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)

cDNA microarray analysis was performed to screen 15,000 genes and expressed sequence tags (ESTs) to identify changes in the ischemia-reperfused (I-R) rat myocardial transcriptome in the early (day 2) and late (day 7) inflammatory phases of acute myocardial infarction. Lists of candidate genes that were affected by I-R transiently (2 or 7 days only) or on a more sustained basis (2 and 7 days) were derived. The candidate genes represented three major functional categories: extracellular matrix, apoptosis, and inflammation. To expand on the findings from microarray studies that dealt with the two above-mentioned time points, tissues collected from days 0, 0.25, 2, 3, 5, and 7 after reperfusion were examined. Acute myocardial infarction resulted in upregulation of IL-6 and IL-18. Genes encoding extracellular matrix proteins such as types I and III collagen were upregulated in day 2, and that response progressively grew stronger until day 7 after I-R. Comparable response kinetics was exhibited by the candidate genes of the apoptosis category. Caspases-2, -3, and -8 were induced in response to acute infarction. Compared with the myocardial tissue from the sham-operated rats, tissue collected from the infarct region stained heavily positive for the presence of active caspase-3. Laser microdissection and pressure catapulting technology was applied to harvest infarct and adjacent noninfarct control tissue from a microscopically defined region in the rat myocardium. Taken together, this work presents the first evidence gained from the use of DNA microarrays to understand the molecular mechanisms implicated in the early and late inflammatory phases of the I-R heart.
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PMID:Transcriptome analysis of the ischemia-reperfused remodeling myocardium: temporal changes in inflammation and extracellular matrix. 1655 47

Childhood chronic inflammatory disease can be associated with transient and permanent growth retardation. This study examined the potential for spontaneous growth recovery following pro-inflammatory cytokine exposure. Murine ATDC5 chondrogenic cells and postnatal metatarsals were exposed to interleukin (IL)-1beta, IL-6 and tumour necrosis factor-alpha (TNFalpha), and their growth and proliferative capacity were determined following recovery. TNFalpha and IL-1beta reduced chondrocyte proliferation and aggrecan and collagen types II and X expression at minimum concentrations of 10 ng/ml and 0.1 ng/ml respectively. TNFalpha but not IL-1beta exposure led to increased caspase-3 activity and altered cellular morphology, consistent with reduced viability. Cytokine exposure particularly inhibited proteoglycan synthesis. This effect was dose and duration dependent. Compared with the control, IL-1beta and TNFalpha led to a 71% and 45% reduction in metatarsal growth after 8 days of exposure respectively (P < 0.05). An additive effect of IL-1beta combined with TNFalpha was observed (110% decrease; P < 0.05). Metatarsals exposed to IL-1beta or TNFalpha individually for a 2-day period, and allowed to recover spontaneously in the absence of cytokines for a further 6 days, showed normal growth trajectories. In combination, growth was 59% lower (P < 0.01) compared with control metatarsals at the end of the recovery period. Exposure to the combination for 4 days followed by a 4-day recovery period resulted in 87% decrement compared with controls (P < 0.05). IL-6 did not alter any parameter studied. IL-1beta and TNFalpha exert diverse inhibitory effects on ATDC5 chondrocyte dynamics and metatarsal growth. The extent of recovery following cytokine exposure depends on the duration of exposure, and may be incomplete following longer periods of exposure.
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PMID:The restricted potential for recovery of growth plate chondrogenesis and longitudinal bone growth following exposure to pro-inflammatory cytokines. 1664 99

Vascular endothelial growth factor (VEGF) and endostatin are angiogenic and anti-angiogenic molecules, respectively, that have been implicated in neurogenesis and neuronal survival. Using alkaline phosphatase fusion proteins, we show that the PC12 neuronal cell line contains cell membrane receptors for VEGF but not for endostatin and the collagen XV endostatin homologue. Immunocytochemistry confirmed that proliferating and differentiated PC12 cells express VEGF receptors 1, 2 and neuropilin-1. While no functional effects of VEGF on PC12 cell proliferation and differentiation could be observed, a slight VEGF-induced reduction of caspase-3 activity in differentiated apoptotic PC12 cells was paralleled by transient activation of ERK1/2 and Akt. In direct comparison, nerve growth factor proved to be a strikingly more potent neuroprotective agent than VEGF.
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PMID:VEGF receptors on PC12 cells mediate transient activation of ERK1/2 and Akt: comparison of nerve growth factor and vascular endothelial growth factor. 1673 52

