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)

Spermine NONOate (SpNO, a nitric oxide donor) induced apoptosis and caspase-3 activity in the macrophage cell line RAW 267.4. RES cells that have been derived from RAW 267.4 cells by repeated exposure to lipopolysaccharide and interferon-gamma (LPS/INF-gamma), followed by outgrowth of viable cells, are resistant to apoptosis and caspase-3 activation upon exposure to SpNO. In this study we have determined that RES cells have lower levels of glutathione (GSH) and a higher oxidative state than RAW cells. Subsequently, RAW and RES cells were depleted of GSH by using l-buthionine-[S,R]-sulfoximine (BSO), a specific inhibitor of GSH synthesis. GSH depleted cells did not undergo apoptosis nor demonstrate caspase-3 activity when they were exposed to SpNO. These results suggest that the redox status of the cell is one of the key factors mediating the apoptotic pathway in which glutathione plays a critical role in mediating apoptosis via NO* and reactive oxygen species (ROS).
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PMID:Glutathione levels determine apoptosis in macrophages. 964 8

Caspase activation has been shown to be a critical step in several models of neuronal apoptosis such as staurosporine treatment of human neuroblastoma SH-SY5Y cells and potassium deprivation of rat cerebellar granule neurons. One common event is the appearance of caspase-mediated 120-kDa nonerythroid alpha-spectrin breakdown product (SBDP120). Second, inhibitors of the caspase family are effective blockers of such neuronal death. In this study, we report the appearance of caspase-mediated SBDP120 in excitotoxin-challenged fetal rat cerebrocortical neurons [N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate] and rat cerebellar granule neurons (NMDA and kainate). A general caspase inhibitor, carbobenzoxy-Asp-CH2OC(O)-2,6-dichlorobenzene (Z-D-DCB), blocked the formation of SBDP120 under these conditions and attenuated the observed NMDA-induced lactate dehydrogenase (LDH) release in both cell types. Furthermore, hydrolytic activity toward a caspase-3-preferred synthetic peptide substrate, acetyl-DEVD-7-amido-4-methylcoumarin, was significantly elevated in NMDA-treated granule neurons. Lastly, oxygen-glucose deprivation (OGD)-challenged cerebrocortical cultures also showed the appearance of SBDP120. Again, Z-D-DCB blocked the SBDP120 formation as well as attenuated the LDH release from the OGD-challenged neurons. Taken together, the presence of caspase-specific SBDP120 and the neuroprotective effects of Z-D-DCB strongly suggest that caspase activation contributes at least in part to excitotoxin- and OGD-induced neuronal death.
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PMID:Evidence for activation of caspase-3-like protease in excitotoxin- and hypoxia/hypoglycemia-injured neurons. 964 65

Polymorphonuclear leukocytes (PMN) isolated from the oral cavity of healthy human volunteers, spontaneously generated superoxide, nitric oxide (NO) and other reactive oxygen species (ROS) which exhibited strong luminol chemiluminescence (LCL). To understand the physiological roles of oral PMN (OPMN), biochemical properties of the cells were analyzed. Biochemical analysis revealed that OPMN were already primed under physiological conditions. Western blot analysis revealed that they strongly expressed the inducible type of NO synthase (NOS II) and exhibited the activity to catalyze tyrosine phosphorylation of various proteins including a 115 kDa protein (cbl product). OPMN also generated H2O2 and .OH by some superoxide dismutase (SOD)-sensitive mechanism and released myeloperoxidase (MPO). Kinetic analysis using specific inhibitors revealed that OCl- generated by OPMN was predominantly responsible for the enhanced LCL. During the incubation under standard culture conditions, OPMN underwent apoptosis which proceeded more rapidly than that of the circulating PMN (CPMN). Immunochemical analysis revealed that expression of apoptosis-related gene products, such as Bcl-2, Bcl-xL and Bax, was below detectable levels with both cell types. However, caspase-3 but not caspase-1 was markedly activated in OPMN. These results indicate that the primed OPMN spontaneously generate ROS and play an important role in the defense mechanism in the oral cavity and that the generated ROS activate caspase-3 thereby inducing apoptosis of the cells.
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PMID:Biochemical properties of human oral polymorphonuclear leukocytes. 970 29

