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At least 1,423 records · Page 79Linked to original sources
PubMed2005

Regulation of the human cyclin C gene via multiple vitamin D3-responsive regions in its promoter.

The candidate human tumor suppressor gene cyclin C is a primary target of the anti-proliferative hormone 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3], but binding sites for the 1alpha,25(OH)2D3 receptor (VDR), so-called 1alpha,25(OH)2D3 response elements (VDREs), have not yet been identified in the promoter of this gene. We screened various cancer cell lines by quantitative PCR and found that the 1alpha,25(OH)2D3 inducibility of cyclin C mRNA expression, in relationship with the 24-hydroxylase (CYP24) gene, was best in MCF-7 human breast cancer cells. To characterize the molecular mechanisms, we analyzed 8.4 kb of the cyclin C promoter by using chromatin immunoprecipitation assays (ChIP) with antibodies against acetylated histone 4, VDR and its partner receptor, retinoid X receptor (RXR). The histone 4 acetylation status of all 23 investigated regions of the cyclin C promoter did not change significantly in response to 1alpha,25(OH)2D3, but four independent promoter regions showed a consistent, 1alpha,25(OH)2D3-dependent association with VDR and RXR over a time period of 240 min. Combined in silico/in vitro screening identified in each of these promoter regions a VDRE and reporter gene assays confirmed their functionality. Moreover, re-ChIP assays monitored simultaneous association of VDR with RXR, coactivator, mediator and RNA polymerase II proteins on these regions. Since cyclin C protein is associated with those mediator complexes that display transcriptional repressive properties, this study contributes to the understanding of the downregulation of a number of secondary 1alpha,25(OH)2D3-responding genes.

Acetylation↗
PubMed2006

Functional interaction between the homeoprotein CDX1 and the transcriptional machinery containing the TATA-binding protein.

We have previously reported that the CDX1 homeoprotein interacts with the TATA-box binding protein (TBP) on the promoter of the glucose-6-phosphatase (G6Pase) gene. We show here that CDX1 interacts with TBP via the homeodomain and that the transcriptional activity additionally requires the N-terminal domain upstream of the homeodomain. CDX1 interacting with TBP is connected to members of the TFIID and Mediator complexes, two major elements of the general transcriptional machinery. Transcription luciferase assays performed using an altered-specificity mutant of TBP provide evidence for the functionality of the interaction between CDX1 and TBP. Unlike CDX1, CDX2 does not interact with TBP nor does it transactivate the G6Pase promoter. Swapping experiments between the domains of CDX1 and CDX2 indicate that, despite opposite functional effects of the homeoproteins on the G6Pase promoter, the N-terminal domains and homeodomains of both CDX1 and CDX2 have the intrinsic ability to activate transcription and to interact with TBP. However, the carboxy domains define the specificity of CDX1 and CDX2. Thus, intra-molecular interactions control the activity and partner recruitment of CDX1 and CDX2, leading to different molecular functions.

Binding Sites↗
PubMed2006

Beta-Catenin stabilizes cyclooxygenase-2 mRNA by interacting with AU-rich elements of 3'-UTR.

Cyclooxygenase-2 (COX-2) mRNA is induced in the majority of human colorectal carcinomas. Transcriptional regulation plays a key role in COX-2 expression in human colon carcinoma cells, but post-transcriptional regulation of its mRNA is also critical for tumorigenesis. Expression of COX-2 mRNA is regulated by various cytokines, growth factors and other signals. beta-Catenin, a key transcription factor in the Wnt signal pathway, activates transcription of COX-2. Here we found that COX-2 mRNA was also substantially stabilized by activating beta-catenin in NIH3T3 and 293T cells. We identified the beta-catenin-responsive element in the proximal region of the COX-2 3'-untranslated region (3'-UTR) and showed that beta-catenin interacted with AU-rich elements (ARE) of 3'-UTR in vitro and in vivo. Interestingly, beta-catenin induced the cytoplasmic localization of the RNA stabilizing factor, HuR, which may bind to beta-catenin in an RNA-mediated complex and facilitate beta-catenin-dependent stabilization of COX-2 mRNA. Taken together, we provided evidences for beta-catenin as an RNA-binding factor and a regulator of stabilization of COX-2 mRNA.

