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)

Growth and development of placentas in all pregnancy periods and that of fetuses in late pregnancy were inhibited after administration of interferon-gamma (IFN-gamma). Apoptosis can be detected by TUNEL at the maternal-fetal interface during normal rat pregnancy. Apoptosis locations at the maternal-fetal interface changed according to the period of pregnancy. The results of immunohistochemistry and the DNA ladder assay showed that IFN-gamma could promote the apoptosis levels during the entire pregnancy, but it did not change the apoptosis locations. IFN regulatory factor-1 (IRF-1), FasL, and p53 expressions were modulated by IFN-gamma during the entire pregnancy. In vitro cell proliferation assay indicated that IFN-gamma could inhibit proliferation of human cytotrophoblast cells, and flow assay showed that this effect was mainly due to apoptosis induction. TUNEL and Hoechst staining also showed that IFN-gamma could induce apoptosis of human cytotrophoblast cells. Expression of IRF-1 was induced and expression of active caspase-3 was promoted by IFN-gamma treatment, but IFN-gamma did not affect the expression of IFNGR and p53.
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PMID:IFN-gamma promotes apoptosis of the uterus and placenta in pregnant rat and human cytotrophoblast cells. 1765 Oct 18

Addition of bacterial lipopolysaccharides (LPS) and interferon-gamma (IFN-gamma) to rat astrocytes in primary culture promotes an early release of arachidonic acid (ARA) associated with an immediate inhibition of neuronal nitric oxide synthase (nNOS). Preventing the release of constitutive nitric oxide (NO) is indeed critical for activation of the nuclear factor kappa B, and for the expression of inducible nitric oxide synthase responsible for the formation of large amounts of NO. LPS/IFN-gamma also promotes an early release of superoxide, via activation of NADPH oxidase, but the generation of peroxynitrite (ONOO-) is prevented by the different timing of superoxide (minutes) and NO (hours) formation. Upstream inhibition of the ARA-dependent nNOS inhibitory signaling, however, caused the parallel release of superoxide and constitutive NO, thereby leading to formation of ONOO- levels triggering loss of ATP and mitochondrial membrane potential followed by the mitochondrial release of cytochrome c, activation of caspase 3 and morphological evidence of apoptosis. Nanomolar levels of exogenous ARA prevented all these events via inhibition of early ONOO- formation. Thus, the ARA-dependent nNOS inhibition observed in astrocytes exposed to pro-inflammatory stimuli, as LPS/IFN-gamma, is critical for both the expression of nuclear factor kappa B-dependent genes and for survival.
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PMID:Early release of arachidonic acid prevents an otherwise immediate formation of toxic levels of peroxynitrite in astrocytes stimulated with lipopolysaccharide/interferon-gamma. 1766 49

Glioblastoma is the deadliest and most prevalent brain tumor, which is not yet amenable to any treatments. Therefore, new and innovative therapeutic strategies need to be developed for treating this deadly disease. We found that all-trans retinoic acid (ATRA) or 13-cis retinoic acid (13-CRA) induced astrocytic differentiation with down regulation of telomerase activity in rat glioblastoma C6 cells and enhanced sensitivity of the cells to interferon-gamma (IFN-gamma) or taxol (TXL) for apoptosis. Sensitivity of differentiated cells to IFN-gamma or TXL was greatly increased for apoptosis with increases in calcineurin expression, Bax:Bcl-2 ratio, mitochondrial release of cytochrome c, and expression and activity of calpain and caspases. Treatment with IFN-gamma activated caspase-8 indicating induction of apoptosis via the receptor-mediated pathway. Notably, IFN-gamma activated the signal transducer and activator of transcription-1 (STAT-1) for signaling via binding to gamma activator sequence (GAS), whereas TXL activated Raf-1 kinase for inactivation of Bcl-2 by its phosphorylation. We confirmed involvement of different proteolytic mechanisms in cell death by pretreating the cells with caspase-8 inhibitor II, calpeptin (calpain inhibitor), and caspase-9 inhibitor I, and caspase-3 inhibitor IV. Results demonstrated that retinoids induced astrocytic differentiation with down regulation of telomerase activity and worked synergistically to enhance sensitivity of cells to the cytotoxic agent IFN-gamma and the cytostatic agent TXL for apoptosis. This combination therapy for differentiation and apoptosis could be highly effective for controlling the malignant growth of glioblastoma.
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PMID:Differentiation decreased telomerase activity in rat glioblastoma C6 cells and increased sensitivity to IFN-gamma and taxol for apoptosis. 1769 33

