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)

Myocarditis and dilated cardiomyopathy (DCM) are common causes of morbidity and mortality in children and adults, most commonly due to infection with coxsackievirus B or adenovirus. Increased expression of the common human coxsackievirus B-adenovirus receptor (CAR) has been reported in patients with DCM. We investigated the CAR gene in patients with acquired or familial myocarditis/DCM for mutations/polymorphisms. Several polymorphisms or intronic substitutions, distant from the intron-exon boundaries, were identified but no mutations. Based upon these data it appears that CAR gene mutations are not a major host determinant in the development of myocarditis and DCM.
Mol Genet Metab 2002 Nov
PMID:Analysis of the coxsackievirus B-adenovirus receptor gene in patients with myocarditis or dilated cardiomyopathy. 1240 75

Retrovirally induced acquired immunodeficiency in humans and mice induces immune dysregulation as well as increased oxidative stress as the disease progresses. Both immunodeficiency and oxidative stress make the host susceptible to the development of heat disease either by physiological changes or by the direct influence of cardiovirulance. Antioxidant supplementation has been shown to influence the onset as well as the degree of cardiopathology due to primary infections or co-infections. An alternative treatment is the use of peptide immunomodulatory therapy to enhance cytokine production, immune cell function and resistance to opportunistic infections. This review compiles our in vivo and in vitro studies on the effects of antioxidant supplementation and peptide therapy on the immune control of coxsackievirus induced cardiopathology in AIDS.
Cell Mol Biol (Noisy-le-grand) 2003 Mar
PMID:Immune control of coxsackievirus-induced cardiopathology. 1288

The transcription factor Elk-1 belongs to the ternary complex factor (TCF) subfamily of Ets proteins. TCFs interact with serum response factor to bind jointly to serum response elements in the promoters of immediate-early genes (IEGs). TCFs mediate the rapid transcriptional response of IEGs to various extracellular stimuli which activate mitogen-activated protein kinase signaling. To investigate physiological functions of Elk-1 in vivo, we generated Elk-1-deficient mice by homologous recombination in embryonic stem cells. These animals were found to be phenotypically indistinguishable from their wild-type littermates. Histological analysis of various tissues failed to reveal any differences between Elk-1 mutant and wild-type mice. Elk-1 deficiency caused no changes in the proteomic displays of brain or spleen extracts. Also, no immunological defects could be detected in mice lacking Elk-1, even upon infection with coxsackievirus B3. In mouse embryonic fibroblasts, Elk-1 was dispensable for c-fos and Egr-1 transcriptional activation upon stimulation with serum, lysophosphatidic acid, or tetradecanoyl phorbol acetate. However, in brains of Elk-1-deficient mice, cortical and hippocampal CA1 expression of c-fos, but not Egr-1 or c-Jun, was markedly reduced 4 h following kainate-induced seizures. This was not accompanied by altered patterns of neuronal apoptosis. Collectively, our data indicate that Elk-1 is essential neither for mouse development nor for adult life, suggesting compensatory activities by other TCFs.
Mol Cell Biol 2004 Jan
PMID:Mice deficient for the ets transcription factor elk-1 show normal immune responses and mildly impaired neuronal gene activation. 1467 63

Inflammatory heart diseases such as myocarditis and rheumatic heart disease result from the infiltration of the myocardium or valve with T cells and macrophages that result in scarring of the myocardium or valve and alteration in cardiac function. Our studies of T cells from these diseases have identified cardiac myosin in both rheumatic carditis and myocarditis as an important autoantigen. In rheumatic heart disease, streptococcal M protein specific T cells migrate to valves. By investigating streptococcal M protein and cardiac myosin in the Lewis rat model of myocarditis and valvulitis, T cell mimicry is supported as a potential mechanism in disease. Structural and immunological mimicry between the streptococcal M protein and cardiac myosin is shown directly in the Lewis rat model. Rat T cell lines demonstrate mimicry between cardiac myosin and M protein, and T cells isolated directly from inflammatory lesions in myocarditis respond to streptococcal M protein peptides. Studies in BALB/c mice also support the immunological crossreactivity of T cells primed against cardiac myosin with streptococcal M protein peptides containing cardiac myosin homologies. T cell lines produced from the Lewis rat specific to the cardiac myosin like sequences of streptococcal M protein migrated to the valves after passive transfer of the M protein specific T cell lines. In coxsackieviral myocarditis in the MRL mouse strain, cardiac myosin mimicking M protein peptide NT4 was found to induce tolerance and prevent coxsackieviral induced myocarditis, suggesting T cell mimicry between coxsackievirus and streptococcal M protein, both of which are associated with inflammatory heart disease. T cell mimicry between cardiac myosin and microbial antigens such as the streptococcal M protein may prime the immune system for inflammatory heart disease.
Mol Immunol 2004 Feb
PMID:T cell mimicry in inflammatory heart disease. 1503 18

