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[PMID]:27894809
[Au] Autor:Xiao LY; Kan WM
[Ad] Endereço:Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
[Ti] Título:Cyclic AMP (cAMP) confers drug resistance against DNA damaging agents via PKAIA in CML cells.
[So] Source:Eur J Pharmacol;794:201-208, 2017 Jan 05.
[Is] ISSN:1879-0712
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Cyclic adenosine monophosphate (cAMP) regulates many vital functions such as metabolism, proliferation, differentiation and death. Depending on cell types and stimulators, cAMP could either promote or attenuate cell death. cAMP signal can be transduced by protein kinase A (PKA) and/or exchange protein directly activated by cAMP (EPAC). In CML cells, cAMP may suppress their proliferation and enhance their differentiation. However, the role of cAMP on DNA damaging agent toxicity and the mechanism involved has not been studied. In this study, we studied the effect of cAMP on the sensitivity of CML cells to DNA damaging agents. We observed that forskolin (FSK) and dibutyryl-cAMP (DBcAMP) decreased cisplatin and etoposide-induced cell death in K562 cells. Moreover, PKA activator prevented K562 cells from DNA damaging agent-induced cell death while EPAC activator had no effect. Furthermore, we found that the PKA subtype, PKAIA, was involved in cAMP-attenuated resistance in K562 cells. Taken together, our results suggest that increased cAMP level confers CML cells to acquire a novel mechanism against DNA damaging agent toxicity via PKAIA. Thus, PKAIA inhibitor may be helpful in overcoming the resistance to DNA damaging agents in CML cells.
[Mh] Termos MeSH primário: Proteína Quinase Tipo I Dependente de AMP Cíclico/metabolismo
AMP Cíclico/farmacologia
Dano ao DNA
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia
[Mh] Termos MeSH secundário: Bucladesina/farmacologia
Morte Celular/efeitos dos fármacos
Cisplatino/farmacologia
Colforsina/farmacologia
Etoposídeo/farmacologia
Seres Humanos
Espaço Intracelular/efeitos dos fármacos
Espaço Intracelular/metabolismo
Células K562
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
1F7A44V6OU (Colforsin); 63X7MBT2LQ (Bucladesine); 6PLQ3CP4P3 (Etoposide); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type I); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170405
[Lr] Data última revisão:
170405
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161130
[St] Status:MEDLINE


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[PMID]:26804598
[Au] Autor:Hussain M; Shah Z; Abbas N; Javeed A; Mukhtar MM; Zhang J
[Ad] Endereço:Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou 510530, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China. Electronic address: muzammal@gibh.ac.cn.
[Ti] Título:Targeting tumor-associated immune suppression with selective protein kinase A type I (PKAI) inhibitors may enhance cancer immunotherapy.
[So] Source:Med Hypotheses;86:56-9, 2016 Jan.
[Is] ISSN:1532-2777
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Despite the tremendous progress in last few years, the cancer immunotherapy has not yet improved disease-free because of the tumor-associated immune suppression being a major barrier. Novel trends to enhance cancer immunotherapy aims at harnessing the therapeutic manipulation of signaling pathways mediating the tumor-associated immune suppression, with the general aims of: (a) reversing the tumor immune suppression; (b) enhancing the innate and adaptive components of anti-tumor immunosurveillance, and (c) protecting immune cells from the suppressive effects of T regulatory cells (Tregs) and the tumor-derived immunoinhibitory mediators. A particular striking example in this context is the cyclic adenosine monophosphate (cAMP)-dependent protein kinase A type I (PKAI) pathway. Oncogenic cAMP/PKAI signaling has long been implicated in the initiation and progression of several human cancers. Emerging data indicate that cAMP/PKAI signaling also contributes to tumor- and Tregs-derived suppression of innate and adaptive arms of anti-tumor immunosurveillance. Therapeutically, selective PKAI inhibitors have been developed which have shown promising anti-cancer activity in pre-clinical and clinical settings. Rp-8-Br-cAMPS is a selective PKAI antagonist that is widely used as a biochemical tool in signal transduction research. Collateral data indicate that Rp-8-Br-cAMPS has shown immune-rescuing potential in terms of enhancing the innate and adaptive anti-tumor immunity, as well as protecting adaptive T cells from the suppressive effects of Tregs. Therefore, this proposal specifically implicates that combining selective PKAI antagonists/inhibitors with cancer immunotherapy may have multifaceted benefits, such as rescuing the endogenous anti-tumor immunity, enhancing the efficacy of cancer immunotherapy, and direct anti-cancer effects.