Resveratrol (trans-3,5,4'-trihydroxystilbene), a polyphenolic compound found in plant products, including red grapes, exhibits anticancer, antioxidant, and anti-inflammatory properties. Using an animal model of multiple sclerosis (MS), we investigated the use of resveratrol for the treatment of autoimmune diseases. We observed that resveratrol treatment decreased the clinical symptoms and inflammatory responses in experimental allergic encephalomyelitis (EAE)-induced mice. Furthermore, we observed significant apoptosis in inflammatory cells in spinal cord of EAE-induced mice treated with resveratrol compared with the control mice. Resveratrol administration also led to significant down-regulation of certain cytokines and chemokines in EAE-induced mice including tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-2, IL-9, IL-12, IL-17, macrophage inflammatory protein-1alpha (MIP-1alpha), monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T-cell expressed and secreted (RANTES), and Eotaxin. In vitro studies on the mechanism of action revealed that resveratrol triggered high levels of apoptosis in activated T cells and to a lesser extent in unactivated T cells. Moreover, resveratrol-induced apoptosis was mediated through activation of aryl hydrocarbon receptor (AhR) and estrogen receptor (ER) and correlated with up-regulation of AhR, Fas, and FasL expression. In addition, resveratrol-induced apoptosis in primary T cells correlated with cleavage of caspase-8, caspase-9, caspase-3, poly(ADP-ribose) polymerase, and release of cytochrome c. Data from the present study demonstrate, for the first time, the ability of resveratrol to trigger apoptosis in activated T cells and its potential use in the treatment of inflammatory and autoimmune diseases including, MS.
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PMID:Resveratrol (trans-3,5,4'-trihydroxystilbene) ameliorates experimental allergic encephalomyelitis, primarily via induction of apoptosis in T cells involving activation of aryl hydrocarbon receptor and estrogen receptor. 1787 69

Glioblastoma is the most malignant and prevalent brain tumor in humans. It is composed of heterogenic abnormal astroglial cells that avoid differentiation, maintain proliferation, and hardly commit apoptosis. N-(4-Hydroxyphenyl)retinamide (4-HPR) induced astrocytic differentiation and increased sensitivity to interferon-gamma (IFN-gamma) for apoptosis in human glioblastoma A172, LN18, and SNB19 cells. Combination of 4-HPR and IFN-gamma significantly inhibited human telomerase reverse transcriptase (hTERT), cyclin dependent kinase 2 (CDK2), and survivin to up-regulate caspase-8, caspase-9, and caspase-3 for increasing apoptosis in all glioblastoma cell lines. Hence, combination of 4-HPR and IFN-gamma should be considered for controlling growth of different human glioblastoma cells.
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PMID:N-(4-Hydroxyphenyl)retinamide induced differentiation with repression of telomerase and cell cycle to increase interferon-gamma sensitivity for apoptosis in human glioblastoma cells. 1816 43

The development of granulomas is a major histopathological feature of tuberculosis. Very little information is available concerning the physiology and functions of different cell types in the tuberculous granulomas. The aim of this study was to compare the epithelioid cells (ECs) and multinucleated giant cells (MGCs) in the granulomas caused by Mycobacterium tuberculosis complex organisms. Lymph node biopsies from 30 cases of lymphadenitis were studied for expression of the secreted mycobacterial protein MPT64, caspase 3 as a marker of apoptosis, apoptosis-related proteins (Fas Ligand, Fas and Bax) and inflammatory cytokines (interleukin-10, transforming growth factor-beta (TGF-beta), tumour necrosis factor-alpha and interferon-gamma) by immunohistochemistry. MGCs more often contained M. tuberculosis secretory antigen MPT64 (p < 0.001) and expressed more TGF-beta (p = 0.004) than ECs. The total number of apoptotic MGCs was higher than the number of apoptotic ECs (p = 0.04). Interestingly, there was a significant negative correlation between apoptosis and MPT64 expression in MGCs (r = -0.569, p = 0.003), but not in ECs, implying that the heavy antigen load would lead to inhibition of apoptosis in these cells. When compared with ECs, higher percentage of MGCs expressed Fas Ligand and Fas (p < 0.004). The role of MGCs may thus be different from surrounding ECs and these cells by virtue of higher mycobacterial antigen load, more TGF-beta and reduced apoptosis may contribute towards persistence of infection.
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PMID:Differential expression of mycobacterial antigen MPT64, apoptosis and inflammatory markers in multinucleated giant cells and epithelioid cells in granulomas caused by Mycobacterium tuberculosis. 1826 5

