Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heme oxygenase-1 (HO-1, HSP32) is an early gene that is responsive to an array of pathological conditions including, but not limited to, hypoxia and cerebral ischemia. HO-1 cleaves the heme molecule and produces carbon monoxide (CO) and biliverdin (an antioxidant) and is essential for iron homeostasis. The purpose of this study was to investigate, using transgenic (Tg) mice, whether overexpression of HO-1 in the brain augments or attenuates cellular injury caused by ischemic stroke. Homozygous HO-1 Tg mice that overexpress HO-1 under the control of the neuron-specific enolase promoter (characterized previously) were used. Under halothane anesthesia and normothermic conditions, wild-type nontransgenic (nTg; n = 22) and HO-1 Tg (n = 24) mice were subjected to middle cerebral artery occlusion (MCAo). Six hours after induction of ischemia, Tg and nTg mice developed infarcts that were 39 +/- 6 and 63 +/- 9 mm3, respectively (p < 0.01). No significant difference between the two strains was observed in the values of brain edema (11.3 +/- 4% in Tg vs. 14.6 +/- 5% in nTg; p < 0.1). At 24 h after MCAo, Tg mice exhibited significant neuroprotection as determined by the stroke volumes (41 +/- 2 mm3 in Tg vs. 74 +/- 5 mm3 in nTg; p < 0.01) and values of ischemic cerebral edema (21 +/- 6% in Tg vs. 35 +/- 11% in nTg; p < 0.01). Data suggest that neuroprotection in Tg mice was, at least in part, related to the following findings: (a) constitutively up-regulated cyclic GMP and bcl-2 levels in neurons; (b) inhibition of nuclear localization of p53 protein; and (c) antioxidant action of HO-1, as detected by postischemic neuronal expression of ferritin, and decreases in iron staining and tissue lipid peroxidation. We suggest that pharmacological stimulation of HO-1 activity may constitute a novel therapeutic approach in the amelioration of ischemic injury during the acute period of stroke.
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PMID:Overexpression of heme oxygenase-1 is neuroprotective in a model of permanent middle cerebral artery occlusion in transgenic mice. 1003 92

Pleomorphic xanthoastrocytoma (PXA) is a rare primary low-grade astrocytic tumor, recently classified as a neuroglial tumor. It generally occurs in children and young adults and shows benign behaviour (WHO II), although an anaplastic variant and malignant potential have been described. Pleomorphic xanthoastrocytomas with malignant transformation have been reported in three out of eight patients operated on for this type of tumor in our department in the last 15 years. The three patients were two adult women and a child, the primary tumors were located in the cortex of the right temporal lobe, and treatment consisted of complete surgical resection. Histological examination revealed simple PXA in two patients and a PXA with anaplastic foci in the other. Mean recurrence time was 5.7 years, with the original xanthoastrocytoma evolving to glioblastoma in two cases and anaplastic astrocytoma in the third. All three patients underwent a second operation, followed by adjuvant therapies. Two died from tumor progression and one from brain edema after intracerebral haemorrhage. A review of the available PXA literature dating back to 1979 revealed 16 cases of primary anaplastic astrocytoma and 21 cases of PXA with malignant transformation. Our experience adds three more cases of malignant transformations, outlining once again the potential malignancy of pleomorphic xanthoastrocytomas and the fact that prognosis in these cases is the same as for primary anaplastic astrocytoma and glioblastoma. Analysis of glioneuronal markers, Ki67 and p53 in all pleomorphic xanthoastrocytomas did not prove to be a discriminating factor to identify a subgroup of xanthoastrocytomas prone to malignancy. Accordingly, these tumors demand close long-term clinical and radiological follow-up.
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PMID:Malignant progression in pleomorphic xanthoastrocytoma: personal experience and review of the literature. 1718 43