3' Untranslated Regions↗
PubMed1997

The clinical spectrum of shunt nephritis.

BACKGROUND: Shunt nephritis is an immune-complex-mediated glomerulonephritis (GN) associated with chronically infected ventriculoatrial shunts inserted for treatment of hydrocephalus. METHODS: Six patients aged 5-22 years with shunt nephritis are reported who have been observed between 1971 and 1994. The clinical course and long-term outcome are analysed in relation to the time of diagnosis and renal histopathology. RESULTS: The time of diagnosis of shunt nephritis ranged from 0.3 to 4.5 years after the last shunt operation. Diagnosis was delayed up to 1.5 years after the first clinical manifestations. All patients had signs of infection, i.e. recurrent fever, hepatosplenomegaly, anaemia, and cerebral symptoms. Renal manifestations consisted of haematuria (macroscopic in 3 patients), proteinuria (heavy in 5), renal insufficiency (4) and hypertension (2). Decreased C3 levels, cryoglobulins, and antinuclear factors were frequent. Cultures of blood and cerebrospinal fluid provided growth mainly of S. epidermidis. Renal biopsy revealed endocapillary GN (1), membranoproliferative GN (1) and endocapillary/extracapillary GN with crescents (2). All patients received antibiotics i.v. Complete recovery was observed in three of four patients in whom the shunt was totally removed, supported by transient external drainage of cerebrospinal fluid, and followed by placement of a ventriculoperitoneal shunt. One child with delayed diagnosis, presenting with a serum creatinine of 3.2 mg/dl, hypertension, and severe scarring on renal biopsy, rapidly progressed to irreversible ESRD within 5 months. Two patients without and only partial removal of the shunt died subsequently from sepsis. CONCLUSIONS: The renal outcome of shunt nephritis is good if early diagnosis and treatment is provided including i.v. antibiotics and total removal of the infected shunt. The possible progression to ESRD requires frequent nephrological monitoring of patients with ventriculoatrial shunts.

Adult↗
PubMed2002

Contribution of genetically engineered animals to the analyses of complement in the pathogenesis of nephritis.

The complement system is indispensable for host defence. Unregulated activation, however, is related to various diseases. In order to elucidate the significance of complement, methodology that disrupts the complement system is essential. Advances in molecular genetics made direct modulations of the genes of complement components and their regulatory proteins feasible. One method is disruption of genes that encode complement components. Several studies have been conducted with these mice in models such as nephrotoxic serum (NTS) nephritis, ischaemia reperfusion and immune complex-mediated glomerulonephritis. These studies all showed that depletion of complement components ameliorated the severity of the diseases. Complement regulatory protein serves a regulatory role in the complement system. Genetically engineered animals that overexpress these proteins have been employed to elucidate their biological roles. Mice overexpressing soluble complement regulatory proteins were protected from the lesion of both NTS and the glomerular endothelial injury model. In contrast, knockout mice that lack expression of decay-accelerating factor (DAF), a complement regulatory protein, developed severe glomerular lesions when subnephritogenic doses of NTS were administered. These genetically engineered animals shed light on the mechanism of initiation and progression of kidney disease.

Animals↗
PubMed2003

Glomerular expression of C-C chemokines in different types of human crescentic glomerulonephritis.

