Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have analysed HLA class II gene-based substructure of the Sardinian population in order to evaluate the possible influence of this parameter in the mapping of common disease loci using association methods. We first examined the distribution of the HLA-DRB1-DQA1-DQB1 haplotypes in 631 newborns from seven different regions of the island, and found that the most frequent haplotypes were uniformly distributed in all regions, but at frequencies unique to Sardinia. Other haplotypes, common in other white European populations, are consistently rare or absent across the whole island. Analysis of molecular variance (AMOVA) showed a very low degree of genetic differentiation between the coastal regions, which have suffered repeated invasions over many years, and the most internal and isolated part of the island. This suggests that there has been little genetic flow from the various populations that have invaded the island during the last 3000 years and that Sardinia is a relatively homogeneous population. The validity of these unrelated control HLA haplotype frequencies and our claim of homogeneity were established by demonstrating the near identity of the affected family-based control (AFBAC) HLA haplotype frequencies in 243 type 1 diabetes and 495 multiple sclerosis families from Sardinia and those of the unrelated controls. These results indicate that robust case-control studies can be carried out in Sardinia offering cost efficiency over certain family-based designs.
Hum Mol Genet 2000 Dec 12
PMID:The inter-regional distribution of HLA class II haplotypes indicates the suitability of the Sardinian population for case-control association studies in complex diseases. 1111 39

RANTES is a beta-family chemokine with potent chemoattractant activity for lymphocytes and monocytes that are implicated in the pathogenesis of multiple sclerosis (MS) lesions. Glial cells have been shown to produce RANTES in response to stimulation with Th1 cytokines (IFN-gamma, TNF-alpha, and IL-1beta) in vitro, and they may be a major source of RANTES production within diseased brain. This study was undertaken to investigate the mechanism underlying the effect of the Th1 cytokines on the induction of RANTES in a model system for human astroglia. We show that IFN-gamma has a synergistic effect with TNF-alpha or IL-1beta on RANTES mRNA and chemokine production in this system. We further show that the combination treatment of IFN-gamma and TNF-alpha, or IFN-gamma and IL-1beta induced 3-fold higher levels of RANTES gene transcription than seen with either TNF-alpha or IL-1beta alone, as measured by in vitro nuclear transcript elongation assays. In addition, we found that IFN-gamma decreased the rate of degradation of RANTES mRNA caused by TNF-alpha or IL-1beta. The t(1/2) of RANTES mRNA was 25+/-1 h in the presence of both IFN-gamma and TNF-alpha, as compared to a t(1/2) of 15+/-1 h in the presence of TNF-alpha alone. This 10 h difference represents an approximate 70% increment in RANTES mRNA half-life. Thus, these results suggest that both increased RANTES gene transcription and increased RANTES mRNA stability may account for the synergistic effect of Th1 cytokines on the up-regulation of RANTES expression in human astroglial cells.
Int J Mol Med 2001 Feb
PMID:Mechanisms underlying the synergistic effect of Th1 cytokines on RANTES chemokine production by human glial cells. 1117 24

We have studied developing oligodendrocytes in tissue sections as they initiate myelination and have found that the transition from premyelinating oligodendrocytes into myelin-bearing cells is accompanied by a dramatic upregulation in expression of the RNA binding QKI proteins. We show that in mature oligodendrocytes in culture, the localization of cytoplasmic QKI isoforms requires an intact cytoskeleton. Together with previous observations, this indicates that cytoplasmic QKI proteins facilitate movement of mRNAs to myelin via the cytoskeleton. In the adult rat brain, we found that a subset of oligodendrocytes displays characteristics of actively myelinating cells seen during development, i.e., connections to myelin sheaths and elevated levels of QKI proteins and also MAP1B. These observations suggest that instead of merely maintaining myelin, oligodendrocytes in the normal adult CNS are capable of responding to demands for new myelin sheaths. This has important implications for the prospect of repair of myelin in demyelinating conditions such as multiple sclerosis.
Mol Cell Neurosci 2001 Feb
PMID:Expression of QKI proteins and MAP1B identifies actively myelinating oligodendrocytes in adult rat brain. 1117 67

