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Calcineurin

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https://www.readbyqxmd.com/read/28934144/the-recognition-of-calmodulin-to-the-target-sequence-of-calcineurin-a-novel-binding-mode
#1
Chia-Lin Chyan, Deli Irene, Sin-Mao Lin
Calcineurin (CaN) is a Ca(2+)/calmodulin-dependent Ser/Thr protein phosphatase, which plays essential roles in many cellular and developmental processes. CaN comprises two subunits, a catalytic subunit (CaN-A, 60 kDa) and a regulatory subunit (CaN-B, 19 kDa). CaN-A tightly binds to CaN-B in the presence of minimal levels of Ca(2+), but the enzyme is inactive until activated by CaM. Upon binding to CaM, CaN then undergoes a conformational rearrangement, the auto inhibitory domain is displaced and thus allows for full activity...
September 21, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28931653/combined-ox40l-and-mtor-blockade-controls-effector-t-cell-activation-while-preserving-treg-reconstitution-after-transplant
#2
Victor Tkachev, Scott N Furlan, Benjamin Watkins, Daniel J Hunt, Hengqi Betty Zheng, Angela Panoskaltsis-Mortari, Kayla Betz, Melanie Brown, John B Schell, Katie Zeleski, Alison Yu, Ian Kirby, Sarah Cooley, Jeffrey S Miller, Bruce R Blazar, Duncan Casson, Phil Bland-Ward, Leslie S Kean
A critical question facing the field of transplantation is how to control effector T cell (Teff) activation while preserving regulatory T cell (Treg) function. Standard calcineurin inhibitor-based strategies can partially control Teffs, but breakthrough activation still occurs, and these agents are antagonistic to Treg function. Conversely, mechanistic target of rapamycin (mTOR) inhibition with sirolimus is more Treg-compatible but is inadequate to fully control Teff activation. In contrast, blockade of OX40L signaling has the capacity to partially control Teff activation despite maintaining Treg function...
September 20, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28927426/the-acid-sensing-ion-channel-asic2-promotes-invasion-and-metastasis-of-colorectal-cancer-under-acidosis-by-activating-the-calcineurin-nfat1-axis
#3
Zhi-Hang Zhou, Jin-Wen Song, Wen Li, Xue Liu, Liu Cao, Lu-Ming Wan, Ying-Xia Tan, Shou-Ping Ji, Yu-Mei Liang, Feng Gong
BACKGROUND: The tumor acidic microenvironment, a common biochemical event in solid tumors, offers evolutional advantage for tumors cells and even enhances their aggressive phenotype. However, little is known about the molecular mechanism underlying the acidic microenvironment-induced invasion and metastasis. METHODS: We examined the expression of the acid-sending ion channel (ASIC) family members after acidic exposure using RT-PCR and immunofluoresence. Gene manipulation was applied to reveal the potential of ASIC2 on invasion, proliferation, colony formation of colorectal cancer (CRC)...
September 19, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28927230/multi-azole-resistant-strains-of-cryptococcus-neoformans-var-grubii-isolated-from-a-flz-resistant-strain-by-culturing-in-medium-containing-voriconazole
#4
Rui Kano, Miki Okubo, Atsuhiko Hasegawa, Hiroshi Kamata
A Cryptococcus neoformans var. grubii strain, NUBS14020, was the first fluconazole (FLZ)-resistant strain isolated from a feline cryptococcosis. Subsequent work demonstrated that multi-azole-resistant strains are readily isolated from FLZ-resistant strains by culturing in medium containing voriconazole (VRZ). The resulting clones were assessed for mutation and expression of known target genes, including the loci encoding lanosterol 14-α demethylase (ERG11), an ATP-binding cassette (ABC) transporter (AFR1), or a multidrug efflux pump (MEP); mutation and/or overexpression of these genes is known to be associated with azole resistance...
September 11, 2017: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
https://www.readbyqxmd.com/read/28925592/defining-a-microrna-mrna-interaction-map-for-calcineurin-inhibitor-induced-nephrotoxicity
#5
Christopher J Benway, John Iacomini
Calcineurin inhibitors induce nephrotoxicity through poorly understood mechanisms thereby limiting their use in transplantation and other diseases. Here we define a microRNA (miRNA)-messenger RNA (mRNA) interaction map that facilitates exploration into the role of miRNAs in cyclosporine-induced nephrotoxicity (CIN) and the gene pathways they regulate. Using photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP), we isolated RNAs associated with Argonaute 2 in the RNA-Induced Silencing Complex (RISC) of cyclosporine A (CsA) treated and control human proximal tubule cells and identified mRNAs undergoing active targeting by miRNAs...
