Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our studies have provided new insights into the biological mechanism of neuroprotection of the anti-Parkinson drug, rasagiline [N-propargyl-(1R)-aminoindan], involving the association of Bcl-2 family proteins with protein kinase C (PKC) pathway. In a model of serum withdrawal-induced apoptosis of rat pheochromocytoma PC12 cells, rasagiline and its propargyl moiety, N-propargylamine, decreased cell death via multiple neuroprotective pathways that include the stimulation of PKC phosphorylation; upregulation of PKCepsilon mRNA; induction of Bcl-X(L), Bcl-w, and brain-derived neurotrophic factor (BDNF) mRNAs; and downregulation of PKCgamma, Bad, and Bax mRNAs. Moreover, these drugs inhibited the cleavage and activation of pro-caspase-3 and poly(ADP-ribose) polymerase (PARP), while PKC inhibitor, GF109203X, reversed these actions. In addition, rasagiline decreased serum-free-induced levels of the important regulator of cell death, Bad, which was also blocked by GF109203X, indicating the involvement of PKC-dependent cell survival activity of rasagiline. Structure activity studies have established that N-propargylamine is essential for the novel neuroprotective and the neuronal cell survival activity of rasagiline since this moiety itself revealed similar protective effects and mechanisms of action. These results have led us to develop several multifunctional neuroprotective drugs containing the propargyl moiety and iron-chelating property for the treatment and/or prevention of neurodegenerative diseases.
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PMID:Novel neuroprotective mechanism of action of rasagiline is associated with its propargyl moiety: interaction of Bcl-2 family members with PKC pathway. 1617 41

Traditional use and clinical reports suggest that the culinary herb sage (Salvia officinalis) may be effective for patients with mild to moderate Alzheimer's disease (AD). In this study, we evaluated the effect of a standardized extract from the leaves of S. officinalis (SOE) and its active ingredient rosmarinic acid on Alzheimer amyloid-beta peptide (Abeta)-induced toxicity in cultured rat pheochromocytoma (PC12) cells. Incubation of PC12 cells with Abeta (fragment 1-42) for 24 h caused cell death, and this effect was reduced by SOE and its active ingredient, rosmarinic acid. Rosmarinic acid reduced a number of events induced by Abeta. These include reactive oxygen species formation, lipid peroxidation, DNA fragmentation, caspase-3 activation, and tau protein hyperphosphorylation. Moreover, rosmarinic acid inhibited phosphorylated p38 mitogen-activated protein kinase but not glycogen synthase kinase 3beta activation. These data show the neuroprotective effect of sage against Abeta-induced toxicity, which could validate the traditional use of this spice in the treatment of AD. Rosmarinic acid could contribute, at least in part, for sage-induced neuroprotective effect.
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PMID:The spice sage and its active ingredient rosmarinic acid protect PC12 cells from amyloid-beta peptide-induced neurotoxicity. 1649 7

Cell volume can be altered by two different ways, swelling and shrinkage. Cell swelling is regulated by volume-regulated Cl- channel (VRC). It is not well understood whether shrinkage is regulated by VRC. We previously found that antisense oligonucleotide specific to ClC-3 (ClC-3 antisense) prevented cell proliferation, which was related to cell swell volume regulation. In the present study, we further studied the role of ClC-3 Cl- channel in cell apoptosis which was related to cell shrinkage volume regulation by using antisense oligonucleotide specific to ClC-3 (ClC-3 antisense) and ClC-3 cDNA transfection techniques. We found that thapsigargin (TG), a specific inhibitor of the endoplasmic reticulum calcium ATPase, evoked apoptotic morphological changes (including cytoplasmic blebbing, condensation of nuclear chromatin, and the formation of apoptotic bodies), DNA laddering, and caspase-3 activation in PC12 cells (Pheochromocytoma-derived cell line). TG increased the cell apoptotic population with a decrease in cell viability. These effects were consistent with the decrease in endogenous ClC-3 protein expression, which was also induced by TG. Overexpression of ClC-3 significantly inhibited TG effect on PC12 cell apoptosis, whereas the ClC-3 antisense produced opposite effects and facilitated apoptosis induced by TG. Our data strongly suggest that ClC-3 channel in PC12 cells mediates TG-induced apoptotic process through inhibitory mechanism. Thus, it appears that ClC-3 Cl- channel mediates both cell proliferation and apoptosis through accelerative and inhibitory fashions, respectively.
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PMID:ClC-3 chloride channel prevents apoptosis induced by thapsigargin in PC12 cells. 1652 Aug 96

