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)

The tripeptide, phenylalanine-glutamate-glycine (FEG) and its d-isomeric form phenylalanine-(D) glutamate-(D) glycine (feG), derived from submandibular gland peptide-T, significantly reduce the allergic inflammatory response and leukocyte trafficking and neutrophil migration into intestine, heart and lungs. Due to these actions, we hypothesized that feG would attenuate the early inflammatory response to spinal cord injury, reduce free radical production and improve neurological outcomes, like other leukocyte-limiting strategies we have used previously. We tested this using a clip compression model of spinal cord injury in rats. Following spinal cord injury at the 4th thoracic cord segment, we quantified leukocyte infiltration, free radical formation and oxidative damage at the lesion site after feG or control peptide phenylalanine-(D) aspartate-(D) glycine treatment. In rats treated with feG at 2 and 12 h, or 6 and 12 h after spinal cord injury, mean myeloperoxidase activity and ED-1 expression were significantly lower ( approximately 40%) than in controls at 24 h. Free radical formation generated in injured spinal cord was detected using 2',7'-dichlorofluorescin-diacetate as a fluorescent probe. Free radical production in the injured cord increased significantly after spinal cord injury and feG treatment significantly reduced this free radical production. Oxidative enzymes, lipid peroxidation and cell death were also significantly ( approximately 40%), gp91 ( approximately 30%), thiobarbituric acid reactive substance levels ( approximately 35%), 4-hydroxynonenal-bound protein ( approximately 35%) and caspase-3 ( approximately 32%). Early administration of feG decreases infiltration of inflammatory cells into the injured spinal cord and intraspinal free radical formation, thereby reducing oxidative damage and secondary cell death after spinal cord injury.
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PMID:The tripeptide phenylalanine-(D) glutamate-(D) glycine modulates leukocyte infiltration and oxidative damage in rat injured spinal cord. 1658 Nov 92

Platycodi Radix is the root of Platycodon grandiflorum and it is widely used in the traditional Oriental medicine as an expectorant for pulmonary diseases and a remedy for respiratory disorders. Platycodin D is the major constituent of triterpene saponins in the root. This study investigates apoptosis by platycodin D in immortalized human keratinocytes (HaCaT). Platycodin D-induced apoptosis in HaCaT cells was confirmed by DNA fragmentation, caspase-3 activation, and caspase-8 activation. Platycodin D could activate inhibitor of nuclear factor-kappaB kinase (IKK)-beta in the nuclear factor-kappaB (NF-kappaB) activation of upstream level, but not IKK-alpha. Pretreated-N-tosyl-l-phenylalanine chloromethyl ketone (TPCK), a potent NF-kappaB inhibitor, could suppress the induction of apoptosis and activation of NF-kappaB of HaCaT cells by platycodin D. We also demonstrated that platycodin D-mediated apoptosis of HaCaT cells upregulates Fas receptor and Fas ligand (FasL) expression, but did not exhibit p53 activation. HaCaT cells were also transfected with pFLF1, which preserves the promoter region of Fas receptor gene containing NF-kappaB binding site. On incubation with platycodin D, the NF-kappaB activity related to Fas receptor increased in a dose-dependent manner. Among the major transcription elements on Fas receptor and FasL promoter, NF-kappaB activation was shown to have an essential role in the expression of the death receptor such as FasL. These results suggest that platycodin D has the ability to induce apoptosis in HaCaT cells through the upregulation of Fas receptor and FasL expression via to NF-kappaB activation in the transcriptional level. These results demonstrate that the NF-kappaB activation plays a crucial role in the induction of apoptosis in human HaCaT cells on treatment with platycodin D.
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PMID:Platycodin D-induced apoptosis through nuclear factor-kappaB activation in immortalized keratinocytes. 1663 Nov 60