[Mh] Termos MeSH primário: Proteína Quinase Tipo I Dependente de AMP Cíclico/antagonistas & inibidores
Proteína Quinase Tipo I Dependente de AMP Cíclico/imunologia
Imunoterapia/métodos
Neoplasias/enzimologia
Neoplasias/terapia
Inibidores de Proteínas Quinases/administração & dosagem
[Mh] Termos MeSH secundário: Antineoplásicos/administração & dosagem
Seres Humanos
Imunidade Celular/efeitos dos fármacos
Imunidade Celular/imunologia
Modelos Imunológicos
Terapia de Alvo Molecular/métodos
Neoplasias/imunologia
Resultado do Tratamento
Microambiente Tumoral/efeitos dos fármacos
Microambiente Tumoral/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Protein Kinase Inhibitors); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type I)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160126
[St] Status:MEDLINE


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[PMID]:26773602
[Au] Autor:Zhao CY; Greenstein JL; Winslow RL
[Ad] Endereço:Department of Biomedical Engineering and the Institute for Computational Medicine, The Johns Hopkins University School of Medicine and Whiting School of Engineering, 3400 N Charles Street, Baltimore, MD 21218, USA. Electronic address: czhao10@jhu.edu.
[Ti] Título:Roles of phosphodiesterases in the regulation of the cardiac cyclic nucleotide cross-talk signaling network.
[So] Source:J Mol Cell Cardiol;91:215-27, 2016 Feb.
[Is] ISSN:1095-8584
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The balanced signaling between the two cyclic nucleotides (cNs) cAMP and cGMP plays a critical role in regulating cardiac contractility. Their degradation is controlled by distinctly regulated phosphodiesterase isoenzymes (PDEs), which in turn are also regulated by these cNs. As a result, PDEs facilitate communication between the ß-adrenergic and Nitric Oxide (NO)/cGMP/Protein Kinase G (PKG) signaling pathways, which regulate the synthesis of cAMP and cGMP respectively. The phenomena in which the cAMP and cGMP pathways influence the dynamics of each other are collectively referred to as cN cross-talk. However, the cross-talk response and the individual roles of each PDE isoenzyme in shaping this response remain to be fully characterized. We have developed a computational model of the cN cross-talk network that mechanistically integrates the ß-adrenergic and NO/cGMP/PKG pathways via regulation of PDEs by both cNs. The individual model components and the integrated network model replicate experimentally observed activation-response relationships and temporal dynamics. The model predicts that, due to compensatory interactions between PDEs, NO stimulation in the presence of sub-maximal ß-adrenergic stimulation results in an increase in cytosolic cAMP accumulation and corresponding increases in PKA-I and PKA-II activation; however, the potentiation is small in magnitude compared to that of NO activation of the NO/cGMP/PKG pathway. In a reciprocal manner, ß-adrenergic stimulation in the presence of sub-maximal NO stimulation results in modest cGMP elevation and corresponding increase in PKG activation. In addition, we demonstrate that PDE2 hydrolyzes increasing amounts of cAMP with increasing levels of ß-adrenergic stimulation, and hydrolyzes increasing amounts of cGMP with decreasing levels of NO stimulation. Finally, we show that PDE2 compensates for inhibition of PDE5 both in terms of cGMP and cAMP dynamics, leading to cGMP elevation and increased PKG activation, while maintaining whole-cell ß-adrenergic responses similar to that prior to PDE5 inhibition. By defining and quantifying reactions comprising cN cross-talk, the model characterizes the cross-talk response and reveals the underlying mechanisms of PDEs in this non-linear, tightly-coupled reaction system.
