UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In our previous studies, we demonstrated the apoptotic cascades protein kinase C (PKC) delta/c-Jun NH2-terminal kinase (JNK)/Fas/caspases induced by penta-acetyl geniposide [(Ac)5GP]. However, the upstream signals mediating PKCdelta activation have not yet been clarified. Ceramide, mainly generated from the degradation of sphingomyelin, was hypothesized upstream above PKCdelta in (Ac)5GP-transduced apoptosis. Furthermore, nerve growth factor (NGF)/p75 is supposed to be involved because(Ac)5GP-induced apoptosis was demonstrated previously in glioma cells. In the present study, (Ac)5GP was shown to activate neutral sphingomyelinase (N-SMase) immediately, with its maximum at 15 min. The NGF and p75 enhanced by (Ac)5GP was inhibited when added with GW4869, the N-SMase inhibitor, indicating NGF/p75 as the downstream signals of N-SMase/ceramide. To investigate whether N-SMase is involved in (Ac)5GP-transduced apoptotic pathway, cells were treated with (Ac)5GP added with or without GW4869. It showed that N-SMase inhibition blocked FasL expression and caspase 3 activation. Likewise, p75 antagonist peptide attenuated the FasL/caspase 3 expression. The PKCdelta translocation induced by (Ac)5GP was also eliminated by GW4869 and p75 antagonist peptide. To further confirm whether N-SMase activation plays an important role in (Ac)5GP-induced apoptosis, cells were analyzed the apoptotic rate by 4', 6-diamidino-2-phenylindole (DAPI) staining. (Ac)5GP-induced apoptosis was reduced 40 and 80% by 10 and 20 microM GW4869, respectively. It indicated that N-SMase activation is pivotal in (Ac)5GP-mediated apoptosis. In conclusion, SMase and NGF/p75 are suggested to mediate upstream above PKCdelta, thus transducing FasL/caspase cascades in (Ac)5GP-induced apoptosis.
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PMID:Penta-acetyl geniposide induce apoptosis in C6 glioma cells by modulating the activation of neutral sphingomyelinase-induced p75 nerve growth factor receptor and protein kinase Cdelta pathway. 1676 91

Copper(2)(II)(3,5-ditertiarybutylsalicylate)(4)(ethanol)(4), Cu(2)(II)(3,5-DTBS)(4)(Eth)(4), was synthesized and characterized for evaluation as an anti-apoptotic superoxide dismutase (SOD)-mimetic in an in vitro 50 microM cis-diamminedichloroplatinum(II), [Pt(II)(NH(3))(2)(Cl)(2)]-treated kidney proximal tubule epithelial cell (LLC-PK) preparation. Synthesized Cu(2)(II)(3,5-DTBS)(4)(Eth)(4) was characterized by elemental analysis, FTIR spectrophotometry, and X-ray crystallography. The IC(50) for SOD-mimetic reactivity of Cu(2)(II)(3,5-DTBS)(4)(Eth)(4), determined with the xanthine/xanthine oxidase/nitroblue tetrazolium (NBT) system, was found to be 2.69 microM for the binuclear chelate. Pretreatment of LLC-PK cells with 20 microM Cu(2)(II)(3,5-DTBS)(4)(Eth)(4) prevented 50 microM Pt(II)(NH(3))(2)(Cl)(2)-induced and superoxide-mediated apoptosis. This SOD-mimetic significantly suppressed Pt(II)(NH(3))(2)(Cl)(2)-induced translocation of pro-apoptotic Bax from the cytosol to the inner mitochondrial membrane, prevented Pt(II)(NH(3))(2)(Cl)(2)-induced release of cytochrome c from the inner mitochondrial membrane and the appearance of cytochrome c in the cytosol, and prevented conversion of procaspase-3 to active caspase-3. Cu(2)(II)(3,5-DTBS)(4)(Eth)(4) treatment inhibited Pt(II)(NH(3))(2)(Cl)(2)-mediated tubular cell injury by preventing activation of cellular mechanisms that lead to proximal tubule kidney cell death. Based on these observations, Pt(II)(NH(3))(2)(Cl)(2)- induced O(2)(-)-mediated apoptosis can be mechanistically overcome with a small molecular mass SOD-mimetic, Cu(2)(II)(3,5-DTBS)(4)(Eth)(4). Prior treatment of patients who are to undergo treatment with Pt(II)(NH(3))(2)(Cl)(2) for their neoplastic disease with Cu(2)(II)(3,5-DTBS)(4)(Eth)(4) may be beneficial to these patients.
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PMID:Prevention of cisplatin-induced kidney epithelial cell apoptosis with a Cu superoxide dismutase-mimetic [copper2II(3,5-ditertiarybutylsalicylate)4(ethanol)4]. 1681 79

Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T cell-dependent, antibody-mediated autoimmune diseases. A dual altered peptide ligand (APL) that is composed of the tandemly arranged two single amino acid analogues of two myasthenogenic peptides, p195-212 and p259-271, was demonstrated to down-regulate in vitro and in vivo MG-associated autoreactive responses. The aims of this study were to investigate the possible role of Fas-FasL-mediated apoptosis in the down-regulatory mechanism of the dual APL. We demonstrate here the effect of the dual APL on expression of key molecules involved in the Fas-FasL pathway, in a p195-212-specific T cell line, in mice immunized with Torpedo acetylcholine receptor and in mice afflicted with EAMG (induced with the latter). In vitro and in vivo results show that the dual APL up-regulated expression of Fas and FasL on the CD4 cells. Expression of the pro-apoptotic molecules, caspase 8 and caspase 3, was significantly up-regulated, while anti-apoptotic cFLIP and Bcl-2 were down-regulated upon treatment with the dual APL. The dual APL also increased phosphorylation of the mitogen-activated protein kinases, c-Jun-NH2-terminal kinase and p-38, known to play a role in the regulation of FasL expression. Further, in the T cell line incubated with the dual APL as well as in mice of the SJL inbred strain immunized with the myasthenogenic peptide and treated concomitantly with the dual APL, the percentage of apoptotic cells increased. Results strongly indicate that up-regulation of apoptosis via the Fas-FasL pathway is one of the mechanisms by which the dual APL reverses EAMG manifestations in C57BL/6 mice.
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PMID:A dual altered peptide ligand down-regulates myasthenogenic T cell responses and reverses experimental autoimmune myasthenia gravis via up-regulation of Fas-FasL-mediated apoptosis. 1682 2

Hint1 is a member of the evolutionarily conserved family of histidine triad proteins that acts as a haplo-insufficient tumor suppressor inducing spontaneous tumor formation in Hint+/- and Hint-/- mouse models. However, the molecular mechanisms for the tumor-suppressing activity are poorly defined. In this respect, we have recently shown that Hint1, by interaction with Pontin and Reptin, inhibits T-cell factor/beta-catenin-mediated transcription of Wnt target genes. In this study, we have found that, after transient transfection with Hint1, SW480 and MCF-7 cells undergo apoptosis as analyzed by pro-caspase-3 and poly(ADP-ribose) polymerase cleavage, M30 CytoDEATH staining, cytochrome c release, and DNA fragmentation enzyme-linked immunosorbent assay. Hint1 is involved in the regulation of apoptotic pathways by inducing an up-regulation of p53 expression coinciding with an up-regulation of the proapoptotic factor Bax and a concomitant down-regulation of the apoptosis inhibitor Bcl-2. Bad and Puma levels remained unchanged. Further analyses revealed that Hint1 is associated with the Bax promoter and is a component of the Tip60 histone acetyltransferase complex and, in this context, appears to be involved in the regulation of Bax expression. Knockdown of Hint1 by short hairpin RNA resulted in down-regulation of p53 and Bax but had no effect on Bcl-2 expression. A mutant Hint1 (H112N) protein defective in enzymatic activity as an AMP-NH2 hydrolase was not impaired in induction of apoptosis, suggesting that the Hint1 pro-apoptotic activity is independent of the Hint1 enzymatic activity.
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PMID:The histidine triad protein Hint1 triggers apoptosis independent of its enzymatic activity. 1683 43

We have demonstrated that lipopolysaccharide (LPS)-mediated reactive oxygen species (ROS) and signal transduction are involved in the regulation of interleukin-1 (IL-1) beta gene expression within macrophages. Because the 90-kDa heat shock protein (Hsp90) plays an important role in the LPS mediation of macrophage activation, using Hsp90 inhibitor geldanamycin A (GA), we analyzed the mechanism of Hsp90 upon LPS-transduced signaling in the regulation of IL-1 expression and determined the function of Hsp90 regarding the viability of human primary macrophages and murine macrophages cell line. In essence, GA decreased LPS-induced Hsp90/pp60Src heterocomplex formation. In addition, Hsp90 is important for IL-1 protein translation, plays a minor role in IL-1 mRNA transcription, and is involved in nuclear factor-kappaB activation and the phosphorylation and activation of p38, c-Jun NH2-terminal kinase, and extracellular signal-regulated kinase; however, Hsp90 plays a more important role in LPS-stimulated p38 activation. In analyzing the function of Hsp90 regarding the cytotoxicity/viability of macrophages, we found that the combination of LPS and GA increases apoptosis, as evidenced by the increased caspase-3 activity and the proportion of nuclear/chromatin condensation. In contrast, N-acetyl-cysteine dramatically blocked GA/LPS-induced ROS production, simultaneously decreasing caspase-3 activity and the presence of apoptotic nuclei. We concluded that Hsp90 plays an indispensable role in the process of LPS-induced IL-1 secretion. Furthermore, we established the mechanism of GA interference with Hsp90 function for LPS-stimulated macrophages, resulting in increased ROS production and caspase-3 activation, and consequently leading to synergistic enhancement of macrophage apoptosis.
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PMID:Geldanamycin interferes with the 90-kDa heat shock protein, affecting lipopolysaccharide-mediated interleukin-1 expression and apoptosis within macrophages. 1686 82

