共查询到20条相似文献,搜索用时 625 毫秒
1.
J. J. Benoliel† A. Mauborgne† S. Bourgoin J. C. Legrand† M. Hamon F. Cesselin† 《Journal of neurochemistry》1992,58(3):916-922
Possible interactions between Met-enkephalin and cholecystokinin (CCK)-containing neurons in the rat substantia nigra were investigated by looking for the effects of various opioid receptor ligands and inhibitors of enkephalin-degrading enzymes on the K(+)-evoked overflow of CCK-like material (CCKLM) from substantia nigra slices. The delta-opioid agonists D-Pen2, D-Pen5-enkephalin (50 microM) and Tyr-D-Thr-Gly-Phe-Leu-Thr (DTLET; 3 microM) enhanced, whereas the mu-opioid agonists Tyr-D-Ala-Gly-MePhe-Gly-ol (DAGO; 10 microM) and MePhe3, D-Pro4-morphiceptin (PL 017; 10 microM) decreased, the K(+)-evoked release of CCKLM. By contrast, the kappa-opioid agonist U-50488 H (5 microM) was inactive. The stimulatory effect of DTLET could be prevented by the delta antagonist ICI-154129 (50 microM), but not by the mu antagonist naloxone (1 microM). Conversely, the latter drug, but not ICI-154129, prevented the inhibitory effect of DAGO and PL 017. A significant increase in CCKLM overflow was observed upon tissue superfusion with the peptidase inhibitors kelatorphan or bestatin plus thiorphan. This effect probably resulted from the stimulation of delta-opioid receptors by endogenous enkephalins protected from degradation, because it could be prevented by ICI-154129 (50 microM). Furthermore the peptidase inhibitors did not enhance CCKLM release further when delta-opioid receptors were stimulated directly by DTLET (3 microM). These data indicate that opioids acting on delta and mu receptors may exert an opposite influence, i.e., excitatory and inhibitory, respectively, on CCK-containing neurons in the rat substantia nigra.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
2.
Eicosanoids mediate cellular and humoral immune responses in the beet armyworm, Spodoptera exigua, including activation of prophenoloxidase (PPO). PPO activation begins with release of its inactive zymogen, PPO, from oenocytoids in response to prostaglandins (PGs). Based on the biomedical literature, we hypothesized that PGs exert their actions via specific G protein-coupled receptor(s) in S. exigua. This study reports a G protein-coupled receptor (Se-hcPGGPCR1) gene, which is expressed in the hemocytes of S. exigua. The Se-hcPGGPCR1 consists of 420 amino acids and belongs to rhodopsin-type GPCRs. The high content of hydrophobic amino acid residues within the Se-hcPGGPCR1 protein is explained by prediction of seven-transmembrane domains that are characteristic of these GPCRs. Except for the eggs, Se-hcPGGPCR1 was expressed in all life stages. During the larval stage, it was expressed in hemocytes and gut, but not in fat body nor in epidermis. Real time quantitative RT-PCR showed that bacterial challenge induced more than 20-fold increases in its expression level. Fluorescence in situ hybridization showed that Se-hcPGGPCR1 was expressed in a specific hemocyte type, the oenocytoids. A specific eicosanoid, PGE2, significantly induced oenocytoid lysis and increased PO activity in the plasma. In contrast, when Se-hcPGGPCR1 expression was suppressed by RNA interference (RNAi), the oenocytoid lysis and the PO activation in response to PGE2 were not elevated above basal levels. A binding assay using intracellular calcium mobilization showed that the RNAi-treated hemocytes were significantly less responsive to PGE2 than the control hemocytes. These results support our hypothesis with the specific finding that PGE2 acts through Se-hcPGGPCR1 to activate PPO by lysing oenocytoids. 相似文献
3.