[Mh] Termos MeSH primário: AMP Cíclico/metabolismo
GMP Cíclico/metabolismo
Redes Reguladoras de Genes
Modelos Cardiovasculares
Miocárdio/enzimologia
Miócitos Cardíacos/enzimologia
Diester Fosfórico Hidrolases/genética
[Mh] Termos MeSH secundário: Animais
Simulação por Computador
Proteína Quinase Tipo I Dependente de AMP Cíclico/genética
Proteína Quinase Tipo I Dependente de AMP Cíclico/metabolismo
Proteína Quinase Tipo II Dependente de AMP Cíclico/genética
Proteína Quinase Tipo II Dependente de AMP Cíclico/metabolismo
Proteínas Quinases Dependentes de GMP Cíclico/genética
Proteínas Quinases Dependentes de GMP Cíclico/metabolismo
Regulação da Expressão Gênica
Isoenzimas/genética
Isoenzimas/metabolismo
Contração Miocárdica
Miocárdio/citologia
Miócitos Cardíacos/citologia
Óxido Nítrico/metabolismo
Diester Fosfórico Hidrolases/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Isoenzymes); 31C4KY9ESH (Nitric Oxide); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type I); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type II); EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases); EC 3.1.4.- (Phosphoric Diester Hydrolases); H2D2X058MU (Cyclic GMP)
[Em] Mês de entrada:1611
[Cu] Atualização por classe:170228
[Lr] Data última revisão:
170228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160117
[St] Status:MEDLINE


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[PMID]:26611881
[Au] Autor:Autenrieth K; Bendzunas NG; Bertinetti D; Herberg FW; Kennedy EJ
[Ad] Endereço:Dept. of Biochemistry, Universitat Kassel, Heinrich Plett Strasse 40, Kassel 34132 (Germany).
[Ti] Título:Defining A-Kinase Anchoring Protein (AKAP) Specificity for the Protein Kinase A Subunit RI (PKA-RI).
[So] Source:Chembiochem;17(8):693-697, 2016 Apr 15.
[Is] ISSN:1439-7633
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:A-Kinase anchoring proteins (AKAPs) act as spatial and temporal regulators of protein kinase A (PKA) by localizing PKA along with multiple proteins into discrete signaling complexes. AKAPs interact with the PKA holoenzyme through an α-helix that docks into a groove formed on the dimerization/docking domain of PKA-R in an isoform-dependent fashion. In an effort to understand isoform selectivity at the molecular level, a library of protein-protein interaction (PPI) disruptors was designed to systematically probe the significance of an aromatic residue on the AKAP docking sequence for RI selectivity. The stapled peptide library was designed based on a high affinity, RI-selective disruptor of AKAP binding, RI-STAD-2. Phe, Trp and Leu were all found to maintain RI selectivity, whereas multiple intermediate-sized hydrophobic substitutions at this position either resulted in loss of isoform selectivity (Ile) or a reversal of selectivity (Val). As a limited number of RI-selective sequences are currently known, this study aids in our understanding of isoform selectivity and establishing parameters for discovering additional RI-selective AKAPs.
[Mh] Termos MeSH primário: Proteínas de Ancoragem à Quinase A/química
Proteína Quinase Tipo I Dependente de AMP Cíclico/química
[Mh] Termos MeSH secundário: Dimerização
Seres Humanos
Interações Hidrofóbicas e Hidrofílicas
Isoenzimas/química
Simulação de Acoplamento Molecular
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (A Kinase Anchor Proteins); 0 (Isoenzymes); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type I)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151128
[St] Status:MEDLINE
[do] DOI:10.1002/cbic.201500632


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[PMID]:26176741
[Au] Autor:Raslan Z; Magwenzi S; Aburima A; Taskén K; Naseem KM
[Ad] Endereço:Centre for Cardiovascular and Metabolic Research, Hull York Medical School, University of Hull, Hull, UK.
[Ti] Título:Targeting of type I protein kinase A to lipid rafts is required for platelet inhibition by the 3',5'-cyclic adenosine monophosphate-signaling pathway.