We have shown recently that diallyl trisulfide (DATS), a cancer-chemopreventive constituent of garlic, inactivates Akt to trigger mitochondrial translocation of proapoptotic protein BAD in human prostate cancer cells. Because Akt activation is implicated in the promotion of endothelial cell survival and angiogenesis, we hypothesized that DATS may inhibit angiogenesis. In the present study, we tested this hypothesis using human umbilical vein endothelial cells (HUVECs) as a model. Survival of HUVECs was reduced significantly in the presence of DATS in a concentration-dependent manner, with an IC50 of approximately 4 microM. The DATS-mediated suppression of HUVEC survival was associated with apoptosis induction characterized by accumulation of subdiploid cells, cytoplasmic histone-associated DNA fragmentation, and cleavage of caspase-3 and poly-(ADP-ribose)-polymerase. The DATS-induced DNA fragmentation was significantly attenuated in the presence of pan-caspase inhibitor zVAD-fmk and specific inhibitors of caspase-9 (zLEHD-fmk) and caspase-8 (zIETD-fmk). DATS treatment inhibited the formation of capillary-like tube structure and migration by HUVECs in association with suppression of vascular endothelial growth factor (VEGF) secretion and VEGF receptor-2 protein level and inactivation of Akt kinase. DATS treatment also caused activation of extracellular signal-regulated kinase 1/2 (ERK1/2) but not c-Jun NH2-terminal kinase (JNK) or p38 mitogen-activated protein kinase (p38MAPK).DATS-mediatedapoptosis induction and inhibition of HUVEC tube formation was partially but statistically significantly attenuated by pharmacologic inhibition of ERK1/2 but not JNK or p38MAPK. The present study demonstrates, for the first time, that DATS has the ability to inhibit angiogenic features of human endothelial cells.
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PMID:Diallyl trisulfide inhibits angiogenic features of human umbilical vein endothelial cells by causing Akt inactivation and down-regulation of VEGF and VEGF-R2. 1696 46

This study was undertaken to characterize preclinical cytotoxic interactions for human malignancies between the multikinase inhibitor sorafenib (BAY 43-9006) and proteasome inhibitors bortezomib or MG132. Multiple tumor cell lines of varying histiotypes, including A549 (lung adenocarcinoma), 786-O (renal cell carcinoma), HeLa (cervical carcinoma), MDA-MB-231 (breast), K562 (chronic myelogenous leukemia), Jurkat (acute T-cell leukemia), MEC-2 (B-chronic lymphocytic leukemia), and U251 and D37 (glioma), as well as cells derived from primary human glioma tumors that are likely a more clinically relevant model were treated with sorafenib or bortezomib alone or in combination. Sorafenib and bortezomib synergistically induced a marked increase in mitochondrial injury and apoptosis, reflected by cytochrome c release, caspase-3 cleavage, and poly(ADP-ribose) polymerase degradation in a broad range of solid tumor and leukemia cell lines. These findings were accompanied by several biochemical changes, including decreased phosphorylation of vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor-beta, and Akt and increased phosphorylation of stress-related c-Jun NH2-terminal kinase (JNK). Inhibition of Akt was required for synergism, as a constitutively active Akt protected cells against apoptosis induced by the combination. Alternatively, the JNK inhibitor SP600125 could also protect cells from apoptosis induced by the combination, indicating that both inhibition of Akt and activation of JNK were required for the synergism. These findings show that sorafenib interacts synergistically with bortezomib to induce apoptosis in a broad spectrum of neoplastic cell lines and show an important role for the Akt and JNK pathways in mediating synergism. Further clinical development of this combination seems warranted.
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PMID:Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. 1698 72

