Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The primary goal of acute myeloid leukemia chemotherapy is to obtain a complete remission. In adults with de novo disease, response rates reach between sixty and seventy per cent with classical '3 + 7' or DAT schemes. Curative postinduction treatments are now available for responsive patients, which makes it mandatory to look for more effective modalities of induction therapy. Experience gathered in recent years shows that idarubicin, cytosine arabinoside, and etoposide together might contribute to the modeling of an improved remission induction regimen: ICE. Because ICE and similar programs are being used with increasing frequency worldwide, we decided to review critically the underlying issues and the evidence supporting this change.
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PMID:Remission induction therapy for adults with acute myelogenous leukemia: towards the ICE age? 775 97

Quantitative cytochemistry of cytochrome oxidase (C.O.) was implemented in human brains to measure C.O. activity in the 3 main divisions of the inferior colliculus (IC): central (ICC), dorsal (ICD), and external (ICE). Units of C.O. activity (micromol/min/g tissue wet weight) were quantified in cellular compartments (overall average, neuropil, perikaryon, and dendrites) at the light microscope level using microdensitometry calibrated with C.O. activity standards measured spectrophotometrically. In a non-AD (Alzheimer's disease) control group (mean age = 79.6 +/- 3.1 years, postmortem time = 6.9 +/- 1.6 h), the ICC and ICD demonstrated higher (p < 0.008) overall average activities (mean = 183.40 +/- 18.7 and 184.98 +/- 45.1 units, respectively) relative to the ICE (56.46 +/- 15.9 units). Comparison of cellular morphometry (soma and nucleus area, perimeter, and diameter) revealed that the ICC contained cells of significantly larger soma size than in both the ICD and ICE (p < 0.002). The distribution of soma diameters in the ICC of controls showed a clear bimodality, enabling the typing of the cells into larger and smaller than average soma diameter. Brains from patients with Alzheimer's disease (AD; mean age = 78.3 +/- 2.9 years, postmortem time = 6.5 +/- 1.3 h) were compared with the non-AD controls. Significant group differences were found only in the large cells of the ICC. The AD large cells showed a decrement in C.O. activity relative to the corresponding controls in overall average activity (p < 0.032) and in peak activity of neuropil near the soma (p < 0.012). These findings provide the first quantitative cytochemical data of C.O. activity in humans. They also suggest that cellular alterations in C.O. metabolism in AD affect predominantly specific groups of larger projection neurons while neighboring neurons are spared.
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PMID:Quantitative cytochemistry of cytochrome oxidase and cellular morphometry of the human inferior colliculus in control and Alzheimer's patients. 910 47

A major component of Alzheimer's disease plaque amyloid beta protein (betaAP) showed the cytolytic activity to rat pheochromocytoma PC 12 cells. Nuclear morphological study revealed that betaAP-induced cytolytic activity is due to necrotic cell death, rather than apoptotic cell death. To examine the molecular machinery of betaAP-induced necrotic cell death in detail, I investigated the direct involvement of caspase. When nerve growth factor-treated and -untreated PC12 cells were incubated with the synthesized tetrapeptide inhibitors of caspase, YVAD-CHO (Ac-Tyr-Val-Ala-Asp-CHO) or DEVD-CHO (Ac-Asp-Glu-Val-Asp-CHO), betaAP-induced necrotic cell death was prevented. In addition, the interleukin-1beta converting enzyme (ICE) subfamily activation preceded CPP32 subfamily activation during betaAP-induced necrotic cell death. On the basis of these findings, I suggest that betaAP induces necrotic cell death mediated by the ICE cascade and that the ICE cascade may possibly be involved in Alzheimer's disease.
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PMID:Amyloid beta-protein induces necrotic cell death mediated by ICE cascade in PC12 cells. 926 Sep 21

