Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Marked hippocampal changes in response to excitatory amino acid agonists occur during pregnancy (e.g. decreased frequency in spontaneous recurrent seizures in rats with KA lesions of the hippocampus) and lactation (e.g. reduced c-Fos expression in response to N-methyl-d,l-aspartic acid but not to kainic acid). In this study, the possibility that lactation protects against the excitotoxic damage induced by KA in hippocampal areas was explored. We compared cell damage induced 24 h after a single systemic administration of KA (5 or 7.5 mg/kg bw) in regions CA1, CA3, and CA4 of the dorsal hippocampus of rats in the final week of lactation to that in diestrus phase. To determine cellular damage in a rostro-caudal segment of the dorsal hippocampus, we used NISSL and Fluorojade staining, immunohistochemistry for active caspase-3 and TUNEL, and we observed that the KA treatment provoked a significant loss of neurons in diestrus rats, principally in the pyramidal cells of CA1 region. In contrast, in lactating rats, pyramidal neurons from CA1, CA3, and CA4 in the dorsal hippocampus were significantly protected against KA-induced neuronal damage, indicating that lactation may be a natural model of neuroprotection.
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PMID:Neuroprotective effects of lactation against kainic acid treatment in the dorsal hippocampus of the rat. 1796 58

We investigated the induction of apoptosis via deamidation of Bcl-xL and translocation of Bax to the mitochondria by treatment with GSH-DXR. GSH-DXR treatment of HepG2 cells, which did not express GST P1-1, exhibited deamidation of Bcl-xL, and the degree of deamidation was related to the activation of caspase-3. Overexpression of GST P1-1 in HepG2 cells decreased both the Bcl-xL deamidation and caspase-3 activation induced by treatment with GSH-DXR. Bcl-xL deamidation and caspase-3 activation were also suppressed by co-treatment with SP600125, a specific inhibitor of JNK activity. Overexpression of wild-type Bcl-xL in HepG2 decreased GSH-DXR-induced apoptosis although deamidation was observed. However, expression of the deamidated mutant of Bcl-xL, in which aspartic acid was substituted for both arginine 52 and 66 (N52,66D-Bcl-xL), exhibited high sensitivity for the induction of apoptosis. Expression of the Bcl-xL mutant, in which alanine was substituted for both arginine 52 and 66 (N52,66A-Bcl-xL), suppressed deamidation and showed resistance to the induction of apoptosis by treatment with GSH-DXR. On the other hand, endogenous Bax and overexpressed Flag-Bax were localized in the cytosolic fraction of HepG2 cells. Treatment of the cells with GSH-DXR caused translocation of Flag-Bax to the mitochondrial fraction following the induction of apoptosis. The induced apoptosis was enhanced by the expression of Flag-Bax. Moreover, Flag-Bax was partly located in the mitochondrial fraction in N52,66D-Bcl-xL-expressed cells without the induction of apoptosis. Therefore, the induction of apoptosis by treatment of HepG2 with GSH-DXR was enhanced, thereby facilitating the release of cytochrome c by both deamidated inactivation of Bcl-xL and functional translocation of Bax to the mitochondria via JNK activation. Deamidation of Bcl-xL might be induced in order to translocate Bax to the mitochondria.
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PMID:The association of deamidation of Bcl-xL and translocation of Bax to the mitochondria through activation of JNK in the induction of apoptosis by treatment with GSH-conjugated DXR. 1863 61