September 19, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28923863/synergistic-effects-of-tacrolimus-and-azoles-against-exophiala-dermatitidis
#6
Lujuan Gao, Yi Sun, Chengyan He, Tongxiang Zeng, Ming Li
In vitro interactions of tacrolimus, a calcineurin inhibitor, and azoles including itraconazole, voriconazole, and posaconazole against planktonic cells and biofilms of Exophiala dermatitidis were assessed via broth microdilution checkerboard technique. A total of 16 clinical isolates were studied. The results revealed favorable synergistic inhibitory activity between tacrolimus and itraconazole, voriconazole, or posaconazole against planktonic cells of E. dermatitidis However, limited synergism was observed against biofilms of E...
September 18, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28923650/does-renal-tubular-injury-induced-local-tissue-hypoxia-involve-post-transplantation-erythrocytosis
#7
A Unal, S Ata, C Karakurkcu, M Z Ciraci, I Kocyigit, M H Sipahioglu, B Tokgoz, O Oymak
BACKGROUND: The pathogenesis of post-transplantation erythrocytosis (PTE) is not well understood and appears to be multifactorial. Our hypothesis in this study was that several factors, including toxicity of calcineurin inhibitor, immunologic factors, and chronic allograft nephropathy, can trigger local tissue hypoxia in peritubular interstitium, which is where production of erythropoietin (EPO) takes place. This local interstitial tissue hypoxia can cause an increase in renal EPO production, which induces the development of PTE...
October 2017: Transplantation Proceedings
https://www.readbyqxmd.com/read/28923619/ten-year-follow-up-of-pharmacokinetics-guided-very-early-cyclosporine-minimization-synchronized-with-everolimus-initiation-in-de-novo-kidney-transplantation
#8
V Sumethkul, P Tankee, S Worawichawong, S Jirasiritham
BACKGROUND: Minimization of calcineurin inhibitor (CNI) from the 1st week after kidney transplantation (KT) may reduce the risk of CNI nephrotoxicity. METHODS: Ten de novo KT recipients who received full exposure cyclosporine (CsA) and prednisolone as initial therapy were enrolled. Initial CsA minimization was 50% and started at day 7 after KT. This was synchronized with everolimus (EVL) initiation. Target trough level of EVL was 3-8 ng/mL. Pharmacokinetics studies of CsA and EVL were studied at week 4...
October 2017: Transplantation Proceedings
https://www.readbyqxmd.com/read/28922497/mutual-independence-of-alkaline-and-calcium-mediated-signalling-in-aspergillus-fumigatus-refutes-the-existence-of-a-conserved-druggable-signalling-nexus
#9
Omar Loss, Margherita Bertuzzi, Yu Yan, Natalie Fedorova, Bethany L McCann, Darius Armstrong-James, Eduardo A Espeso, Nick D Read, William C Nierman, Elaine M Bignell
Functional coupling of calcium- and alkaline responsive signalling occurs in multiple fungi to afford efficient cation homeostasis. Host microenvironments exert alkaline stress and potentially toxic concentrations of Ca(2+) , such that highly conserved regulators of both calcium- (Crz) and pH- (PacC/Rim) responsive signalling are crucial for fungal pathogenicity. Drugs targeting calcineurin are potent antifungal agents but also perturb human immunity thereby negating their use as anti-infectives, abrogation of alkaline signalling has therefore been postulated as an adjunctive antifungal strategy...
September 18, 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28922070/defective-calcineurin-nfat-signaling-in-myeloid-cells-and-susceptibility-to-aspergillosis-in-post-transplant-patients
#10
Seyedmojtaba Seyedmousavi, Michael J Davis
No abstract text is available yet for this article.
