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)

Statins, HMG-CoA reductase inhibitors could be associated with the risk reduction of colorectal cancer. We previously demonstrated that simvastatin inhibits NF-kappaB signaling in human intestinal epithelial cells and ameliorates acute murine colitis. The aim of our study was to evaluate the effects of simvastatin on the apoptotic pathways related to NF-kappaB signaling in colon cancer cells, and on anticancer effects in 2 different animal models. We treated cell lines (COLO 205 and HCT 116) with simvastatin or vehicle and determined apoptosis by cell cycle analysis, Annexin V-FITC staining, caspase-3 activity assay and confocal microscopy. We assessed the expression of antiapoptotic factors by RT-PCR and Western blotting. In the colitis-associated colon cancer (CAC) model, we induced colonic tumors in C57/BL6 mice by azoxymethane and dextran sulfate sodium administration, and evaluated simvastatin's effect on tumor growth. In the xenograft model, we evaluated its effect on the inoculated tumor growth. In both cell lines, simvastatin caused dose- and time-dependent cell death. Annexin V staining significantly increased after simvastatin treatment. It augmented caspase-3 activity and downregulated the expression of Bcl-2, Bcl-xL, cIAP1 and cFLIP. In the CAC model, simvastatin significantly reduced tumor development. In the xenograft model, tumors from animals treated with simvastatin had smaller volumes, larger necrotic areas, lower expression of VEGF and higher apoptotic scores. In conclusion, simvastatin inhibited colon cancer development by induction of apoptosis and suppression of angiogenesis. These results suggest that simvastatin could be a potential chemopreventive and therapeutic agent of CAC as well as de novo colon cancer.
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PMID:Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis-associated colon cancer in mice. 1852 6

Neurofibrillary tangles (NFTs), comprising human intracellular microtubule-associated protein tau, are one of the hallmarks of tauopathies, including Alzheimer's disease. Recently, a report that caspase-cleaved tau is present in NFTs has led to the hypothesis that the mechanisms underlying NFT formation may involve the apoptosis cascade. Here, we show that adenoviral infection of tau into COS-7 cells induces activation of c-jun N-terminal kinase (JNK), followed by excessive phosphorylation of tau and its cleavage by caspase. However, JNK activation alone was insufficient to induce sodium dodecyl sulfate (SDS)-insoluble tau aggregation and additional phosphorylation by GSK-3beta was required. In SH-SY5Y neuroblastoma cells, overexpression of active JNK and GSK-3beta increased caspase-3 activation and cytotoxicity more than overexpression of tau alone. Taken together, these results indicate that, although JNK activation may be a primary inducing factor, further phosphorylation of tau is required for neuronal death and NFT formation in neurodegenerative diseases, including those characterized by tauopathy.
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PMID:Active c-jun N-terminal kinase induces caspase cleavage of tau and additional phosphorylation by GSK-3beta is required for tau aggregation. 1854 Aug 81

We investigated whether the effect of beta-cryptoxanthin (CRP) on osteoclastic cells formed in the mouse marrow culture system in vitro is enhanced by culture with zinc. Bone marrow cells were isolated from mice. The macrophage colony-stimulating factor (M-CSF)-dependent bone marrow macrophages were cultured in the presence of M-CSF (10 ng/ml) and receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL; 50 ng/ml) for 96 h. The osteoclastic cells formed were further cultured for 24 or 72 h in a medium containing either vehicle, CRP, zinc sulfate (zinc), or CRP plus zinc with or without M-CSF (10 ng/ml) and RANKL (50 ng/ml). The number of osteoclastic cells was significantly decreased after culture with the combination of CRP (10(-7) M) and zinc (10(-5) M) in the presence or absence of M-CSF and RANKL for 24 or 72 h as compared with the value for CRP or zinc alone. Agarose gel electrophoresis showed the presence of low-molecular weight deoxyribonucleic acid (DNA) fragments of adherent cells cultured with CRP (10(-7) M) plus zinc (10(-5) M) for 24 or 72 h in the presence of M-CSF and RANKL, indicating that the combination of the two chemicals induces apoptotic cell death. CRP plus zinc-induced decrease in osteoclastic cells was significantly inhibited in the presence of caspase-3 inhibitor (10(-8) or 10(-7) M). Culture with CRP (10(-7) M) plus zinc ((10(-5) M) for 24 or 72 h caused a significant increase in caspase-3 mRNA expression in the presence or absence of M-CSF and RANKL as compared with the value for each chemical alone. CRP plus zinc-induced increase in caspase-3 mRNA expression was completely inhibited in the presence of cycloheximide (10(-7) M), an inhibitor of protein synthesis, or 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DBR; 10(-6) M), an inhibitor of transcription activity. The mRNA expression of tartrate-resistant acid phosphatase (TRACP) and cathepsin K was significantly decreased after culture with CRP plus zinc in the presence or absence of M-CSF and RANKL for 72 h as compared with CRP or zinc alone. Nuclear factor of activated T cells c1 (NFATc1) mRNA expression was significantly decreased after culture with CRP plus zinc in the presence or absence of M-CSF and RANKL for 72 h as compared with each chemical alone, while NF-kappaB mRNA expression was not significantly changed. This study demonstrated that the combination of CRP and zinc has potent suppressive effects on osteoclastic cells in vitro.
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PMID:Combination of beta-cryptoxanthin and zinc has potent effects on apoptotic cell death and suppression of bone resorption-related gene expression in osteoclastic cells. 1863 77

