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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Necrosis and apoptosis are the two fundamental hallmarks of neuronal death in stroke. Nevertheless, thrombolysis, by using the recombinant serine protease t-PA, remains until now the only approved treatment of stroke in man. 2. Over the last years, the cytokine termed Transforming Growth Factor-beta1 (TGF-beta1) has been found to be strongly up-regulated in the central nervous system following ischemia-induced brain damage. 3. Recent studies have shown a neuroprotective activity of TGF-beta1 against ischemia-induced neuronal death. In vitro, TGF-beta1 protects neurons against excitotoxicity by inhibiting the t-PA-potentiated NMDA-induced neuronal death through a mechanism involving the up-regulation of the type-1 plasminogen activator inhibitor (PAI-1) in astrocytes 4. In addition, TGF-beta1 has been recently characterized as an antiapoptotic factor in a model of staurosporine-induced neuronal death through a mechanism involving activation of the extracellular signal-regulated kinase 1/2 (Erk1/2) and a concomitant increase phosphorylation of the antiapoptotic protein Bad. 5. Altogether, these observations suggest that either TGF-beta signaling or TGF-beta1-modulated genes could be good targets for the development of new therapeutic strategies for stroke in man.
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PMID:Transforming growth factor-beta and ischemic brain injury. 1451 14

Inflammation, upregulation of cytokines, proapoptotic molecules, and apoptosis are accepted widely as crucial players in stroke-induced brain damage. Induction of brain tolerance against ischemia by pretreatment with nonlethal stressors (preconditioning) has been found to influence expression of different molecules, in addition to reduction of infarct size. It remains unclear, however, whether and how preconditioning changes expression of cytokines after subsequent brain ischemia. We sought to analyze cortical expression of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, Fas, and Fas ligand (FasL) mRNA after a transient, focal brain ischemia in rats subjected to preconditioning. The mRNA levels were determined using a semiquantitative RT-PCR in the ischemic and contralateral cortex, separately. Transient ischemia was induced by 90-min middle cerebral artery occlusion (MCAo) and neurologic deficits as well as infarct size were quantified. Preconditioning was carried out by a short-term MCAo or an injection of 3-nitropropionic acid 3 days before MCAo. In both preconditioning paradigms, similar effects on investigated mRNA levels were observed. IL-1beta and IL-6 levels were decreased in tolerant rats compared to those in nontolerant ones. Changes in TNF-alpha, TGF-beta, and Fas levels were comparable independently of tolerance state. FasL mRNA was at similar level in rats subjected to chemical preconditioning but lower after ischemic preconditioning. Our findings demonstrate that both preconditioning methods exert a very similar effect on the expression of investigated cytokines. Interestingly, we observed a selective effect of preconditioning on IL-1beta and IL-6 expression that suggests different functional properties as well as different regulation of analyzed molecules during an induction of the brain tolerance against ischemia.
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PMID:Influence of chemical and ischemic preconditioning on cytokine expression after focal brain ischemia. 1537 97

Sickle cell anemia (SCA) is a paradigmatic single gene disorder caused by homozygosity with respect to a unique mutation at the beta-globin locus. SCA is phenotypically complex, with different clinical courses ranging from early childhood mortality to a virtually unrecognized condition. Overt stroke is a severe complication affecting 6-8% of individuals with SCA. Modifier genes might interact to determine the susceptibility to stroke, but such genes have not yet been identified. Using Bayesian networks, we analyzed 108 SNPs in 39 candidate genes in 1,398 individuals with SCA. We found that 31 SNPs in 12 genes interact with fetal hemoglobin to modulate the risk of stroke. This network of interactions includes three genes in the TGF-beta pathway and SELP, which is associated with stroke in the general population. We validated this model in a different population by predicting the occurrence of stroke in 114 individuals with 98.2% accuracy.
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PMID:Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia. 1580 Jun 45

