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)

Oxidative stress, resulting from excessive production of reactive oxygen species (ROS), is a pathological state that causes profound cellular damage and eventual death resulting from the overactivation of glutamate receptors, and the generation of nitric oxide, superoxide and hydrogen peroxide (H(2)O(2)). As such, H(2)O(2) represents an important model for studying the neuropathology of oxidative stress in a variety of CNS disorders. The effects of H(2)O(2) on the viability of post-natal cerebellar granule neurons (CGNs), the nature of the cell death involved and the potential protection by adenosine receptors against the damage were examined in the current study. Hydrogen peroxide (10-400 microM) reduced CGN viability in a concentration- and time-dependent manner. The addition of catalase (100 U/ml) prevented this effect, and the non-specific COX inhibitor aspirin (1 mM) also alleviated the damage. A combination of H(2)O(2) (5 microM) and Cu(2+) (0.5 mM) resulted in a significant damage that was not prevented by the hydroxyl radical scavenger mannitol (50 mM). The permeability transition pore blocker cyclosporin A, the caspase-3 inhibitor Z-DEVD-fmk (40 microM) and the PARP-1 inhibitor DPQ (10 microM) each significantly protected against peroxide damage. While the A(1) adenosine receptor agonist CPA and the A(2A) receptor antagonist ZM241385 (each at 100 nM) elicited protection, the A(1) adenosine receptor blocker DPCPX and the A(2A) receptor agonist CGS21680 (each at 100 nM) showed no effect. The data demonstrate that H(2)O(2) induced oxidative stress in CGNs, involving both apoptotic and necrotic death, and this can be ameliorated by A(1) receptor activation or A(2A) receptor blockade.
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PMID:Cell death in rat cerebellar granule neurons induced by hydrogen peroxide in vitro: mechanisms and protection by adenosine receptor ligands. 1718 58

Placental oxidative stress has been implicated in many complications of human pregnancy, including preterm delivery and preeclampsia. It is now appreciated that reactive oxygen species can induce a spectrum of changes, ranging from homeostatic induction of enzymes to apoptotic cell death. Little is known regarding the occurrence of placental oxidative stress in other species. We investigated markers of oxidative stress in the labyrinthine (LZ) and junctional (JZ) zones of the murine placenta across gestational age, and correlated these with expression of the cyclooxygenase enzymes COX-1 and COX-2, and apoptosis. We tested a causal link between the two by subjecting placental explants to hypoxia-reoxygenation (H/R) in vitro, a known stimulus for generation of oxidative stress. Western blotting demonstrated significant increases in the concentrations of hydroxynonenal (HNE), COX-1 and COX-2 with gestational age. Dual-labelling demonstrated co-localisation of HNE, and COX-1 and COX-2 within the trophoblast of the LZ, and glycogen cells of the JZ. An apoptotic index based on TUNEL-positivity demonstrated an increase with gestational age, and dual-labelling showed co-localisation of TUNEL labelling with HNE and active caspase-3 within the trophoblast of the LZ. H/R significantly increased oxidative stress, induction of COX-1 and COX-2, and the apoptotic index. Co-localisation demonstrated the increases in COX to be within the trophoblast of the LZ, and in particular the glycogen cells of the JZ. Apoptosis was restricted to the LZ. We speculate that the induction of COX enzymes is a physiological response to oxidative stress, and may play a role in initiating or augmenting parturition. Generation of oxidative stress may also play a role in influencing the growth trajectory of the placenta, and its component cell types. The mouse may provide an experimental genetic model in which to investigate these phenomena.
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PMID:Oxidative stress and the induction of cyclooxygenase enzymes and apoptosis in the murine placenta. 1722 4

