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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
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
Xiaokui Gu, Wei Xue, Yajing Yin, Hongwei Liu, Shaojie Li, Xianyun Sun
Heat Shock Protein 90 (Hsp90) is essential for tumor progression in humans and drug resistance in fungi. However, the roles of its many co-chaperones in antifungal resistance are unknown. In this study, by susceptibility test of Neurospora crassa mutants lacking each of 18 Hsp90/Calcineurin system member genes (including 8 Hsp90 co-chaperone genes) to antifungal drugs and other stresses, we demonstrate that the Hsp90 co-chaperones Sti1 (Hop1 in yeast), Aha1, and P23 (Sba1 in yeast) were required for the basal resistance to antifungal azoles and heat stress...
2016: Frontiers in Microbiology
Rita I Jabr, Fiona S Hatch, Samantha C Salvage, Alejandro Orlowski, Paul D Lampe, Christopher H Fry
Cardiac arrhythmias are associated with raised intracellular [Ca(2+)] and slowed action potential conduction caused by reduced gap junction (GJ) electrical conductance (Gj). Ventricular GJs are composed of connexin proteins (Cx43), with Gj determined by Cx43 phosphorylation status. Connexin phosphorylation is an interplay between protein kinases and phosphatases but the precise pathways are unknown. We aimed to identify key Ca(2+)-dependent phosphorylation sites on Cx43 that regulate cardiac gap junction conductance and action potential conduction velocity...
October 19, 2016: Pflügers Archiv: European Journal of Physiology
Felix Krenzien, Markus Quante, Timm Heinbokel, Midas Seyda, Koichiro Minami, Hirohito Uehara, Hector Rodriguez Cetina Biefer, Jeroen M Schuitenmaker, Steven Gabardi, Katrin Splith, Moritz Schmelzle, Athena K Petrides, Haruhito Azuma, Johann Pratschke, Xian C Li, Abdallah ElKhal, Stefan G Tullius
Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age-specific effects of the calcineurin inhibitor Tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T-cells. Old recipient mice exhibited prolonged skin graft survival when compared to young animals following TAC administration. More importantly, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce pro-inflammatory IFN-γ cytokine production and promote IL-10 production in old CD4(+) T-cells...
October 18, 2016: American Journal of Transplantation
Meghan MacKenzie, Richard Hall
PURPOSE: Knowledge of how alterations in pharmacogenomics and pharmacogenetics may affect drug therapy in the intensive care unit (ICU) has received little study. We review the clinically relevant application of pharmacogenetics and pharmacogenomics to drugs and conditions encountered in the ICU. SOURCE: We selected relevant literature to illustrate the important concepts contained within. PRINCIPAL FINDINGS: Two main approaches have been used to identify genetic abnormalities - the candidate gene approach and the genome-wide approach...
October 17, 2016: Canadian Journal of Anaesthesia, Journal Canadien D'anesthésie
Imen Gorsane, I Helal, I Yacoub, F Ben Hamida, E Abderrahim, T Ben Abdallah
Focal and segmental glomerulosclerosis (FSGS) is a heterogeneous entity. Previous few studies have evaluated the efficacy of calcineurin inhibitors in primary FSGS and have suggested positive benefit. In this single-center, retrospective study (1975-2014), we report our experience in Tunisian adults with primary FSGS treated with cyclosporine A (CsA). It includes patients histologically proven FSGS and managed in the Charles Nicolle Hospital at Tunis, Tunisia. The dose of CsA was adjusted to maintain a whole blood trough level of 80-150 ng/mL...
September 2016: Saudi Journal of Kidney Diseases and Transplantation
Wael M Hamza, Hanan H Ali, Samia M Gabal, Sawsan A Fadda
The chronic dysfunction stands as the most common cause of renal allograft loss. During the nineties of the past century, this condition was referred to as chronic allograft nephropathy (CAN). Since 2005, CAN has been assigned by the eighth Banff schema to four main categories via histopathological and immunohistochemical findings including chronic antibodymediated rejection (CAMR), chronic T-cell-mediated rejection (CTMR), chronic cyclosporine toxicity (CNITOX), and "interstitial fibrosis (IF)/tubular atrophy; not otherwise specified (NOS)" to eliminate the term CAN...