BACKGROUND: Crescentic glomerulonephritis (CGN) presents a rapidly progressive glomerulonephritis clinically, in which macrophages play a crucial role in the pathogenesis. However, the precise molecular mechanism of macrophage recruitment and activation has not been fully elucidated. C-C chemokines, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha and beta (MIP-1alpha and MIP-1beta), are major chemoattractants for macrophages. We attempted to study the expression of C-C chemokines and their correlation with CD68-positive macrophages in crescentic glomeruli to investigate further their possible roles in crescent formation and progression to fibrosis in different types of human CGN. METHODS: The expression of MCP-1, MIP-1alpha, MIP-1beta and CD68 was detected in glomeruli with different forms of crescents (cellular, fibrocellular and fibrous crescents) by immunohistochemistry in serial sections of renal biopsies taken from 32 patients with biopsy-proven CGN including eight patients with anti-glomerular basement membrane (GBM) disease (type I CGN), 12 patients with immune complex-mediated CGN (type II CGN) and another 12 patients with pauci-immune CGN (type III CGN) enrolled in this study. Eight normal human kidneys were obtained from cadaveric renal transplant donors whose kidneys were technically unsuitable for transplantation, serving as controls. RESULTS: MCP-1, MIP-1alpha, MIP-1beta and CD68 were undetectable in glomeruli of normal kidney. In crescentic biopsies, MCP-1, MIP-1alpha, MIP-1beta and CD68 were detected in fibrocellular crescents and were even more prominent in cellular crescents, but were undetectable in fibrous crescents. Using consecutive sections for staining, it was demonstrated that a high proportion of infiltrating CD68-positive macrophages, mainly localized to the area of the expression of chemokines, were MCP-1, MIP-1alpha and MIP-1beta positive in crescents. Chemokines were expressed mainly by CD68-positive macrophages and parietal epithelial cells in crescents. The number of MCP-1- and MIP-1alpha-positive cells in glomeruli with cellular crescents was positively correlated with the number of CD68-positive cells (r = 0.568 and 0.749, respectively, both P < 0.01). The number of MCP-1- and MIP-1alpha-positive cells and the incidence of Bowman's capsule rupture in glomeruli of patients with type I CGN were higher than those of type II and type III CGN. CONCLUSIONS: These observations suggest that the expressed C-C chemokines, MCP-1, MIP-1alpha and MIP-1beta, may mediate the inflammatory process of crescent formation and progression to fibrosis. The strong correlation of MCP-1 and MIP-1alpha with infiltrating macrophages within glomeruli with cellular crescents suggested that these chemokines might be of particular importance for macrophage recruitment to this site. MCP-1 and MIP-1alpha were correlated to type I CGN with its more severe inflammatory course and worse prognosis. The variance of glomerular expression of C-C chemokines may contribute to the difference in histopathological features and prognosis in these three types of CGN.

Adolescent↗
PubMed1995

Inner ear involvement in mixed cryoglobulinaemia patients.

In order to evaluate the nature and prevalence of audiovestibular disturbances in mixed cryoglobulinaemia (MC), 32 consecutive MC patients were studied by a wide audiological and vestibular examination. Pure tone audiometry, impedance audiometry, brainstem response audiometry and vestibular function were performed. Patients with a previous history of ear damage due to other well-known agents were excluded from the study. In MC patients we found a rather frequent audiovestibular involvement (34.3%). Bilateral sensorineural hearing loss was found in seven MC patients (22%) and altered vestibular function test values in other seven subjects (22%). Moreover, anamnestic and clinical data revealed a high incidence of benign positional paroxysmal vertigo in our MC series. We can suppose that immune complex-mediated microvascular involvement of the labyrinthine vessels may be responsible for inner ear damage in MC. Thus, audiovestibular disturbances may be included among various organ involvement of the MC.

Adult↗
PubMed2005

B cells: a fundamental role in the pathogenesis of rheumatoid arthritis?

