Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To assess a potential immunoregulatory role of Schwann cells in the peripheral nervous system we examined whether they are able to secrete nitric oxide metabolites. Schwann cells treated with IFN-gamma and TNF-alpha upregulated iNOS-specific mRNA within 12 hr and released nitrite in a time- and dose-dependent manner, reaching a plateau of secretion after 3 days. Nitrite secretion was inhibited by NMMA, suggesting that Schwann cells are endowed with a cytokine-inducible NO synthase. TGF-beta and IL-1 failed to modulate nitrite release. When assessing their role as APC, we note that Schwann cells activated CD4+ antigen-specific T-cell lines, but in contrast to professional thymic APC this ability declined markedly after Day 1. Theoretically diminished T-cell proliferation and finally death might be achieved by secretion of nitric oxide metabolites by Schwann cells. Inhibition of NO production by NMMA did not restore T-cell proliferation after Day 2 or prevent apoptosis of T-cells. However, in a coculture model Schwann cells exerted a strong suppressive effect on T-cell activation by thymic APC, which was almost completely abrogated by addition of NMMA. We suggest that Schwann cells may exert potent immunoregulatory functions beyond their role as APC. They may terminate immunoinflammatory reactions in the peripheral nervous system by releasing NO.
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PMID:Secretion of nitrite by Schwann cells and its effect on T-cell activation in vitro. 859 41

Recipient IgG immunity against leukoreduced donor platelets is dependent on indirect T-cell allorecognition and is suppressed in vivo by inhibitors (aminoguanidine, AMG) of inducible nitric oxide synthase (iNOS). To examine recipient processing pathways of donor platelet antigens, enriched macrophages (antigen-presenting cells [APC]) from BALB/c (H-2(d)) mice were pulsed with allogeneic C57BL/6 (H-2(b)) platelets and transfused weekly into naive BALB/c mice. Platelet-pulsed APC stimulated IgG antidonor antibody production in 45% of recipients by the second transfusion and in 100% by the sixth transfusion; this response was enhanced by pulsing in the presence of interferon-gamma. By the sixth transfusion, high-titer IgG1 (mean titer 4990) and IgG2a (1933) isotypes specific for donor major histocompatibility complex (MHC) class I antigens were detected. Platelet pulsing in the presence of AMG or colchicine significantly inhibited the ability of APC to stimulate IgG alloantibodies; only 50% (P <.005) and 20% (P <.0001) of recipients, respectively, produced antibodies by the sixth transfusion. AMG inhibition was reversed by the addition of L-arginine, the substrate for iNOS. In contrast, pulsing in the presence of chloroquine, the proteasome inhibitory peptide MG115, or Brefeldin A enhanced APC immunity (70-100% of recipients antibody positive by the second transfusion [P <.05]); these agents allowed the pulsed APC to stimulate IgG2a but inhibited IgG1 production and this correlated with a reduction in serum interleukin (IL)-4 levels. The results suggest that for donor platelet antigens to stimulate IgG alloantibodies, recipient APC use the essential generation of nitric oxide and a noncytosolic, pH-independent processing pathway, which can be exploited as an effective immunotherapy target to further inhibit alloimmunization against leukoreduced platelets. (Blood. 2000;95:1735-1742)
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PMID:Unique processing pathways within recipient antigen-presenting cells determine IgG immunity against donor platelet MHC antigens. 1068 32

Activation of the beta-catenin/T cell factor-mediated transcription pathway through mutations of the APC or beta-catenin gene is suggested to play an important role in colon carcinogenesis and there is great interest in the target genes. We have described the frequent mutation and an altered cellular localization of beta-catenin in rat colon adenocarcinomas induced by azoxymethane (AOM), along with up-regulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2. In the present study, the relation between beta-catenin alteration and expression of iNOS and COX-2 in AOM-induced rat colon carcinogenesis was examined in hyperplastic and dysplastic type aberrant crypt, adenoma and adenocarcinoma samples. K-ras gene mutations were also investigated. Mutation analysis by the PCR-single strand conformation polymorphism method and direct sequencing demonstrated the beta-catenin gene to be mutated in two of three dysplastic aberrant crypt foci (ACF), two of six adenomas and 20 of 26 adenocarcinomas, while K-ras was mutated in seven of 10 hyperplastic ACF and seven of 26 adenocarcinomas. Immunohistochemical staining showed an alteration in cellular localization of beta-catenin in all dysplastic ACF, adenomas and adenocarcinomas examined. iNOS expression was also observed in all but one of the lesions in which beta-catenin alterations were observed. Neither iNOS expression nor beta-catenin alterations were observed in any hyperplastic ACF. COX-2 expression in stromal elements was found even in normal colon mucosa and increased in adenomas and adenocarcinomas, while epithelial cells were only positive in large adenocarcinomas. These results show that beta-catenin alterations may be related to induction of iNOS expression, these being early events in AOM-induced colon tumorigenesis which may play important roles in causing dysplastic changes.
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PMID:Altered expression of beta-catenin, inducible nitric oxide synthase and cyclooxygenase-2 in azoxymethane-induced rat colon carcinogenesis. 1087 9