Fibroblast/myofibroblast expansion is critical in the pathogenesis of pulmonary fibrosis. To date, most research has focused on profibrotic mediators, whereas studies on antifibrotic factors are scanty. In this study, we explored the effects of acidic fibroblast growth factor (FGF-1) and FGF-1 plus heparin (FGF-1+H) on fibroblast growth rate, apoptosis, and myofibroblast differentiation. Heparin was used because it participates in FGF-1 signaling. Growth rate was evaluated by WST-1 colorimetric assay, DNA synthesis by [(3)H]thymidine incorporation, and apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and cleaved caspase 3. Expression of alpha-smooth muscle actin (alpha-SMA) was examined by immunocytochemistry, flow cytometry, real-time PCR, and immunoblotting. Despite the induction of DNA synthesis, FGF-1+H significantly reduced fibroblast growth rate. This correlated with a significant increase in apoptosis, evaluated by TUNEL (41.6 +/- 1.4% vs. 12.5 +/- 0.6% from controls; P < 0.01) and cleaved caspase 3 (295 +/- 32 vs. 200 +/- 19 ng/10(6) cells from controls; P < 0.05). Double immunostaining (alpha-SMA-TUNEL) revealed that the levels of induced apoptosis were similar in fibroblasts and myofibroblasts. FGF-1+H inhibited the effect of TGF-beta1 on myofibroblast differentiation. alpha-SMA-positive cells were reduced by immunocytochemistry from 44.5 +/- 6.5% to 10.9 +/- 1.9% and by flow cytometry from 30.6 +/- 2.5% to 7.7 +/- 0.6% (P < 0.01). Also, FGF-1+H significantly inhibited the TGF-beta1 induction of alpha-SMA quantified by real-time PCR and Western blot. This decrease was associated with a 35% reduction in TGF-beta1-induced collagen gel contraction. The effect of FGF-1+H was mediated by a significant decrease of TGF-beta1-induced Smad2 phosphorylation. FGF-1 alone exhibited similar but lower effects. These findings suggest that FGF-1 can have an antifibrogenic role, inducing apoptosis of fibroblasts and inhibiting myofibroblast differentiation.
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PMID:Acidic fibroblast growth factor decreases alpha-smooth muscle actin expression and induces apoptosis in human normal lung fibroblasts. 1676 79

Cartilage loss in osteoarthritis is characterized by cartilage degradation and chondrocyte death. Cartilage degradation is induced by activation of matrix-metalloproteinases (MMPs) activity and degradation of glycosaminoglycan (GAG) and collagen. Also, chondrocyte death is induced by the apoptosis through the activation of MAP kinase and caspases activities. On the basis of this background, our study was designed to examine the cartilage protective and anti-apoptotic effect of Aralia cordata. Cartilage explants and Chondrocytes were cultured from rabbit knee joint cartilage and treated by 5 ng/ml IL-1alpha. Cartilage and chondroprotective effects of Aralia cordata were determined by measuring (1) GAG and collagen expression, (2) GAG and collagen degradation, (3) TIMP and MMPs expression, and (4) TIMP and MMPs activity. Anti-apoptotic effects of Aralia cordata were determined by measuring (1) JNK and p38 MAP kinase expression, (2) apoptotic cells by flow cytometry, and (3) caspase-3 activity. In cartilage explants and chondroctyes treated by IL-1alpha, Aralia cordata showed the decrease of GAG and collagen degradation, decrease of MMPs (MMP-1, -3, -13) activity, and increase of TIMP-1 activity in a dose-dependent manner. Aralia cordata also showed anti-apoptotic effect by inhibition of early and late apoptotic cells, sub-G1 phase cells, and caspase-3 activity through the downregulation of JNK and p38 MAP kinase signaling pathway. Aralia cordata inhibited the cartilage and chondrocyte destruction through the downregulation of MMPs activities and the inhibition of proteoglycan and collagen degradation. Also, Aralia cordata inhibited the chondrocyte apoptosis through the downregulation of JNK and p38 MAP kinase signal, and the inhibition of caspase-3 activity.
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PMID:Effect of Aralia cordata extracts on cartilage protection and apoptosis inhibition. 1681 82