Prostaglandin E1 and E2 and 15(S)-15-methyl PGE2 methyl ester stimulate the accumulation of radioactive cyclic AMP in brain slices from Sprague-Dawley rats, labelled during a prior incubation with [14C] adenine. Prostaglandins A1 and B1 have marginal effects and prostaglandin F1α has no effect. Relatively high concentrations of about 80 μM PGE1, PGE2 and 15(S)-15-methyl PGE2 are required to elicit a maximal 2–5 fold increase in accumulation of cyclic AMP in slices from cerebrum, but significant increases are elicited by 3.5 μM prostaglandin. Similar increases are elicited in slices from neocortex, striatum or midbrain-thalamus-hypothalamus, while lesser increases pertain in slices from cerebellum, medulla-pons or hippocampus. The accumulation of cyclic AMP elicited by PGE1 in slices from cerebrum was not blocked by naloxone, propranololphentolamine, tetracaine, theophylline, or by nearly equimolar concentrations of either of two prostaglandin antagonists, 7-oxa-13-prostynoic acid and the dibenzoxazepine hydrazide, SC 19220. Morphine potentiated the effects of PGE1. The combination of 85 μM PGE1 with either isoproterenol, norepinephrine, adenosine or veratridin did not increase the accumulation of cycli AMP significantly above those elicited by the isoproterenol, norepinephrine, adenosine or veratridine alone. The combined effect of PGE1 and norepinephrine in the presence of a β-adrenergic antagonist, sotalol, was, however, additive. The results indicate that PGE1 stimulates cyclic AMP formation in rat brain slices, but that it either has antagonist activity with respect to accumulations of cyclic AMP-elicited by other agents or has no detectable agonist activity when cyclases are maximally stimulated by other agents. 相似文献
4.
Woller MJ Meyer S Ada-Nguema A Waechter-Brulla D 《Experimental biology and medicine (Maywood, N.J.)》2004,229(1):56-64
The control of reproductive function is manifested centrally through the control of hypothalamic release of gonadotropin-releasing hormone (GnRH) in episodic events or pulses. For GnRH release to occur in pulses, GnRH neurons must coordinate release events periodically to elicit a bolus of GnRH. We used a perifusion culture system to examine the release of GnRH from both intact hypothalami and enzymatically dispersed hypothalamic cells after challenge with GnRH analogs to evaluate the role of anatomical neuronal connections on autocrine/paracrine signals by GnRH on GnRH neurons. The potent GnRH agonist des-Gly(10)-D-Ala(6)-GnRH N-ethylamide, potent GnRH antagonists D-Phe(2)-D-Ala(6)-GnRH and D-Phe(2,6)-Pro(3)-GnRH or vehicle were infused, whereas GnRH release from hypothalamic tissue and cells were measured. PULSAR analysis of GnRH release profiles was conducted to evaluate parameters of pulsatile GnRH release. Infusion of the GnRH agonist resulted in a decrease in mean GnRH (P < 0.001), pulse nadir (P < 0.01), and pulse frequency (P < 0.05) but no effect on pulse amplitude. Infusion of GnRH antagonists resulted in an increase in mean GnRH (P < 0.001), pulse nadir (P < 0.05), and pulse frequency (P < 0.05) and in GnRH pulse amplitude only in dispersed cells (P < 0.05). These results are consistent with the hypothesis that GnRH inhibits endogenous GnRH release by an ultrashort-loop feedback mechanism and that treatment of hypothalamic tissue or cells with GnRH agonist inhibits ultrashort-loop feedback, whereas treatment with antagonists disrupts normal feedback to GnRH neurons and elicits an increased GnRH signal. 相似文献
5.