Antisense oligonucleotides and ribozymes have been used widely to regulate gene expression by targeting mRNAs in a sequence-specific manner. Long RNAs, however, are highly structured molecules. Thus, up to 90% of putative cleavage sites have been shown to be inaccessible to classical RNA based ribozymes or DNAzymes. Here, we report the use of modified nucleotides to overcome barriers raised by internal structures of the target RNA. In our attempt to cleave a broad range of picornavirus RNAs, we generated a DNAzyme against a highly conserved sequence in the 5' untranslated region (5' UTR). While this DNAzyme was highly efficient against the 5' UTR of the human rhinovirus 14, it failed to cleave the identical target sequence within the RNA of the related coxsackievirus A21 (CAV-21). After introduction of 2'-O-methyl RNA or locked nucleic acid (LNA) monomers into the substrate recognition arms, the DNAzyme degraded the previously inaccessible virus RNA at a high catalytic rate even to completion, indicating that nucleotides with high target affinity were able to compete successfully with internal structures. We then adopted this strategy to two DNAzymes that we had found to be inactive in our earlier experiments. The modified DNAzymes proved to be highly effective against their respective target structures. Our approach may be useful for other ribozyme strategies struggling with accessibility problems, especially when being restricted to unique target sites.
J Mol Biol 2004 May 28
PMID:Gaining target access for deoxyribozymes. 1513 38

Recently, an integrated cell culture/polymerase chain reaction (ICC/PCR) technique has been developed for the detection of viruses in environmental samples providing a reliable method for practical analysis and direct monitoring of environmental samples for viral pathogens. CC/PCR allows for detection of infectious viruses in hours to days compared with the days or weeks necessary with cell culture alone. Bacterial indicator organisms are commonly used to evaluate environmental samples with respect to fecal contamination and potential public health impacts. These organisms do not correlate well with the presence of viruses, but a rapid, reliable method was not previously available for direct virus testing. Using ICC/PCR, environmental samples may be directly surveyed for pathogenic viruses, in a timely manner. Direct virus analysis will lead to better assessment of the presence and risk of human enteric viruses in the environment, so that control measures may be developed with true virus occurrence data. The ICC/PCR approach combines two previously applied virus detection methods, conventional cell culture and PCR amplification, utilizing the major advantages and overcoming the major limitations of each methodology when used alone. Cell culture assay is the standard method for the detection of viable human viruses (i.e., poliovirus, coxsackievirus, echovirus, adenovirus, hepatitis A virus, reovirus, and rotavirus) in environmental samples, serving as the method against which all newer technologies are evaluated. Although cell culture is theoretically capable of detecting a single viable virus in relatively large volumes of sample, the time required for confirmed results with conventional cell culture makes it an impractical method for routine monitoring of environmental samples. Furthermore, cell culture does not detect noncytopathogenic viruses (viruses that are viable, infecting cells, and continually spreading to neighboring cells but that do not cause a visible cytopathogenic effect [CPE] on the cell monolayer). Rotavirus and most wild-type hepatitis A viruses (HAV) are infectious to cell cultures but do not produce a clear CPE.
Methods Mol Biol 2004
PMID:Integrated cell culture/PCR for detection of enteric viruses in environmental samples. 1515 19

This chapter describes four murine models of autoimmune diseases: two related to autoimmune myocarditis and two related to autoimmune thyroiditis. The first model, Coxsackie virus B3 (CB3)-induced myocarditis, results in the development of acute myocarditis in susceptible as well as resistant mouse strains, whereas chronic myocarditis develops only in genetically susceptible mice. CB3-induced myocarditis closely resembles the course of human myocarditis, which is believed to be initiated by viral infection. Mouse cardiac myosin heavy chain has been identified as the major antigen associated with the late chronic phase of viral myocarditis. The second model is cardiac myosin-induced experimental autoimmune myocarditis (EAM) and, in a modification, cardiac alpha-myosin heavy chain peptide-induced myocarditis. In the EAM model, cardiac myosin or the relevant peptide in Freund's complete adjuvant (FCA) is injected subcutaneously into mice. The immune response, the histological changes, and the genetic susceptibility seen in EAM are similar to those of CB3-induced myocarditis. The third model is experimental autoimmune thyroiditis (EAT). EAT can be induced in genetically susceptible strains of mice by immunization with mouse thyroglobulin in FCA or lipopolysaccharide. Mice susceptible to EAT have the H-2A(k), H-2A(s), or H-2A(q) alleles. We describe here a standard technique for the induction of EAT; it was developed in our laboratory and is widely used as a model for studying Hashimoto's thyroiditis. The fourth model presented in this chapter is that of spontaneous autoimmune thyroiditis in NOD.H2h4 mice. These mice express the H-2A(k) allele on an NOD genetic background and develop spontaneous thyroiditis, which is exacerbated with dietary iodine.
Methods Mol Med 2004
PMID:Animal models for autoimmune myocarditis and autoimmune thyroiditis. 1528 86

