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)

Apoptosis of vascular smooth muscle cells plays an important role in vascular calcification (VC). However, the potential mechanism remains poorly understood. Previous studies showed that apoptosis mediated by endoplasmic reticulum stress (ERS) participates in several diseases with VC. We prepared two rat models of calcification, vitamin D(3) plus nicotine (VDN) and rapid calcification (RC), to investigate whether ERS-mediated apoptosis is activated in VC. TUNEL staining and cleaved caspase 3 protein levels illustrated enhanced apoptosis in calcification groups. Western blot analysis revealed the ERS hallmarks GRP78 and GRP94 increased by 43.9% and 91.7%, respectively, in the VDN group and GRP78 elevated by 84.0% in the RC group (all P<0.05) as compared with controls. Moreover, two molecules of ERS-induced apoptosis, caspase 12 and C/EBP homologous protein, were up-regulated nearly 3-fold (P<0.05) in the VDN group and 10-fold (P<0.01) in the RC group. Our results indicated that ERS-induced apoptosis may be involved in VC, and amelioration of ERS could be a novel strategy to prevent and treat the related diseases.
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PMID:Endoplasmic reticulum stress-mediated apoptosis is activated in vascular calcification. 1962 43

Epidemiologic and laboratory studies suggest that paraquat can be an environmental etiologic factor in Parkinson's disease (PD). One mechanism by which paraquat may mediate cell death of dopaminergic neurons is by inducing endoplasmic reticulum (ER) stress, as suggested in a recent report. In this study, we further investigated this linkage by examining ER stress cascades. To this aim, human neuroblastoma cells (SH-SY5Y cells) were treated with paraquat and the signaling cascades through which ER stress results in apoptosis were examined. Then, it was examined whether ER stress is produced by paraquat. Paraquat increased ER stress biomarker proteins, glucose-regulated protein 78 (GRP78), ER degradation-enhancing alpha-mannosidae-like protein (EDEM), and C/EBP homologous protein (CHOP). Then, it was investigated which ER stress cascades are affected by paraquat. Paraquat activated inositol-requiring enzyme 1 (IRE1), apoptosis signal regulating kinase 1 (ASK1), and c-jun kinase (JNK). Also, paraquat activated calpain and caspase 3, but did not affect the levels of intracellular calcium and the activity of caspase 12. Finally, apoptotic DNA damage by paraquat was investigated and this damage was attenuated by salubrinal (ER stress inhibitor), thioredoxin (ASK1 inhibitor) and SP600125 (JNK inhibitor). Therefore, current data indicate that paraquat activates the IRE1/ASK1/JNK cascade associated with apoptosis in SY5Y cells.
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PMID:Paraquat activates the IRE1/ASK1/JNK cascade associated with apoptosis in human neuroblastoma SH-SY5Y cells. 1973 4

Astrocytes are essential cells for maintaining brain integrity. We have recently shown that the transcription factor C/EBP homologous protein (CHOP), associated with endoplasmic reticulum (ER) stress, plays a key role in the astrocyte death induced by ischemia. Meanwhile, mediators of apoptosis downstream of CHOP in the ER stress-dependent pathway remain to be elucidated. Our aim in this work was to determine whether caspase-11, able to activate apoptotic and proinflammatory pathways, is implicated in ER stress-dependent astrocyte death in ischemic conditions. According to our results, caspase-11 is up-regulated in primary astrocyte cultures following either oxygen and glucose deprivation (OGD) or treatment with the ER-stress inducers thapsigargin and tunicamycin. Moreover, these same stimuli increased caspase-11 mRNA levels and luciferase activity driven by a caspase-11 promoter, indicating that caspase-11 is regulated at the transcriptional level. Our data also illustrate the involvement of ER stress-associated CHOP in caspase-11 regulation, insofar as CHOP overexpression by means of an adenoviral vector caused a significant raise in caspase-11. In turn, caspase-11 suppression with siRNA rescued astrocytes from OGD- and ER stress-induced death, supporting the idea that caspase-11 is responsible for the deleterious effects of ischemia on astrocytes. Finally, inhibition of caspase-1 and caspase-3 significantly reduced astrocyte death, which indicates that these proteases act as death effectors of caspase-11. In conclusion, our work contributes to clarifying the pathways leading to astrocyte death in response to ischemia by defining caspase-11 as a key mediator of the ER stress response acting downstream of CHOP.
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PMID:Caspase-11 mediates ischemia-induced astrocyte death: involvement of endoplasmic reticulum stress and C/EBP homologous protein. 1989 Sep 20