The role of T cells in the pathogenesis of RA is well established, whereas to date the precise contribution of B cells is less well defined. B cells have many potential key roles: they can act as antigen-presenting cells, secrete pro-inflammatory cytokines (including tumour necrosis factor-alpha), produce rheumatoid factor (RF) and other autoantibodies and activate T cells. B cells act as antigen-presenting cells by processing and presenting antigenic peptides to T cells, which become activated, proliferate and exert pro-inflammatory activities. RF may also play a role in perpetuating B-cell activation and antigen presentation to T cells, thus leading to sustained production of RF. This, combined with RF immune-complex-mediated complement activation, may contribute to the sustained inflammatory response. Studies have shown that the use of an anti-CD20 monoclonal antibody in RA depletes circulating B cells, resulting in improvement in disease activity for up to 1 yr. It is thus evident that B cells play a central role in the pathophysiology of RA and therefore merit further investigation as a therapeutic target.

Arthritis, Rheumatoid↗
PubMed1999

Expression of trophinin, tastin, and bystin by trophoblast and endometrial cells in human placenta.

Trophinin, tastin, and bystin comprise a complex mediating a unique homophilic cell adhesion between trophoblast and endometrial epithelial cells at their respective apical cell surfaces. In this study, we prepared mouse monoclonal antibodies specific to each of these molecules. The expression of these molecules in the human placenta was examined immunohistochemically using the antibodies. In placenta from the 6th week of pregnancy, trophinin and bystin were found in the cytoplasm of the syncytiotrophoblast in the chorionic villi, and in endometrial decidual cells at the utero placental interface. Tastin was exclusively present on the apical side of the syncytiotrophoblast. Tissue sections were also examined by in situ hybridization using RNA probes specific to each of these molecules. This analysis showed that trophoblast and endometrial epithelial cells at the utero placental interface express trophinin, tastin, and bystin. In wk 10 placenta, trophinin and bystin were found in the intravillous cytotrophoblast, while tastin was not found in the villi. After wk 10, levels of all three proteins decreased and then disappeared from placental villi.

Antibodies, Monoclonal↗
PubMed2000

Dopamine transporter proline mutations influence dopamine uptake, cocaine analog recognition, and expression.

Analyses of mutation effects can aid in understanding how large proteins act. The dopamine transporter (DAT) mediates complex actions in recognizing cocaine and in recognizing and translocating dopamine, sodium, and chloride. DAT proline residues, especially those in transmembrane (TM) domains, are good candidates for involvement in these DAT actions. We now report production of mutants substituting alanine and/or glycine residues for 16 prolines located in or near putative DAT TM domains. We examine effects of these modifications on DAT expression, dopamine uptake, and cocaine analog binding. Mutants in prolines located in five DAT TM domains and four connecting loops alter apparent DAT membrane targeting. Five mutations decrease dopamine affinities more than threefold without significantly decreasing cocaine analog affinities. One decreases cocaine analog affinity without decreasing dopamine affinity. Two mutations decrease affinities for both dopamine and cocaine analog. P101 is especially implicated in dopamine uptake. Alanine substitution for this proline yields dopamine V(max) values of less than 3% of wild-type values despite dopamine affinities more than fourfold higher than wild-type and normal Na(+) and Cl(-) dependence. These DAT proline mutants identify DAT regions likely for dopamine translocation and for recognition of dopamine and cocaine.

Amino Acid Sequence↗
PubMed2003

Activation of the hypoxia-inducible factor-pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors.

