共查询到20条相似文献,搜索用时 9 毫秒
1.
G. Spoto M. della Malva C. Rubini M. Fioroni A. Piattelli E. Serra 《Nucleosides, nucleotides & nucleic acids》2013,32(9-11):1113-1117
The aim of this study was to evaluate differences of cAMP-PDE activity in human salivary glands, between a control group and some different benign tumours groups and, where present, with 2 malignant tumors groups. The value of the enzymatic activity in the groups analysed was 50% lower than control samples. The differences between the control group (82 ± 7.9 nmols/mg of protein) and the 3 pathologic groups (Benign A: 44 ± 6.2; Malignant A: 40 ± 16; Benign B: 40 ± 14.2; Malign A: 9.1; Benign C: 22 nmols/mg of protein) are statistically significant. 相似文献
2.
Neutrophil superoxide production is implicated in the pathogenesis of gastric mucosal damage induced by various ulcerative agents and Helicobacter pylori infection. We investigated here the effects of an anti-ulcer drug irsogladine [2, 4-diamino-6-(2, 5-dichlorophenyl)-s-triazine maleate] on cAMP formation in isolated human neutrophils. The cAMP level in human neutrophils was elevated by a phosphodiesterase (PDE) type 4 selective inhibitor rolipram, but not by any inhibitors of PDE1, PDE2 and PDE3. Irsogladine also increased cAMP formation in a concentration-dependent manner in neutrophils. A non-selective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) alone significantly increased cAMP level, whereas irsogladine was unable to further increase cAMP level in the presence of IBMX. Irsogladine inhibited concentration-dependently the superoxide (O(2)(-)) production induced by various stimuli including formyl-methionyl-leucyl-phenylalanine, opsonized zymosan, guanosine 5'-[gamma-thio] triphosphate, A23187 and phorbol 12-myristate 13-acetate. These effects of irsogladine were mimicked by rolipram, IBMX and dibutyryl cAMP. The inhibitory effects of irsogladine and rolipram on the O(2)(-) production were reversed by a protein kinase A inhibitor H-89. These results indicate that irsogladine inhibits the superoxide production in human neutrophils by the increase of cAMP content by PDE 4 inhibition, which in turn contributing to the anti-ulcer effects of irsogladine on gastric mucosal lesions associated with oxidative stress. 相似文献
3.
Effects of phosphodiesterase inhibitors on spontaneous nuclear maturation and cAMP concentrations in bovine oocytes 总被引:3,自引:0,他引:3
Bilodeau-Goeseels S 《Theriogenology》2003,60(9):1679-1690
It was previously demonstrated that inhibition of cAMP degradation with phosphodiesterase type 3 (PDE3) inhibitors resulted in the maintenance of bovine cumulus–oocyte complexes (COC) and denuded oocytes (DO) in meiotic arrest, while a PDE4 inhibitor was without effect. In this study, different inhibitors of PDE3 and PDE4 were tested for their effects on bovine oocyte nuclear maturation. Bovine COC and DO were cultured in TCM-199+10% fetal bovine serum (FBS) with or without different concentrations of the PDE inhibitors. The PDE3 inhibitor trequinsin significantly increased the percentage of COC remaining at the germinal vesicle (GV) stage after 7 h of culture (19.3, 60.3, and 67.8% GV for control and trequinsin 10 and 50 nM, respectively) while Ro 20-1724 (a PDE4 inhibitor) was without effect. In DO, only trequinsin at 10 nM had a significant effect after 7 h of culture (51.3 and 86.1% GV for control and trequinsin 10 nM, respectively). Trequinsin reduced the percentage of COC reaching the mature phase after 22 h, but was without effect on DO. The protein kinase A (PKA) inhibitor H-89 reversed the inhibitory effect of trequinsin in COC and DO, indicating that inhibition of nuclear maturation by trequinsin involves activation of PKA. Trequinsin increased cAMP concentrations in COC but not in DO, suggesting that cumulus cells may also contain a PDE3 isoenzyme. 相似文献
4.