In order to characterize cell death mechanisms involved in Alzheimer disease (AD), we quantitated the expression of ced-3 and ced-9 homologs in AD frontal cortex. Positive (ICE, ICErel-II, ICErel-III, Ich-1L, CPP32, mch2, mch3, bcl-xS, bax and bak) and negative (bcl-2, bcl-xL, MCL1 and Ich-1S) regulators of apoptosis were successively examined using a semi-quantitative technique of reverse transcription-polymerase chain reaction (RT-PCR). Total RNA was extracted from postmortem frontal cortex of AD patients (n = 7) and controls (n = 7) matched for age and autolysis time. Baseline levels of message were detected for 3 ced-3 (CPP32, Ich-1 and ICE) and 4 ced-9 homologs (bcl-x, MCL1, bcl-2 and bax) in the frontal cortex. There was an overexpression of the ICEalpha cDNA in AD patients as compared with age-matched controls (P = 0.03). Our results indicate that several ced-3 and ced-9 homologs are expressed in the adult human brain, and suggest that neuronal cell death in AD might involve an aberrant expression of ICEalpha.
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PMID:Expression of ced-3 and ced-9 homologs in Alzheimer's disease cerebral cortex. 957 87

Neurodegenerative processes are generally characterized by the long-lasting course of neuronal death and the selectivity of the neuronal population or brain structure involved in the lesion. This is the case for Alzheimer's, Parkinson's or Huntington's diseases, or amyotrophic lateral sclerosis (ALS). The reasons for such a specificity are largely unknown as are generally the mechanisms of the diseases. One common feature of these diseases, however, is that the neuronal death is thought to involve apoptosis, at least partly. Interestingly, apoptosis in the brain would involve specific gene products similar to that identified in the nematode c. elegans, partly corresponding in mammals to ICE-related compounds and Bcl2 protein. The involvement of calcium as well as of oxydative stress mechanisms in such neuronal death is to be fully proved but putative modulation by external signals (such as those provided through trophic factors or even neurotransmitters) represents an interesting way to validate the current hypothesis of neuronal death in neurodegenerative diseases in humans.
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PMID:[Cellular bases of neurodegenerative processes]. 977 96

Recent studies have shown that deficient functioning of glutamate transporters (GTs) in Alzheimer disease (AD) might lead to neurodegeneration via excitotoxicity; however, the characteristics of cell death and pathways involved are not yet clear. The main objective of the present study was to determine if deficient GT functioning in AD could be associated with cell damage and caspase activation. For this purpose, we analyzed the levels of caspase-1 and 3 immunoreactivity in AD and control brains and correlated this data with the numbers of cells displaying DNA fragmentation, GT activity, and amyloid precursor protein (APP) mRNA expression. Compared to controls, AD cases showed extensive positive labeling of neurons and glial cells with an assay for DNA fragmentation suggestive of cell damage, as well as increased neuronal caspase-3 and Bcl-2 immunoreactivity. Linear regression analysis showed a strong negative correlation between GT activity and apoptosis, and between deficient GT functioning and caspase-3 immunoreactivity. Neurons displaying DNA fragmentation presented more intense caspase-3 immunoreactivity than intact neurons. In addition, the altered ratio between the spliced forms of APP correlated with DNA fragmentation and caspase-3 immunolabeling. Taken together, these results support the possibility that excitotoxic injury associated with deficient GT functioning and an imbalance in ratio of spliced APP forms might lead to cell death via caspase-3 activation.
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PMID:Caspase dependent DNA fragmentation might be associated with excitotoxicity in Alzheimer disease. 982 41

This overviews recent understanding of the mechanisms of apoptosis on ischemia-induced neuronal cell death. Apoptosis is a prominent feature of the developing nervous system. Several lines of evidence suggest that apoptosis is also an important mechanism of cell death in adult brain in acute or chronic diseases such as stroke and Alzheimer's disease. In animal models of stroke, markers of apoptosis such as cytoplasmic and nuclear condensation and DNA fragmentation appear in neurons. A variety of physiological and pathological stimuli can activate signal-transduction pathways that result in the sequential proteolytic activation of caspase family members. The activation of caspases can be inhibited by several molecules, including peptide aldehydes (caspase-1 and or caspase-3 inhibitors) and crmA that target the active-site cysteine of caspase family members, Bcl-2, IAP (inhibitor of apoptosis protein) and NAIP (neuronal apoptosis inhibitory protein). Once activated, caspase-1 protease can activate the caspase family members and hydrolyze a discrete set of cellular targets. Poly (ADP-ribose)polymerase (PARP), which appears to facilitate apoptosis, was recognized as a substrate of activated caspase-3. These results suggest that caspase family, bcl-2 family, IAP family and substrates such PARP contribute to mechanisms of cell death in ischemic brain injury. Inhibition of the caspase family, particularly by non-peptide inhibitors that cross the blood-brain barrier and easily penetrate neurons and glia, could provide novel treatments for stroke and other forms of brain and spinal cord injury in humans.
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PMID:[Involvement of caspase on apoptosis in ischemia-induced neuronal cell death: usefulness of caspase inhibitors for stroke therapy]. 1020 84