The inducible nitric oxide synthase (iNOS) gene is expressed by hepatocytes in a number of physiologic and pathophysiologic conditions affecting the liver including septic and hemorrhagic shock. The molecular regulation of iNOS expression is complex and occurs at multiple levels in the gene expression pathway. The cytokines TNF-alpha, IL-1beta, and INF-gamma synergistically activate iNOS expression in the liver, and the human iNOS gene was first cloned from cytokine-stimulated hepatocytes. iNOS expression requires the transcription factor NF-kappaB and is down-regulated by steroids, TGF-beta, the heat shock response, p53, and nitric oxide (NO) itself. In vivo, hepatic iNOS induction is differentially regulated from the typical acute-phase reactants and is not expressed as a mandatory component of the acute phase response. Thus, numerous mechanisms have evolved to regulate iNOS expression during hepatocellular injury. Studies of the effects of NO in the liver demonstrate that induced NO synthesis plays an important role in hepatocyte function and protects the liver during sepsis and ischemia reperfusion. Its cytoprotective role is best exemplified in a rodent model of endotoxemia. Here the addition of the nonspecific NOS inhibitors significantly increased hepatic damage. NO exerts a protective effect through its ability to prevent intravascular thrombosis by inhibiting platelet adhesion and neutralizing toxic oxygen radicals. NO also exerts a protective effects both in vivo and in vitro by blocking TNF-alpha-induced apoptosis and hepatotoxicity, in part by a thiol-dependent inhibition of caspase-3-like protease activity. These studies demonstrate the cytoprotective effects of NO in the liver and suggest hepatic iNOS expression functions as an adaptive response to minimize inflammatory injury. In addition, NO has anti-tumor effects as well as known mutagenic effects, is involved in the systemic vasodilatation of cirrhosis, and has potent antimicrobial properties.
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PMID:Inducible nitric oxide synthase in the liver: regulation and function. 972 29

Murine L929 fibrosarcoma cells were transfected with the human Fas (APO-1/CD95) receptor, and the role of various caspases in Fas-mediated cell death was assessed. Proteolytic activation of procaspase-3 and -7 was shown by Western analysis. Acetyl-Tyr-Val-Ala-Asp-chloromethylketone and benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethylketone++ +, tetrapeptide inhibitors of caspase-1- and caspase-3-like proteases, respectively, failed to block Fas-induced apoptosis. Unexpectedly, the broad-spectrum caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone and benzyloxycarbonyl-Asp(OMe)-fluoromethylketone rendered the cells even more sensitive to Fas-mediated cell death, as measured after 18 h incubation. However, when the process was followed microscopically, it became clear that anti-Fas-induced apoptosis of Fas-transfected L929 cells was blocked during the first 3 h, and subsequently the cells died by necrosis. As in tumor necrosis factor (TNF)-induced necrosis, Fas treatment led to accumulation of reactive oxygen radicals, and Fas-mediated necrosis was inhibited by the oxygen radical scavenger butylated hydroxyanisole. However, in contrast to TNF, anti-Fas did not activate the nuclear factor kappaB under these necrotic conditions. These results demonstrate the existence of two different pathways originating from the Fas receptor, one rapidly leading to apoptosis, and, if this apoptotic pathway is blocked by caspase inhibitors, a second directing the cells to necrosis and involving oxygen radical production.
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PMID:Dual signaling of the Fas receptor: initiation of both apoptotic and necrotic cell death pathways. 973 Aug 93

