Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stroke produces a region of complete cell death and areas of partial damage, injury, and gliosis. The spatial relationship of these regions of damage to the infarct core and within spared neuronal circuits has not been identified. A model of cortical stroke was developed within functional subsets of the somatosensory cortex. Infarct size, regions of apoptosis, oxidative DNA damage, heat shock protein induction, and subtypes of reactive gliosis were precisely mapped with the somatosensory body map, quantified, and interrelated. Three tissue microenvironments were recognized: zones of partial ischemic damage, heat shock protein induction, and distributed gliosis. These three zones involved progressively more distant cortical regions, each larger than the infarct core. The zone of partial ischemic damage represents an overlap region of apoptotic cell death, oxidative DNA damage, loss of synaptic connections, and local reactive gliosis. The zone of distributed gliosis occupies distinct functional areas of the somatosensory cortex. The tissue reorganization induced by stroke is much larger than the stroke site itself. Adjacent tissue microenvironments are sites of distinct reactive cellular signaling and may serve as a link between the processes of acute cell death and delayed neuronal plasticity after focal stroke.
 ...
PMID:Tissue microenvironments within functional cortical subdivisions adjacent to focal stroke. 1297 16

In their role as molecular chaperones, heat shock proteins serve as central integrators of protein homeostasis within cells. As part of this function, they guide the folding, assembly, intracellular disposition and proteolytic turnover of many key regulators of cell growth, differentiation and survival. Not surprisingly then, heat shock proteins are over expressed in many types of cancer, and induction of the stress response may actually be required for cells to tolerate the genetic disarray characteristic of malignant transformation. Regulation of heat shock protein levels via the stress response is complex, but recent data indicate that the molecular chaperone Hsp90 plays a key role. Specifically, Hsp90 inhibitors alter the multi-chaperone complexes associated with Heat Shock Factor 1 (HSF1), the dominant transcription factor controlling induction of the stress response, and stimulate HSF1-activated heat shock gene expression. Induction of this heat shock response has now emerged as an important consideration in the further clinical development of Hsp90 inhibitors for several reasons. First, tumors in which the stress response is compromised appear particularly sensitive to Hsp90 inhibition. Second, induction of the stress response by Hsp90 inhibitors provides a sensitive pharmacodynamic endpoint with which to monitor drug action in individual patients. Third, Hsp90 inhibitors display important therapeutic interactions with both conventional DNA-targeted chemotherapeutics and newer molecularly targeted agents. These interactions are, at least in part, due to modulation of the stress response by these drugs. Lastly, stress response induction by Hsp90 inhibitors may have therapeutic benefits in non-neoplastic disorders such as heart disease, stroke and neurodegenerative diseases. These benefits are just beginning to be explored.
 ...
PMID:The stress response: implications for the clinical development of hsp90 inhibitors. 1452 86

Retrospective and cross-sectional studies have suggested that both bacterial and viral infections may be risk factors for atherosclerosis, ischemic stroke and acute coronary events. The correlation between Chlamydia pneumoniae and atherosclerosis remains a source of controversy. Our case-control study is aimed at evaluating the frequency of C. pneumoniae infection in a cohort of young adults with recent cerebrovascular disease and in particular etiologic stroke subtypes. Chlamydia pneumoniae IgG, IgM and IgA antibodies were evaluated by microimmunofluorescence method and antibody titers to both recombinant antigens chlamydial outer protein 2 and 60-kDa chlamydial heat shock protein (HSP60) by ELISA. The two groups differed with regard to the prevalence of C. pneumoniae IgA (P < 0.001) and IgG (P < 0.0001), as well as the titer of anti-R-HSP60 IgG (P < 0.001). We found an increase in IgA titers, suggestive of persistent, chronic active infection, in 16 patients in whom the etiology of the cerebral ischemic event was large-vessel atherothrombosis. Persistent, active C. pneumoniae infection may be an additional risk factor for ischemic stroke mainly of atherotrombotic origin in young subjects. However, a large-scale prospective confirmation of our findings is required.
 ...
PMID:Chlamydia pneumoniae infection in young stroke patients: a case--control study. 1514 25