Using [3H]naloxone at a concentration of 4.5 nm , the potent opiate agonist etorphine as well as the potent antagonist diprenorphine displace only about 75% of specific naloxone binding P2 fractions from rat whole forebrain, without additive effect. Several other opiates and antagonists completely displace specific naloxone binding. This indicates that etorphine and diprenorphine specifically bind to one and the same naloxone binding site (type I) while leaving another naloxone binding site (type II) unaffected. Type I binding sites are much more thermo-labile than type II. [3H]Naloxone binding to type I sites is unaffected by incubation temperature in the range 10 to 25°C. while binding type II sites decreases rapidly with increasing incubation temperature, no specific type II binding being detectable at or above 20°C. The two naloxone receptor types also differ with respect to pH dependence, and affinity for naloxone with types I and II having affinity constants (Kd) of 2 and 16 nm , respectively, at 0°C. The two binding sites have different regional distributions with high relative levels of type II receptors in cerebellum and low relative levels in pons-medulla and striatum. In whole rat brain there are about 4 times as many type II receptors as type I. These results suggest that naloxone and several other opiate agonists and antagonists bind to two distinct receptor types which are probably not agonist/antagonist aspects of the same receptor. 相似文献
6.
Alpha-adrenergic receptors on human platelets. 总被引:4,自引:0,他引:4
[3H] dihydroergocyrptine, an α-adrenergic antagonist, binds specifically to sites on human platelet membranes. Prostaglandin E1 (PGE1) stimulates the production of cyclic AMP (cAMP) in human platelets. Alpha-adrenergic agonists, 1-epinephrine and 1-norepinephrine, and antagonists, phentolamine, phenoxybenzamine, and dihydroergocyrptine inhibit the binding of [3H] dihydroergocryptine. The α-adrenergic agonists inhibit PGE1-stimulated cAMP production and the α-adrenergic antagonists phentolamine and dihydroergocryptine reverse this inhibition. The β-adrenergic agonist 1-isoproterenol and the β-adrenergic antagonists d1-propranolol and 1-alprenolol do not significantly alter binding or PGE1-stimulated cAMP production. Clonidine, dopamine, and serotonin inhibit binding, but clonidine and dopamine are weak inhibitors of PGE1-stimulated cAMP production, and serotonin is without effect. Tyramine, an amine without direct adrenergic activity fails to inhibit binding. Alpha-adrenergic agonists decrease the apparent affinity of a PGE1-receptor activating cAMP production. The inhibition of PGE1-stimulated cAMP production is a physiological measure of α-adrenergic agonist binding to the α-receptor. 相似文献
7.
Masaki Inada Morichika Takita Satoshi Yokoyama Kenta Watanabe Tsukasa Tominari Chiho Matsumoto Michiko Hirata Yoshiro Maru Takayuki Maruyama Yukihiko Sugimoto Shuh Narumiya Satoshi Uematsu Shizuo Akira Gillian Murphy Hideaki Nagase Chisato Miyaura 《The Journal of biological chemistry》2015,290(50):29781-29793
The stromal cells associated with tumors such as melanoma are significant determinants of tumor growth and metastasis. Using membrane-bound prostaglandin E synthase 1 (mPges1−/−) mice, we show that prostaglandin E2 (PGE2) production by host tissues is critical for B16 melanoma growth, angiogenesis, and metastasis to both bone and soft tissues. Concomitant studies in vitro showed that PGE2 production by fibroblasts is regulated by direct interaction with B16 cells. Autocrine activity of PGE2 further regulates the production of angiogenic factors by fibroblasts, which are key to the vascularization of both primary and metastatic tumor growth. Similarly, cell-cell interactions between B16 cells and host osteoblasts modulate mPGES-1 activity and PGE2 production by the osteoblasts. PGE2, in turn, acts to stimulate receptor activator of NF-κB ligand expression, leading to osteoclast differentiation and bone erosion. Using eicosanoid receptor antagonists, we show that PGE2 acts on osteoblasts and fibroblasts in the tumor microenvironment through the EP4 receptor. Metastatic tumor growth and vascularization in soft tissues was abrogated by an EP4 receptor antagonist. EP4-null Ptger4−/− mice do not support B16 melanoma growth. In vitro, an EP4 receptor antagonist modulated PGE2 effects on fibroblast production of angiogenic factors. Our data show that B16 melanoma cells directly influence host stromal cells to generate PGE2 signals governing neoangiogenesis and metastatic growth in bone via osteoclast erosive activity as well as angiogenesis in soft tissue tumors. 相似文献
8.
