Дисертації з теми "PKC inhibitors"
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Aaltonen, V. (Vesa). "PKC and neurofibromin in the molecular pathology of urinary bladder carcinoma:the effect of PKC inhibitors on carcinoma cell junctions, movement and death." Doctoral thesis, University of Oulu, 2007. http://urn.fi/urn:isbn:9789514285899.
Повний текст джерелаRatnayake, Wishrawana Sarathi Bandara. "Role of Oncogenic Protein Kinase C-iota in Melanoma Progression; A Study Based on Atypical Protein Kinase-C Inhibitors." Scholar Commons, 2019. https://scholarcommons.usf.edu/etd/7895.
Повний текст джерелаPanek, Anna [Verfasser]. "Rolle des Connective Tissue Growth Factors (CTGF) und des PKC-enhanced Protein-Phosphatase 1 Inhibitors (KEPI) für die Funktion des adulten Herzen : Studien an transgenen Tiermodellen / Anna Naila Panek." Berlin : Freie Universität Berlin, 2008. http://d-nb.info/1023375095/34.
Повний текст джерелаLakshmanan, Aparna. "Modulation of Sodium Iodide Symporter-mediated Thyroidal Radioiodide Uptake by Small Molecule Inhibitors, Natural Plant-based Products and microRNAs." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429407914.
Повний текст джерелаEsvan, Yannick. "Conception et synthèse de nouveaux composés hétéroaromatiques inhibiteurs potentiels de kinases." Thesis, Clermont-Ferrand 2, 2016. http://www.theses.fr/2016CLF22743.
Повний текст джерелаIn 1950’s protein kinases were found to play a critical role in cell signaling, rising strong research potential for this enzyme family. Initially investigated for their implications in cancerogenesis they were more recently found to be involved in a wide variety of diseases including neurodegenerative pathologies. Herein will be presented two research projects that offer bright new perspectives for the inhibition of kinases involved whether in neurodegenerative diseases or cancers.First, the design and synthesis of new pyrido[3,4-g]quinazoline derivatives will be described as well as their protein kinase inhibitory potencies toward five CMGC family members (CDK5, CK1, GSK3, CLK1 and DYRK1A) that are known to play a potential role in Alzheimer’s disease. The interest for this original tricyclic heteroaromatic scaffold as modulators of CLK1/ DYRK1A activity was validated by nanomolar potencies. CLK1 co-crystal structures with two inhibitors revealed the binding mode of these compounds within the ATP-binding pocket and led to the synthesis of new diversely substituted pyrido[3,4-g]quinazolines.Then the synthesis of a new derivative of the staurosporine aglycon (K252c), in which the lactam ring was replaced by a pyrazole moiety, will be depicted. The resulting indolopyrazolocarbazole inhibited Pim isoforms 1–3 whereas it did not impair the activity of two known targets of K252c, protein kinase C isoforms α and γ . The lead compound exhibited same cytotoxic activity as K252c toward both human leukemia and colon carcinoma cell lines (K562 and HCT116), strongly suggesting that this new scaffold deserves further investigations for treatment of malignancies associated with kinases activities
Trachsel, Sébastien Auguste Charles. "Selective responses (Actin polymerization, shape changes, locomotion, pinocytosis) to the PKC-inhibitor Ro 31-8220 suggest thath PKC discriminately regulates functions of human blood lymphocytes /." [S.l : s.n.], 1996. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
Повний текст джерелаMakhoul, Stephanie [Verfasser]. "GPIb-V-IX- and GPVI-specific intracellular signaling and their regulation by PKA/PKG-dependent inhibitory pathways in washed human platelets / Stephanie Makhoul." Mainz : Universitätsbibliothek Mainz, 2019. http://d-nb.info/1194096891/34.
Повний текст джерелаHofstetter, Barbara. "Klinisch relevante PKC-Inhibitoren als radiosensibilisierende Substanzen für Tumorzellen genaue Untersuchung der Wirkung auf die PI3K/Akt-Signalübermittlungskaskade /." Zürich : ETH, Eidgenössische Technische Hochschule Zürich, Departement Angewandte Biowissenschaften, Institut für Pharmazeutische Wissenschaften, 2001. http://e-collection.ethbib.ethz.ch/show?type=dipl&nr=5.
Повний текст джерелаHeinzmann, Kathrin. "Investigating the effects or AKT/PKB inhibitors on [18F]-FDG uptake in cancer cells." Thesis, Institute of Cancer Research (University Of London), 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.553702.
Повний текст джерелаGottlieb, Rachel. "Use of S. pombe to Characterize Mammalian Adenylyl Cyclases and Their Inhibitors." Thesis, Boston College, 2015. http://hdl.handle.net/2345/bc-ir:104220.
Повний текст джерелаThe study of mammalian cAMP signaling has often been confounded by the fact that ten different genes encode adenylyl cyclases (ACs) that produce cAMP from ATP and 16 different genes encode phosphodiesterases (PDEs) that hydrolyze cAMP to AMP. In this study, mammalian AC cDNAs were cloned and integrated into strains of the fission yeast Schizosaccharomyces pombe that lack their endogenous AC to determine the basal activity of all ten AC isoforms. In addition, response to the stimulatory mammalian Gsα was determined by co-expression of a mutationally-activated form of the human GNAS1 gene. AC activity was assessed using an fbp1-GFP reporter that is repressed by cAMP production and PKA activity. Results confirm that all ten isoforms have detectable basal activity, and AC1-9 definitively respond to Gsα stimulation. When matched with a sufficiently potent mammalian phosphodiesterase (PDE), strains expressing mammalian ACs make good candidates for small molecule high throughput screening (HTS) to detect AC inhibitors. A 100,000 compound screen was recently performed to detect AC and Gsα inhibitors as well as PDE activators. A promising “hit” was progesterone, which has been previously suggested to inhibit ACs in Xenopus. Initial results suggest that progesterone inhibits AC1 and the closely-related AC3. These data demonstrate the utility of using S. pombe as an effective platform for identifying inhibitors of both basal and GNAS1-stimulated AC activity
Thesis (BS) — Boston College, 2015
Submitted to: Boston College. College of Arts and Sciences
Discipline: Departmental Honors
Discipline: Biology
Lali, Ferdinand Vuciri. "An investigation of the role of p38 MAP kinase and p13-kinase/PKB pathways in IL-2-induced lymphocyte proliferation." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342220.
