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Abhik Sen, Thomas J Nelson, Daniel L Alkon, Jarin Hongpaisan
Oxidative stress and amyloid-β (Aβ) oligomers have been implicated in Alzheimer's disease (AD). The growth and maintenance of neuronal networks are influenced by brain derived neurotrophic factor (BDNF) expression, which is promoted by protein kinase C epsilon (PKCɛ). We investigated the reciprocal interaction among oxidative stress, Aβ, and PKCɛ levels and subsequent PKCɛ-dependent MnSOD and BDNF expression in hippocampal pyramidal neurons. Reduced levels of PKCɛ, MnSOD, and BDNF and an increased level of Aβ were also found in hippocampal neurons from autopsy-confirmed AD patients...
2018: Journal of Alzheimer's Disease: JAD
Julia Ney, Katleen Hoffmann, Patrick Meybohm, Andreas Goetzenich, Sandra Kraemer, Carina Benstöm, Nina C Weber, Johannes Bickenbach, Rolf Rossaint, Gernot Marx, Kai Zacharowski, Jürgen Bernhagen, Christian Stoppe
In contrast to several smaller studies, which demonstrate that remote ischemic preconditioning (RIPC) reduces myocardial injury in patients that undergo cardiovascular surgery, the RIPHeart study failed to demonstrate beneficial effects of troponin release and clinical outcome in propofol-anesthetized cardiac surgery patients. Therefore, we addressed the potential biochemical mechanisms triggered by RIPC. This is a predefined prospective sub-analysis of the randomized and controlled RIPHeart study in cardiac surgery patients ( n = 40) that was recently published...
April 5, 2018: International Journal of Molecular Sciences
Gordana Ilievska, Suzana Dinevska-Kjovkarovska, Biljana Miova
Exposure to sublethal heat stress activates a complex cascade of signaling events, such as activators (NO), signal molecules (PKCε), and mediators (HSP70 and COX-2), leading to implementation of heat preconditioning, an adaptive mechanism which makes the organism more tolerant to additional stress. We investigated the time frame in which these chemical signals are triggered after heat stress (41 ± 0.5°С/45 min), single or repeated (24 or 72 h after the first one) in heart tissue of male Wistar rats...
November 24, 2017: Cell Stress & Chaperones
Luiz F Ferrari, Eugen V Khomula, Dioneia Araldi, Jon D Levine
We studied, in male Sprague Dawley rats, the role of the cognate hyaluronan receptor, CD44 signaling in the antihyperalgesia induced by high molecular weight hyaluronan (HMWH). Low molecular weight hyaluronan (LMWH) acts at both peptidergic and nonpeptidergic nociceptors to induce mechanical hyperalgesia that is prevented by intrathecal oligodeoxynucleotide antisense to CD44 mRNA, which also prevents hyperalgesia induced by a CD44 receptor agonist, A6. Ongoing LMWH and A6 hyperalgesia are reversed by HMWH. HMWH also reverses the hyperalgesia induced by diverse pronociceptive mediators, prostaglandin E2 , epinephrine, TNFα, and interleukin-6, and the neuropathic pain induced by the cancer chemotherapy paclitaxel...
January 10, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Rachel J Perry, Liang Peng, Gary W Cline, Yongliang Wang, Aviva Rabin-Court, Joongyu D Song, Dongyan Zhang, Xian-Man Zhang, Yuichi Nozaki, Sylvie Dufour, Kitt Falk Petersen, Gerald I Shulman
Caloric restriction rapidly reverses type 2 diabetes (T2D), but the mechanism(s) of this reversal are poorly understood. Here we show that 3 days of a very-low-calorie diet (VLCD, one-quarter their typical intake) lowered plasma glucose and insulin concentrations in a rat model of T2D without altering body weight. The lower plasma glucose was associated with a 30% reduction in hepatic glucose production resulting from suppression of both gluconeogenesis from pyruvate carboxylase (VPC ), explained by a reduction in hepatic acetyl-CoA content, and net hepatic glycogenolysis...