Thein vivo effect of the mu agonist morphine and antagonist naloxone on [3H]nimodipine receptor binding in rat brain regions has been investigated. Morphine administration (15 mg/s.c.) for thirty minutes produced a 19% decrease in [3H]nimodipine receptor binding (B
max 158.2 fmol to 128.9 fmol) in cortex and 29% decrease in cerebellum (65.3 fmol to 46.0 fmol). Lesser changes were observed in hippocampal and striatal regions with no changes in hypothalamus and brain stem. All effects were completely antagonized by naloxone pretreatment (1 mg/kg). The studies suggest that opiates in vivo can alter [3H]nimodipine binding to the Ca2+ channel receptor protein. These findings agree with the previously observed decreases in Ca2+ influx in nerve ending preparations and inhibition of ICa
2+ following opiate treatment and suggest opiates reduce Ca2+-dependent neurotransmitter release by altering the Ca2+ channel receptor protein in an allosteric fashion. 相似文献
9.
Grozio A Millo E Guida L Vigliarolo T Bellotti M Salis A Fresia C Sturla L Magnone M Galatini A Damonte G De Flora A Bruzzone S Bagnasco L Zocchi E 《Biochemical and biophysical research communications》2011,(4):696-701
The phytohormone abscisic acid (ABA), in addition to regulating several important physiological functions in plants, is also produced and released by human granulocytes and monocytes where it stimulates cell activities involved in the innate immune response.Here we describe the properties of an ABA synthetic analog that competes with the hormone for binding to human granulocyte membranes and to purified recombinant LANCL2 (the human ABA receptor) and inhibits several ABA-triggered inflammatory functions of granulocytes and monocytes in vitro: chemotaxis, phagocytosis, reactive oxygen species production and release of prostaglandin E2 (PGE2) by human granulocytes, release of PGE2 and of monocyte chemoattractant protein-1 by human monocytes. This observation provides a proof of principle that ABA antagonists may represent a new class of anti-inflammatory agents. 相似文献
10.
《Prostaglandins & other lipid mediators》2007,82(3-4):150-161
Accumulating evidence suggests that COX-2-derived prostaglandin E2 (PGE2) plays an important role in esophageal adenocarcinogenesis. Recently, PGE2 receptors (EP) have been shown to be involved in colon cancer development. Since it is not known which receptors regulate PGE2 signals in esophageal adenocarcinoma, we investigated the role of EP receptors using a human Barrett's-derived esophageal adenocarcinoma cell line (OE33). OE33 cells expressed COX-1, COX-2, EP1, EP2 and EP4 but not EP3 receptors as determined by real time RT-PCR and Western-blot. Treatment with 5-aza-dC restored expression, suggesting that hypermethylation is involved in EP3 downregulation. Endogenous PGE2 production was mainly due to COX-2, since this was significantly suppressed with COX-2 inhibitors (NS-398 and SC-58125), but not COX-1 inhibitors (SC-560). Cell proliferation (3H-thymidine uptake) was significantly inhibited by NS-398 and SC-58125, the EP1 antagonist SC-51322, AH6809 (EP1/EP2 antagonist), and the EP4 antagonist AH23848B, but was not affected by exogenous PGE2. However, treatment with the selective EP2 agonist Butaprost or 16,16-dimethylPGE2 significantly inhibited butyrate-induced apoptosis and stimulated OE33 cell migration. The effect of exogenous PGE2 on migration was attenuated when cells were first treated with EP1 and EP4 antagonists. These findings suggest a potential role for EP selective antagonists in the treatment of esophageal adenocarcinoma. 相似文献
11.
