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)

Presenilin (PS1) and (PS2) are the centers of gamma-secretase that release Abeta from APP in Alzheimer's disease (AD). They cleave signaling proteins like Notch and downregulate beta-catenin to modulate Wnt signaling. Inactivation of PS1 or PS1 and PS2 causes a prenatally lethal 'Notch phenotype,' which has hampered investigation of PS function in adulthood seriously. We have thus turned towards PS1+/-PS2-/- mice which carry the most severe reduction of PS alleles compatible with survival, to analyze the consequences of impaired PS function especially in adulthood. In these 'partial deficient' mice, PS1 protein concentration is considerably lowered, functionally reflected by reduced gamma-secretase activity and impaired beta-catenin downregulation. Their phenotype is normal up to approximately 6 months, when the majority of the mice develop an autoimmune disease characterized by dermatitis, glomerulonephritis, keratitis and vasculitis, as seen in human systemic lupus erythematosus. Besides B-cell dominated infiltrates, we observe a hypergammaglobulinemia with immune complex deposits in several tissues, high-titer nuclear autoantibodies and an increased CD4+/CD8+ ratio. The mice further develop a benign skin hyperplasia similar to human seborrheic keratosis as opposed to malignant keratocarcinomata observed in skin-specific PS1 'full' knockouts. A partial reduction of PS function in PS1+/-PS2-/- mice causes a novel phenotype in adulthood unrelated to the developmental defects of full knockouts. As PS1+/-PS2+/- mice remain healthy, this points towards a sharply defined minimum of PS function. Skin and immune system appear to be especially sensitive targets of impaired PS function and may need careful monitoring if gamma-secretase inhibitors are envisaged for treating AD.
Hum Mol Genet 2004 Jul 01
PMID:Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice. 1512 3

Anti-neutrophil cytoplasm antibodies (ANCA) with specificity for myeloperoxidase (MPO) are implicated as pathogenic agents in pauci-immune systemic vasculitis. In agreement with previously published observations we show that human neutrophils incubated with an MPO-specific IgG class monoclonal antibody are pro-adhesive and undergo apoptosis more readily in vitro. If apoptotic neutrophils are incubated with this antibody they are readily phagocytosed by macrophages and we show that 'blocking' antibodies to FcgammaRIIa (CD32) on the macrophage inhibit this process. We also examined the effect of E3MPO, a monoclonal anti-MPO antibody derived from a patient with severe systemic vasculitis. E3MPO is closely related to the cold-agglutinins and bears an epitope recognized by the monoclonal antibody 9G4 which is expressed on antibodies derived from the V4-34 germ-line immunoglobulin gene. In previous studies, we have shown that anti-MPO antibodies present in sera from patients with vasculitis often bear this epitope. In contrast to the IgG-class antibody, incubation of neutrophils with E3MPO inhibited neutrophil adhesion and apoptosis. Apoptotic neutrophils however were phagocytosed more readily by macrophages in the presence of E3MPO. The effects of E3MPO on neutrophil adhesion and apoptosis were inhibited by piceatannol, an inhibitor of Syk-family kinases; activation of which is associated with cross-linking of the beta(2)-integrins. We show that surface-expressed MPO co-localizes with these beta(2)-integrins and suggest that cross-linking of beta(2)-integrin-bound MPO by polyvalent antibodies could result in signaling through these receptors. We have demonstrated that there are different consequences of Fcgamma-receptor-dependent and -independent signaling mediated by ANCA.
Mol Immunol 2004 Jun
PMID:An IgM class anti-neutrophil cytoplasm antibody inhibits neutrophil adhesion and apoptosis via a Syk dependent signaling cascade. 1516 42