Interferon-gamma (IFN-gamma), traditionally associated with a variety of physiological and pathological processes of the immune system, manifests an array of biological effects on cells of the nervous system. Clinical and in vitro studies support a key role for IFN-gamma in the pathogenesis of immune-mediated demyelinating disorders such as multiple sclerosis (MS). To investigate the role of this cytokine within the central nervous system (CNS), transgenic mice were derived in which IFN-gamma transgene expression was selectively targeted to astrocytes, a potentially important cellular source of this cytokine. Here we report that astrocyte-directed expression of IFN-gamma results in regional hypomyelination and selective disruption of brain histogenesis, which included severe cerebellar and hippocampal dysplasia. Transgenic mice were markedly ataxic and the majority died prior to reaching sexual maturity. This study demonstrates that astrocyte-directed expression of IFN-gamma profoundly affects the differentiation and morphogenesis of the brain and provides additional evidence that this cytokine has deleterious consequences on myelin-producing cells, independent of the cellular source.
J Mol Neurosci 2000 Aug
PMID:Regional hypomyelination and dysplasia in transgenic mice with astrocyte-directed expression of interferon-gamma. 1121 Dec 36

RANTES is a basic 8-kDa polypeptide of the C-C chemokine subfamily with strong chemoattractant activity for T lymphocytes and monocytes/macrophages that are implicated in the pathogenesis of multiple sclerosis (MS) lesions. Glatiramer acetate is a drug recently approved for the treatment of MS. We therefore investigated the effect of glatiramer acetate on RANTES expression in glial cells in vitro. Treatment of human U-251 MG astroglial cells with glatiramer acetate blocks IL-1beta-induced RANTES chemokine production in a dose- and time-dependent manner. Glatiramer acetate also decreased steady-state levels of RANTES mRNA in these cells, which was attributable to reduced transcription, as assessed by nuclear run-on assays. In addition, we showed that NF-kappaB may be the transcriptional activator responsible for the IL-1beta-mediated RANTES gene expression in this system. Our data indicated that the IL-1beta-induced increase in RANTES was associated with an increase in in vitro nuclear extract binding activity specific for the NF-kappaB site in the promoter region of the RANTES gene. The increases in RANTES mRNA and protein expression were suppressed by the NF-kappaB inhibitors gliotoxin, isohelenin, and pyrrolidine dithiocarbamate (PDTC). Furthermore, we demonstrated that the increase in NF-kappaB DNA-binding activity was prevented by pretreatment with glatiramer acetate or the NF-kappaB inhibitors. Our results suggest that glatiramer acetate may inhibit IL-1beta-stimulated RANTES expression in human glial cells by blocking NF-kappaB activation, thus identifying part of the molecular basis for its anti-inflammatory and immunosuppressive effects in demyelinating diseases.
Brain Res Mol Brain Res 2001 Feb 19
PMID:Glatiramer acetate blocks interleukin-1-dependent nuclear factor-kappaB activation and RANTES expression in human U-251 MG astroglial cells. 1122 59

Cannabinoids, the active components of Cannabis sativa (marijuana), and their derivatives produce a wide spectrum of central and peripheral effects, some of which may have clinical application. The discovery of specific cannabinoid receptors and a family of endogenous ligands of those receptors has attracted much attention to cannabinoids in recent years. One of the most exciting and promising areas of current cannabinoid research is the ability of these compounds to control the cell survival/death decision. Thus cannabinoids may induce proliferation, growth arrest, or apoptosis in a number of cells, including neurons, lymphocytes, and various transformed neural and nonneural cells. The variation in drug effects may depend on experimental factors such as drug concentration, timing of drug delivery, and type of cell examined. Regarding the central nervous system, most of the experimental evidence indicates that cannabinoids may protect neurons from toxic insults such as glutamaergic overstimulation, ischemia and oxidative damage. In contrast, cannabinoids induce apoptosis of glioma cells in culture and regression of malignant gliomas in vivo. Breast and prostate cancer cells are also sensitive to cannabinoid-induced antiproliferation. Regarding the immune system, low doses of cannabinoids may enhance cell proliferation, whereas high doses of cannabinoids usually induce growth arrest or apoptosis. The neuroprotective effect of cannabinoids may have potential clinical relevance for the treatment of neurodegenerative disorders such as multiple sclerosis, Parkinson's disease, and ischemia/stroke, whereas their growth-inhibiting action on transformed cells might be useful for the management of malignant brain tumors. Ongoing investigation is in search for cannabinoid-based therapeutic strategies devoid of nondesired psychotropic effects.
J Mol Med (Berl) 2001
PMID:Control of the cell survival/death decision by cannabinoids. 1126 8

Multiple sclerosis is a chronic inflammatory disease of the nervous system in which a T-cell-mediated inflammatory process is associated with destruction of myelin sheaths. Although demyelination is the primary event, axons are also destroyed in the lesions, and the loss of axons correlates with permanent functional deficit. Here, we discuss evidence that demyelination and axonal destruction follow different pathogenetic pathways in subgroups of patients. This might, at least in part, explain the heterogeneity in genetic susceptibility, clinical presentation and response to treatment observed between individuals.
Trends Mol Med 2001 Mar
PMID:Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. 1128 82