N,N-Dimethylformamide (DMF) is an organic solvent extensively used in industries such as synthetic leather, fibers and films, and induces liver toxicity and carcinogenesis. Despite a series of experimental and clinical reports on DMF-induced liver failure, the mechanism of toxicity is yet unclear. This study investigated whether DMF in combination with a low dose of hepatotoxicant enhances hepatotoxicity, and if so, on what mechanistic basis. Treatment of rats with either DMF (50-500mg/kg/day, for 3 days) or a single low dose of CCl(4) (0.2ml/kg) alone caused small increases in plasma transaminases and lactate dehydrogenase activities. However, combinatorial treatment of DMF with CCl(4) markedly increased blood biochemical changes. Histopathology confirmed the synergism in hepatotoxicity. Moreover, DMF+CCl(4) caused PARP cleavage and caspase-3 activation, but decreased the level of Bcl-xL, all of which confirmed apoptosis of hepatocytes. Consistently, DMF+CCl(4) treatment markedly increased lipid peroxidation. By contrast, treatment of DMF in combination with lipopolysaccharide, acetaminophen or d-galactosamine caused no enhanced hepatotoxicity. Given the link between endoplasmic reticulum (ER) dysfunction and cell death, ER stress response was monitored after DMF and/or CCl(4) treatment. Whereas either DMF or CCl(4) treatment alone marginally changed the expression levels of glucose-regulated protein 78 and 94 and phosphorylated PKR-like ER-localized eIF2alpha kinase, concomitant treatment with DMF and CCl(4) synergistically induced them with increases in glucose-regulated protein 78 and C/EBP homologous protein mRNAs. Our results demonstrate that DMF treatment in combination with CCl(4) synergistically increases hepatocyte death, which may be associated with the induction of severe ER stress.
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PMID:Synergistic hepatotoxicity of N,N-dimethylformamide with carbon tetrachloride in association with endoplasmic reticulum stress. 2009 84

Several studies have shown that gallic acid (GA) induces apoptosis in different cancer cell lines, whereas the mechanism of action of GA-induced apoptosis at the molecular level in human non-small-cell lung cancer NCI-H460 cells is not well-known. Here, GA decreasing the percentage of viable NCI-H460 cells was investigated; GA-induced apoptosis involved G2/M phase arrest and intracellular Ca(2+) production, the loss of mitochondrial membrane potential (DeltaPsi(m)), and caspase-3 activation. The efficacious induction of apoptosis and DNA damage was observed at 50-500 microM for 24 and/or 48 h as examined by flow cytometry, DAPI staining, and Comet assay methods. Western blotting and flow cytometric analysis also demonstrated that GA increased protein levels of GADD153 and GRP78, activation of caspase-8, -9, and -3, loss of DeltaPsi(m) and cytochrome c, and AIF release from mitochondria. Moreover, apoptosome formation and activation of caspase cascade were associated with apoptotic cell death. GA increased Bax and Bad protein levels and decreased Bcl-2 and Bcl-xL levels. GA may also induce apoptosis through a caspase-independent AIF pathway. In nude mice bearing NCI-H460 xenograft tumors, GA inhibited tumor growth in vivo. The data suggest that GA induced apoptosis in NCI-H460 lung cancer cells via a caspase-3 and mitochondrion-dependent pathway and inhibited the in vivo tumor growth of NCI-H460 cells in xenograft models.
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PMID:Gallic acid induces apoptosis via caspase-3 and mitochondrion-dependent pathways in vitro and suppresses lung xenograft tumor growth in vivo. 2034 25