September 2016: Saudi Journal of Kidney Diseases and Transplantation
Tengku Siti Hajar Haryuna, Wibi Riawan, Ardyansyah Nasution, Suprapto Ma'at, Juliandi Harahap, Indri Adriztina
Introduction The structural changes underlying permanent noise-induced hearing loss (NIHL) include loss of the sensory hair cells, damage to their stereocilia, and supporting tissues within the cochlear lateral wall. Objective The objective of this study is to demonstrate curcumin as a safe and effective therapeutic agent in the prevention and treatment for fibroblasts damage within the cochlear supporting tissues and lateral wall through cell death pathway. Methods We divided 24 Rattus norvegicus into 4 groups, Group 1: control; Group 2: noise (+); Group 3: noise (+), 50 mg/day curcumin (+); Group 4: noise (+), 100 mg/day curcumin (+)...
October 2016: International Archives of Otorhinolaryngology
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
Jesús M Gómez-Salinero, Marina M López-Olañeta, Paula Ortiz-Sánchez, Javier Larrasa-Alonso, Alberto Gatto, Leanne E Felkin, Paul J R Barton, Inmaculada Navarro-Lérida, Miguel Ángel Del Pozo, Pablo García-Pavía, Balaji Sundararaman, Giovanna Giovinazo, Gene W Yeo, Enrique Lara-Pezzi
Embryonic stem cells (ESC) have the potential to generate all the cell lineages that form the body. However, the molecular mechanisms underlying ESC differentiation and especially the role of alternative splicing in this process remain poorly understood. Here, we show that the alternative splicing regulator MBNL1 promotes generation of the atypical calcineurin Aβ variant CnAβ1 in mouse ESCs (mESC). CnAβ1 has a unique C-terminal domain that drives its localization mainly to the Golgi apparatus by interacting with Cog8...
September 28, 2016: Cell Chemical Biology
I Velázquez-López, E León-Cruz, J P Pardo, A Sosa-Peinado, M González-Andrade
Eight new fluorescent biosensors of human calmodulin (hCaM) using Alexa Fluor(®) 350, 488, 532, and 555 dyes were constructed. These biosensors are thermodynamically stable, functional, and highly sensitive to ligands of the CaM. They resolve the problem of CaM ligands with similar spectroscopic properties to the intrinsic and extrinsic fluorophores of other biosensors previously reported. Additionally, they can be used in studies of protein-protein interaction through Förster resonance energy transfer (FRET)...
October 12, 2016: Analytical Biochemistry
Yihung Huang, Evan Farkash
As both T cell and antibody-mediated rejection can have a subclinical phase, protocol biopsies provide an early opportunity to intervene before the onset of clinical allograft dysfunction. Protocol biopsies are usually done after reperfusion to establish baseline, between 3 and 6 months to identify subclinical rejection, and at 6-12 months to assess chronicity and persistent inflammation that have prognostic implication. Treatment of both subclinical T cell and antibody-mediated rejection prevents progression of rejection and development of interstitial fibrosis/tubular atrophy or transplant glomerulopathy...
September 2016: Advances in Chronic Kidney Disease
Umberto Maggiore, Julio Pascual
Cancer immunotherapy, especially the use of checkpoint inhibitors, is expanding and can be efficacious in organ transplant recipients with malignant neoplasia. In this review, we summarize clinical findings and evolution of several patients treated with CTL4-4 or PD-1 inhibitors reported in the literature. The CTL-4 inhibitor ipilimumab has been safely used in several liver and kidney allograft recipients. PD1-inhibitors look promising for tumor shrinking, but acute rejection is the rule, so they should be avoided in recipients of life-saving organs...
