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Wojciech Jurczak, Monika Długosz-Danecka, Michael Wang
Although advances in mantle cell lymphoma (MCL) therapy have improved overall survival (OS), managing relapsed/refractory (R/R) cases remains a great challenge. Bruton tyrosine kinase (BTK) inhibitors have broadened therapeutic options in MCL and became the backbone of second-line strategies. Areas covered: Ibrutinib, the first-in-class BTK inhibitor registered for MCL therapy, is efficient, with clear benefits of its use. However, ibrutinib-related adverse events due to off-target inhibition of other kinases led to the development of more selective molecules with comparable efficacy and better safety profiles...
March 2019: Expert Review of Clinical Pharmacology
Seo Jung Mo, Yongsang Cho, Byung-Il Choi, Dongmin Lee, Hyun Kim
Microtubule-associated end-binding protein 3 (EB3) accumulates asymmetrically at the tip-end of growing microtubules, providing a central platform for linking various cellular components. EB3 orchestrates microtubule dynamics and targeting, enabling diverse processes within neurons. Inositol 1, 4, 5-trisphosphate 3-kinase A (IP3K-A; also known as ITPKA) is a neuron-enriched protein that binds to microtubules by PKA-dependent manners. In this study, we found that IP3K-A binds to EB3 and their binding affinity is precisely regulated by protein kinase A (PKA)-dependent phosphorylation of IP3K-A at Ser119 (pSer119)...
November 19, 2018: Biochemical and Biophysical Research Communications
Byungil Choi, Hyun Woo Lee, Seojung Mo, Jin Yong Kim, Hyun Wook Kim, Im Joo Rhyu, Eunhwa Hong, Yeon Kyung Lee, June-Seek Choi, Chong-Hyun Kim, Hyun Kim
Inositol 1,4,5-trisphosphate 3-kinase A (IP3K-A) regulates the level of the inositol polyphosphates, inositol trisphosphate (IP3) and inositol tetrakisphosphate to modulate cellular signaling and intracellular calcium homeostasis in the central nervous system. IP3K-A binds to F-actin in an activity-dependent manner and accumulates in dendritic spines, where it is involved in the regulation of synaptic plasticity. IP3K-A knockout mice exhibit deficits in some forms of hippocampus-dependent learning and synaptic plasticity, such as long-term potentiation in the dentate gyrus synapses of the hippocampus...
2018: PloS One
You Li, Li-Zhen Zhang, Yao Yi, Wan-Wan Hu, Ya-Hui Guo, Zhi-Jiang Zeng, Zachary-Y Huang, Zi-Long Wang
The honeybee is a model organism for studying learning and memory formation and its underlying molecular mechanisms. While DNA methylation is well studied in caste differentiation, its role in learning and memory is not clear in honeybees. Here, we analyzed genome-wide DNA methylation changes during olfactory learning and memory process in A. mellifera using whole genome bisulfite sequencing (WGBS) method. A total of 853 significantly differentially methylated regions (DMRs) and 963 differentially methylated genes (DMGs) were identified...
December 5, 2017: Scientific Reports
Sooyoung Chung, Il Hwan Kim, Dongmin Lee, Kyungjoon Park, Joo Yeon Kim, Yeon Kyung Lee, Eun Joo Kim, Hyun Woo Lee, June-seek Choi, Gi Hoon Son, Woong Sun, Ki Soon Shin, Hyun Kim
Inositol 1,4,5-trisphosphate 3-kinase A (IP3K-A) is a molecule enriched in the brain and neurons that regulates intracellular calcium levels via signaling through the inositol trisphosphate receptor. In the present study, we found that IP3K-A expression is highly enriched in the central nucleus of the amygdala (CeA), which plays a pivotal role in the processing and expression of emotional phenotypes in mammals. Genetic abrogation of IP3K-A altered amygdala gene expression, particularly in genes involved in key intracellular signaling pathways and genes mediating fear- and anxiety-related behaviors...