[So] Source:J Thromb Haemost;13(9):1721-34, 2015 Sep.
[Is] ISSN:1538-7836
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Platelet adhesion to von Willebrand factor (VWF) is modulated by 3',5'-cyclic adenosine monophosphate (cAMP) signaling through protein kinase A (PKA)-mediated phosphorylation of glycoprotein (GP)Ibß. A-kinase anchoring proteins (AKAPs) are proposed to control the localization and substrate specificity of individual PKA isoforms. However, the role of PKA isoforms in regulating the phosphorylation of GPIbß and platelet response to VWF is unknown. OBJECTIVES: We wished to determine the role of PKA isoforms in the phosphorylation of GPIbß and platelet activation by VWF as a model for exploring the selective partitioning of cAMP signaling in platelets. RESULTS: The two isoforms of PKA in platelets, type I (PKA-I) and type II (PKA-II), were differentially localized, with a small pool of PKA-I found in lipid rafts. Using a combination of Far Western blotting, immunoprecipitation, proximity ligation assay and cAMP pull-down we identified moesin as an AKAP that potentially localizes PKA-I to rafts. Introduction of cell-permeable anchoring disruptor peptide, RI anchoring disruptor (RIAD-Arg11 ), to block PKA-I/AKAP interactions, uncoupled PKA-RI from moesin, displaced PKA-RI from rafts and reduced kinase activity in rafts. Examination of GPIbß demonstrated that it was phosphorylated in response to low concentrations of PGI2 in a PKA-dependent manner and occurred primarily in lipid raft fractions. RIAD-Arg11 caused a significant reduction in raft-localized phosphoGPIbß and diminished the ability of PGI2 to regulate VWF-mediated aggregation and thrombus formation in vitro. CONCLUSION: We propose that PKA-I-specific AKAPs in platelets, including moesin, organize a selective localization of PKA-I required for phosphorylation of GPIbß and contribute to inhibition of platelet VWF interactions.
[Mh] Termos MeSH primário: Proteínas de Ancoragem à Quinase A/sangue
Proteína Quinase Tipo I Dependente de AMP Cíclico/sangue
AMP Cíclico/fisiologia
Microdomínios da Membrana
Adesividade Plaquetária/fisiologia
Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo
Processamento de Proteína Pós-Traducional
Sistemas do Segundo Mensageiro/fisiologia
[Mh] Termos MeSH secundário: Proteínas de Ancoragem à Quinase A/fisiologia
Sequência de Aminoácidos
Proteína Quinase Tipo I Dependente de AMP Cíclico/antagonistas & inibidores
Epoprostenol/farmacologia
Seres Humanos
Microdomínios da Membrana/metabolismo
Proteínas dos Microfilamentos/metabolismo
Dados de Sequência Molecular
Fragmentos de Peptídeos/síntese química
Fragmentos de Peptídeos/farmacologia
Fosforilação
Glicoproteínas da Membrana de Plaquetas/metabolismo
Ligação Proteica
Isoformas de Proteínas/sangue
Inibidores de Proteínas Quinases/farmacologia
Fator de von Willebrand/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (A Kinase Anchor Proteins); 0 (Microfilament Proteins); 0 (Peptide Fragments); 0 (Platelet Glycoprotein GPIb-IX Complex); 0 (Platelet Membrane Glycoproteins); 0 (Protein Isoforms); 0 (Protein Kinase Inhibitors); 0 (von Willebrand Factor); 0 (von Willebrand factor receptor); 144131-77-1 (moesin); DCR9Z582X0 (Epoprostenol); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type I)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:150905
[Lr] Data última revisão:
150905
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150716
[St] Status:MEDLINE
[do] DOI:10.1111/jth.13042


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[PMID]:25765284
[Au] Autor:Wang Y; Ho TG; Franz E; Hermann JS; Smith FD; Hehnly H; Esseltine JL; Hanold LE; Murph MM; Bertinetti D; Scott JD; Herberg FW; Kennedy EJ
[Ad] Endereço:†Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602, United States.
