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Alexander Bernt, Ashraf Y Rangrez, Matthias Eden, Andreas Jungmann, Sylvia Katz, Claudia Rohr, Oliver J Müller, Hugo A Katus, Samuel T Sossalla, Tatjana Williams, Oliver Ritter, Derk Frank, Norbert Frey
The objective of this study was to identify unknown modulators of Calcineurin (Cn)-NFAT signaling. Measurement of NFAT reporter driven luciferase activity was therefore utilized to screen a human cardiac cDNA-library (~10(7) primary clones) in C2C12 cells through serial dilutions until single clones could be identified. This extensive screening strategy culminated in the identification of SUMO2 as a most efficient Cn-NFAT activator. SUMO2-mediated activation of Cn-NFAT signaling in cardiomyocytes translated into a hypertrophic phenotype...
October 21, 2016: Scientific Reports
Emilia Pachulec, Vanessa Neitzke-Montinelli, João P B Viola
Nuclear factor of activated T cells (NFAT) 2 null mutant mice die in utero of cardiac failure, precluding analysis of the role of NFAT2 in lymphocyte responses. Only the NFAT2(-/-)/Rag-1(-/-) chimeric mice model gave insight into the role of NFAT2 transcription factor in T lymphocyte development, activation, and differentiation. As reports are mainly focused on the role of NFAT2 in CD4(+) T lymphocytes activation and differentiation, we decided to investigate NFAT2's impact on CD8(+) T lymphocyte responses...
2016: Frontiers in Immunology
Matías Hernández, Susana Wicz, Ricardo S Corral
BACKGROUND: Diverse cardiovascular signaling routes have been considered critical for Chagas cardiomyopathy caused by the protozoan parasite Trypanosoma cruzi. Along this line, T. cruzi infection and endothelin-1 (ET-1) have been shown to cooperatively activate the Ca(2+)/NFAT cascade in cardiomyocytes, leading to cyclooxygenase type 2 (COX-2) induction and increased release of prostanoids and prohypertrophic peptides. PURPOSE: To determine whether the well-known cardioprotective and anti-inflammatory effects of curcumin (Cur) could be helpful to interfere with this key machinery for pathogenesis of Chagas myocarditis...
November 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Fabiana de Salvi Guimarães, Wilson Max Almeida Monteiro de Moraes, Luis Henrique Marchesi Bozi, Pâmela R Souza, Ednei Luiz Antonio, Danilo Sales Bocalini, Paulo José Ferreira Tucci, Daniel Araki Ribeiro, Patricia Chakur Brum, Alessandra Medeiros
Dexamethasone is a potent and widely used anti-inflammatory and immunosuppressive drug. However, recent evidences suggest that dexamethasone cause pathologic cardiac remodeling, which later impairs cardiac function. The mechanism behind the cardiotoxic effect of dexamethasone is elusive. The present study aimed to verify if dexamethasone-induced cardiotoxicity would be associated with changes in the cardiac net balance of calcium handling protein and calcineurin signaling pathway activation. Wistar rats (~400 g) were treated with dexamethasone (35 µg/g) in drinking water for 15 days...
October 19, 2016: Molecular and Cellular Biochemistry
Jiae Kim, Su-Min Kim, Jung-Min Na, Hoh-Gyu Hahn, Sung-Woo Cho, Seung-Ju Yang
We recently reported the anti-inflammatory effects of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride (KHG26792) on the ATP-induced activation of the NFAT and MAPK pathways through the P2X7 receptor in microglia. To further investigate the underlying mechanism of KHG26792, we studied its protective effects on hypoxia-induced toxicity in microglia. The administration of KHG26792 significantly reduced the hypoxia-induced expression and activity of caspase-3 in BV-2 microglial cells. KHG26792 also reduced hypoxia-induced inducible nitric oxide synthase protein expression, which correlated with reduced nitric oxide accumulation...
October 19, 2016: BMB Reports
Nadia Soudani, Crystal M Ghantous, Zein Farhat, Wassim N Shebaby, Kazem Zibara, Asad Zeidan
Background and Aims: Hypertension and obesity are important risk factors of cardiovascular disease. They are both associated with high leptin levels and have been shown to promote vascular hypertrophy, through the RhoA/ROCK and ERK1/2 phosphorylation. Calcineurin/NFAT activation also induces vascular hypertrophy by upregulating various genes. This study aimed to decipher whether a crosstalk exists between the RhoA/ROCK pathway, Ca(2+)/calcineurin/NFAT pathway, and ERK1/2 phosphorylation in the process of mechanical stretch-induced vascular smooth muscle cell (VSMC) hypertrophy and leptin synthesis...
2016: Frontiers in Physiology
Liming Wang, L Zhu, R Luan, L Wang, J Fu, X Wang, L Sui
Dilated cardiomyopathy (DCM) is characterized by ventricular dilatation, and it is a common cause of heart failure and cardiac transplantation. This study aimed to explore potential DCM-related genes and their underlying regulatory mechanism using methods of bioinformatics. The gene expression profiles of GSE3586 were downloaded from Gene Expression Omnibus database, including 15 normal samples and 13 DCM samples. The differentially expressed genes (DEGs) were identified between normal and DCM samples using Limma package in R language...
