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)

The domain V within the internal ribosome entry segment (IRES) of poliovirus (PV) is expected to be important in its own neurovirulence because it contains an attenuating mutation in each of the Sabin vaccine strains. In this study, we try to find out if the results observed in the case of Sabin vaccine strains of PV can be extrapolated to another virus belonging to the same genus of enteroviruses but with a different tropism. To test this hypothesis, we used the coxsackievirus B3 (CVB3), known to be the most common causal agent of viral myocarditis. The introduction of the three PV Sabin-like mutations in the equivalent positions (nucleotides 484, 485, and 473) to the domain V of the CVB3 IRES results in significant reduced viral titer of the Sabin3-like mutant (Sab3-like) but not on those of Sab1- and Sab2-like mutants. This low titer was correlated with poor translation efficiency in vitro when all mutants were translated in rabbit reticulocyte lysates. However, elucidation by biochemical probing of the secondary structure of the entire domain V of the IRES of Sabin-like mutants reveals no distinct profiles in comparison with the wild-type counterpart. Prediction of secondary structure by MFOLD program indicates a structural perturbation of the stem containing the Sab3-like mutation, suggesting that specific protein-viral RNA interactions are disrupted, preventing efficient viral translation.
Mol Genet Genomics 2006 Oct
PMID:Effects of the Sabin-like mutations in domain V of the internal ribosome entry segment on translational efficiency of the Coxsackievirus B3. 1690 84

Coxsackie adenovirus receptor (CAR) is involved in immunological processes, and its soluble isoforms have antiviral effects on coxsackievirus B3 (CVB3) infection in vitro. We explored in this study the impact of CAR4/7, a soluble CAR isoform, on CVB3-induced myocarditis in BALB/c mice. BALB/c mice were treated daily with recombinant CAR4/7, beta-galactosidase (beta-Gal; as control protein) or buffer for 9 days. Half of each group was infected with CVB3 on day 3, and all mice were killed on day 9. Myocardial CVB3 titer, histology, and serology were analyzed. Treatment with CAR4/7 led to a significant reduction of myocardial CVB3 titer, whereas the application of beta-Gal had no detectable effect on the myocardial virus load. CAR4/7 application, however, resulted in increased myocardial inflammation and tissue damage in CVB3-infected hearts, whereas beta-Gal caused a degree of cardiac inflammation and injury similar to that in buffer-treated CVB3-infected control animals. CAR4/7 and beta-Gal treatment induced the production of antibodies against the respective antigens. CAR4/7-, but not beta-Gal-specific, virus-negative sera reacted against myocardial tissue and cellular membranous CAR, and significantly inhibited CVB3 infection in vitro. Thus, CAR4/7 suppressed CVB3 infection in vivo, supporting the concept of receptor analog in antiviral therapy. However, CAR4/7 treatment also leads to an aggravation of myocardial inflammation and injury most likely secondary to an autoimmune process.
J Mol Med (Berl) 2006 Oct
PMID:Treatment of coxsackievirus-B3-infected BALB/c mice with the soluble coxsackie adenovirus receptor CAR4/7 aggravates cardiac injury. 1692 71

Acute myocarditis is a non-ischemic inflammatory disease of the myocardium for which there is currently no specific treatment. We have previously shown that mesenchymal stem cells (MSC) can ameliorate heart injury during acute ischemia and in dilated cardiomyopathy; however, the therapeutic potential in acute myocarditis is unclear. In this study, we investigated the ability of MSC to attenuate myocardial injury and dysfunction during the acute phase of experimental myocarditis. Ten-week-old male Lewis rats were injected with porcine myosin to induce myocarditis. Cultured MSC (3x10(6) cells/rat) were injected intravenously 7 days after myosin injection. At 3 weeks, myosin injection resulted in severe inflammation and significant deterioration of cardiac function. MSC transplantation attenuated increases in CD68-positive inflammatory cells and monocyte chemoattractant protein-1 (MCP-1) expression in myocardium, and improved cardiac function in this model. Furthermore, myocardial capillary density was higher in myocarditis tissue, and was further increased by MSC transplantation. In vitro, cultured adult rat cardiomyocytes were injured in response to MCP-1, whereas this effect was attenuated by MSC-derived conditioned medium, suggesting cardioprotective effects of MSC acting in a paracrine manner. MSC transplantation attenuated myocardial injury and dysfunction in a rat model of acute myocarditis, at least in part through paracrine effects of MSC.
J Mol Cell Cardiol 2007 Jan
PMID:Transplantation of mesenchymal stem cells attenuates myocardial injury and dysfunction in a rat model of acute myocarditis. 1710 Nov 47

Cardiovascular pathologies are an enormous burden in human health and despite the vast amount of research; the molecular mechanisms and pathways that control the underlying pathologies are still not fully appreciated. The Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway has recently been shown to be an integral part of the response of the myocardium to various cardiac insults, including myocardial infarction, oxidative damage, myocarditis, hypertrophy and remodeling, in addition to having a prominent role in cardioprotective therapies such as ischaemic preconditioning. Here, recent advances in the understanding of how the JAK-STAT pathway orchestrates the response to cellular damage in the myocardium are discussed, along with the potential benefits and challenges in manipulating this pathway in cardiovascular therapy.
Trends Mol Med 2007 Feb
PMID:Role of the JAK-STAT pathway in myocardial injury. 1719 25