Oligemia is blood flow reduction without acute tissue damage that occurs in shock, migraine, and stroke penumbra. We developed a mouse model of oligemia by lowering mean arterial pressure to 30-40 mm Hg, resulting in a 50% reduction in cerebral blood flow as measured by laser Doppler, and reperfusing the blood after 30 min. Control experiments included anesthesia-only and surgery without blood withdrawal. Using immunohistochemistry, we localized the transcription factors Nrf2, which regulates expression of antioxidant and detoxification protein, and c-Fos, a marker of neuronal activation. Nrf2 was found only in oligemia mice and was localized in neurons of the cingulate cortex and cerebellar Purkinje cells. By contrast, c-Fos was found widely expressed in both groups and was localized in neurons in regions associated with response to stress, immunomodulation, and fluid homeostasis, including the periaqueductal gray and periventricular nucleus. These data indicate that c-Fos expression occurs as a result of surgical stress, but Nrf-2 upregulation is specific to oligemia. The CLONTECH Atlas 1.2 Mouse Array was used to assess genes that were up or down-regulated in oligemia versus surgery controls. Of 1176 genes, 29 differed between oligemia and surgery groups. Upregulation of oxidative stress induced (OSI) protein, heat shock protein (HSP) 84 and transthyretin (TTR) precursor in the oligemia group was confirmed with RT-PCR. The expression of HSP 84, transthyretin precursor, and OSI genes adds further evidence that oligemia induces an oxidative stress response in the brain.
 ...
PMID:Response of the brain to oligemia: gene expression, c-Fos, and Nrf2 localization. 1520 16

Aged individuals experience the highest rate of stroke and have less functional recovery, but do not have larger infarcts. We hypothesized that aged individuals experience greater sublethal damage in peri-infarct cortex. Focal cortical stroke was produced in aged and young adult animals. After 30 min, 1, 3 and 5 days brain sections and Western blot were used to analyze markers of apoptotic cell death, oxidative DNA and protein damage, heat shock protein (HSP) 70 induction, total neuronal number and infarct size. Focal stroke produces significantly more oxidative DNA and protein damage and fewer cells with HSP70 induction in peri-infarct cortex of aged animals. There is no difference in infarct size or the number of cells undergoing apoptosis between aged and young adults. Stroke in the aged brain is associated with a greater degree of DNA and protein damage and a reduced stress response in intact, surviving tissue that surrounds the infarct.
 ...
PMID:Increased oxidative protein and DNA damage but decreased stress response in the aged brain following experimental stroke. 1575 69

This study tested the application of an immunoisotopic assay for immunohistochemical localization and quantification of proteins in brain sections from rats without or with transient focal ischemia. We assessed the hypothesis that measurements of protein levels in injured brain determined by an isotopic assay using [(125)I]-protein A have greater reliability than those made by conventional immunoperoxidase labeling using diaminobenzidine. Quantification of immunoreactivities for glial fibrillary acidic protein (GFAP), glutamate transporter-1 (GLT-1) and heat shock protein-70 (HSP-70) was determined by optical density signal in the immunoisotopic and immunoperoxidase assays. In ischemic brain, the immunoisotopic assay detected protein increases (cortical penumbra HSP-70, 151+/-6%), protein decreases (cortical ischemic core GLT-1, 61+/-6%) and no changes in GFAP levels compared to controls animals. These results differed from the protein levels found by the immunoperoxidase assay, which showed elevated HSP-70, GLT-1 and GFAP in all ischemic regions. We conclude that nonspecific immunosignal confounds assessments of protein expression in injured brain and that the immunoisotopic method is a valid approach to regionally localize and quantify proteins after brain injury. The disadvantage of the falsely positive overestimation of protein immunoreactivity after stroke with the immunoperoxidase method has to be weighted with the advantage of the cellular resolution.
 ...
PMID:In situ immunoradiographic method for quantification of specific proteins in normal and ischemic brain regions. 1581 55

Neuregulins are a family of growth factors with potent neuroprotective properties. We recently demonstrated that neuregulin-1 blocked delayed neuronal death following focal ischemic stroke in the rat. Focal ischemia results in the release of pro-inflammatory cytokines that produce profound changes in gene expression and contribute to cell death associated with stroke. Inflammatory and stress mediators are involved in the pathogenesis of focal ischemic brain damage. We examined whether neuregulin-1 can influence inflammatory and stress gene expression in the rat brain following transient middle cerebral artery occlusion (MCAO). In this study, we compared gene expression profiles in animals treated with neuregulin-1beta (NRG-1) or vehicle followed by MCAO. We used the Affymetrix GeneChip system to analyze gene expression in focal ischemia of the rat brain. Several inflammatory and stress genes were significantly induced following MCAO compared to sham controls including heat shock protein-70 (HSP70), interleukin-1beta, and macrophage chemotattractant protein-1 (JE/MCP-1). Treatment with NRG-1 attenuated the expression of many of these genes by 50% or more. In vitro studies demonstrated that NRG-1 suppressed inflammatory gene expression in activated macrophages. NRG-1 also prevented neuronal death induced by oxygen-glucose deprivation in a rat neuroblastoma cell line, suggesting that NRG-1 may have both direct and indirect neuroprotective capacity. These results demonstrate that NRG-1 can regulate inflammatory and stress gene expression and may give new insight to the molecular mechanisms involved in the neuroprotective role of neuregulins in stroke.
 ...
PMID:Neuroprotection by neuregulin-1 following focal stroke is associated with the attenuation of ischemia-induced pro-inflammatory and stress gene expression. 1602 88