September 18, 2017: Virulence
https://www.readbyqxmd.com/read/28921505/nfatc1-activation-by-dna-hypomethylation-in-chronic-lymphocytic-leukemia-correlates-with-clinical-staging-and-can-be-inhibited-by-ibrutinib
#11
Christine Wolf, Angela Garding, Katharina Filarsky, Jasmin Bahlo, Sandra Robrecht, Natalia Becker, Manuela Zucknick, Arefeh Rouhi, Anja Weigel, Rainer Claus, Dieter Weichenhan, Barbara Eichhorst, Kirsten Fischer, Michael Hallek, Florian Kuchenbauer, Christoph Plass, Hartmut Döhner, Stephan Stilgenbauer, Peter Lichter, Daniel Mertens
B cell receptor (BCR) signaling is key for survival of chronic lymphocytic leukemia (CLL) cells, and BCR signaling inhibitors are clinically active. However, relapse and resistance to treatment require novel treatment options. In order to detect novel candidate therapeutic targets, we performed a genome-wide DNA methylation screen with custom arrays and identified aberrant promoter DNA methylation in 2192 genes. The transcription factor NFATC1 that is a downstream effector of BCR signaling was among the top hypomethylated genes and was concomitantly transcriptionally upregulated in CLL...
September 18, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28920919/age-dependent-human-%C3%AE-cell-proliferation-induced-by-glucagon-like-peptide-1-and-calcineurin-signaling
#12
Chunhua Dai, Yan Hang, Alena Shostak, Greg Poffenberger, Nathaniel Hart, Nripesh Prasad, Neil Phillips, Shawn E Levy, Dale L Greiner, Leonard D Shultz, Rita Bottino, Seung K Kim, Alvin C Powers
Inadequate pancreatic β cell function underlies type 1 and type 2 diabetes mellitus. Strategies to expand functional cells have focused on discovering and controlling mechanisms that limit the proliferation of human β cells. Here, we developed an engraftment strategy to examine age-associated human islet cell replication competence and reveal mechanisms underlying age-dependent decline of β cell proliferation in human islets. We found that exendin-4 (Ex-4), an agonist of the glucagon-like peptide 1 receptor (GLP-1R), stimulates human β cell proliferation in juvenile but not adult islets...
September 18, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28915690/efficacy-and-safety-of-a-reduced-calcineurin-inhibitor-dose-combined-with-mycophenolate-mofetil-in-liver-transplant-patients-with-chronic-renal-dysfunction
#13
Pusen Wang, Weitao Que, Hao Li, Lvnan Yan, Zhiren Fu, Qifa Ye, Guihua Chen, Kefeng Dou, Shichun Lu, Zhanyu Yang, Zhijun Zhu, Zhihai Peng, Lin Zhong
Calcineurin inhibitors (CNIs) are frequently given at a reduced dose in combination with mycophenolate mofetil (MMF) to avoid nephrotoxicity, but the optimal reduction in CNI dose has not been established. In this prospective, open-label, multicenter study, liver transplant recipients with chronic renal dysfunction who were administered a CNI-based immunosuppressive regimen were included in the intent-to-treat (ITT) population. The primary endpoint was declination in renal function, which was defined as a ≥ 20% decrease in the glomerular filtration rate during the year following regimen adjustment...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28912999/tacrolimus-aggravated-tube-feeding-syndrome-with-acute-renal-failure-in-a-pediatric-liver-transplant-recipient
#14
R Kula, M Melter, J Kunkel, C Dörfler, S Alikadic, B Knoppke, R Zant
Acute renal failure can be caused by calcineurin inhibitors (CNIs), due to arteriolopathy and altered tubular function. Within this context, we present the case of a 14-month-old liver transplant recipient who suffered an acute polyuric renal failure during a short episode of hypercaloric feeding. In our case, CNI-induced distal RTA led to nephrocalcinosis and therefore to secondary nephrogenic diabetes insipidus. The diet with high renal solute load consequently resulted in an acute polyuric renal failure with severe hypernatremic dehydration...
2017: Case Reports in Transplantation
https://www.readbyqxmd.com/read/28906028/graft-outcomes-following-diagnosis-of-posttransplant-lymphoproliferative-disease-in-pediatric-kidney-recipients-a-retrospective-study
#15
Nele K Kanzelmeyer, Britta Maecker-Kolhoff, Henriette Zierhut, Christian Lerch, Murielle Verboom, Dieter Haffner, Lars Pape
Data related to graft outcomes following posttransplant lymphoproliferative disease (PTLD) in pediatric kidney transplantation are scarce. Data were analyzed retrospectively from 12 children (8 boys) for three years after diagnosis of PTLD, with a loss of follow-up after 2 years in 2/12. In all cases, intensity of immunosuppressive therapy was reduced, with switch from calcineurin inhibitor to a mammalian target of rapamcyin (mTOR) inhibitor in 6 cases. Nine children were treated with 6 doses of rituximab according to the PED-PTLD-2005 protocol, with additional treatment in one child as per protocol...
