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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...
February 28, 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...
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
Y Zaid, N Senhaji, A Naya, C Fadainia, K Kojok
The protein kinase C (PKC) family has been implicated in several physiological processes regulating platelet activation. Each isoform of PKC expressed on platelets, may have a positive and/or negative role depending on the nature and concentration of the agonist. Mice lacking PKCα show much reduced thrombus formation in vivo, while PKCθ(-/-) showed inhibition of aggregation in response to PAR4. On the other hand, PKCδ by associating with Fyn, inhibits platelet aggregation. In addition, PKCβ by interacting with its receptor RACK1 has been implicated in the primary phases of signaling via the αIIbβ3 and finally PKCɛ appears to be involved in platelet function downstream GPVI...
December 2015: Pathologie-biologie
Henrik Andersson, Karin Björnström, Christina Eintrei, Tommy Sundqvist
Propofol activates the γ-aminobutyric acid type A receptor (GABAA R) and causes a reversible neurite retraction, leaving a thin, thread-like structure behind; it also reverses the transport of vesicles in rat cortical neurons. The awakening peptide orexin A (OA) inhibits this retraction via phospholipase D (PLD) and protein kinase Cɛ (PKCɛ). The human SH-SY5Y cells express both GABAA Rs and orexin 1 and 2 receptors. These cells are used to examine the interaction between OA and the GABAA R. The effects of OA are studied with flow cytometry and immunoblotting...
November 2015: Journal of Neuroscience Research
E Masselli, C Carubbi, G Gobbi, P Mirandola, D Galli, S Martini, S Bonomini, M Crugnola, L Craviotto, F Aversa, M Vitale
Among the three classic Philadelphia chromosome-negative myeloproliferative neoplasms, primary myelofibrosis (PMF) is the most severe in terms of disease biology, survival and quality of life. Abnormalities in the process of differentiation of PMF megakaryocytes (MKs) are a hallmark of the disease. Nevertheless, the molecular events that lead to aberrant megakaryocytopoiesis have yet to be clarified. Protein kinase Cɛ (PKCɛ) is a novel serine/threonine kinase that is overexpressed in a variety of cancers, promoting aggressive phenotype, invasiveness and drug resistance...
November 2015: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
To Ha Loi, Pei Dai, Stephen Carlin, Junia V Melo, David D F Ma
Durable responses to imatinib monotherapy are rarely seen in aggressive forms of Philadelphia chromosome positive (Ph+) leukemias. To investigate the possible cause of treatment failure we examined the role of protein kinase C epsilon (PKCE), an oncogene highly implicated in the development of solid tumors and resistance to chemotherapy. We found high levels of PKCE transcripts in Ph+ acute lymphoblastic leukemia (ALL) cells from patients and cell lines, and imatinib resistant chronic myeloid leukemia, which were also less responsive to imatinib-induced apoptosis than Ph+ cells with lower PKCE expression...
April 22, 2015: Leukemia & Lymphoma
Wei Zhao, Ping Wang, Jun Ma, Yun-Hui Liu, Zhen Li, Zhi-Qing Li, Zhen-Hua Wang, Liang-Yu Chen, Yi-Xue Xue
MicroRNA-34a (miR-34a) functions to regulate protein expression at the posttranscriptional level by binding the 3' UTR of target genes and regulates functions of vascular endothelial cells. However, the role of miR-34a in regulating blood-tumor barrier (BTB) permeability remains unknown. In this study, we show that miR-34a overexpression leads to significantly increased permeability of BTB, whereas miR-34a silencing reduces the permeability of the BTB. In addition, miR-34a overexpression significantly down-regulates the expression and distribution of tight junction-related proteins in glioma endothelial cells (GECs), paralleled by protein kinase Cε (PKCε) reduction...
May 15, 2015: Molecular Biology of the Cell
Santosh K Katiyar
Extensive exposure to solar UVR is a well-recognized etiologic factor for cutaneous non-melanoma skin cancer. In this issue of the Journal, Singh et al. show that topical treatment of the skin with 17-[allylamino]-17-demethoxygeldanamycin (17AAG), a heat-shock protein 90 (Hsp90) inhibitor, prevents UVR-induced squamous cell carcinomas (SCCs) in mice. The inhibitory effect of 17AAG on SCC was associated with the inhibition of the UVR-induced (i) hyperplastic response, (ii) Hsp90β-PKCɛ interaction, and (iii) pStat3 and pAkt expression in mouse skin...
April 2015: Journal of Investigative Dermatology
E Lau, J Sedy, C Sander, M A Shaw, Y Feng, M Scortegagna, G Claps, S Robinson, P Cheng, R Srivas, S Soonthornvacharin, T Ideker, M Bosenberg, R Gonzalez, W Robinson, S K Chanda, C Ware, R Dummer, D Hoon, J M Kirkwood, Z A Ronai
The resistance of melanoma to current treatment modalities represents a major obstacle for durable therapeutic response, and thus the elucidation of mechanisms of resistance is urgently needed. The crucial functions of activating transcription factor-2 (ATF2) in the development and therapeutic resistance of melanoma have been previously reported, although the precise underlying mechanisms remain unclear. Here, we report a protein kinase C-ɛ (PKCɛ)- and ATF2-mediated mechanism that facilitates resistance by transcriptionally repressing the expression of interferon-β1 (IFNβ1) and downstream type-I IFN signaling that is otherwise induced upon exposure to chemotherapy...
November 12, 2015: Oncogene
Yu Song, Xin Cheng, Xiaoxia Yang, Rong Zhao, Peili Wang, Yang Han, Zhen Luo, Yanhua Cao, Chengliang Zhu, Ying Xiong, Yingle Liu, Kailang Wu, Jianguo Wu
Enterovirus 71 (EV71) infections can cause hand, foot and mouth disease (HFMD), meningoencephalitis, neonatal sepsis, and even fatal encephalitis in children. Unfortunately, there is currently no effective treatment for EV71 infection due to the lack of understanding of viral replication and infection; and viral infections have emerged as an imperative global hazard. Thus, it is extremely important to understand the mechanism of EV71 replication in order to prevent and control the diseases associated with EV71 infections...
May 2015: International Journal of Biochemistry & Cell Biology
Yanju Bao, Yebo Gao, Wei Hou, Liping Yang, Xiangying Kong, Honggang Zheng, Conghuang Li, Baojin Hua
Pain is one of the most common and distressing symptoms suffered by patients with progression of cancer. Using a rat model of bone cancer, recent findings suggest that proteinase-activated receptor 2 (PAR2) signaling pathways contribute to neuropathic pain and blocking PAR2 amplifies antinociceptive effects of systemic morphine. The purpose of our study was to examine the underlying mechanisms responsible for the role of PAR2 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...
September 15, 2015: International Journal of Cancer. Journal International du Cancer
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