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https://www.readbyqxmd.com/read/28381577/understanding-the-mechanism-of-the-broad-spectrum-antiviral-favipiravir-t-705-key-role-of-the-f1-motif-of-the-viral-polymerase
#1
Rana Abdelnabi, Ana Theresa Silveira de Morais, Pieter Leyssen, Isabelle Imbert, Stéphanie Beaucourt, Hervé Blanc, Mathy Froeyen, Marco Vignuzzi, Bruno Canard, Johan Neyts, Leen Delang
Favipiravir (T-705) is a broad-spectrum antiviral agent that has been approved in Japan for treatment of influenza virus infections. T-705 also inhibits the replication of various RNA viruses including chikungunya virus (CHIKV). We demonstrated earlier that the K291R mutation in the F1 motif of the RNA-dependent RNA polymerase (RdRp) of CHIKV is responsible for low-level resistance to T-705. Interestingly, this lysine is highly conserved in the RdRp of positive-sense single-stranded RNA [+ssRNA] viruses. To obtain insights into the unique broad-spectrum antiviral activity of T-705, we explored the role of this lysine using another +ssRNA virus, namely Coxsackievirus B3 (CVB3)...
April 5, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28359509/autosomal-recessive-cardiomyopathy-presenting-as-acute-myocarditis
#2
Serkan Belkaya, Amy R Kontorovich, Minji Byun, Sonia Mulero-Navarro, Fanny Bajolle, Aurelie Cobat, Rebecca Josowitz, Yuval Itan, Raphaelle Quint, Lazaro Lorenzo, Soraya Boucherit, Cecile Stoven, Sylvie Di Filippo, Laurent Abel, Shen-Ying Zhang, Damien Bonnet, Bruce D Gelb, Jean-Laurent Casanova
BACKGROUND: Myocarditis is inflammation of the heart muscle that can follow various viral infections. Why children only rarely develop life-threatening acute viral myocarditis (AVM), given that the causal viral infections are common, is unknown. Genetic lesions might underlie such susceptibilities. Mouse genetic studies demonstrated that interferon (IFN)-α/β immunity defects increased susceptibility to virus-induced myocarditis. Moreover, variations in human TLR3, a potent inducer of IFNs, were proposed to underlie AVM...
April 4, 2017: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/28341822/berberine-restricts-coxsackievirus-b-type-3-replication-via-inhibition-of-c-jun-n-terminal-kinase-jnk-and-p38-mapk-activation-in-vitro
#3
Qian Dai, Di Zhang, Hua Yu, Wei Xie, Rong Xin, Lei Wang, Xiaohui Xu, Xiaomei He, Junzhi Xiong, Halei Sheng, Le Zhang, Kebin Zhang, Xiaomei Hu
BACKGROUND At present, the treatment of coxsackievirus-induced myocarditis remains difficult. Berberine (BBR), an isoquinoline alkaloid isolated from traditional medicine herbs, exhibits significant anti-viral efficacy against various viruses. However, the underlying mechanism by which BBR controls CVB3 infection has not yet been reported. The purpose of this study was to investigate the anti-viral efficacy of BBR against CVB3 infection and its mechanism. MATERIAL AND METHODS In our experiments, the protein levels of VP1 and MAPKs signal pathway were measured by Western blot...
March 25, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/28278207/pa28-modulates-antigen-processing-and-viral-replication-during-coxsackievirus-b3-infection
#4
Dorota Respondek, Martin Voss, Ina Kühlewindt, Karin Klingel, Elke Krüger, Antje Beling
The function of the proteasome is modulated at the level of subunit expression and by association with its regulatory complexes. During coxsackievirus B3 (CVB3) myocarditis, IFN-induced formation of immunoproteasomes (ip) is known to be critical for regulating immune modulating molecules. The function of the IFN-γ-inducible proteasome regulator subunits PA28 α and β, however, in this context was unknown. During viral myocarditis, we found an increased abundance of PA28β subunits in heart tissue. PA28α/β exists in PA28-20S-PA28 and PA700-20S-PA28 hybrid proteasome complexes in cells both with either predominant ip and standard proteasome (sp) expression...