September 2016: Advances in Chronic Kidney Disease
David Wojciechowski, Flavio Vincenti
Kidney transplantation immunosuppression relies on a calcineurin inhibitor backbone. Calcineurin inhibitors have reduced early-acute rejection rates but failed to improve long-term allograft survival. Their nephrotoxicity has shifted the focus of investigation to calcineurin inhibitor-free regimens. Costimulation blockade with belatacept, a second generation, higher avidity variant of CTLA4-Ig, has emerged as part of a calcineurin inhibitor-free regimen. Belatacept has demonstrated superior glomerular filtration rate compared with calcineurin inhibitors albeit with an increased risk of early and histologically severe rejection...
September 2016: Advances in Chronic Kidney Disease
Joshua Augustine, Donald E Hricik
Although calcineurin inhibitor drugs have been the mostly used therapy in modern immunosuppression in kidney transplantation, their effect on kidney allograft dysfunction has been suboptimal as far as preservation of kidney function is concerned. Additionally, there are metabolic and other nonmetabolic effects including increased risk of malignancy that has necessitated the use of mammalian target of rapamycin inhibitors to reduce exposure to calcineurin inhibitors. Mammalian target of rapamycin inhibitors, both sirolimus and everolimus, have been studied in several trials to facilitate preservation of kidney function with variable effects on kidney allograft function and immunogenicity...
September 2016: Advances in Chronic Kidney Disease
Rohini Prashar, K K Venkat
Kidney transplantation is well established as the best treatment option for end-stage kidney disease. It confers not only a better quality of life but also a significant survival advantage compared to dialysis. However, despite significant improvement in short-term kidney transplant graft survival over the past three decades, long-term graft survival remains suboptimal. Concerns about the possible contribution of chronic calcineurin inhibitor (CNI) nephrotoxicity to late allograft failure and other serious adverse effects of currently used immunosuppressive agents (especially corticosteroids) have led to increasing interest in developing regimens which may better preserve kidney allograft function and minimize other immunosuppression-related problems without increasing the risk of rejection...
September 2016: Advances in Chronic Kidney Disease
M Gastaca, I Bilbao, M Jimenez, J Bustamante, C Dopazo, R Gonzalez, R Charco, J Santoyo, J Ortiz de Urbina
Our aim was to study the safety and efficacy of immunosuppression with everolimus (EVL) within the 1st month after orthotopic liver transplantation (LT) when calcineurin inhibitors are not recommended. For this purpose, 28 recipients who had been treated with EVL within the 1st month after adult LT were eligible to enter in a retrospective multicenter study. Patients were followed up for 12 months after LT. EVL therapy was initiated at a median of 14 days (range, 4-24) after LT. The reason for early EVL was neurotoxicity in 14 cases, renal dysfunction in 12, and acute cellular rejection combined with renal impairment in 2...
September 2016: Transplantation Proceedings
C M Cruz, S Pereira, J Gandara, S Ferreira, V Lopes, J Daniel, H P Miranda
Calcineurin inhibitors (CNI) are the base of immunosuppressive regimens in liver transplantation but they are associated with significant side effects, namely nephrotoxicity, which leads to increased morbidity and mortality. Through time, mycophenolate mofetil (MMF) as monotherapy has been suggested as an alternative in patients with CNI-related toxicity, but still no consensus has been reached as to its efficacy. We have evaluated the safety, efficacy, and tolerability of MMF monotherapy in selected patients, developing CNI-associated events, focusing primarily on kidney dysfunction...
September 2016: Transplantation Proceedings
M Pereira, J Guerra, M Neves, J Gonçalves, A Santana, C Nascimento, A G da Costa
INTRODUCTION: The optimal immunosuppressive induction therapy in kidney transplant recipients with low immunologic risk of acute rejection (AR) is still controversial. The use of basiliximab (BSX) has led to a significant decrease of AR with a low side effect profile. OBJECTIVE: This study sought to evaluate predictive risk factors for AR in low immunologic risk patients subjected to immunosuppressive induction therapy with BSX. METHODS: We reviewed all low immunologic risk patients (panel reactive antibody [PRA] level <50%, who had undergone a first deceased-donor transplant) subjected to immunosuppressive induction therapy with BSX, calcineurin inhibitor, mycophenolate mofetil, and prednisolone (n = 346)...
September 2016: Transplantation Proceedings
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