There is evidence that zinc may be involved in the pathogenesis of Parkinson's disease by an apoptotic pathway. However, the mechanisms underlying zinc-induced apoptosis are unknown. Previous studies showed that 6-hydroxydopamine (6-OHDA)-enhanced potassium channels are involved in apoptosis of dopaminergic neurons. Our study was designed to test whether zinc-induced apoptosis was mediated by potassium channels. First we demonstrated cell apoptosis with zinc treatment by Hoechst staining assay. The results showed that 13.38% +/- 0.6% of MES23.5 cells were apoptotic after 24 hr of incubation with 60 microM zinc sulfate. Then we observed that the tyrosine hydroxylase (TH) protein expression and the dopamine content decreased, as detected by Western blots and high-performance liquid chromatography-electrochemical detection (HPLC-ECD). We further elucidated the mechanism of cell apoptosis by using whole-cell patch clamp recording. The data demonstrated that MES23.5 cells exhibited a tetraethylammonium (TEA)-sensitive outward K(+) current with delayed rectifier characteristics. Increases of K(+) current density were recorded following the treatment with 60 microM zinc for 4-8 hr. After incubation with 20 mM TEA, the zinc-induced enhancement of K(+) currents was fully blocked. Furthermore, incubation with TEA blocked zinc-mediated caspase-3 activation and cell apoptosis. These data suggest that zinc-induced apoptosis of MES23.5 dopaminergic cells may due to the enhancement of TEA-sensitive K(+) channel activity.
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PMID:Potassium channels are involved in zinc-induced apoptosis in MES23.5 cells. 1875 20

To investigate the effect of apolipoprotein B (apoB) on cell viability, we used lipid-free apoB as a model for denatured apoB. Lipid-free apoB had cytotoxicity to J774 macrophages, CHO cells and HepG2 cells, whereas apoB bound to low density lipoprotein (LDL) and lipid-free apolipoprotein A-I had no effect on cell viability. Lipid-free apoB induced apoptosis in J774 macrophages assessed by caspase-3 activation and annexin V binding. LDL receptor, heparan sulfate proteoglycans, and class A scavenger receptor were involved in the binding/uptake of lipid-free apoB, but lipid-free apoB binding/uptake by the cells did not correlate with cytotoxicity. Lipid-free apoB disrupted the lipid bilayer of large unilamellar vesicles containing calcein. We evaluated the interaction between apoB and cellular membrane by monitoring the change in intracellular Ca(2+) concentration using Fura-2, and found that lipid-free apoB rapidly disrupted the cellular membrane in the absence or presence of the inhibitors for cellular binding/uptake mediated by the receptors. Therefore, it is suggested that lipid-free apoB induces cell death by disturbance of the plasma membrane. In addition to other lipid component in modified LDL, apoB itself has an ability to induce apoptosis and plays a crucial role in the development of atherosclerotic lesions.
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PMID:Cytotoxicity of lipid-free apolipoprotein B. 1878 85