Повний текст джерелаMcDougal, Robert A. "Excitatory-Inhibitory Interactions as the Basis of Working Memory." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1313004219.
Повний текст джерелаPlo, Isabelle. "Activation des voies anti-apoptotiques par les ligands de mort et les médicaments antitumoraux." Toulouse 3, 2002. http://www.theses.fr/2002TOU30048.
Повний текст джерелаZOUKHRI, DRISS. "Caracterisation de la proteine kinase c des glandes lacrymales de rat. Effets des esters de phorbol et des inhibiteurs de la pkc sur la secretion." Paris 11, 1992. http://www.theses.fr/1992PA112350.
Повний текст джерелаLafont, Florian. "Implication des modifications post-traductionnelles de DNA-PKcs dans la régulation de la réponse aux dommages à l'ADN." Thesis, Nantes, 2017. http://www.theses.fr/2017NANT1023/document.
Повний текст джерелаHuman cells are subjected to stresses inducing DNA double-strand breaks mainly repaired by the NHEJ pathway, where the kinase DNA-PKcs plays a central role. The activity of DNA-PKcs, regulated by numerous phosphorylations, is crucial for the maintenance of genomic integrity. More recently, it has been shown that this protein is also modified by O-GlcNAcylation in the COS7 cell line. Knowing the balance between phosphorylation and O-GlcNAcylation, we studied the role of this new PTM in the regulation of DNA-PKcs activity. We have shown that DNA-PKcs is O-GlcNAcylated in HeLa cells. We then showed that the modulation of DNA-PKcs O-GlcNAcylation affects its autophosphorylation on Ser2056, suggesting an O-GlcNAcylation/phosphorylation balance, as well as the ability of cells to repair DSBs by NHEJ pathway. Moreover, our results allow us to consider that this modification may play a role in protein stability. DNA-PKcs is a potential target in anticancer strategies. We studied the impact of a chemical compound on DNA-PKcs activity. This molecule causes a reduction in the amount and activity of DNA-PKcs, through its ubiquitinylation and its degradation by the proteasome and leading to sensitization of the cells to genotoxic treatment. In this context, we have developed an antibody microarray to evaluate the phosphoprotein level of DNA repair pathways and thus estimate the effect of DNA-PKcs inhibitors. All these results contribute to a better understanding of the regulation of DNA-PKcs
Tautu, Michel Théodore. "Etude de nouveaux rôles de la DNA-PKcs, indépendants de NHEJ, dans la sensibilité aux inhibiteurs de Topoisomérase I de la famille des camptothécines." Bordeaux 2, 2008. http://www.theses.fr/2008BOR21576.
Повний текст джерелаDNA topoisomerase 1 (Top 1) is a conserved nuclear enzyme that constitutes the cellular target of the camptothecin (CPT) class of chemotherapeutics. These drugs reversibly stabilize covalent Top1-DNA intermediates, which are converted into potentially lethal DNA lesions during S-phase. The enhanced CPT sensitivity of mammalian cell lines that are deficient for DNA-PKcs, the catalytic subunit of DNAdependent protein kinase, suggests that error-prone nonhomologous end joining (NHEJ) is a critical determinant of tumor cell sensitivity to drugs that poison Top1. However, contrary to this view, we report that the loss of the DNA-PKcs protein scaffold, rather than DNA-PK kinase activity, enhances mammalian cell sensivity to CPT. DNA-PKcs associated with the N-terminal domain of Top1, in the absence of Ku70 and Ku80, to suppress DNA cleavage by Top1. Interestingly, DNA-PKcs (-/-) cells exhibited increased basal levels of covalent Top1-DNA complexes, which were abolished by siRNAtargeted downregulation of Top1. Our data support a model whereby DNA-PKcs binding to Top1 limits DNA binding and consequently, the levels of covalent Top1-DNA complexes in vivo. This NHEJ-independent regulation of Top1 catalysis directly impacts cell sensitivity to CPT by regulating the steady state levels of the cellular target of this important class of chemotherapeutics. Moreover, we posit that this mechanism impacts cellular responses to other genotoxic stress, such as ionizing radiation and oxidative damage, that can also induce endogenous Top1-DNA adducts
Roche, Emmanuel. "Etude des mécanismes de résistance des cancers de prostate aux inhibiteurs de topoisomérases I de la famille des camptothécines." Thesis, Bordeaux, 2014. http://www.theses.fr/2014BORD0423/document.