Current theories suggest that atherosclerosis, plaque rupture, stroke, and restenosis after angioplasty may involve defective apoptotic mechanisms in vascular cells. Prior work has demonstrated that cells from human atherosclerotic lesions, and cells from the aorta of aged rats, exhibit functional resistance to apoptosis induced by TGF-beta and glucocorticoids. The present studies demonstrate that human lesion-derived cells (LDC) are also resistant to apoptosis induced by fas ligation compared to cells derived from the adjacent media, and that in vitro expansion of LDC causes acquired resistance to apoptosis. Microarray profiling of fas-resistant versus sensitive cells identified a set of genes including STATs, caspase 1, cyclin D1, Bcl-xL, VDAC2, and BAD. The STAT proteins have been implicated in resistance to apoptosis, potentially via their ability to modulate caspase 1 (ICE), Bcl-xL, and cyclin D1 expression. Western blot analysis of sensitive and resistant LDC clonal lines confirmed increases in cyclin D1, STAT6, Bcl-xL, and BAD, with decreased expression of caspase 1. Thus, transcript profiling has identified a potential pathway of apoptotic regulation in subsets of lesion cells. The resistant phenotype may contribute to plaque stability and excessive vascular repair, while sensitive cells may be involved in plaque rupture and infarction. The data suggests both genetic interventions and novel small-molecule inhibitors that may be effective modulators of apoptosis in atherosclerosis, angina, and in-stent restenosis.
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PMID:Genomic profiling of acquired resistance to apoptosis in cells derived from human atherosclerotic lesions: potential role of STATs, cyclinD1, BAD, and Bcl-XL. 1600 68

Multiple mechanisms of tolerance are induced by oral antigen. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral antigen induces T-helper 2 [interleukin (IL)-4/IL-10] and Th3 [transforming growth factor (TGF)-beta] T cells plus CD4+CD25+ regulatory cells and latency-associated peptide+ T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-beta, cholera toxin B subunit, Flt-3 ligand, and anti-CD40 ligand. Oral (and nasal) antigen administration suppresses animal models of autoimmune diseases including experimental autoimmune encephalitis, uveitis, thyroiditis, myasthenia, arthritis, and diabetes in the non-obese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, graft rejection, allergy, colitis, stroke, and models of Alzheimer's disease. Oral tolerance has been tested in human autoimmune diseases including multiple sclerosis (MS), arthritis, uveitis, and diabetes and in allergy, contact sensitivity to dinitrochlorobenzene (DNCB), and nickel allergy. Although positive results have been observed in phase II trials, no effect was observed in phase III trials of CII in rheumatoid arthritis or oral myelin and glatiramer acetate (GA) in MS. Large placebo effects were observed, and new trials of oral GA are underway. Oral insulin has recently been shown to delay onset of diabetes in at-risk populations, and confirmatory trials of oral insulin are being planned. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time, and antigen-specific mechanisms of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy, and early therapy.
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PMID:Oral tolerance. 1604 53

Strokes due to transmural vasculitis associated with coccidioidal meningitis result in significant morbidity and mortality. The immunological and inflammatory processes responsible are poorly understood. To determine the inflammatory mediators, i.e. cytokines, chemokines, iNOS, matrix metalloproteinase-9 (MMP-9), that possibly contribute to vasculitis, temporal mRNA expression in brain basilar artery samples and MMP-9 protein in the CSF of male NZW rabbits infected intracisternally with 6.5 x 10(4) arthroconidia of Coccidioides immitis were assessed. Five infected and 3 sham-injected rabbits at each time point were euthanized 4, 9, 14 and 20 days post infection. All infected rabbits had neurological abnormalities and severe vasculitis in the basilar arteries on days 9-20. In basilar arteries of infected animals versus controls, mRNAs encoding for IL-6, iNOS, IFN-gamma, IL-2, MCP-1, IL-1beta, IL-10, TNF-alpha, CCR-1, MMP-9, TGF-beta, as well as MMP-9 protein in CSF, were found to be significantly up-regulated. Thus, this study identified inflammatory mediators associated with CNS vasculitis and meningitis due to C. immitis infection. Assessment of the individual contribution of each mediator to vasculitis may offer novel approaches to the treatment of coccidioidal CNS infection. This study also provides unique methodology for immunology studies in a rabbit model.
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PMID:Temporal expression of inflammatory mediators in brain basilar artery vasculitis and cerebrospinal fluid of rabbits with coccidioidal meningitis. 1648 45

