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Nesly Dotan, Vera Gayder, Itai Bloch, Maayan Gal
Calcineurin is a phosphatase that targets the transcription factor, nuclear factor of activated T-cells (NFAT) dephosphorylates multiple sites along NFAT's regulatory domain. The calcineurin-NFAT complex interaction is mediated through two conserved binding motifs known as the PxIxIT and LxVP, which are located at the N- and C- terminus to the phosphorylation sites. The vast range of cellular processes regulated by the calcineurin-NFAT interaction has aroused great interest in the investigation of the structural aspects that govern their complex formation and in the discovery of protein-protein interaction inhibitors; the latter interfere with calcineurin-NFAT complex formation while keeping calcineurin's catalytic site free...
March 16, 2018: Analytical Biochemistry
Franziska Just, Michael Oster, Kirsten Büsing, Luisa Borgelt, Eduard Murani, Siriluck Ponsuksili, Petra Wolf, Klaus Wimmers
BACKGROUND: In monogastric animals, phosphorus (P) homeostasis is maintained by regulating intestinal absorption, bone mobilization, and renal excretion. Since P is a non-renewable resource, a shortage is imminent due to widespread over-usage in the farming and animal husbandry industries. As a consequence, P efficiency should be improved in pig production. We sought to characterize the transcriptional response in re-/absorbing and excreting tissues in pigs to diets varying in calcium: phosphorus ratios...
March 20, 2018: BMC Genomics
Andrea Mencarelli, Hanif Javanmard Khameneh, Jan Fric, Maurizio Vacca, Sary El Daker, Baptiste Janela, Jing Ping Tang, Sabrina Nabti, Akhila Balachander, Tong Seng Lim, Florent Ginhoux, Paola Ricciardi-Castagnoli, Alessandra Mortellaro
The intestinal immune system can respond to invading pathogens yet maintain immune tolerance to self-antigens and microbiota. Myeloid cells are central to these processes, but the signaling pathways that underlie tolerance versus inflammation are unclear. Here we show that mice lacking Calcineurin B in CD11chigh MHCII+ cells (Cnb1CD11c mice) spontaneously develop intestinal inflammation and are susceptible to induced colitis. In these mice, colitis is associated with expansion of T helper type 1 (Th1) and Th17 cell populations and a decrease in the number of FoxP3+ regulatory T (Treg) cells, and the pathology is linked to the inability of intestinal Cnb1-deficient CD11chigh MHCII+ cells to express IL-2...
March 16, 2018: Nature Communications
Yue Ma, Chunquan Zheng, Le Shi
Background: Chronic rhinosinusitis (CRS), commonly divided into CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP) is an inflammatory disease which mechanism remain unclear. Leucine-rich repeat kinase 2 (LRRK2) has been proved to be a negative regulator of inflammation response while its role in pathogenesis of CRS has yet to be revealed. This research study was designed to investigate the relationship between the expression level and biologic role of LRRK2 in CRS. Methods: Expression of LRRK2 mRNA and noncoding repressor of NFAT (NRON) were examined by qRT-PCR...
2018: Clinical and Translational Allergy
Daniela Sorriento, Gaetano Santulli, Michele Ciccarelli, Angela Serena Maione, Maddalena Illario, Bruno Trimarco, Guido Iaccarino
We have recently demonstrated that the amino-terminal domain of G protein coupled receptor kinase (GRK) type 5, (GRK5-NT) inhibits NFκB activity in cardiac cells leading to a significant amelioration of LVH. Since GRK5-NT is known to bind calmodulin, this study aimed to evaluate the functional role of GRK5-NT in the regulation of calcium-calmodulin-dependent transcription factors. We found that the overexpression of GRK5-NT in cardiomyoblasts significantly reduced the activation and the nuclear translocation of NFAT and its cofactor GATA-4 in response to phenylephrine (PE)...