Повний текст джерелаType I and II DNA Topoisomerases (Top) are essential enzymes involved in the removal of DNA torsional constraints induced by most DNA transactions. They are the targets of various anticancer agents used in the clinic. Among them, Top1 inhibitors from the camptothecins (CPT) family exert their cytotoxicity by producing DNA double-strand breaks that are generated by the collision of advancing replication forks with DNA-Top1 complexes that are stabilized by these inhibitors. CPT derivatives are approved for the treatment of colon, ovary and lung cancers but resistance mechanisms are developed and lead to treatment failure. Prostate cancers are refractory to CPT, but few studies have addressed the mechanisms of such “intrinsic” resistance. This work was aimed at identifying such mechanisms based on (1) previous results from the laboratory showing that interaction of Top1 with DNA-PKcs, a kinase that is essential for non-homologous end-joining, could regulate cell sensitivity to CPT independently of DNA repair and (2) a study that showed an interaction of DNA-PKcs with ERG, a transcription factor from the ETS family which is rearranged in more than 50% of prostate tumors. Our results show for the first time that ERG is indeed involved in the regulation of prostate cancer cell response to CPT as its repression sensitized VCaP cells displaying the TMPRSS2-ERG gene fusion to CPT but not to the Top2 inhibitor etoposide. This effect is accompanied with an increase in Top1-DNA complexes. This could be due to either an effect of ERG on DNA-PKcs/Top1 interaction, or to the transcriptional regulation of genes involved in cell response to CPT, including Top1 itself. We confirmed the latter hypothesis by showing that ERG can regulate the transcription levels of the microRNA miR-24 and that Top1 expression relies, at least in part, on miR24 levels in VCaP cells. We obtained similar results in LNCaP cells (characterized by a TMPRSS2-ETV1 gene fusion), in which ETV1 repression also sensitizes cells to CPT. In parallel, we also searched for inhibitors of DNA-PKcs/Top1 interaction in order to use these compounds to potentiate CPT derivatives in the clinic. We screened a chemical library of 320 natural compounds using the AlphaScreen technology. The results were disappointing as we only identified compounds that are catalytic inhibitors of Top1. Nevertheless, we could show that among them, mahanimbine displayed a potent cytotoxic activity towards CPT-resistant colon cancer cell lines and could efficiently inhibit the growth of VCaP cells that are highly resistant to CPT. This opens new avenues for the development of new classes of Top1 catalytic inhibitors that could be used to circumvent the clinical resistance to CPT derivatives
Blakeney, Bryan Adam. "Branched Short Chain Fatty Acid Isovaleric Acid Causes Smooth Muscle Relaxation via cAMP/PKA Pathway, Inhibits Gastrointestinal Motility, and Disrupts Peristaltic Movement." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5548.
Повний текст джерелаCevirgen, Ceyhun [Verfasser], Ali [Akademischer Betreuer] El-Armouche, Elisabeth [Gutachter] Zeisberg, and Martin [Gutachter] Oppermann. "Analyse des antifibrotischen Potenzials der betaadrenergen Signalkaskade und des PKA-Effektors Protein-Phosphatase-Inhibitor-1 / Ceyhun Cevirgen ; Gutachter: Elisabeth Zeisberg, Martin Oppermann ; Betreuer: Ali El-Armouche." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2017. http://d-nb.info/1136471324/34.
Повний текст джерелаVisseq, Alexia. "Conception et synthèse d’inhibiteurs sélectifs de protéines kinases pour le traitement de l’allodynie mécanique." Thesis, Université Clermont Auvergne (2017-2020), 2019. http://www.theses.fr/2019CLFAC048.
Повний текст джерелаChronic pain is a global public health priority which affects more than 20% of Europeans. Mechanical allodynia, a pain in response to normally innocuous stimuli, is one of the most prevalent pain symptoms. Despite intensive research toward the study of pain mechanisms, currently available treatments of pain are not always effective, and can produce side-effects. In this context, the aim of the project is to design, synthesize and evaluate selective inhibitors of protein kinases for the treatment of mechanical allodynia. During this PhD work, new selective inhibitors of the protein kinase p38α has been discovered. This protein kinase is known for its implication in chronic pain and mechanical allodynia. A structure-activity relationship study was performed to identify the important structural features allowing a gain of activity of molecules in vitro and in vivo using an animal model. The best compounds showed submicromolar IC50 values toward p38α and a strong inhibition of mechanical allodynia in vivo
Rancillac, Armelle. "Propriétés fonctionnelles et plasticité des synapses glutamatergiques afférentes aux cellules de Purkinje et aux interneurones inhibiteurs de la couche moléculaire du cortex cérébelleux chez le rongeur." Paris 6, 2003. http://www.theses.fr/2003PA066278.
Повний текст джерелаTronel, Claire. "Evaluation des effets de molécules à visée neuroprotectrice dans un modèle in vivo de neuroinflammation chez le rat : étude mécanistique et caractérisation du modèle au cours du temps." Thesis, Tours, 2013. http://www.theses.fr/2013TOUR3806/document.
Повний текст джерелаNeuroinflammation is a key part of the physiopathology of neurodegenerative diseases and is an interesting target in their treatment. In this PhD work, we studied the effects of two potentially anti-inflammatory and neuroprotective molecules, hemin and C16, in an in vivo rat model of neuroinflammation by intrastriatal injection of quinolinic acid (QA). We showed that heme oxygenase 1 (HO-1) induction by hemin has deleterious effects whereas inhibition of the protein kinase RNA activated (PKR) by C16 treatment induced neuroprotective and anti-inflammatory effects. Concurrently, we evaluated longitudinal evolution of neuroinflammation in our model. Results showed the kinetic of the inflammatory phenomena; the ability of cerebral tissue to recover integrity and the capability of this model to evaluate potential neuroprotective and anti-inflammatory drugs in a long-time study
Humphrey, Peter Saah. "Signal transduction mechanisms for stem cell differentation into cardiomyocytes." Thesis, University of Hertfordshire, 2009. http://hdl.handle.net/2299/3760.
Повний текст джерелаWang, Jen-Jui, and 王仁瑞. "Inhibitory Mechanism of Midazolam in PKC-induced MMPs Expression in Chondrocytes." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/42636205848281078456.