Hereditary Haemorrhagic Telangiectasia, or Rendu-Osler-Weber syndrome, is a rare autosomal dominant disorder involving the vascular system and is characterised by a highly variable expressivity and age-dependent penetrance. Diagnosis is based on the presence of at least three of four of the following symptoms: spontaneous epistaxis, cutaneous telangiectases, arteriovenous malformations in internal organs and familiarity. Recurrent complications are severe anaemia, stroke, portal and pulmonary hypertension. The peculiar characteristic of this disease is the diffusion of arteriovenous malformations, that is, localised abnormal arteriovenous connections affecting both microvasculature and large vessels. HHT is actually a heterogenous genetic disorder, divided into two clinically indistinguishable forms: HHT1 caused by mutations in endoglin gene mapping on chromosome 9q, and HHT2 caused by mutations in ALK1 located on chromosome 12q. Haploinsufficiency is the underlying mechanism for endoglin and most ALK1 mutations. Such mutations lead to a deficiency in angiogenesis, i.e. the sprouting of new vessels from pre-existing ones. To date, little is still known about the mechanism(s) responsible for lesion formation, development and slow growth. Current models focus on the role that TGF-beta superfamily members, a vast group of multifunctional cytokines, play in endothelial responses to angiogenic stimuli. As both genes seem to act in TGF-beta signal transduction pathways, SMAD proteins are also thought to be involved. There is no clear explanation accounting for the strong variability shown even among members of the same family despite the sharing of the same disease-causing mutation, and why lesions are spatially discrete.
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PMID:Hereditary Haemorrhagic Telangiectasia (HHT): genetic and molecular aspects. 1661 Oct 99

We morphologically examined human brains several years after a territorial ischemic stroke to assess the development of progressing white matter damage and its pathomechanisms. Our investigations focused on the role of TGF-beta, one of the factors whose expression increases after tissue damage, and its receptor endoglin in the propagation of postischemic injury. Examination of the white matter adjacent to the postapoplectic cavity revealed structural changes in the capillary vessels, disturbed microcirculation, and deep endothelial cell damage with DNA fragmentation in the TUNEL reaction. Many oligodendrocytes also revealed DNA damage and an increased expression of caspase-3. In the rarefied white matter, the microvessel immune reaction to TGF-beta was diminished while the expression of endoglin was heterogeneous: absent in some capillaries but increased in others in comparison to the vessels located more peripherally from the cavity and in the control material. We conclude that endoglin and TGF-beta can be involved in the development of the microangiopathy responsible for the propagation of postischemic white matter injury in humans. We suggest that disturbances in endoglin expression can influence TGF-beta signaling and, consequently, vessel structure and function. Pronounced endoglin expression can lead to decreased vessel wall integrity while a lack of the constitutively expressed protein is probably a mirror of deep vessel damage.
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PMID:Role of endoglin and transforming growth factor-beta in progressive white matter damage after an ischemic stroke. 1696 Oct 65

The regulation of macrophage cholesterol homoeostasis is of crucial importance in the pathogenesis of atherosclerosis, an underlying cause of heart attack and stroke. Several recent studies have revealed a critical role for the cytokine TGF-beta (transforming growth factor-beta), a key regulator of the immune and inflammatory responses, in atherogenesis. We discuss here the TGF-beta signalling pathway and its role in this disease along with the outcome of our recent studies on the action of the cytokine on the expression of key genes implicated in the uptake or efflux of cholesterol by macrophages and the molecular mechanisms underlying such regulation.
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PMID:Transforming growth factor-beta-regulated expression of genes in macrophages implicated in the control of cholesterol homoeostasis. 1707 70

Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-beta) regulatory T cells (Tregs) plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-beta, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy and early therapy.
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PMID:Oral tolerance: therapeutic implications for autoimmune diseases. 1716 57


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