2017: PloS One
https://www.readbyqxmd.com/read/28264039/in-vivo-t2-weighted-mri-visualizes-cardiac-lesions-in-murine-models-of-acute-and-chronic-viral-myocarditis
#5
Xavier Helluy, Martina Sauter, Yu-Xiang Ye, Gunthard Lykowsky, Jakob Kreutner, Ali Yilmaz, Roland Jahns, Valerie Boivin, Reinhard Kandolf, Peter M Jakob, Karl-Heinz Hiller, Karin Klingel
OBJECTIVE: Acute and chronic forms of myocarditis are mainly induced by virus infections. As a consequence of myocardial damage and inflammation dilated cardiomyopathy and chronic heart failure may develop. The gold standard for the diagnosis of myocarditis is endomyocardial biopsies which are required to determine the etiopathogenesis of cardiac inflammatory processes. However, new non-invasive MRI techniques hold great potential in visualizing cardiac non-ischemic inflammatory lesions at high spatial resolution, which could improve the investigation of the pathophysiology of viral myocarditis...
2017: PloS One
https://www.readbyqxmd.com/read/28247213/microrna-20b-suppresses-the-expression-of-zfp-148-in-viral-myocarditis
#6
Hong-Fei Xu, Xiang-Ting Gao, Jun-Yi Lin, Xue-Hua Xu, Jun Hu, Yu-Jie Ding, Shao-Hua Zhu
Viral myocarditis is a common cardiovascular disease, which seriously endangers the health of people and even leads to sudden unexpected death. MicroRNAs play very important roles in various physical and pathological processes including cardiogenesis and heart diseases. In recent years, miR-20b has been implicated in various diseases such as breast cancer, gastric cancer, hepatocellular carcinoma, cardiovascular diseases. However, the function of miR-20b in the pathological progress of viral myocarditis has not been reported...
February 28, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28186704/mesenchymal-stromal-cells-modulate-monocytes-trafficking-in-coxsackievirus-b3-induced-myocarditis
#7
Kapka Miteva, Kathleen Pappritz, Muhammad El-Shafeey, Fengquan Dong, Jochen Ringe, Carsten Tschöpe, Sophie Van Linthout
Mesenchymal stromal cell (MSC) application in Coxsackievirus B3 (CVB3)-induced myocarditis reduces myocardial inflammation and fibrosis, exerts prominent extra-cardiac immunomodulation, and improves heart function. Although the abovementioned findings demonstrate the benefit of MSC application, the mechanism of the MSC immunomodulatory effects leading to a final cardioprotective outcome in viral myocarditis remains poorly understood. Monocytes are known to be a trigger of myocardial tissue inflammation. The present study aims at investigating the direct effect of MSC on the mobilization and trafficking of monocytes to the heart in CVB3-induced myocarditis...
April 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28176833/transmissible-endoplasmic-reticulum-stress-from-myocardiocytes-to-macrophages-is-pivotal-for-the-pathogenesis-of-cvb3-induced-viral-myocarditis
#8
Hui Zhang, Yan Yue, Tianle Sun, Xuejie Wu, Sidong Xiong
Infiltrating macrophages have been proven as a pivotal pathological inflammatory cell subset in coxsackievirus B3 (CVB3) induced viral myocarditis. However, the mechanisms underlying the initiation and promotion of macrophage pro-inflammatory responses are still blur. We previously reported that cardiac ER stress contributed to CVB3-induced myocarditis by augmenting inflammation. In this study, we focused on the influence of ER stress on the macrophage inflammatory responses in the viral myocarditis. We found that ER stress was robustly induced in the cardiac infiltrating macrophages from CVB3-infected mice, and robustly facilitated the production of pro-inflammatory cytokines (IL-6, IL-12, MCP-1 and IP-10)...
February 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28174228/profiling-subcellular-protein-phosphatase-responses-to-coxsackievirus-b3-infection-of-cardiomyocytes
#9
Millie Shah, Christian M Smolko, Sarah Kinicki, Zachary D Chapman, David L Brautigan, Kevin A Janes
Cellular responses to stimuli involve dynamic and localized changes in protein kinases and phosphatases. Here, we report a generalized functional assay for high-throughput profiling of multiple protein phosphatases with subcellular resolution and apply it to analyze coxsackievirus B3 (CVB3) infection counteracted by interferon signaling. Using on-plate cell fractionation optimized for adherent cells, we isolate protein extracts containing active endogenous phosphatases from cell membranes, the cytoplasm, and the nucleus...
April 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28148910/intein-mediated-backbone-cyclization-of-vp1-protein-enhanced-protection-of-cvb3-induced-viral-myocarditis
#10
Xingmei Qi, Sidong Xiong
CVB3 is a common human pathogen to be highly lethal to newborns and causes viral myocarditis and pancreatitis in adults. However, there is no vaccine available for clinical use. CVB3 capsid protein VP1 is an immunodominant structural protein, containing several B- and T-cell epitopes. However, immunization of mice with VP1 protein is ineffective. Cyclization of peptide is commonly used to improve their in vivo stability and biological activity. Here, we designed and synthesizd cyclic VP1 protein by using engineered split Rma DnaB intein and the cyclization efficiency was 100% in E...