The potential of RNA interference (RNAi) to inhibit virus propagation has been well established in recent years. In several studies, however, emergence of viral escape mutants after prolonged exposure to RNAi has been observed, raising a major hurdle for a possible therapeutic application of this strategy. Here, we report the design and characterisation of a vector that allows the simultaneous expression of two short hairpin RNAs (shRNAs), thereby maintaining high silencing activity even against a viral RNA bearing mutations in one of the target sites. Two short interfering RNAs (siRNAs) against the 3D-RNA dependent RNA polymerase of coxsackievirus B3 were identified that displayed efficient inhibition of virus propagation in HeLa cells and reduced the virus titre by up to 90%. We generated two expression vectors encoding these newly identified siRNAs and evaluated their silencing efficiency against the target gene in a reporter assay. Viral escape was then simulated by introducing a point mutation into either of the target sites. This substitution led to complete abrogation of silencing by the respective vector. To bypass this blockade of silencing, an siRNA double expression vector (SiDEx) was constructed to achieve simultaneous expression of both siRNAs from one plasmid. The silencing efficiency of both siRNAs generated by SiDEx was comparable to that of the individual mono-expression vectors. In contrast to the conventional expression vectors, SiDEx displayed substantial gene regulation also of the mutated target RNA. As our approach of expressing various shRNAs from one vector is based on a simple and universally applicable cloning strategy, SiDEx may be a helpful tool to achieve sustained silencing of viruses, ultimately reducing the risk of emergence of viable mutants. An additional application of SiDEx vectors will be the simultaneous knockdown of two targeted genes for functional studies.
J Mol Biol 2005 Feb 18
PMID:Maintaining inhibition: siRNA double expression vectors against coxsackieviral RNAs. 1567 May 96

Endomyocardial biopsy often fails to show myocardial inflammation for patients with clinically suspected myocarditis. The serum isoforms of troponin T (cTnT) level is a very sensitive marker of myocardial injury and it is elevated even in the absence of myocardial inflammation. We investigated the correlations for myocardial injury, virus titers and inflammation in acute viral infection. Using the murine coxsackievirus group B3 (CVB3) myocarditis model, the histopathologic findings and virus titers in mouse hearts were compared with the serum cTnT levels measured by ELISA at various time points. Viable virus titers in the hearts peaked at 3 days after infection (8.22 +/- 0.13 log10 PFU/100 mg of heart); they decreased at day 7 and no viable virus was detected from day 14. Myocardial inflammation was minimal at day 3, peaked at day 7 and markedly decreased at day 14. The individual serum TnT levels were significantly increased at day 3 (7.37 +/- 1.46 ng/ml), persisted to day 7 (0.73 +/- 0.08 ng/ml), and normalized at day 14. Serum cTnT levels were correlatable with virus titers in the heart (r = 0.744, P <0.01), but the serum cTnT levels were not correlated with the degrees of inflammation. Using the less myocarditic strain of CVB3, similar relationships were observed between the changes for the serum cTnT levels and the heart virus titers. During the course of viral infection, myocardial injury precedes the pathologic evidence of inflammation, and the elevated cTnT levels provide evidence of myocardial injury even in the absence of any histologic findings of myocarditis.
Exp Mol Med 2005 Feb 28
PMID:Myocardial injury occurs earlier than myocardial inflammation in acute experimental viral myocarditis. 1576 Dec 52

Efficient myocardial gene transfer in the intact adult heart is difficult using conventional transfer vectors. Since coxsackievirus B3 (CVB3) is cardiotropic, it may be possible to exploit its cardiotropic characteristics to design a vector for gene transfer to the intact heart. We generated a recombinant CVB3 cDNA by inserting a green fluorescent protein (GFP) gene immediately upstream from the VP0 capsid protein of CVB3. The infectious virus (rCVB3-GFP) was recovered from the supernatants of the transfected Cos-7 cells, and was grown in HeLa cells to titers of 10(11) pfu/ml. In the rCVB3-GFP infected HeLa cells and neonatal rat cardiac myocytes, GFP protein expression was documented by immunoblot and by fluorescent microscopy. GFP expression was maintained after five passages in HeLa cells. To test in vivo expression of GFP, we infected 8-week-old inbred female Balb/C mice with 10(6) pfu of rCVB3-GFP, intraperitoneally. GFP was present in up to 30% of cardiac myocytes over the 8 weeks post infection (p.i.) and it was co-localized with CVB3 infection. Surprisingly, in spite of detection of GFP up to at least 8 weeks after infection, there was no mortality in the mice. It is possible to express exogenous proteins in the intact heart after an intraperitoneal (i.p.) injection of recombinant coxsackievirus. The duration of expression persisted for at least 8 weeks with little immune response nor mortality. These results demonstrated that the cardiac tropism of CVB3 could be used to design vectors for efficient gene expression in the intact heart.
J Mol Cell Cardiol 2005 May
PMID:Long-term cardiac gene expression using a coxsackieviral vector. 1585 May 68


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