Autoimmune myocarditis develops after the presentation of heart-specific antigens to autoaggressive CD4(+) T cells and after inflammation has infiltrated the tissues. To shed light on global changes in the gene expression of autoimmune myocarditis and to gain further insight into the molecular mechanisms underlying the genesis of myocarditis, we conducted a comprehensive microarray analysis of mRNA using an experimental mouse autoimmune myocarditis model via immunization with alpha-myosin heavy chain-derived peptides. Of over 39,000 transcripts on a high density oligonucleotide microarray, 466 were under-expressed and 241 over-expressed by >or= 1.5-fold compared with the controls in BALB/C mouse with autoimmune myocarditis. In this paper, we list the top 50 up-regulated genes related to the immune response. These altered genes encode for leukocyte-specific markers and receptors, the histocompatibility complex, cytokines/receptors, chemokines/receptors, adhesion molecules, components of the complement cascade, and signal transduction-related molecules. Interestingly, matrix metalloproteinases (MMPs) such as MMP-3 and MMP-9 were up-regulated, as further revealed by the reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry assays. This indicates that MMPs may act as major regulators of the cytokine profile. Together, these findings provide new insight into the molecular events associated with the mechanism of the autoimmune genesis of myocarditis.
Cell Mol Biol Lett 2007
PMID:Microarray analysis reveals the role of matrix metalloproteinases in mouse experimental autoimmune myocarditis induced by cardiac myosin peptides. 1723 37

Experimental autoimmune myocarditis (EAM) is a T-cell-mediated autoimmune disease. CCR5, which is expressed mostly on activated T cells and monocytes/macrophages, are potent chemotactic factors for autoimmune myocarditis. We investigated the role of CCR5 in the formation of experimental autoimmune myocarditis. Expression of CCR5 and its cognate ligands was assessed by RT-PCR and immunohistochemical analysis. Single-cell suspension of splenocytes and whole blood specimens from EAM mice were subjected to flow-cytometry analysis. We investigated the critical role of CCR5 in EAM mice by adoptively transferring CCR5-positive/negative T cells to mice and by neutralizing CCR5 with monoclonal antibody to observe the influence on the severity and prevalence of myocarditis. In this report, we found that CCR5-positive cells predominate in infiltrated inflammatory cells in cardiac tissue of EAM mice and CCR5-positive T cells in peripheral blood increased markedly in EAM mice compared with controls. Moreover, we demonstrated that the severity of myocarditis was significantly reduced when CCR5-negative T cells from EAM mice were adoptively transferred. When administrated with CCR5-positive T cells, the myocarditis was significantly aggravated. We also demonstrated that blockade of CCR5 with monoclonal antibodies significantly reduced severity of myocarditis in EAM mice. Overall, these findings indicate that CCR5 is important in the induction of EAM and inhibition of CCR5 with monoclonal antibody significantly reduces the severity of myocarditis. CCR5 may have the potential to become a new therapy target against autoimmune myocarditis.
J Mol Cell Cardiol 2007 Apr
PMID:Increased expression of CCR5 in experimental autoimmune myocarditis and reduced severity induced by anti-CCR5 monoclonal antibody. 1736 85

Most individuals have viral infections at some point in their life, however, only few develop autoreactivity to cardiac myosin following infection resulting in myocarditis suggesting a genetic predisposition. Most mouse models of myocarditis are induced by viral infection or by immunization with cardiac myosin. We generated HLA-DR3.Abetao and HLA-DQ8.Abetao transgenic mice in NOD and HLA-DQ8.Abetao in B10 background to study spontaneous autoimmunity. A high mortality was observed in NOD.DQ8 female mice 16 weeks or older. Echocardiography showed marked systolic dysfunction. Histopathology of various organs revealed an enlarged heart with mononuclear infiltrate consisting of CD4 and Mac-1+ cells and myocyte necrosis. The autoimmunity was associated with the presence of spontaneous autoreactive T cells and antibodies to cardiac myosin. Serologically, mice were negative for all known mouse viruses. NOD.DR3.Abetao, the transgene negative littermates, NOD, and B10.DQ8 Abetao mice had no gross or microscopic cardiac pathology. Spontaneous cellular and humoral response to cardiac myosin suggests that NOD.DQ8 may harbor autoreactive cells that can lead to spontaneous myocarditis and dilated cardiomyopathy. HLA-DQ8 is required for the predisposition to the spontaneous autoreactivity while NOD background influences onset and progression of disease. This model of myocarditis occurs predominantly in female mice and may provide insight into the pathogenesis of heart disease in women.
J Mol Cell Cardiol 2007 Jun
PMID:Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice. 1749 68