April 7, 2016: Scientific Reports
Fedor A Balabin, Anastasia N Sveshnikova
Blood platelet activation is required to allow their participation in hemostasis and thrombosis. It is regulated by a complicated signaling network, whose functioning has been recently attracting attention for basic research and pharmacological purposes. Phospholipase С (PLC) is an enzyme playing an important role in platelet calcium signaling and responsible for release of inositol triphosphate (IP3) into platelet cytoplasm thus controlling intracellular calcium concentration. Using a comprehensive computational model of platelet calcium signaling, we studied the influence of the positive feedback executed by cytosolic calcium on the PLC isoform β2 during platelet activation...
June 2016: Mathematical Biosciences
A J Berens, E A Tibbetts, A L Toth
Few animals are known to individually recognize conspecifics, i.e. learn and recall unique individuals during subsequent encounters, and nearly all are social vertebrates. Remarkably, the social paper wasp Polistes fuscatus has recently been discovered to possess this ability, which is useful for remembering identities during competitive social interactions. We analyzed brain gene expression in staged encounters between pairs of individuals to explore potential mechanisms underlying wasps' ability to recall familiar individuals using real-time qRT-PCR...
February 2016: Journal of Comparative Physiology. A, Neuroethology, Sensory, Neural, and Behavioral Physiology
Cigdem Usul Afsar, Berksoy Sahin, Meral Gunaldi, Emine Kılıc Bagir, Derya Gumurdulu, Refik Burgut, Melek Erkisi, Ismail Oguz Kara, Semra Paydas, Feryal Karaca, Vehbi Ercolak
AIM: Non-small cell lung carcinoma is the leading cause of cancer related to death in the world. Squamous cell lung carcinoma (SqCLC) is the second most frequent histological subtype of lung carcinomas. Recently, growth factors, growth factor receptors, and signal transduction system-related gene amplifications and mutations are extensively under investigation to estimate the prognosis and to develop individualized therapies in SqCLC. In this study, besides the signal transduction molecule phosphatidyl inositol-3-phosphate kinase (IP3K) p110α, we explored the expressions of fibroblast growth factor 2 (FGF2) and receptor-1 (FGFR1) in tumor tissue and also their clinical and prognostic significance in patients with early/advanced SqCLC...
2015: International Journal of Clinical and Experimental Pathology
T Angelone, A M Quintieri, T Pasqua, E Filice, P Cantafio, F Scavello, C Rocca, S K Mahata, A Gattuso, M C Cerra
The myocardial response to mechanical stretch (Frank-Starling law) is an important physiological cardiac determinant. Modulated by many endogenous substances, it is impaired in the presence of cardiovascular pathologies and during senescence. Catestatin (CST:hCgA352-372), a 21-amino-acid derivate of Chromogranin A (CgA), displays hypotensive/vasodilatory properties and counteracts excessive systemic and/or intra-cardiac excitatory stimuli (e.g., catecholamines and endothelin-1). CST, produced also by the myocardium, affects the heart by modulating inotropy, lusitropy and the coronary tone through a Nitric Oxide (NO)-dependent mechanism...
November 15, 2015: Nitric Oxide: Biology and Chemistry
M C Sekar, K Shahiwala, L Leloup, A Wells
Epidermal growth factor [EGF] mediated stimulation of its receptor in endothelial cell [EC] is accompanied by phosphorylation of the EGF-receptor [EGFR] and activation of phospholipase C-γ, resulting in the breakdown of phosphatidylinositol(4,5)-bisphosphate and generating inositol (1,4,5)-trisphosphate [IP3] and diacylglycerol. IP3 thus formed can be further converted to inositol (1,3,4,5)-tetrakisphosphate [IP4] by an enzyme called IP3-kinase [IP3K]. In this study we have investigated the effect of modulation of intracellular IP3K activity by the use of an inhibitor, 2-trifluoromethyl [6-(4-nitrobenzyl)-purine] [IP3KI] and siRNA against IP3KB on EGF-induced ERK-phosphorylation and cell motility...