Adjuvant therapy for severe sepsis and shock can be divided into 4 groups. The first group comprises those compounds with proven efficacy in human studies (activated protein C and recombinant bacterial permeability-increasing protein). The second group includes compounds with potential efficacy (heparin), while the third group represents those with no demonstrated efficacy in randomised clinical trials (tumour necrosis factor and interleukin-1 antibodies and receptor antagonists). The fourth group includes those drugs which have been found to be potentially effective in animal studies, but which have not yet been evaluated in humans (i.e., tyrosine kinase inhibitors, selective inducible nitric oxide synthase inhibitors, polyadenosine-diphosphate-ribose-polymerase and caspase III (apoptosis) inhibitors). Formal clinical comparisons between the various treatment options are necessary to assist the clinician in selecting the appropriate form of therapy.
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PMID:[Adjuvant therapies for sepsis and shock: which are more effective?]. 1157 77

Several substances interfering with colorectal carcinogenesis may reduce or prevent adenoma formation in familial adenomatous polyposis (FAP), an inherited predisposition to colorectal cancer. This study determined the expression of genes coding for putative anticancer targets (COX-2, iNOS, MMP-7, ODC, PKCbeta, PPARgamma, RXRalpha, RXRbeta, RXRgamma) in FAP patients to provide one of the rationales for the design of chemotherapy and -prevention strategies. Gene expression was assessed by TaqMan analysis in colonic tissue of 9 FAP patients with mutations in the APC gene (APCpos), 5 FAP patients without identified genetic defect (APCneg), and 3 healthy individuals. Among the examined genes, PKCbeta and MMP-7 were most consistently altered in adenoma tissue relative to matched mucosa. Intriguingly, ODC was clearly overexpressed in polyps from APCpos but not APCneg patients. Furthermore, PKCbeta, MMP-7, ODC, and COX-2 as well as all RXRs displayed altered expression in apparently healthy FAP mucosa as opposed to that of healthy individuals. Our data suggests PKCbeta and MMP-7 to be the most suited as anticancer targets among the genes studied.
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PMID:Expression of putative anticancer targets in familial adenomatous polyposis and its association with the APC mutation status. 1171 87

Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is a well-characterized murine model of the chronic-progressive form of human multiple sclerosis (MS) characterized by the activation of myelin-specific autoreactive CD4 Th1 cells via epitope spreading. To gain an understanding of the potential role of central nervous system (CNS)-resident cells in the presentation of endogenous myelin epitopes, we determined the individual antigen presentation and effector potential of resident microglia vs. infiltrating macrophages in the CNS of mice with ongoing TMEV-IDD by performing functional analysis of these populations separated to high purity by flow cytometric sorting based on their level of CD45 expression. Unlike microglia from nai;ve mice, peptide-pulsed CD45(lo) microglia isolated at the onset of clinical disease were as efficient as CNS-infiltrating CD45(hi) macrophages in activating proliferation and IFN-gamma production by myelin-peptide specific Th1 cells. In contrast, during the chronic stages of TMEV-IDD, CNS-infiltrating macrophages were more highly activated than the resident microglia as reflected both by higher expression of cell surface molecules associated with APC function and enhanced functional ability of spinal cord-infiltrating macrophages to stimulate T cell proliferation in vitro. Interestingly, both microglia and infiltrating macrophages expressed similar profiles of effector molecules such as IL-1, IL-6, IL-12 p40, TNF-alpha, and iNOS. Collectively, this is the first report comparing the antigen-presenting phenotype and function of microglia and infiltrating macrophages in a virus-induced model of CNS demyelination demonstrating that the resident microglia are capable APCs and may play an important role in antigen presentation at the onset of clinical disease and contribute to effector myelin destruction.
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PMID:Microglia are activated to become competent antigen presenting and effector cells in the inflammatory environment of the Theiler's virus model of multiple sclerosis. 1459

Since the first detection of aberrant crypt foci (ACF) in carcinogen-treated mice, there have been numerous studies focusing on these microscopically visible lesions both in rodents and in humans. ACF have been generally accepted as precancerous lesions in regard to histopathological characteristics, biochemical and immunohistochemical alterations, and genetic and epigenetic alterations. ACF show variable histological features, ranging from hyperplasia to dysplasia. ACF in human colon are more frequently located in the distal parts than in the proximal parts, which is in accordance with those in colorectal cancer (CRC). The immunohistochemical expressions of carcinoembryonic antigen (CEA), beta-catenin, placental cadherin (P-cadherin), epithelial cadherin (E-cadherin), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), and P16INK4a are found to be altered. Genetic mutations of K-ras, APC and p53, and the epigenetic alterations of CpG island methylation of ACF have also been demonstrated. Genomic instabilities due to the defect of mismatch repair (MMR) system are detectable in ACF. Two hypotheses have been proposed. One is the "dysplasia ACF-adenoma-carcinoma sequence", the other is "heteroplastic ACF-adenoma-carcinoma sequence". The malignant potential of ACF, especially dysplastic ACF, makes it necessary to reveal the nature of these lesions, and to prevent CRC from the earliest possible stage. The technique of magnifying chromoscope makes it possible to detect "in vivo" ACF, which is beneficial to colon cancer research, identifying high-risk populations for CRC, and developing preventive procedures.
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PMID:Aberrant crypt foci as microscopic precursors of colorectal cancer. 1466 4

