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https://www.readbyqxmd.com/read/28912066/the-camp-effectors-pka-and-epac-activate-endothelial-no-synthase-through-pi3k-akt-pathway-in-human-endothelial-cells
#1
Verónica García-Morales, María Luaces-Regueira, Manuel Campos-Toimil
3',5'-cyclic adenosine monophosphate (cAMP) exerts an endothelium-dependent vasorelaxant action by stimulating endothelial NO synthase (eNOS) activity, and the subsequent NO release, through cAMP protein kinase (PKA) and exchange protein directly activated by cAMP (Epac) activation in endothelial cells. We have here investigated the mechanism by which the cAMP-Epac/PKA pathway activates eNOS. cAMP-elevating agents (forskolin and dibutyryl-cAMP) and the joint activation of PKA (6-Bnz-cAMP) and Epac (8-pCPT-2'-O-Me-cAMP) increased cytoplasmic Ca(2+) concentration ([Ca(2+)]c) in ≤ 30% of fura-2-loaded isolated human umbilical vein endothelial cells (HUVEC)...
September 11, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28867536/nitric-oxide-and-camkii-critical-steps-in-the-cardiac-contractile-response-to-igf-1-and-swim-training
#2
Juan I Burgos, Alejandra M Yeves, Jorge P Barrena, Enrique L Portiansky, Martín G Vila-Petroff, Irene L Ennis
Cardiac adaptation to endurance training includes improved contractility by a non-yet clarified mechanism. Since IGF-1 is the main mediator of the physiological response to exercise, we explored its effect on cardiac contractility and the putative involvement of nitric oxide (NO) and CaMKII in control and swim-trained mice. IGF-1 increased cardiomyocyte shortening (128.1±4.6% vs. basal; p˂0.05) and accelerated relaxation (time to 50% relengthening: 49.2±2.0% vs. basal; p˂0.05), effects abrogated by inhibition of: AKT with MK-2206, NO production with the NO synthase (NOS) inhibitor L-NAME and the specific NOS1 inhibitor nitroguanidine (NG), and CaMKII with KN-93...
September 1, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28859293/impaired-calcium-homeostasis-is-associated-with-sudden-cardiac-death-and-arrhythmias-in-a-genetic-equivalent-mouse-model-of-the-human-hrc-ser96ala-variant
#3
Christos Tzimas, Daniel M Johnson, Demetrio J Santiago, Elizabeth Vafiadaki, Demetrios A Arvanitis, Constantinos H Davos, Aimilia Varela, Nikolaos C Athanasiadis, Constantinos Dimitriou, Michalis Katsimpoulas, Stephan Sonntag, Mariya Kryzhanovska, Doron Shmerling, Stephan E Lehnart, Karin R Sipido, Evangelia G Kranias, Despina Sanoudou
Aims: The histidine-rich calcium-binding protein (HRC) Ser96Ala variant has previously been identified as a potential biomarker for ventricular arrhythmias and sudden cardiac death in patients with idiopathic dilated cardiomyopathy. Herein, the role of this variant in cardiac pathophysiology is delineated through a novel mouse model, carrying the human mutation in the homologous mouse position. Methods and results: The mouse HRC serine 81, homologous to human HRC serine 96, was mutated to alanine, using knock-in gene targeting...
September 1, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28836001/the-reduced-myofilament-responsiveness-to-calcium-contributes-to-the-negative-force-frequency-relationship-in-rat-cardiomyocytes-role-of-reactive-oxygen-species-and-p-38-map-kinase
#4
María Sofía Espejo, Ignacio Aiello, Marisa Sepúlveda, Martín G Vila Petroff, Ernesto A Aiello, Verónica C De Giusti
The force-frequency relationship (FFR) is an important intrinsic regulatory mechanism of cardiac contractility. However, a decrease (negative FFR) or no effect (flat FFR) on contractile force in response to an elevation of heart rate is present in the normal rat or in human heart failure. Reactive oxygen species (ROS) can act as intracellular signaling molecules activating diverse kinases as calcium-calmodulin-dependent protein kinase II (CaMKII) and p-38 MAP kinase (p-38K). Our aim was to elucidate the intracellular molecules implicated in the FFR of isolated rat ventricular myocytes...