Wegener's granulomatosis (WG) is a complex autoimmune syndrome that is characterised by upper/lower respiratory necrotising granulomatosis, glomerulonephritis and small-vessel vasculitis. Since Wegener's 1936 description, considerable advances in recognition and treatment have changed this disease from a rapidly and uniformly fatal illness to a chronic disease characterised by remissions and relapses. The serendipitous discovery of anti-neutrophil cytoplasmic antibodies (ANCAs) as a marker associated with WG focused attention on the potential pathogenic role of these antibodies and has recently led to the development of novel animal models that might facilitate our understanding of the disease pathogenesis. Future animal models of this disease will have to account for the role of both ANCA-mediated pathology and granulomatous inflammation to enable us to understand the chronic and persistent features of WG in humans.
Expert Rev Mol Med 2005 May 13
PMID:Pathogenesis of Wegener's granulomatosis: current concepts. 1589 83

The authors describe four patients with symptomatic lung disease morphologically representing a septal capillary injury syndrome temporally associated with serologic and culture evidence of active cytomegalovirus (CMV) infection but without classic cytopathic changes. The authors conducted a thorough review of clinical data, microscopic examination, and in situ hybridization to detect CMV mRNA encoding immediate early protein. The assay detects transcripts that encode early and immediate early proteins. In two cases additional tissue was available for direct immunofluorescent studies. The disease process in each of the patients was morphologically indistinguishable from the pattern of organ injury associated with autoimmune diseases including a small vessel microvascular injury syndrome involving skin and lung and immune complex- mediated glomerulonephritis. Cytopenias were seen in all cases, most commonly thrombocytopenia. All treated patients demonstrated improvement on combined ganciclovir and low-dose steroid therapy. CMV infection may be of pathogenetic importance in some cases of alveolar hemorrhage, especially when accompanied by peripheral blood cytopenia in otherwise healthy patients and if clinical worsening occurs in the setting of a traditional immunosuppressive regimen typically used to treat vasculitis.
Appl Immunohistochem Mol Morphol 2005 Sep
PMID:Cytomegalovirus-associated pulmonary septal capillary injury sine inclusion body change: a distinctive cause of occult or macroscopic pulmonary hemorrhage in the immunocompetent host. 1608 54

Iron-derived reactive oxygen species are implicated in the pathogenesis of numerous vascular disorders including atherosclerosis, microangiopathic hemolytic anemia, vasculitis, and reperfusion injury. One abundant source of redox active iron is heme, which is inherently dangerous when released from intracellular heme proteins. The present review concerns the involvement of heme in vascular endothelial cell damage and the strategies used by endothelium to minimize such damage. Exposure of endothelium to heme greatly potentiates cell killing mediated by polymorphonuclear leukocytes and other sources of reactive oxygen. Free heme also promotes the conversion of low-density lipoprotein (LDL) into cytotoxic oxidized products. Only because of its abundance, hemoglobin probably represents the most important potential source of heme within the vascular endothelium; hemoglobin in plasma, when oxidized, transfers heme to endothelium and LDL, thereby enhancing cellular susceptibility to oxidant-mediated injury. As a defense against such toxicity, upon exposure to heme or hemoglobin, endothelial cells up-regulate heme oxygenase-1 and ferritin. Heme oxygenase-1 is a heme-degrading enzyme that opens the porphyrin ring, producing biliverdin, carbon monoxide, and the most dangerous product - free redox active iron. The latter can be effectively controlled by ferritin via sequestration and ferroxidase activity. Ferritin serves as a protective gene by virtue of antioxidant, antiapoptotic, and antiproliferative actions. These homeostatic adjustments have been shown effective in the protection of endothelium against the damaging effects of exogenous heme and oxidants. The central importance of this protective system was recently highlighted by a child diagnosed with heme oxygenase-1 deficiency, who exhibited extensive endothelial damage.
Mol Nutr Food Res 2005 Nov
PMID:Heme, heme oxygenase and ferritin in vascular endothelial cell injury. 1620 35

