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https://www.readbyqxmd.com/read/28106828/bajijiasu-abrogates-osteoclast-differentiation-via-the-suppression-of-rankl-signaling-pathways-through-nf-%C3%AE%C2%BAb-and-nfat
#1
Guoju Hong, Lin Zhou, Xuguang Shi, Wei He, Haibin Wang, Qiushi Wei, Peng Chen, Longkai Qi, Jennifer Tickner, Li Lin, Jiake Xu
Pathological osteolysis is commonly associated with osteoporosis, bone tumors, osteonecrosis, and chronic inflammation. It involves excessive resorption of bone matrix by activated osteoclasts. Suppressing receptor activator of NF-κB ligand (RANKL) signaling pathways has been proposed to be a good target for inhibiting osteoclast differentiation and bone resorption. Bajijiasu-a natural compound derived from Morinda officinalis F. C. How-has previously been shown to have anti-oxidative stress property; however, its effect and molecular mechanism of action on osteoclastogenesis and bone resorption remains unclear...
January 19, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28103134/the-role-of-nuclear-factor-of-activated-t-cells-in-pulmonary-arterial-hypertension
#2
Rui Chen, Jinchuan Yan, Peijing Liu, Zhongqun Wang, Cuiping Wang, Wei Zhong, Liangjie Xu
Nuclear factor of activated T cells (NFAT) was first identified as a transcription factor about three decades ago and was not well studied until the development of immunosuppressant. Numerous studies confirm that calcineurin/NFAT signaling is very important in the development of vasculature and cardiovascular system during embryogenesis and is involved in the development of vascular diseases such as hypertension, atherosclerosis and restenosis. Recent studies demonstrated that NFAT proteins also regulate immune response and vascular cells in the pulmonary microenvironment...
January 19, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28100021/identifying-the-biphasic-role-of-calcineurin-nfat-signaling-enables-replacement-of-sox2-in-somatic-cell-reprogramming
#3
Sherif Khodeer, Takumi Era
Induction of pluripotency with defined factors (Oct4, Sox2, Klf4, c-Myc) raises hopes for successful clinical trials. Despite considerable efforts, the molecular mechanism of reprogramming remains poorly understood. The aim of the present study was to identify the role of calcineurin/nuclear factor of activated T cells (NFAT) in reprogramming. Our results demonstrated a biphasic role for calcineurin/NFAT signaling during reprogramming. In the early phase of reprogramming, calcineurin activity is required to maintain proper cell cycle division and for mesenchymal-epithelial transition...
January 18, 2017: Stem Cells
https://www.readbyqxmd.com/read/28062691/activating-mutations-and-translocations-in-the-guanine-exchange-factor-vav1-in-peripheral-t-cell-lymphomas
#4
Francesco Abate, Ana C da Silva-Almeida, Sakellarios Zairis, Javier Robles-Valero, Lucile Couronne, Hossein Khiabanian, S Aidan Quinn, Mi-Yeon Kim, Maria Antonella Laginestra, Christine Kim, Danilo Fiore, Govind Bhagat, Miguel Angel Piris, Elias Campo, Izidore S Lossos, Olivier A Bernard, Giorgio Inghirami, Stefano Pileri, Xosé R Bustelo, Raul Rabadan, Adolfo A Ferrando, Teresa Palomero
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas frequently associated with poor prognosis and for which genetic mechanisms of transformation remain incompletely understood. Using RNA sequencing and targeted sequencing, here we identify a recurrent in-frame deletion (VAV1 Δ778-786) generated by a focal deletion-driven alternative splicing mechanism as well as novel VAV1 gene fusions (VAV1-THAP4, VAV1-MYO1F, and VAV1-S100A7) in PTCL. Mechanistically these genetic lesions result in increased activation of VAV1 catalytic-dependent (MAPK, JNK) and non-catalytic-dependent (nuclear factor of activated T cells, NFAT) VAV1 effector pathways...