August 23, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28792844/trpa1-ion-channel-stimulation-enhances-cardiomyocyte-contractile-function-via-a-camkii-dependent-pathway
#5
Spencer R Andrei, Monica Ghosh, Pritam Sinharoy, Souvik Dey, Ian N Bratz, Derek S Damron
RATIONALE: Transient receptor potential channels of the ankyrin subtype-1 (TRPA1) are non-selective cation channels that show high permeability to calcium. Previous studies from our laboratory have demonstrated that TRPA1 ion channels are expressed in adult mouse ventricular cardiomyocytes (CMs) and are localized at the z-disk, costamere and intercalated disk. The functional significance of TRPA1 ion channels in the modulation of CM contractile function have not been explored. OBJECTIVE: To identify the extent to which TRPA1 ion channels are involved in modulating CM contractile function and elucidate the cellular mechanism of action...
August 9, 2017: Channels
https://www.readbyqxmd.com/read/28754591/camkii-inhibition-mitigates-ischemia-reperfusion-elicited-calpain-activation-and-the-damage-to-membrane-skeleton-proteins-in-isolated-rat-hearts
#6
Ling-Heng Kong, Xiao-Ming Gu, Feng Wu, Zhen-Xiao Jin, Jing-Jun Zhou
Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) has been implicated in myocardial ischemia/reperfusion (IR) injury. The aim of this study was to determine the effect of CaMKII on the damage to membrane skeleton proteins, which is an important cause of IR injury. Isolated rat hearts were subjected to 45-min global ischemia/2-h reperfusion. Both KN-62 and KN-93 were used to inhibit CaMKII. Compared with controls, the hearts in the IR group exhibited remarkable myocardial injury area, LDH release, cell apoptosis and contractile dysfunction, along with an increase in the phosphorylation of CaMKII and its substrate phospholamban...
September 23, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28735419/modulation-of-human-kv4-3-kchip2-channel-inactivation-kinetics-by-cytoplasmic-ca%C3%A2-%C3%A2-%C2%BA
#7
Christiane Groen, Robert Bähring
The transient outward current (I to) in the human heart is mediated by Kv4.3 channels complexed with Kv channel interacting protein (KChIP) 2, a cytoplasmic Ca(2+)-binding EF-hand protein known to modulate Kv4.3 inactivation gating upon heterologous co-expression. We studied Kv4.3 channels co-expressed with wild-type (wt) or EF-hand-mutated (?EF) KChIP2 in human embryonic kidney (HEK) 293 cells. Co-expression took place in the absence or presence of BAPTA-AM, and macroscopic currents were recorded in the whole-cell patch-clamp configuration with different free Ca(2+) concentrations in the patch-pipette...
July 22, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28558386/periodic-mechanical-stress-induces-chondrocyte-proliferation-and-matrix-synthesis-via-camkii-mediated-pyk2-signaling
#8
Wenwei Liang, Zeng Li, Zhen Wang, Jinchun Zhou, Huanghe Song, Shun Xu, Weiding Cui, Qing Wang, Zhefeng Chen, Feng Liu, Weimin Fan
BACKGROUND/AIMS: Periodic mechanical stress can promote chondrocyte proliferation and matrix synthesis to improve the quality of tissue-engineered cartilage. Although the integrin β1-ERK1/2 signal cascade has been implicated in periodic mechanical stress-induced mitogenic effects in chondrocytes, the precise mechanisms have not been fully established. The current study was designed to probe the roles of CaMKII and Pyk2 signaling in periodic mechanical stress-mediated chondrocyte proliferation and matrix synthesis...