The endoplasmic reticulum (ER) stress results from disrupted protein folding triggered by protein mutation or oxidation, reduced proteasome activity, and altered Ca2+ homeostasis. ER stress is accompanied by activation of the unfolded protein response (UPR) and cell death pathway. We examined if the UPR and cell death pathway would be activated in Alzheimer's disease (AD). RT-PCR experiments revealed increased splicing of X-box binding protein-1 (XBP-1), an UPR transcription factor, in AD compared with age-matched control. Among target genes of XBP-1, expression of protein disulfide isomerase (PDI), but not glucose-regulated protein 78 (GRP78), was increased in AD, suggesting disturbed activation of the UPR in AD. C/EBP homologous protein (CHOP), caspase-3, caspase-4, and caspase-12, downstream mediators of cell death pathway, were activated in AD. Neither the UPR nor cell death pathway was induced in aged Tg2576 mice, a transgenic mouse model of Alzheimer's disease that reveals both plaque pathology and some cognitive deficits. The present study suggests that disturbed induction of the UPR and activation of the pro-apoptotic proteins contribute to neuropathological process in AD irrespective of amyloid beta and senile plaque.
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PMID:Induction of the unfolded protein response and cell death pathway in Alzheimer's disease, but not in aged Tg2576 mice. 2036 88

Transmembrane protein 132A (TMEM132A) is a novel GRP78 binding protein that we recently discovered. However, the biological functions of TMEM132A are merely characterized because it does not encode any known structural domains. In this study, we down regulated intrinsic TMEM132A by RNA interference and identified a variety of genes that fluctuated during TMEM132A gene silencing using microarray analysis. TMEM132A-knockdown in Neuro2a cells caused neurite-like projection without any stimuli and enhanced the expression of ATF6 mRNA, an ER stress transducer, and GADD153 mRNA, a stress inducible gene. Under serum-deprived condition, TMEM132A-knockdown cells gradually retarded neurite-like projection and decreased cell viability. Moreover, TMEM132A knockdown markedly induced GADD153 expression due to serum starvation without affecting the level of cleaved caspase-3. Our data suggest that TMEM132A is an important factor of cell survival in regulating certain ER stress-related gene expression in neuronal cells.
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PMID:Knockdown of transmembrane protein 132A by RNA interference facilitates serum starvation-induced cell death in Neuro2a cells. 2045 9

It has been reported that curcumin inhibited various types of cancer cells in vitro and in vivo. However, mechanisms of curcumin-inhibited cell growth and -induced apoptosis in human non-small cell lung cancer cells (NCI-H460) still remain unclear. In this study, NCI-H460 cells were treated with curcumin to determine its anticancer activity. Different concentrations of curcumin were used for different durations in NCI-H460 cells and the subsequent changes in the cell morphology, viability, cell cycle, mRNA and protein expressions were determined. Curcumin induced apoptotic morphologic changes in NCI-H460 cells in a dose-dependent manner. After curcumin treatment, BAX and BAD were up-regulated, BCL-2, BCL-X(L) and XIAP were down-regulated. In addition, reactive oxygen species (ROS), intracellular Ca(2+) and endoplasmic reticulum (ER) stress were increased in NCI-H460 cells after exposure to curcumin. These signals led to a loss of mitochondrial membrane potential (Delta Psi(m)) and culminated in caspase-3 activation. Curcumin-induced apoptosis was also stimulated through the FAS/caspase-8 (extrinsic) pathway and ER stress proteins, growth arrest- and DNA damage-inducible gene 153 (GADD153) and glucose-regulated protein 78 (GRP78) were activated in the NCI-H460 cells. Apoptotic cell death induced by curcumin was significantly reversed by pretreatment with ROS scavenger or caspase-8 inhibitor. Furthermore, the NCI-H460 cells tended to be arrested at the G(2)/M cell cycle stage after curcumin treatment and down-regulation of cyclin-dependent kinase 1 (CDK1) may be involved. In summary, curcumin exerts its anticancer effects on lung cancer NCI-H460 cells through apoptosis or cell cycle arrest.
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PMID:Curcumin induces apoptosis in human non-small cell lung cancer NCI-H460 cells through ER stress and caspase cascade- and mitochondria-dependent pathways. 2065 61