Ghrelin is an endogenous ligand for the GH secretagogue receptor, produced and secreted mainly from the stomach. Ghrelin stimulates GH release and induces positive energy balances. Previous studies have reported that ghrelin inhibits apoptosis in several cell types, but its antiapoptotic effect in neuronal cells is unknown. Therefore, we investigated the role of ghrelin in ischemic neuronal injury using primary hypothalamic neurons exposed to oxygen-glucose deprivation (OGD). Here we report that treatment of hypothalamic neurons with ghrelin inhibited OGD-induced cell death and apoptosis. Exposure of neurons to ghrelin caused rapid activation of ERK1/2. Ghrelin-induced activation of ERK1/2 and the antiapoptotic effect of ghrelin were blocked by chemical inhibition of MAPK, phosphatidylinositol 3 kinase, protein kinase C, and protein kinase A. Ghrelin attenuated OGD-induced activation of c-Jun NH2-terminal kinase and p-38 but not ERK1/2. We also investigated ghrelin regulation of apoptosis at the mitochondrial level. Ghrelin protected cells from OGD insult by inhibiting reactive oxygen species generation and stabilizing mitochondrial transmembrane potential. In addition, ghrelin-treated cells showed an increased Bcl-2/Bax ratio, prevention of cytochrome c release, and inhibition of caspase-3 activation. Finally, in vivo administration of ghrelin significantly reduced infarct volume in an animal model of ischemia. Our data indicate that ghrelin may act as a survival factor that preserves mitochondrial integrity and inhibits apoptotic pathways.
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PMID:Ghrelin inhibits apoptosis in hypothalamic neuronal cells during oxygen-glucose deprivation. 1705 24

Ionizing radiation can induce DNA damage and cell death by generating reactive oxygen species (ROS). The objective of this study was to investigate the radioprotective effect of paeoniflorin (PF, a main bioactive component in the traditional Chinese herb peony) on irradiated thymocytes and discover the possible mechanisms of protection. We found 60Co gamma-ray irradiation increased cell death and DNA fragmentation in a dose-dependent manner while increasing intracellular ROS. Pretreatment of thymocytes with PF (50-200 microg/ml) reversed this tendency and attenuated irradiation-induced ROS generation. Hydroxyl-scavenging action of PF in vitro was detected through electron spin resonance assay. Several anti-apoptotic characteristics of PF, including the ability to diminish cytosolic Ca2+ concentration, inhibit caspase-3 activation, and upregulate Bcl-2 and downregulate Bax in 4Gy-irradiated thymocytes were determined. Extracellular regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 kinase were activated by 4Gy irradiation, whereas its activations were partly blocked by pretreatment of cells with PF. The presence of ERK inhibitor PD98059, JNK inhibitor SP600125 and p38 inhibitor SB203580 decreased cell death in 4Gy-irradiated thymocytes. These results suggest PF protects thymocytes against irradiation-induced cell damage by scavenging ROS and attenuating the activation of the mitogen-activated protein kinases.
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PMID:Protective effect of paeoniflorin on irradiation-induced cell damage involved in modulation of reactive oxygen species and the mitogen-activated protein kinases. 1709 10

Nitrogen Dioxide (NO2) is a product of high-temperature combustion and an environmental oxidant of concern. We have recently reported that early changes in NO2-exposed human bronchial epithelial cells are causally linked to increased generation of proinflammatory mediators, such as nitric oxide/nitrite and cytokines like interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and IL-8. The objective of the present in vitro study was to further delineate the cellular mechanisms of NO2-mediated toxicity, and to define the nature of cell death that ensues upon exposure of normal human bronchial epithelial (NHBE) cells to a brief high dose of NO2. Our results demonstrate that the NHBE cells undergo apoptotic cell death during the early post-NO2 period, but this is independent of any significant increase in caspase-3 activity. However, necrotic cell death was more prevalent at later time intervals. Interestingly, an increased expression of HO-1, a redox-sensitive stress protein, was observed in NO2-exposed NHBE cells at 24 h. Since neutrophils (PMNs) play an active role in acute lung inflammation and resultant oxidative injury, we also investigated changes in human PMN-NHBE cell interactions. As compared to normal cells, increased adhesion of PMNs to NO2-exposed cells was observed, which resulted in an increased NHBE cell death. The latter was also increased in the presence of IL-8 and TNF-alpha + interferon (IFN)-gamma, which correlated with upregulation of intercellular adhesion molecule-1 (ICAM-1). Our results confirmed an involvement of nitric oxide (NO) in NO2-induced cytotoxicity. By using NO synthase inhibitors such as L-NAME and 3-aminoguanidine (AG), a significant decrease in cell death, PMN adhesion, and ICAM-1 expression was observed. These findings indicate a role for the L-arginine/NO synthase pathway in the observed NO2-mediated toxicity in NHBE cells. Therapeutic strategies aimed at controlling excess generation of NO and/or inflammatory cytokines may be useful in alleviating NO2-mediated adverse effects on the bronchial epithelium.
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PMID:Effects of nitrogen dioxide on the expression of intercellular adhesion molecule-1, neutrophil adhesion, and cytotoxicity: studies in human bronchial epithelial cells. 1716 65

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