Polyaspartoyl l-arginine (PDR) is an anti-thrombotic agent and its anti-thrombotic effect is related with endothelial cells. This study is to investigate the effect of PDR on the endothelial cells. In cell injury assay 1.7-170 microg/ml of PDR significantly increased the viability of rat aorta endothelial cells (RAECs) injured by H(2)O(2), this effect was comparable with that of 95 microg/ml of alpha-tocopherol, and was more powerful than that of l-arginine. Nitric oxide synthase(NOS) inhibitor, L-NAME, almost abolished the effect of PDR, but not influence the effect of alpha-tocopherol or l-arginine. PDR enhanced the viability of RAECs injured by oxidized- low density lipoprotein (ox-LDL) either, which was comparable to that of alpha-tocopherol, whereas l-arginine, l-aspartic acid alone or their combined use failed to showed effects. PDR (17-170 microg/ml) raised nitrite level in RAEC medium, which is the major end-product of NO, but l-arginine (170 microg/ml) produced insignificant nitrite level rise. In addition, in the absence of RAEC PDR and l-arginine but alpha-tocopherol failed to lower the concentration of oxidative product (Fe(3+)) in a cell free system, whereas in the presence of RAEC PDR, l-arginine or alpha-tocopherol all significantly reduced the concentration of Fe(3+). In cell apoptosis assay PDR (17-170 microg/ml) lowered the percentage of early apoptotic and late apoptotic RAECs, consequently increased the percentage of normal cells. Furthermore PDR significantly inhibited caspase-3 activity in RAECs; this effect is comparable with alpha-tocopherol and more potent than that of l-arginine. In conclusion, PDR is a cell protector, it protects endothelial cell against oxidative injury and apoptosis; its cell protective effect against H(2)O(2) injuries is NOS dependent and is related with NO production; PDR is anti-oxidant, its anti-oxidant effect needs endothelial cell's participation. The findings suggest PDR may play a much better beneficial role than l-arginine in the prevention and treatment for those diseases with endothelial dysfunction.
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PMID:Polyaspartoyl l-arginine protects endothelial cells against injury. 1885 83

Apoptosis of host cells plays an important role in modulating the pathogenesis of many infectious diseases. It has been reported that Leptospira interrogans, the causal agent of leptospirosis, induces apoptosis in macrophages and hepatocytes. However, the molecular mechanisms responsible for host cell death remained largely unknown. Here we demonstrate that L. interrogans induced apoptosis in a macrophage-like cell line, J774A.1, and primary murine macrophages in a time- and dose-dependent manner. Apoptosis was associated with the activation of cysteine aspartic acid-specific proteases (caspase-3, caspase-6, and caspase-8), the increased expression of Fas-associated death domain (FADD), and the cleavage of the caspase substrates poly(ADP-ribose) polymerase (PARP) and nuclear lamina protein (lamin A and lamin C). Caspase-9 was activated to a lesser extent, whereas no release of cytochrome c from mitochondria was detectable. Inhibition of caspase-8 impaired L. interrogans-induced caspase-3 and -6 activation, as well as PARP and lamin A/C cleavage and apoptosis, suggesting that apoptosis is initiated via caspase-8 activation. Furthermore, caspase-3 was required for the activation of caspase-6 and seemed to be involved in caspase-9 activation through a feedback amplification loop. These data indicate that L. interrogans-induced apoptosis in macrophages is mediated by caspase-3 and -6 activation through a FADD-caspase-8-dependent pathway, independently of mitochondrial cytochrome c-caspase-9-dependent signaling.
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PMID:Leptospira interrogans induces apoptosis in macrophages via caspase-8- and caspase-3-dependent pathways. 1902 1

PU.1 is one of key regulators of hematopoietic cell development, a tightly-regulated lineage-specific process. Here we provide the first evidence that PU.1 protein is cleaved into two fragments of 24 kDa and 16 kDa during apoptosis progression in leukemic cell lines and primary leukemic cells. Further experiments with specific capase-3 inhibitor Z-DEVD-fmk and the in vitro proteolytic system confirmed that PU.1 is a direct target of caspase-3. Using site-directed mutagenesis analyses, the aspartic acid residues at positions 97 and 151 of PU.1 protein were identified as capsase-3 target sites. More intriguingly, the suppression of PU.1 expression by small interfering RNAs (siRNAs) significantly inhibits DNA-damaging agents NSC606985 and etoposide-induced apoptosis in leukemic cells, together with the up-regulated expression of anti-apoptotic bcl-2 gene. These results would provide new insights for understanding the mechanism of PU.1 protein in hematopoiesis and leukemogenesis.
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PMID:PU.1, a novel caspase-3 substrate, partially contributes to chemotherapeutic agents-induced apoptosis in leukemic cells. 1928 94

