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)

To investigate a pathway to apoptosis which may involve ceramides and to elucidate the minimum structure which leads to apoptosis, we synthesized several novel acylamides. Although the four synthesized compounds were different in structure from C2-ceramide, they caused Jurkat cells to undergo apoptosis. The most effective of them was N-myristoyl-D-alaninol (D-MA), as shown by DNA fragmentation (detected with propidium iodide) and a decrease in the mitochondrial transmembrane potential (DeltaPsi(m)) (detected with rhodamine 123). Nevertheless, peripheral blood leukocytes exhibited no change after D-MA exposure, like after C2-ceramide or anti-Fas antibody treatment. The DNA fragmentation and DeltaPsi(m) caused by D-MA were blocked by a caspase-3 specific inhibitor as in the case of anti-Fas antibody stimulation. Quantification of ceramides by metabolic labeling with [(14)C]palmitic acid and HPTLC showed no increases in the ceramide levels on stimulation with D-MA, C2-ceramide or anti-Fas antibodies. Furthermore, D-MA had an apoptosis-inducing effect on an anti-Fas-resistant subline of Jurkat cells. These data suggest that D-MA may cause apoptosis of Jurkat cells without distinct ceramide formation and that this apoptotic pathway is very comparable, i.e. not identical, to that induced by anti-Fas antibodies.
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PMID:Induction of apoptosis by novel synthesized acylamides of human lymphocytes. 1060

During ischemia and reperfusion, increased palmitate oxidation is associated with diminished function of the myocardium. Palmitate, but not oleate, has been implicated in the induction of apoptosis in isolated neonatal rat ventricular myocytes. We report that extended incubation (20 h) of cultured neonatal rat cardiomyocytes, in the presence of palmitate, causes a decrease in the ability of these cells to oxidize fatty acids, an increase in cellular malonyl-CoA and a decrease in the activity of 5' AMP-activated protein kinase (AMPK) compared to myocytes incubated in the presence of oleate. While palmitate decreases the oxidative metabolism of fatty acids, it increases the formation of intracellular triglyceride and ceramide. Increased ceramide formation is associated with an increase in apoptosis in many cell systems and we also observe an increase in caspase-3 like activity and DNA-laddering in these cells. At the onset of cardiac failure, a switch in myocardial substrate utilization from fatty acids to glucose occurs. Our data suggest that decreased palmitate oxidation in cardiac myocytes in culture may signal the initiation of programmed cell death and ceramide elevation previously documented in ischemic, reperfused hearts.
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PMID:Palmitate-mediated alterations in the fatty acid metabolism of rat neonatal cardiac myocytes. 1073 49

After cardiac ischemia, long-chain fatty acids, such as palmitate, increase in plasma and heart. Palmitate has previously been shown to cause apoptosis in cardiac myocytes. Cultured neonatal rat cardiac myocytes were studied to assess mitochondrial alterations during apoptosis. Phosphatidylserine translocation and caspase 3-like activity confirmed the apoptotic action of palmitate. Cytosolic cytochrome c was detected at 8 h and plateaued at 12 h. The mitochondrial membrane potential (DeltaPsi) in tetramethylrhodamine ethyl ester-loaded cardiac myocytes decreased significantly in individual mitochondria by 8 h. This loss was heterogeneous, with a few energized mitochondria per myocyte remaining at 24 h. Total ATP levels remained high at 16 h. The DeltaPsi loss was delayed by cyclosporin A, a mitochondrial permeability transition inhibitor. Mitochondrial swelling accompanied changes in DeltaPsi. Carnitine palmitoyltransferase I activity fell at 16 h; this decline was accompanied by ceramide increases that paralleled decreased complex III activity. We conclude that carnitine palmitoyltransferase I inhibition, ceramide accumulation, and complex III inhibition are downstream events in cardiac apoptosis mediated by palmitate and occur independent of events leading to caspase 3-like activation.
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PMID:A metabolic role for mitochondria in palmitate-induced cardiac myocyte apoptosis. 1104 45