Increased expression of interleukin-1 in Alzheimer disease (AD) has been implicated as a driving force in neurodegenerative cascades that underlie the formation of neuritic plaques and neurofibrillary tangles, the spread of these neuropathological lesions across cerebral cortical regions, and the accompanying neuronal cell injury and loss. The beta isoform of interleukin-1 is generated from an inactive, 33-kDa precursor through the action of a specific interleukin-1beta converting enzyme (ICE), also known as caspase-1. We used mesial temporal tissue (hippocampus and parahippocampal cortex) obtained postmortem from Alzheimer and control patients for determinations of endogenous tissue ICE activity and for Western immunoblot analysis of tissue ICE concentrations. ICE activity in Alzheimer tissue was elevated 50-100% (p < 0.002, or better, at incubation times of 30 min to 10 h), and ICE protein level was elevated 180% (p = 0.01). Parahippocampal cortex of Alzheimer patients showed increased numbers of neurons with in situ evidence of DNA damage. Increased DNA degradation was also evident upon electrophoresis of isolated DNA. Overexpression and increased activity of ICE may contribute to neurodegeneration in AD through generation of biologically active interleukin-1, with consequent activation of interleukin-1-driven neurodegenerative cascades.
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PMID:Increased interleukin-1beta converting enzyme expression and activity in Alzheimer disease. 1037 48

Senile plaques of Alzheimer's brain are characterized by activated microglia and immunoreactivity for the peptide chromogranin A. We have investigated the mechanisms by which chromogranin A activates microglia, producing modulators of neuronal survival. Primary cultures of rat brain-derived microglia display a reactive phenotype within 24 h of exposure to 10 nM chromogranin A, culminating in microglial death via apoptotic mechanisms mediated by interleukin-1beta converting enzyme. The signalling cascade initiated by chromogranin A triggers nitric oxide production followed by enhanced microglial glutamate release, inhibition of which prevents microglial death. The plasma membrane carrier inhibitor aminoadipate and the type II/III metabotropic glutamate receptor antagonist (RS)-alpha-methyl-4-sulphonophenylglycine are equally protective. A significant amount of the released glutamate occurs from bafilomycin-sensitive stores, suggesting a vesicular mode of release. Inhibition of this component of release affords significant microglial protection. Conditioned medium from activated microglia kills cerebellar granule cells by inducing caspase-3-dependent neuronal apoptosis. Brain-derived neurotrophic factor is partially neuroprotective, as are ionotropic glutamate receptor antagonists, and, when combined with boiling of conditioned medium, full protection is achieved; nitric oxide synthase inhibitors are ineffective.
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PMID:Apoptotic pathways mobilized in microglia and neurones as a consequence of chromogranin A-induced microglial activation. 1042 49

beta-amyloid (Abeta) has been proposed to play a role in the pathogenesis of Alzheimer's disease (AD). Deposits of insoluble Abeta are found in the brains of patients with AD and are one of the pathological hallmarks of the disease. It has been proposed that Abeta induces death by oxidative stress, possibly through the generation of peroxynitrite from superoxide and nitric oxide. In our current study, treatment with nitric oxide generators protected against Abeta-induced death, whereas inhibition of nitric oxide synthase afforded no protection, suggesting that formation of peroxynitrite is not critical for Abeta-mediated death. Previous studies have shown that aggregated Abeta can induce caspase-dependent apoptosis in cultured neurons. In all of the neuronal populations studied here (hippocampal neurons, sympathetic neurons, and PC12 cells), cell death was blocked by the broad spectrum caspase inhibitor N-benzyloxycarbonyl-val-ala-asp-fluoromethyl ketone and more specifically by the downregulation of caspase-2 with antisense oligonucleotides. In contrast, downregulation of caspase-1 or caspase-3 did not block Abeta(1-42)-induced death. Neurons from caspase-2 null mice were totally resistant to Abeta(1-42) toxicity, confirming the importance of this caspase in Abeta-induced death. The results indicate that caspase-2 is necessary for Abeta(1-42)-induced apoptosis in vitro.
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PMID:Caspase-2 mediates neuronal cell death induced by beta-amyloid. 1066 29


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