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 competence is central to the prevention of cancer. Frequency of apoptotic cells, after a sample of colonic tissue is stressed, can be used to gauge apoptosis competence and, thus, possible susceptibility to colon cancer. The gold standard for assessment of apoptosis is morphological evaluation, but this requires an experienced microscopist. Easier-to-use immunohistochemical markers of apoptosis, applicable in archived paraffin-embedded tissue, have been commercially developed. Potentially useful apoptosis markers include cleaved cytokeratin-18 (c-CK18), cleaved caspase-3 (c-cas-3), cleaved lamin A (c-lam-A), phosphorylated histone H2AX (gammaH2AX), cleaved poly(ADP ribose) polymerase (c-PARP), and translocation of apoptosis-inducing factor (AIF). When tissue samples from freshly resected colon segments were challenged ex vivo with the bile acid deoxycholate, approximately 50% of goblet cells became apoptotic by morphologic criteria. This high level of morphologic apoptosis allowed quantitative comparison with the usefulness and specificity of immunohistochemical markers of apoptosis. The antibody to c-CK18 was almost as useful and about as specific as morphology for identifying apoptotic colonic epithelial cells. Antibodies to c-cas-3, c-lam-A, and gammaH2AX, though specific for apoptotic cells, were less useful. The antibody to c-PARP, though specific for apoptotic cells, had low usefulness, and the antibody to AIF was relatively nonspecific, under our conditions.
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PMID:Assessment of apoptosis by immunohistochemical markers compared to cellular morphology in ex vivo-stressed colonic mucosa. 1568 35

Celecoxib exhibits cancer preventive and therapeutic effects in animal models and clinical trials. It presumably acts through selective inhibition of cyclooxygenase-2 (COX-2) and subsequent reduction of prostaglandin (PG) synthesis. However, the concentrations of celecoxib required for growth inhibition and apoptosis induction in vitro are higher than those needed for suppression of PGs. Moreover, those concentrations are not achievable in humans raising a controversy regarding the clinical relevance of in vitro data. We investigated the activity of celecoxib alone and in combination with the pro-apoptotic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) on growth and apoptosis of human nonsmall cell lung cancer (NSCLC) cell lines. Celecoxib inhibited growth of thirteen NSCLC cell lines with IC50 values ranging from 19 to 33 microM regardless of their COX-2 expression. Apoptosis was induced in cells with high (A549) as well as low (H1792) COX-2 levels but only at a concentration of 75 microM celecoxib. However, treatment with pharmacologically feasible concentrations of celecoxib (< or = 10 microM) in combination with 4HPR (< or = 2 microM) resulted in a marked suppression of NSCLC cell growth and colony formation. Apoptosis mediated by activation of caspase-3, cleavage of PARP and lamin A was suppressed by addition of antioxidants, suggesting that the generation of reactive oxygen species was partially involved. This study indicates, that celecoxib combined with 4HPR is more effective than treatment with either agent alone in inhibition of growth and induction of apoptosis in NSCLC cells. It suggests further investigations of this combination for lung cancer treatment.
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PMID:Enhanced growth inhibition and apoptosis induction in NSCLC cell lines by combination of celecoxib and 4HPR at clinically relevant concentrations. 1622 24

Neuroblastoma frequently shows spontaneous regression in which two distinct types of programmed cell death, ie, caspase-dependent apoptosis and H-Ras-mediated autophagic degeneration, have been suggested to play a key role. The current study was conducted to determine which of these cell suicide pathways predominated in this tumor regression. Periodic acid-Schiff (PAS) staining and immunostaining for H-Ras and for the full-length and cleaved forms of caspase-3, poly (ADP-ribose) polymerase (PARP), and lamin A were carried out on 55 archival tumor specimens. The incidence of caspase-dependent apoptosis in each tumor was quantified by cleaved lamin A staining and compared with clinicopathologic prognostic factors. Although a recent report has shown that neuroblastic cells undergoing autophagic degeneration were readily detectable by PAS and H-Ras staining, we could not confirm this result in any of our samples with the exception of one tumor. Instead, many of our neuroblastoma samples showed nonspecific PAS and Ras staining in areas of necrosis, suggesting that autophagic "degeneration" indeed corresponds to coagulation necrosis or oncosis. Unexpectedly, the incidence of caspase-dependent apoptosis was significantly correlated with indicators of a poor prognosis in these tumors, including Shimada's unfavorable histology, MYCN amplification, and a higher mitosis-karyorrhexis index, but not with factors related to tumor regression such as clinical stage and mass screening. These results indicate that neither caspase-dependent apoptosis nor autophagic "degeneration" may be involved in spontaneous neuroblastoma regression. This suggests that other mechanisms, perhaps such as tumor maturation, may be responsible for this phenomenon.
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PMID:Increased occurrence of caspase-dependent apoptosis in unfavorable neuroblastomas. 1719 32