Some neurosteroids show neuroprotective action in in vitro and in vivo studies, but their interaction with apoptotic/necrotic processes has been only partially unraveled. The aim of the present study was to examine the effect of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), pregnenolone (PGL) and allopregnanolone (Allo) on staurosporine-, glutamate-, and NMDA-induced damage in primary cortical neuronal culture. DHEA, DHEAS and PGL (0.1 and 1 microM) inhibited the staurosporine-evoked LDH release and decreased the number of apoptotic cells as shown by Hoechst;s staining, whereas Allo was without effect. The neurosteroids affected neither the staurosporine-evoked changes in caspase-3 activity nor the decrease in mitochondrial membrane potential. It was also shown that protective effects of DHEA, DHEAS and PGL against staurosporine-induced LDH release were attenuated by extracellular signal-regulated kinase (ERK)--mitogen-activated protein kinase (MAPK) inhibitor--PD 98059 (5 microM) but not by phosphatidylinositol-3-kinase (PI3-K) inhibitors such as LY 294002 (1 microM) or wortmannin (10 nM). The involvement of ERK2-MAPK in protective effects of neurosteroids was confirmed by Western blot study. Further study demonstrated that glutamate-induced cell damage was attenuated by DHEA, DHEAS, and PGL, but not by Allo. None of the steroids influenced NMDA-induced LDH release. The results of the present in vitro studies suggest that excitatory neurosteroids DHEA, DHEAS and PGL at physiological concentrations participate in the inhibition of cortical neuronal degeneration elicited by staurosporine and glutamate, whereas the most potent positive modulator of GABA(A) receptor--Allo--has no effect. Moreover, neurosteroids appear to attenuate the staurosporine-induced cell damage in a caspase-3 independent way and their neuroprotective mechanism of action involves the increase in ERK-MAPK phosphorylation.
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PMID:Excitatory neurosteroids attenuate apoptotic and excitotoxic cell death in primary cortical neurons. 1895 90

Diabetes mellitus is an important risk factor for CVD. A previous study showed that high glucose induced the apoptosis of human umbilical vein endothelial cells (HUVEC) via the sequential activation of reactive oxygen species, Jun N-terminal kinase (JNK) and caspase-3. The apoptosis cascade could be blocked by ascorbic acid at the micromolar concentration (100 microm). In addition to ascorbic acid, quercetin, the most abundant dietary flavonol, has been recently actively studied in vascular protection effects due to its antioxidant effect at low micromolar concentrations (10-50 microm). Quercetin sulfate/glucuronide, the metabolite of quercetin in blood, however, has been rarely evaluated. In the present study, we investigated the effect of quercetin sulfate/glucuronide on the prevention of high glucose-induced apoptosis of HUVEC. HUVEC were treated with media containing high glucose (33 mm) in the presence or absence of ascorbic acid (100 microm) or quercetin sulfate/glucuronide (100 nm, 300 nm and 1 microm). For the detection of apoptosis, a cell death detection ELISA assay was used. The level of intracellular H2O2 was measured by flow cytometry. JNK and caspase-3 were evaluated by a kinase activity assay and Western blot analysis. The results showed that high glucose-induced apoptosis was inhibited by quercetin sulfate/glucuronide in a dose-dependent manner. The effect of quercetin sulfate/glucuronide on H2O2 quenching, inhibition of JNK and caspase-3 activity at the nanomolar concentration (300 nm) was similar to that of ascorbic acid at the micromolar concentration (100 microm). The findings of the present study may shed light on the pharmacological application of quercetin in CVD.
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PMID:The antioxidant effects of quercetin metabolites on the prevention of high glucose-induced apoptosis of human umbilical vein endothelial cells. 1900 52