Повний текст джерела臺北醫學大學
醫學科學研究所
98
Midazolam, a benzodiazepine, has a hypnotic effect and is widely used as a sedative. The role of midazolam in activation of chondrocytes during inflammation is not known. The aim of this study was to evaluate the anti-inflammatory actions of midazolam in cultured chondrocytes. Using a chondrosarcoma cell line, SW1353 cells, the inhibitory effect of midazolam on protein kinase C (PKC) activator phorbol-12-myristate-13-acetate (PMA) induced matrix metalloproteinases (MMPs) was assessed by Western blot and gelatin zymography. Our results show that PMA-induced up-regulation of MMPs 1, 9 and 13 expressions was significantly inhibited by midazolam in a concentration-dependent manner (5-20 μM). Midazolam also inhibited PMA-mediated activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinases but had no effect on c-Jun N-terminal kinase. Treatment with midazolam enhanced re-synthesis of a concentration dependant PMA mediated IκB-α degradation. Thus, overall our results revealed that the inhibitory mechanism of midazolam on MMPs involves depressed expression of p38 and ERK 1/2 and facilitated recovery of IκB-α degradation in an induced chondrosarcoma SW1353 cell line. Midazolam has an anti-inflammatory action by inhibiting activity, synthesis and the expression of inducible MMPs through MAPKs and NF- κB/IκB pathways. These findings may considerably be provided the novel molecular basis of midazolam.
Alam, Mohammad Intakhab [Verfasser]. "Investigation of the role of PKCα [PKC-alpha] for influenza A virus-induced signalling and of the inhibitory effect of verapamil on virus replication / vorgelegt von Mohammad Intakhab Alam". 2008. http://d-nb.info/989046486/34.
Повний текст джерелаSyu, Ya-Ting, and 徐雅婷. "PMC Inhibits PDGF-BB-Induced Proliferation of Vascular Smooth Muscle Cells through PKC-delta." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/43780639479372376569.
Повний текст джерела臺北醫學大學
藥理學研究所
93
Abnormal proliferation of vascular smooth muscle cells (VSMCs) results in neointima plays an important role in many coronary diseases including atherosclerosis and restenosis. This research was shown the inhibitory mechanisms of PMC (2, 2, 5, 7, 8 -pentamethyl-6-hydroxychromane), as a derivative of -tocopherol, on VSMCs proliferation. By MTT assay and microscopy, we found that PMC (20, 50 and 100 M) inhibited PDGF-BB-induced vascular smooth muscle cells proliferation in a concentration dependent manner. Rottlerin (PKC--specific inhibitor) and Gö6976 (PKC--specific inhibitor) inhibited PDGF-BB-induced vascular smooth muscle cells proliferation. Evidence suggests that PMC may inhibit PDGF-BB-induced vascular smooth muscle cells proliferation through PKC- or PKC- By Western blot analysis and confocal microscopy, we found that PMC inhibited the translocation of PKC- from the cytosolic to membrane fraction stimulated by PDGF-BB in a concentration dependent manner. After stimulating with PDGF-BB, PKC-would not be translocate from the cytosolic to membrane fraction. Upon treating cells PMC, the distruction of PKC-would not be affect. Evidence suggests that PMC may inhibit PDGF-BB-induced vascular smooth muscle cells proliferation through inhibiting the specific translocation of PKC- PMC inhibited the translocation of PKC- and IB degradation, while rottlerin (PKC--specific inhibitor) didn’t inhibit PDGF-BB-induced vascular smooth muscle cells IB degradation. On the other hand, PMC inhibited Akt phosphorylation and IB degradation, while LY294002 (PI3K inhibitor) didn’t inhibit PDGF-BB-induced vascular smooth muscle cells IB degradation. In order to clarify the cross-talk between PKC- and Akt, we found that rottlerin (PKC--specific inhibitor) didn’t inhibit PDGF-BB-induced vascular smooth muscle cells Akt phosphorylation. By Western blot analysis, PMC (100 M) may induce apoptosis by increasing the expression of active caspase-3 stimulated by PDGF-BB. In the Western blot analysis of protein levels of cyclin D1, Cdk4 and 21cip1 in rat vascular smooth muscle cells treated with PMC (100 M) stimulated with PDGF-BB (10 ng/ml), protein levels of cyclin D1, Cdk4 and 21cip1 would not be affected. In conclusion, PMC inhibited vascular smooth muscle cells proliferation through inhibiting the translocation of PKC-Akt phosphorylation, and IBdegradation. In the privous studies, PMC inhibited cell cycle progression by arresting in the G0/G1 phase to S phase and inhibited cell proliferation. PMC (100 M) may induce apoptosis by increasing the expression of active caspase-3 although protein levels of cyclin D1, Cdk4 and 21cip1 would not be affected. Further efforts would be focused on investigating the effects of PMC on other molecular regulators of cell cycle and apoptosis. Effects of anti-aggregation and anti-oxidation of PMC were proven. This research showed PMC inhibited VSMCs proliferation. Because of the anti-proliferation effect of PMC, the further efforts to evaluate the anti-angiogenesis and anti-cancer effects of PMC might be worthwhile.
萩原, 和美. "Prox 1 overexpression of Hela cells inhibits PKC beta II transcription through promoter DNA methylation." Thesis, 2012. http://hdl.handle.net/2237/16914.
Повний текст джерелаchi, Wang szu, and 王思琪. "Virtual Screening of PKA Inhibitors Using Docking Computation:Effect of Flexible Side Chain." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/44642027663578608742.