October 10, 2016: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
Shangfu Li, Bu Yang, Dian Teguh, Lin Zhou, Jiake Xu, Limin Rong
Osteoporosis and Alzheimer's disease (AD) are common chronic degenerative disorders which are strongly associated with advanced age. We have previously demonstrated that amyloid beta peptide (Aβ), one of the pathological hallmarks of AD, accumulated abnormally in osteoporotic bone specimens in addition to having an activation effect on osteoclast (Bone 2014,61:164-75). However, the underlying molecular mechanisms remain unclear. Activation of NF-κB, extracellular signal-regulated kinase (ERK) phosphorylates, and calcium oscillation signaling pathways by receptor activator NF-κB ligand (RANKL) plays a pivotal role in osteoclast activation...
October 10, 2016: International Journal of Molecular Sciences
Riikka Kivelä, Ida Salmela, Yen Hoang Nguyen, Tatiana V Petrova, Heikki A Koistinen, Zoltan Wiener, Kari Alitalo
The remarkable adaptive and regenerative capacity of skeletal muscle is regulated by several transcription factors and pathways. Here we show that the transcription factor Prox1 is an important regulator of myoblast differentiation and of slow muscle fibre type. In both rodent and human skeletal muscles Prox1 is specifically expressed in slow muscle fibres and in muscle stem cells called satellite cells. Prox1 activates the NFAT signalling pathway and is necessary and sufficient for the maintenance of the gene program of slow muscle fibre type...
October 12, 2016: Nature Communications
Masashi Asai, Aimi Kinjo, Shoko Kimura, Ryotaro Mori, Takashi Kawakubo, Keiro Shirotani, Sosuke Yagishita, Kei Maruyama, Nobuhisa Iwata
Down syndrome (DS), the most common genetic disorder, is caused by trisomy 21. DS is accompanied by heart defects, hearing and vision problems, obesity, leukemia, and other conditions, including Alzheimer's disease (AD). In comparison, most cancers are rare in people with DS. Overexpression of dual specificity tyrosine-phosphorylation-regulated kinase 1A and a regulator of calcineurin 1 located on chromosome 21 leads to excessive suppression of the calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway, resulting in reduced expression of a critical angiogenic factor...
2016: Biological & Pharmaceutical Bulletin
Wei Zhang, Jie-Fei Bai, Meng-Xuan Zuo, Xin-Xin Cao, Miao Chen, Yan Zhang, Xiao Han, Ding-Rong Zhong, Dao-Bin Zhou
The aim of the study was to investigate the relationship between PD-1 expression on the surface of CD4(+) T cells and prognosis of patients with diffuse large B-cell lymphoma (DLBCL). Sixty patients who were newly diagnosed with DLBCL and 39 healthy controls were enrolled. In CD4(+) T cells of DLBCL patients, the median MFI of PD-1 were 541.5 (range: 348.25-758.75), significantly higher than 250 (range: 211-326) in healthy controls (P < 0.001). The ZAP70, PI3K, and NFAT mRNA expression levels of patients were 0...
October 5, 2016: Cancer Medicine
Musheng Bao, York Wang, Ying Liu, Peiqing Shi, Hongbo Lu, Wenwen Sha, Leiyun Weng, Shino Hanabuchi, Jun Qin, Joel Plumas, Laurence Chaperot, Zhiqiang Zhang, Yong-Jun Liu
Plasmacytoid dendritic cells (pDCs) rapidly produce large amounts of type 1 interferon (IFN) after Toll-like receptor 7 and 9 engagements. This specialized function of type 1 IFN production is directly linked to the constitutive expression of IRF7, the master transcription factor for type 1 IFN production. However, the IRF7 regulatory network in pDCs remains largely unknown. In this study, we identify that the transcription factor NFATC3 specifically binds to IRF7 and enhances IRF7-mediated IFN production. Furthermore, knockout of NFATC3 greatly reduced the CpG DNA-induced nuclear translocation of IRF7, which resulted in impaired type 1 IFN production in vitro and in vivo...
October 3, 2016: Journal of Experimental Medicine
Adam S Helms, Francisco J Alvarado, Jaime Yob, Vi T Tang, Francis Pagani, Mark W Russell, Héctor H Valdivia, Sharlene M Day
BACKGROUND: -Aberrant calcium signaling may contribute to arrhythmias and adverse remodeling in hypertrophic cardiomyopathy (HCM). Mutations in sarcomere genes may distinctly alter calcium handling pathways. METHODS: -We analyzed gene expression, protein levels, and functional assays for calcium regulatory pathways in human HCM surgical samples with (n=25) and without (n=10) sarcomere mutations compared with control hearts (n=8). RESULTS: -Gene expression and protein levels for calsequestrin, L-type calcium channel, sodium-calcium exchanger, phospholamban (PLN), calcineurin, and calcium/calmodulin-dependent protein kinase type II (CaMKII) were similar in HCM compared to controls...