January 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28062573/deficiency-of-n-myristoylation-reveals-calcineurin-activity-as-regulator-of-ifn-%C3%AE-producing-%C3%AE-%C3%AE-t-cells
#5
Francesca Rampoldi, Fabian Brunk, Mahnaz Bonrouhi, Giuseppina Federico, Damir Krunic, Stefan Porubsky, Hermann-Josef Gröne, Zoran V Popovic
γδ T cell subsets can be characterized, in part, by their secretion of select proinflammatory cytokines. The molecular mechanisms driving the diverse fates of γδ T cells have not been elucidated. We have previously shown that the attachment of myristic acid to the N-terminal glycine of proteins, termed N-myristoylation, is essential for αβ T cell development and activation. Here, we explore the potential role of this lipid modification on the activation of γδ T cells. In the absence of N-myristoylation, the CD27(+) γδ T cell subset was dominantly affected...
January 6, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28058586/key-genes-in-stomach-adenocarcinoma-identified-via-network-analysis-of-rna-seq-data
#6
Li Shen, Lizhi Zhao, Jiquan Tang, Zhiwei Wang, Weisong Bai, Feng Zhang, Shouli Wang, Weihua Li
RNA-seq data of stomach adenocarcinoma (STAD) were analyzed to identify critical genes in STAD. Meanwhile, relevant small molecule drugs, transcription factors (TFs) and microRNAs (miRNAs) were also investigated. Gene expression data of STAD were downloaded from The Cancer Genome Atlas (TCGA). Differential analysis was performed with package edgeR. Relationships with correlation coefficient > 0.6 were retained in the gene co-expression network. Functional enrichment analysis was performed for the genes in the network with DAVID and KOBASS 2...
January 5, 2017: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/28056508/fk506-an-immunosuppressive-drug-induces-autophagy-by-binding-to-the-v-atpase-catalytic-subunit-a-in-neuronal-cells
#7
Dongyoung Kim, Hui-Yun Hwang, Jin Young Kim, Ju Yeon Lee, Jong Shin Yoo, György Marko-Varga, Ho Jeong Kwon
The drug FK506 (tacrolimus, fujimycin) exerts its immunosuppressive effects by regulating the nuclear factor of the activated T-cell (NFAT) family of transcription factors. However, FK506 also exhibits neuroprotective effects, but its direct target proteins that mediate these effects have not been determined. To identify the target proteins responsible for FK506's neuroprotective effects, the drug affinity responsive target stability (DARTS) method was performed using label-free FK506, and LC-MS/MS analysis of the FK506-treated proteome was also performed...
January 6, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28027307/population-heterogeneity-in-the-epithelial-to-mesenchymal-transition-is-controlled-by-nfat-and-phosphorylated-sp1
#8
Russell Gould, David M Bassen, Anirikh Chakrabarti, Jeffrey D Varner, Jonathan Butcher
Epithelial to mesenchymal transition (EMT) is an essential differentiation program during tissue morphogenesis and remodeling. EMT is induced by soluble transforming growth factor β (TGF-β) family members, and restricted by vascular endothelial growth factor family members. While many downstream molecular regulators of EMT have been identified, these have been largely evaluated individually without considering potential crosstalk. In this study, we created an ensemble of dynamic mathematical models describing TGF-β induced EMT to better understand the operational hierarchy of this complex molecular program...
December 2016: PLoS Computational Biology
https://www.readbyqxmd.com/read/28025957/correlation-between-pharmacokinetics-of-tacrolimus-and-pharmacodynamics-on-nfat-regulated-gene-expression-in-stable-kidney-transplant-recipients%C3%A2
#9
Frieder Keller, Claudia Sommerer, Thomas Giese, Martin Zeier, Bernd Schröppel
Gene expression regulated by the transcription factor NFAT (nuclear factor of activated T-cells) has been proposed for monitoring the pharmacodynamic effect of calcineurin inhibitors. We aimed to correlate the pharmacokinetics of tacrolimus with the suppression of NFAT-regulated gene expression. Tacrolimus trough (C<sub>trough</sub>) and peak concentrations (C<sub>peak</sub>) were measured by LC-MS. The effect on NFAT-regulated gene expression at trough (E<sub>trough</sub>) and at peak levels (E<sub>peak</sub>) were determined by qRT-PCR...
