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Calcium leak

Marilen Federico, Enrique L Portiansky, Leandro Sommese, Francisco J Alvarado, Paula G Blanco, Carolina N Zanuzzi, John Dedman, Marcia Kaetzel, Xander H T Wehrens, Alicia Mattiazzi, Julieta Palomeque
Background The impact of cardiac apoptosis in pre-diabetic stages of diabetic cardiomyopathy is unknown. We described that myocytes from fructose-rich diet (FRD) animals exhibit arrhythmias produced by exacerbated Ca(2+) /calmodulin-protein kinase (CaMKII) activity, ryanodine receptors (RyR2) phosphorylation and sarcoplasmic reticulum (SR) Ca(2+) leak. We tested the hypothesis that this mechanism also underlies cardiac apoptosis in pre-diabetes. Methods and Results We generated a pre-diabetic model in mice fed with FRD...
January 20, 2017: Journal of Physiology
Mallory A Ballinger, Christine Schwartz, Matthew T Andrews
During hibernation, thirteen-lined ground squirrels (Ictidomys tridecemlineatus) regularly cycle between bouts of torpor and interbout arousal (IBA).  Most of the brain is electrically quiescent during torpor, but regains activity quickly upon arousal to IBA resulting in extreme oscillations in energy demand during hibernation.  We predicted increased functional capacity of brain mitochondria during hibernation compared to spring to accommodate the variable energy demands of hibernation.  To address this hypothesis, we examined mitochondrial bioenergetics in the ground squirrel brain across three time points: spring (SP), torpor (TOR), and IBA...
January 11, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Mohammad Al Rajeh, Juan José Hidalgo Diaz, Sybille Facca, Anne Sophie Matheron, Stéphanie Gouzou, Philippe Liverneaux
The gold standard treatment for enchondroma in the hand is curettage and filling of the defect. The goal of this study was to evaluate the results when injectable calcium phosphate cement is used to fill the bone defect. Eight patients having a mean age of 44 years were operated through a minimally invasive skin incision. After a small bone window was made, curettage of the lesion was performed and verified by intraosseous endoscopy. The defect was filled with injectable calcium phosphate cement (JectOS/AREX(®)BONE, Kasios, L'Union France)...
February 2017: European Journal of Orthopaedic Surgery & Traumatology: Orthopédie Traumatologie
Tal Gazitt, Christian Lood, Keith B Elkon
Anti-citrullinated protein antibodies (ACPAs) are highly specific serologic markers for rheumatoid arthritis (RA) and can pre-date clinical disease onset by up to 10 years, also predicting erosive disease. The process of citrullination, the post-translational conversion of arginine to citrulline residues, is mediated by peptidylarginine deiminase (PAD) enzymes present in polymorphonuclear cells (PMNs). Calcium ions (Ca(2+)) are required for PAD activation, but the intracellular Ca(2+) concentration in normal cells is much lower than the optimal Ca(2+) concentration needed for PAD activation...
October 31, 2016: Rambam Maimonides Medical Journal
D B Raina, A Gupta, M M Petersen, W Hettwer, M McNally, M Tägil, M-H Zheng, A Kumar, L Lidgren
OBJECTIVES: We have observed clinical cases where bone is formed in the overlaying muscle covering surgically created bone defects treated with a hydroxyapatite/calcium sulphate biomaterial. Our objective was to investigate the osteoinductive potential of the biomaterial and to determine if growth factors secreted from local bone cells induce osteoblastic differentiation of muscle cells. MATERIALS AND METHODS: We seeded mouse skeletal muscle cells C2C12 on the hydroxyapatite/calcium sulphate biomaterial and the phenotype of the cells was analysed...
