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

Lipid peroxidation of membranes by oxygen free radicals has been implicated in various disease states. Different antioxidants and iron chelators have been used to reduce lipid peroxidation. Lazaroids have been used for the acute treatment of central nervous system disorders such as trauma and ischemia wherein lipid peroxidative processes take place. In this study we evaluated the effect of lazaroids (U-78518F and U-74389F) on the release of acid phosphatase activity and formation of malondialdehyde (MDA) in rat liver lyosomes subjected to exogenously generated oxygen free radicals. There was a significant increase in the acid phosphatase release and MDA formation in the presence of oxygen free radicals. This was prevented by both the lazaroids. In a separate study the effect of lazaroid U-74389F was seen on the zymosan-stimulated polymorphonuclear (PMN) leukocyte-derived chemiluminescence. The PMN leukocyte chemiluminescent activity was attenuated by the lazaroid in a dose-dependent manner. These studies suggest that lazaroids may inhibit lipid peroxidation and stabilize the membrane.
Mol Cell Biochem 1994 Jul 27
PMID:Protective effects of lazaroids against oxygen-free radicals induced lysosomal damage. 784 65

There is a dearth of good mouse models for central nervous system (CNS) disorders. However, the development of gene-targeted technology and the recognition of the importance of the mouse as a model organism have led to the development of a range of behavioural tests for mice. Spontaneous mutations in mice have already provided important information about the role of novel gene products in disorders such as epilepsy and deafness. This has provided the impetus to the establishment of large-scale mutagenesis programmes to generate new mutations. Tests of sensory and motor function have previously been most frequently used as these are simple to perform and the phenotypes are relatively obvious. Subtle phenotypes, of relevance to pyschiatric disorders such as anxiety and schizophrenia, can be detected using more complex tests. Screens such as prepulse inhibition and startle have been adapted for mice and these can be run with relatively high throughput using fully automated equipment. Other behaviours such as sleep and circadian rhythms, learning and memory and nociception can also be assessed. New technological advances in non-invasive imaging and neurochemical analyses have meant that these techniques can be readily applied to mouse phenotyping. The use of these screens together with mutagenesis is already beginning to increase the numbers of mouse models of potential relevance to CNS diseases.
Hum Mol Genet 2000 Apr 12
PMID:Towards new models of disease and physiology in the neurosciences: the role of induced and naturally occurring mutations. 1076 12

By optimizing the previously described strategy for obtention of spheres enriched in PSA-NCAM+ precursors, we prepared PSA-NCAM-immunoselected cell populations from cerebral hemispheres of neonatal MBP-LacZ transgenic mice. These cells expressed Nestin, exhibited clonal expansion potential and formed spheres, which were initially enriched in PSA-NCAM+ cells but became enriched in GD3+ oligodendrocyte progenitors after 1 week in B104 contionned medium. One month after their periventricular transplantation into the brain of wild-type and/or shiverer newborn mice, cells from PSA-NCAM+ spheres exhibited a higher rostral migration potential than cells from GD3+ spheres, and clearly contributed to myelination in the olfactory bulb. In shiverer hosts, both sphere populations generated oligodendrocytes with similar myelination potential. In addition PSA-NCAM+ sphere cells generated GFAP+ astrocytes and NeuN+ neurons, depending on their site of insertion. These results evidence the high plasticity of newborn PSA-NCAM+ neural precursors and suggest that they are promising tools for cell therapy of CNS diseases, including myelin disorders.
Mol Cell Neurosci 2001 Jun
PMID:Migration and multipotentiality of PSA-NCAM+ neural precursors transplanted in the developing brain. 1141 88

The discovery, design and evaluation of new medicines is critically dependent on the elucidation of protein mechanisms involved in human diseases. Since the proteome of a cell or tissue is not a simple reflection of its transcriptome, direct protein-based analysis is needed. Advances in proteomic technologies are improving the analysis of membrane proteins and signaling complexes with increased speed and molecular detail. Changes in protein isoforms due to post-translational modifications, such as phosphorylation induced by cell signaling events and alternative splice forms of receptors, may be mapped to an altered protein expression pattern in clinically relevant cell populations with a causative or diagnostic disease link. A CNS proteome database derived from primary human tissues may avoid ambiguities of experimental models. It will also accelerate the development of more specific diagnostic and prognostic disease markers as well as new selective therapeutics. Proteomics is also being applied to resolve in silico gene prediction uncertainties by direct open reading frame verification. These advances hold great promise for improvements in the understanding, diagnosis and therapy of central nervous system disorders.
Curr Opin Mol Ther 2002 Jun
PMID:Proteomic approaches to central nervous system disorders. 1213 11