Ting Zhang Zhenglan Han Xuerui Shi Weidong Zhao Zilong Wang Run Zhang Biao Xu Mengna Zhang Qinqin Zhang Jian Xiao Hanwen Zhu Ting Zheng Quan Fang 《Bioorganic & medicinal chemistry》2019,27(4):630-643
It is well known that opioid analgesics produce side effects including tolerance and constipation. Since neuropeptide FF (NPFF) receptor antagonists reversed opioid-induced hyperalgesia and analgesic tolerance, the present work was performed to synthetize two branched peptidomimetics, EKR and RKE, containing the opioid peptide endomorphin-2 (EM-2) and the NPFF receptor antagonist RF9. Our data obtained from the in vitro cyclic adenosine monophosphate experiment demonstrated that EKR functioned as a mixed mu-, delta-opioid receptors agonist and NPFF1 receptor antagonist/NPFF2 receptor partial agonist, whereas RKE acted as a multi-functional peptidomimetic with the mu-opioid agonism and the NPFF1 antagonism/NPFF2 partial agonism. Furthermore, EKR and RKE completely blocked the NPFF2 receptor-mediated neurite outgrowth of Neuro 2A cells. In vivo antinociception studies found that supraspinal administration of EKR and RKE dose-dependently produced potent antinociception via the mu-opioid receptor in the tail-flick test. In carrageenan inflammatory pain model, spinal administration of EKR and RKE induced dose-related analgesia, which was significantly reduced by the opioid antagonist naloxone and the NPFF antagonist RF9. Notably, compared with morphine, intracerebroventricular repeated administration of EKR and RKE maintained prolonged antinociceptive effectiveness. In addition, at the antinociceptive doses, these two branched peptidomimetics did not significantly inhibit gastrointestinal transit. Taken together, the present work suggest that EKR and RKE behave as multi-functional ligands with the opioid agonism and the NPFF1 antagonism/NPFF2 partial agonism, and produce prolonged antinociception with limited side effects. Moreover, our results imply that EKR and RKE might be interesting pharmacological tools for further investigating the biological function of the NPFF and opioid systems. 相似文献
12.
Abstract: The present article investigates chronic opioid regulation of the stimulatory adenylate cyclase-coupled prostaglandin E1 (PGE1) receptor system in neuroblastoma × glioma (NG108-15) hybrid cells. Persistent activation of δ-opioid receptors by morphine (10 µmol/L; 3 days) substantially down-regulates the number of PGE1 binding sites by ~30%, without affecting their affinity. Radioligand binding studies performed in the presence of GTPγS (100 µmol/L) further revealed that the remaining PGE1 binding sites are still capable of interacting functionally with their associated stimulatory G proteins, Gs. On the postreceptor level, neither changes in the abundance nor in the intrinsic activity of the α subunit of Gs (Gsα) were found during the state of opioid dependence, as has been verified by western blot and S49 cyc? reconstitution experiments, respectively. Evaluation of the functional interaction between PGE1 receptors and Gs by means of receptor-stimulated, cholera toxin-catalyzed ADP-ribosylation of Gsα revealed a significant increase in the ability of PGE1 receptors to activate Gsα (3.3-fold increase in EC50; p < 0.05) in cells chronically exposed to morphine. This effect was completely blocked by coincubation of the cells together with the opiate antagonist naloxone (100 µmol/L; 3 days), whereas precipitation of morphine withdrawal by naloxone (100 µmol/L) had no further effect on sensitization in PGE1 receptor/Gs coupling. These findings provide evidence that the stimulatory adenylate cyclase-coupled PGE1 receptor system represents a potential target of chronic δ-opioid receptor activation in NG108-15 hybrid cells. They further suggest that sensitization in stimulatory signal transduction plays a critical role in the generation of opioid dependence. 相似文献
13.