October 2016: Bone & Joint Research
Robyn T Rebbeck, Maram M Essawy, Florentin R Nitu, Benjamin D Grant, Gregory D Gillispie, David D Thomas, Donald M Bers, Razvan L Cornea
Using time-resolved fluorescence resonance energy transfer (FRET), we have developed and validated the first high-throughput screening (HTS) method to discover compounds that modulate an intracellular Ca(2+) channel, the ryanodine receptor (RyR), for therapeutic applications. Intracellular Ca(2+) regulation is critical for striated muscle function, and RyR is a central player. At resting [Ca(2+)], an increased propensity of channel opening due to RyR dysregulation is associated with severe cardiac and skeletal myopathies, diabetes, and neurological disorders...
October 19, 2016: Journal of Biomolecular Screening
Marisa Sepúlveda, Luis A Gonano, Manuel Viotti, Malena Morell, Paula Blanco, Micaela López Alarcón, Isalira Peroba Ramos, Adriana Bastos Carvalho, Emiliano Medei, Martín Vila Petroff
OBJECTIVES: Sepsis is associated with cardiac contractile dysfunction attributed to alterations in Ca handling. We examined the subcellular mechanisms involved in sarcoplasmic reticulum Ca loss that mediate altered Ca handling and contractile dysfunction associated with sepsis. DESIGN: Randomized controlled trial. SETTING: Research laboratory SUBJECTS:: Male wild type and transgenic mice INTERVENTIONS:: We induced sepsis in mice using the colon ascendens stent peritonitis model...
September 19, 2016: Critical Care Medicine
Elena Popugaeva, Ekaterina Pchitskaya, Ilya Bezprozvanny
Alzheimer's disease (AD) is the disease of lost memories. Synaptic loss is a major reason for memory defects in AD. Signaling pathways involved in memory loss in AD are under intense investigation. The role of deranged neuronal calcium (Ca(2+)) signaling in synaptic loss in AD is described in this review. Familial AD (FAD) mutations in presenilins are linked directly with synaptic Ca(2+) signaling abnormalities, most likely by affecting endoplasmic reticulum (ER) Ca(2+) leak function of presenilins. Excessive ER Ca(2+) release via type 2 ryanodine receptors (RyanR2) is observed in AD spines due to increase in expression and function of RyanR2...
September 15, 2016: Biochemical and Biophysical Research Communications
Kafa Walweel, Ye Win Oo, Derek R Laver
Cardiac output and rhythm depend on the release and the take-up of calcium from the sarcoplasmic reticulum (SR). Excessive diastolic calcium leak from the SR due to dysfunctional calcium release channels (RyR2) contributes to the formation of delayed after-depolarizations, which underlie the fatal arrhythmias that occur in heart failure and inherited syndromes. Calmodulin (CaM) is a calcium-binding protein that regulates target proteins and acts as a calcium sensor. CaM is comprised of two calcium-binding EF-hand domains and a flexible linker...
January 2017: Clinical and Experimental Pharmacology & Physiology
M A McNally, J Y Ferguson, A C K Lau, M Diefenbeck, M Scarborough, A J Ramsden, B L Atkins
AIMS: Chronic osteomyelitis may recur if dead space management, after excision of infected bone, is inadequate. This study describes the results of a strategy for the management of deep bone infection and evaluates a new antibiotic-loaded biocomposite in the eradication of infection from bone defects. PATIENTS AND METHODS: We report a prospective study of 100 patients with chronic osteomyelitis, in 105 bones. Osteomyelitis followed injury or surgery in 81 patients...
September 2016: Bone & Joint Journal
Andrew J Bryant, Edward W Scott
Pulmonary hypertension complicating idiopathic pulmonary fibrosis, also known as secondary pulmonary hypertension, represents a major source of morbidity and mortality in affected patients. While the study of primary pulmonary arterial hypertension has yielded several therapies, the same is not true for the treatment of pulmonary hypertension secondary to pulmonary fibrosis. Recent studies have indicated an important role of hypoxia-inducible factor (HIF) - a regulatory protein that is vital in adaptation to hypoxic conditions - in the development of secondary pulmonary hypertension...