One of the serious unwanted effects of the anthracycline anticancer drug doxorubicin (Dox, adriamycin) is its neurotoxicity, which can be evoked by the activation of extracellular (FAS/CD95/Apo-1) pathway of apoptosis in cells. Since memantine, a clinically used N-methyl-D: -aspartic acid (NMDA) receptor antagonist, shows antiapoptotic action in several models of neuronal cell damage, in this study we evaluated the effect of memantine on the cell death induced by Dox in primary neuronal cell cultures. First, we investigated the effect of different concentrations of Dox (0.1-5 microM) on mouse neocortical, hippocampal, striatal, and cerebellar neurons on 7- and 12-day in vitro (DIV). The 7 DIV neuronal cell cultures were more prone to Dox-induced cell death than 12 DIV cultures. The cerebellar neurons were the most resistant to Dox-induced apoptosis in comparison to neuronal cell cultures derived from the forebrain. Memantine (0.1-2 microM) attenuated the Dox-evoked lactate dehydrogenase release in 7 DIV neuronal cell cultures with no significant effect on 12 DIV cultures. The ameliorating effect of memantine on Dox-mediated cell death was also confirmed by an increase in cell viability measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay. There was no effect of memantine on Dox-induced caspase-8 and -3 activity and Dox-evoked decrease in mitochondrial potential, although attenuation in the number of cells with apoptotic DNA fragmentation was observed. We also showed that the antiapoptotic effect of memantine in our model was NMDA receptor-independent, since two other antagonists of this receptor, MK-801 and AP-5, did not attenuate Dox-induced cell death. Furthermore, memantine did not influence the Dox-evoked increase in cytoplasmic Ca2+ level. The obtained data suggest developmental regulation of both, the Dox-mediated neurotoxicity and efficacy of memantine in alleviating the Dox-induced cell damage in neuronal cell cultures. Moreover, this neuroprotective effect of memantine seems not to be dependent on caspase-3 activity and on the antagonistic action on NMDA receptor.
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PMID:Protective effect of memantine against Doxorubicin toxicity in primary neuronal cell cultures: influence a development stage. 1938 85

Lunasin is a naturally occurring peptide with arginine-glycine-aspartic acid motif associated to its reported biological activity. We aimed to determine the potential of lunasin from soybean to stimulate apoptosis in HT-29 colon cancer cells. Lunasin caused cytotoxicity to HT-29 cells and induced G2/M cell cycle arrest with simultaneous increased in p21 expression. Lunasin-induced apoptosis as evidenced by a twofold increase in the percentage of cells undergoing apoptosis, decreased Bcl-2:Bax ratio from 8.5 to 0.4, increased caspase-3 activity by 77% and increased expression of pro-apoptotic nuclear clusterin by five fold when compared to untreated cells. In conclusion, lunasin stimulated apoptosis in HT-29 cells by activating apoptotic mitochondrial pathways and inducing expression of the pro-apoptotic nuclear clusterin.
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PMID:Lunasin promotes apoptosis in human colon cancer cells by mitochondrial pathway activation and induction of nuclear clusterin expression. 2020 42

The ability to form functional polymeric patterning structures has important implications for the studies of cell biology, tissue engineering, and medical diagnostics. We have developed a novel enzyme-assisted photolithography (EAPL) method for spatial functionalization of hydrogels via a high throughput fashion. A bisacrylated peptide crosslinker, containing a protease cleavable amino acid sequence and caged by a photolabile moiety, is used during hydrogel polymerization. A facile two-step process is employed, including UV exposure to decage the peptide crosslinker at a desired area and protease development to specifically digest gels at UV treated regions only. Importantly, proteolysis of the peptide bonds generates free nucleophilic amine groups at the patterned area that can be further functionalized. Using this strategy and caspase-3 as the enzyme developer, we demonstrate the simultaneous generation of topographical and functional patterns into poly(ethylene glycol) (PEG) hydrogels. We show that 20 microm-wide line arrays functionalized with arginine-glycine-aspartic acid (RGD)-containing peptides can be used to generate cell patterns with individual cell resolution. We also fabricated arrays 20 mum diameter cavities decorated with B lymphocyte specific anti-CD19, which was used to achieve a 600-fold enrichment of B-cells from a 0.1% starting B-cell mixture. The simple fabrication process, straightforward chemistry and an all-aqueous based biocompatible and environmentally friendly approach render EAPL a versatile platform to construct biologically responsive 2D patterns or 3D scaffolds for lab-on-a-chip systems and tissue engineering.
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PMID:Enzyme-assisted photolithography for spatial functionalization of hydrogels. 2043 69