Amyloid beta (Abeta) is considered to be responsible for the pathogenesis of Alzheimer's disease (AD). Mitochondrial and ER apoptotic pathways are considered to be involved in this process. Galantamine is an acetylcholinesterase (AChE) inhibitor widely used for patients with AD. In this study, we investigated the neuroprotective effects of galantamine on Abeta(25-35)-induced apoptosis in PC12 cells and the underlying mechanisms. Exposure of PC12 cells to 20 microM Abeta(25-35) caused significant cell viability loss and apoptosis, Abeta aggregation, mitochondrial and ER morphological changes, as well as mitochondrial membrane potential dissipation, reactive oxygen species (ROS) production, intracellular calcium elevation, and cytochrome c release from mitochondria. Pretreatment with 10 microM galantamine for 24 h prior to Abeta(25-35) exposure significantly reduced Abeta(25-35)-induced apoptosis not only by preventing Abeta aggregation, mitochondrial and ER morphological changes, mitochondrial membrane potential dissipation, ROS production, intracellular calcium elevation, and cytochrome c release, but also via reversing Bcl-2/Bax ratio and suppressing the activity of GADD153, Grp78/94, caspase-9, caspase-12, and caspase-3. All these data indicate that galantamine protects PC12 cells against Abeta(25-35)-induced apoptosis by preventing mitochondrial dysfunction and endoplasmic reticulum (ER) stress.
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PMID:Protective effects of galantamine against Abeta-induced PC12 cell apoptosis by preventing mitochondrial dysfunction and endoplasmic reticulum stress. 2065 46

Tanshinone IIA (Tan-IIA) is extracted from Danshen, Salviae miltiorrhizae Radix, which has been widely adopted in traditional herbal medicine to treat cardiovascular and hepatic diseases. Tan-IIA induces apoptosis and inhibits proliferation in human hepatocellular carcinoma (HCC) cells. However, the molecular mechanisms of Tan-IIA on human HCC cells are not understood clearly. In the present study, the cytotoxicity of Tan-IIA as well as its molecular mechanisms in human HCC J5 cells was investigated. The cytotoxicity was assayed by MTT. The protein expression of p53, p21, Bax, Bcl-2, Cdc25c, Cdc2, calreticulin, caspase 12, GADD153, caspase 3 and beta-actin in J5 cells were determined by Western blotting. The cell cycles were analyzed by FACS. The protein expression of caspase 12, GADD1533 and caspase 3 were detected by immunocytochemical staining. The results showed that Tan-IIA inhibited J5 cells in a dose- and time-dependent manner. The protein expression of p53, p21, Bax, calreticulin, caspase 12, caspase 3 and GADD153 were increased, but Bcl-2, Cdc25c and Cdc2 were decreased in J5 cells. In addition, the results also showed that Tan-IIA arrested J5 cells in the G2/M phase. Immunocytochemistry staining showed that J5 cells treated with Tan-IIA up-regulated the protein expression of caspase 12, 3 and GADD153. Taken together, the findings suggest that Tan-IIA inhibits and induces apoptosis in J5 cells through novel molecular targets, calreticulin, caspase 12 and GADD153.
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PMID:Tanshinone IIA inhibits Hep-J5 cells by increasing calreticulin, caspase 12 and GADD153 protein expression. 2066 54


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