Hypoxia-inducible transcription factors (HIF) mediate complex adaptations to reduced oxygen supply, including neoangiogenesis. Regulation of HIF occurs mainly through oxygen-dependent destruction of its alpha subunit. In the presence of oxygen, two HIFalpha prolyl residues undergo enzymatic hydroxylation, which is required for its proteasomal degradation. We therefore tested whether pharmacological activation of HIFalpha by hydroxylase inhibitors may provide a novel therapeutic strategy for the treatment of ischemic diseases. Three distinct prolyl 4-hydroxylase inhibitors-l-mimosine (L-Mim), ethyl 3,4-dihydroxybenzoate (3,4-DHB), and 6-chlor-3-hydroxychinolin-2-carbonic acid-N-carboxymethylamid (S956711)-demonstrated similar effects to hypoxia (0.5% O2) by inducing HIFalpha protein in human and rodent cells. L-Mim, S956711, and, less effectively, 3,4-DHB also induced HIF target genes in cultured cells, including glucose transporter 1 and vascular endothelial growth factor, as well as HIF-dependent reporter gene expression. Systemic administration of L-Mim and S956711 in rats led to HIFalpha induction in the kidney. In a sponge model for angiogenesis, repeated local injection of the inhibitors strongly increased invasion of highly vascularized tissue into the sponge centers. In conclusion, structurally distinct inhibitors of prolyl hydroxylation are capable of inducing HIFalpha and HIF target genes in vitro and in vivo and induce adaptive responses to hypoxia, including angiogenesis.

Animals↗
PubMed1999

Cutaneous Waldenstrom macroglobulinemia in transformation.

Waldenstrom macroglobulinemia is a low-grade B-cell lymphoproliferative disorder of the elderly with characteristic monoclonal IgM-producing neoplastic infiltrates of the bone marrow, lymph node, and spleen. Cutaneous manifestations are usually nonspecific such as purpura, ulcers, and urticarial lesions. These lesions are caused by hyperviscosity of the blood, immune complex-mediated vascular damage, paraprotein deposition, and amyloid deposition. Specific skin lesions occur rarely and generally consist of translucent, flesh-colored papules composed of monoclonal IgM deposits. Rarely, there may be violaceous lesions composed of low-grade lymphoplasmacytic infiltrates characteristic of Waldenstrom macroglobulinemia. Both cutaneous manifestations of the disease, as well as disease transformation to high-grade, large cell lymphoma are rare. We report two very unusual cases of Waldenstrom macroglobulinemia with documented skin disease that demonstrated transformation to high-grade lymphoma. Both patients were elderly men with long-standing Waldenstrom macroglobulinemia involving the bone marrow, who subsequently developed skin involvement by the disease. Waldenstrom macroglobulinemia can rarely manifest as cutaneous disease, sometimes as a high-grade transformation of low-grade Waldenstrom macroglobulinemia elsewhere. Distinction of cases of transformed Waldenstrom macroglobulinemia from de novo cutaneous large cell lymphoma may be important, because the two entities are likely biologically different.

Aged↗
PubMed2000

Angioendotheliomatosis in a woman with rheumatoid arthritis.

Reactive angioendotheliomatosis (RA) is a rare self-limited skin condition characterized histopathologically by a proliferation of endothelial cells within vascular lumina, usually as a result of different stimuli such as systemic infections, cryoproteinemias, monoclonal gammopathies, allergic conditions, severe peripheral vascular atherosclerotic disease, and iatrogenic arteriovenous fistulas. We report on a 67-year-old woman with a 20-year history of seropositive rheumatoid arthritis who presented with violaceous swelling of her left forearm. A skin biopsy revealed the histopathologic finding of RA with focal glomeruloid features and deposition of periodic acid-Schiff-positive material. In this systemic disorder, cutaneous manifestations may occur secondary to an immune complex-mediated vasculitic mechanism.

Aged↗
PubMed1993

Reduced transferrin binding in Down syndrome: a route to senile plaque formation and dementia.

Plasma transferrin binding in Down syndrome and Alzheimer's disease is significantly reduced compared with age matched controls and it was thought this may help elucidate a pathological time sequence for the onset of dementia in Down syndrome. In Down syndrome, there was a reduction in gallium and aluminium transferrin binding both with age and the onset of dementia. Non-transferrin bound gallium species were identified as non-transportable phosphate or silicate. Thus, the route of entry of metals into the brain must be via a transferrin mediated complex only. A clear sequence of pathological events has been demonstrated in Down syndrome which shows the pathway to development of plaques and dementia and this is believed to have an immunological origin.