June 1, 2014: Journal of Pharmaceutical Sciences and Pharmacology
Chao Guo, Run Liu, Hong-Bin Zhao, Guan-Hua Qin
OBJECTIVE: To explore the molecule mechanism of Salidroside inducing directional differentiation of mouse mesenchymal stem cells (MSCs) into neuronal cells. METHODS: The mouse multipotent mesenchymal precursor cell line (D1) was taken as the objective. Cultured MSCs were divided into the negative control group (complete culture solution), the positive control group (containing 1 mmol/L β-mercaptoethanol), the Salidroside induced group (20 mg/L Salidroside), and the blocked group (20 ng/ ml DKK1, a special inhibitor of Wnt/β-catenin signal pathway)...
March 2015: Chinese Journal of Integrated Traditional and Western Medicine
Huanchen Wang, Eugene F DeRose, Robert E London, Stephen B Shears
Inositol trisphosphate kinases (IP3Ks) and inositol hexakisphosphate kinases (IP6Ks) each regulate specialized signalling activities by phosphorylating either InsP3 or InsP6 respectively. The molecular basis for these different kinase activities can be illuminated by a structural description of IP6K. Here we describe the crystal structure of an Entamoeba histolytica hybrid IP6K/IP3K, an enzymatic parallel to a 'living fossil'. Through molecular modelling and mutagenesis, we extrapolated our findings to human IP6K2, which retains vestigial IP3K activity...
June 24, 2014: Nature Communications
M J Sisalli, A Secondo, A Esposito, V Valsecchi, C Savoia, G F Di Renzo, L Annunziato, A Scorziello
Ischemic preconditioning (IPC), an important endogenous adaptive mechanism of the CNS, renders the brain more tolerant to lethal cerebral ischemia. The molecular mechanisms responsible for the induction and maintenance of ischemic tolerance in the brain are complex and still remain undefined. Considering the increased expression of the two sodium calcium exchanger (NCX) isoforms, NCX1 and NCX3, during cerebral ischemia and the relevance of nitric oxide (NO) in IPC modulation, we investigated whether the activation of the NO/PI3K/Akt pathway induced by IPC could regulate calcium homeostasis through changes in NCX1 and NCX3 expression and activity, thus contributing to ischemic tolerance...
July 2014: Cell Death and Differentiation
Dongmin Lee, Seungrie Han, Seungkyun Woo, Hyun Woo Lee, Woong Sun, Hyun Kim
Inositol 1,4,5-trisphosphate 3-kinase A (IP3K-A, alternative name: ITPKA) is a neuron-specific enzyme that converts 1,4,5-trisphosphate (IP3) into inositol 1,3,4,5-tetrakisphosphate (IP4) through its kinase domain. In addition, transient overexpression of IP3K-A induces morphological changes in dendritic spines of excitatory synapses in a kinase-independent manner, apparently by modulating the organization of the neuronal cytoskeleton. Although the procurement of a purified recombinant IP3K-A protein would be indispensable for the biochemical elucidation of its physiological roles, production of recombinant IP3K-A has proven technically challenging in conventional Escherichia coli expression systems...
May 2014: Protein Expression and Purification
Júlia Láng, Virág Rákász, Anna Magyar, Éva Pállinger, László Kohidai
Naturally occurring aroma compounds are able to elicit physiological and migratory responses such as chemotaxis even at nano to femtomolar concentrations in organisms at different levels of phylogeny. Despite the amazing chemical variety of these substances the apparatus by which they can be detected i.e. the chemosensory receptors and the signaling pathways seem to be rather uniform and evolutionary well-conserved. The intracellular signaling process is supposed to be mediated by either cAMP or inositol 1,4,5-trisphosphate...
