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)

To examine the possibility that staurosporine is applicable for the treatment of abnormal scar formation such as hypertrophic scar and keloid, the cellular process during staurosporine-induced apoptosis was analyzed in myofibroblasts isolated from a rat granulation tissue pouch. Staurosporine induced myofibroblast apoptosis in a time- and dose-dependent manner with typical morphologic changes. Staurosporine (1 microM) activated caspase-3 up to 3.6-fold by cleaving pro-caspase-3 (32 kDa) to active forms (17, 19, and 20 kDa). Microfilaments mainly composed of alpha-smooth muscle actin, a contractile protein characterizing myofibroblasts, were degraded during staurosporine-induced apoptosis. The degradation of alpha-smooth muscle actin bundles was detected as early as 1 h after the treatment with staurosporine. Recombinant active caspase-3 and staurosporine-stimulated caspase-3 both cleaved purified alpha-smooth muscle actin in vitro. These results suggested that alpha-smooth muscle actin is directly degraded by caspase-3 in response to apoptotic stimuli in myofibroblasts. In addition, bleomycin (100 ng per ml) and cisplatin (1 mM) also induced myofibroblast apoptosis by activating caspase-3, suggesting that these agents have a potential therapeutic value for abnormal scar formation.
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PMID:Staurosporine-induced cleavage of alpha-smooth muscle actin during myofibroblast apoptosis. 1244 85

To examine the possibility that staurosporine is applicable for the treatment of abnormal scar formation such as hypertrophic scar and keloid, the cellular process during staurosporine-induced apoptosis was analyzed in myofibroblasts isolated from a rat granulation tissue pouch. Staurosporine induced myofibroblast apoptosis in a time- and a dose-dependent manner with typical morphological changes. Staurosporine activated caspase-3 up to 3.6-fold by cleaving pro-caspase-3 to active forms. Alpha-smooth muscle actin was degraded during staurosporine-induced apoptosis. The degradation of alpha-smooth muscle actin was detected at an early stage of staurosporine-induced apoptosis. Recombinant active caspase-3 and staurosporine-stimulated caspase-3 both cleaved purified alpha-smooth muscle actin in vitro. These results suggested that alpha-smooth muscle actin is directly degraded by caspase-3 in response to apoptotic stimuli in myofibroblasts.
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PMID:[Caspase-3-mediated alpha-smooth muscle actin cleavage during staurosporine-induced myofibroblast apoptosis]. 1249 92

Precision-cut rat lung slices have been employed in combination with an extensive immunohistochemistry of paraffin-embedded slices for monitoring of early pathohistological changes after exposure to CdCl(2)/TGF-beta(1). Three days of CdCl(2) exposure in combination with TGF-beta(1) seem to be sufficient to induce lung injury with alterations similar to changes observed in early lung fibrogenesis: (1) extracellular matrix accumulation and myofibroblast transdifferentiation (Sirius red staining, collagen type IV, alpha-smooth muscle actin), (2) type I cell injury with loss of type I cell antigens (T1alpha antigen, aquaporin-5, RAGE), (3) increased apoptosis of pulmonary cells (active caspase-3, vimentin cleavage product V1 of caspase-9), and (4) activation of microvascular endothelial cells (podocalyxin, caveolin-1). Western blot analysis confirmed the increasing amount of alpha-smooth muscle actin, the loss of T1alpha antigen, and the increase in caveolin-1 immunoreactivity. The explant culture using CdCl(2)/TGF-beta(1) provides a suitable tool for the study of other factors involved in pulmonary pathology including transcription factors, cytokines, and other metabolites involved in early stages of fibrogenesis.
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PMID:Early signs of lung fibrosis after in vitro treatment of rat lung slices with CdCl2 and TGF-beta1. 1475 65