Heat shock proteins are ubiquitous members of a family of molecular chaperones that protect various cell populations from injury. Up-regulation of heat shock proteins, particularly the 70 kDa species, bind selectively to denatured or partially damaged polypeptides that would otherwise perturb cell function and initiate cell death programs. In this regard, induction of heat shock proteins provides protection from cerebral ischemia in animal models of stroke. Endothelial cells, in particular, are intimately involved in the above protective event as these cells mount a stress response with induction of the 70 kDa heat shock protein. However, the coupling of heat shock proteins and the neurovascular response are not yet known. Here we show that blood content is an important factor in this stress response as rats devoid of blood content do not display a heat shock response in the microvasculature of the hippocampal formation. This lack of stress response, however, is reversed when rats are reperfused with exogenous rat or human blood content. We propose a new ischemic-sensing role for blood that serves to integrate information about protein-damaging conditions and heat shock protein levels in the neurovascular network. Further characterization of this sensing role could represent an attractive new approach to treatment of global ischemia and other microvascular pathologies.
 ...
PMID:Blood content modulates the induction of heat shock proteins in the neurovascular network. 1702 66

In recent years, there are an increasing number of proteomics studies that investigated the alterations in the protein expression relevant to human diseases but none for stroke. We, therefore, attempted such a study in a paradigm of focal cerebral ischemia in rat. Rats were subjected to cerebral ischemia by unilateral occlusion of the middle cerebral artery. Global protein analysis was performed after 24h on the lesioned and sham-control cerebral cortex using two-dimensional gel electrophoresis. Protein spots with more than a 3-fold change in intensity were identified by mass spectrometry. Middle cerebral artery occlusion (MCAO) caused infarct volume of 18-22% predominantly in the cortex of the lesioned hemisphere. Two-dimensional gel electrophoresis resolved about 1500 protein spots of which only 12 were significantly upregulated by 3-46-fold. Three spots were identified to be dihydropyrimidinase-related protein 2 (DRP-2, also known as collapsin response mediator protein 2 (CRMP-2) or turned on after division, 64 kD protein (TOAD-64)). The spots varied in pI values only and this may reflect different phosphorylation status of the same protein. Two spots were identified as spectrin alpha II chain (rat fragment, also known as alpha-fodrin or non-erythroid alpha chain, SPNA-2); and one spot each for heat shock cognate protein 70 pseudogene 1 (HSC70-ps1, also known as heat shock protein 8 pseudogene 1), and tropomodulin 2 (Tmod2). The upregulation of protein expression was corroborated by observed upregulation of mRNA expression. The remaining five spots were not identified satisfactorily. As DRP-2, spectrin, and Tmod2 are involved in axonal and neurite growth as well as synaptic plasticity and maturation, the presently observed upregulation of the expression of these proteins may indicate active neuroregeneration and repair at 24h after the induction of cerebral ischemia.
 ...
PMID:Upregulation of dihydropyrimidinase-related protein 2, spectrin alpha II chain, heat shock cognate protein 70 pseudogene 1 and tropomodulin 2 after focal cerebral ischemia in rats--a proteomics approach. 1719 11

This paper reviews the evidence for the interaction of oral disease (more specifically, periodontal infections) with cardiovascular disease. Cardiovascular disease is a major cause of death worldwide, with atherosclerosis as the underlying aetiology in the vast majority of cases. The importance of the role of infection and inflammation in atherosclerosis is now widely accepted, and there has been increasing awareness that immune responses are central to atherogenesis. Chronic inflammatory periodontal diseases are among the most common chronic infections, and a number of studies have shown an association between periodontal disease and an increased risk of stroke and coronary heart disease. Although it is recognised that large-scale intervention studies are required, pathogenic mechanism studies are nevertheless required so as to establish the biological rationale. In this context, a number of hypotheses have been put forward; these include common susceptibility, inflammation via increased circulating cytokines and inflammatory mediators, direct infection of the blood vessels, and the possibility of cross-reactivity or molecular mimicry between bacterial and self-antigens. In this latter hypothesis, the progression of atherosclerosis can be explained in terms of the immune response to bacterial heat shock proteins (HSPs). Because the immune system may not be able to differentiate between self-HSP and bacterial HSP, an immune response generated by the host directed at pathogenic HSP may result in an autoimmune response to similar sequences in the host. Furthermore, endothelial cells express HSPs in atherosclerosis, and cross-reactive T cells exist in the arteries and peripheral blood of patients with atherosclerosis. Each of these hypotheses is reviewed in light of current research. It is concluded that although atherosclerotic cardiovascular disease is almost certainly a multifactorial disease, there is now strong evidence that infection and inflammation are important risk factors. As the oral cavity is one potential source of infection, it is wise to try to ensure that any oral disease is minimised. This may be of significant benefit to cardiovascular health and enables members of the oral health team to contribute to their patients' general health.
 ...
PMID:Cardiovascular and oral disease interactions: what is the evidence? 1746 39


<< Previous 1 2 3 4 5 6 7 Next >>