Cathepsin B is a cysteine proteinase, considered to have an important role in apoptosis, which is activated by D-galactosamine and tumor necrosis factor-alpha (D-GalN/TNF-alpha). Benzyloxycarbonyl-L-phenylalanine fluoromethyl ketone (Z-FA.FMK) is a cathepsin B inhibitor used in research on apoptotic pathways. The aim of this study was to investigate the role of Z-FA.FMK on apoptotic cell death, cell proliferation and liver damage induced by a D-GalN/TNF-alpha combination in mice. In the study, 1 h after administration of 8 mg/kg Z-FA.FMK by intravenous injection, D-GalN (700 mg/kg) and TNF-alpha (15 microg/kg) were administered by a single intraperitoneal injection. In the group given D-GalN/TNF-alpha, the following results were found: Degenerative changes in the liver tissue, significant increase in the number of both TUNEL and activated caspase-3-positive hepatocytes, a decrease in the number of PCNA-positive hepatocytes, an increase in lipid peroxidation (LPO) levels and a decrease in glutathione (GSH) and DNA levels in the liver tissue. In contrast, in the group given D-GalN/TNF-alpha and Z-FA.FMK, a decrease in the damage of the liver tissue, a significant decrease in TUNEL and activated caspase-3-positive hepatocytes, a significant increase in the number of PCNA-positive hepatocytes, a decrease in the LPO levels, an increase in GSH and DNA levels in the liver tissue were found. As a result, microscopic and biochemical evaluations indicate that Z-FA.FMK plays a protective role against liver injury induced by D-GalN/TNF-alpha and it has an inverse effect on hepatocyte apoptosis and proliferation in BALB/c mice.
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PMID:The effect of Z-FA.FMK on D-galactosamine/TNF-alpha-induced liver injury in mice. 1685 May 24

Glutamate induced glutathione (GSH) depletion in C6 rat glioma cells, which resulted in cell death. This cell death seemed to be apoptosis through accumulation of reactive oxygen species (ROS) or hydroperoxides representing cytochrome c release from mitochondria and internucleosomal DNA fragmentation. A significant increase of 12-lipoxygenase enzyme activity was observed in the presence of arachidonic acid (AA) under GSH depletion induced by glutamate. AA promoted the glutamate-induced cell death, which reduced caspase-3 activity and diminished internucleosomal DNA fragmentation. Furthermore, AA reduced intracellular NAD, ATP and membrane potentials, which indicated dysfunction of the mitochondrial membrane. Protease inhibitors such as N-alpha-tosyl-L-phenylalanine chloromethyl ketone (TPCK) and 3, 4-dichloroisocumarin (DCI) but no Ac-DEVD, a caspase inhibitor, suppressed the glutamate-induced cell death. AA reduced the inhibitory effect of TPCK and DCI on the glutamate-induced cell death. These results suggest that AA promotes cell death by inducing necrosis from caspase-3-independent apoptosis. This might occur through lipid peroxidation initiated by ROS or lipid hydroperoxides generated during GSH depletion in C6 cells.
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PMID:Arachidonic acid promotes glutamate-induced cell death associated with necrosis by 12- lipoxygenase activation in glioma cells. 1740 Feb 55

Phenylketonuria (PKU) is caused by deficiency of phenylalanine hydroxylase, resulting in an accumulation of phenylalanine in brain tissue and cerebrospinal fluid of phenylketonuria patients. Phenylketonuria is neuropathologically characterized by neuronal cell loss, white matter abnormalities, dendritic simplification, and synaptic density reduction. The neuropathological effect may be due to the "toxicity" of the high concentration of phenylalanine, while the underlying mechanism remains unclear. In this study, we found that cultured cerebral cortical neurons underwent mitochondria-mediated apoptosis when exposed to phenylalanine. We further demonstrated that phenylalanine induced RhoA activation. Phenylalanine also promoted myosin light chain (MLC) phosphorylation, which might be the result of the activation of Rho-associated kinase (ROCK). The RhoA antagonist, C3 transferase (C3), Rho-associated kinase specific inhibitor, Y-27632, and the overexpression of either dominant negative RhoA or dominant negative Rho-associated kinase inhibited phenylalanine-induced caspase-3 activation and rescued neurons from apoptosis, indicating that the RhoA/Rho-associated kinase signalling pathway plays an important role in phenylalanine-induced neuronal apoptosis.
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PMID:Phenylalanine activates the mitochondria-mediated apoptosis through the RhoA/Rho-associated kinase pathway in cortical neurons. 1742 60