February 2017: Clinical Nephrology
https://www.readbyqxmd.com/read/28011865/leukotrienes-provide-an-nfat-dependent-signal-that-synergizes-with-il-33-to-activate-ilc2s
#10
Jakob von Moltke, Claire E O'Leary, Nora A Barrett, Yoshihide Kanaoka, K Frank Austen, Richard M Locksley
Group 2 innate lymphoid cells (ILC2s) and type 2 helper T cells (Th2 cells) are the primary source of interleukin 5 (IL-5) and IL-13 during type 2 (allergic) inflammation in the lung. In Th2 cells, T cell receptor (TCR) signaling activates the transcription factors nuclear factor of activated T cells (NFAT), nuclear factor κB (NF-κB), and activator protein 1 (AP-1) to induce type 2 cytokines. ILC2s lack a TCR and respond instead to locally produced cytokines such as IL-33. Although IL-33 induces AP-1 and NF-κB, NFAT signaling has not been described in ILC2s...
January 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28003191/calcineurin-inhibitor-cyclosporine-a-activates-renal-na-k-cl-cotransporters-via-local-and-systemic-mechanisms
#11
Katharina Ilse Blankenstein, Aljona Borschewski, Robert Labes, Alexander Paliege, Christin Boldt, James A McCormick, David H Ellison, Michael Bader, Sebastian Bachmann, Kerim Mutig
Calcineurin dephosphorylates NFAT transcription factors, thereby facilitating T-cell mediated immune responses. Calcineurin inhibitors are instrumental for immunosuppression after organ transplantation, but may cause side effects including hypertension and electrolyte disorders. Kidneys were recently shown to display activation of the furosemide-sensitive Na-K-2Cl cotransporter (NKCC2) of the thick ascending limb and the thiazide-sensitive Na-Cl cotransporter (NCC) of the distal convoluted tubule upon calcineurin inhibition using cyclosporin A (CsA)...
December 21, 2016: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28002487/long-term-transcriptomic-effects-of-prebiotics-and-synbiotics-delivered-in-ovo-in-broiler-chickens
#12
Anna Slawinska, Arkadiusz Plowiec, Maria Siwek, Marcin Jaroszewski, Marek Bednarczyk
In ovo delivery of prebiotics and synbiotics in chickens allows for the development of intestinal microflora prior to hatching, which boosts their robustness. The goal of this study was to determine the transcriptomic profile of the spleen (S), cecal tonsils (CT), and large intestine (LI) of adult chickens injected with prebiotics and synbiotics in ovo. On day 12 of embryo development, incubating eggs were injected with prebiotics: inulin alone (P1) or in combination with Lactococcus lactis subsp. lactis IBB2955 (S1), galactooligosaccharides (GOS) alone (P2) or in combination with Lactococcus lactis subsp...
2016: PloS One
https://www.readbyqxmd.com/read/27992507/trpc4%C3%AE-and-trpc4%C3%AE-similarly-affect-neonatal-cardiomyocyte-survival-during-chronic-gpcr-stimulation
#13
Nadine Kirschmer, Sandra Bandleon, Viktor von Ehrlich-Treuenstätt, Sonja Hartmann, Alice Schaaf, Anna-Karina Lamprecht, Erick Miranda-Laferte, Tanja Langsenlehner, Oliver Ritter, Petra Eder
The Transient Receptor Potential Channel Subunit 4 (TRPC4) has been considered as a crucial Ca2+ component in cardiomyocytes promoting structural and functional remodeling in the course of pathological cardiac hypertrophy. TRPC4 assembles as homo or hetero-tetramer in the plasma membrane, allowing a non-selective Na+ and Ca2+ influx. Gαq protein-coupled receptor (GPCR) stimulation is known to increase TRPC4 channel activity and a TRPC4-mediated Ca2+ influx which has been regarded as ideal Ca2+ source for calcineurin and subsequent nuclear factor of activated T-cells (NFAT) activation...