Ischemia-induced acute renal failure (ARF) is a disorder with high morbidity and mortality. ARF is characterized by a regeneration phase, yet its molecular basis is still under study. Changes in gene expression have been reported in ARF, and some of these genes are specific for nephrogenic processes. We tested the hypothesis that the regeneration process developed after ischemia-induced ARF can be characterized by the reexpression of important regulatory proteins of kidney development. The distribution pattern and levels of nephrogenic proteins in rat kidneys after ischemia were studied by immunohistochemistry and immunoblot analysis. Ischemic damage was assessed by conventional morphology, serum creatinine, and the apoptotic markers terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and caspase 3. The hypoxia levels induced by ischemia were assessed by specific markers: hypoxia induced factor (HIF)-1alpha and 2-pimonidazole. In kidneys with ARF, an important initial damage was observed through periodic acid Schiff staining, by the induction of damage markers alpha-smooth muscle actin (alpha-SMA) and macrophages (ED-1) and by apoptosis induction. In agreement with diminishing renal damage at the initial reparation phase, the expression of the mesenchymal proteins vimentin, neural cell adhesion molecules (Ncam), and the epithelial markers, Pax-2, Noggin, and basic fibroblast growth factor was observed; after, in a second phase, the tubular markers bone morphogen protein 7, Engrailed, and Lim-1, as well as the transcription factors Smad and p-Smad, were observed. Additionally, the endothelial markers VEGF and Tie-2 were induced at the initial and middle stages of regeneration phase, respectively. The expression of these proteins was restricted in time and space, as well as spatially and temporally. Because all of these proteins are important in maintaining a functional kidney, these results suggest that during the regeneration process after induced hypoxia, these nephrogenic proteins can be reexpressed in a similar fashion to that observed during development, thus restoring mature kidney function.
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PMID:Ischemic acute renal failure induces the expression of a wide range of nephrogenic proteins. 1628 88

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

The regulatory role of regucalcin on cell responses for tumor necrosis factor-alpha (TNF-alpha) or transforming growth factor-beta1 (TGF-beta1) was investigated using the cloned normal rat kidney proximal tubular epithelial NRK52E cells overexpressing regucalcin. NRK52E cells (wild type) and stable regucalcin (RC)/pCXN2-transfected cells (transfectant) were cultured for 72 h in a medium containing 5% bovine serum (BS) to obtain subconfluent monolayers. After culture, cells were further cultured for 24-72 h in medium without BS containing either vehicle, TNF-alpha (0.1 or 1.0 ng/ml of medium), or TGF-beta1 (1.0 or 5.0 ng/ml). Culture with TNF-alpha or TGF-beta1 caused a significant decrease in the number of wild-type cells. This decrease was significantly prevented in transfectants overexpressing regucalcin. Agarose gel electrophoresis showed the presence of low-molecular-weight deoxyribonucleic acid (DNA) fragments of adherent wild-type cells cultured with TNF-alpha (1.0 ng/ml) or TGF-beta1 (5.0 ng/ml). This DNA fragmentation was significantly suppressed in transfectants. TNF-alpha- or TGF-beta1-induced cell death was significantly prevented in culture with caspase-3 inhibitor (10(-8) M). Nitric oxide (NO) synthase activity in wild-type cells was significantly increased by addition of calcium chloride (10 microM) and calmodulin (5 microg/ml) into the enzyme reaction mixture. This increase was significantly suppressed in transfectants. Culture with TNF-alpha caused a significant increase in NO synthase activity in wild-type cells. The effect of TNF-alpha was not seen in transfectants. Culture with TGF-beta1 did not cause a significant increase in NO synthase activity in wild-type cells and transfectants. Culture with TNF-alpha or TGF-beta1 caused a remarkable increase in alpha-smooth muscle actin in wild-type cells. This increase was significantly prevented in transfectants. The expression of Smad 2 or NF-kappaB mRNAs was significantly increased in transfectants as compared with that of wild-type cells. Smad 3 or glyceroaldehyde-3-phosphate dehydrogenase (G3PDH) mRNA expression was not significantly changed in transfectants. NF-kappaB mRNA expression in wild-type cells was significantly increased with culture of TNF-alpha. Smad 2 mRNA expression was significantly enhanced in wild-type cells cultured with TGF-beta1. These effects of TNF-alpha or TGF-beta1 were not significantly enhanced in transfectants. This study demonstrates that overexpression of regucalcin has suppressive effects on cell responses which are mediated through intracellular signaling pathways of TNF-alpha or TGF-beta1 in kidney NRK52E cells.
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PMID:Overexpression of regucalcin suppresses cell response for tumor necrosis factor-alpha or transforming growth factor-beta1 in cloned normal rat kidney proximal tubular epithelial NRK52E cells. 1706 80