Nitric oxide (NO) is one of the smallest molecules synthesised in the human body. It is produced by three distinct nitric oxide synthase isoenzymes (NOS) and plays a number of physiological functions in many organs and tissues. Among its numerous properties is the ability to influence programmed cell death. NO can either inhibit or induce apoptosis depending on the context of its production. In the liver, NO is produced in greater amounts especially during inflammation. The effect of NO in liver physiology and pathophysiology can be both beneficial and detrimental. Therefore, the aim of our study was to examine NO effect on cell viability and cell death in primary rat hepatocyte culture. By using NO donor, S-nitroso-N-acetylpenicillamine (SNAP), the potential of exogenously delivered NO to influence spontaneous cell death in culture was examined. The morphological approach was used in order to discriminate between apoptotic and necrotic cell death. The nitrite level, urea production and alanine aminotransferase leakage were determined in the culture medium. The immunocytochemical detection of three apoptotic markers: cleaved caspase-3, cleaved caspase-9 and lamin A, was performed. Immunocytochemical analysis of hepatocyte apoptosis revealed different labelling pattern for each method, while the detection of cleaved caspase-3 best correlated with defined phenotypical criteria. Our data showed that under present conditions NO improved the viability of primary rat hepatocytes compared to untreated cells. This was manifested by the increase of viable hepatocytes in contrast to the decrease of necrotic and apoptotic hepatocytes as assessed by the morphological examination of cell culture. The NO effect was dose-dependent in the range of SNAP concentration between 200-800 microM.
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PMID:The morphological and immunocytochemical evaluation of primary rat hepatocytes undergoing spontaneous cell death: modulation by the nitric oxide donor S-nitroso-N-acetylpenicillamine. 1693 4

Cadmium is a heavy metal toxic for living organisms even at low concentrations. It does not have any biological role, and since it is a permanent metal ion, it is accumulated by many organisms. In the present paper we have studied the apoptotic effects of continuous exposure to subacute/sublethal cadmium concentrations on a model system: Paracentrotus lividus embryos. We demonstrated, by atomic absorption spectrometry, that the intracellular amount of metal increased during exposure time. We found, using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, that long treatments with cadmium triggered a severe DNA fragmentation. We demonstrated, by immunocytochemistry on whole-mount embryos, that treatment with cadmium causes activation of caspase-3 and cleavage of death substrates alpha-fodrin and lamin A. Incubating the embryos since fertilization with Z-DEVD FMK, a caspase-3 inhibitor, we found, by immunocytochemistry, that cleavage by caspase-3 and cleavage of death substrates were inactivated.
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PMID:Cadmium induces an apoptotic response in sea urchin embryos. 1744 6

Cell death induction by apoptosis is an important process in the maintenance of tissue homeostasis as well as tissue destruction during various pathological processes. Consequently, detection of apoptotic cells in situ represents an important technique to assess the extent and impact of cell death in the respective tissue. While scoring of apoptosis by histological assessment of apoptotic cells is still a widely used method, it is likely biased by sensitivity problems and observed-based variations. The availability of caspase-mediated neo-epitope-specific antibodies offers new tools for the detection of apoptosis in situ. Here, we discuss the use of immunohistochemical detection of cleaved caspase 3 and lamin A for the assessment of apoptotic cells in paraffin-embedded liver tissue. Furthermore, we evaluate the effect of tissue pretreatment and antigen retrieval on the sensitivity of apoptosis detection, background staining and maintenance of tissue morphology.
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PMID:Detection of apoptosis in vivo using antibodies against caspase-induced neo-epitopes. 1831 57

Platycodin D (PD), a major constituent of triterpene saponins in Platycodon grandiflorum, has also become an interesting candidate for cancer chemotherapy; however, little is known about apoptotic mechanisms on cancer cells. We herein investigated the mechanisms that are related to PD-induced antiproliferation and cell death in human leukemia cells (U937, THP-1 and K562 cells). Cell growth was assessed with proliferation assays, cell counting, flow cytometry, phase contrast microscopy and Western blot assay. Microtubule (MT) formation was measured with immunofluorescent staining and in vitro tubulin polymerization assay. Apoptotic effect was analyzed by assessing increase in annexin V-staining and caspase-3 activity. Treatment of synchronized leukemia cells with varying concentrations of PD resulted in significant mitotic arrest and endoreduplication (END) via downregulation of Cdc2/cyclin B1 and upregulation of wee1 expression, and elevated the Cdk2 protein via downregulation of p21 within 48 hr. We also researched PD's induction of polyploidy through the MT polymerization. Immunofluorescent microscopy and Western blot analysis revealed that PD significantly caused MT polymerization in leukemia cells. We also found that very high concentrations of PD (>200 microM) were required to directly induce MT polymerization in vitro. Finally, PD exposure induced apoptosis in U937 cells through caspase-3-dependent PARP and lamin A cleavage. We conclude that the primary antileukemia activity of PD is induction of endoreduplication and mitotic arrest, as a consequence of suppressing spindle MT dynamics and in promoting apoptosis in human leukemia cells.
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PMID:Platycodin D induces mitotic arrest in vitro, leading to endoreduplication, inhibition of proliferation and apoptosis in leukemia cells. 1835 45