February 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28137624/incorporation-of-a-bi-functional-protein-fimh-enhances-the-immunoprotection-of-chitosan-pvp1-vaccine-against-coxsackievirus-b3-induced-myocarditis
#11
Xiangmei Fan, Yan Yue, Sidong Xiong
Viral myocarditis is a common clinical cardiovascular disease mainly induced by coxsackievirus B3 (CVB3) with no effective therapeutic measures. Induction of efficient mucosal immune responses is very critical against CVB3-induced myocarditis. FimH is an Escherichia coli (E. coli)-derived protein, which possesses an M cell-targeting property and functions as a TLR4 agonist. In this study, we introduced the recombinant FimH protein, into our previously developed CVB3 mucosal vaccine chitosan (CS)-pVP1, aiming to provoke more efficient mucosal immune responses and immunoprotection against CVB3-induced myocarditis...
April 2017: Antiviral Research
https://www.readbyqxmd.com/read/28131843/inhibition-of-drp1-attenuates-mitochondrial-damage-and-myocardial-injury-in-coxsackievirus-b3-induced-myocarditis
#12
Lin Lin, Ming Zhang, Rui Yan, Hu Shan, Jiayu Diao, Jin Wei
Viral myocarditis (VMC) is closely related to apoptosis, oxidative stress, innate immunity, and energy metabolism, which are all linked to mitochondrial dysfunction. A close nexus between mitochondrial dynamics and cardiovascular disease with mitochondrial dysfunction has been deeply researched, but there is still no relevant report in viral myocarditis. In this study, we aimed to explore the role of Dynamin-related protein 1 (Drp1)-linked mitochondrial fission in VMC. Mice were inoculated with the Coxsackievirus B3 (CVB3) and treated with mdivi1 (a Drp1 inhibitor)...
March 11, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28129450/viral-encephalitis-after-haplo-identical-hematopoietic-stem-cell-transplantation-causative-viral-spectrum-characteristics-and-risk-factors
#13
Xiao-Hui Zhang, Jia-Min Zhang, Wei Han, Huan Chen, Yu-Hong Chen, Feng-Rong Wang, Jing-Zhi Wang, Yuan-Yuan Zhang, Xiao-Dong Mo, Yao Chen, Yu Wang, Ying-Jun Chang, Lan-Ping Xu, Kai-Yan Liu, Xiao-Jun Huang
OBJECTIVE: To retrospectively identify characteristics and risk factors of viral encephalitis (VE) in patients who underwent a haplo-identical hematopoietic stem cell transplant (HSCT). METHODS: A nested case-control study was designed. Cases with VE and controls were identified from a cohort composed of 1274 patients who underwent a haplo-identical HSCT from 2012 to 2015. RESULTS: VE was identified in 30 patients (2.4%). The median time from HSCT to diagnosis was 144...
January 27, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28123495/effects-of-the-mapk-pathway-and-the-expression-of-car-in-a-murine-model-of-viral-myocarditis
#14
Ling Niu, Chunli Li, Zhenzhou Wang, Hui Xu, Xinjiang An
The pathogenesis of viral myocarditis (VMC) is not fully understood. This study aimed to examine the relationship between coxsackie-adenovirus receptor (CAR) and the p38 mitogen activated protein kinase (MAPK) pathway mechanisms in a mouse model. Three groups of mice were established: 5 mice in a control group injected with saline, 15 in the model group injected with coxsackie virus B3 (CVB) and 15 in the intervention group injected with CVB3 but treated with the p38 MAPK inhibitor SB203580. Mice were sacrificed at days 1, 5, 10, 15 and 30 and cardiac tissues were isolated to perform the tests...
January 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28110209/expansion-of-cd11b-ly-6c-myeloid-derived-suppressor-cells-mdscs-driven-by-galectin-9-attenuates-cvb3-induced-myocarditis
#15
Yingying Zhang, Mengying Zhang, Xueqin Li, Zongsheng Tang, Ling He, Kun Lv
Galectin-9 is known to play a role in the modulation of innate and adaptive immunity to ameliorate CVB3-induced myocarditis. In the present study, we found that galectin-9 induced the expansion of CD11b(+)Ly-6C(+) myeloid-derived suppressor cells (MDSCs) in the heart from CVB3-infected mice. Adoptive transfer of CD11b(+)Ly-6C(+) MDSCs significantly alleviated myocarditis accompanied by increased Th2 and Treg frequency and anti-inflammatory cytokines expression in the heart tissue. Moreover, Ly6C(+) MDSCs, but not Ly6G(+) cells, expressed Arg-1 and NOS2, and suppressed CD4(+) T cell proliferation in vitro in an Arg-1-dependent mechanism; an event that was reversed with treatment of either an Arg-1 inhibitor or addition of excess l-arginine...
