface activation seen in wild-type mice.
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PMID:Osteocyte and osteoblast apoptosis and excessive bone deposition accompany failure of collagenase cleavage of collagen. 1103 54

Intracerebral hemorrhage (ICH) is a severe complication in diabetic patients. Currently, physical exercise is recommended as a behavioral intervention to promote functional recovery in brain diseases, including ICH. Recently, hyperglycemia is known to aggravate brain injury in experimental ICH. Here, we examined the effect of treadmill exercise on the intrastriatal hemorrhage-induced neuronal cell death and cell proliferation in the dentate gyrus of hyperglycemic rats. Hyperglycemia was induced by the intraperitoneal injection of 50 mg/kg streptozotocin (STZ). Intrastriatal hemorrhage was induced by the infusion of 0.2 U collagenase into the striatum using stereotaxic instrument. Rats in the exercise groups were forced to run on a treadmill for 30 min daily for 10 days. Apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Cell proliferation was assessed by the 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry. Our data showed that in rats started treadmill exercise 24 h after ICH induction, the size of lesion induced by hemorrhage and the number of apoptotic cells were decreased significantly. The number of proliferating cells in the dentate gyrus was significantly decreased in hyperglycemic rats. Treadmill exercise markedly enhanced cell proliferation in the dentate gyrus of hyperglycemic rats. The data suggest that treadmill exercise may provide therapeutic value to ICH patients with hyperglycemia by suppressing neuronal apoptosis and increasing cell proliferation.
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PMID:Early treadmill exercise decreases intrastriatal hemorrhage-induced neuronal cell death and increases cell proliferation in the dentate gyrus of streptozotocin-induced hyperglycemic rats. 1626 Mar 51

Thrombin is thought to play an important role in brain damage associated with intracerebral hemorrhage (ICH). We previously showed that activation of mitogen-activated protein (MAP) kinases and recruitment of microglia are crucial for thrombin-induced shrinkage of the striatal tissue in vitro and thrombin-induced striatal damage in vivo. Here we investigated whether the same mechanisms are involved in ICH-induced brain injury. A substantial loss of neurons was observed in the center and the peripheral region of hematoma at 3 days after ICH induced by intrastriatal injection of collagenase in adult rats. Intracerebroventricular injection of argatroban or cycloheximide, both of which prevent thrombin cytotoxicity in vitro, exhibited a significant neuroprotective effect against ICH-induced injury. ICH-induced neuron loss was also prevented by a MAP kinase kinase inhibitor (PD98059) and a c-Jun N-terminal kinase inhibitor (SP600125). These drugs had no effect on hematoma size or ICH-induced brain edema. Activation of extracellular signal-regulated kinase in response to ICH was observed in both neurons and microglia. Despite their neuroprotective effects, MAP kinase inhibitors did not decrease the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells appearing after ICH. Identification of cell types revealed that TUNEL staining occurred prominently in neurons but not in microglia, whereas inhibition of MAP kinases resulted in appearance of TUNEL staining in microglia. These results suggest that thrombin and the activation of MAP kinases are involved in ICH-induced neuronal injury, and that neuroprotective effects of MAP kinases are in part mediated by arrestment of microglial activities.
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PMID:Involvement of thrombin and mitogen-activated protein kinase pathways in hemorrhagic brain injury. 1749 98

Angiotensin II exerts its central nervous system effects primarily via its receptors AT1 and AT2, and it participates in the pathogenesis of ischemia via AT1. The selective AT1 receptor blocker (ARB) is used in the hypertension treatment, and it exerts a variety of pleiotropic effects, including antioxidative, antiapoptotic, and anti-inflammatory effects. In this study, we investigated the therapeutic effect of the ARB telmisartan in experimental intracerebral hemorrhage (ICH) in normotensive rats. ICH was induced via the collagenase infusion or autologous blood injection. Either telmisartan at 30 mg/kg/dose or phosphate-buffered saline was orally administered 2 h after ICH induction. We evaluated hemorrhage volume, brain water content, and functional recovery, and we performed the histological analysis for terminal deoxynucleotidyl transferase dUTP nick-end labeling, leukocyte infiltration, and microglia activation. A variety of intracellular signals, in terms of oxidative stress, apoptotic molecules, and inflammatory mediators, were also measured. Telmisartan reduced hemorrhage volume, brain edema, and inflammatory or apoptotic cells in the perihematomal area. Telmisartan was noted to induce the expression of endothelial nitric-oxide synthase and peroxisome proliferator-activated receptor gamma and decrease oxidative stress, apoptotic signal, tumor necrosis factor-alpha, and cyclooxygenase-2 expression. The telmisartan-treated rats exhibited less pronounced neurological deficits and recovered better. Thus, telmisartan seems to offer neural protection, including antiapoptosis, anti-inflammatory, and antioxidant benefits in the intracerebral hemorrhage rat model.
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PMID:Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. 1753 8