January 9, 2018: Cell Metabolism
Daniela Di Marcantonio, Esteban Martinez, Simone Sidoli, Jessica Vadaketh, Margaret Nieborowska-Skorska, Anushk Gupta, Jake M Meadows, Francesca Ferraro, Elena Masselli, Grant A Challen, Michael D Milsom, Claudia Scholl, Stefan Fröhling, Siddharth Balachandran, Tomasz Skorski, Benjamin A Garcia, Prisco Mirandola, Giuliana Gobbi, Ramiro Garzon, Marco Vitale, Stephen M Sykes
Purpose: The intracellular redox environment of acute myeloid leukemia (AML) cells is often highly oxidized compared to healthy hematopoietic progenitors and this is purported to contribute to disease pathogenesis. However, the redox regulators that allow AML cell survival in this oxidized environment remain largely unknown. Experimental Design: Utilizing several chemical and genetically-encoded redox sensing probes across multiple human and mouse models of AML, we evaluated the role of the serine/threonine kinase PKC-epsilon (PKCε) in intracellular redox biology, cell survival and disease progression...
February 1, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Kyung In Baek, Rongsong Li, Nelson Jen, Howard Choi, Amir Kaboodrangi, Peipei Ping, David Liem, Tyler Beebe, Tzung K Hsiai
AIMS: Hemodynamic shear stress participates in maintaining vascular redox status. Elucidating flow-mediated endothelial metabolites enables us to discover metabolic biomarkers and therapeutic targets. We posited that flow-responsive vascular endothelial growth factor receptor (VEGFR)-protein kinase C isoform epsilon (PKCɛ)-6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signaling modulates glycolytic metabolites for vascular repair. RESULTS: Bidirectional oscillatory flow (oscillatory shear stress [OSS]: 0...
January 1, 2018: Antioxidants & Redox Signaling
Charles H Cohan, Holly M Stradecki-Cohan, Kahlilia C Morris-Blanco, Nathalie Khoury, Kevin B Koronowski, Mehdi Youbi, Clinton B Wright, Miguel A Perez-Pinzon
Global cerebral ischemia is a debilitating injury that damages the CA1 region of the hippocampus, an area important for learning and memory. Protein kinase C epsilon (PKCɛ) activation is a critical component of many neuroprotective treatments. The ability of PKCɛ activation to regulate AMPA receptors (AMPARs) remains unexplored despite the role of AMPARs in excitotoxicity after brain ischemia. We determined that PKCɛ activation increased expression of a protein linked to learning and memory, activity-regulated cytoskeleton-associated protein (arc)...
December 2017: Journal of Cerebral Blood Flow and Metabolism
Thomas J Nelson, Miao-Kun Sun, Chol Lim, Abhik Sen, Tapan Khan, Florin V Chirila, Daniel L Alkon
Bryostatin 1, a potent activator of protein kinase C epsilon (PKCɛ), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of Alzheimer's disease (AD), Fragile X, stroke, and other neurological disorders. In a single-dose (25 μg/m2) randomized double-blind Phase IIa clinical trial, bryostatin levels reached a maximum at 1-2 h after the start of infusion. In close parallel with peak blood levels of bryostatin, an increase of PBMC PKCɛ was measured (p = 0.0185) within 1 h from the onset of infusion...
2017: Journal of Alzheimer's Disease: JAD
Zhenchang Wang, Quanqiang Li, Mingpeng Xiang, Fengying Zhang, Dongyu Wei, Zhixi Wen, Ying Zhou
BACKGROUND/AIMS: Astragaloside (AGS) extracted from radix astragalin (Huangqi) has been considered to be beneficial to liver diseases. In this study, we examined the role played by AGS in alleviating hepatic fibrosis function via protease-activated receptor-2 (PAR2) mechanisms. We hypothesized that AGS affects PAR2 signaling pathway thereby improving hepatic function in rats with hepatic fibrosis induced by carbon tetrachloride (CCl4). We further hypothesized that AGS attenuates impaired hepatic function evoked by CCl4 to a greater degree in diabetic animals...