Glioblastoma is the deadliest brain tumor that remains incurable. We examined efficacy of combination of retinoid and interferon-gamma (IFN-gamma) in human glioblastoma T98G and U87MG cells. We conjectured that retinoid could induce differentiation with down regulation of telomerase activity to increase sensitivity to IFN-gamma for apoptosis in glioblastoma cells. Indeed, treatment of cells with 1 muM all-trans retinoic acid (ATRA) or 1 muM 13-cis retinoic acid (13-CRA) for 7 days induced astrocytic differentiation with upregulation of glial fibrillary acidic protein (GFAP) and down regulation of telomerase activity. Wright staining and ApopTag assay showed, respectively, morphological and biochemical features of apoptosis in glioblastoma cells following exposure to 200 units/ml IFN-gamma for 48 h. Induction of differentiation was associated with decreases in levels of nuclear factor kappa B (NFkappaB), inducible nitric oxide synthase (iNOS), and production of nitric oxide (NO) so as to increase sensitivity to IFN-gamma for apoptosis. Notably, IFN-gamma induced signal transducer and activator of transcription-1 (STAT-1) to bind to gamma-activated sequence (GAS) of the target gene. Also, IFN-gamma activated caspase-8 and cleaved Bid to truncated Bid (tBid) for translocation to mitochondria. Fura-2 assay showed increases in intracellular free [Ca2+] and activation of calpain in apoptotic cells. Besides, increases in Bax:Bcl-2 ratio and mitochondrial release of cytochrome c and Smac into the cytosol activated caspase-9 and caspase-3 for apoptosis. Taken together, our results showed that retinoid induced astrocytic differentiation with down regulation of telomerase activity and enhanced sensitivity to IFN-gamma for increasing apoptosis in human glioblastoma cells.
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PMID:Molecular mechanisms of the combination of retinoid and interferon-gamma for inducing differentiation and increasing apoptosis in human glioblastoma T98G and U87MG cells. 1836 85

The protease cathepsin D (Cath D) and its proteolytically inactive proform, procathepsin D (ProCath D), turned out to be multifunctional within and outside the cell. Elevated levels of ProCath D occur in malignant tumors and in organs under chronic inflammation. One important source for this increase of ProCath D might be endothelial cells. Here we examined the expression of Cath D in the human endothelial cell line EA.hy 926 and in primary endothelial cells isolated from human umbilical cord veins (HUVEC). After serum-free incubation with or without human interferon-gamma (hIFN-gamma) and/or human tumor necrosis factor-alpha (hTNF-alpha) immature and mature Cath D forms were examined in cell extracts and in cell-conditioned medium concentrates by Western blotting. Lysates of EA.hy 926 cells as well as of HUVEC contained active Cath D as two-chain form, but only negligible amounts of ProCath D and Cath D intermediates. Yet both endothelial cell cultures accumulated ProCath D in their conditioned media in the absence of any stimulus. The treatment with hIFN-gamma and/or hTNF-alpha had little effect on intracellular levels of Cath D, whereas the cytokine stimulation increased the extracellular presence of ProCath D in both endothelial cell cultures. The extracellular increase of ProCath D was not related to induction of apoptosis, as validated by cleaved caspase-3 in cell lysates. Acidification of cytokine-treated media converted ProCath D into Cath D, which was associated with cathepsin-like activity using a fluorogenic substrate-linked assay. We conclude, in vitro, endothelial cells are a cytokine-dependent source for extracellular ProCath D.
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PMID:Inflammatory cytokines increase extracellular procathepsin D in permanent and primary endothelial cell cultures. 1838 91