Lung transplantation has come of age with the development of a critical mass of experienced clinicians who are committed to pooling their knowledge to solve the clinical problems that continue to confound the benefits individual patients may enjoy from these life-saving procedures. Adequately powered clinical trials are in progress to assist decision making regarding the role of newer immunosuppressive agents. Therapeutic drug monitoring has become critical to minimizing preventable complications such as renal dysfunction with calcineurin inhibitors. Fibroproliferation inhibitors are used more widely to ameliorate the abnormal healing response to allodependent or alloindependent injury, the latter perhaps related to underrecognized gastroesophageal reflux disease for which fundoplication is now proposed as an effective preventative measure. Cumulative damage to the graft from low-grade rejection is now appreciated as a potential cause of graft loss perhaps via an insidious small vessel vasculitis causing bronchiolar ischemic injury. Clearly, despite some progress, substantive challenges remain.
Methods Mol Biol 2006
PMID:Current status of lung transplantation. 1679 Aug 48

The role of interleukin-6 (IL-6) in granulomatous vasculitis is not well understood. To investigate its involvement in this type of vasculitis a model of glucan-induced pulmonary vasculitis employed interleukin-6 deficient (IL-6-/-) mice. Briefly, IL-6-/- mice and C57B/J6 wild type (IL-6+/+) mice were injected intravenously with a suspension of glucan isolated from the cell wall of bakers yeast which results in a granulomatous vasculitis primarily in the pulmonary vasculature. Histological examination demonstrated no significant difference in the number of infiltrating leukocytes between the IL-6+/+ and IL-6-/- glucan-injured mice. Similar numbers of granulomas were noted in both the IL-6+/+ and IL-6-/- injured animals, while no granulomas were seen in saline injected control mice. Cells recovered from the bronchoalveolar lavage (BAL) fluid were differentially stained and counted. While there was a significant increase in infiltrating leukocytes recovered from the BAL following glucan-induced injury, there was no significant difference between the IL-6+/+ and IL-6-/- mice. In addition, no difference was demonstrated in total protein content in the BAL fluid between IL-6+/+ and IL-6-/- mice. However, myeloperoxidase (MPO) activity in the lungs of the IL-6-/- mice was less than in their IL-6+/+ counterparts suggesting that these animals have a partial defect in their ability to recruit neutrophils in this model. Studies done to look for levels of other cytokines/chemokines in these animals to compensate for the loss of IL-6 revealed that only IL-10 in the sera (p<0.016) and BAL fluid (p<0.05) of IL-6-/- mice was significantly higher then their IL-6+/+-injured counterparts. These studies suggest that IL-6, while possibly involved in early neutrophil accumulation in this model does not appear critical to the development of the TH-2 mediated granulomatous vasculitis.
Exp Mol Pathol 2007 Apr
PMID:Role of interleukin-6 in a glucan-induced model of granulomatous vasculitis. 1722 22

The gastrointestinal mucosa is a richly perfused vascular bed directly juxtaposed with the anaerobic and nonsterile lumen of the gut. As such, intestinal epithelial cells, which line the mucosa, experience a uniquely steep physiologic oxygen gradient in comparison with other cells of the body. Inflammation associated with a loss of epithelial barrier function and unregulated exposure of the mucosal immune system to luminal antigens leads to inflammatory bowel disease (IBD), a relatively common disorder with severe morbidity and a limited therapeutic repertoire. During IBD, increased tissue metabolism and vasculitis renders the chronically inflamed mucosa and particularly the epithelium hypoxic, giving rise to the activation of the hypoxia-responsive transcription factor hypoxia-inducible factor (HIF). Recent studies utilizing conditional intestinal epithelial hif1a-null mice have revealed a protective role for epithelial HIF-1alpha in murine models of IBD. Such protection occurs, at least in part, through HIF-dependent induction of barrier-protective genes in the epithelium. More recently, studies employing pharmacologic activation of HIF via inhibition of HIF prolyl hydroxylases revealed a profoundly protective effect of these agents in murine models of colitis. In this paper, we review this pathway in detail and examine the therapeutic potential for targeting HIF hydroxylases in intestinal mucosal inflammatory disease.
J Mol Med (Berl) 2007 Dec
PMID:Hypoxia and gastrointestinal disease. 1802 19