2017: Cellular Physiology and Biochemistry
Tanya Pike, Nicola Brownlow, Svend Kjaer, Jeremy Carlton, Peter J Parker
The 'NoCut', or Aurora B abscission checkpoint can be activated if DNA is retained in the cleavage furrow after completion of anaphase. Checkpoint failure leads to incomplete abscission and a binucleate outcome. These phenotypes are also observed after loss of PKCɛ in transformed cell models. Here we show that PKCɛ directly modulates the Aurora B-dependent abscission checkpoint by phosphorylating Aurora B at S227. This phosphorylation invokes a switch in Aurora B specificity, with increased phosphorylation of a subset of target substrates, including the CPC subunit Borealin...
December 22, 2016: Nature Communications
Marek Schwendt, M Foster Olive
Type 5 metabotropic glutamate receptors (mGluR5) activate protein kinase C (PKC) via coupling to Gαq/11 protein signaling. We have previously demonstrated that the epsilon isoform of PKC (PKCɛ) is a critical downstream target of mGluR5 in regulating behavioral and biochemical responses to alcohol. Recent evidence suggests that PKC-mediated phosphorylation of mGluR5 can lead to receptor desensitization and internalization. We therefore sought to examine the specific involvement of PKCɛ in the regulation of mGluR5 surface expression in the nucleus accumbens (NAc), a key regulator of alcohol-associated behaviors...
April 2017: Journal of Neuroscience Research
Jin Yang, Alexander G Bassuk, Juliane Merl-Pham, Chun-Wei Hsu, Diana F Colgan, Xiaorong Li, Kit Sing Au, Lijuan Zhang, Scott Smemo, Sally Justus, Yasunori Nagahama, Andrew J Grossbach, Matthew A Howard, Hiroto Kawasaki, Neil A Feldstein, William B Dobyns, Hope Northrup, Stefanie M Hauck, Marius Ueffing, Vinit B Mahajan, Stephen H Tsang
Inactivating mutations of the TSC1/TSC2 complex (TSC1/2) cause tuberous sclerosis (TSC), a hereditary syndrome with neurological symptoms and benign hamartoma tumours in the brain. Since TSC effectors are largely unknown in the human brain, TSC patient cortical tubers were used to uncover hyperphosphorylation unique to TSC primary astrocytes, the cell type affected in the brain. We found abnormal hyperphosphorylation of catenin delta-1 S268, which was reversible by mTOR-specific inhibitors. In contrast, in three metastatic astrocytoma cell lines, S268 was under phosphorylated, suggesting S268 phosphorylation controls metastasis...
October 1, 2016: Human Molecular Genetics
S L K Bowers, P R Norden, G E Davis
During capillary network formation, ECs establish interconnecting tubes with defined lumens that reside within vascular guidance tunnels (physical spaces generated during EC tubulogenesis). Pericytes are recruited to EC tubes within these tunnels and capillary basement membrane deposition occurs to facilitate tube maturation. Here, we discuss molecular mechanisms controlling EC tubulogenesis demonstrating the involvement of integrins, MT1-MMP, extracellular matrix, Cdc42, Rac1, Rac2, k-Ras, Rap1b, and key downstream effectors including Pak2, Pak4, IQGAP1, MRCKβ, and Rasip1...
2016: Advances in Pharmacology
Mark A Herman, Varman T Samuel
Epidemiological studies link fructose consumption with metabolic disease, an association attributable in part to fructose-mediated lipogenesis. The mechanisms governing fructose-induced lipogenesis and disease remain debated. Acutely, fructose increases de novo lipogenesis through the efficient and uninhibited action of ketohexokinase and aldolase B which yields substrates for fatty-acid synthesis. Chronic fructose consumption further enhances the capacity for hepatic fructose metabolism by activating several key transcription factors (i...