Megumi Goto Kumiko Kadoshima-Yamaoka Hidekazu Inoue Yasuhiro Hayashi Takashi Nakatsuka Kenji Chamoto Takashi Nishimura 《Cellular immunology》2009,258(2):147-151
A possible involvement of phosphodiesterase 7A (PDE7A) in proliferation and function of NKT cells was examined using ASB16165, a selective inhibitor for PDE7A. Stimulation of isolated murine NKT cells with anti-CD3 antibody plus IL-2 induced not only cell proliferation but production of cytokines including IFN-γ, TNF-α, IL-17 and IL-22. ASB16165 significantly inhibited the CD3/IL-2-stimulated cell proliferation and production of all the cytokines examined. Forskolin (an activator of adenylyl cyclase) and dibutyryl cAMP also exerted inhibitory effects on the cell proliferation and cytokine production of NKT cells. In addition, Rp-8-Br-cAMPS, an inhibitor of protein kinase A (PKA), reversed the suppressive effects of ASB16165 against NKT cells. These results suggest that PKA/cAMP as well as PDE7A is involved in regulation of cell proliferation and cytokine production of NKT cells, and that the inhibitory effects of ASB16165 in NKT cells shown here are mediated by increase in cellular cAMP level. Our findings also raise the possibility that PDE7A inhibitor including ASB16165 may be useful for treatment of the diseases in which NKT cells have pathogenic roles. 相似文献
5.
The small heat shock proteins (sHSPs) are a highly conserved family of molecular chaperones that are ubiquitously expressed throughout nature. They are transiently upregulated in many tissue types following stressful stimuli. Recently, one member of the sHSP family, HSP20 (HspB6), has been shown to be highly effective as a protective mediator against a number of debilitating pathological conditions, including cardiac hypertrophy and Alzheimer's disease. Hsp20 is also an important modulator of vital physiological processes, such as smooth muscle relaxation and cardiac contractility. This review focuses on the molecular mechanisms employed by HSP20 that allow it to act as an innate protector in the context of cardiovascular and neurological diseases. Emerging evidence for a possible role as an anti-cancer agent is also presented. 相似文献
6.
Trapidil (N,N-diethyl-5-methyl[l,2,4]triazolo[l,5-α]pyrimidine-7-amine) inhibits platelet spreading and aggregation induced by arachidonic acid (AA), a stable analogue of prostaglandin (PG) endoperoxides (U46619), ADP, and low concentrations of thrombin, but not by A23187 and high concentrations of thrombin. Trapidil does not affect platelet adenylate cyclase but inhibits the cAMP PDE by approx. 50%. PDE inhibition proceeds via a competitive mechanism (Ki = 0.52 mM) and is not mediated by calmodulin inhibition. Trapidil does not change the platelet basal cAMP level but potentiates an increase of cAMP induced by the stable prostacyclin analogue (6β-PGIi). These results suggest that trapidil antiplatelet effects may be due to the inhibition of platelet PDE. 相似文献
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Breckler M Berthouze M Laurent AC Crozatier B Morel E Lezoualc'h F 《Cellular signalling》2011,23(8):1257-1266
Epac proteins respond to the second messenger cyclic AMP (cAMP) and are activated by Gs coupled receptors. They act as specific guanine nucleotide exchange factors (GEFs) for the small G proteins, Rap1 and Rap2 of the Ras family. A plethora of studies using 8-pCPT-2′-O-Me-cAMP, an Epac agonist, has revealed the importance of these multi-domain proteins in the control of key cellular functions such as cell division, migration, growth and secretion. Epac and protein kinase A (PKA) may act independently but are often associated with the same biological process, in which they fulfill either synergistic or opposite effects. In addition, compelling evidence is now accumulating about the formation of molecular complexes in distinct cellular compartments that influence Epac signaling and cellular function. Epac is spatially and temporally regulated by scaffold protein and its effectors are interconnected with other signaling pathways. Pathophysiological changes in Epac signaling may underlie certain diseases. 相似文献
9.