Our previous study demonstrated that p53 plays an orchestrating role in the vasospasm and apoptotic cell death after subarachnoid hemorrhage (SAH). We now hypothesize that p53 also plays an important role in brain edema by up-regulating the expression of MMP-9 via the NF-kappaB molecular signaling pathway. Adult male rats (300-350 g) were divided into five groups (n=20 each): Sham, SAH treatment with DMSO or PFT-alpha (0.2 mg/kg and 2.0 mg/kg), intraperitoneally. The monofilament puncture model was used to induce SAH and animals were subsequently sacrificed at 24 h. The blood-brain barrier (BBB) disruption, brain water content, MMP-9 activity, immunohistochemistry, treble fluorescence labeling, Western blot, and ultra-structural observations were performed. Evans blue extravagation, BBB diffuse leakage of IgG protein and brain water content were significantly reduced by PFT-alpha treatment; and the expression of p53, NF-kappaB and MMP-9 were significantly increased. The tight junction protein (Occludin) in endothelia cells and Collage IV in basal lamina were decreased in the brain of SAH rats, and were also modified by PFT-alpha treatment. Ultra-structural changes included disruption of endothelial tight junction and widening of the inter-endothelial spaces. Treble labeling showed p53 colocalized with NF-kappaB and MMP-9 in cerebral endothelia cells. We thus conclude that the level of p53 in cerebral microvasculature significantly affects the BBB permeability and brain edema after 24 h of SAH in rats. This can be at least partially ascribed to p53 inducing a significant up-regulation of MMP-9 via NF-kappaB in the endothelium, which in turn opened the tight junction by degrading Occludin and disrupting the basal lamina by degrading collagen IV.
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PMID:The role of p53 in brain edema after 24 h of experimental subarachnoid hemorrhage in a rat model. 1869 72

Cytotoxic brain edema, due principally to astrocyte swelling, is a major neurological complication of the acute form of hepatic encephalopathy (HE) (acute liver failure, ALF), a condition likely caused by elevated levels of brain ammonia. Potential mediators of ammonia-induced astrocyte swelling include oxidative/nitrosative stress (ONS), the mitochondrial permeability transition (mPT), mitogen-activated protein kinases (MAPKs) and nuclear factor-kappaB (NF-kappaB), since blockade of these factors reduces the extent of astrocyte swelling. As p53, a tumor suppressor protein and transcription factor, is a downstream target of ONS and MAPKs, we examined its potential role in the mechanism of ammonia-induced astrocyte swelling. Astrocytes exposed to NH(4)Cl (5mM) showed increased phosphorylation (activation) of p53((Ser392)) at 1h and such phosphorylation was significantly reduced by inhibitors of MAPKs (ERK1/2, JNK and p38-MAPK), antioxidants (vitamin E, catalase, PBN, desferoxamine, MnTBAP), as well as by L-NAME, an inhibitor of nitric oxide synthase, indicating a key role of oxidative/nitrosative stress and MAPKs in the ammonia-induced activation of p53. Since p53 is known to induce the mPT and to activate NF-kappaB (factors leading to ONS and implicated in ammonia-induced astrocyte swelling), we examined whether inhibition of p53 activation blocked mPT induction, NF-kappaB activation, as well as cell swelling. Pifithrin-alpha (PFT), an inhibitor of p53, blocked these processes. Impairment of astrocytic glutamate uptake is another important feature of HE and hyperammonemia. We therefore examined the potential role of p53 in the ammonia-induced inhibition of glutamate uptake and found that PFT also reversed the ammonia-induced inhibition of glutamate uptake. Our results indicate that a potentially important downstream target of ammonia neurotoxicity is p53, whose activation contributes to astrocyte swelling and glutamate uptake inhibition, processes likely a consequence of ONS derived from the mPT and activation of NF-kappaB.
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PMID:Ammonia-induced activation of p53 in cultured astrocytes: role in cell swelling and glutamate uptake. 1942 12

During neonatal hypoxic-ischemic brain injury, activation of transcription of a series of genes is induced to stimulate erythropoiesis, anti-apoptosis, apoptosis, necrosis and angiogenesis. A key factor mediating these gene transcriptions is hypoxia-inducible factor-1alpha (HIF-1alpha). During hypoxia, HIF-1alpha protein is stabilized and heterodimerizes with HIF-1beta to form HIF-1, subsequently regulating the expression of target genes. HIF-1alpha participates in early brain development and proliferation of neuronal precursor cells. Under pathological conditions, HIF-1alpha is known to play an important role in neonatal hypoxic-ischemic brain injury: on the one hand, HIF-1alpha has neuroprotective effects whereas it can also have neurotoxic effects. HIF-1alpha regulates the transcription of erythropoietin (EPO), which induces several pathways associated with neuroprotection. HIF-1alpha also promotes the expression of vascular endothelial cell growth factor (VEGF), which is related to neovascularization in hypoxic-ischemic brain areas. In addition, HIF-1alpha has an anti-apoptotic effect by increasing the expression of anti-apoptotic factors such as EPO during mild hypoxia. The neurotoxic effects of HIF-1alpha are represented by its participation in the apoptotic process by increasing the stability of the tumor suppressor protein p53 during severe hypoxia. Moreover, HIF-1alpha plays a role in cell necrosis, by interacting with calcium and calpain. HIF-1alpha can also exacerbate brain edema via increasing the permeability of the blood-brain barrier (BBB). Given these properties, HIF-1alpha has both neuroprotective and neurotoxic effects after hypoxia-ischemia. These events are cell type specific and related to the severity of hypoxia. Unravelling of the complex functions of HIF-1alpha may be important when designing neuroprotective therapies for hypoxic-ischemic brain injury.
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PMID:The role and regulation of hypoxia-inducible factor-1alpha expression in brain development and neonatal hypoxic-ischemic brain injury. 1978 48