October 2016: Trends in Endocrinology and Metabolism: TEM
Ying-Hsi Lin, Chad M Warren, Jieli Li, Timothy A McKinsey, Brenda Russell
The mechanotransduction signaling pathways initiated in heart muscle by increased mechanical loading are known to lead to long-term transcriptional changes and hypertrophy, but the rapid events for adaptation at the sarcomeric level are not fully understood. The goal of this study was to test the hypothesis that actin filament assembly during cardiomyocyte growth is regulated by post-translational modifications (PTMs) of CapZβ1. In rapidly hypertrophying neonatal rat ventricular myocytes (NRVMs) stimulated by phenylephrine (PE), two-dimensional gel electrophoresis (2DGE) of CapZβ1 revealed a shift toward more negative charge...
August 2016: Cellular Signalling
Robert Büttner, Alexander Berndt, Christina Valkova, Petra Richter, Alexander Korn, Christian Kosan, Claus Liebmann
INTRODUCTION: Receptors of the ErbB family belong to the key players in cancer development and are targets of several therapeutic approaches. Their functional dependency on the tumor microenvironment, especially on CAFs is albeit still poorly understood. Our objective was to investigate the impact of CAF secretome on ErbB receptor expression and signaling behavior in OSCC. METHODS: Stimulation of PE/CA-PJ15 OSCC cells with conditioned media of TGF-β1-activated fibroblasts was used as model system for CAF to cancer cell communication...
February 2017: Journal of Receptor and Signal Transduction Research
H He, Z-H Zhao, F-S Han, X-H Liu, R Wang, Y-J Zeng
We assessed the effects of protein kinase C ɛ (PKCɛ) for improving stem cell therapy for acute myocardial infarction (AMI). Primary mesenchymal stem cells (MSCs) were harvested from rat bone marrow. PKCɛ-overexpressed MSCs and control MSCs were transplanted into infarct border zones in a rat AMI model. MSCs and PKCɛ distribution and expression of principal proteins involved in PKCɛ signaling through the stromal cell-derived factor 1 (SDF-1)/CXC chemokine receptor type 4 (CXCR4) axis and the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) pathway were analyzed by immunofluorescence and western blot 1 day after transplantation...
January 21, 2016: Cell Death & Disease
Fang Zheng, Anne Puppel, Sabine E Huber, Andrea S Link, Volker Eulenburg, Johannes F van Brederode, Christian P Müller, Christian Alzheimer
Activin, a member of the transforming growth factor-β family, exerts multiple functions in the nervous system. Originally identified as a neurotrophic and -protective agent, increasing evidence implicates activin also in the regulation of glutamatergic and GABAergic neurotransmission in brain regions associated with cognitive and affective functions. To explore how activin impacts on ethanol potentiation of GABA synapses and related behavioral paradigms, we used an established transgenic model of disrupted activin receptor signaling, in which mice express a dominant-negative activin receptor IB mutant (dnActRIB) under the control of the CaMKIIα promoter...
July 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Zongming Jiang, Shaoyong Wu, Xiujuan Wu, Junfeng Zhong, Anqing Lv, Jing Jiao, Zhonghua Chen
The current study was to examine the underlying mechanisms responsible for the role of mammalian target of rapamycin (mTOR) in regulating bone cancer-evoked pain and the tolerance of systemic morphine. Breast sarcocarcinoma Walker 256 cells were implanted into the tibia bone cavity of rats and this evoked significant mechanical and thermal hyperalgesia. Our results showed that the protein expression of p-mTOR, mTOR-mediated phosphorylation of 4E-binding protein 4 (4E-BP1), p70 ribosomal S6 protein kinase 1 (S6K1) as well as phosphatidylinositide 3-kinase (p-PI3K) pathways were amplified in the superficial dorsal horn of the spinal cord of bone cancer rats compared with control rats...
April 15, 2016: International Journal of Cancer. Journal International du Cancer
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