March 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28109785/novel-12n-substituted-matrinanes-as-potential-anti-coxsackievirus-agents
#16
Ying-Hong Li, Sheng Tang, Yu-Huan Li, Xin-Yue Cheng, Xin Zhang, Yan-Xiang Wang, Feng Su, Dan-Qing Song
A series of novel 12N-substituted matrinane derivatives were synthesized and evaluated for their activities against coxsackievirus type B3 (CVB3) taking compound 1 as the lead. SAR analysis indicated that the introduction of a suitable heteroaromatic ring on the 12N-atom might be beneficial for the activity. Among them, compound 8a exhibited the highest potency against all CVB serotypes as well as CVA16 with IC50 values ranging from 2.02μM to 7.41μM, indicating a broad-spectrum anti-coxsackieviruse effect...
January 10, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28100612/sex-dependent-intestinal-replication-of-an-enteric-virus
#17
Christopher M Robinson, Yao Wang, Julie K Pfeiffer
Coxsackievirus is an enteric virus that initiates infection in the gastrointestinal tract before disseminating to peripheral tissues to cause disease, but intestinal factors that influence viral replication are understudied. Furthermore, a sex bias for severe sequelae from coxsackievirus infections has been observed in humans. While mouse models mimicking human pathogenesis have been well characterized, many of these experiments use intraperitoneal injection of coxsackievirus to infect mice, bypassing the intestine...
April 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28095607/heat-shock-protein-70-promotes-coxsackievirus-b3-translation-initiation-and-elongation-via-akt-mtorc1-pathway-depending-on-activation-of-p70s6k-and-cdc2
#18
Fengping Wang, Ye Qiu, Huifang M Zhang, Paul Hanson, Xin Ye, Guangze Zhao, Ronald Xie, Lei Tong, Decheng Yang
We previously demonstrated that coxsackievirus B3 (CVB3) infection upregulated heat shock protein 70 (Hsp70) and promoted CVB3 multiplication. Here, we report the underlying mechanism by which Hsp70 enhances viral RNA translation. By using an Hsp70-overexpressing cell line infected with CVB3, we found that Hsp70 enhanced CVB3 VP1 translation at two stages. First, Hsp70 induced upregulation of VP1 translation at the initiation stage via upregulation of internal ribosome entry site trans-acting factor lupus autoantigen protein and activation of eIF4E binding protein 1, a cap-dependent translation suppressor...
January 17, 2017: Cellular Microbiology
https://www.readbyqxmd.com/read/28041873/il-33-enhances-macrophage-m2-polarization-and-protects-mice-from-cvb3-induced-viral-myocarditis
#19
Chao Wang, Chunsheng Dong, Sidong Xiong
Viral myocarditis is the inflammation caused by myocardial virus infection, and the coxsackievirus group B3 virus (CVB3) is the most common pathogen. An efficient therapeutic agent against viral myocarditis is currently unavailable. IL-33, a new member of the IL-1 cytokine superfamily, exhibits potential immunotherapeutic effect against inflammatory and autoimmune diseases. However, the functional role of IL-33 in viral myocarditis has not been investigated. To examine the therapeutic role of IL-33 in viral myocarditis, an IL-33 overexpression plasmid (pDisplay-IL-33) and IL-33 knockdown plasmid (pLL3...
February 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28018858/coxsackievirus-b3-directly-induced-th17-cell-differentiation-by-inhibiting-nup98-expression-in-patients-with-acute-viral-myocarditis
#20
Qi Long, Yu-Hua Liao, Yu Xie, Wei Liang, Xiang Cheng, Jing Yuan, Miao Yu
Th17 cells play a key role in the progression of coxsackievirus B3 (CVB3)-induced acute viral myocarditis (AVMC). However, the direct effect of virus on Th17 cell differentiation is still unknown. Recently, nucleoporin (Nup) 98 has been proved to be associated with lymphocyte differentiation. Therefore, we investigated whether Nup98 mediated Th17 cell differentiation in AVMC. In our study, patients with AVMC and healthy controls were recruited. The results showed that CVB3 could enter into the CD4(+) T cells in AVMC patients and healthy controls...
2016: Frontiers in Cellular and Infection Microbiology
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