Kawasaki disease (KD) is an acute febrile vasculitis in childhood that is associated with inflammatory cytokines, in which the vascular inflammation results in damage to the coronary arteries. The active form of vitamin D, 1alpha,25-dihydroxyvitamin D(3) {1alpha,25-(OH)(2)D(3)} exhibits anti-inflammatory activities. In this study, we determined the mRNA and protein expression of the vitamin D receptor in human coronary arterial endothelial cells (HCAEC) by RT-PCR and Western blotting, respectively. We examined whether or not 1alpha,25-(OH)(2)D(3) inhibits the tumor necrosis factor-alpha (TNF-alpha)-induced activation of nuclear transcription factor-kappaB (NF-kappaB), which is essential for the expression of proinflammatory cytokines in HCAEC, by ELISA. In addition, we determined the inhibitory effect of 1alpha,25-(OH)(2)D(3) on E-selectin expression induced by TNF-alpha in HCAEC by flow cytometry. RT-PCR revealed mRNA for the vitamin D receptor in HCAEC. Western blotting demonstrated vitamin D receptor protein in HCAEC. ELISA showed that pretreatment with 1alpha,25-(OH)(2)D(3) significantly inhibited the TNF-alpha-induced NF-kappaB activation in HCAEC. Moreover, flow cytometry revealed that pretreatment with 1alpha,25-(OH)(2)D(3) significantly inhibited the TNF-alpha-induced expression of E-selectin on HCAEC. Our results suggest that adjunctive 1alpha,25-(OH)(2)D(3) may modulate the inflammatory response during KD vasculitis.
J Steroid Biochem Mol Biol 2009 Jan
PMID:Anti-inflammatory effect of 1alpha,25-dihydroxyvitamin D(3) in human coronary arterial endothelial cells: Implication for the treatment of Kawasaki disease. 1913 39

This review analyzes the impact of 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET) in the diagnostic work-up of classic fever of unknown origin (FUO) according to the criteria first proposed by Petersorf in 1961 and later modified by Durack et al. in 1991. Algorithms currently used in this diagnostic process are not strictly evidence based up to now. FDG accumulates in malignant tissues, but also in inflammatory cells by the overexpression of facultative glucose transporter-isotypes (mainly GLUT-1 and GLUT-3) and by an overproduction of glycolytic enzymes. Therefore, this technique covers a broad spectrum of possible etiologies for FUO. Once imaged, these lesions can be further investigated by other (e.g. invasive) and more specific methods. Until now, four prospective studies using FDG-PET in patients with classic FUO, encompassing 167 patients in total are published. Three retrospective studies with 125 patients are also available. These studies are discussed and weighted according to the control of selection-bias that was performed. An interstudy-bias may also be present resulting from a considerable variability in causes of FUO. A low number of diagnostic scans in a study may sometimes be related to a high rate of fevers caused by miscellaneous disorders or to a high rate of undiagnosed patients. In these disease categories, focal pathologies that can be imaged with FDG-PET, are rare. A high number of diagnostic scans is always related to a high prevalence of patients with medium- and large-vessel vasculitis. Available data indicate that FDG-PET has the potential to play an important role as a second line procedure in the management of about 1/3 of patients with classic FUO. It is expected that hybrid imaging (PET/computed tomography [CT]; PET/magnetic resonance imaging [MRI]) will improve the diagnostic impact of FDG-PET further, but prospective data about the value of this methods are currently not available. The question as to how these new techniques can be implemented into an evidence based diagnostic algorithm, can only be resolved within a multidisciplinary setting, avoiding both selection- and interstudy-bias whenever possible.
Q J Nucl Med Mol Imaging 2009 Feb
PMID:FDG-PET in patients with fever of unknown origin: the importance of diagnosing large vessel vasculitis. 1918 28


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