5-Azacytidine (5-aza-CR) is a DNA-hypomethylating antineoplastic agent used because of its inhibitory activity on DNA methyltransferases. Today, it is approved as an epigenetically active drug therapy for treatment of myelodysplastic disorders, with a contraindication as to pre-existing liver diseases. Because the mechanism of its hepatotoxicity is still unknown, we investigated the pharmacodynamic properties of 5-aza-CR with regard to death receptor/ligand-induced apoptosis and the mode of execution of cell death. In a time- and concentration-dependent manner, primary murine, human hepatocytes and HepG2 cells exposed to 5-aza-CR became highly sensitive toward cell death induced by CD95L, tumor necrosis factor (TNF)-related apoptosis-inducing ligand, or TNF. Cell death was characterized as apoptotic by membrane blebbing, chromatin condensation, and exposure of phosphatidylserine on the outer membrane. Neither 5-aza-2'-deoxycytidine nor the common DNA methyltransferase inhibitors S-(5'-adenosyl)-L-homocysteine or RG 108 showed any significant effects under these conditions. Despite the complete protection of HepG2 by high concentrations of the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethyl ketone (z-VAD-fmk), effector caspase-3/7 activity was completely abolished at approximately a 20-fold lower concentration of z-VAD-fmk. Under these conditions, the serine protease inhibitors N,alpha-tosyl-L-phenylalanine chloromethyl ketone, N,p-tosyl-L-lysine chloromethyl ketone, and 4-(2-aminoethyl)-benzenesulfonyl fluoride, respectively, conferred protection against death receptor ligands. We conclude that this caspase-independent apoptosis is executed by a yet-unidentified serine protease.
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PMID:Sensitization by 5-azacytidine toward death receptor-induced hepatic apoptosis. 1882 27

Phenylalanine analog, rho-fluorophenylalanine (pFPhe)-mediated cytotoxicity and several apoptotic events including mitochondrial cytochrome c release, activation of caspase-9, -3, and -8, Bid cleavage, degradation of PARP and PLCgamma-1, and DNA fragmentation were more significant in p56(lck)-deficient Jurkat T cells (JCaM1.6) than in wild-type Jurkat T cells (E6.1). The susceptibility of JCaM1.6 toward apoptogenic activity of pFPhe decreased after acquisition of p56(lck) by transfection. The p56(lck) kinase activity increased 1.6-fold at 15-30 min after pFPhe treatment. The pan-caspase inhibitor (z-VAD-fmk) completely blocked the pFPhe-mediated apoptotic changes except caspase-9 activation. The caspase-8 inhibitor (z-IETD-fmk), which failed to influence pFPhe-induced caspase-9 activation, completely blocked caspase-8 activation and PLCgamma-1 degradation with a marked reduction in caspase-3 activation and PARP degradation, indicating pFPhe-induced caspase-8 activation as a downstream event of mitochondria-dependent activation of caspase-9. These results indicate that the deficiency of p56(lck) augments pFPhe-induced mitochondrial cytochrome c release and resultant apoptotic cell death in Jurkat T cells.
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PMID:Protein tyrosine kinase p56lck-deficiency confers hypersusceptibility to rho-fluorophenylalanine (pFPhe)-induced apoptosis by augmenting mitochondrial apoptotic pathway in human Jurkat T cells. 1884 26