Calcium-independent phospholipase A(2) (iPLA(2)) plays a pivotal role in phospholipid remodeling and many other biological processes, including inflammation and cancer development. iPLA(2) can be activated by caspase-3 via a proteolytic process in apoptotic cells. In this study we identify novel signaling and functional loops of iPLA(2) activation leading to migration of non-apoptotic human ovarian cancer cells. The extracellular matrix protein, laminin-10/11, but not collagen I, induces integrin- and caspase-3-dependent cleavage and activation of overexpressed and endogenous iPLA(2). The truncated iPLA(2) (amino acids 514-806) generates lysophosphatidic acid and arachidonic acid. Arachidonic acid is important for enhancing cell migration toward laminin-10/11. Lysophosphatidic acid activates Akt that in turn acts in a feedback loop to block the cleavage of poly-(ADP-ribose) polymerase and DNA fragmentation factor as well as prevent apoptosis. By using pharmacological inhibitors, blocking antibodies, and genetic approaches (such as point mutations, dominant negative forms of genes, and siRNAs against specific targets), we show that beta(1), but not beta(4), integrin is involved in iPLA(2) activation and cell migration to laminin-10/11. The role of caspase-3 in iPLA(2) activation and cell migration are supported by several lines of evidence. 1) Point mutation of Asp(513) (a cleavage site of caspase-3 in iPLA(2)) to Ala blocks laminin-10/11-induced cleavage and activation of overexpressed iPLA(2), whereas mutation of Asp(733) to Ala has no such effect, 2) treatment of inhibitors or a small interfering RNA against caspase-3 results in decreased cell migration toward laminin-10/11, and 3) selective caspase-3 inhibitor blocks cleavage of endogenous iPLA(2) induced by laminin-10/11. Importantly, small interfering RNA-mediated down-regulation of endogenous iPLA(2) expression in ovarian carcinoma HEY cells results in decreased migration toward laminin, suggesting that our findings are pathophysiologically important.
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PMID:Caspase-3-dependent activation of calcium-independent phospholipase A2 enhances cell migration in non-apoptotic ovarian cancer cells. 1688 68

Lysophosphatidic acid (LPA) is a phospholipid messenger with diverse effects mediated via receptors LPA1, LPA2 and LPA3. Our previous study revealed that serum LPA level is elevated after myocardial infarction (MI). However, very little is known about the effects of LPA on cardiac fibroblasts (CFs) that play a crucial role in left ventricular remodeling after MI. Here we demonstrated that LPA dose-dependently induced proliferation and collagen synthesis with the maximum stimulation at 10 microM that was preferentially mediated by LPA3. LPA also dose-dependently induced apoptotic cell death, as estimated by MTT assay, hoechst staining, TUNEL and flow cytometric analysis, with an IC(50) of 50 microM. Moreover, apoptotic cell death may involve mitochondrial dysfunction and activation of caspase-3. Apoptosis induced by LPA might be mediated by LPA1. These data suggest that LPA exerts dual proliferative and proapoptotic actions mediated by specific LPA receptor subtypes.
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PMID:Specific receptor subtype mediation of LPA-induced dual effects in cardiac fibroblasts. 1689 Feb 24

Class 3 semaphorins (sema 3) are secreted guidance proteins. Sema 3A expressed by endothelial cells controls vascular morphogenesis through integrin inhibition. Sema 3C is required for normal cardiovascular patterning. Here we examined the potential role of sema 3C as regulator of endothelial cell function in vitro using mouse glomerular endothelial cells (MGEC). We determined that MGEC express sema 3C mRNA and protein and its receptors mRNA. Recombinant sema 3C induced MGEC proliferation 18 +/- 2% above control, as assessed by bromodeoxyuridine (BrdU) incorporation, and reduced starvation-induced apoptosis by 46 +/- 3%, as indicated by an in situ marker of activated caspase 3. Sema 3C increased MGEC adhesion to fibronectin 79 +/- 13% and to collagen 55 +/- 12% as compared with control. Sema 3C-induced MGEC adhesion was prevented by integrin blocking antibodies and involved beta1 integrin serine phosphorylation. Sema 3C-induced MGEC adhesion and proliferation were similar to those induced by vascular endothelial growth factor (VEGF)-A. Sema 3C induced a 44 +/- 11% increase in MGEC directional migration and stimulated MGEC capillary-like network formation on collagen I gels. Collectively, our data indicate that sema 3C promotes glomerular endothelial cell proliferation, adhesion, directional migration, and tube formation in vitro by stimulating integrin phosphorylation and VEGF120 secretion, functions that are similar to VEGF-A and opposite to sema 3A.
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PMID:Semaphorin 3C regulates endothelial cell function by increasing integrin activity. 1694 Apr 38