Adolescent↗
PubMed2000

Depolarizing/hyperpolarizing effects of the GABA(A) synapse have a beneficial role in synaptic weight resetting in the hippocampus.

To eliminate undesirable memory traces from the short-term memory system, it is a crucial question to reorganize the activity induced synaptic efficiency. Here we suggest a possible solution for this mechanism. In the first part of the paper we demonstrate, that under different physiological conditions even in the case of adult animals, the GABA(A) synapse may mediate a depolarizing effect on the membrane potential. Considering the GABA(A) receptor-mediated complex effects on the membrane potential of adult mammalian central neurons we raised the question of the properties of the network, which has elements in the synaptic weight matrix with changing signs. The second part pinpoints the beneficial learning ability of such a network.

Animals↗
PubMed1997

Cellular immune mechanisms in inflammatory myopathies.

The inflammatory myopathies include dermatomyositis, polymyositis, and inclusion body myositis. In dermatomyositis, muscle fiber injury is secondary to an antibody- or immune-complex-mediated immune response against a vascular-endothelial component. In polymyositis and inclusion body myositis, CD8+ T cells and macrophages invade and eventually destroy initially nonnecrotic muscle fibers. The autoaggressive T cells have the phenotype of activated (HLA-DR+) memory (CD45RO+) cells. T-cell receptor analyses indicate that the autoaggressive T cells are oligoclonal. In inflammatory lesions, muscle fibers express various cytoplasmic and surface molecules that are not detectable in normal fibers. These molecules, which include HLA class I antigens, heat-shock proteins, adhesion molecules, and Fas, are probably induced by locally secreted cytokines. The autoaggressive CD8+ T cells harbor granules containing perforin that aggregate near the contact zone with the target muscle fiber. This is consistent with a perforin- and secretion-dependent mechanism of muscle fiber injury. Many invaded muscle fibers also express the Fas "death receptor," but signs of apoptosis are absent.

Cell Adhesion Molecules↗
PubMed2001

Autoimmune keratolysis in a patient with leukocytoclastic vasculitis: unusual erythema elevatum diutinum with granulomatous pattern.

PURPOSE: Leukocytoclastic vasculitis (LCCV) is an immune complex-mediated, small vessel disease that is clinically characterized by the presence of palpable purpuric lesions, most often in association with rheumatic diseases. Ocular manifestations of LCCV are rare. METHODS: We describe a patient with an unusual granulomatous pattern of erythema elevatum diutinum (EED) associated with autoimmune keratolysis. RESULTS: We studied a 64-year-old man with decreased visual acuity and nodular lesions in both hands. Ocular examination revealed bilateral superior corneal melting with perforation in the left eye and conjunctival thickening in both eyes, in association with a severe inflammatory reaction. Histopathologic examination of the conjunctiva revealed granulomatous vasculitis with neutrophilic infiltrate, giant cells, and fibroblastic proliferation. A punch biopsy taken from his skin showed similar characteristics that suggested EED; however, there were no giant cells. CONCLUSION: To our knowledge, autoimmune keratolysis secondary to cutaneous LCCV (EED) has not been described previously, and there has been no description of granulomatous reaction (in the conjunctiva) in EED.

Autoimmune Diseases↗
PubMed1985

Nephritis associated with an infected peritoneovenous LeVeen shunt.

A patient with chronic active hepatitis and medically unmanageable ascites developed staphylococcal bacteremia after insertion of a peritoneovenous LeVeen shunt. The patient developed glomerulonephritis, manifested by moderate proteinuria, microscopic hematuria with red cell casts, azotemia, and evidence of complement activation. The protracted infection, urinary, and renal abnormalities subsided after removal of the LeVeen shunt and a 3-week course of antibiotics. The clinical course of this patient is typical of the immune-complex mediated glomerulonephritis that has been previously well described in hydrocephalic patients with chronically infected ventriculoatrial shunts.

Ascites↗