Several steroids, in particular progesterone, are toxic for the filamentous fungus Rhizopus nigricans and, at high concentrations, inhibit its growth. Previous studies on this microorganism revealed progesterone specific receptors coupled to G proteins at the plasma membrane. In this study, the next step of steroid signalling in R. nigricans following G protein activation is investigated, together with the possible impact of this pathway on fungal growth inhibition. The intracellular level of cAMP decreased in the presence of steroids, demonstrating the probable involvement of cAMP signalling in the response of R. nigricans to steroids. Results of the growth analysis in the presence of cAMP increasing agents suggest that the role of cAMP in fungal growth inhibition by steroids cannot be ruled out, but it would appear to be minor and not make a major contribution to growth inhibition. 相似文献
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Bovine sperm motility and respiration were stimulated by the triazine dye Cibacron Blue F3GA (CB), which may operate as a nucleotide mimic. CB stimulation of respiration was half-maximal at about 35 μM and respiration reached maximal levels about 1.5 minutes after CB addition. Respiratory stimulation was preceded by a transient increase in cytosolic cAMP. Sperm cAMP titers were elevated from 5 to 10 pmoles/108 cells within 30 seconds of CB addition, but rapidly dropped to a stable level of about 7.5 pmoles/108 cells. CB was a potent inhibitor of sperm membrane adenylyl cyclase and inhibited respiration in permeabilized cells. Taken together, the data indicated that CB stimulation was not manifested via the cytosol. In addition, a nonpermeant blue dextran preparation synthesized with CB also stimulated sperm respiration and motility. CB inhibited sperm membrane phosphodiesterase activity, suggesting that the transient pulse of cAMP resulted from CB interaction with this enzyme in the sperm membrane. © 1995 wiley-Liss, Inc. 相似文献
12.
Tizanidine, an alpha2-adrenergic receptor agonist with myospasmolytic action, is indicated for the treatment of back pain either as monotherapy or in combination with nonsteridal anti-inflammatory drugs (NSAIDs). Tizanidine (0.25-1.0 mg/kg) significantly produced analgesic and anti-inflammatory effect in acetic acid induced writhing in mice and carrageenan-induced paw edema in rats, respectively. The effects were comparable with clonidine (0.25 and 0.50 mg/kg), another alpha2-agonist. Yohimbine (1 mg/kg), alpha2-adrenergic antagonist reversed the effect of tizanidine. Tizanidine (0.25 mg/kg) and clonidine (0.25 mg/kg) significantly potentiated the antinociceptive and anti-inflammatory effect of NSAIDs (nimesulide, meloxicam and naproxen). Tizanidine (1 mg/kg) did not alter basal pH, acidity (free and total) of gastric content and did not produce any mucosal injury in fasted rats. Tizanidine (1 mg/kg) significantly reduced meloxicam (UD50 3.21 mg/kg), nimesulide (UD50 24.52 mg/kg) and naproxen (UD50 14.10 mg/kg)-induced ulcerogenic effect (ulcer index, pH and free/total acidity). It is expected that tizanidine exerted gastrotprotection through stimulation of gastric and central alpha2-adrenergic receptors. Present investigation suggested that tizanidine not only enhance the analgesic and anti-inflammatory effect of NSAIDs but also improved gatstrointestinal tolerability of NSAIDs through modulation of central alpha-2-receptors. From this study, it can be speculated that tizanidine and NSAID combination therapy would prove to be a novel approach to treat nociceptive/inflammatory conditions with improved gastric tolerability of NSAIDs. 相似文献
13.