September 14, 2017: Transplant International: Official Journal of the European Society for Organ Transplantation
https://www.readbyqxmd.com/read/28904958/transcriptomic-analysis-reveals-genes-mediating-salt-tolerance-through-calcineurin-ccha-independent-signaling-in-aspergillus-nidulans
#16
Sha Wang, Hongchang Zhou, Jun Wu, Jiangyu Han, Shasha Li, Shengwen Shao
Adaptation to changes in the environment is crucial for the viability of all organisms. Although the importance of calcineurin in the stress response has been highlighted in filamentous fungi, little is known about the involvement of ion-responsive genes and pathways in conferring salt tolerance without calcium signaling. In this study, high-throughput RNA-seq was used to investigate salt stress-induced genes in the parent, ΔcnaB, and ΔcnaBΔcchA strains of Aspergillus nidulans, which differ greatly in salt adaption...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28904428/collapsing-glomerulopathy-a-troublemaker-for-the-renal-allograft-lessons-learnt
#17
K V Kanodia, A V Vanikar, L K Nigam, R D Patel, K S Suthar, H V Patel, H L Trivedi
Collapsing glomerulopathy (CG) is a well-recognized distinct morphological pattern of proliferative parenchymal injury leading to rapid graft failure. We conducted a single-center retrospective study to evaluate the prevalence, clinicopathological features, and prognosis of CG in renal transplant recepient. We analyzed 2518 renal allograft biopsies performed from 2007 to 2015 and correlated their clinicopathological features. The prevalence of CG was 0.83% (21 out of 2518) of allograft biopsies with a higher prevalence of 1...
September 2017: Indian Journal of Nephrology
https://www.readbyqxmd.com/read/28902407/trpc6-expression-in-neurons-is-differentially-regulated-by-nr2a-and-nr2b-containing-nmda-receptors
#18
Zhongwei Qu, Yuqing Wang, Xia Li, Lin Wu, Yizheng Wang
The expression of transient receptor potential canonical 6 (TRPC6) in central nervous system (CNS) is important for neuronal functions and certain neural disorders. However, the regulatory mechanism of TRPC6 expression in neurons is still obscure. In the current study, we show that TRPC6 expression in the primary cultured cortical neurons is bidirectionally regulated by glutamate. Activation of NR2A-containing NMDARs induces TRPC6 transcription through a calcineurin-dependent pathway. In contrast, activation of NR2B-containing NMDARs causes TRPC6 degradation through calpain...
September 13, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28901449/fk506-suppresses-hypoxia%C3%A2-induced-inflammation-and-protects-tight-junction-function-via-the-can%C3%A2-nfatc1-signaling-pathway-in-retinal-microvascular-epithelial-cells
#19
Yaguang Hu, Boyu Yang, Yue Xu, Li Jiang, Ching-Kit Tsui, Xiaoling Liang
The present study aimed to identify whether FK506 suppresses hypoxia‑induced inflammation and protects tight junction function via the calcineurin‑nuclear factor of activated T‑cells 1 (CaN‑NFATc1) signaling pathway in mouse retinal microvascular endothelial cells (mRMECs). The mRMECs were treated with FK506 at different concentrations following the induction of hypoxia. Trans‑epithelial electrical resistance (TEER) and cell permeability were examined to measure the integrity of the tight junctions...
September 12, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28900930/cardiac-remodeling-and-disease-soce-and-trpc-signaling-in-cardiac-pathology
#20
Petra Eder
TRPC channels have been suggested as potential candidates mediating store-operated Ca(2+) entry (SOCE) in cardiomyocytes. There is increasing evidence that the TRPC isoforms TRPC1 and TRPC4 might fulfill the function as SOCs, in concert with or in parallel to the key players of SOCE, Orai1, and STIM1. Several other isoforms, e.g., TRPC3, TRPC6, and TRPC7, might rather associate to receptor-activated diacylglycerol (DAG)-sensitive ion channels. However, the exact activation mode has not been elucidated yet, given the characteristic of TRPC channels to heteromerize to unpredictable ion channel assemblies...
2017: Advances in Experimental Medicine and Biology
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