September 29, 2016: Circulation
Syed Zahid Ali Shah, Tariq Hussain, Deming Zhao, Lifeng Yang
Accumulation of misfolded/unfolded aggregated proteins in the brain is a hallmark of many neurodegenerative diseases affecting humans and animals. Dysregulation of calcium (Ca(2+)) and disruption of fast axonal transport (FAT) are early pathological events that lead to loss of synaptic integrity and axonal degeneration in early stages of neurodegenerative diseases. Dysregulated Ca(2+) in the brain is triggered by accumulation of misfolded/unfolded aggregated proteins in the endoplasmic reticulum (ER), a major Ca(2+) storing organelle, ultimately leading to neuronal dysfunction and apoptosis...
September 28, 2016: Cellular and Molecular Life Sciences: CMLS
Zhen Tan, Jianwen Cheng, Qian Liu, Lin Zhou, Jacob Kenny, Tao Wang, Xixi Lin, Jinbo Yuan, Julian M W Quinn, Jennifer Tickner, Guoju Hong, An Qin, Jinmin Zhao, Jiake Xu
Excessive bone resorption by osteoclasts plays an important role in osteoporosis. Bone loss occurs in ovariectomised (OVX) mice in a similar manner to that in humans, so this model is suitable for evaluating potential new therapies for osteoporosis. Neohesperidin (NE) is a flavonoid compound isolated from citrus fruits. Its role in bone metabolism is unknown. In this study we found that neohesperidin inhibits osteoclast differentiation, bone resorption and the expression of osteoclast marker genes, tartrate-resistant acid phosphatase and cathepsin K...
September 21, 2016: Molecular and Cellular Endocrinology
Xue Wang, Bing Sun, Christelle Mbondji, Santanu Biswas, Jiangqin Zhao, Indira Hewlett
Macrophages contribute to HIV-1 pathogenesis by forming a viral reservoir that serve as a viral source for the infection of CD4 T cells. The relationship between HIV-1 latent infection and superinfection in macrophages has not been well studied. Using susceptible U1 cells chronically infected with HIV-1, we studied the effects of HIV superinfection on latency and differences in superinfection with HIV-1 and HIV-2 in macrophages. We found that HIV-1 (MN) superinfection displayed increased HIV-1 replication in a time-dependent manner; while cells infected with HIV-2 (Rod) initially showed increased HIV-1 replication, followed by a decrease in HIV-1 RNA production...
September 23, 2016: Journal of Cellular Physiology
Emaad Abdel-Kahaar, Thomas Giese, Claudia Sommerer, Hannah Rieger, Maria Shipkova, Eberhard Wieland
BACKGROUND: Analysis of residual gene expression (RGE) of NFAT-regulated genes has been developed as a pharmacodynamic biomarker to monitor therapy with calcineurin inhibitors (CNI). The availability of commercial primer sets (Search-LC, Heidelberg) and the well-established assay protocol make this biomarker a promising candidate to be utilized clinically in different laboratories. However, implementation of the method in routine practice requires analytical robustness and comparable results across laboratories...
September 16, 2016: Therapeutic Drug Monitoring
Min Fang, Pei Zhang, Yanxin Zhao, Aiping Jin, Xueyuan Liu
Sigma receptor is an endoplasmic reticulum protein and belongs to non-opioid receptor. Increasing evidence shows that Sigma receptor activation can significantly attenuate AD induced neurological dysfunction and the functional deficiency of Sigma receptor plays an important role in the Aβ induced neuronal loss. This study aimed to investigate the influence of extracellular accumulation of Aβ on the Sigma receptor expression. Our results showed the increase in extracellular Aβ had little influence on the mRNA expression of Sigma receptor, but gradually reduced its protein expression...
2016: American Journal of Translational Research
Seung-Hwa Kwak, Jung-Ah Kang, Minjeong Kim, So-Deok Lee, Jin-Hee Park, Sung-Gyoo Park, Hyojin Ko, Yong-Chul Kim
The quinolinone skeleton has been utilized to develop various mechanism-based immune modulators. However, the effects of quinolinone derivatives on the release of T cell-associated interleukin-2 (IL-2) have not been established. In this study, a series of novel quinolinone derivatives was synthesized, and their immunosuppressive activity was evaluated by measuring suppression of IL-2 release from activated Jurkat T cells. Optimizing the three side chains around the quinolinone skeleton revealed the most active compound: 11l...
November 1, 2016: Bioorganic & Medicinal Chemistry
Zhong Wang, Yibin Wang, Xiaodi Tian, Haitao Shen, Yang Dou, Haiying Li, Gang Chen
Transient receptor potential channel 1/4 (TRPC1/4) are considered to be related to subarachnoid hemorrhage (SAH)-induced cerebral vasospasm. In this study, a SAH rat model was employed to study the roles of TRPC1/4 in the early brain injury (EBI) after SAH. Primary cultured hippocampal neurons were exposed to oxyhemoglobin to mimic SAH in vitro. The protein levels of TRPC1/4 increased and peaked at 5 days after SAH in rats. Inhibition of TRPC1/4 by SKF96365 aggravated SAH-induced EBI, such as cortical cell death (by TUNEL staining) and degenerating (by FJB staining)...
2016: Scientific Reports
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