[Ti] Título:PKA-type I selective constrained peptide disruptors of AKAP complexes.
[So] Source:ACS Chem Biol;10(6):1502-10, 2015 Jun 19.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A-Kinase Anchoring Proteins (AKAPs) coordinate complex signaling events by serving as spatiotemporal modulators of cAMP-dependent protein kinase activity in cells. Although AKAPs organize a plethora of diverse pathways, their cellular roles are often elusive due to the dynamic nature of these signaling complexes. AKAPs can interact with the type I or type II PKA holoenzymes by virtue of high-affinity interactions with the R-subunits. As a means to delineate AKAP-mediated PKA signaling in cells, we sought to develop isoform-selective disruptors of AKAP signaling. Here, we report the development of conformationally constrained peptides named RI-STapled Anchoring Disruptors (RI-STADs) that target the docking/dimerization domain of the type 1 regulatory subunit of PKA. These high-affinity peptides are isoform-selective for the RI isoforms, can outcompete binding by the classical AKAP disruptor Ht31, and can selectively displace RIα, but not RIIα, from binding the dual-specific AKAP149 complex. Importantly, these peptides are cell-permeable and disrupt Type I PKA-mediated phosphorylation events in the context of live cells. Hence, RI-STAD peptides are versatile cellular tools to selectively probe anchored type I PKA signaling events.
[Mh] Termos MeSH primário: Proteínas de Ancoragem à Quinase A/antagonistas & inibidores
Proteína Quinase Tipo II Dependente de AMP Cíclico/antagonistas & inibidores
Proteína Quinase Tipo I Dependente de AMP Cíclico/antagonistas & inibidores
Peptídeos/química
Inibidores de Proteínas Quinases/química
Subunidades Proteicas/antagonistas & inibidores
[Mh] Termos MeSH secundário: Proteínas de Ancoragem à Quinase A/química
Proteínas de Ancoragem à Quinase A/metabolismo
Sequência de Aminoácidos
Sítios de Ligação/efeitos dos fármacos
Linhagem Celular Tumoral
Permeabilidade da Membrana Celular
Proteína Quinase Tipo I Dependente de AMP Cíclico/química
Proteína Quinase Tipo I Dependente de AMP Cíclico/metabolismo
Proteína Quinase Tipo II Dependente de AMP Cíclico/química
Proteína Quinase Tipo II Dependente de AMP Cíclico/metabolismo
Seres Humanos
Cinética
Dados de Sequência Molecular
Peptídeos/farmacologia
Fosforilação
Ligação Proteica/efeitos dos fármacos
Conformação Proteica
Inibidores de Proteínas Quinases/farmacologia
Subunidades Proteicas/química
Subunidades Proteicas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (A Kinase Anchor Proteins); 0 (AKAP1 protein, human); 0 (Peptides); 0 (Protein Kinase Inhibitors); 0 (Protein Subunits); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type I); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type II)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150314
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.5b00009


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[PMID]:24758084
[Au] Autor:Song CM; Yang HM; Lu J; Zhou N; Lu S; Duan YC; Ma HR; Xu HZ; Du HL
[Ti] Título:[Effect of Bushen Tiaojing Recipe containing serum on FSH/cAMP-PKA pathway in in vitro cultured human ovarian granular cells].
[So] Source:Zhongguo Zhong Xi Yi Jie He Za Zhi;34(3):317-23, 2014 Mar.