March 15, 2018: International Journal of Molecular Sciences
Manjula Karpurapu, Yong Gyu Lee, Ziqing Qian, Jin Wen, Megan N Ballinger, Luiza Rusu, Sangwoon Chung, Jing Deng, Feng Qian, Brenda F Reader, Teja Srinivas Nirujogi, Gye Young Park, Dehua Pei, John W Christman
Specific therapies targeting cellular and molecular events of sepsis induced Acute Lung Injury (ALI) pathogenesis are lacking. We have reported a pivotal role for Nuclear Factors of Activated T cells (NFATc3) in regulating macrophage phenotype during sepsis induced ALI and subsequent studies demonstrate that NFATc3 transcriptionally regulates macrophage CCR2 and TNFα gene expression. Mouse pulmonary microvascular endothelial cell monolayer maintained a tighter barrier function when co-cultured with LPS stimulated NFATc3 deficient macrophages whereas wild type macrophages caused leaky monolayer barrier...
February 13, 2018: Oncotarget
Jieyu Liu, Peiyu Jin, Xiaoli Lin, Qing Zhou, Fei Wang, Shengnan Liu, Shuhua Xi
To understand the direct link between Cyclin D1, and nuclear factor of activated T cells 2 (NFAT2) and nuclear factor (NF)-κB in arsenic-treated bladder cells, as well as the association between MAPK and NFAT signaling, we determined whether or not the Ca2+ /NFAT pathway is activated in an arsenic-treated normal urothelial cell line and determined the roles of NFAT and NF-κB signals in the regulation of Cyclin D1 expression. The SV-40 immortalized human uroepithelial cell line, SV-HUC-1, was treated with NaAsO2 for 24 h (0, 1, 2, 4, 8, and 10 μM) and 10, 20, 30, and 40 weeks (0 and 0...
March 12, 2018: Metallomics: Integrated Biometal Science
Sabrina Giampaolo, Gabriela Wójcik, Stefan Klein-Hessling, Edgar Serfling, Amiya K Patra
The role of NFAT family transcription factors in erythropoiesis is so far unknown, although their involvement has been suggested previously. We have shown recently that Il2 -/- mice develop severe anemia due to defects in KLF1 activity during BM erythropoiesis. Although, KLF1 activity is indispensable for erythropoiesis, the molecular details of Klf1 expression have not yet been elucidated. Here we show that an enhanced NFATc1 activity induced by increased integrin-cAMP signaling plays a critical role in the dysregulation of Klf1 expression and thereby cause anemia in Il2 -/- mice...
February 9, 2018: Oncotarget
Andrea Mencarelli, Maurizio Vacca, Hanif Javanmard Khameneh, Enzo Acerbi, Alicia Tay, Francesca Zolezzi, Michael Poidinger, Alessandra Mortellaro
Calcineurin (Cn) is a protein phosphatase that regulates the activation of the nuclear factor of activated T-cells (NFAT) family of transcription factors, which are key regulators of T-cell development and function. Here, we generated a conditional Cnb1 mouse model in which Cnb1 was specifically deleted in CD4+ T cells (Cnb1CD4 mice) to delineate the role of the Cn-NFAT pathway in immune homeostasis of the intestine. The Cnb1CD4 mice developed severe, spontaneous colitis characterized at the molecular level by an increased T helper-1-cell response but an unaltered regulatory T-cell compartment...
2018: Frontiers in Immunology
Yassan Abdolazimi, Sooyeon Lee, Haixia Xu, Paul Allegretti, Timothy M Horton, Benjamin Yeh, Hannah P Moeller, Robert J Nichols, David McCutcheon, Aryaman Shalizi, Mark Smith, Neali A Armstrong, Justin P Annes
Pharmacologic expansion of endogenous β-cells is a promising therapeutic strategy for diabetes. To elucidate the molecular pathways that control β-cell growth we screened ∼2,400 bioactive compounds for rat β-cell replication-modulating activity. Numerous hit compounds impaired or promoted rat β-cell replication, including CC-401, an advanced clinical candidate previously characterized as a c-Jun N-terminal kinase (JNK) inhibitor. Surprisingly, CC-401 induced rodent (in vitro and in vivo) and human (in vitro) β-cell replication via dual specificity tyrosine-phosphorylation-regulated kinases (DYRK1A/B) inhibition...