Advanced glycation end products (AGEs) are elevated in aged and diabetic individuals and are associated with pathological changes associated with both. Previously we demonstrated that the AGE N(epsilon)-(carboxymethyl)lysine (CML)-collagen induced fibroblast apoptosis through the cytoplasmic and mitochondrial pathways and the global induction of proapoptotic genes. In the present study we investigated upstream mechanisms of CML-collagen-induced apoptosis. CML-collagen induced activation of the proapoptotic transcription factor FOXO1 compared with unmodified collagen. When FOXO1 was silenced, CML-collagen-stimulated apoptosis was reduced by approximately 75% compared with fibroblasts incubated with nonsilencing small interfering RNA, demonstrating the functional significance of FOXO1 activation (P < 0.05). CML-collagen but not control collagen also induced a 3.3-fold increase in p38 and a 5.6-fold increase in JNK(1/2) activity (P < 0.05). With the use of specific inhibitors, activation of p38 and JNK was shown to play an important role in CML-collagen-induced activation of FOXO1 and caspase-3. Moreover, inhibition of p38 and JNK reduced CML-collagen-stimulated apoptosis by 48 and 57%, respectively, and by 89% when used together (P < 0.05). In contrast, inhibition of the phosphatidylinositol 3-kinase/Akt pathway enhanced FOXO1 activation. p38 and JNK stimulation by CML-collagen was almost entirely blocked when formation of ROS was inhibited and was partially reduced by NO and ceramide inhibitors. These inhibitors also reduced apoptosis to a similar extent. Together these data support a model in which AGE-induced apoptosis involves the formation of ROS, NO, and ceramide and leads to p38 and JNK MAP kinase activation, which in turn induces FOXO1 and caspase-3.
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PMID:Advanced glycation end products induce apoptosis in fibroblasts through activation of ROS, MAP kinases, and the FOXO1 transcription factor. 1700 4

Expansion of articular chondrocytes in monolayer culture leads to loss of the unique chondrocyte phenotype and the cells' redifferentiation capacity. Dedifferentiation of chondrocytes in monolayer culture is a challenging problem for autologous chondrocyte transplantation (ACT). It is well established that Igf-I exerts positive anabolic effects on chondrocytes in vivo and in vitro. Accordingly, in this study, we examined whether the anabolic insulin-like growth factor-I (Igf-I) is capable of extending the chondrogenic potential of dedifferentiated chondrocytes in vitro. Chondrocyte monolayers were cultured up to 10 passages. At each passage chondrocytes were stimulated with Igf-I (10ng/ml) and introduced to high-density cultures for up to 7 days. Expression of collagen type II, cartilage-specific proteoglycans, activated caspase-3, integrin beta1, extracellular signal-regulated kinase (Erk) and Sox9 was examined by Western blotting, immunoprecipitation and immunomorphological techniques. Monolayer chondrocytes rapidly lost their differentiated phenotype. When introduced to high-density cultures, only chondrocytes from P1-P4 redifferentiated. In contrast, Igf-I treated cells from P1 up to P7 redifferentiated and formed cartilage-like tissue in high-density culture. P8-P10 cells exhibited apoptotic alterations and produced significantly less matrix. Igf-I markedly increased expression of integrin beta1, Erk and Sox9. Immunoprecipitation revealed that phosphorylated Erk1/2 physically interacts with Sox9 in chondrocyte nuclei, suggesting a previously unreported functional association which was markedly enhanced by Igf-I. Treatment of chondrocyte cultures with Igf-I stabilizes chondrogenic potential, stimulates Sox9 and promotes molecular interactions between Erk and Sox9. These effects appear to be regulated by the integrin/MAPK signaling pathways.
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PMID:Igf-I extends the chondrogenic potential of human articular chondrocytes in vitro: molecular association between Sox9 and Erk1/2. 1701 Sep 43


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