There are contradictory findings regarding the effects of free fatty acids on vascular smooth muscle cell (VSMC) growth. In the present study we investigated the effects of fatty acids released from hydrolysis of human VLDL triglycerides by lipoprotein lipase and of the fatty acids most abundant in the hydrolysed VLDL, namely oleic, linoleic, palmitic and myristic acid, all non albumin-bound, on VSMC growth. The effect of fatty acids on VSMC growth was assessed by [(3)H]-thymidine incorporation, colourimetrically, by cell counting, by determination of the cytoplasmic histone-associated DNA fragments and the caspase 3 activity. The fatty acid concentrations were determined by gas chromatography-mass spectrometry. Stimulation of ERK1/2 and p38 was determined by the chemiluminescence Western blotting method. Incubation of VSMC with purified VLDL (100 microg ml(-1)) and lipoprotein lipase (35 u ml(-1)) led to almost complete cell death although the ERK1/2 and the p38 MAP kinases were stimulated. The EC(50) of oleic, linoleic, myristic and palmitic acid were 4.6+/-1.3, 2.4+/-0.2, 116+/-10 and 287+/-30 microM, respectively. The estimated EC(50) of myristic and palmitic acid when derived from hydrolysed VLDL were 10 and 8 times, respectively, lower than when used alone. Apoptosis was not involved in the fatty acid-induced VSMC growth suppression/death. We conclude that (a) non albumin-bound fatty acids cause VSMC necrosis in a dose-dependent manner with a parallel ERK1/2 and p38 stimulation, (b) unsaturated fatty acids are more toxic to VSMC than saturated, and (c) saturated fatty acids are more toxic to VSMC in the hydrolysed VLDL than when used individually.
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PMID:Effects of authentic and VLDL hydrolysis-derived fatty acids on vascular smooth muscle cell growth. 1130 44

Macrophage (MPhi) apoptosis, an important innate microbial defense mechanism induced by Mycobacterium tuberculosis (Mtb) H37Ra, depends on the induction of TNF-alpha synthesis. When protein synthesis is blocked, both infection with Mtb and addition of TNF-alpha are required to induce caspase 9 activation, caspase 3 activation and apoptosis. In this study, we show that the second protein synthesis-independent signal involves activation of group IV cytosolic phospholipase A2 (cPLA2). Apoptosis of Mtb-infected MPhi and concomitant arachidonic acid release are abrogated by group IV cPLA2 inhibitors (methyl arachidonyl fluorophosphate and methyl trifluoromethyl ketone), but not by inhibitors of group VI Ca2+-independent (iPLA2; bromoenol lactone) or of secretory low molecular mass PLA2. In MPhi homogenates, the predominant PLA2 activity showed the same inhibitor sensitivity pattern and preferred arachidonic acid over palmitic acid in substrates, also indicating the presence of one or more group IV cPLA2 enzymes. In concordance with these findings, MPhi lysates contained transcripts and protein for group IV cPLA2-alpha and cPLA2-gamma. Importantly, group IV cPLA2 inhibitors significantly reduced MPhi antimycobacterial activity and addition of arachidonic acid, the major product of group IV cPLA2, to infected MPhi treated with cPLA2 inhibitors completely restored the antimycobacterial activity. Importantly, addition of arachidonic acid alone to infected MPhi significantly reduced the mycobacterial burden. These findings indicate that Mtb induces MPhi apoptosis by independent signaling through at least two pathways, TNF-alpha and cPLA2, which are both also critical for antimycobacterial defense of the MPhi.
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PMID:Cytosolic phospholipase A2 participates with TNF-alpha in the induction of apoptosis of human macrophages infected with Mycobacterium tuberculosis H37Ra. 1139 May