2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28554967/basal-late-sodium-current-is-a-significant-contributor-to-the-duration-of-action-potential-of-guinea-pig-ventricular-myocytes
#9
Yejia Song, Luiz Belardinelli
In cardiac myocytes, an enhancement of late sodium current (INaL) under pathological conditions is known to cause prolongation of action potential duration (APD). This study investigated the contribution of INaL under basal, physiological conditions to the APD Whole-cell INaL and the APD of ventricular myocytes isolated from healthy adult guinea pigs were measured at 36°C. The INaL inhibitor GS967 or TTX was applied to block INaL The amplitude of basal INaL and the APD at 50% repolarization in myocytes stimulated at a frequency of 0...
May 2017: Physiological Reports
https://www.readbyqxmd.com/read/28436159/modulation-of-late-sodium-current-by-ca-2-calmodulin-dependent-protein-kinase-ii-protein-kinase-c-and-ca-2-during-hypoxia-in-rabbit-ventricular-myocytes
#10
Chen Fu, Jie Hao, Mengliu Zeng, Yejia Song, Wanzhen Jiang, Peihua Zhang, Antao Luo, Zhenzhen Cao, Luiz Belardinelli, Jihua Ma
What is the central question of this study? Hypoxia-induced increase in late sodium current (INa,L ) is associated with conditions causing cellular Ca(2+) overload and contributes to arrhythmogenesis in the ventricular myocardium. The INa,L is an important drug target. We investigated intracellular signal transduction pathways involved in modulation of INa,L during hypoxia. What is the main finding and its importance? Hypoxia caused increases in INa,L , reverse Na(+) -Ca(2+) exchange current and diastolic [Ca(2+) ], which were attenuated by inhibitors of Ca(2+) -calmodulin-dependent protein kinase II (CaMKII) and protein kinase C and by a Ca(2+) chelator...
July 1, 2017: Experimental Physiology
https://www.readbyqxmd.com/read/28431901/clozapine-reduces-toll-like-receptor-4-nf-%C3%AE%C2%BAb-mediated-inflammatory-responses-through-inhibition-of-calcium-calmodulin-dependent-akt-activation-in-microglia
#11
Seunghyun Jeon, Se Hyun Kim, Soon Young Shin, Young Han Lee
Clozapine is an atypical antipsychotic agent used in the treatment of schizophrenia and severe mood disorders. Accumulating evidence suggests that neuroinflammation is closely associated with the pathogenesis of various neurodegenerative diseases and psychiatric disorders. Clozapine exerts anti-inflammatory activity. However, the molecular mechanism underlying the anti-inflammatory activity of clozapine is poorly understood. In this study, we found that clozapine suppressed lipopolysaccharide (LPS)-induced phosphorylation of IκBα at Ser-32 and of p65/RelA at Ser-468, as well as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-dependent transcriptional activity in microglial cells...
April 18, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/28352365/heart-failure-modulates-electropharmacological-characteristics-of-sinoatrial-nodes
#12
Shih-Lin Chang, Hui-Lun Chuang, Yao-Chang Chen, Yu-Hsun Kao, Yung-Kuo Lin, Yung-Hsin Yeh, Shih-Ann Chen, Yi-Jen Chen
The impact of heart failure (HF) on sinoatrial node (SAN) channel regulation and electropharmacological responses has remained elusive. The present study aimed to investigate the effects of HF on the electrical activity of SANs with and without pharmacological interventions. Action potentials (APs) were recorded in isolated SANs from normal rabbits (control) and those with HF (rapid ventricular pacing for 4 weeks) prior to and after administration of a funny current blocker (ivabradine; 0.1, 0.3, 3 or 10 µM), a calmodulin kinase II inhibitor (KN-93; 0...