Herpes Simplex Virus Type 1 (HSV-1) is ubiquitous, neurotropic, and the most common pathogenic causes of sporadic acute encephalitis in humans. Herpes simplex encephalitis is associated with a high mortality rate and significant neurological, neuropsychological, and neurobehavioral sequelae, which afflict patients for life. HSV-1 infects limbic system structures in the central nervous system and has been suggested as an environmental risk factor for Alzheimer's disease. However, the possible mechanisms that link HSV-1 infection with the neurodegenerative process are still largely unknown. In a previous study we demonstrated that HSV-1 triggers hyperphosphorylation of tau epitopes serine202/threonine205 and serine396/serine404 in neuronal cultures, resembling what occurs in neurodegenerative diseases. Therefore, the aim of the present study was to evaluate at the cellular level if another event associated with neurodegeneration, such as caspase-3 induced cleavage of tau, could also be triggered by HSV-1 infection in primary neuronal and astrocyte cultures. As expected, induction of caspase-3 activation and cleavage of tau protein at its specific site (aspartic acid 421) was observed by Western blot and immunofluorescence analyses in mice neuronal primary cultures infected with HSV-1. In agreement with our previous study on tau hyperphosphorylation, tau cleavage was also observed during the first 4 hours of infection, before neuronal death takes place. This tau processing has been previously demonstrated to increase the kinetics of tau aggregation in vitro and has also been observed in neurodegenerative pathologies. In conclusion, our findings support the idea that HSV-1 could contribute to induce neurodegenerative processes in age-associated pathologies such as Alzheimer's disease.
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PMID:Tau cleavage at D421 by caspase-3 is induced in neurons and astrocytes infected with herpes simplex virus type 1. 2109 75

Caspases-3, a member of the cysteine-aspartic acid protease (caspase) family, plays critical roles in the execution of apoptotic pathway. In this study, a caspase-3 homologue was cloned and characterized from large yellow croaker (Pseudosciaena crocea). The full-length cDNA of large yellow croaker caspase-3 (Lyccasp3) is 2222bp with an open reading frame of 858 bp encoding a polypeptide of 285 amino acids (aa). Lyccasp3 exhibited a conserved caspase-3 architecture including a prodomain, a large subunit and a small subunit. Moreover, several residues known to be critical in the caspase-3 catalytic centre and binding pocket, as well as the active-site pentapeptide motif Q(172)ACRG(176) were present in the deduced Lyccasp3. Recombinant Lyccasp3 (rLyccasp3) produced in Escherichia coli exhibited obvious hydrolyzing activity against synthetic peptide substrate Ac-DEVD-pNA. The Lyccasp3 was constitutively expressed in all the tissues examined, although the expression levels varied from tissue to tissue. Real-time PCR analysis revealed that Lyccasp3 transcript in spleen and kidney was quickly increased after stimulation with either poly (I:C) or inactivated trivalent bacterial vaccine. Enzyme activities of Lyccasp3 were also up-regulated in these two tissues post-stimulation when analyzed by hydrolyzing activity assay. Since the activity of large yellow croaker caspase-9 (Lyccasp9) in the spleen and kidney also increased when the fish was stimulated with the poly(I:C) or bacterial vaccine [1], we therefore proposed that the intrinsic apoptotic pathway, which is initiated by caspase-9 and executed by caspase-3, was activated during the immune response induced by poly(I:C) or bacterial vaccine in large yellow croaker.
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PMID:Molecular cloning and characterization of caspase-3 in large yellow croaker (Pseudosciaena crocea). 2128 91


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