December 2011: Journal of Receptor and Signal Transduction Research
Zhenghong Zhang, Debing Yu, Dingzhong Yin, Zhengchao Wang
We recently reported that HIF-1α plays a critical role in the regulation of vascular endothelial growth factor (VEGF) expression in the developing letual cells (LCs) and VEGF-dependent angiogenesis is essential for normal luteal development. Although it is believed that hypoxia is the primary inducer of VEGF, recent reports have also shown that human chorionic gonadotrophin (hCG) up-regulates VEGF expression in developing corpus luteum (CL). Therefore the present study was designed to test the induced effects of hCG on the expression of VEGF and HIF-1α in LCs under normoxic and hypoxic conditions...
May 2011: Animal Reproduction Science
Marcus M Nalaskowski, Ralf Fliegert, Olga Ernst, Maria A Brehm, Werner Fanick, Sabine Windhorst, Hongying Lin, Susanne Giehler, Jamin Hein, Yuan-Na Lin, Georg W Mayr
Recent studies have shown that inositol 1,4,5-trisphosphate 3-kinase isoform B (IP3KB) possesses important roles in the development of immune cells. IP3KB can be targeted to multiple cellular compartments, among them nuclear localization and binding in close proximity to the plasma membrane. The B isoform is the only IP3K that is almost ubiquitously expressed in mammalian cells. Detailed mechanisms of its targeting regulation will be important in understanding the role of Ins(1,4,5)P(3) phosphorylation on subcellular calcium signaling and compartment-specific initiation of pathways leading to regulatory active higher phosphorylated inositol phosphates...
February 11, 2011: Journal of Biological Chemistry
Andriana Margariti, Anna Zampetaki, Qingzhong Xiao, Boda Zhou, Eirini Karamariti, Daniel Martin, Xiaoke Yin, Manuel Mayr, Hongling Li, Zhongyi Zhang, Elena De Falco, Yanhua Hu, Gillian Cockerill, Qingbo Xu, Lingfang Zeng
RATIONALE: Histone deacetylase (HDAC)7 is expressed in the early stages of embryonic development and may play a role in endothelial function. OBJECTIVE: This study aimed to investigate the role of HDAC7 in endothelial cell (EC) proliferation and growth and the underlying mechanism. METHODS AND RESULTS: Overexpression of HDAC7 by adenoviral gene transfer suppressed human umbilical vein endothelial cell (HUVEC) proliferation by preventing nuclear translocation of beta-catenin and downregulation of T-cell factor-1/Id2 (inhibitor of DNA binding 2) and cyclin D1, leading to G(1) phase elongation...
April 16, 2010: Circulation Research
Sabine Windhorst, Christine Blechner, Hong-Ying Lin, Christian Elling, Marcus Nalaskowski, Tanja Kirchberger, Andreas H Guse, Georg W Mayr
In the present study, effects of increased IP3K-A [Ins(1,4,5)P(3) 3-kinase-A] expression were analysed. H1299 cells overexpressing IP3K-A formed branching protrusions, and under three-dimensional culture conditions, they exhibited a motile fibroblast-like morphology. They lost the ability to form actin stress fibres and showed increased invasive migration in vitro. Furthermore, expression levels of the mesenchymal marker proteins vimentin and N-cadherin were increased. The enzymatic function of IP3K-A is to phosphorylate the calcium-mobilizing second messenger Ins(1,4,5)P(3) to (Ins(1,3,4,5)P(4)...
September 15, 2008: Biochemical Journal
Michael J Schell, Robin F Irvine
The structure of the actin cytoskeleton in dendritic spines is thought to underlie some forms of synaptic plasticity. We have used fixed and live-cell imaging in rat primary hippocampal cultures to characterize the synaptic dynamics of the F-actin binding protein inositol trisphosphate 3-kinase A (IP3K), which is localized in the spines of pyramidal neurons derived from the CA1 region. IP3K was intensely concentrated as puncta in spine heads when Ca(2+) influx was low, but rapidly and reversibly redistributed to a striated morphology in the main dendrite when Ca(2+) influx was high...
November 2006: European Journal of Neuroscience
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