Повний текст джерела國立臺灣師範大學
化學系
98
Protein kinase A (PKA) is a kinase protein that has several functions in cell, including regulation of glycogen, sugar, and lipid metabolism. It also plays significant role in a number of biochemical reaction networks associated with diseases, including lung cancer and colorectal cancers. In the present study, we used docking computation to aid in design and discovery of PKA inhibitors. First, we carried out docking computations for 20 PKA-inhibitor complexes from protein data bank to examine their reproducibility. The results showed that the computed fitnesses values of ligands are in good accord with the experimental IC50 values. Second, crossing docking of selected 5 complexes was carried out to investigate if and how ligand conformations can be regained when a protein structure from different complexes were used. In addition, thirdly, the protein structures from these 5 complexes were used to undergo a virtual screening to see if 10 active compounds can be screened out of 1000 compounds selected from a database. In these computations, the several side chains at active site were allowed to move to examine how this effect affects the docking results. The results showed that better results were obtained in the case of allowing 4 residues to move. Finally, a virtual screening for 24535 compounds was carried out. The interactions between top-ranked compounds and PKA were analyzed and discussed. These computed results and analysis should be of aid in design and discovery of PKA inhibitors.
Shan-Meei, Tang, and 唐善美. "Involvement of PKC in the inhibitory effects of 18 beta-GA on gap junction in the cardiac myoblast." Thesis, 2001. http://ndltd.ncl.edu.tw/handle/66373002464052138250.
Повний текст джерела國立臺灣大學
解剖學暨細胞生物學研究所
89
Abstract Gap junctions are intercellular channels ensuring electrical and metabolic coupling and are responsible for the synchronous contraction of cardiomyocytes. The major gap junctional protein in working cardiomyocytes is connexin43(Cx43). In this study, immunofluorescence microscopy and Lucifer yellow dye coupling assays were used to investigate the role of protein kinase C (PKC) in the inhibitory effects of 18b-glycyrrhetinic(18b-GA) acid on gap junctions in H9c2(2-1) rat cardiac myoblast cells. The inhibitory effect of 18b-GA on gap junction of H9c2(2-1) cells is dose-dependent. There was no significant change in the immunofluorescence staining of Cx43 when H9c2(2-1) cells were treated with 60 mM of 18b-GA for two hours. When the concentration of 18b-GA was raised to 100 mM, a decrease of Cx43 immunostaining intensity was found on H9c2(2-1) cell membranes. The dye coupling of gap junctions was reduced from 62% in controls to 5% in 100 mM 18b-GA treated H9c2(2-1) cells. Treatment of H9c2(2-1) cells with 100 nM PMA or 100 mM 18b-GA plus 100 nM PMA led to disappearing of Cx43 immunostaining spots from cell membranes and the dye coupling of gap junctions were reduced to 8% and 1.6%, respectively. When H9c2(2-1) cells were treated with 2.5 mM chelerythrine, large Cx43 immunostaining spots were detected on the cell membranes and dye coupling was increased to 85%. Likewise, treatment of H9c2(2-1) cells with 0.5 mM calphostin C also led to accumulation of Cx43 immunostaining spots on cell membrane and a slightly increase of dye coupling to 68%. Co-treatment with 100 mM 18b-GA plus 2.5 mM chelerythrine or 100 mM 18b-GA plus 0.5 mM calphostin C both led to a weaker immunostaining intensity of Cx43 in drug-treated groups than in controls and the dye coupling of gap junctions was restored to 30% and 31%, respectively. These results suggest that the inhibitory effects of 18b-GA on gap junctions were attenuated by co-treatment of PKC inhibitors, which can restore partial immunostaining intensity of Cx43 on cell membrane and dye coupling between H9c2(2-1) cells.
Chang, Pei-Yun, та 張沛昀. "Study on how DAPK inhibits the activation of PKCθ in T cells". Thesis, 2013. http://ndltd.ncl.edu.tw/handle/87897947530085202221.
Повний текст джерела國立臺灣大學
免疫學研究所
101
Death-associated protein kinase (DAPK) is well known as a tumor suppressor. Previous studies from our lab have shown that DAPK is activated after TCR stimulation. DAPK inhibits T cell activation through suppression of NF-κB signaling. Furthermore, DAPK specifically inhibits the TCR-induced NF-κB activation but not TNFα- or IL-1β-induced NF-κB activation. Results from our lab also demonstrated that DAPK inhibits TCR-induced PKCθ phosphorylation, but the exact biochemical process targeted by DAPK to inhibit PKCθ activation remains unclear. The specific aim of this study is to delineate the molecular mechanism on how DAPK inhibits TCR-induced PKCθ phosphorylation. MAP4K3/GLK is recently identified as the kinase that phosphorylates and activates PKCθ after TCR stimulation. We found that DAPK interacted with both PKCθ and MAP4K3/GLK in HEK293T cells and Jurkat JE6.1 T cells. We also identified several domains of DAPK that mediate the binding to PKCθ and MAP4K3/GLK. Using in vitro kinase assay, we found that DAPK did not phosphorylate PKCθ. DAPK did not phosphorylate MAP4K3/GLK, but DAPK inhibited MAP4K3/GLK auto-phosphorylation and kinase activity. We also found that DAPK bound SLP-76, the adaptor protein which binds MAP4K3/GLK and is required for MAP4K3/GLK activation. In vitro binding analysis demonstrated that the presence of DAPK decreased the binding between SLP-76 and MAP4K3/GLK. DAPK also inhibited the association between SLP-76 and MAP4K3/GLK in Jurkat JE6.1 T cells. Therefore, DAPK uses at least two different mechanisms to inhibit TCR-induced PKCθ activation: one by suppressing MAP4K3/GLK kinase activity, the other by reducing the binding of MAP4K3/GLK to SLP-76. Further characterization on the processes underlying the inactivation of MAP4K3/GLK and the reduced association of MAP4K3/GLK-SLP-76 by DAPK may help to understand the exact inhibitory mechanism of DAPK in TCR-induced NF-κB signaling.