This study was designed to explore the role of simvastatin and its effects on the Akt/GSK3beta survival signal and apoptosis pathway after experimental subarachnoid hemorrhage (SAH). SAH was induced by blood injection into the cisterna magna in New Zealand white rabbits. Increased expression of phospho-Akt and phospho-GSK3beta was observed in brain tissue after SAH. Apoptosis and related proteins, including P53, apoptosis-inducing factor (AIF), cytochrome C, and cleaved caspase-3, were also activated. Simvastatin, at both low dose (10 mg/kg) and high dose (40 mg/kg), further increased expression of phospho-Akt and phospho-GSK3beta, decreased activation of caspase-3, and inhibited apoptosis. Preserved blood-brain barrier and attenuated brain edema were observed following simvastatin treatment. In addition, the neuroprotective effects of simvastatin were blocked by wortmannin (2.5 microg/kg/min), an irreversible PIK3 inhibitor. P53, AIF, and cytochrome C were not affected by simvastatin treatment. Findings from the present study suggest that simvastatin ameliorates acute brain injury after SAH. The potential mechanisms of action include activation of the Akt/GSK3beta survival signal and inhibition of caspase-dependent apoptosis pathway.
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PMID:Simvastatin activates Akt/glycogen synthase kinase-3beta signal and inhibits caspase-3 activation after experimental subarachnoid hemorrhage. 2000 38

Stroke is the second leading cause of death worldwide and the number one cause of adult disability in the United States and Europe. A subtype of stroke, subarachnoid hemorrhage (SAH), accounts for 7% of all strokes each year and claims one of the highest mortalities and morbidities. Many therapeutic interventions have been used to treat brain injury following SAH but none have reached the level of effectiveness needed to clinically reduce mortality. Ginsenoside Rb1 (GRb1), a major component of the Chinese traditional medicine Panax Ginseng, has been shown to reduce ischemic brain injury and myocardial injury via anti-apoptotic pathways. In the present study, we investigated the use of GRb1 on SAH induced brain injury in rats. Four groups were used: sham, vehicle (SAH), low dose treatment (SAH+ 5mg/kg GRb1), and high dose treatment (SAH+ 20mg/kg GRb1). Post assessment included wall thickness and mean cross-section area of basilar artery were measured for evaluating cerebral vasospasm, Evans blue extravasations to assess blood brain barrier (BBB) permeability, immunohistochemistry and Western Blot analysis looking for specific pro-apoptotic markers, and tunnel staining for cell death assessment. In addition, mortality, neurological function and brain edema were investigated. The results showed that high dose GRb1 treatment significantly enlarged mean cross-sectional area and decreased wall thickness of basilar artery, reduced neurological deficits, brain edema, BBB disruption, and TUNEL positive cell expression. Same time, we found that the proteins expression of P53, Bax and Caspase-3 were significantly reduced, whereas the expression of bcl-2 was up-regulated in Rb1 treatment. The results of this study suggest that GRb1 could relieve cerebral vasospasm and potentially provide neuroprotection in SAH victims. The underlying mechanisms may be partly related to inhibition of P53 and Bax dependent proapoptosis pathway. More studies will be needed to confirm these results and determine its potential as a long term agent.
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PMID:Ginsenoside Rbeta1 reduces neurologic damage, is anti-apoptotic, and down-regulates p53 and BAX in subarachnoid hemorrhage. 2035 83

Emerging evidence has demonstrated that postconditioning with sevoflurane provided neuroprotection. In this study, we investigated the neuroprotective effect of different concentrations of sevoflurane in rats with middle cerebral artery occlusion (MCAO). Furthermore, we tested the hypothesis that the neuroprotective effect of postconditioning with sevoflurane is associated with inhibition of apoptosis and mediated by activation of the phosphoinositide-3-kinase/Akt (PI3K/Akt) pathway. Adult male Sprague-Dawley rats were subjected to MCAO for 90 min and then treated with sevoflurane at the beginning of reperfusion. The infarct volume, neurological deficit scores and brain edema were evaluated at 24 hours. Spatial learning and memory was examined by Morris water maze. Apoptosis and apoptosis-related proteins were studied by TUNEL, immunohistochemistry and western blot. The neuroprotective effect and the amount of p-Akt after sevoflurane administration with or without wortmannin were analyzed. Postconditioning with sevoflurane 1.0 minimum alveolar concentration (MAC) and 1.5 MAC significantly decreased neurological deficit scores, infarct volume and brain edema and markedly improved spatial learning and memory. Postconditioning also reduced apoptotic cells, upregulated Bcl-2 and downregulated P53 and Bax. Wortmannin abolished the neuroprotective effect and prevented the increasing of p-Akt. Our data suggest postconditioning with sevoflurane (1.0 MAC and 1.5 MAC) not only reduced infarct volume but also improved learning and memory. Our study further showed that this neuroprotective effect may be partly due to the activation of PI3K/Akt pathway and inhibiting neuronal apoptosis.
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PMID:Postconditioning with sevoflurane protects against focal cerebral ischemia and reperfusion injury via PI3K/Akt pathway. 2070 63