Ryutaro Utsumi Manjiro Noda Makoto Kawamukai Tohru Komano 《FEMS microbiology letters》1988,50(2-3):217-221
Abstract An adenylate cyclase gene ( cya ) mutant was mutagenized and an adenosine 3,5-cyclic monophosphate (cAMP)-requiring mutant (KM8161) was obtained on Davis minimal medium containing glucose in the presence or absence of cAMP. KM8161 also required N -acetylglucosamine for its growth instead of cAMP. Furthermore, the mutant could use neither glucosamine nor N -acetylglucosamine as the carbon source. These results indicate that the cAMP-requiring property is due to multiple mutations of a few genes involved in amino sugar metabolism in addition to cya . By genetic analysis of KM8161, one gene, which was tentatively termed cidA and located near 2 min on the chromosomal map, proved to be defective. Reversion of cidA mutation in KM8161 resulted in recovery of not only the cAMP-requiring phenotype but also non-utilization of amino sugars. When both cAMP and N -acetylglucosamine or glucosamine were added to the culture medium for KM8161, only N -acetylglucosamine could be utilized as the carbon source. These studies s strongly suggest that the cidA or cya mutation in KM8161 causes deficiency in different stages of amino sugar metabolism and the regulatory circuit of growth by cAMP is mediated via control of N -acetylglucosamine metabolism. 相似文献
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Epac and PKA: a tale of two intracellular cAMP receptors 总被引:1,自引:0,他引:1
cAMP-mediated signaling pathways regulate a multitude of important biological processes under both physiological and pathological conditions, including diabetes, heart failure and cancer. In eukaryotic cells, the effects of cAMP are mediated by two ubiquitously expressed intracellular cAMP receptors, the classic protein kinase A (PKA)/cAMP-dependent protein kinase and the recently discovered exchange protein directly activated by cAMP (Epac)/cAMP-regulated guanine nucleotide exchange factors. Like PKA, Epac contains an evolutionally conserved cAMP binding domain that acts as a molecular switch for sensing intracellular second messenger cAMP levels to control diverse biological functions. The existence of two families of cAMP effectors provides a mechanism for a more precise and integrated control of the cAMP signaling pathways in a spatial and temporal manner. Depending upon the specific cellular environments as well as their relative abundance, distribution and localization, Epac and PKA may act independently, converge synergistically or oppose each other in regulating a specific cellular function. 相似文献
16.
Anchored cAMP signaling: Onward and upward – A short history of compartmentalized cAMP signal transduction 总被引:1,自引:1,他引:0
Intracellular signal transduction pathways require a high degree of spatial and temporal resolution in order to deliver the appropriate outputs. Specific signaling mediated by the ubiquitous second messenger cAMP and its effector, the cAMP-dependent protein kinase (PKA), is governed by the spatial organization of different pathway components by A-kinase anchoring proteins (AKAPs). This review discusses the history and future of anchored cAMP signaling pathways. 相似文献
17.
Lissandron V Terrin A Collini M D'alfonso L Chirico G Pantano S Zaccolo M 《Journal of molecular biology》2005,354(3):546-555
F?rster resonance energy transfer (FRET) technology has been used to develop genetically encoded fluorescent indicators for a variety of intracellular molecular events. Often, however, the poor dynamic range of such reporters prevents detection of subtle but physiologically relevant signals. Here we present a strategy for improving FRET efficiency between donor and acceptor fluorophores in a green fluorescent protein (GFP)-based protein indicator for cAMP. Such indicator is based on protein kinase A (PKA) and was generated by fusion of CFP and YFP to the regulatory and catalytic subunits of PKA, respectively. Our approach to improve FRET efficiency was to perform molecular dynamic simulations and modelling studies of the linker peptide (L11) joining the CFP moiety and the regulatory subunit in order to define its structure and use this information to design an improved linker. We found that L11 contains the X-Y-P-Y-D motif, which adopts a turn-like conformation that is stiffly conserved along the simulation time. Based on this finding, we designed a new linker, L22 in which the YPY motif was doubled in order to generate a stiffer peptide and reduce the mobility of the chromophore within the protein complex, thus favouring CFP/YFP dipole-dipole interaction and improving FRET efficiency. Molecular dynamic simulations of L22 showed, unexpectedly, that the conformational behaviour of L22 was very loose. Based on the analysis of the three principal conformational states visited by L22 during the simulation time, we modified its sequence in order to increase its rigidity. The resulting linker L20 displayed lower flexibility and higher helical content than L22. When inserted in the cAMP indicator, L20 yielded a probe showing almost doubled FRET efficiency and a substantially improved dynamic range. 相似文献
18.