Cevirgen, Ceyhun. "Analyse des antifibrotischen Potenzials der betaadrenergen Signalkaskade und des PKA-Effektors Protein-Phosphatase-Inhibitor-1." Doctoral thesis, 2017. http://hdl.handle.net/11858/00-1735-0000-0023-3E46-4.
Повний текст джерелаChiu, Po-Hsuan, and 裘博媗. "Activation of P2X7 Receptors Inhibits Proliferation by Arresting Cell Cycle Progression via Ca2+/PKC/ERK1/2 Signal Pathways of Neural Progenitor Cells." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/19397030143482074823.
Повний текст джерела國立陽明大學
神經科學研究所
101
ABSTRACT ATP is an extracellular signaling molecule that regulates multiple physiological functions during CNS development. Recent studies implicated that purinergic signaling is involved in neural development, including proliferation. Previous studies also demonstrated the P2X7 purinergic receptor emerged at the stage of neurogenesis. However, the exact role of P2X7 receptors during neural development has not been thoroughly examined. The aim of this study is to investigate the effect of P2X7 receptors on proliferation of neural progenitor cells (NPCs) and elucidate the underlying molecular mechanisms involved. In this study, we found that NPCs expressed functional P2X7 purinergic receptors. Treatment of NPCs with P2X7 receptors selective agonist BzATP decreased cell number, cell viability, and the number of bromouridine (BrdU)-incorporated cells, but did not affect cell survival in trypan blue exclusion test. The effect was inhibited by the action of a P2X7 receptor selective antagonist A 438079 and by using P2X7 shRNA to knockdown the receptor expression. Using flow cytometry, BzATP treatment arrested cell cycle at the S phase. Thus, activation P2X7 receptor decreased proliferation and altered cell cycle progression of NPCs. To further examine the molecular mechanism involved, we also found that BzATP stimulated ERK1/2 activation in a time-dependent manner. By using EGTA to chelate extracellular Ca2+, or by using GF 109203X to inhibit PKC or PD98059 to inhibit MEK, significantly attenuated the BzATP-induced ERK1/2 activation. In contrast the ERK1/2 activation was not affected by using CaMKII inhibitor KN 93, or by using PI3K inhibitor LY294002. In addition, BzATP induced cytosol-to-membrane translocation of PKC α, γ, ε isozymes. Moreover, either PD98059 or GF 109203X blocked the BzATP-decreased proliferation of these cells. The physiological ligand of P2X7 receptors, ATP also inhibited proliferation of NPCs and that was suppressed by P2X7 receptors antagonist but not by P2X1-6 receptor antagonist, TNP-ATP. ATP also induced transient ERK1/2 activation. Together, these results indicated that activation of P2X7 receptors inhibits proliferation by arresting cell cycle progression and that is via Ca2+-PKC-ERK1/2 signal pathway in NPCs.
Hsu, Ching-Chueh, and 許競爵. "I. The mRNA expressions of PKC isoforms during decidulization at pseudopregnant rats. II. Estimation of the inhibitory effect of Chinese herb extract on liver fibrosis." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/14799440415691413118.
Повний текст джерела中山醫學大學
生物化學研究所
90
Part I. Our previous study have demonstrated that the protein levels of PKC isoforms were altered in the proliferation stages of decidualization at pseudopregnant and pregnant rats. In this study, we measured the mRNA expressions of the PKC isoforms and their down-stream related genes by using RT-PCR. The product of RT-PCR was also checked by DNA sequence analysis. The results showed that the levels of PKCα mRNA was significantly increased from day 2 to day 9 in the decidualization. The mRNA expression of the transcription factors (c-jun and c-fos) were also significantly increased during the same times. These specified that the alterations in the PKCα may signify their activation in decidual tissues. In addition, the mRNA levels of the other PKC isoforms (PKCλ and PKCδ were also significantly increased during the decidualization. The increase in the PKCλ mRNA was paralleled with the increase in the mRNA levels of the proliferation markers (cdc2 and cyclin D1). Thus, These data confirmed that the expression of PKC isoforms may be involved in the development of the decidualization. Part II. Hepatitis is one of the most common diseases in Taiwan. Patients with hepatitis may lead to liver fibrosis and cirrhosis. Liver fibrogenesis, which is a dynamic, complex, and progressive process, may be reversible at initial stages. Recently, many labs are extremely focus on discovering new drugs from Chinese herb for anti-fibrosis of liver. According to previous research, to activate hepatic stellate cells have been clearly identified as the major cause of liver fibrogenesis. The present studies aim to set up a fast selective cell model to estimate the anti-fibrotic effects by Chinese herbs. LD50 was determined by the actived/inactived HSCs when treated with water extracts of 36 kinds of Chinese herb. Our results showed that totally 31 kinds of Chinese herbs (86.1%) were detected with the antifibrotic effects. Within these 31 herbs, there are 22 kinds (61.1%) have less damage on inactived HSCs compared with actived. Taken together, our results indicated that the HSCs model may be more suitable to estimate the anti-fibrotic effects of Chinese herbs than animal models.
Maiuri, Tamara Lise. "Specificity in PI3K-PKB/AKT-PTEN Signaling: Subcellular Locus-specific Functions of Pathway Targets." Thesis, 2010. http://hdl.handle.net/1807/26370.
