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Chen Fu, Jie Hao, Mengliu Zeng, Yejia Song, Wanzhen Jiang, Peihua Zhang, Antao Luo, Zhenzhen Cao, Luiz Belardinelli, Jihua Ma
Hypoxia leads to augmentation of late sodium current (INa.L ) and cellular Na(+) loading, increased reverse Na(+) -Ca(2+) exchange current (reverse INCX ) and intracellular Ca(2+) loading in rabbit ventricular myocytes. The purpose of this study was to determine the intracellular signal transduction pathways involved in the modulation of INa.L during hypoxia in ventricular myocytes. Whole-cell and cell-attached patch clamp techniques were used to record INa.L , and the whole-cell mode was also used to record reverse INCX and to study intercellular signal transduction mechanisms that mediate the increased INa...
April 24, 2017: Experimental Physiology
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
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
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...
March 27, 2017: Anesthesiology
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...
February 28, 2017: Biochimica et Biophysica Acta
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
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
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
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
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
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
Thao T Ha, Shalimar T Burwell, Matthew L Goodwin, Jacob A Noeker, Sara J Heggland
The heavy metal cadmium is a widespread environmental contaminant that has gained public attention due to the global increase in cadmium-containing electronic waste. Human exposure to cadmium is linked to the pathogenesis of osteoporosis. We previously reported cadmium induces apoptosis and decreases alkaline phosphatase mRNA expression via extracellular signal-regulated protein kinase (ERK) activation in Saos-2 bone-forming osteoblasts. This study examines the mechanisms of cadmium-induced osteotoxicity by investigating roles of Ca(+2)/calmodulin-dependent protein kinase (CAMK) pathways...
October 17, 2016: Toxicology Letters
Xinhong Li, Lirui Wang, Yuhua Li, Na Zhao, Linqing Zhen, Jieli Fu, Qiangzhen Yang
Considering the importance of calcium (Ca(2+)) in regulating sperm capacitation, hyperactivation and acrosome reaction, little is known about the molecular mechanism of action of this ion in this process. In the present study, assessment of the molecular mechanism from the perspective of energy metabolism occurred. Sperm motility variables were determined using computer-assisted sperm analysis (CASA) and the phosphorylation of PKA substrates, tyrosine residues and AMP-activated protein kinase (AMPK) were analyzed by Western blot...
September 2016: Animal Reproduction Science
Hilde Eikemo, Lise Román Moltzau, Cam H T Nguyen, Finn Olav Levy, Tor Skomedal, Jan-Bjørn Osnes
In cardiac tissue, regulatory light chain (RLC, myosin light chain 2) phosphorylation (Ser(15)) leads to modulation of muscle contraction through Ca(2+)-sensitization. To elucidate which kinases that are involved in the basal (diastolic phase) RLC phosphorylation, we studied non-contracting adult rat cardiomyocytes. RLC kinase activities in situ were unmasked by maximally inhibiting myosin light chain phosphatase (MLCP) by calyculin A in the absence and presence of various protein kinase inhibitors. Surprisingly MLCK did not contribute to the phosphorylation of RLC in the non-contracting cardiomyocytes...
August 12, 2016: Biochemical and Biophysical Research Communications
Tetsuya Nakamura, Jun Kamishikiryo, Tetsuo Morita
BACKGROUND: Prazosin is an α1 adrenoceptor antagonist used in pharmacotherapy for the treatment of hypertension. Prazosin alters lipid metabolism in vivo, but the involved mechanism is not fully understood. In this study, we investigated the mechanism underlying the alteration of lipid metabolism. We show that the prazosin-stimulated release of hepatic triacylglyceride lipase (HTGL) from primary cultured rat hepatocytes involved Ca(2+)/calmodulin-dependent protein kinase II (CaMK-II) activation...
June 2016: Pharmacological Reports: PR
Ji Luo, Wei-dong Zhang, Yi-meng Du
The calcium channel blocker (CCB), nifedipine, is a more effective treatment for early- than late-stage cardiac hypertrophy. We investigated the effects of early- and late-stage nifedipine administration on calcium homeostasis, CaMKII (Ca(2+) /calmodulin-dependent protein kinase II) activity and apoptosis of cardiomyocytes under hypertrophic stimulation with angiotensin II (AngII). Primary rat cardiomyocytes were divided into five treatment groups: AK, AngII plus the CaMKII inhibitor, KN-93; AN-1 (early-stage), AngII plus nifedipine × 48 h; AN-2 (late-stage), AngII × 48 h, then AngII plus nifedipine × 48 h; C, untreated; and A, AngII × 48 h...
April 2016: Cell Biochemistry and Function
Tomohiro Koga, Kotaro Otomo, Masayuki Mizui, Nobuya Yoshida, Masataka Umeda, Kunihiro Ichinose, Atsushi Kawakami, George C Tsokos
OBJECTIVE: The recruitment of interleukin-17 (IL-17)-producing T helper (Th17) cells to inflammatory sites has been implicated in the development of organ damage in inflammatory and autoimmune diseases including systemic lupus erythematosus (SLE). To define the mechanism of calcium/calmodulin-dependent kinase IV (CaMKIV) activation of Th17 cell recruitment to target tissues, we performed anti-glomerular basement membrane antibody-induced glomerulonephritis (AIGN) experiments in mice and studied samples from patients with SLE...
August 2016: Arthritis & Rheumatology
Hongtao Shi, Qinghua Han, Jianrong Xu, Wenyuan Liu, Tingting Chu, Li Zhao
Although studies have shown that Urotensin II (UII) can induce cardiomyocyte hypertrophy and UII-induced cardiomyocyte hypertrophy model has been widely used for hypertrophy research, but its precise mechanism remains unknown. Recent researches have demonstrated that UII-induced cardiomyocyte hypertrophy has a relationship with the changes of intracellular Ca(2+) concentration. Therefore, the aim of this study was to investigate the mechanisms of cardiomyocyte hypertrophy induced by UII and to explore whether the calcium/calmodulin-dependent protein kinase II (CaMKII)-mediated up-regulating of phospholamban (PLN) Thr17-phosphorylation signaling pathway contributed to UII-induced cardiomyocyte hypertrophy...
May 25, 2016: Gene
BingBing Shen, Yue He, Shan Zhou, Hongwen Zhao, Mei Mei, Xiongfei Wu
BACKGROUND The aim of this study was to explore the potential role of TRPC6 in the pathophysiology of HK-2 cell injury following ischemia reperfusion (I/R). MATERIAL AND METHODS TRPC6 expression was analyzed by immunofluorescence staining. siRNA was transfected to knockout of TRPC6 in HK-2 cells, and in vitro I/R was then induced. Cell apoptosis and necrosis were determined by Annexin V-FITC/PI staining. Necroptosis was determined by necrostatin-1 and expressions of necroptosis-related proteins were evaluated...
February 25, 2016: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Qian Li, Na Wu, Peng Cui, Feng Gao, Wen-Jing Qian, Yanying Miao, Xing-Huai Sun, Zhongfeng Wang
Dopamine plays an important role in regulating neuronal functions in the central nervous system by activating the specific G-protein coupled receptors. Both D1 and D2 dopamine receptors are extensively distributed in the retinal neurons. In the present study, we investigated the effects of D1 receptor signaling on outward K(+) currents in acutely isolated rat retinal ganglion cells (RGCs) by patch-clamp techniques. Extracellular application of SKF81297 (10 μM), a specific D1 receptor agonist, significantly and reversibly suppressed outward K(+) currents of the cells, which was reversed by SCH23390 (10 μM), a selective D1 receptor antagonist...
March 15, 2016: Brain Research
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