[Is] ISSN:1003-5370
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:OBJECTIVE: To explore the potential molecular mechanisms for Bushen Tiaojing Recipe (BTR) improving the endocrine function of ovarian granular cells by observing the effect of BTR containing serum on follicle stimulating hormone/cyclic adenosine monophosphate-protein kinase A (FSH/ cAMP-PKA) pathway in in vitro cultured human ovarian granular cells. METHODS: The primary ovarian granular cells collected from in vitro fertilization-embryo transfer patients were cultured for 24 h. The human and rat serum containing different concentrations of BTR (low, medium, high dose), and their normal serums were co-incubated with ovarian granular cells for 48 h respectively, and then they were divided into the low, medium, high dose BTR groups and the control group. The levels of estradiol (E2), progesterone (P), and cyclic adenosine monophosphate (cAMP) in the culture medium were measured by radioimmunoassay. The protein expression of FSHR in ovarian granular cells was detected by Western Blot. The mRNA expression of follicle stimulating hormone receptor (FSHR) and P450 aromatase (P450arom) in ovarian granular cells were detected by Real-time PCR. RESULTS: In human BTR containing serum groups: Compared with control group, the levels of E2 and cAMP in the culture medium were higher (both P < 0.05) in the medium and high dose BTR groups; the levels of P in the culture medium decreased in the medium dose BTR group (P < 0.01). The protein and mRNA expression of FSHR in ovarian granular cells increased (all P < 0.01), the mRNA expressions of P450arom in ovarian granular cells were higher (P < 0.05, P< 0.01) in the medium and high dose BTR groups. In rat BTR containing serum groups: Compared with the control group, the levels of E2 in the culture medium were higher (all P < 0.01), cAMP in the culture medium were higher (P < 0.05, P < 0.01) in the medium and high dose BTR group; the levels of P in the culture medium decreased in the medium dose BTR group (P < 0.01). The protein and mRNA expression of FSHR in ovarian granular cells were higher (all P < 0.01), the mRNA expression of P450arom in ovarian granular cells increased in the medium and high dose BTR groups (P < 0.05, P < 0.01). CONCLUSION: BTR could possibly improve the endocrine function of ovarian granular cells by regulating main effector molecules FSHR, cAMP, P450arom, and E2 in FSH/cAMP-PKA pathway of ovarian granular cells.
[Mh] Termos MeSH primário: Medicamentos de Ervas Chinesas/farmacologia
Células da Granulosa/efeitos dos fármacos
Células da Granulosa/metabolismo
[Mh] Termos MeSH secundário: Células Cultivadas
Proteína Quinase Tipo I Dependente de AMP Cíclico/metabolismo
Feminino
Hormônio Foliculoestimulante/metabolismo
Células da Granulosa/citologia
Seres Humanos
Soro/química
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:ENGLISH ABSTRACT; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Drugs, Chinese Herbal); 9002-68-0 (Follicle Stimulating Hormone); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type I)
[Em] Mês de entrada:1501
[Cu] Atualização por classe:161018
[Lr] Data última revisão:
161018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140425
[St] Status:MEDLINE


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[PMID]:24601788
[Au] Autor:Degraaf AJ; Zaslona Z; Bourdonnay E; Peters-Golden M
[Ad] Endereço:Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
[Ti] Título:Prostaglandin E2 reduces Toll-like receptor 4 expression in alveolar macrophages by inhibition of translation.
[So] Source:Am J Respir Cell Mol Biol;51(2):242-50, 2014 Aug.
[Is] ISSN:1535-4989
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Alveolar macrophages (AMs) represent the first line of innate immune defense in the lung. AMs use pattern recognition receptors (PRRs) to sense pathogens. The best studied PRR is Toll-like receptor (TLR)4, which detects LPS from gram-negative bacteria. The lipid mediator prostaglandin (PG)E2 dampens AM immune responses by inhibiting the signaling events downstream of PRRs. We examined the effect of PGE2 on TLR4 expression in rat AMs. Although PGE2 did not reduce the mRNA levels of TLR4, it decreased TLR4 protein levels. The translation inhibitor cycloheximide reduced TLR4 protein levels with similar kinetics as PGE2, and its effects were not additive with those of the prostanoid, suggesting that PGE2 inhibits TLR at the translational level. The action of PGE2 could be mimicked by the direct stimulator of cAMP formation, forskolin, and involved E prostanoid receptor 2 ligation and cAMP-dependent activation of unanchored type I protein kinase A. Cells pretreated with PGE2 for 24 hours exhibited decreased TNF-α mRNA and protein levels in response to LPS stimulation. Knockdown of TLR4 protein by small interfering RNA to the levels achieved by PGE2 treatment likewise decreased TNF-α mRNA and protein in response to LPS, establishing the functional significance of this PGE2 effect. We provide the first evidence of a lipid mediator acting through its cognate G protein-coupled receptor to affect PRR translation. Because PGE2 is produced in abundance at sites of infection, its inhibitory effects on AM TLR4 expression have important implications for host defense in the lung.