1. Cytoprotection by H(2)O(2) preconditioning against oxidative stress-induced apoptosis of PC12 cells has been demonstrated previously. In the present study, we investigated the effects of H(2)O(2) preconditioning on nuclear factor (NF)-kappaB activation and the role of NF-kappaB in the adaptive cytoprotection of H(2)O(2) preconditioning in PC12 cells. 2. The PC12 cells were preconditioned with 100 micromol/L H(2)O(2) for 90 min, followed by 24 h recovery and subsequent exposure to 300 micromol/L H(2)O(2) for a further 12 h. 3. The results showed that preconditioning with 100 micromol/L H(2)O(2) upregulated NF-kappaB expression and enhanced its nuclear translocation and DNA binding activity. In addition to its own effects on NF-kappaB expression, H(2)O(2) preconditioning also promoted the overexpression of NF-kappaB induced by a lethal concentration of H(2)O(2) (300 micromol/L). 4. N-Tosyl-l-phenylalanine chloromethyl ketone (TPCK; 20 micromol/L), an inhibitor of NF-kappaB, was administered 20 min before preconditioning with 100 micromol/L H(2)O(2). At this concenteration, TPCK blocked the overexpression of NF-kappaB induced by H(2)O(2) preconditioning, accompanied by attenuation of H(2)O(2) preconditioning-induced cytoprotection. The inhibition of NF-kappaB by TPCK enhanced caspase 3 activity induced by 300 micromol/L H(2)O(2). 5. The findings of the present study provide novel evidence for the effects of preconditioning with H(2)O(2) on constitutive activation of NF-kappaB, which contributes to the adaptive cytoprotection of H(2)O(2) preconditioning against PC12 cells apoptosis.
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PMID:Nuclear factor-kappaB mediates cytoprotection of hydrogen peroxide preconditioning against apoptosis induced by oxidative stress in PC12 cells. 1898 27

The EphA2 receptor tyrosine kinase is selectively expressed on the surface of many different human tumors. We have previously shown that tumor cells can be targeted by EphA2 monoclonal antibodies and that these antibodies function, in part, by inducing EphA2 internalization and degradation. In this report, we describe the isolation and characterization of a fully human monoclonal antibody (1C1) that selectively binds both the human and rodent EphA2 receptor. After cell binding, the antibody induces rapid tyrosine phosphorylation, internalization, and degradation of the EphA2 receptor. Because monoclonal antibodies that selectively bind tumor cells and internalize provide a vehicle for targeted delivery of cytotoxics, 1C1 was conjugated to the microtubule inhibitor monomethylauristatin phenylalanine using a stable maleimidocaproyl linker. The anti-EphA2 antibody-drug conjugate [1C1-maleimidocaproyl-MMAF (mcMMAF)] stimulated the activation of caspase-3/caspase-7 and the death of EphA2-expressing cells with IC(50) values as low as 3 ng/mL. Similarly, the conjugate induced degradation of the EphA2 receptor and inhibited tumor growth in vivo. Administration of 1C1-mcMMAF at doses as low as 1 mg/kg once weekly resulted in significant growth inhibition of EphA2-expressing tumors without any observable adverse effects in mouse xenograft and rat syngeneic tumor models. Our data support the use of an antibody-drug conjugate approach to selectively target and inhibit the growth of EphA2-expressing tumors.
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PMID:A human antibody-drug conjugate targeting EphA2 inhibits tumor growth in vivo. 1901 Sep 11

A vagus nerve-mediated, efferent cholinergic protective pathway activated by melanocortins is operative in circulatory shock and myocardial ischemia. Moreover, melanocortins have neuroprotective effects against brain damage after ischemic stroke. Here we investigated cerebral and systemic pathophysiologic reactions to focal cerebral ischemia in rats induced by intrastriatal microinjection of endothelin-1, and the possible protective role of the melanocortin-activated vagal cholinergic pathway. In the striatum and liver of saline-treated control rats, the activation of extracellular signal-regulated kinases, c-jun N-terminal kinases, and caspase-3, the increase in tumor necrosis factor-alpha (TNF-alpha) concentration and DNA fragmentation, as well as the increase in TNF-alpha plasma levels, occurred 10 and 20 h after the ischemic insult suggesting an activation of inflammatory and apoptotic responses. Treatment with [Nle(4), D-Phe(7)]alpha-melanocyte-stimulating hormone (NDP-alpha-MSH; 3 or 9 h after stroke) suppressed the inflammatory and apoptotic cascades at central and peripheral level. Bilateral vagotomy and pharmacologic blockade of peripheral nicotinic acetylcholine receptors blunted the protective effect of NDP-alpha-MSH. The present results show that focal brain ischemia in rats causes significant effects not only in the brain, but also in the liver. Moreover, our data support the hypothesis that a protective, melanocortin-activated, vagal cholinergic pathway is likely operative in conditions of ischemic stroke.
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PMID:Vagus nerve mediates the protective effects of melanocortins against cerebral and systemic damage after ischemic stroke. 1901 69


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