Wengert M Adão-Novaes J Assaife-Lopes N Leão-Ferreira LR Caruso-Neves C 《Archives of biochemistry and biophysics》2007,467(2):261-267
In the present work, we demonstrate that adenine reduced Na+-ATPase activity in isolated basolateral membrane (BLM) of proximal tubule in a dose-dependent manner. Adenine metabolism was ruled out by TLC analysis of the potential [3H]adenine derived-metabolites. Specific binding of [3H]adenine to isolated BLM was observed in a dose-dependent manner with Kd and Bmax of 242.6 ± 27.6 nM and 2749.9 ± 104.9 fmol mg−1, respectively. Adenine increased the [35S]GTPγS specific binding and it was completely abolished by 10−6 M GDPβS (G protein inhibitor) but it was not modified by DPCPX, DMPX and MRS1523, selective antagonists for A1, A2 and A3 receptors, respectively. Furthermore, the inhibitory effect of adenine on the Na+-ATPase activity was blocked by 10−6 M GDPβS, 1 μg/ml pertussis toxin (Gi protein inhibitor), 10−6 M foskolin (adenylyl cyclase activator) and 10−8 M cAMP. These data demonstrate that adenine inhibits the proximal tubule Na+-ATPase activity through the Gi protein-coupled receptor. 相似文献
19.
Tribulova N Ravingerova T Okruhlicova L Gabauer I Fickova M Pancza D Slezak J Manoach M 《Molecular and cellular biochemistry》2000,210(1-2):75-80
Tedisamil is antiarrhythmic class III drug with antifibrillating/defibrillating potency linked to enhancement of intermyocyte gap junctional electrical coupling most likely via its sympathomimetic cAMP-related mechanisms. This study was designed to examin the effect of tedisamil on cAMP level in guinea pig hearts in vivo and in vitro in Langendorff preparation. The drug was administered either as a bolus into vena jugularis in dosage 1.0 and 1.5 mg/kg or into the perfusion solution at a concentration of 1.5 × 10-6 mol/l. In additional experiments, this period was followed by brief 10 min global ischemia, induced by clamping of the aorta or perfusion. After 10 min from the onset of tedisamil administration as well as after 10 min of ischemia the ventricular tissue was immediately frozen for cAMP immunoassay Tedisamil caused in normal heart small but significant dose-dependent increase of myocardial cAMP (pmol/mg) level in vivo 1.8 and 2.5 vs. 1.4 as well as in vitro 1.1 vs. 0.8 (p < 0.05) conditions. Ischemia itself induced accumulation of cAMP in both, in vitro and in vitro experiments, 2.6 vs. 1.4 and 1.3 vs. 0.8, respectively. The preischemic elevation of cAMP by tedisamil was not potentiated by following ischemia, on the contrary, decline of the cyclic nucleotide was detected comparing to ischemia itself. In conclusion, tedisamil increased cAMP level in normal heart and prevented additional ischemia-related elevation of this nucleotide. The results indicate modulation of myocardial cAMP level by tedisamil, which may account for its protective effect on gap junctional electrical coupling. 相似文献
20.
Silva IV Caruso-Neves C Azeredo IM Carvalho TL Lara LS de Mello MC Lopes AG 《Archives of biochemistry and biophysics》2002,406(2):183-189
In the present work we studied the modulation of the effect of urea on the renal (Na+ + K+)ATPase by cAMP. We observed that urea inhibits the (NA+ + K+)ATPase activity in a dose-dependent manner, reaching 60% of inhibition at the concentration of 1M. This effect was completely reversed by dibutyryl-cAMP (dBcAMP) at 5 x 10(-4)M. The effect of dBcAMP was mimicked by 50 units of the catalytic subunit of protein kinase A and completely abolished by 5 x 10(-7)M H89, an inhibitor of protein kinase A. Addition of 1M urea decreases basal phosphorylation of the immunoprecipitated (NA+ + K+)ATPase in 50%, with this effect completely reversed by 5 x 10(-4)M dBcAMP. Furthermore, 5 x 10(-4)M dBcAMP by itself induced (NA+ + K+)ATPase phosphorylation. Taken together these data indicate that cAMP could be, in addition to the organic solutes already known, an important physiological modulator of the deleterious effect of urea on enzyme activity. 相似文献