Liver fibrosis and cirrhosis may be reversible, possibly through the selective clearance of activated hepatic stellate cells/myofibroblasts by apoptosis. Hepatic stellate cells transdifferentiate into myofibroblast-phenotype cells in culture, a process that recapitulates hepatic stellate cell activation in vivo. Bakuchiol, a prenylated phenolic terpene isolated from the seed of Psoralea corylifolia L. (Leguminosae), reduced activated hepatic stellate cells when treated to rats during liver injury recovery period as demonstrated by alpha-smooth muscle actin immunostaining in rat liver and induced apoptosis in activated hepatic stellate cells/myofibroblasts as demonstrated by DNA fragmentation, activation of caspase-3, release of cytochrome c into the cytoplasm, translocation of Bax into mitochondria, and the proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) in vitro. Bakuchiol-induced apoptosis was prevented by z-DEVD-fmk, a specific inhibitor of caspase-3, and z-VAD-fmk, a general caspase inhibitor, suggesting that bakuchiol-induced apoptosis occurs through a caspase-3-dependent pathway in vitro. Bakuchiol treatment stimulated the activation of extracellular signal-regulated kinase 1/2 (ERK), c-Jun NH2-terminal protein kinase (JNK), and p38 mitogen-activated protein kinases (MAPK) in vitro. Pretreatment with SP600125 attenuated the bakuchiol-induced translocation of Bax into mitochondria, cytochrome c release into the cytosol, caspase-3 activation, and PARP cleavage. In contrast, preincubation with SB203580, a p38 MAPK inhibitor, and U0126, an ERK inhibitor, had no effect on bakuchiol-induced cell death and caspase-3 activity. Taken together, these findings indicate that bakuchiol induces caspase-3-dependent apoptosis through the activation of JNK, followed by Bax translocation into mitochondria in rat liver myofibroblasts.
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PMID:Bakuchiol-induced caspase-3-dependent apoptosis occurs through c-Jun NH2-terminal kinase-mediated mitochondrial translocation of Bax in rat liver myofibroblasts. 1729 78

Apoptosis of alveolar epithelial cells (AECs) is believed to be critical for the development of bleomycin (BLEO)-induced pulmonary fibrosis. Previous studies showed that apoptosis of alveolar epithelial cells in response to BLEO could be abrogated by antisense oligonucleotides against angiotensinogen (AGT) mRNA and requires angiotensin II (ANG II) synthesis de novo [17]. In this study we hypothesized that blockade of local pulmonary ANG II synthesis by intratracheal (I.T.) administration of antisense oligonucleotides against AGT mRNA might attenuate BLEO-induced apoptosis of AECs and prevent pulmonary fibrosis. In a BLEO-induced rat model of lung fibrosis, endogenous lung AGT was upregulated in vivo as early as 3 hours after BLEO instillation, as detected by RT-PCR, in situ hybridization and immunohistochemistry. AGT mRNA and angiotensin peptides were localized in type II alveolar epithelial cells and also colocalized with alpha-smooth muscle actin (alpha-SMA), a marker of myofibroblasts. Tagged antisense administered I.T. was specifically accumulated by the lung relative to liver and kidney, and localized primarily in the epithelium of airways and cells within alveolar walls. The intratracheal AGT antisense reduced BLEO-induced pulmonary fibrosis measured by lung hydroxyproline assay, decreased lung AGT and active caspase-3 proteins, and reduced the number of apoptotic epithelial cells but had no effect on the serum ANG II concentration. These data are consistent with the hypothesis that lung-derived AGT and local pulmonary ANG II are required for BLEO-induced pulmonary fibrosis, and suggest the possibility of antisense-based manipulation of the local angiotensin system as a potential treatment of fibrotic lung diseases.
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PMID:Attenuation of bleomycin-induced pulmonary fibrosis by intratracheal administration of antisense oligonucleotides against angiotensinogen mRNA. 1750 34

CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is a key component in endoplasmic reticulum (ER) stress-mediated apoptosis. The goal of the study was to investigate the role of CHOP in cholestatic liver injury. Acute liver injury and liver fibrosis were assessed in wild-type (WT) and CHOP-deficient mice following bile duct ligation (BDL). In WT livers, BDL induced overexpression of CHOP and Bax, a downstream target in the CHOP-mediated ER stress pathway. Liver fibrosis was attenuated in CHOP-knockout mice. Expression levels of alpha-smooth muscle actin and transforming growth factor-beta1 were reduced, and apoptotic and necrotic hepatocyte death were both attenuated in CHOP-deficient mice. Hepatocytes were isolated from WT and CHOP-deficient mice and treated with 400 microM glycochenodeoxycholic acid (GCDCA) for 8 h to examine bile acid-induced apoptosis and necrosis. GCDCA induced overexpression of CHOP and Bax in isolated WT hepatocytes, whereas CHOP-deficient hepatocytes had reduced cleaved caspase-3 expression and a lower propidium iodide index after GCDCA treatment. In conclusion, cholestasis induces CHOP-mediated ER stress and triggers hepatocyte cell death, and CHOP deficiency attenuates this cell death and subsequent liver fibrosis. The results demonstrate an essential role of CHOP in development of liver fibrosis due to cholestatic liver damage.
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PMID:CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury. 1817 71

The clinicopathologic and immunohistochemical features of 69 pediatric examples of infantile digital fibroma/fibromatosis (IDF) were analyzed. Thirty males, 26 females, and 1 child (sex unstated) ranging from newborn to 120 months of age (median, 12 mo) manifested 74 lesions (5 identified in follow-up) involving the toe or finger (n=71) and the hand or foot (n=3). Tumors ranged in size from 3 to 35 (median, 10) mm. All but 4 study members presented with a solitary lesion. Metachronous IDFs developed in 7 patients within 17 to 82 months. Microscopically, a cytologically bland, fibroproliferative lesion was observed forming a dome-shaped/polypoid nodule directly beneath the epidermis and invading dermal adnexa. Mitotic figures per 20 high-powered fields ranged from 0 to 7 (median, 1). Paranuclear cytoplasmic inclusions were identified in 57 tumors. Tumor cells immunohistochemically expressed calponin (11 of 11 tumors), desmin (9/9), alpha-smooth muscle actin (11/11), CD99 (11/11), CD117 (6/8), heavy caldesmon (2/11 and scattered cytoplasmic inclusions in 4 tumors), CD10 (1/9), nuclear beta-catenin (2/11), and CD34 (1/11), but not muscle actin (HUC1-1), keratins, estrogen/progesterone receptor proteins, or activated caspase-3. Twenty-eight of 38 patients (74%) experienced recurrent/persistent disease (single in 22; multiple in 6) (median, 4 mo after surgery). One recurrent tumor spontaneously regressed and the size of another remained unchanged for almost 17 years before reexcision. All 23 patients with >5 years follow-up are currently disease free (median disease-free interval, 23 y). Minor postoperative functional/cosmetic complaints were reported in 47%. No patient with adequate clinical data developed the digitocutaneous dysplasia syndrome or a conventional fibromatosis, or relayed a family history of IDF/conventional fibromatosis. Our results indicate that IDF is a unique myofibroblastic process separable from conventional fibromatoses and from histologic mimics. Conservative excision or observation after biopsy (with additional surgery employed as necessary) are recommended treatment options.
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PMID:Infantile digital fibroma/fibromatosis: a clinicopathologic and immunohistochemical study of 69 tumors from 57 patients with long-term follow-up. 1883 Jan 28


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