Повний текст джерелаMontrobert, Ariane [Verfasser]. "Vergleich der Apoptoseaktivierung anhand der Caspase-3-Verteilung in einer Gliomzelllinie und Astrozytenkultur nach Inkubation mit TNF-α [TNF-alpha] und PKC-Inhibitoren / vorgelegt von Ariane Montrobert". 2010. http://d-nb.info/1007453540/34.
Повний текст джерелаHussain, Munir, N. Bracken, W. Kent, and C. Pearman. "H-89 inhibits transient outward (Ito) and inward rectifier (IK1) potassium currents independently of pka-mediated phosphorylation in isolated rat ventricular myocytes." 2006. http://hdl.handle.net/10454/3310.
Повний текст джерелаVoltage clamp was used to investigate the effects of N-[2-p-bromo-cinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), a potent inhibitor of PKA, on transient outward K+ current (Ito) and inward rectifying K+ current (IK1) in rat cardiac muscle. Initial experiments, performed using descending voltage ramps, showed that H-89 inhibited both the outward and inward ramp currents in a concentration-dependent manner at concentrations between 5 and 60 ¿mol l¿1. A similar degree of inhibition was observed when Ito and IK1 were recorded using square wave depolarising and hyperpolarising voltage steps, respectively. The IC50 was 35.8 ¿mol l¿1 for Ito and 27.8 ¿mol l¿1 for IK1 compared to 5.4 ¿mol l¿1 for L-type Ca2+ current (ICa). The Hill coefficients for Ito, IK1 and ICa were ¿1.97, ¿1.60 and ¿1.21, respectively. In addition to inhibiting Ito amplitude, H-89 also accelerated the time to peak and the rate of voltage-dependent inactivation so that the time course of Ito was abbreviated. Paired-pulse protocols were performed to study the effects of H-89 on steady-state activation and inactivation as well as recovery from voltage-dependent inactivation. H-89 produced a concentration-dependent rightward shift in voltage-dependent activation but had no significant effect on steady-state inactivation. Recovery from voltage-dependent inactivation was delayed, although this was only visible at the highest concentration (60 ¿mol l¿1) used. In experiments investigating the effects of elevated cyclic AMP, the ß-adrenergic agonist isoprenaline and the phosphatase inhibitor calyculin A had no major effects on Ito or IK1. Data suggest that the effects of H-89 on K+ currents are more complex than simple inhibition of PKA-mediated phosphorylation.
Yun-Wen, Chen, and 陳韻雯. "Effects of ketone body on the expression and ubiquitination of transcription factor Smads and cyclin-dependent kinase inhibitior p21Waf1and p27Kip1 in LLC-PK1." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/87526157800905178631.
Повний текст джерела高雄醫學大學
生物化學研究所
90
Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetic patients. The hallmark of DN is cellular hyperplasia, hypertrophy, expansion of extracellular matrix and deranged growth factors (e.g. transforming growth factor-β, TGF-β and its downstream smads) and cell cycle regulators (e.g.p21Waf1and p27Kip1) in the gomeruli and renal tubules. Hypertrophy consists of increased synthesis and/or decreased degradation of protein. Ubiquitination and proteasome pathway is one of the important mechanisms for protein degradation (e.g.Smad, p21Waf1and p27Kip1). But the role of protein ubiquitination in DN remains unknown. High glucose and advanced glycation end-product(AGE) have been proposed to be essential factors in DN. For example, we had shown that high glucose decreased cellular mitogenesis while increasing cellular hypertrophy and collage synthesis by inducing TGF-β1 protein expression in the proximal tubule-like LLC-PK1 cells. Apart from patients with diabetic ketoacidosis, serum ketone body (e.g.β- hydroxybutyrate) level is also often elevated in patients with type I or type II diabetes mellitus. However, the effects of ketone body on proximal tubule is still unknown. Therefore, the purpose of this study was to elucidate the effects of -hydroxybutyrate in LLC-PK1 cells in terms of cellular growth. We found that high glucose (500mg/dl) and β-hydroxybutyrate (10mM) decreased cellular proliferation in LLC-PK1 cells at 48 h. Meanwhile, -hydroxybutyrate also increased TGF-β, p21Waf1 and p27Kip1 transcriptional activity at 18-24 h. Interestingly, dominant negative Smad2 and Smad3 plasmids reversed -hydroxy- butyrate—inhibited cellular proliferation. They also reversed β-hydroxy- butyrate—induced p21Waf1 and p27Kip1 protein expression and TGF-β transcriptional activity. Additionally, β-hydroxybutyrate decreased p27Kip1 ubiquitination. In conclusion, β-hydroxybutyrate—inhibited cellular proliferation by inducing TGF-β/Smad2/3, p21Waf1 and p27Kip1 in LLC-PK1 cells. Moreover, β-hydroxybutyrate-induced p27Kip1 protein expression was accompanied by decreased p27Kip1 ubiquitination .
Chao, Wen-Yu, та 趙文瑜. "HE-145-111 inhibits hepatitis B virus via down-regulation of the metabolic co-activator PGC-1-α in human hepatoma cells". Thesis, 2013. http://ndltd.ncl.edu.tw/handle/51373510279816831400.