Our recent study (Singla DK, Hacker TA, Ma L, Douglas PS, Sullivan R, Lyons GE, Kamp TJ, J Mol Cell Cardiol 40: 195-200, 2006) suggests that transplanted embryonic stem (ES) cells subsequent to myocardial infarction differentiate into the major cell types in the heart and improve cardiac function. However, the extent of regeneration is relatively meager compared with the observed functional improvement. The mechanisms underlying their improved function are completely unknown. In this report, we provide evidence using a cell culture model system for novel mechanisms that involve the release of cytoprotective, anti-apoptotic factor(s) from ES cells and inhibit H(2)O(2)-induced apoptosis in the rat cardiomyocyte-derived cell line H9c2. Conditioned medium (CM) from growing mouse ES cells treated with and without H(2)O(2) was generated. Apoptosis was induced after exposure to H(2)O(2) in H9c2 cells for 2 h followed by replacement with fresh cell culture or ES cell-CM. After 24 h, H9c2 cells treated with both ES cell-CMs demonstrated significantly decreased apoptosis, as determined by terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling staining, apoptotic ELISA, caspase-3 activity, and DNA ladder. Next, using Luminex technology, we examined the presence of antiapoptotic proteins cystatin c, osteopontin, and clusterin and anti-fibrotic, tissue inhibitor of metalloproteinase-1 (TIMP-1) in both ES cell-CMs. The levels of released factors were 2- to 170-fold higher than those in H9c2 cell-CM. Antiapoptotic effects of ES cell-CM were significantly inhibited with TIMP-1 antibody, suggesting that TIMP-1 is an important factor to inhibit apoptosis. Furthermore, we used CM from an TIMP-1-overexpressing cell line and demonstrated that H(2)O(2)-induced apoptosis in the H9c2 cells was significantly inhibited. These observations demonstrate that factors released from ES cells contain antiapoptotic factors and that the effects are mediated by TIMP-1. Moreover, these findings suggest that released factors might be useful for therapeutic applications in ischemic heart disease as well as for many other diseases.
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PMID:Factors released from embryonic stem cells inhibit apoptosis of H9c2 cells. 1798 32

Cellular growth and differentiation are readouts of multiple signaling pathways from the intercellular and/or extracellular milieu. The extracellular matrix through the activation of cellular receptors transmits these signals. Therefore, extracellular matrix proteolysis could affect cell fate in a variety of biological events. However, the biological consequence of inadequate extracellular matrix degradation in vivo is not clear. We developed a mouse model expressing human collagenase (matrix metalloproteinase-1, MMP-1) under the control of Col2a1 promoter. The mice showed significant growth retardation during embryogenesis and a loss of the demarcation of zonal structure and columnar array of the cartilage. Immunological examination revealed increased degradation of type II collagen and upregulation of fibronectin and alpha(5)-integrin subunit in the transgenic cartilage. The resting zone and proliferating zone of the growth plate cartilage exhibited a simultaneous increase in bromodeoxyuridine (BrdU)-incorporated proliferating cells and terminal deoxynucleotidyl transferase-mediated X-dUTP nick-end labeling-positive apoptotic cells, respectively. Chondrocyte differentiation was not disturbed in the transgenic mice as evidenced by normal expression of the Ihh and type X collagen expression. These data demonstrate that type II collagen proteolysis is an important determinant for the skeletal outgrowth through modulation of chondrocyte survival and cartilagenous growth.
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PMID:Bone growth retardation in mouse embryos expressing human collagenase 1. 1765 26