March 5, 2018: Endocrinology
Matthias Weider, Laura Julia Starost, Katharina Groll, Melanie Küspert, Elisabeth Sock, Miriam Wedel, Franziska Fröb, Christian Schmitt, Tina Baroti, Anna C Hartwig, Simone Hillgärtner, Sandra Piefke, Tanja Fadler, Marc Ehrlich, Corinna Ehlert, Martin Stehling, Stefanie Albrecht, Ammar Jabali, Hans R Schöler, Jürgen Winkler, Tanja Kuhlmann, Michael Wegner
Oligodendrocytes produce myelin for rapid transmission and saltatory conduction of action potentials in the vertebrate central nervous system. Activation of the myelination program requires several transcription factors including Sox10, Olig2, and Nkx2.2. Functional interactions among them are poorly understood and important components of the regulatory network are still unknown. Here, we identify Nfat proteins as Sox10 targets and regulators of oligodendroglial differentiation in rodents and humans. Overall levels and nuclear fraction increase during differentiation...
March 2, 2018: Nature Communications
Nhung T Nguyen, Lian He, Margie Martinez-Moczygemba, Yun Huang, Yubin Zhou
Tools capable of modulating gene expression in living organisms is very useful for interrogating the gene regulatory network and controlling biological processes. The catalytically-inactive CRISPR/Cas9 (dCas9), when fused with repressive or activating effectors, functions as a versatile platform to reprogram gene transcription at targeted genomic loci. However, without temporal control, the application of these reprogramming tools will likely cause off-target effects and lack strict reversibility. To overcome this limitation, we report herein the development of a chemical or light-inducible transcriptional reprogramming device that combines photoswitchable genetically-encoded calcium actuators with dCas9 to control gene expression...
February 28, 2018: ACS Synthetic Biology
Florence Mailleux, Christophe Beauloye, Jean-Luc Balligand, Sandrine Horman, Luc Bertrand
Pathological cardiac hypertrophy, which is a compensatory mechanism established to maintain cardiac function in response to neurohormonal or mechanical stresses, becomes maladaptive with time and frequently leads to heart failure. AMP-activated protein kinase (AMPK) has been extensively described in the literature to act as a break in cardiac hypertrophy development. Its anti-hypertrophic action mostly correlates with the inhibition of several important players of cardiac hypertrophy including protein synthesis and pro-hypertrophic gene expression pathways involving the transcription factor nuclear factor of activated T cells (NFAT) and the mitogen-activated protein kinases ERK1/2...
2018: Methods in Molecular Biology
Alicia Yoke Wei Wong, Vasilis Oikonomou, Giuseppe Paolicelli, Antonella De Luca, Marilena Pariano, Jan Fric, Hock Soon Tay, Paola Ricciardi-Castagnoli, Teresa Zelante
The Parkinson's disease-associated protein, Leucine-rich repeat kinase 2 (LRRK2), a known negative regulator of nuclear factor of activated T cells (NFAT), is expressed in myeloid cells such as macrophages and dendritic cells (DCs) and is involved in the host immune response against pathogens. Since, the Ca2+ /NFAT/IL-2 axis has been previously found to regulate DC response to the fungus Aspergillus , we have investigated the role played by the kinase LRRK2 during fungal infection. Mechanistically, we found that in the early stages of the non-canonical autophagic response of DCs to the germinated spores of Aspergillus , LRRK2 undergoes progressive degradation and regulates NFAT translocation from the cytoplasm to the nucleus...
2018: Frontiers in Immunology
Guo-Min Deng
PURPOSE OF REVIEW: The second most common clinical expression in lupus patients is skin damage that the pathogenesis remains unclear. We discuss the role of pathological factors in the development of skin damage in SLE. RECENT FINDINGS: Skin deposited IgG is a crucial pathologic factor in the development of skin damage in SLE. Macrophages and signaling of TNFα/TNFR1 and IFN/IFNR play an important role in the skin injury of SLE. The intracellular molecules including Syk and calcium/calmodulin 4 and NFAT are involved in the manifestation of skin damage in lupus-prone mice...