The rat pheochromocytoma PC12 cell line has been widely used as a model to study neuronal differentiation. In particular, after serum depletion, PC12 cells stop to proliferate and undergo apoptosis. Under such conditions, treatment with pituitary adenylate cyclase-activating polypeptide (PACAP) promotes cell survival and induces neurite outgrowth. The identification of the proteins regulated by PACAP in PC12 cells under apoptotic conditions should provide valuable information concerning the mechanisms controlling neuronal cell survival and differentiation. To this aim, PC12 cells cultured in serum-free medium were treated with PACAP (10(-7) M), proteins were extracted, separated by two-dimensional gel electrophoresis (2-DE), and identified by MALDI-ToF mass spectrometry. The comparison between 16 2-DE maps led to the characterization of 110 proteins regulated by PACAP among which 22 have been identified by automatic query of the Mascot, Aldente, and Profound servers with the ProGeR-CDD database. Seventy-six percent of these proteins, including the p17 subunit of caspase-3, the heat shock protein hsp60, and the GTPase ran were found to be repressed whereas the others notably hsp27, tubulin beta-5, and calmodulin were overexpressed. Investigation of the putative functions indicated that some of the proteins regulated by PACAP and identified in the present article could control cell survival or differentiation.
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PMID:Identification of proteins regulated by PACAP in PC12 cells by 2D gel electrophoresis coupled to mass spectrometry. 1688 96

Nerve growth factor (NGF) differentiated pheochromocytoma PC12 cells exposed to 1-methyl-4-phenylpyridinium (MPP+) toxin were used as an in vitro pharmacological model of Parkinson's disease to examine the neuroprotective effects of 4-hydroxy-2,2,6,6-tetramethyl piperidine-n-oxyl (Tempol), a free radical scavenger and a superoxide dismutase-mimetic compound. MPP+-induced PC12 cell death was measured 72 h after exposure to 1.5 mM MPP+ by the release of lactate dehydrogenease, caspase-3 activation and stimulation of survival and stress mitogen-activated protein kinases. Exposure of PC12 cells to MPP+ activated ERK1 and ERK2 (forty-fold over control after 72 h), JNK1 and JNK2 (fourfold after 48 h) and p-38alpha (tenfold after 24 h). Pretreatment of PC12 cells with 500 microM Tempol, 1 h before induction of the MPP+ insult, reduced by 70% the release of LDH into the medium, inhibited caspase-3 activity by 30% and improved by 33% mitochondrial function, effects correlated with a 70% reduction in ERK1 and ERK2 phosphorylation activity. These findings support the neuroprotective effect of Tempol in the MPP+-induced PC12 cell death model and its use as a potential drug for treatment of Parkinson's disease.
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PMID:Neuroprotective effects of the stable nitroxide compound Tempol on 1-methyl-4-phenylpyridinium ion-induced neurotoxicity in the Nerve Growth Factor-differentiated model of pheochromocytoma PC12 cells. 1698 7

The aim of the present study was to challenge potential mechanisms of action underlying the inhibition of tumor cell proliferation by agmatine. Agmatine inhibited proliferation of the human hepatoma cells HepG2, the human adenocarcinoma cells HT29, the rat hepatoma cells McRH7777, and the rat pheochromocytoma cells PC-12. Inhibition of proliferation of HepG2 cells was associated with an abolition of expression of ornithine decarboxylase (ODC) protein and a doubling of mRNA content encoding ODC. In HepG2 cells, silencing of ODC-antizyme-1, but not of antizyme inhibitor, by RNA interference resulted in an increase of agmatine's antiproliferative effect. Thus, the distinct decrease in intracellular polyamine content by agmatine was due to a reduced translation of the synthesizing protein ODC but was not essentially mediated by induction of ODC-antizyme or blockade of antizyme inhibitor. In interaction experiments 1 mM L-arginine, 1 mM D-arginine, 1 mM citrulline, 100 microM N(omega)-nitro-L-arginine methyl ester, 1 and 10 microM sodium nitroprusside, and 1 microM N1-guanyl-1,7-diaminoheptane failed to alter agmatine's antiproliferative effect. Hence, the antiproliferative effect of agmatine in HT29 and HepG2 cells is due to an interaction with neither the NO synthases, the hypusination of eIF5A, nor an agmatine-induced reduction in availability of intracellular L-arginine. L-Arginine and citrulline, but not d-arginine, inhibited tumor cell proliferation by themselves. Their inhibitory effect was abolished after silencing of arginine decarboxylase (ADC) expression by RNA interference indicating the conversion to agmatine by ADC. Finally, in the four cell lines under study, agmatine-induced inhibition of cell proliferation was paralleled by an increase in intracellular caspase-3 activity, indicating a promotion of apoptosis.
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PMID:Molecular basis for the antiproliferative effect of agmatine in tumor cells of colonic, hepatic, and neuronal origin. 1704 95

Previous studies have reported that alcohol exposure reduces the number of neuronal-like pheochromocytoma (PC12) cells in culture. In this study, the interactive effect of coexposure of alcohol and nicotine on PC12 cell numbers was examined in comparison with the effect derived from alcohol or nicotine exposure individually. Moreover, the role of apoptosis in mediating changes in PC12 cell numbers was also investigated. It was hypothesized that alcohol would result in cell loss, and the presence of nicotine would attenuate the damaging effects of alcohol. PC12 cells were exposed to alcohol (100 mM), nicotine (10 microM), or both alcohol and nicotine for 24, 48, 72, or 96 h. Caspase-3 activity and DNA fragmentation, markers for apoptotic cell death, were measured to determine the role of apoptosis in mediating decreases in PC12 cell numbers. The findings indicated that both alcohol and nicotine exposure significantly decreased PC12 cell numbers when compared with the control treatment. Furthermore, the coexposure of these two drugs caused a significantly greater decrease in cell numbers when compared with cells exposed to either alcohol or nicotine alone. This additive effect was related to the duration of exposure with a marked reduction in cell numbers following 96 h of coexposure to alcohol and nicotine. Neither alcohol nor nicotine exposure appeared to alter caspase-3 activity or DNA fragmentation levels, suggesting that the reduction in PC12 cell numbers following alcohol and/or nicotine exposure may possibly be due to factors other than apoptosis, such as interference with proliferation rates.
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PMID:The interactive effect of alcohol and nicotine on NGF-treated pheochromocytoma cells. 1713 58