Mice exposed to 100% O2 die after 3 or 4 d with diffuse alveolar damage and alveolar edema. Extensive cell death is evident by electron microscopy in the alveolar septa, affecting both endothelial and epithelial cells. The damaged cells show features of both apoptosis (condensation and margination of chromatin) and necrosis (disruption of the plasma membrane). The electrophoretic pattern of lung DNA indicates both internucleosomal fragmentation, characteristic of apoptosis, and overall degradation, characteristic of necrosis. Hyperoxia induces a marked increase in RNA or protein levels of p53, bax, bcl-x, and Fas, which are known to be expressed in certain types of apoptosis. However, we did not detect an increased activity of proteases belonging to the apoptosis "executioner" machinery, such as CPP32 (caspase 3), ICE (caspase 1), or cathepsin D. Furthermore, administration of an ICE-like protease inhibitor did not significantly enhance the resistance to oxygen. Additionally, neither p53-deficient mice nor lpr mice (Fas null) manifested an increased resistance to hyperoxia-induced lung damage. These results show that both necrosis and apoptosis contribute to cell death during hyperoxia. Multiple apoptotic pathways seem to be involved in this, and an antiapoptotic strategy does not attenuate alveolar damage.
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PMID:Oxygen toxicity in mouse lung: pathways to cell death. 976 53

A newly synthesized cyclic hydroxamic acid compound, BMD188 [cis-1-hydroxy-4-(1-naphthyl)-6-octylpiperidine-2-one], was found to induce the apoptotic death of cultured prostate cancer cells by activating caspase-3. Orally administered BMD188 significantly inhibited the primary growth of prostate cancer cells (Du145) orthotopically implanted into SCID mice. Mechanistic studies indicated that BMD188 did not alter the protein levels of several Bcl-2 family members. In contrast, the BMD188 effect required three essential factors: reactive oxygen species (ROS), the mitochondrial respiratory chain function, and proteases. First, the apoptosis-inducing effect of BMD188 could be blocked by ROS scavengers such as Desferal. Second, both BMD188-induced PARP cleavage as well as PC3 cell apoptosis could be dramatically inhibited by several complex-specific mitochondrial respiration blockers. The involvement of mitochondria was also supported by the observations that BMD188 dramatically altered the mitochondrial distribution and morphology without affecting the cellular ATP levels. Finally, the apoptosis-inducing effect of BMD188 in PC3 cells could be significantly inhibited by serine protease inhibitors (TPCK and TLCK) as well as by caspase inhibitors (zVAD-fmk and DEVD-CHO). Collectively, the present study suggests that BMD188 and its analogs may find clinical applications in the treatment of prostate cancer patients by inducing apoptotic death of prostate cancer cells.
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PMID:BMD188, A novel hydroxamic acid compound, demonstrates potent anti-prostate cancer effects in vitro and in vivo by inducing apoptosis: requirements for mitochondria, reactive oxygen species, and proteases. 976 36

A novel anticancer drug, cytotrienin A, isolated from Streptomyces sp., induces apoptosis (or programmed cell death) in human promyelocytic leukemia HL-60 cells within 4 h. To elucidate the mechanism of this process, we performed an in-gel kinase assay using myelin basic protein (MBP) as a substrate and found the activation of kinase with an apparent molecular mass of 36 kDa (p36 MBP kinase). The dose of cytotrienin A required to activate p36 MBP kinase was consistent with that required to induce apoptotic DNA fragmentation in HL-60 cells. This p36 MBP kinase was activated with kinetics distinct from the activation of JNK (c-Jun N-terminal kinase)/stress-activated protein kinase and p38 MAPK (mitogen-activated protein kinase). Importantly, the p36 MBP kinase was immunologically different from MAPK superfamily molecules such as ERK1, JNK isoforms, and p38 MAPK. In addition, the p36 MBP kinase activation and apoptotic DNA fragmentation were inhibited by antioxidants such as N-acetylcysteine and reduced-form glutathione. The p36 MBP kinase activation was also observed during hydrogen peroxide (H2O2) and okadaic acid-induced apoptosis. Although a specific inhibitor of caspase-3-like proteases (Ac-DEVD-CHO) or a specific inhibitor of caspase-1-like proteases (Ac-YVAD-CHO) did not block the cytotrienin A-, H2O2-, or okadaic acid-induced apoptosis, a broad specificity inhibitor of caspases (Z-Asp-CH2-DCB) strongly inhibited the apoptosis of HL-60 cells. Surprisingly, Z-Asp-CH2-DCB inhibited the activation of p36 MBP kinase induced by cytotrienin A or H2O2, but did not inhibit the activation of JNK/stress-activated protein kinase and p38 MAPK. Taken together, these results indicate that p36 MBP kinase activation is downstream of the activation of Z-Asp-CH2-DCB-sensitive caspases, and reactive oxygen species could be included in the apoptotic events. Moreover, according to the Western blotting using the antibodies against MST1/Krs2 or MST2/Krs1, it is suggested that the p36 MBP kinase is an active proteolytic product of MST1/Krs2 and MST2/Krs1, which are originally cloned by virtue of its homology to the budding yeast Ste20 kinase. Thus, the p36 MBP kinase might be a common component of the diverse signaling pathways leading to apoptosis, and controlling this p36 MBP kinase pathway might be a novel strategy for cancer chemotherapy.
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PMID:Caspase-mediated activation of a 36-kDa myelin basic protein kinase during anticancer drug-induced apoptosis. 980 95