February 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28346321/growth-arrest-and-dna-damage-inducible-protein-45%C3%AE-mediated-dna-demethylation-of-voltage-dependent-t-type-calcium-channel-3-2-subunit-enhances-neuropathic-allodynia-after-nerve-injury-in-rats
#13
Cheng-Yuan Lai, Ming-Chun Hsieh, Yu-Cheng Ho, An-Sheng Lee, Hsueh-Hsiao Wang, Jen-Kun Cheng, Yat-Pang Chau, Hsien-Yu Peng
BACKGROUND: Growth arrest and DNA-damage-inducible protein 45β reactivates methylation-silenced neural plasticity-associated genes through DNA demethylation. However, growth arrest and DNA-damage-inducible protein 45β-dependent demethylation contributes to neuropathic allodynia-associated spinal plasticity remains unclear. METHODS: Adult male Sprague-Dawley rats (654 out of 659) received a spinal nerve ligation or a sham operation with or without intrathecal application of one of the following: growth arrest and DNA-damage-inducible protein 45β messenger RNA-targeted small interfering RNA, lentiviral vector expressing growth arrest and DNA-damage-inducible protein 45β, Ro 25-6981 (an NR2B-bearing N-methyl-D-aspartate receptor antagonist), or KN-93 (a calmodulin-dependent protein kinase II antagonist) were used for behavioral measurements, Western blotting, immunofluorescence, dot blots, detection of unmodified cytosine enrichment at cytosine-phosphate-guanine site, chromatin immunoprecipitation quantitative polymerase chain reaction analysis, and slice recordings...
June 2017: Anesthesiology
https://www.readbyqxmd.com/read/28257804/characterization-and-cellular-localization-of-human-5-lipoxygenase-and-its-protein-isoforms-5-lo%C3%AE-13-5-lo%C3%AE-4-and-5-lop12
#14
Ann-Katrin Ball, Kim Beilstein, Sandra Wittmann, Duran Sürün, Meike J Saul, Frank Schnütgen, Nicolas Flamand, Ricardo Capelo, Astrid S Kahnt, Helena Frey, Liliana Schaefer, Rolf Marschalek, Ann-Kathrin Häfner, Dieter Steinhilber
Human 5-lipoxygenase (5-LO-WT) initiates the leukotriene (LT) biosynthesis. LTs play an important role in diseases like asthma, atherosclerosis and in many types of cancer. In this study, we investigated the 5-LO isoforms 5-LO∆13, 5-LO∆4 and 5-LOp12, lacking the exons 13, 4 or a part of exon 12, respectively. We were able to detect the mRNA of the isoforms 5-LO∆13 and 5-LOp12 in B and T cell lines as well as in primary B and T cells and monocytes. Furthermore, we found that expression of 5-LO and particularly of the 5-LO∆13 and 5-LOp12 isoforms is increased in monocytes from patients with rheumatoid arthritis and sepsis...
May 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28130334/blockade-of-camkii-depresses-conduction-preferentially-in-the-right-ventricular-outflow-tract-and-promotes-ischemic-ventricular-fibrillation-in-the-rabbit-heart
#15
Mark Warren, Katie J Sciuto, Tyson G Taylor, Vivek Garg, Natalia S Torres, Junko Shibayama, Kenneth W Spitzer, Alexey V Zaitsev
Calcium/calmodulin-dependent protein kinase II (CaMKII) regulates the principle ion channels mediating cardiac excitability and conduction, but how this regulation translates to the normal and ischemic heart remains unknown. Diverging results on CaMKII regulation of Na(+) channels further prevent predicting how CaMKII activity regulates excitability and conduction in the intact heart. To address this deficiency, we tested the effects of the CaMKII blocker KN93 (1 and 2.75 μM) and its inactive analog KN92 (2...