Expression of cyclooxygenase-2 (COX-2) is involved in the chronic inflammation-related development of Barrett's adenocarcinoma and the use of selective COX-2 inhibitors (coxibs) might provide new chemoprevention strategy for Barrett's adenocarcinoma (BA). Despite an excellent gastrointestinal (GI) safety profile of coxibs, their use is limited because of the possible cardiovascular complications. The coupling of NSAIDs with a NO-donating moiety has led to the birth of a new class of anti-inflammatory drugs, called the COX-inhibiting nitric oxide donators (CINODs). The member of this group, NO-aspirin (NO-ASA) retains the anti-inflammatory properties of traditional aspirin (ASA), but the release of NO accounts for anti-thromboembolic effect and better GI safety profile. The role of NO-ASA in the prevention of Barrett's adenocarcinoma (BA) has not been studied so far. Therefore, the aim of the present study was: 1) to analyse the expression of COX-2 in the biopsies obtained from BE; 2) to compare the effect of NO-ASA with that of ASA on proliferation rate in Barrett''s adenocarcinoma cell line (OE-33 cells); 3) to determine the effect of both compounds on the apoptosis rate using FACS analysis and expression of 32-kDa procaspase-3 and active proapoptotic 20-kDa caspase-3 in OE-33 cell line. The expression of COX-2 was assessed in biopsies obtained from the Barrett's mucosa and normal squamous epithelial esophageal mucosa from 20 BE patients by RT-PCR and Western blot analysis, respectively. The BA cell line (OE-33) was incubated with NO-ASA or ASA (10-1000 microM). The cell proliferation and apoptosis rate was measured by BrdU and FACS-analysis, respectively. The expression of caspase-3 (active and inactive form) was analyzed by Western blot. In Barrett's mucosa a significant up-regulation of COX-2 was observed. Compared with traditional ASA, NO-ASA caused a significantly stronger induction of apoptosis (dose-dependently). Inhibition of cell proliferation in OE-33 cells observed under NO-ASA treatment was due to the apoptosis induction. The increase in apoptotic rate was accompanied by the upregulation of active 20-kDa caspase-3. At the highest concentration (1000 microM), a necrotic death of OE-33 cells was observed under NO-ASA treatment. We conclude that: NO-ASA caused induction of apoptosis in BA cell line and slight growth inhibition. These results indicate that this compound may represent a promising chemopreventive agent for Barrett's adenocarcinoma.
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PMID:NO-releasing aspirin exerts stronger growth inhibitory effect on Barrett's adenocarcinoma cells than traditional aspirin. 1724 51

The naked mole rat (NMR; Heterocephalus glaber) is the longest-living rodent known [maximum lifespan potential (MLSP): >28 yr] and is a unique model of successful aging showing attenuated declines in most physiological function. This study addresses age-related changes in endothelial function and production of reactive oxygen species in NMR arteries and vessels of shorter-living Fischer 344 rats (MLSP: approximately 3 yr). Rats exhibit a significant age-dependent decline in acetylcholine-induced responses in carotid arteries over a 2-yr age range. In contrast, over a 10-yr age range nitric oxide (NO)-mediated relaxation responses to acetylcholine and to the NO donor S-nitrosopencillamine (SNAP) were unaltered in NMRs. Cellular superoxide anion (O(2)(*-)) and H(2)O(2) production significantly increased with age in rat arteries, whereas they did not change substantially with age in NMR vessels. Indicators of apoptotic cell death (DNA fragmentation rate, caspase 3/7 activity) were significantly enhanced ( approximately 250-300%) in arteries of 2-yr-old rats. In contrast, vessels from 12-yr-old NMRs exhibited only a approximately 50% increase in apoptotic cell death. In the hearts of NMRs (2 to 26 yr old), expression of endothelial NO synthase, antioxidant enzymes (Cu,Zn-SOD, Mn-SOD, catalase, and glutathione peroxidase), the NAD(P)H oxidase subunit gp91(phox), and mitochondrial proteins (COX-IV, ATP synthase, and porin, an indicator of mitochondrial mass) did not change significantly with age. Thus long-living NMRs can maintain a youthful vascular function and cellular oxidant-antioxidant phenotype relatively longer and are better protected against aging-induced oxidative stress than shorter-living rats.
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PMID:Vascular aging in the longest-living rodent, the naked mole rat. 1746 32

Primary cultures of human lung cells can serve as a model system to study the mechanisms underlying the effects of irritants in air and to get a deeper insight into the (patho)physiological roles of the xenobiotic detoxification systems. For 99 human lung cancer cases the culture duration for bronchial epithelium and peripheral lung cells (PLC) are given in term of generations and weeks. Using this system, we investigated whether and how prostaglandins (PG) modify multidrug resistance related protein (MRP) function in normal human lung cells. PGF2alpha had no effect on MRP function, whereas PGE2 induced MRP activity in cultured NHBECs. The transport activity study of MRP in NHBEC, PLC, and A549 under the effect of exogenously supplied PGF2alpha (10 microM, 1 day) using single cell fluorimetry revealed no alteration in transport activity of MRP. PG concentrations were within the physiological range. COX I and II inhibitors indomethacin (5, 10 microM) and celecoxib (5, 10 microM) could substantially decrease the transport activity of MRP in NHBEC, PLC, and A549 in 1- and 4-day trials. Prostaglandin E2 did not change cadmium-induced caspase 3/7 activation in NHBECs and had no own effect on caspase 3/7 activity. Cadmium chloride (5, 10 microM) was an effective inducer of caspase 3/7 activation in NHBECs with a fivefold and ninefold rise of activity. In primary human lung cells arachidonic acid activates MRP transport function only in primary epithelial lung cells by prostaglandin E2 but not by F2alpha mediated pathways and this effect needs some time to develop.
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PMID:Arachidonic acid pathway activates multidrug resistance related protein in cultured human lung cells. 1794 74