2016: Receptors & Clinical Investigation
Hitoshi Uchinoumi, Yi Yang, Tetsuro Oda, Na Li, Katherina M Alsina, Jose L Puglisi, Ye Chen-Izu, Razvan L Cornea, Xander H T Wehrens, Donald M Bers
Diastolic calcium (Ca) leak via cardiac ryanodine receptors (RyR2) can cause arrhythmias and heart failure (HF). Ca/calmodulin (CaM)-dependent kinase II (CaMKII) is upregulated and more active in HF, promoting RyR2-mediated Ca leak by RyR2-Ser2814 phosphorylation. Here, we tested a mechanistic hypothesis that RyR2 phosphorylation by CaMKII increases Ca leak by promoting a pathological RyR2 conformation with reduced CaM affinity. Acute CaMKII activation in wild-type RyR2, and phosphomimetic RyR2-S2814D (vs. non-phosphorylatable RyR2-S2814A) knock-in mouse myocytes increased SR Ca leak, reduced CaM-RyR2 affinity, and caused a pathological shift in RyR2 conformation (detected via increased access of the RyR2 structural peptide DPc10)...
September 2016: Journal of Molecular and Cellular Cardiology
Nicola Improda, Pratik Shah, Maria Güemes, Clare Gilbert, Kate Morgan, Neil Sebire, Detlef Bockenhauer, Khalid Hussain
BACKGROUND: The p.R63W mutation in the hepatocyte nuclear factor-4 alpha (HNF4A) results in macrosomia and atypical Fanconi syndrome, in addition to hyperinsulinaemic hypoglycaemia (HI). We describe 2 infants carrying this mutation, presenting with additional features. Cases Series: Patient 1, a male born with a birth weight of 1.7 SDS, was diagnosed with HI on day 2 of life. He responded to 3-10 mg/kg/day of diazoxide. Raised serum creatinine led to the investigation of renal tubular function, showing leaking of electrolytes and protein...
2016: Hormone Research in Pædiatrics
Leroy C Joseph, Prakash Subramanyam, Christopher Radlicz, Chad M Trent, Vivek Iyer, Henry M Colecraft, John P Morrow
BACKGROUND: Diabetes and obesity are associated with an increased risk of arrhythmia and sudden cardiac death. Abnormal lipid accumulation is observed in cardiomyocytes of obese and diabetic patients, which may contribute to arrhythmia, but the mechanisms are poorly understood. A transgenic mouse model of cardiac lipid overload, the peroxisome proliferator-activated receptor-γ (PPARg) cardiac overexpression mouse, has long QT and increased ventricular ectopy. OBJECTIVE: The purpose of this study was to evaluate the hypothesis that the increase in ventricular ectopy during cardiac lipid overload is caused by abnormalities in calcium handling due to increased mitochondrial oxidative stress...
August 2016: Heart Rhythm: the Official Journal of the Heart Rhythm Society
Jun-Tang Li, Wei-Qi Wang, Ling Wang, Ning-Ning Liu, Ya-Li Zhao, Xiao-Shan Zhu, Qin-Qin Liu, Chun-Fang Gao, An-Gang Yang, Lin-Tao Jia
Neutrophil release of NO/ONOO- induces endothelial cell barrier dysfunction in inflammatory acute lung injury (ALI). Previous studies using zymosan-triggered inflammation and ALI model revealed that zymosan promotes inducible NO synthase (iNOS) expression in neutrophils, and that isoflurane inhibits zymosan-induced oxidative stress and iNOS biosynthesis. However, the underlying mechanisms remain largely unknown. We found here that in zymosan-primed neutrophils, iNOS is transcriptionally activated by NF-κB, whose nuclear translocation is triggered by excessive reactive oxygen species (ROS) and consequently activated p38 MAPK...