Activation of the complement cascade represents an important event during ischemia/reperfusion injury (IRI). This work was designed to investigate the role of the membrane attack complex (MAC; C5b-9) in the pathogenesis of hepatic IRI. Livers from B&W/Stahl/rC6(+) and C6(-) rats were harvested, stored for 24 hours at 4 degrees C, and then transplanted [orthotopic liver transplantation (OLT)] to syngeneic recipients. There were 4 experimental groups: (1) C6(+)-->C6(+), (2) C6(+)-->C6(-), (3) C6(-)-->C6(+), and (4) C6(-)-->C6(-). At day +1, C6(-) OLTs showed decreased vascular congestion/necrosis, contrasting with extensive necrosis in C6(+) livers, that was independent of the recipient C6 status (Suzuki score: 7.2 +/- 0.9, 7.3 +/- 1.3, 4.5 +/- 0.6, and 4.8 +/- 0.4 for groups 1-4, respectively, P < 0.05). The liver function improved in recipients of C6(-) grafts (serum glutamic oxaloacetic transaminase: 2573 +/- 488, 1808 +/- 302, 1170 +/- 111, and 1188 +/- 184 in groups 1-4, respectively, P < 0.05). Intragraft macrophage infiltration (ED-1 immunostaining) and neutrophil infiltration (myeloperoxidase activity) were reduced in C6(-) grafts versus C6(+) grafts (P = 0.001); these data were confirmed by esterase staining (naphthol). The expression of proinflammatory interferon-gamma, interleukin-1beta, and tumor necrosis factor messenger RNA/protein was also reduced in C6(-) OLTs in comparison with C6(+) OLTs. Western blot-assisted expression of proapoptotic caspase-3 was decreased in C6(-) OLTs versus C6(+) OLTs (P = 0.006), whereas antiapoptotic Bcl-2/Bag-1 was enhanced in C6(-) OLTs compared with C6(+) OLTs (P = 0.001). Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining of apoptotic cells was enhanced (P < 0.05) in C6(+) OLTs compared with C6(-) OLTs. Thus, the terminal products of the complement system are essential in the mechanism of hepatic IRI. This is the first report using a clinically relevant liver cold ischemia model to show that local MAC inhibition attenuates IRI cascade in OLT recipients.
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PMID:The membrane attack complex (C5b-9) in liver cold ischemia and reperfusion injury. 1866 46

MicroRNAs (miRNA) are endogenously expressed non-coding RNAs that regulate gene expression post-transcriptionally. Let-7a miRNA is a founding member in the let-7 family and its down-regulation in association with over-expression of RAS and HMGA2 oncogenes has previously been reported. In the present study, caspase-3, the executioner caspase, was confirmed to be the target of let-7a as ectopic expression of let-7a decreased the luciferase activity of a reporter construct containing the 3' untranslated region of caspase-3 and at the same time repressed the enzyme expression in human squamous carcinoma A431 cells and hepatocellular carcinoma HepG2 cells. Moreover, let-7a was over-expressed while caspase-3 was down-regulated in A10A cells, a doxorubicin-resistant A431 subline. Enforced let-7a expression increased the resistance in A431 cells and HepG2 cells to apoptosis induced by therapeutic drugs such as interferon-gamma, doxorubicin and paclitaxel. On the other hand, down-regulation of let-7a by the anti-let-7a inhibitor increased the doxorubicin-induced apoptosis in A431 parent cells, A10A cells and HepG2 cells while the increase was suppressed by caspase-3 inhibitor. Both anti-let-7a inhibitor and caspase-3 inhibitor however failed to affect the drug-induced apoptosis in human breast cancer MCF7 cells, the cells that do not express caspase-3. Therefore, let-7a by targeting caspase-3 may play a functional role in modulating drug-induced cell death in human cancer cells.
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PMID:Let-7a microRNA suppresses therapeutics-induced cancer cell death by targeting caspase-3. 1875 60


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