Повний текст джерела國立陽明大學
生化暨分子生物研究所
101
Hepatitis B virus (HBV) infection may result in cirrhosis and hepatocellular carcinoma. Although currently there is hepatitis B vaccine can prevent HBV infection, for already infected patients, the clinical therapies for HBV have many side effects. Therefore, development of new anti-hepatitis B drugs is still one of the important research topics. Previous studies from our laboratory, it has showed that natural compound Helioxanthin, HE-145 can suppress both HBV gene expression and secretion of viral particles in human hepatoma HepG2/A2 cells. The role of inhibition by HE-145 is via interfering with the host transcriptional machinery of viral promoter. It also found that HE-145-111, one of derivatives of HE-145 may suppress HBV core promoter activity and gluconeogenesis genes, such as glucose-6-phosphatase (G6Pase) and phosphoenolcarboxykinase (PEPCK) expression in human hepatoma cells. In my study, it is interested to know whether the anti-HBV activity is through regulating of gluconeogenesis gene expression, and further to suppress HBV core promoter activity. It has been demonstrated that the inhibition of HBV by HE-145-111 is through down-regulating of the metabolic co-activator PGC-1α. It was found that HE-145-111 suppressed HBV surface antigen secretion and core protein in Hep3B/T2 cells and 1.3ES2 cells respectively. In order to understand the relationships between suppression of HBV and gluconeogenesis by HE-145-111 in Hep3B/T2 cells, the combination of 8-bromo-cAMP (cAMP) and dexamethasone had a synergistic effect on the induction of HBV core promoter activity and mRNA levels of G6Pase, PEPCK, and PGC-1α; and on the induction of PGC-1α protein levels. Also the identification of CPD2 (nt1656-1675) as a response element in the HBV core promoter using serial deletion as well as point mutation at different regions of the core promoter. The overexpression of PGC-1α construct plasmid can reverse the inhibition of core promoter activity. HE-145-111 suppressed gluconeogenesis, G6Pase, PEPCK and PGC-1αmRNAs and PGC-1α protein and HBV core promoter together identifying CPD2 (nt 1656-1675) as binding sequences of core promoter. In 1.3ES2 cells, it was confirmed that HE-145-111 not only suppressed HBV mRNA and core protein levels but also suppressed the mRNA levels of G6Pase, PEPCK and transcription co-activator PGC-1α. In conclusion, HE-145-111 represses the HBV gene expression by down-regulation PGC-1α protein and through regulating directly the host gluconeogenesis. This mechanism study which HBV is controlled by the hepatic metabolic gluconeogenesis may broaden our understanding of the regulation of HBV expression.
Hempsch, Birgit [Verfasser]. "Experimentelle Therapie der chronischen lymphatischen Leukämie vom B-Zell-Typ (B-CLL) mit den Small-molecule-Inhibitoren CGP 049090 und PKF 115-584 / vorgelegt von Birgit Hempsch." 2009. http://d-nb.info/994578628/34.
Повний текст джерелаPark, Sung Woo (Calvin). "Activation of EPAC Inhibits the Aquisition of Nucleus Accumbens Amphetamine Place Preference in a Dose-Dependent Manner in Rats." Thesis, 2008. http://hdl.handle.net/1974/1176.
Повний текст джерелаThesis (Master, Neuroscience Studies) -- Queen's University, 2008-04-25 13:29:37.857
Lin, Yu-Chen, та 林昱蓁. "Docosahexaenoic Acid Inhibits Tumor Necrosis Factor α-Induced Intercellular Adhesion Molecule-1 Expression through Upregulation of DNA Methyltransferase-3b-Depedent DNA Methylation and Suppression of PKCζ/ERK/Sp1 Pathway in EA.hy926 cells". Thesis, 2014. http://ndltd.ncl.edu.tw/handle/w6m477.
Повний текст джерела中國醫藥大學
營養學系碩士班
102
Epigenetic regulation is a key mechanism in either the activation or the silencing of gene transcription. Tumor necrosis factor alpha (TNFα), a potent inflammatory mediator, has multiple effects on the pathogenesis of atherosclerosis. Specificity protein 1 (Sp1), a zinc finger transcription factor, binds to the GC-rich elements in the promoter of inducible genes. Docosahexaenoic acid (DHA), an n-3 fatty acid (n-3 FA), has potent anti-inflammatory effect. A previous study showed that Sp1 is activated by TNFα and induces intercellular adhesion molecule 1 (ICAM-1) expression. In our previous study, we have demonstrated that DHA inhibits TNFα-induced ICAM-1 experssion via enhancing HO-1 expression. In this study, we try to investigate the involvement of Sp1 and epigenetic mechanism in DHA inhibition of TNFα-induced ICAM-1 expression in EA.hy 926 cells. Treatment with the DNA methylation inhibitor reagent 5-aza-dC reversed DHA inhibition of TNFα-induced ICAM-1 expression. Transfection with shDNMT-3b knocks down DNMT-3b expresson and abolished DHA inhibition of TNFα-induced ICAM-1 expression. TNFα induces phosphorylation of Akt, p38 MAPK, ERK1/2 and PKCζ as well as Sp1. Treatment with ERK inhibitor (PD98059), PKCζ pseudo-substrate inhibitor and PKC inhibitor (Rottlerine) blocked TNFα-induced ICAM-1 expression. Transfection with shSp1 knocked down Sp1expresson and blocked TNFα-induced ICAM-1 expression. DHA inhibited TNFα-induced phosphorylation of Sp1.Taken together, the anti-inflammatory effect of DHA is associated with down-regulation of TNFα-induced phosphorylation of ERK1/2 and PKCζ and subsequent Sp1 phosphorylatio which increases ICAM-1 expression in endothelial cells. In addition, an increase in ICAM-1 DNA methylation by DHA may contribute to the down-regulation of TNFα-induced ICAM-1 expression.
Hofman, Tomáš. "Vliv malých DNA virů na regulaci tvorby interferónu." Master's thesis, 2018. http://www.nusl.cz/ntk/nusl-380361.
Повний текст джерелаSurup, Frank. "Metagenom-Technologie zur Wirkstoffsuche sowie Untersuchungen der Iromycine aus Streptomyces sp." Doctoral thesis, 2007. http://hdl.handle.net/11858/00-1735-0000-0006-ACA7-B.
Повний текст джерела