Inhibitors of cyclooxygenase 2 (COX 2) and the mammalian target of rapamycin (mTOR) show direct and indirect antitumor effects in a variety of cancers. This study was designed to investigate the effects of the mTOR antagonist rapamycin and the COX 2 inhibitor celecoxib on cell growth and apoptosis in malignant melanoma. Cell proliferation was analysed by the cell proliferation ELISA BrdU and alamarBlue assay and apoptosis was measured by caspase 3 and 7 activity in two out of six melanoma cell lines (A375 and Mel Ho) that were selected for the heterogeneous levels of the COX 2 mRNA expression. The quantitative real-time reverse transcription polymerase chain reaction showed a 337-fold higher COX 2 mRNA level in the A375 than in the Mel Ho melanoma cells. However, both celecoxib and rapamycin caused significant growth inhibition in the two cell lines. By combining both agents, additive growth inhibitory effects were observed in the A375 cells. Treatment with celecoxib, but not rapamycin, increased apoptosis in the two cell lines. Our data indicate that rapamycin and celecoxib inhibit melanoma cell growth as single agents and a combination of both drugs have additive antitumor effects. Notably, the antiproliferative and proapoptotic effects of celecoxib seem to be independent of the COX 2 expression. Both rapamycin and celecoxib represent promising drugs for the palliative therapy of metastasised malignant melanoma and should be considered for future trials.
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PMID:Antiproliferative and proapoptotic effects of rapamycin and celecoxib in malignant melanoma cell lines. 1820 6

Nitric oxide (NO) is a potent extracellular and intracellular physiological messenger. However, NO liberated in excessive amounts can be involved in macromolecular and mitochondrial damage in brain aging and in neurodegenerative disorders. The molecular mechanism of its neurotoxic action is not fully understood. Our previous data indicated involvement of NO in the release of arachidonic acid (AA), a substrate for cyclo- and lipoxygenases (COX and LOX, respectively). In this study we investigated biochemical processes leading to cell death evoked by an NO donor, sodium nitroprusside (SNP). We found that SNP decreased viability of pheochromocytoma (PC12) cells in a concentration- and time-dependent manner. SNP at 0.1 mM caused a significant increase of apoptosis-inducing factor (AIF) protein level in mitochondria. Under these conditions 80% of PC12 cells survived. The enhancement of mitochondrial AIF level might protect most of PC12 cells against death. However, NO released from 0.5 mM SNP induced massive cell death but had no effect on protein level and localization of AIF and cytochrome c. Caspase-3 activity and poly(ADP-ribose) polymerase-1 (PARP-1) protein levels were not changed. However, PARP activity significantly decreased in a time-dependent manner. Inhibition of both COX isoforms and of 12/15-LOX significantly lowered the SNP-evoked cell death. We conclude that AIF, cytochrome c and caspase-3 are not responsible for the NO-mediated cell death evoked by SNP. The data demonstrate that NO liberated in excess decreases PARP-1 activity. Our results indicate that COX(s) and LOX(s) are involved in PC12 cell death evoked by NO released from its donor, SNP.
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PMID:Molecular mechanism of PC12 cell death evoked by sodium nitroprusside, a nitric oxide donor. 1856 Jun 9