The present study was undertaken to validate a battery of cytotoxicity assays performed in a multiplex format to screen pharmaceutical compounds at an early stage of drug development. Two experiments were performed on HepG2 cells and the parameters were measured in 96-well plates. Biological and technical triplicates were performed to evaluate the reproducibility of the assay. In the first experiment, HepG2 cells were exposed to tamoxifen, staurosporine, phenobarbital and triton X-100 for 2 and 24h. The following nine cytotoxicity parameters were analyzed, cell viability, lactate dehydrogenase (LDH), adenosine triphosphate (ATP), caspase-3/7, aspartate aminotransferase (AST), glutamate dehydrogenase (GLDH), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and alpha-glutathione-S-transferase (alpha-GST). In the second experiment, HepG2 cells were exposed to doxorubicin, t-butyl hydroperoxide, ferrous sulfate and sulfamoxole for 2 and 24h. Based on the results of the first experiment, six cytotoxicity parameters were selected for further evaluation (cell viability, ATP, LDH, caspase, AST and GLDH). ALT (activity always below detection limit), ALP (no response to drug treatment) and alpha-GST (too labor intensive and not possible to multiplex) were eliminated. The analysis of the data revealed that the reproducibility of the assays was accurate according to principal component analysis. Our data also clearly indicated that the potential of this battery of selected assays measured in a multiplex format not only made it possible to rank and select the most promising drug candidates based on their cytotoxic potential, but also to gather information that may help to understand some of the toxic events occurring in the cells.
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PMID:Selection of cytotoxicity markers for the screening of new chemical entities in a pharmaceutical context: a preliminary study using a multiplexing approach. 1911 50

Growth plate cartilage is responsible for long bone growth in children and adolescents and is regulated by vitamin D metabolites in a cell zone-specific manner. Resting zone chondrocytes (RC cells) are regulated by 24,25-dihydroxyvitamin D3 via a phospholipase D-dependent pathway, suggesting downstream phospholipid metabolites are involved. In this study, we showed that 24R,25(OH)2D3 stimulates rat costochondral RC chondrocytes to release lysophosphatidic acid (LPA) and, therefore sought to determine the role of LPA signaling in these cells. RC cells expressed the G-protein coupled receptors LPA1-5 and peroxisome proliferator-activated receptor gamma (PPAR-gamma). LPA and the LPA1/3 selective agonist OMPT increased proliferation and two maturation markers, alkaline phosphatase activity and [35S]-sulfate incorporation. LPA and 24R,25(OH)2D3's effects were inhibited by the LPA1/3 selective antagonist VPC32183(S). Furthermore, apoptosis induced by either inorganic phosphate or chelerythrine was attenuated by LPA, based on DNA fragmentation, TUNEL staining, caspase-3 activity, and Bcl-2:Bax protein ratio. LPA prevented apoptotic signaling by decreasing the abundance, nuclear localization, and transcriptional activity of the tumor-suppressor p53. LPA treatment also regulated the expression of the p53-target genes Bcl-2 and Bax to enhance cell survival. Collectively, these data suggest that LPA promotes differentiation and survival in RC chondrocytes, demonstrating a novel physiological function of LPA-signaling.
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PMID:Lysophosphatidic acid signaling promotes proliferation, differentiation, and cell survival in rat growth plate chondrocytes. 1923 32

Chondrogenic ATDC5 cells were used as a model of in vitro endochondral maturation to study the role of inorganic phosphate (Pi) in the regulation of growth plate chondrocytes by vitamin D3 metabolites. ATDC5 cells that were cultured for 10 days post-confluence in differentiation media and then treated for 24 h with Pi produced a type II collagen matrix based on immunohistochemistry and expressed mRNAs for several chondrocytic markers, including aggrecan, collagen types II and X, cartilage oligomeric matrix protein, and SOX9. Pi also caused a decrease in [(35)S]-sulfate incorporation and stimulated apoptosis, as evidenced by increased DNA fragmentation and caspase-3 activity. In addition, treatment with Pi induced sensitivity to 24,25-dihydroxyvitamin D3 and this effect was both dose-dependent and was blocked by phosphonoformic acid (PFA), a specific inhibitor of sodium dependent type III Pi transporters. Treatment with 24R,25(OH)(2)D(3) reduced cell number and increased alkaline phosphatase specific activity in a dose-dependent manner. Moreover, 24R,25(OH)(2)D(3) reversed the Pi-induced decrease in incorporation of [(3)H]-thymidine and [(35)S]-sulfate incorporation, as well as the Pi-induced increase in apoptosis. These results suggest that Pi acts as an early chondrogenic differentiation factor, inducing response to 24R,25(OH)(2)D(3); treatment of committed chondrocytes with Pi induces apoptosis, but 24R,25(OH)(2)D(3) mitigates these effects, indicating a possible inhibitory feedback loop.
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PMID:Inorganic phosphate modulates responsiveness to 24,25(OH)2D3 in chondrogenic ATDC5 cells. 1928 98


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