Colon cancer evolves through epithelial cell deregulation and inappropriate proliferation. These histopathological characteristics are exemplified in the biochemical, immunohistochemical, genetic and epigenetic elements detected within colonic mucosa. Early detection is paramount for the prevention of colon cancer deaths. Aberrant crypt foci (ACF) are thought to be the earliest identifiable neoplastic lesions in the colon carcinogenetic model. The progression of ACF to polyp and, subsequently, to cancer parallels the accumulation of several biochemical alterations and mutations whereby a small fraction of ACF evolve to colon cancer. Recent data indicate that, not uncommonly, some ACF bypass the polyp stage in their carcinogenesis thus reinforcing the importance of their early detection and our understanding of their pathogenesis. Since ACF were first detected in carcinogen-treated mice, research efforts have focused on these microscopically visible lesions both in animal and human models. ACF show variable histological features, characterized by Kudo (20) and, therefore, can be grouped into differing categories by in vivo examination with high-magnification-chromoscopic-colonoscopy (HMCC). As expected, ACF are more frequently detected in distal animal and human colons coinciding with the geographic distribution of colorectal cancer (CRC). Various proteomic (Prot) markers may be altered within ACF suggesting possible prospective pathological changes. These markers include Calreticulin, Transgelin, Serotransferrin, Triphosphate isomerase and Carbonic anhydrase II. Other markers of importance include carcinoembryonic antigen (CEA), B-catenin, placental cadherin (P-cadherin), epithelial cadherin (E-cadherin), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2) and P16INK4a. Genetic mutations of K-ras, B-Raf APC and p53 have been demonstrated in ACF as well as the epigenetic alterations of CpG island methylation. Genomic instabilities (GI), illustrated by a higher GI Index (GII), microsatellite instability (MSI), loss of heterozygosity (LOH) and defects in mismatch repair (MMR) systems, are also expressed. These transformations may lead to the identification of the earliest pathological features initiating colon tumorigenesis. In this review, the advances in ACF research as precursors of CRCs are highlighted.
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PMID:Aberrant crypt foci. 1647 86

The current report summarized animal models of heatstroke experimentation that advance our current knowledge of therapeutic effects on cerebrovascular dysfunction, hypercoagulable state and/or systemic inflammation with various agents in the setting of heatstroke. This was a narrative review of selected published primary basic literature from MEDLINE for 1973-2006. It was found that rodents shared with humans almost the same heatstroke reactions such as hyperpyrexia, hypotension, hyperventilation, pulmonary edema, hepatic and renal failure, hypercoagulable state, metabolic acidosis, systemic inflammation, and cerebral ischemia, injury and dysfunction. Therefore, the rodent model would allow testing of new therapeutic strategies for heatstroke. It was found that brain cooling produced by infusion of cold (4 degrees C) normal saline via the jugular vein or whole body cooling improved survival during heatstroke by reducing cerebrovascular dysfunction, multiple organ failure, systemic inflammation and hypercoagulable state. However, even under the absence of brain or whole body cooling, these heatstroke reactions still could be reversed by treating with the following agents: (1) free radical scavengers; (2) human recombinant protein C: (3) platonin; (4) hyperbaric oxygen; (5) hydroxyethyl starch, hypertonic solution, or human albumin; (6) glucocorticoids; (7) interleukin-1 receptor antagonists; (8) L-arginine; (9) estrogen; and (10) human umbilical cord blood cells or CD +34 cells. Before initiation of heat stress, prior manipulations with one of the following measures were found to be able to protect against heatstroke syndromes: (1) systemic delivery of inducible nitric oxide synthase inhibitors, mu-opioid receptor antagonists, endothelin-1A receptor antagonists, dopaminergic or serotoninergic nerve depletor or receptor antagonists, or glutamate receptor antagonists; or (2) heat shock protein 72 preconditioning.
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PMID:Prevention and repair of circulatory shock and cerebral ischemia/injury by various agents in experimental heatstroke. 1716 3

The severe impairment of the microcirculation plays a substantial role in the pathogenesis of severe sepsis and septic shock, and leads to multiple organ failure and death. Therapeutic strategies to resuscitate the microcirculatory blood flow and to improve the functional capillar density are therefore essential to surmount the microcirculatory pathology and to avoid tissue hypoxia. Based on reasonable scientific evidence, early fluid resuscitation directed by defined haemodynamic and metabolic goals (EGDT) as well as the application of activated protein C (rhAPC) according to the guidelines could be recommended. Dobutamine is the first choice to improve cardiac output and to overcome myocardial depression in septic shock whereas phosphodiesterase-III-inhibitors and levosimendane are still experimental options. Furthermore selective inhibitors of iNOS, nitroglycerol, as well as vasopressin have to be investigated relating to their specific effects on the microcirculation and their influence on survival in seevere sepsis and septic shock.
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PMID:[Therapeutic options to improve the microcirculation in sepsis and septic shock]. 1727 78


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