Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RelB, originally identified as an immediate early gene product, is a member of the Rel/NF-kappa B family of transcription factors important for the regulation of genes involved in immune and inflammatory processes. RelB by itself is inactive due to its inability to homodimerize and to bind to kappa B sequences. However, in the presence of the Rel/NF-kappa B proteins p50 or p52, RelB is a potent transactivator. Transcriptional activation domains were identified in the NH2 and COOH termini of RelB separated by the approximately 300 amino acids spanning the Rel homogy domain (RHD). The last 120 amino acids of this domain are necessary for the dimerization of RelB and were analyzed in detail by in vitro mutagenesis. RelB forms complexes with p50 and p52 but not with RelA and c-Rel. In contrast to RelA-containing complexes, RelB-containing complexes are only weakly inhibited in their activity by I kappa B alpha. Furthermore, in lymphoid tissues RelB is not associated with I kappa B alpha. In contrast to other members of the Rel/NF-kappa B family, high expression of RelB is limited to interdigitating dendritic cells. Mice with a targeted disrupted relB locus show phenotypic abnormalities including multifocal, mixed inflammatory cell infiltration in several organs, myeloid hyperplasia, splenomegaly due to extramedullary hematopoiesis, and a reduced population of thymic dendritic cells.
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PMID:RelB, a member of the Rel/NF-kappa B family of transcription factors. 907 Mar 78

The proband is a 50 year-old woman born from a consanguineous marriage. She has been suffering from angina pectoris since the age of 38 and underwent coronary bypass surgery for three-vessel disease at 48. The presence of low plasma levels of total cholesterol and high density lipoprotein (HDL) cholesterol (2.4 and 0.1 mmol/l) and apo AI (<15 mg/dl), associated with corneal lesions and a mild splenomegaly suggested the diagnosis of Tangier disease. However, none of the other features of Tangier disease, including hepatomegaly, anemia and peripheral neuropathy, were present. The analysis of the dinucleotide microsatellites located in chromosome 9q31 region demonstrated that the proband was homozygous for the alleles of D9S53, D9S1784 and D9S1832. The mother and son of the proband, both with low levels of HDL cholesterol, shared one of the proband's haplotypes, whereas neither of these haplotypes was present in the normolipidemic proband's sister. The sequence of ATP-binding cassette transporter 1 (ABC1-1) cDNA obtained by reverse transcription-PCR (RT-PCR) of total RNA isolated from cultured fibroblasts showed that the proband was homozygous for a C>T transition in exon 13, which caused a tryptophane for arginine substitution (R527W). This mutation was confirmed by direct sequencing of exon 13 amplified from genomic DNA. It can be easily screened, as the nucleotide change introduces a restriction site for the enzyme Afl III. R527W substitution occurs in a highly conserved region of the NH2 cytoplasmic domain of ABC1 protein. R527W co-segregates with the low HDL phenotype in the family and was not found in 200 chromosomes from normolipidemic individuals.
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PMID:A point mutation in ABC1 gene in a patient with severe premature coronary heart disease and mild clinical phenotype of Tangier disease. 1125 60

Nitrogen-containing bisphosphonates (NBPs) are powerful anti-bone-resorptive drugs, but they frequently induce various inflammatory side effects. Recent clinical applications have disclosed an unexpected new side effect, jaw-bone necrosis and exposure. In vitro studies suggest that the inflammatory effects of NBPs are due to Vgamma2Vdelta2 T-cells, stimulated directly and/or indirectly [the latter via isopentenylpyrophosphate (IPP) in the mevalonate pathway]. Rats and mice, however, lack Vgamma2Vdelta2 T-cells, yet NBPs still induce necrotic and inflammatory reactions. In mice, NBPs induce IL-1-dependent inflammatory reactions, such as inductions of histidine decarboxylase (HDC, the histamine-forming enzyme) in the liver, lung, spleen, and bone marrow, an increase in granulocytic cells in the peritoneal cavity, pleural exudation, and splenomegaly. Here, we examined the involvement of IPP, TNF, macrophages, and T-cells in the inflammatory actions of alendronate (a typical NBP) in mice. Various statins (mevalonate-synthesis inhibitors) suppressed the alendronate-induced HDC inductions, while mevalonate itself augmented such inductions. IPP injection also induced HDC. Like IL-1-deficient mice, TNF-deficient mice were resistant to alendronate-stimulated HDC induction. Alendronate-stimulated HDC inductions were significantly weaker in macrophage-depleted mice and in nude mice than in control mice. Similar, though generally less clear-cut, results were obtained when other alendronate-induced inflammatory reactions were examined. These results suggest that (i) inhibition of the mevalonate pathway causes and/or modifies at least some inflammatory actions of alendronate in mice, (ii) in addition to IL-1, TNF is also involved in the inflammatory actions of alendronate, and (iii) alendronate may act on a variety of cells, including macrophages and T-cells.
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PMID:Histidine decarboxylase-stimulating and inflammatory effects of alendronate in mice: involvement of mevalonate pathway, TNFalpha, macrophages, and T-cells. 1717 81