The influence of tyrosine nitration of cytochrome c and caspase 3 on apoptosis induction was investigated in an established squamous carcinoma cell line, OSC-4. The intracellular NO and O2(-) levels were increased up to about 110-120% and 140-180% of the control levels, respectively, after the treatment of OSC-4 cells with 5-FU (100 microg/ml), PLM (10 microg/ml), CDDP (10 microg/ml), or gamma-rays (20 Gy). The treatment of OSC-4 cells with ONOO(-) (1 mM) and the above anticancer agents induced tyrosine nitration of 14, 32 kDa protein among others and nitration of tyrosine residues of cytochrome c and caspase 3 was identified by the Western blotting of immunoprecipitates obtained by antibodies to these proapoptotic proteins. When cytochrome c and procaspase 3 were treated with ONOO(-), tyrosine nitration was increased in a ONOO(-)-dose dependent manner. Tyrosine nitration of cleaved (17 kDa) caspase 3, however, was not induced by ONOO(-). Procaspase 3 in the cytosol of HeLa cells was activated by the addition of ONOO(-)-treated as well as ONOO(-)-untreated cytochrome c. In addition, cleavage of ICAD and PARP were not suppressed in OSC-4 cells by pretreatment with ONOO(-). Activity of cleaved caspase 3 was not suppressed at low concentrations or by treatment with ONOO(-) or NO donors, SIN-1 and SNP. Furthermore, apoptosis of OSC-4 cells by the anticancer agents was not suppressed by ONOO(-). In conclusion, these results suggest that nitration of tyrosine residues of cytochrome c and procaspase 3 is induced by chemoradiotherapy but their nitration does not suppress cancer cell apoptosis.
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PMID:Tyrosine-nitration of caspase 3 and cytochrome c does not suppress apoptosis induction in squamous cell carcinoma cells. 1251 89

We report here that monounsaturated fatty acids and polyunsaturated fatty acids (PUFAs) provoke the accumulation of neutral lipids and apoptosis in retinoic acid-treated HL-60 cells in a concentration- and time-dependent manner. The PUFAs (arachidonic acid, docosahexanoic acid and eicosapentaenoic acid) provoked higher levels of HL-60 apoptosis compared with the monounsaturated oleic acid or the saturated palmitic acid. Cell size and granularity were also altered by fatty acid treatment. The PUFA-induced apoptosis was correlated with increased activity of caspase 3 and caspase 9. Lipid peroxidation was also increased in the presence of PUFAs, but was not responsible for activating cell apoptosis. Lipid derived metabolites may be responsible for activation of caspases and induction of cell apoptosis.
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PMID:Polyunsaturated and monounsaturated fatty acids increase neutral lipid accumulation, caspase activation and apoptosis in a neutrophil-like, differentiated HL-60 cell line. 1254 39

Apoptotic cell death has been proposed to play a role in the neuronal loss observed following traumatic injury in the CNS and PNS. The present study uses an in vitro tissue culture model to investigate whether free fatty acids (FFAs), at concentrations comparable to those found following traumatic brain injury, trigger cell death. Nerve growth factor (NGF)-differentiated PC12 cells exposed to oleic and arachidonic acids (2 : 1 ratio FFA/BSA) showed normal cell survival. However, when cells were exposed to stearic and palmitic acids, there was a dramatic loss of cell viability after 24 h of treatment. The cell death induced by stearic acid and palmitic acid was apoptotic as assessed by morphological analysis, and activation of caspase-8 and caspase-3-like activities. Western blotting showed that differentiated PC12 cells exposed to stearic and palmitic acids exhibited the signature apoptotic cleavage fragment of poly (ADP-ribose) polymerase (PARP). Interestingly, blockade of caspase activities with the pan-caspase inhibitor z-VAD-fmk failed to prevent the cell death observed induced by palmitic or stearic acid. RT-PCR and RNA blot experiments showed an up-regulation of the Fas receptor and ligand mRNA. These findings are consistent with our hypothesis that FFAs may play a role in the cell death associated with trauma in the CNS and PNS.
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PMID:Palmitic and stearic fatty acids induce caspase-dependent and -independent cell death in nerve growth factor differentiated PC12 cells. 1256 10