Dilated cardiomyopathy (DCM) as a consequence of viral myocarditis is a worldwide cause of morbidity and death. The deposition of matrix proteins, such as collagen, in the course of ongoing viral myocarditis results in cardiac remodeling and finally in cardiac fibrosis, the hallmark of DCM. To identify mediators of virus-induced cardiac fibrosis, microarray analysis was conducted in a murine model of chronic coxsackievirus B3 (CVB3) myocarditis. By this attempt, we identified connective tissue growth factor (CTGF) as a novel factor highly expressed in infected hearts. Further investigations by quantitative reverse transcription polymerase chain reaction and Western blot analysis confirmed a strong induction of cardiac CTGF expression in the course of CVB3 myocarditis. By in situ hybridization and immunohistochemistry, basal CTGF messenger ribonucleic acid (mRNA) and protein expression were confined in noninfected control hearts mainly to endothelial cells, whereas in CVB3-infected hearts, also numerous fibroblasts were found to express CTGF. Regulation of CTGF is known to be basically mediated by transforming growth factor (TGF)-beta. In the course of CVB3 myocarditis, CTGF upregulation coincided with increased cardiac TGF-beta and procollagen type I mRNA expression, preceding the formation of fibrotic lesions. In in vitro experiments, we found that downregulation of CVB3 replication by means of small interfering RNAs (siRNAs) reverses the upregulation of CTGF mRNA expression. In contrast, downregulation of CTGF by siRNA molecules did not significantly reduce viral load, indicating that CTGF is not essential for CVB3 life cycle. The significantly enhanced transcript levels of TGF-beta, CTGF, and procollagen type I in cultivated CVB3-infected primary cardiac fibroblasts substantiate the role of fibroblasts as a relevant cell population in cardiac remodeling processes. We conclude that CTGF is a crucial molecule in the development of fibrosis in ongoing enteroviral myocarditis. Thus, downregulation of cardiac CTGF expression may open novel therapeutic approaches counteracting the development of cardiac fibrosis and subsequent heart muscle dysfunction.
J Mol Med (Berl) 2008 Jan
PMID:Connective tissue growth factor: a crucial cytokine-mediating cardiac fibrosis in ongoing enterovirus myocarditis. 1808 Jan 5

Pediatric myocarditis is a serious disease resulting in significant morbidity and mortality. Tracheal aspirate (TA) has been demonstrated to be a sensitive diagnostic tool to detect viral agents responsible for respiratory disorders and myocardial dysfunction. Tumor necrosis factor alpha (TNFalpha) is thought to play an important role in the pathogenesis of these disorders. The aim of the present study was to investigate the presence of different viruses and the expression of TNFalpha in children with clinical suspicion of myocarditis. Forty-five TAs from children (20 males/25 females, mean age 4.4+/-5.0 y) with myocardial dysfunction and respiratory symptoms were analyzed for detection of viral genomes by using molecular techniques. In 10 cases endomyocardial biopsy was also performed due to a severe and rapid progression of heart failure. TNFalpha mRNAs of TA and TNFalpha protein plasma levels were quantified. Viral etiology was detected in 25/45 (56%) cases: the most frequent etiology was enterovirus (19 cases, 59%). Polymerase chain reaction viral concordance was found in TA and endomyocardial biopsy. TNFalpha mRNA and TNFalpha serum levels were significantly more expressed in viral cases than nonviral cases (1.26+/-0.76 vs. 0.56+/-0.76, P=0.001). More impaired cardiac function (particularly ejection fraction) was detected in viral positive than in viral negative cases (39.91+/-20.09 vs. 55.61+/-20.36, P=0.04). TA seems to be an excellent tool for viral investigation in pediatric patients with suspicion of myocarditis. The analysis of TNFalpha in TA may represent an important marker to better define patient status.
Diagn Mol Pathol 2008 Mar
PMID:Viral detection and tumor necrosis factor alpha profile in tracheal aspirates from children with suspicion of myocarditis. 1830 10

Statins, inhibitors of 3-hydroxy-3-methylglutary-coenzyme A (HMG-CoA) reductase, have been recognized as a new type of immunomodulator and reported to have anti-inflammatory effect. To investigate the effect of simvastatin, a lipophilic statin, on myocarditis, we explored whether simvastatin is able to inhibit experimental autoimmune myocarditis (EAM) and adoptive transfer of EAM in rats. We found that administration of simvastatin not only interfered with the development of EAM, but also inhibited the transfer. Antigen presenting cells (APCs) were proved to be important for the development of EAM. The ability of myocarditic splenocytes to transfer myocarditis was enhanced after co-culture with APCs. During co-culture of the myocarditic splenocytes and the APCs, simvastatin not only decreased percentages of CD28 expression in CD4-positive myocarditic splenocytes, and CD80 and CD86 expressions in APCs, but also inhibited the production of tumor necrosis factor (TNF)-partial differential in the CD4-positive myocarditic splenocytes and the APCs. These results indicate that simvastatin was able to ameliorate EAM through the inhibition of cross-talk between lymphocytes and APCs, suggesting beneficial role of simvastatin in the treatment of autoimmune myocarditis.
J Mol Cell Cardiol 2008 Jun
PMID:Amelioration of myocarditis by statin through inhibiting cross-talk between antigen presenting cells and lymphocytes in rats. 1847 27


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