April 1, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28097237/oxidized-camkii-promotes-asthma-through-the-activation-of-mast-cells
#16
Jingjing Qu, Danh C Do, Yufeng Zhou, Elizabeth Luczak, Wayne Mitzner, Mark E Anderson, Peisong Gao
Oxidation of calmodulin-dependent protein kinase II (ox-CaMKII) by ROS has been associated with asthma. However, the contribution of ox-CaMKII to the development of asthma remains to be fully characterized. Here, we tested the effect of ox-CaMKII on IgE-mediated mast cell activation in an allergen-induced mouse model of asthma using oxidant-resistant CaMKII MMVVδ knockin (MMVVδ) mice. Compared with WT mice, the allergen-challenged MMVVδ mice displayed less airway hyperresponsiveness (AHR) and inflammation...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28094445/presynaptic-inhibition-of-transient-receptor-potential-vanilloid-type-1-trpv1-receptors-by-noradrenaline-in-nociceptive-neurons
#17
Saikat Chakraborty, Vincent Elvezio, Martin Kaczocha, Mario Rebecchi, Michelino Puopolo
KEY POINTS: The transient receptor potential vanilloid type 1 (TRPV1) receptor is a polymodal molecular integrator in the pain pathway expressed in Aδ- and C-fibre nociceptors and is responsible for the thermal hyperalgesia associated with inflammatory pain. Noradrenaline strongly inhibited the activity of TRPV1 channels in dorsal root ganglia neurons. The effect of noradrenaline was reproduced by clonidine and antagonized by yohimbine, consistent with contribution of α2 adrenergic receptors...
April 15, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28025122/protective-effect-of-rutaecarpine-against-t-bhp-induced-hepatotoxicity-by-upregulating-antioxidant-enzymes-via-the-camkii-akt-and-nrf2-are-pathways
#18
Sun Woo Jin, Yong Pil Hwang, Chul Yung Choi, Hyung Gyun Kim, Se Jong Kim, Yongan Kim, Young Chul Chung, Kyung Jin Lee, Tae Cheon Jeong, Hye Gwang Jeong
Rutaecarpine, an indolopyridoquinazolinone alkaloid isolated from the unripe fruit of Evodia rutaecarpa, has been shown to have cytoprotective potential, but the molecular mechanism underlying this activity remains unclear. Our study was designed to investigate the cytoprotective effect of rutaecarpine against tert-butyl hydroperoxide (t-BHP) and to elucidate its action mechanism of action of rutaecarpine in a cultured HepG2 cell line and in mouse liver. Rutaecarpine decreased t-BHP-induced reactive oxygen species (ROS) production, cytotoxicity, and apoptosis in HepG2 cells...
February 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/27889915/constitutive-regulation-of-the-glutamate-aspartate-transporter-eaat1-by-calcium-calmodulin-dependent-protein-kinase-ii
#19
Aarti R Chawla, Derrick E Johnson, Agnes S Zybura, Benjamin P Leeds, Ross M Nelson, Andy Hudmon
Glutamate clearance by astrocytes is an essential part of normal excitatory neurotransmission. Failure to adapt or maintain low levels of glutamate in the central nervous system is associated with multiple acute and chronic neurodegenerative diseases. The primary excitatory amino acid transporters in human astrocytes are EAAT1 and EAAT2 (GLAST and GLT-1, respectively, in rodents). While the inhibition of calcium/calmodulin-dependent kinase (CaMKII), a ubiquitously expressed serine/threonine protein kinase, results in diminished glutamate uptake in cultured primary rodent astrocytes (Ashpole et al...
February 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27734911/novelty-during-a-late-postacquisition-time-window-attenuates-the-persistence-of-fear-memory
#20
Cynthia Katche, Micol Tomaiuolo, Guido Dorman, Jorge H Medina, Haydee Viola
Learning to avoid threats in the environment is highly adaptive. However, sometimes a dysregulation of fear memories processing may underlie fear-related disorders. Despite recent advances, a major question of how to effectively attenuate persistent fear memories in a safe manner remains unresolved. Here we show experiments employing a behavioural tool to target a specific time window after training to limit the persistence of a fear memory in rats. We observed that exposure to a novel environment 11 h after an inhibitory avoidance (IA) training that induces a long-lasting memory, attenuates the durability of IA memory but not its formation...
October 13, 2016: Scientific Reports
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