Ultraviolet irradiation is a major environmental cause of skin cancers, whereas ultraviolet-induced DNA repair and apoptosis are defense mechanisms that rescue and/or protect keratinocytes from this risk. Multiple pathways are involved in ultraviolet-induced keratinocyte apoptosis, including activation of p38-mitogen-activated protein kinase, protein kinase C, and CD95, each of which are associated with caspase activation. Alternatively, ceramides could serve as ultraviolet-induced, second messenger lipids, because they induce cell cycle arrest and apoptosis in a variety of cell types, including keratinocytes. We investigated the role of ceramide versus caspase, and the responsible pathway for ceramide generation in ultraviolet B-induced apoptosis of cultured normal human keratinocytes maintained in low calcium (0.07 mm) medium. Ultraviolet B (40 mJ per cm2) significantly inhibited cultured normal human keratinocyte proliferation, assessed as [3H-methyl]thymidine-thymidine incorporation into DNA, 2 h after irradiation. Terminal nick deoxynucleotide end-labeling-positive apoptotic cells (14.8% at 24 h and 34.4% at 48 h) and trypan blue-positive apoptotic cells (8.4% at 24 h and 28.6% at 48 h) became evident in a time-dependent manner after ultraviolet B irradiation, in parallel with activation of caspase-3. The ceramide content of irradiated cultured normal human keratinocytes increased significantly by 8 h, whereas glucosylceramide only modestly increased, and sphingomyelin content remained unaltered. Metabolic studies with radiolabeled serine, palmitic acid, and phosphorylcholine revealed that the ultraviolet B-induced increase in ceramide results primarily from increased de novo synthesis rather than accelerated sphingomyelin hydrolysis. Increased ceramide synthesis, in turn, could be attributed to increased activity of ceramide synthase (i.e., 1.7-fold increase 8 h after ultraviolet B irradiation), whereas serine palmitoyltransferase activity did not change. Both fumonisin B1, an inhibitor of ceramide synthase, and ISP-1, myriocin an inhibitor of serine palmitoyltransferase, significantly attenuated the ultraviolet B-induced apoptosis in a caspase-3-independent fashion, whereas co-incubation with a caspase-3 inhibitor (Ac-DEVD-chloromethyl-ketone) further attenuated the ultraviolet B-induced apoptosis. Thus, increased de novo ceramide synthesis signals ultraviolet B-induced apoptosis, by a pathway independent of, but in concert with, caspase-3 activation.
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PMID:De novo ceramide synthesis participates in the ultraviolet B irradiation-induced apoptosis in undifferentiated cultured human keratinocytes. 1264 32

Whereas uncoupling protein 1 (UCP-1) is clearly involved in thermogenesis, the role of UCP-2 is less clear. Using hybridization, cloning techniques and cDNA array analysis to identify inducible neuroprotective genes, we found that neuronal survival correlates with increased expression of Ucp2. In mice overexpressing human UCP-2, brain damage was diminished after experimental stroke and traumatic brain injury, and neurological recovery was enhanced. In cultured cortical neurons, UCP-2 reduced cell death and inhibited caspase-3 activation induced by oxygen and glucose deprivation. Mild mitochondrial uncoupling by 2,4-dinitrophenol (DNP) reduced neuronal death, and UCP-2 activity was enhanced by palmitic acid in isolated mitochondria. Also in isolated mitochondria, UCP-2 shifted the release of reactive oxygen species from the mitochondrial matrix to the extramitochondrial space. We propose that UCP-2 is an inducible protein that is neuroprotective by activating cellular redox signaling or by inducing mild mitochondrial uncoupling that prevents the release of apoptogenic proteins.
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PMID:Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. 1285 70


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