Subarachnoid hemorrhage (SAH) is a devastating stroke subtype accounting for approximately 3 to 7% of cases each year. Despite its rarity among the various stroke types, SAH is still responsible for approximately 25% of all stroke fatalities. Although various preventative and therapeutic interventions have been explored for potential neuroprotection after SAH, a considerable percentage of patients still experience serious neurologic and/or cognitive impairments as a result of the primary hemorrhage and/or secondary brain damage that occurs. Z-ligustilide (LIG), the primary lipophilic component of the Chinese traditional medicine radix Angelica sinensis, has been shown to reduce ischemic brain injury via antiapoptotic pathways. Accordingly, in our study, we investigated the neuroprotective potential of LIG after experimental SAH in rats. Rats with SAH that was induced using the established double hemorrhage model were studied with and without LIG treatment. Mortality, neurobehavioral evaluation, brain water content, blood-brain barrier (BBB) permeability, and vasospasm assessment of the basilar artery were measured on days 3 and 7 after injury. Additional testing was done to evaluate for apoptosis using TdT-mediated dUTP-biotin nick end labeling staining as well as immunohistochemistry and Western blotting to identify key proapoptotic/survival proteins, i.e., p53, Bax, Bcl-2, and cleaved caspase-3. The results showed that LIG treatment reduced mortality, neurobehavioral deficits, brain edema, BBB permeability, and cerebral vasospasm. In addition, treatment reduced the number of apoptotic cells in the surrounding brain injury site, which accompanied a marked down-regulation of proapoptotic proteins, p53, and cleaved caspase-3. Our data suggest that LIG may be an effective therapeutic modality for SAH victims by altering apoptotic mechanisms.
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PMID:Treatment with Z-ligustilide, a component of Angelica sinensis, reduces brain injury after a subarachnoid hemorrhage in rats. 2139 13

The blood-brain barrier (BBB) plays a vital role as both a physiologic and physical barrier in regulating the movement of water from the vasculature to the brain. During a subarachnoid hemorrhage (SAH), the BBB is disrupted by a variety of mediators, one of which can result in endothelial cell death. As a result, in the present study, we investigated the role of PUMA (p53 upregulated modulator of apoptosis) following SAH injury in rats. Specifically evaluating whether through the endoplasmic reticulum (ER), PUMA could orchestrate the induction of endothelial cell apoptosis and cause a disruption in the blood-brain barrier integrity. One hundred twelve male Sprague-Dawley rats were randomly divided into 4 groups: sham, SAH, SAH+control siRNA, SAH+PUMA siRNA. Outcomes measured include mortality rate, brain edema, BBB disruption, and neurobehavioral testing. We also used Western blotting techniques to measure the expression of key pro-apoptotic proteins such as BAX, BAK, and DRP1. PUMA siRNA treatment significantly reduced the mortality rate, cerebral edema, neurobehavioral deficits, and BBB disruption as measured by Evans blue assay following SAH injury. The T2WI images showed there was an increase in vasogenic edema in the brain following SAH, which could be alleviated by PUMA siRNA. Immunohistochemical staining and Western blot analysis demonstrated an increased expression of PUMA, BAX, BAK, GRP78 and DRP1 in the microvascular endothelial cells of the hippocampus, which was accompanied with endothelium apoptosis. This study showed that PUMA induced endothelial cell apoptosis may in fact play a significant role in BBB disruption following SAH and its mediation may be through the endoplasmic reticulum. By blocking the activity of PUMA using siRNA, we were able to prevent the accumulation of cerebral edema that occurs following BBB disruption. This translated into a preservation of functional integrity and an improvement in mortality.
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PMID:Blood-brain barrier disruption following subarchnoid hemorrhage may be faciliated through PUMA induction of endothelial cell apoptosis from the endoplasmic reticulum. 2158 87


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