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)

Apoptosis of neurones, macrophages, and microglia occurs in the brains of paediatric patients with human immunodeficiency virus (HIV) type 1 encephalitis, which is often associated with pre-mortem neurological disease (progressive encephalopathy). We have previously reported that TUNEL-positive neurones in brain tissue from paediatric patients with HIV type 1 encephalitis and progressive encephalopathy are strikingly devoid of the pro-apoptotic gene product Bax, in marked contrast to brain-resident macrophages and microglia. Using immunocytochemical methods, the present study demonstrate that neurones in patients with HIV type 1 encephalitis and progressive encephalopathy, as well as macrophages and microglia, but not astrocytes, overexpress caspase-3, a pro-apoptotic enzyme that is proteolytically activated downstream of Bax-Bcl-2 dysregulation. Co-localization of neuronal cytoplasmic caspase-3 and nuclear TUNEL staining, a marker for fragmented DNA, was also infrequently observed in brain tissue from patients with HIV type 1 encephalitis and progressive encephalopathy. These findings suggest that vulnerable neurones in brain tissue from patients with HIV virus type 1 encephalitis and progressive encephalopathy undergo apoptosis by a mechanism that involves upregulation of caspase-3 in a pathway that is independent of Bax-Bcl-2 dysregulation. Furthermore, caspase-3 upregulation in apoptotic neurones likely occurs prior to DNA fragmentation.
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PMID:Expression of caspase-3 in brains from paediatric patients with HIV-1 encephalitis. 1056 27

Much interest has recently been shown in apoptosis-mediated roles in the pathophysiology of mitochondrial diseases, because mitochondrial defects are implicated in a wide variety of degenerative diseases. We investigated whether apoptotic events occurred in skeletal muscles of patients with mitochondrial diseases, including chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayer syndrome (KSS), and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). In a immunohistochemical study, stainings for 8-hydroxy-deoxyguanosine (8-OH-dG), 4-hydroxy-nonenal (4-HNE), Mn-SOD, Bcl-2, cytochrome c, DNase I and Bcl-x L showed a pronounced granular distribution in the cytochrome c oxidase (COX)-negative ragged-red fibers (RRFs). On the other hand, the signals for Bax, p53, Fas and caspase 3 were not obviously increased in RRFs. In situ labeling of DNA breaks demonstrated preferential signals not only in myonuclei but also in subsarcolemmal regions of RRFs, indicating that mitochondrial as well as myonuclear DNA is fragmented in RRFs. An immunoblotting study demonstrated that cytochrome c was increased in the cytosol of diseased muscles and that DNase I was increased in mitochondria, compared to that of normal muscles. No difference was observed between protein bands at 20 kDa corresponding to caspase 3 in diseased and normal muscles. These findings demonstrate that these mitochondrial diseases harbor unique apoptosis-related changes that differ from caspase 3-dependent apoptosis. It is thought that these changes are induced by superoxide overproduction and cytochrome c release resulting from an inherent mitochondrial defect and that the events are associated with DNase I activation.
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PMID:Apoptosis-related changes in skeletal muscles of patients with mitochondrial diseases. 1181 Jan 83

Caspase-3 mediated cleavage of the amyloid precursor protein (APP) has been proposed as a putative mechanism underlying amyloidosis and neuronal cell death in Alzheimer's disease (AD). We utilized an antibody that selectively recognizes the neo epitope generated by caspase-3 mediated cleavage of APP (alphadeltaC(csp)-APP) to determine if this proteolytic event occurs in senile plaques in the inferior frontal gyrus and superior temporal gyrus of autopsied AD and age-matched control brains. Consistent with a role for caspase-3 activation in AD pathology, alphadeltaC(csp)-APP immunoreactivity colocalized with a subset of TUNEL-positive pyramidal neurons in AD brains. AlphadeltaC(csp)-APP immunoreactivity was found in neurons and glial cells, as well as in small- and medium-size particulate elements, resembling dystrophic terminals and condensed nuclei, respectively, in AD and age-matched control brains. There were a larger number of alphadeltaC(csp)-APP immunoreactive elements in the inferior frontal gyrus and superior temporal gyrus of subjects with AD pathology than age-matched controls. AlphadeltaC(csp)-APP immunoreactivity in small and medium size particulate elements were the main component colocalized with 30% of senile plaques in the inferior frontal gyrus and superior temporal gyrus of AD brains. In some control brains, alphadeltaC(csp)-APP immunoreactivity appeared to be associated with a clinical history of metabolic encephalopathy. Our results suggest that apoptosis contributes to cell death resulting from amyloidosis and plaque deposition in AD.
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PMID:Caspase-cleaved amyloid precursor protein in Alzheimer's disease. 1240 29