2016: PloS One
https://www.readbyqxmd.com/read/27941787/recruitment-of-calcineurin-to-the-tcr-positively-regulates-t-cell-activation
#14
Debjani Dutta, Valarie A Barr, Itoro Akpan, Paul R Mittelstadt, Laishram I Singha, Lawrence E Samelson, Jonathan D Ashwell
Calcineurin is a phosphatase whose primary targets in T cells are NFAT transcription factors, and inhibition of calcineurin activity by treatment with cyclosporin A (CsA) or FK506 is a cornerstone of immunosuppressive therapies. Here we found that calcineurin was recruited to the T cell antigen receptor (TCR) signaling complex, where it reversed inhibitory phosphorylation of the tyrosine kinase Lck on Ser59 (Lck(S59)). Loss of calcineurin activity impaired phosphorylation of Tyr493 of the tyrosine kinase ZAP-70 (ZAP-70(Y493)), as well as some downstream pathways in a manner consistent with signaling in cells expressing Lck(S59A) (Lck that cannot be phosphorylated) or Lck(S59E) (a phosphomimetic mutant)...
February 2017: Nature Immunology
https://www.readbyqxmd.com/read/27941640/fibroblast-growth-factor-23-a-potential-uremic-toxin
#15
REVIEW
Piotr Kuczera, Marcin Adamczak, Andrzej Wiecek
Fibroblast growth factor-23 (FGF23) is a circulating member of the FGF family produced mainly by the osteocytes and osteoblasts that can act as a hormone. The main action of FGF23 is to lower phosphatemia via the reduction of urinary phosphate reabsorption and the decrease of 1,25(OH)₂-D generation in the kidney. In the course of chronic kidney disease (CKD), plasma FGF23 concentration rises early, most probably to compensate the inability of the deteriorating kidneys to excrete an adequate amount of phosphate...
December 8, 2016: Toxins
https://www.readbyqxmd.com/read/27941330/hyperosmolarity-and-benzalkonium-chloride-differently-stimulate-inflammatory-markers-in-conjunctiva-derived-epithelial-cells-in-vitro
#16
Elise Warcoin, Chloé Clouzeau, Christophe Roubeix, Anne-Laure Raveu, David Godefroy, Luisa Riancho, Christophe Baudouin, Françoise Brignole-Baudouin
Tear hyperosmolarity is known to cause ocular surface inflammation in dry eye syndrome. Benzalkonium chloride (BAK), an eyedrop preservative, is known to induce dry eye in long-term-treated patients. Analyzing the modulation of the proinflammatory potential of hyperosmolarity in the presence of BAK on the conjunctiva could give new insights into the effect of this preservative on the disease. In a hyperosmolar model on a conjunctiva-derived cell line, and in the presence of BAK, we evaluated key inflammatory markers [CCL2, IL-8, IL-6, macrophage migration inhibitory factor (MIF) and intercellular adhesion molecule (ICAM)-1] as well as the osmoprotectant element nuclear factor of activated T cells (NFAT)5 using ELISA, RT-qPCR or immunofluorescence staining...
December 10, 2016: Ophthalmic Research
https://www.readbyqxmd.com/read/27939672/dynamic-changes-in-chromatin-accessibility-occur-in-cd8-t-cells-responding-to-viral-infection
#17
James P Scott-Browne, Isaac F López-Moyado, Sara Trifari, Victor Wong, Lukas Chavez, Anjana Rao, Renata M Pereira
In response to acute infection, naive CD8(+) T cells expand, differentiate into effector cells, and then contract to a long-lived pool of memory cells after pathogen clearance. During chronic infections or in tumors, CD8(+) T cells acquire an "exhausted" phenotype. Here we present genome-wide comparisons of chromatin accessibility and gene expression from endogenous CD8(+) T cells responding to acute and chronic viral infection using ATAC-seq and RNA-seq techniques. Acquisition of effector, memory, or exhausted phenotypes was associated with stable changes in chromatin accessibility away from the naive T cell state...