RANTES is a C-C (beta)-family chemokine that is implicated in the migration of peripheral blood leukocytes to brain lesions in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS). Glial cells are active participants in the inflammatory response in the CNS, and they have been shown to respond to and produce a number of cytokines and chemokines in vivo and in vitro. Recently, we have shown inducibility of RANTES gene expression by TNF-alpha in human astrocytic cells. Therefore, the goal of the current study was to investigate the transcription activating factor involved in the process. We found that the induction of RANTES mRNA and protein by TNF-alpha in human astrocytic cells is associated with increased NF-kappaB DNA-binding activity. p65 and p50 were determined to be the components of the activated NF-kappaB transcription factor complex by supershift assay. In addition, the blockade of NF-kappaB activation by three known NF-kappaB inhibitors markedly reduced the TNF-alpha-induced RANTES expression at the mRNA and protein levels. Furthermore, the reduction in NF-kappaB binding activity to the promoter of the human RANTES gene caused by the NF-kappaB inhibitors parallels a decrease in RANTES expression in these cells. Our data suggest that NF-kappaB may mediate the induction of RANTES gene expression, in human glial cells, through its cognate cis-acting element.
Int J Mol Med 2001 May
PMID:Induction of RANTES chemokine expression in human astrocytic cells is dependent upon activation of NF-kappaB transcription factor. 1129 16

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by destruction of myelin. Recent studies have indicated that axonal damage is involved in the pathogenesis of the progressive disability of this disease. To study the role of axonal damage in the pathogenesis of MS-like disease induced by myelin oligodendrocyte glycoprotein (MOG), we compared experimental autoimmune encephalomyelitis (EAE) in wild-type (WT) and transgenic mice expressing the human bcl-2 gene exclusively in neurons under the control of the neuron-specific enolase (NSE) promoter. Our study shows that, following EAE induction with pMOG 35-55, the WT mice developed significant clinical manifestations with complete hind-limb paralysis. In contrast, most of the NSE-bcl-2 mice (16/27) were completely resistant, whereas the others showed only mild clinical signs. Histological examination of CNS tissue sections showed multifocal areas of perivascular lymphohistiocytic inflammation with loss of myelin and axons in the WT mice, whereas only focal inflammation and minimal axonal damage were demonstrated in NSE-bcl-2 mice. No difference could be detected in the immune potency as indicated by delayed-type hypersensitivity (DTH) and T-cell proliferative responses to MOG. We also demonstrated that purified synaptosomes from the NSE-bcl-2 mice produce significantly lower level of reactive oxygen species (ROS) following exposure to H2O2 and nitric oxide (NO) than WT mice. In conclusion, we demonstrated that the expression of the antiapoptotic gene, bcl-2, reduces axonal damage and attenuates the severity of MOG-induced EAE. Our results emphasize the importance of developing neuroprotective therapies, in addition to immune-specific approaches, for treatment of MS.
J Mol Neurosci 2000 Dec
PMID:Mice overexpressing Bcl-2 in their neurons are resistant to myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). 1130 81

Multiple sclerosis (MS) is believed to be an autoimmune process occurring in genetically susceptible individuals after an appropriate environmental exposure. We have exploited the homogeneous Afrikaner population of European ancestry to investigate the likelihood that iron dysregulation, in association with infectious and/or autoimmune disease susceptibility, may underlie the MS phenotype in a subgroup of patients. The functional Z-DNA forming repeat polymorphism of the natural resistance-associated macrophage protein-1 (NRAMP1) gene was analyzed in 104 patients diagnosed with MS and 522 Caucasian controls. A family-based control group consisting of 32 parental alleles not transmitted to MS offspring was additionally studied to exclude the likelihood of population substructures. Statistically significant differences in allelic distribution were observed between the patient and control samples drawn from the same population (P < 0.01). Evidence is furthermore provided that alleles considered to be detrimental in relation to autoimmune disease susceptibility may be maintained in the population as a consequence of improved survival to reproductive age following infectious disease challenge. Although it remains to be determined whether the disease phenotype in MS patients with allele 5 of the NRAMP1 promoter polymorphism is directly related to dysregulation of iron or modified susceptibility to viral infection and/or autoimmunity, a combination of these processes most likely underlies the disease phenotype in these patients. In view of the emerging role of polymorphic variants in complex diseases and minimizing of possible confounding factors in this association study, we conclude that allelic variation in the NRAMP1 promoter may contribute significantly to MS susceptibility in the South African Caucasian population.
Blood Cells Mol Dis
PMID:Analysis of the NRAMP1 gene implicated in iron transport: association with multiple sclerosis and age effects. 1135 58


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