May 31, 2016: Oncotarget
Xinyuan Li, Pu Fang, Yafeng Li, Yin-Ming Kuo, Andrew J Andrews, Gayani Nanayakkara, Candice Johnson, Hangfei Fu, Huimin Shan, Fuyong Du, Nicholas E Hoffman, Daohai Yu, Satoru Eguchi, Muniswamy Madesh, Walter J Koch, Jianxin Sun, Xiaohua Jiang, Hong Wang, Xiaofeng Yang
OBJECTIVE: Hyperlipidemia-induced endothelial cell (EC) activation is considered as an initial event responsible for monocyte recruitment in atherogenesis. However, it remains poorly defined what is the mechanism underlying hyperlipidemia-induced EC activation. Here, we tested a novel hypothesis that mitochondrial reactive oxygen species (mtROS) serve as signaling mediators for EC activation in early atherosclerosis. APPROACH AND RESULTS: Metabolomics and transcriptomics analyses revealed that several lysophosphatidylcholine (LPC) species, such as 16:0, 18:0, and 18:1, and their processing enzymes, including Pla2g7 and Pla2g4c, were significantly induced in the aortas of apolipoprotein E knockout mice during early atherosclerosis...
June 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Douglas L Theobald
Presenilin is an integral membrane aspartate protease that regulates cellular processes by cleaving proteins within the cell membrane. The recent crystal structure of presenilin reveals a conspicuous pore in a bundle of nine α-helices, which was originally thought to adopt a novel protein fold. However, here I show that the presenilin fold is a variant of the ClC chloride channel/transporter fold. This observation may have important implications for presenilin's postulated biological role as a calcium leak channel...
July 2016: Protein Science: a Publication of the Protein Society
Yu-Si Cheng, De-Zai Dai, Yin Dai, Dong-Dong Zhu, Bi-Cheng Liu
OBJECTIVES: Hydrogen sulphide (H2 S) has been found to be involved in cardiovascular diseases, but the exact mechanism has not been clarified. The purpose of this study was to investigate whether sodium hydrogen sulphide (NaHS), the donor of H2 S, can improve diabetic cardiomyopathy by reversing disordered calcium-handling system in sarcoplasmic reticulum (SR). METHODS: Sprague Dawley rats were injected with streptozotocin (STZ, 60 mg/kg, i.p.) to build diabetic model...
March 2016: Journal of Pharmacy and Pharmacology
Ignacio Rivero Berti, María Laura Dell' Arciprete, María Laura Dittler, Alejandro Miñan, Mónica Fernández Lorenzo de Mele, Mónica Gonzalez
The delivery capacity and mechanical stability of calcium phosphate (CaP) coated 1,2-dioleoyl-sn-glycero-3-phosphate (DOPA) liposomes free and adsorbed on bacterial surface was investigated introducing either acridine orange (AO) or 5,10,15,20-Tetrakis(1-methyl-4-pyridinio)porphyrin (TMP) in the aqueous core of the liposomes. The obtained nanomaterials were thoroughly characterized by electron and optical microscopy and by fluorescence techniques. Distribution of the AO and TMP molecules between the aqueous liposomes core and the outer solution was demonstrated by the band shifts and broadening of the excitation-emission matrices and the modified Stern-Volmer model for fluorescence quenching...
June 1, 2016: Colloids and Surfaces. B, Biointerfaces
Yu-Hsun Kao, Jung-Chieh Hsu, Yao-Chang Chen, Yung-Kuo Lin, Baigalmaa Lkhagva, Shih-Ann Chen, Yi-Jen Chen
BACKGROUND: ZFHX3 plays an important role in the genesis of atrial fibrillation. However, the atrial electrophysiological effects of ZFHX3 are not clear. This study sought to investigate roles of ZFHX3 in atrial electrophysiology and calcium homeostasis by using HL-1 atrial myocytes knocked-down with ZFHX3. METHODS: Patch clamp, confocal fluorescence microscopy and Western blot were used to study electrical activity, ionic currents, calcium homeostasis and protein expressions in stable ZFHX3 shRNA cells...
May 1, 2016: International Journal of Cardiology
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