OSU03012 is a non-COX inhibiting celecoxib derivative with growth inhibiting and apoptotic activity in many cancer cell lines. To investigate mechanisms related to cell cycle proteins in growth inhibition and apoptosis induced by OSU03012, the primary human oral epithelial cell line, TE1177, was transformed with HPV16 E6 (TE/E6), HPV16 E7 (TE/E7) or empty vector (TE/V). TE/E6 cell lines exhibiting low levels of p53 and undetectable levels of p21(WAF1/CIP1) were sensitized to the growth inhibiting and apoptotic effects of OSU03012. The TE/E7 cell lines expressing low levels of Rb and elevated levels of p53 and p21(WAF1/CIP1) were resistant. OSU03012 reduced the number of cells in the S phase of the TE/E7 and TE/V cell lines with intact p53-p21(WAF1/CIP1) checkpoint, but not in the checkpoint defective TE/E6 cell lines. Treatment with OSU03012 also markedly reduced the levels of cyclin A and Cdk2 in TE/E7 and TE/V, but not in TE/E6 cell lines, which had significantly enhanced basal levels of cyclin A and Cdk2. Consistent with the TE/E6 cell line, p21(WAF1/CIP1)-/- mouse embryo fibroblasts were more sensitive to OSU03012-induced apoptosis as evidenced by PARP and caspase 3 cleavages. These data suggest that p21(WAF1/CIP1) is an important factor in the sensitivity of cells to the growth inhibiting and apoptotic effects of OSU03012.
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PMID:Sensitivity to the non-COX inhibiting celecoxib derivative, OSU03012, is p21(WAF1/CIP1) dependent. 1879 66

Hypothalamic growth hormone-releasing hormone (GHRH) controls the release of growth hormone and acts as a growth factor in various tumors. Potent antagonistic analogues of GHRH have been synthesized that strongly suppress the growth of diverse cancers through several mechanisms. However, the influence of GHRH antagonists on the redox (reduction/oxidation) status of cancers has not been investigated. Cellular generation of reactive oxygen species (ROS) is central to redox signaling and is implicated in the initiation, development, and progression of cancer. In this study, we evaluated by Western blot the effects in vitro of GHRH and its antagonist JMR-132 on proliferating cell nuclear antigen, tumor suppressor protein p53, transcription factor NF-kappaB p50 and its phosphorylated form, caspase 3, and cleaved caspase 3 in the LNCaP human prostate cancer cell line. GHRH stimulated and GHRH antagonist inhibited the expression of the major antioxidant enzymes, as well as the expression of COX 2 and cytochrome c oxidase IV, which are enzymes involved in the generation of ROS. GHRH augmented and GHRH antagonist suppressed lipid and protein oxidative stress markers, as well as the intracellular generation of ROS. In all these tests, GHRH antagonists exerted strong antioxidant activity. Because the metabolism of ROS and oxidative stress have been associated with initiation and progression of not only prostate tumors but also other malignancies, our findings reinforce previous experimental evidence that GHRH antagonists could be useful for cancer therapy.
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PMID:Antioxidant activity of growth hormone-releasing hormone antagonists in LNCaP human prostate cancer line. 1907 33

Mitochondrial dysfunction and associated apoptosis have been reported in the pathogenesis of neuron degeneration. The effects of eicosapentaenoic acid (EPA) and arachidonic acid (AA) on the mitochondrial membrane potential, mitochondrial biogenesis, and mitochondrial function of rat C6 glioma cells were determined in this study. Increased cytochrome c release and activated caspase-3 expression were determined in cells treated with >20 microM C(2) ceramide. There were significant repressive effects on ceramide-induced cell death with 25-100 microM EPA and 25 microM AA pretreatment. However, significantly increased membrane potentials were detected in cells pretreated with 25 and 50 microM EPA compared to ceramide-treated cells, but not in AA pretreatment groups. In cells pretreated with EPA, ATP production loss was prevented from ceramide-induced mitochondrial dysfunction. In mitochondrial biogenesis related assay, both EPA and AA enhanced peroxisome proliferator-activated receptor gamma-coactivator-1alpha (PGC-1alpha) and mitochondrial transcription factor A (Tfam) transcriptional activities. However, elevated PGC-1alpha transcriptional activities in groups pretreated with 25, 50, and 100 microM EPA and only in the 100 microM AA group were analyzed. The Tfam transcriptional activities were enhanced in groups pretreated with 25 and 50 microM EPA and AA. Increased NADH dehydrogenase subunit 6 (ND6) mRNA expression was determined in cells pretreated with 25 and 50 microM EPA and 25 microM AA. Elevated protein levels of Tfam, flavoprotein, and cytochrome oxidase subunit III (COX III) were determined in cells pretreated with 25 and 50 microM EPA. The EPA-provided a more protective effect than AA against ceramide-induced cell death, which might mainly be due to maintaining the membrane potential and sustaining the mitochondrial ATP production function. EPA has more potential to elevate mitochondrial biogenesis through enhanced PGC-1alpha, and Tfam transcriptional activities may provide partial protection against ceramide cytotoxicity.
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PMID:Functional modulation of mitochondria by eicosapentaenoic acid provides protection against ceramide toxicity to C6 glioma cells. 1992 18


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