Although digitalis has been used in clinical treatment extensively, the precise mechanism of its toxic actions on cardiovascular system remained unclear, it would be of interest to study the differential proteomic analysis of vascular endothelial cells in response to toxic concentrations of digitalis thus to provide new agents for treatment of digitalis-induced cytotoxicity. We employed human umbilical vein endothelial cells (HUVEC) as our model system. HUVEC were exposed to increasing concentrations (0.1 nM-10 microM) of digoxin at 12-96 h intervals. Cell viability tests revealed that digoxin played dual effects on cell growth. Apoptosis detection confirmed that apoptosis was primarily responsible for digoxin-induced cell death. Proteomics analysis further revealed that the digoxin-induced apoptosis was accompanied by regulated expression of ATP synthase beta chain, cystatin A, electron transfer flavoprotein, heterogeneous nuclear ribonucleoproteins H3, lamin A, profilin-1, proteasome subunit 5, succinyl-CoA ligase beta chain and heat shock protein 60 (HSP60). Deep study on the overexpression of HSP60 confirmed that HSP60 exerted a protective role in digoxin-induced apoptosis through inhibition of caspase-3 activity in HUVEC. These results provided an impetus for further delineation of mechanism of digoxin-induced cytotoxicity and offered new agents that help attenuate its toxicity.
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PMID:Comparative proteomics analysis reveals role of heat shock protein 60 in digoxin-induced toxicity in human endothelial cells. 1869 61

Apoptosis of host cells plays an important role in modulating the pathogenesis of many infectious diseases. It has been reported that Leptospira interrogans, the causal agent of leptospirosis, induces apoptosis in macrophages and hepatocytes. However, the molecular mechanisms responsible for host cell death remained largely unknown. Here we demonstrate that L. interrogans induced apoptosis in a macrophage-like cell line, J774A.1, and primary murine macrophages in a time- and dose-dependent manner. Apoptosis was associated with the activation of cysteine aspartic acid-specific proteases (caspase-3, caspase-6, and caspase-8), the increased expression of Fas-associated death domain (FADD), and the cleavage of the caspase substrates poly(ADP-ribose) polymerase (PARP) and nuclear lamina protein (lamin A and lamin C). Caspase-9 was activated to a lesser extent, whereas no release of cytochrome c from mitochondria was detectable. Inhibition of caspase-8 impaired L. interrogans-induced caspase-3 and -6 activation, as well as PARP and lamin A/C cleavage and apoptosis, suggesting that apoptosis is initiated via caspase-8 activation. Furthermore, caspase-3 was required for the activation of caspase-6 and seemed to be involved in caspase-9 activation through a feedback amplification loop. These data indicate that L. interrogans-induced apoptosis in macrophages is mediated by caspase-3 and -6 activation through a FADD-caspase-8-dependent pathway, independently of mitochondrial cytochrome c-caspase-9-dependent signaling.
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PMID:Leptospira interrogans induces apoptosis in macrophages via caspase-8- and caspase-3-dependent pathways. 1902 1

Keratinization is a kind of cell death called terminal differentiation and includes various patterns such as epidermal keratinization (EK), trichilemmal keratinization (TK), and shadow cell differentiation (SCD), whereas these have not been comparatively investigated from a standpoint of cell death. In the present study, surgically extirpated specimens of epidermal cyst, trichilemmal cyst, and pilomatricoma (10 cases in each) were subjected to immunohistochemistry for single-strand DNA (ssDNA), gamma-H2AX, cleaved caspase-3, cleaved lamin A, caspase-14, and CD138 to compare the modes of cell death and keratinization pattern. Transitional cells in pilomatricoma were immunoreactive, although not in whole part, for ssDNA and gamma-H2AX, and negative for cleaved caspase-3 and cleaved lamin A. Epidermal and trichilemmal cyst were negative for these 4 markers, except for ssDNA or cleaved lamin A in a small number of parakeratotic cells in a few cases. The keratinizing component showed caspase-14(+)/CD138(-) in epidermal cyst, caspase-14(-)/CD138(+) in trichilemmal cyst, and caspase-14(-)/CD138(-) in pilomatricoma. These results indicate that EK, TK, and SCD have a common property of apoptosis-like programmed cell death without caspase-3 activation or nuclear fragmentation. Meanwhile, they show different characteristics one another as follows: (A), DNA double-strand breaks occur in the transitional cells of SCD but not in EK/TK; and (B), EK, TK, and SCD can be distinguished by expression pattern of caspase-14 and CD138 in the keratinizing component.
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PMID:Comparative immunohistochemical analyses on the modes of cell death/keratinization in epidermal cyst, trichilemmal cyst, and pilomatricoma. 2104 91


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