[Mh] Termos MeSH primário: Dinoprostona/metabolismo
Macrófagos Alveolares/metabolismo
Receptor 4 Toll-Like/metabolismo
Transcrição Genética
[Mh] Termos MeSH secundário: Adenilil Ciclases/metabolismo
Animais
AMP Cíclico/metabolismo
Proteína Quinase Tipo I Dependente de AMP Cíclico/metabolismo
Regulação para Baixo
Feminino
Seres Humanos
Imunidade Inata
Mediadores da Inflamação/metabolismo
Macrófagos Alveolares/imunologia
Interferência de RNA
RNA Mensageiro/metabolismo
Ratos
Ratos Wistar
Receptores de Prostaglandina E/metabolismo
Transdução de Sinais
Fatores de Tempo
Receptor 4 Toll-Like/genética
Transfecção
Fator de Necrose Tumoral alfa/genética
Fator de Necrose Tumoral alfa/metabolismo
Células U937
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Inflammation Mediators); 0 (RNA, Messenger); 0 (Receptors, Prostaglandin E); 0 (TLR4 protein, human); 0 (Tlr4 protein, rat); 0 (Toll-Like Receptor 4); 0 (Tumor Necrosis Factor-alpha); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type I); EC 4.6.1.1 (Adenylyl Cyclases); K7Q1JQR04M (Dinoprostone)
[Em] Mês de entrada:1409
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140308
[St] Status:MEDLINE
[do] DOI:10.1165/rcmb.2013-0495OC


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[PMID]:24190886
[Au] Autor:Isensee J; Diskar M; Waldherr S; Buschow R; Hasenauer J; Prinz A; Allgöwer F; Herberg FW; Hucho T
[Ad] Endereço:University Hospital Cologne, Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, Robert Koch Str. 10, 50931 Cologne, Germany.
[Ti] Título:Pain modulators regulate the dynamics of PKA-RII phosphorylation in subgroups of sensory neurons.
[So] Source:J Cell Sci;127(Pt 1):216-29, 2014 Jan 01.
[Is] ISSN:1477-9137
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Knowledge about the molecular structure of protein kinase A (PKA) isoforms is substantial. In contrast, the dynamics of PKA isoform activity in living primary cells has not been investigated in detail. Using a high content screening microscopy approach, we identified the RIIß subunit of PKA-II to be predominantly expressed in a subgroup of sensory neurons. The RIIß-positive subgroup included most neurons expressing nociceptive markers (TRPV1, NaV1.8, CGRP, IB4) and responded to pain-eliciting capsaicin with calcium influx. Isoform-specific PKA reporters showed in sensory-neuron-derived F11 cells that the inflammatory mediator PGE2 specifically activated PKA-II but not PKA-I. Accordingly, pain-sensitizing inflammatory mediators and activators of PKA increased the phosphorylation of RII subunits (pRII) in subgroups of primary sensory neurons. Detailed analyses revealed basal pRII to be regulated by the phosphatase PP2A. Increase of pRII was followed by phosphorylation of CREB in a PKA-dependent manner. Thus, we propose RII phosphorylation to represent an isoform-specific readout for endogenous PKA-II activity in vivo, suggest RIIß as a novel nociceptive subgroup marker, and extend the current model of PKA-II activation by introducing a PP2A-dependent basal state.