Adipose-derived stem cells (ASCs) are readily accessible multipotent mesenchymal stem cells and are known to secrete multiple growth factors, and thereby to have cytoprotective effects in various injury models. In the present study, the authors investigated the neuroprotective effect of ASCs in an intracerebral hemorrhage (ICH) model. ICH was induced via the stereotaxic infusion of collagenase, and human ASCs (three million cells per animal) isolated from human fresh fat tissue, were intravenously administered at 24 h post-ICH induction. Acute brain inflammation markers, namely, cell numbers positively stained for terminal transferase dUTP nick end labeling (TUNEL), myeloperoxidase (MPO), or OX-42, and brain water content were checked at 3 days post-ICH. In addition, the authors quantified brain degeneration by measuring hemispheric atrophy and perihematomal glial thickness at 6 weeks post-ICH, and determined modified limb placing behavioral scores weekly over 5 weeks post-ICH. The results showed that brain water content, TUNEL+, and MPO+ cell numbers were significantly reduced in the ASC-transplanted rats. ASC transplantation attenuated neurological deficits from 4 to 5 weeks post-ICH, and reduced both the brain atrophy and the glial proliferation at 6 weeks. Transplanted ASCs were found to densely populate perihematomal areas at 6 weeks, and to express endothelial markers (von Willebrand factor and endothelial barrier antigen), but not neuronal or glial markers. In summary, ASCs transplantation in the ICH model reduced both acute cerebral inflammation and chronic brain degeneration, and promoted long-term functional recovery.
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PMID:Systemic transplantation of human adipose stem cells attenuated cerebral inflammation and degeneration in a hemorrhagic stroke model. 1792 May 70

Intracerebral hemorrhage (ICH) initiates an inflammatory response with secondary growth of hemorrhage and cell death. Matrix metalloproteinase (MMP) gelatinolytic activity is increased in ICH, and synthetic inhibitors to MMPs reduce edema and hemorrhage size. Recently, we found that tissue inhibitor of metalloproteinase-3 (TIMP-3) is elevated after ischemia and colocalizes with TUNEL (terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end-labeled)-labeled cells. Tissue inhibitor of metalloproteinase-3 promotes neuronal apoptosis in vitro by blocking the shedding of the tumor necrosis factor (TNF) superfamily of death receptors/ligands by stromelysin-1 (MMP-3). However, the effect of TIMP-3 and synthetic MMP inhibitors on cell death in ICH is unclear. Therefore, we used the collagenase-induced intracerebral hemorrhage (CIH) model in Timp-3 knockout and C57Bl/6 wild-type mice to study MMP expression, hemorrhage volume, and cell death. Real-time PCR showed an increase in Mmp-3 mRNA in CIH, but similar Mmp-2 and -9 mRNA expression levels in CIH and saline-injected mice. Protein levels of pro and cleaved MMP-3 were increased in CIH, and zymographic gelatinolytic activity of MMP-9 was elevated after CIH at 72 h, suggesting an exogenous source. Apoptosis was shown by increased caspase-3 levels at 2 and 72 h, and active caspase-8 by 2 and 24 h. The Timp-3 null mouse and wild types had similar hemorrhage sizes and TUNEL-labeled cells. Unexpectedly, the broad-spectrum MMP inhibitor BB-94 increased hemorrhage size and TUNEL-labeled cells. Our results fail to implicate TIMP-3 in apoptosis in CIH, but show that BB-94 increased apoptosis in CIH, possibly by blocking shedding of TNF death receptors and/or their ligands.
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PMID:Matrix metalloproteinase inhibition facilitates cell death in intracerebral hemorrhage in mouse. 1797 90

The present study was conducted to examine the role of hecogenin-3-O-beta-D-glucopyranosyl(1-->4)-beta-D-galactopyranoside (1), which is a triterpene saponin of Tribulus terrestris in cardiocytes during chemical hypoxia-ischaemia in vitro. Neonatal rat ventricular myocytes were isolated by collagenase digestion and treated with NaCN for 12 h. Cell apoptosis was defined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) and flow cytometry. [Ca(2+)] was measured by confocal microscopy. There was a marked increase in the expression of the anti-apoptotic protein, Bcl-2, by NaCN. This change was increased by the saponin 1. PKCepsilon protein contents were increased in the cardiocyte membrane fraction in response to NaCN. PKCepsilon activation was augmented by the saponin 1. Inhibition of PKCepsilon with inhibitory peptide prevented Bcl-2 expression. Moreover, the saponin attenuated the apoptosis in cardiocyte in response to NaCN. It is therefore suggested that the saponin 1 may play a role in cardiocyte survival via PKCepsilon and Bcl-2.
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PMID:A triterpene saponin from Tribulus terrestris attenuates apoptosis in cardiocyte via activating PKC signalling transduction pathway. 1805 79


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