During influenza epidemics in Japan, the number of children with acute encephalopathies and encephalitis has recently increased. Although the pathophysiologies remain unclear, there is usually brain edema with evidence of damage to the blood-brain-barrier (BBB). We investigated the glial reaction and apoptosis in brains of eight such cases comprising two of acute necrotizing encephalopathy and six of influenza encephalopathy, and compared the results with those in five control brains. Apoptosis, evidenced by chromatin condensation and fragmentation in hematoxylin sections, in situ end labeling of fragmented DNA (TUNEL) and DNA laddering, was observed in neurons and glial cells in four brains with influenza encephalopathy. In the TUNEL-positive brains, the increase in microglia was greater than in the TUNEL-negative brains. Immunoreactivity for active-caspase 3, demonstrated by immunohistochemistry, and the overexpression of a caspase-cleaved fragment of poly(ADP-ribose) polymerase, demonstrated by Western blotting, indicated that activation of caspase 3 is involved in the apoptotic pathway in the brains of influenza encephalopathy cases. Apoptosis or specific pathological processes that cause apoptosis may give rise to aggravated encephalopathy.
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PMID:Apoptosis and microglial activation in influenza encephalopathy. 1255 9

Neuronal loss is, frequently found in brains of patients with human immunodeficiency virus (HIV)-encephalopathy. Extensive apoptosis of neurons is probably involved in the development of HIV-encephalopathy. The present study was designed to investigate the mechanism of neuronal apoptosis. For this purpose, we examined autopsy brains of two patients with HIV-encephalopathy. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells and active forms of caspase-3- and -8-positive cells, including neurons, were found in the perivascular regions of the brains. In these regions, TNF-related apoptosis-inducing ligand (TRAIL)+ macrophages were also observed. We also examined brains of HIV-1-infected mouse model inoculated with human cells. In these brains, TUNEL+ neurons were also found in the perivascular region, the site where infiltrated HIV-1-infected and TRAIL-expressing macrophages were observed. Using an in vitro-culture system, we also demonstrated that the HIV-1-infected monocyte-derived macrophages preferentially expressed TRAIL and that the addition of HIV-1-infected macrophages or human TRAIL-overexpressing mouse cells to cultured mouse primary neurons/glia resulted in neuronal apoptosis. Our results suggest the involvement of TRAIL expressed on HIV-1-infected macrophages in the induction of neuronal apoptosis in infected brain.
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PMID:TNF-related apoptosis-inducing ligand (TRAIL) induces neuronal apoptosis in HIV-encephalopathy. 1271 15

Alpers-Huttenlocher disease (AHD) is a rare encephalopathy of infancy and childhood characterized by myoclonic seizures and progressive neurological deterioration, usually associated with signs and symptoms of liver dysfunction. There is no biological marker of the disease, and ultimate diagnosis still relies on pathological examination. Features of clinical progression and pathological findings suggest AHD to be secondary to a genetically determined disorder of mitochondrial function. We report on four AHD patients and focus on their pathological features in brain, liver and muscle. Liver and muscle biopsy specimens were examined using histochemical markers of the oxidative pathways, probes to immunodetect molecules of the apoptotic cascades and electron microscopy. In liver (but not in muscle) biopsy samples, activated caspases were detected by immunohistochemistry: foci of caspase-9-positive cells were seen in a child affected with chronic, progressive fibrosis. In an 18-year-old boy, who suffered from valproic acid-associated acute hepatitis, caspase-3 cells were clustered among the necrotic foci and the foamy cells. In both patients electron microscopy revealed apoptotic nuclei. Normal muscle biopsy specimens were observed in two children, 2 and 8 years-old respectively; in the 18-year-old patient cytochrome oxidase-negative fibers as well as ultrastructural findings of mitochondrial abnormalities were observed. In no patient was there biochemical evidence of impaired oxidative metabolism. Neuropathological examination of the brains of two patients (13 months and 19 years old, respectively) showed focal distribution of the lesions affecting the telencephalic cortex and, to a lesser extent, subcortical gray nuclei. Along with the necrotizing lesions, characterized by neuronal loss, neuropil microcysts and newly formed vessels, we also observed acutely shrunken neurons and features of apoptotic cell death in the cerebral cortex only. Severe neuronal loss without necrotizing features was observed in the cerebellar cortex. The presence of both anoxic and apoptotic nuclei in brain and liver, the target tissues of the disease, is consistent with the hypothesis that abnormal activation of mitochondrion-related cell death pathways might be involved in the pathogenesis of AHD.
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PMID:Features of cell death in brain and liver, the target tissues of progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher disease). 1272 99