[Mh] Termos MeSH primário: Capsaicina/farmacologia
Nociceptividade/efeitos dos fármacos
Proteína Fosfatase 2/genética
Células Receptoras Sensoriais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Biomarcadores/metabolismo
Peptídeo Relacionado com Gene de Calcitonina/genética
Peptídeo Relacionado com Gene de Calcitonina/metabolismo
Cálcio/metabolismo
Colforsina/farmacologia
AMP Cíclico/metabolismo
Subunidade RIIbeta da Proteína Quinase Dependente de AMP Cíclico/genética
Subunidade RIIbeta da Proteína Quinase Dependente de AMP Cíclico/metabolismo
Proteína Quinase Tipo I Dependente de AMP Cíclico/genética
Proteína Quinase Tipo I Dependente de AMP Cíclico/metabolismo
Ciclosporina/farmacologia
Dinoprostona/farmacologia
Regulação da Expressão Gênica
Masculino
Canal de Sódio Disparado por Voltagem NAV1.8/genética
Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo
Fosforilação
Cultura Primária de Células
Proteína Fosfatase 2/metabolismo
Ratos
Ratos Sprague-Dawley
Células Receptoras Sensoriais/citologia
Células Receptoras Sensoriais/metabolismo
Transdução de Sinais
Canais de Cátion TRPV/genética
Canais de Cátion TRPV/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Biomarkers); 0 (Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit); 0 (NAV1.8 Voltage-Gated Sodium Channel); 0 (Scn10a protein, rat); 0 (TRPV Cation Channels); 0 (Trpv1 protein, rat); 1F7A44V6OU (Colforsin); 83652-28-2 (Calcitonin Gene-Related Peptide); 83HN0GTJ6D (Cyclosporine); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type I); EC 3.1.3.16 (Protein Phosphatase 2); K7Q1JQR04M (Dinoprostone); S07O44R1ZM (Capsaicin); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1408
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131106
[St] Status:MEDLINE
[do] DOI:10.1242/jcs.136580


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[PMID]:24319977
[Au] Autor:Levchuk NI
[Ti] Título:[Influence of metanandamide on steroidogenesis in rat adrenocorticocytes in vitro].
[So] Source:Ukr Biokhim Zh (1999);85(4):90-3, 2013 Jul-Aug.
[Cp] País de publicação:Ukraine
[La] Idioma:ukr
[Ab] Resumo:It is known from literature about antioxidant, anti-inflammatory, membrane protective and adreniregulatory properties of N-acetylethanolamines, but data concerning their participation in regulation of steroidogenesis are insufficient. In order to study the influence of a synthetic analogue of endogenous canabinoid anandamide - metanandamide - on the intensity of steroidogenesis the influence of different concentrations of the drug on the contents of 11-hydroxicorticosteroides (11-HCS) in the culture medium after incubation of adrenal tissue in rats of both sexes was investigated. The quantitative determination of 11-HCS was conducted by fluorometric micromethod. It was shown that the incubation of tissue sections with metanandamide leads to a reduction of 11-HCS in males and an increase of their content in females. It was concluded that the inhibition of corticosteroid secretion and synthesis in males may be due to reduction of cAMP and inhibition of cAMP-dependent protein kinase A (PKA) under the effect of metanandamide. The opposite and dose-dependent effects of the preparation in females may be connected with the estrogen influence on the mechanisms of drug effect realization.
[Mh] Termos MeSH primário: Corticosteroides/biossíntese
Córtex Suprarrenal/efeitos dos fármacos
Ácidos Araquidônicos/farmacologia
Etanolaminas/farmacologia
[Mh] Termos MeSH secundário: Córtex Suprarrenal/metabolismo
Corticosteroides/agonistas
Corticosteroides/antagonistas & inibidores
Animais
AMP Cíclico/metabolismo
Proteína Quinase Tipo I Dependente de AMP Cíclico/metabolismo
Relação Dose-Resposta a Droga
Feminino
Fluorometria
Masculino
Microtomia
Ratos
Ratos Wistar
Fatores Sexuais
Técnicas de Cultura de Tecidos
[Pt] Tipo de publicação:ENGLISH ABSTRACT; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adrenal Cortex Hormones); 0 (Arachidonic Acids); 0 (Ethanolamines); 150314-39-9 (methanandamide); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type I)
[Em] Mês de entrada:1312
[Cu] Atualização por classe:150803
[Lr] Data última revisão:
150803
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131211
[St] Status:MEDLINE



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