Reactive oxygen species (ROS) and caspases have been implicated as potential mediators of cell death. However, their mechanistic relationship remains to be elucidated. Here we investigated the roles of caspases in apoptosis and necrosis induced by ROS, generated by the mixture of xanthine and xanthine oxidase (X/XO). A low concentration of XO (0.025 U/ml) induced DNA fragmentation with little cellular membrane damage 3 h after treatment, suggesting the induction of apoptosis. The same treatment induced membrane blebbing, a morphological change typical of apoptosis, 15 min after treatment. A high concentration of XO (0.1 U/ml) damaged cell membranes with little concomitance of DNA fragmention, suggesting the induction of necrosis. ROS also activated caspase 3-like proteases and caspase 3 itself together with the release of cytochrome c which might be the cause of caspase activation. Apoptosis induced by low concentrations of XO and necrosis induced by high concentrations of XO was inhibited by z-DEVD-CH2F, an irreversible inhibitor of caspase 3. However, rapid induction of membrane blebbing was not inhibited by z-DEVD-CH2F. These results suggest that both apoptosis and necrosis could be induced by ROS through the activation of caspase 3-like protease; however, caspase 3 activation is not needed for ROS-induced membrane blebbing.
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PMID:Regulation of reactive oxygen species-induced apoptosis and necrosis by caspase 3-like proteases. 984 Sep 39

We have attempted to elucidate the mechanism of apoptotic cell death induced by hypoxia (very low oxygen conditions) in neuronal cells. Human neuroblastoma SK-N-MC cells under hypoxic conditions resulted in apoptosis in a time-dependent manner estimated by DNA fragmentation assay and nuclear morphology stained with fluorescent chromatin dye. Pretreatment with Z-Asp-CH2-DCB, a caspase inhibitor, suppressed the DNA ladder in response to hypoxia in a concentration-dependent manner. An increase in caspase-3-like protease (DEVDase) activity was observed during apoptosis, but no caspase-1 activity (YVADase) was detected. To confirm the involvement of caspase-3 during apoptosis, Western blot analysis was performed using anti-caspase-3 antibody. The 20- and 17-kDa proteins, corresponding to the active products of caspase-3, were generated in hypoxia-challenged lysates in which processing of the full length form of caspase-3 was evident. With a time course similar to this caspase-3 activation, hypoxic stress caused the cleavage of PARP, yielding an 85-kDa fragment typical of caspase activity. In addition, caspase-2 was also activated by hypoxia, and the stress elicited the release of cytochrome c into the cytosol during apoptosis. These results suggest that caspase activation and cytochrome c release play roles in hypoxia-induced neuronal apoptosis.
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PMID:Hypoxia induces apoptosis in human neuroblastoma SK-N-MC cells by caspase activation accompanying cytochrome c release from mitochondria. 984


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