The neuropathological correlates of encephalopathy and autonomic dysfunction in septic shock are unclear. We performed post mortem analysis of 5 brain areas susceptible to ischemia and 5 autonomic nuclei (AN) in 23 patients who had died in our intensive care unit (ICU) from septic shock and 8 dying from non-septic shock as well as 5 controls who had died suddenly from extracranial injury. Proinflammatory cytokine (IL1-beta and TNF-alpha) and inducible nitric oxide synthase (iNOS) expression was assessed by immunocytochemistry. Abnormalities in septic shock were: hemorrhages (26%), hypercoagulability syndrome (9%), micro-abscesses (9%), multifocal necrotizing leukoencephalopathy (9%) and ischemia (100%). The incidence of cerebral hemorrhage or hypercoagulability syndrome was not related to clotting disturbances. The intensity of ischemia within susceptible areas was the same in both ICU groups, but more pronounced in the autonomic centers of septic patients (P < 0.0001). Neuronal apoptosis assessed using anti-caspase 3 immunocytochemistry and in situ end labeling was more pronounced in the autonomic nuclei of septic patients. (P < 0.0001). TNF-alpha expression did not differ between groups but vascular iNOS expression assessed by immunocytochemistry was higher in sepsis (P<0.0001) and correlated with autonomic center neuronal apoptosis (P < 0.02). We conclude that septic shock is associated with diffuse cerebral damage and specific autonomic neuronal apoptosis which may be due to circulating factors particularly iNOS.
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PMID:The neuropathology of septic shock. 1499 34

Inflammatory mediators play a crucial role in the pathophysiology of several neurodegenerative diseases including acquired immune deficiency syndrome dementia complex. In the present study we identified a link between CXCL10 overexpression in the brain and human immunodeficiency virus dementia and demonstrated the presence of the chemokine CXCL10 and its receptor, CXCR3, in the neurons in the brains of macaques with simian human immunodeficiency virus encephalitis. Using human fetal brain cultures, we showed that treatment of these cells with either SHIV89.6P or viral gp120 resulted in induction of CXCL10 in neurons. Cultured neurons treated with the chemokine developed increased membrane permeability followed by apoptosis via activation of caspase-3. We confirmed the relevance of these findings in sections of human and macaque brains with encephalopathy demonstrating that neurons expressing CXCL10 also expressed caspase-3.
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PMID:Neuronal apoptosis is mediated by CXCL10 overexpression in simian human immunodeficiency virus encephalitis. 1511 2

Neonatal hypoxic-ischaemic (HI) brain injury resulting in encephalopathy is a leading cause of morbidity and mortality with no effective treatment. Here we show that caffeic acid phenethyl ester (CAPE), an active component of propolis, administered either before or after an HI insult, significantly prevents HI-induced neonatal rat brain damage in the cortex, hippocampus and thalamus. In addition to blocking HI-induced caspase 3 activation, CAPE also inhibits HI-mediated expression of inducible nitric oxide synthase and caspase 1 in vivo and potently blocks nitric oxide-induced neurotoxicity in vitro. Furthermore, CAPE directly inhibits Ca2+-induced cytochrome c release from isolated brain mitochondria. Thus, CAPE induces neuroprotection against HI-induced neuronal death, possibly by blocking HI-induced inflammation and/or directly inhibiting the HI-induced neuronal death pathway. CAPE may therefore be a novel effective therapy for preventing neonatal HI injury.
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PMID:Caffeic acid phenethyl ester prevents neonatal hypoxic-ischaemic brain injury. 1546 48

We have previously shown that hippocampal neuronal apoptosis accompanied by impaired cognitive functions occurs in type 1 diabetic BB/Wor rats. To differentiate the contribution by insulin deficiency vs. that by hyperglycemia on neuronal apoptosis, we examined the activities of various apoptotic pathways in hippocampi from type 1 diabetic BB/Wor rats (hyperglycemic and insulinopenic) and type 2 diabetic BBZDR/Wor rats (hyperglycemic and hyperinsulinemic). DNA fragmentation was demonstrated by LM-PCR in type 1 diabetic BB/Wor rats, but was not detectable in duration- and hyperglycemia-matched type 2 BBZDR/Wor rats. Of various apoptotic pathways, Fas activations, 8-OHdG expression, and caspase-12 were demonstrated in type 1 diabetic BB/Wor rats only. In contrast, perturbations of the IGF and NGF systems and PARP activation were demonstrated in type 1 and to a lesser extent in type 2 diabetes. Expressions of Bax and active caspase-3 were significantly increased in type 1, but not in type 2, diabetic rats. These data suggest a lesser apoptogenic stress in type 2 vs. type 1 diabetes. These differences translated into a more profound neuronal loss in the hippocampus of type 1 rats. The results demonstrate that caspase-dependent apoptotic activities dominate in type 1 diabetes, whereas PARP-mediated caspase-independent apoptotic stress is present in both type 1 and type 2 diabetes. The findings suggest that insulin deficiency plays a compounding role to that of hyperglycemia in neuronal apoptosis underpinning primary diabetic encephalopathy.
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PMID:The role of impaired insulin/IGF action in primary diabetic encephalopathy. 1577 48


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