PEC-60 is a 60-residue peptide originally isolated from pig intestine. It inhibits glucose-induced insulin secretion from perfused pancreas in a hormonal manner and also has biological activity in the immune system. PEC-60-like immunoreactive material has been reported in catecholamine neurons of the central and peripheral nervous systems, but the peptide has not been identified from that material. We have now isolated PEC-60 from pig and rat brains with a method that combines column purification procedures with the specificity of a radioimmunoassay and the sensitivity of mass spectrometry to directly identify the peptide. The results show that PEC-60, like many other peptides, is expressed in the gastrointestinal tract and the central nervous system. The specific regional brain distribution and interaction with classical neurotransmitters raise the possibility that PEC-60 may play a role in the central nervous system disorders involving dopamine dysregulation.
Cell Mol Life Sci 2003 Feb
PMID:Identification of the bioactive peptide PEC-60 in brain. 1267

Gene therapy to treat primary and secondary CNS diseases, including neuro-AIDS, has not yet been effective. New approaches to delivering therapeutic genes to the central nervous system are therefore required. Recombinant SV40 vectors (rSV40) transduce both dividing and quiescent cells efficiently, and so we tested them for their ability to deliver anti-HIV-1 transgenes to terminally differentiated human NT2-derived neurons (NT2-N). These vectors transduced >95% of immature as well as mature human neurons efficiently, without detectable toxicity and without requiring selection. rSV40 gene delivery was stable to retinoic acid-induced neuronal differentiation. The rSV40 vectors used in these studies, SV(RevM10) and SV(AT), respectively carried the cDNAs for RevM10, a trans-dominant mutant of HIV-1 Rev, and human alpha1-antitrypsin. As measured by HIV-1 p24 antigen assays and by immunostaining for gp120, NT2-N treated with these vectors strongly resisted challenge with different strains of HIV-1. Protection from HIV replication and HIV-induced cytotoxicity was conferred by SV(AT) and SV(RevM10) and remained constant throughout retinoic acid-induced neuronal differentiation and for the duration of these studies (> or =11 weeks). rSV40 transduction of human neurons might therefore be a practicable approach to gene delivery for the treatment of CNS diseases, including neuro-AIDS.
Mol Ther 2003 Jun
PMID:Inhibiting AIDS in the central nervous system: gene delivery to protect neurons from HIV. 1278 54

The blood-brain barrier is the main obstacle to efficient delivery of therapeutic reagents, including viral vectors, into the central nervous system (CNS) for treating global CNS diseases. In this study, the effects of mannitol infusions on global brain gene expression of a novel AAV vector were examined after intravenous (i.v.) or intracisternal injection. Initially, a self-complementary adeno-associated virus serotype 2 vector (scAAV) was compared to traditional single-stranded AAV2 vector for reporter gene expression in the brain of adult mice with or without pretreatment of an i.v. mannitol infusion. One to two months postinjection, analysis of vector-transduced green fluorescent protein (GFP) expression in the brain revealed that vector delivery to the CNS via i.v. injection required pretreatment with mannitol. This expression was observed only when scAAV vectors were used. Using these conditions, transgene expression was observed in various neurons and glial cells throughout the brain. The peripherally administered scAAV vectors also transduced the cells in multiple somatic tissues with efficient expression in liver (20-30% of hepatocytes), but was less efficient in other somatic tissues. Intracisternal injection of scAAV vector produced a broad and intense transgene expression in both neurons and glial cells in the CNS of injected mice ranging from the olfactory area to the brain stem and spinal cord. More than 50% of the Purkinje cells in the cerebellum expressed GFP. Intravenous infusion of mannitol before intracisternal injection of the scAAV vector enhanced the dispersion of the vector in the CNS. Further optimization of these steps combining peripheral and intracisternal scAAV gene delivery should facilitate the development of treatments for global CNS diseases, especially diseases involving both the somatic system and the CNS, such as lysosomal storage disorders.
Mol Ther 2003 Dec
PMID:Self-complementary adeno-associated virus serotype 2 vector: global distribution and broad dispersion of AAV-mediated transgene expression in mouse brain. 1466 93