February 21, 2018: Current Rheumatology Reports
Wei Zhang, Terunao Takahara, Takuya Achiha, Hideki Shibata, Masatoshi Maki
NFAT is a cytoplasm-localized hyper-phosphorylated transcription factor that is activated through dephosphorylation by calcineurin, a Ca2+ /calmodulin-dependent phosphatase. A non-palindromic NFAT-response element (RE) found in the IL2 promoter region has been commonly used for a Ca2+ -response reporter gene system, but requirement of concomitant activation of AP-1 (Fos/Jun) often complicates the interpretation of obtained results. A new nanoluciferase (NanoLuc) reporter gene containing nine-tandem repeats of a pseudo-palindromic NFAT-RE located upstream of the IL8 promoter was designed to monitor Ca2+ -induced transactivation activity of NFAT in human embryonic kidney (HEK) 293 cells by measuring luciferase activities of NanoLuc and co-expressed firefly luciferase for normalization...
February 18, 2018: International Journal of Molecular Sciences
Nadia Madrid-Elena, María Laura García-Bermejo, Sergio Serrano-Villar, Alberto Díaz-de Santiago, Beatriz Sastre, Carolina Gutiérrez, Fernando Dronda, María Coronel Díaz, Ester Domínguez, María Rosa López-Huertas, Beatriz Hernández-Novoa, Santiago Moreno
Maraviroc is a CCR5 antagonist used in the treatment of HIV-1 infection. We and others have suggested that maraviroc could reactivate latent HIV-1. To test the latency reversing potential of maraviroc and the mechanisms involved, we performed a phase-II, single-center, open-label study in which maraviroc was administered for 10 days to 20 HIV-1-infected individuals on suppressive antiretroviral therapy (Eudra CT: 2012-003215-66). All patients completed full maraviroc dosing and follow up. The primary endpoint was to study whether maraviroc may reactivate HIV-1 latency, eliciting signalling pathways involved in the viral reactivation...
February 14, 2018: Journal of Virology
Mohsen Sarikhani, Sangeeta Maity, Sneha Mishra, Aditi Jain, Ankit K Tamta, Venkatraman Ravi, Kondapalli M Spurthi, Perumal A Desingu, Danish Khan, Shweta Kumar, Swathi Rao, Meena Inbaraj, Pandit A Shriniwas, Nagalingam Ravi Sundaresan
Heart failure is an aging-associated disease, which is the leading cause of death world-wide. Sirtuin family members have been largely studied in the context of aging and aging-associated diseases. Sirtuin 2 (SIRT2) is a cytoplasmic protein in the family of sirtuins that are NAD+-dependent class III histone deacetylases. In this work, we studied the role of SIRT2 in regulating NFAT transcription factor and the development of cardiac hypertrophy. Confocal microscopy analysis indicated that SIRT2 is localized in the cytoplasm of cardiomyocytes and SIRT2 levels are reduced during pathological hypertrophy of the heart...
February 13, 2018: Journal of Biological Chemistry
Sandeep Chhabra, Patrick Fischer, Koh Takeuchi, Abhinav Dubey, Joshua J Ziarek, Andras Boeszoermenyi, Daniel Mathieu, Wolfgang Bermel, Norman E Davey, Gerhard Wagner, Haribabu Arthanari
Studies over the past decade have highlighted the functional significance of intrinsically disordered proteins (IDPs). Due to conformational heterogeneity and inherent dynamics, structural studies of IDPs have relied mostly on NMR spectroscopy, despite IDPs having characteristics that make them challenging to study using traditional 1H-detected biomolecular NMR techniques. Here, we develop a suite of 3D 15N-detected experiments that take advantage of the slower transverse relaxation property of 15N nuclei, the associated narrower linewidth, and the greater chemical shift dispersion compared with those of 1H and 13C resonances...
February 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Franco H Falcone, Daniel Wan, Nafal Barwary, Ronit Sagi-Eisenberg
Since their establishment in 1981, RBL-2H3 cells have been widely used as a mast cell (MC) model. Their ability to be easily grown in culture in large amounts, their responsiveness to FcεRI-mediated triggers and the fact that they can be genetically manipulated, have provided advantages over primary MCs, in particular for molecular studies relying on genetic screening. Furthermore, the ability to generate clones that stably express proteins of interest, for example, a human receptor, have marked the RBL cells as an attractive MC model for drug screening...
March 2018: Immunological Reviews
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