December 20, 2016: Immunity
https://www.readbyqxmd.com/read/27939300/characterization-of-fc%C3%AE-riiia-effector-cells-used-in-in-vitro-adcc-bioassay-comparison-of-primary-nk-cells-with-engineered-nk-92-and-jurkat-t-cells
#18
Yao-Te Hsieh, Poonam Aggarwal, David Cirelli, Ling Gu, Teresa Surowy, Ned M Mozier
Antibody-dependent cell-mediated cytotoxicity (ADCC) is an important mechanism of action (MOA) of several therapeutic antibody drugs and evaluation in ADCC bioassays is important in antibody drug development and maintenance. Three types of effector cells now routinely used in bioassay evaluation of ADCC are natural killer cells from human donors (FcγRIIIA+primary NK), FcγRIIIA engineered NK-92 cells and FcγRIIIA/NFAT-RE/luc2 engineered Jurkat T cells. Engineered effector cells were developed to address need for improved precision and accuracy of classic NK cell ADCC bioassays...
December 8, 2016: Journal of Immunological Methods
https://www.readbyqxmd.com/read/27935966/the-transcription-factor-nfatc2-regulates-%C3%AE-cell-proliferation-and-genes-associated-with-type-2-diabetes-in-mouse-and-human-islets
#19
Mark P Keller, Pradyut K Paul, Mary E Rabaglia, Donnie S Stapleton, Kathryn L Schueler, Aimee Teo Broman, Shuyun Isabella Ye, Ning Leng, Christopher J Brandon, Elias Chaibub Neto, Christopher L Plaisier, Shane P Simonett, Melkam A Kebede, Gloria M Sheynkman, Mark A Klein, Nitin S Baliga, Lloyd M Smith, Karl W Broman, Brian S Yandell, Christina Kendziorski, Alan D Attie
Human genome-wide association studies (GWAS) have shown that genetic variation at >130 gene loci is associated with type 2 diabetes (T2D). We asked if the expression of the candidate T2D-associated genes within these loci is regulated by a common locus in pancreatic islets. Using an obese F2 mouse intercross segregating for T2D, we show that the expression of ~40% of the T2D-associated genes is linked to a broad region on mouse chromosome (Chr) 2. As all but 9 of these genes are not physically located on Chr 2, linkage to Chr 2 suggests a genomic factor(s) located on Chr 2 regulates their expression in trans...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27932059/classical-transient-receptor-potential-6-trpc6-channels-support-myofibroblast-differentiation-and-development-of-experimental-pulmonary-fibrosis
#20
Katharina Hofmann, Susanne Fiedler, Sarah Vierkotten, Jonas Weber, Stephan Klee, Jie Jia, Wolfgang Zwickenpflug, Veit Flockerzi, Ursula Storch, Ali Önder Yildirim, Thomas Gudermann, Melanie Königshoff, Alexander Dietrich
Pulmonary fibrosis (PF) is a chronic progressive lung disease without effective medical treatment options leading to respiratory failure and death within 3-5years of diagnosis. The pathological process of PF is driven by aberrant wound-healing involving fibroblasts and myofibroblasts differentiated by secreted profibrotic transforming growth factor β (TGF-β1). Classical transient receptor potential 6 (TRPC6), a Na(+)- and Ca(2+)-permeable cation channel, is able to promote myofibroblast conversion of primary rat cardiac and human dermal fibroblasts and TRPC6-deficiency impaired wound healing after injury...
February 2017: Biochimica et Biophysica Acta
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