Brain transplantation of neural precursor cells (NPCs) has been proposed to enhance CNS regeneration. As the pathogenesis of most acute CNS diseases involves an inflammatory component, we studied whether NPC transplantation affects brain inflammation. Newborn rat multipotential NPCs were transplanted intraventriculary into acute experimental allergic encephalomyelitis (EAE) rats, a model for disseminated brain inflammation. Cells migrated into inflamed white matter and differentiated into glial cells. NPC transplantation attenuated the clinical severity of EAE and the brain inflammation, indicated by reduction in perivascular infiltrates and decreased expression of ICAM-1 and LFA-1. NPCs inhibited basal proliferation and proliferative responses to Concavalin-A and to MOG peptide of EAE rat-derived lymphocytes in vitro. Purified astrocytes inhibited lymphocyte proliferation in vitro, but did not migrate into EAE brains in vivo, and did not reduce EAE severity or brain inflammation. Thus, transplanted NPCs attenuate acute EAE via an anti-inflammatory mechanism which depends on cell ability to migrate into inflamed brain tissue.
Mol Cell Neurosci 2003 Dec
PMID:Intraventricular transplantation of neural precursor cell spheres attenuates acute experimental allergic encephalomyelitis. 1469 70

The induction of synthesis or release of endogenous neurotrophic factors in the brain by low-molecular-weight drugs could be a feasible alternative for the direct administration of neurotrophic factors for the treatment of central nervous system disorders. Recent data suggest that several drugs already in clinical use increase the synthesis, release, or signaling of neurotrophins. Antidepressant drugs increase the synthesis and signaling of brain-derived neurotrophic factor (BDNF), and BDNF signaling appears to be both sufficient and necessary for the antidepressant-induced behavioral effects. Furthermore, neurotrophins and other neurotrophic factors play a role in the acute and chronic responses produced by addictive drugs. Moreover, several neuroprotective drugs influence neurotrophin synthesis or signaling, although the significance of these effects is still unclear. These findings reveal a wider role for neurotrophic factors in drug action than has previously been expected, and they suggest that neurotrophin-induced trophic responses in neuronal connectivity and plasticity may be involved in the mechanism of action of several classes of CNS drugs. Improved assay systems are needed for the systematic screening of the effects of putative neuroprotective drugs on the synthesis, release, and signaling of neurotrophic factors, and for the evaluation of the functional role of these factors in the action of novel drug candidates.
Mol Neurobiol 2004 Jun
PMID:Neurotrophins as mediators of drug effects on mood, addiction, and neuroprotection. 1518 Dec 40

Phenotypes produced by expression of human amyloid precursor protein (APP) transgenes vary depending on the genetic background of the mouse. FVB/N mice overexpressing human APP695 develop a central nervous system disorder and die prematurely, precluding development of Abeta peptide amyloid plaques. 129S6 mice are resistant to the lethal effects of APP overexpression, allowing sufficient levels of Abeta expression for the development of amyloid plaques and age-dependent memory deficits. To identify the genes that determine susceptibility or resistance to APP we analyzed crosses involving FVB/NCr and 129S6.Tg2576 mice that overexpress 'Swedish' mutant (K670N, M671L) APP695. APP transgene-positive FVB129S6F1 (F1) mice are resistant to the lethal effects of APP overexpression, so FVBxF1 backcross and F2 intercross offspring were produced. Analysis of age of death as a quantitative trait revealed significant linkage to loci on proximal chromosome 14 and on chromosome 9; 129S6 alleles protect against the lethal effects of APP. Within the chromosome 14 interval are segments homologous to regions on human chromosome 10 that have been linked to late onset Alzheimer's disease or to levels of Abeta peptide in plasma. However, analysis of plasma Abeta peptide concentrations at 6 weeks in backcross offspring produced no significant linkage. Similarly, elevation of human Abeta peptide concentrations by expression of mutant presenilin transgenes did not increase the proportion of mice dying prematurely, suggesting that early death reflects effects of APP or fragments other than Abeta.
Hum Mol Genet 2004 Sep 15
PMID:Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression. 1525 13


1 2 3 4 5 6 7 8 9 10 Next >>