A number of studies indicate that reactive oxygen species (ROS) are involved in neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The neuroprotective effects of salvianolic acid B (SalB) from Radix Salviae miltiorrhizae (RSM) against hydrogen peroxide (H2O2)-induced rat pheochromocytoma line PC12 injury were evaluated in the present study. Vitamin E, a potent antioxidant, was employed as a positive control agent. Following exposure of cells to H2O2 (150 microM), a marked decrease in cell survival and activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), as well as increased levels of malondialdehyde (MDA) production and lactate dehydrogenase (LDH) release were observed. In parallel, H2O2 caused significant elevation in intracellular Ca2+ level and caspase-3 activity, and induced apoptotic death as determined by flow cytometric assay. However, pretreatment of the cells with SalB (0.1-10 microM) prior to H2O2 exposure blocked these H2O2-induced cellular events noticeably. Moreover, SalB exhibited significantly higher potency as compared to Vitamin E. The present findings indicated that SalB exerts neuroprotective effects against H2O2 toxicity, which might be of importance and contribute to its clinical efficacy for the treatment of neurodegenerative diseases.
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PMID:Protection of PC12 cells from hydrogen peroxide-induced cytotoxicity by salvianolic acid B, a new compound isolated from Radix Salviae miltiorrhizae. 1717 50

While Newcastle disease virus (NDV) causes serious infections in birds, it is apparently nonpathogenic in mammalian species, including humans. Previous observations and small-scale clinical trials indicated that NDV exerts oncolytic effects. Isolates of NDV were found to have selective affinity to transformed cells. We previously showed that the attenuated NDV strain MTH-68/H causes apoptotic cell death in cultures of PC12 rat pheochromocytoma cells. The aim of the present study was to extend MTH-68/H cytotoxicity testing with human tumor cell lines and to analyze certain biochemical aspects of its oncolytic effect. MTH-68/H was found to be able to kill a wide range of transformed cells by apoptosis. While caspase-8 and caspase-9 are not involved in MTH-68/H-induced apoptosis, activation of caspase-3 and caspase-12 was detected in virus-infected PC12 cells. A human glioblastoma cell line with repressible expression of the p53 protein did not show any difference in MTH-68/H sensitivity in its p53-expressing and p53-depleted states, indicating that the apoptotic process induced by MTH-68/H does not depend on p53. Apoptosis was accompanied by virus replication in two tumor cell lines tested (PC12 cells and HeLa human cervical cells), and signs of endoplasmic reticulum stress (phosphorylation of protein kinase R-like endoplasmic reticulum kinase and eIF2alpha) were also detected in transformed cells. In contrast, proliferation of nontransformed mouse and rat fibroblast cell lines and human primary fibroblasts was not affected by MTH-68/H treatment. MTH-68/H thus selectively kills tumor cell cultures by inducing endoplasmic reticulum stress leading to p53-independent apoptotic cell death.
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PMID:p53-independent endoplasmic reticulum stress-mediated cytotoxicity of a Newcastle disease virus strain in tumor cell lines. 1721 92

Epigallocatechin-3-gallate (EGCG) is a major constituent of green tea polyphenols. This study was aimed to investigate the possible mechanisms of EGCG-mediated inhibition against apoptosis in rat pheochromocytoma PC12 cells by exposure to CoCl(2). Exposure to CoCl(2) caused the generation of ROS and induced cell death with appearance of apoptotic morphology and DNA fragmentation. However, EGCG rescued the loss of viability in the cells exposed to CoCl(2) and led the reduction of DNA fragmentation and sub-G(1) fraction of cell cycle. Also, EGCG attenuated the CoCl(2)-induced disruption of mitochondrial membrane potential (DeltaPsim), release of cytochrome c from the mitochondria to cytosol and abolished the CoCl(2)-stimulated activities of the caspase cascades, caspase-9 and caspase-3. In addition, EGCG ameliorated the increase in the Bax to Bcl-2 ratio, a marker of apoptosis proceeding, induced by CoCl(2) treatment. Taken together, the present results suggest that EGCG inhibit the CoCl(2)-induced apoptosis of PC12 cells through the mitochondria-mediated apoptosis pathway involved in modulating the Bcl-2 family.
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PMID:Inhibition by epigallocatechin gallate of CoCl2-induced apoptosis in rat PC12 cells. 1724 Apr 4


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