To evaluate the details of the adrenergic stimulation of urinary prostaglandins in man, ten normal volunteers were given various agonists and antagonists. The effect of 4 hour IV infusions of norepinephrine (NE), NE + phentolamine (PHT), NE + phenoxybenzamine (PHB), NE + prazosin (PZ), isoproterenol (ISO), and PHT alone on urinary PGE2 and PGI2 (6 keto PGF1α) were determined. PGE2 and 6 keto PGF1α were measured by radioimmunoassay from 4 hour urine samples. NE stimulated both PGE2 (196±40 to 370±84 ng/4 hrs/g creatinine and 6 keto PGF1α(184±30 to 326±36), both p<0.01. In contrast, ISO had no effect on either PGE2 or 6 keto PGF1α excretion. Alpha blockade with PHT. PHB, or PZ inhibited the NE induced systemic pressor effect. However, the effect of the alpha blockers on the NE induced stimulation of PGE2 and 6 keto PGF1α varied. PHT did not alter the NE stimulated PGE2 or 6 keto PGF1α release (370±84 vs. 381±80) PGE2 and (326±50 vs. 315±40) 6 keto PGF1α, both p>0.2). PHT alone stimulated only 6 keto PGF1α. PHB and the specific α1 antagonist PZ similarly eliminated the NE induced prostaglandin release. These results suggest that adrenergically mediated urinary prostaglandin release in man is via an alpha receptor with α1 characteristics. 相似文献
14.
VIP is more potent and produces a greater effect compared to PGE1 as a stimulant of fluid secretion in the rat jejunum. VIP-stimulated fluid secretion is inhibited by morphine in a dose-related fashion and naloxone antagonizes this inhibitory action of morphine, suggesting the effect is mediated by an opiate receptor. Pretreatment of rats with indomethacin and naloxone do not reveal prostaglandin or enkephalins respectively as tonic modulators of fluid transport. The possibility of a reflex release of enkephalins when challenged with a secretagogue was studied by the use of naloxone. The results indicate that VIP does not release an enkephalin-like substance, and there is no conclusive evidence of release by PGE1. 相似文献
15.
The release of the inhibitory amino acid taurine is markedly enhanced under ischemic conditions in both adult and developing
brain stem, together with a pronounced increase in the release of the neuromodulator adenosine. We now studied the effects
of adenosine receptor agonists and antagonists on [3H]taurine release in the brain stem in normoxia and ischemia, using a superfusion system. Under standard conditions, the adenosine
A1 receptor agonist N6-cyclohexyladenosine (CHA) potentiated basal taurine release in adult mice, which response was blocked by the antagonist 8-cyclopentyl-1,3-dipropylxanthine
(DPCPX). CHA and the A2a receptor agonist 2-p-(2-carboxyethyl)phenylamino-5′-N-ethylcarboxaminoadenosinehydrochloride (CGS 21680) had no effect on the release in developing mice. In ischemia, CHA depressed
both basal and K+-stimulated taurine release in developing mice in a receptor-mediated manner, blocked by DPCPX. The A2a receptor agonist CGS 21680 was also inhibitory. Taurine and adenosine may thus not cooperate in developing mice to prevent
ischemic neuronal damage. On the other hand, CGS 21680 enhanced taurine release in the adult brain stem in ischemia, both
basal and K+-stimulated release being affected. These effects were abolished by the antagonist 3,7-dimethyl-1-propargylxanthine (DMPX),
indicating a receptor-mediated process. In this case elevated levels of taurine could be beneficial, protecting against hyperexcitation
and excitotoxicity. 相似文献
16.
Using flow cytometry and sandwich-immunoenzyme assay, we showed that nicotinic acetylcholine receptors with a subunit α7 (nAChRs
α7) expressed in the outer mitochondrial membrane are involved in the control of mitochondria-dependent apoptosis. Pre-incubation
of the mitochondria with an nAChRs α7 agonist, choline, decreased dissipation of the membrane potential of these organelles
induced by the action of 0.5 mM hydrogen peroxide (H2O2) but did not influence the analogous effect of a high Ca2+ concentration (90 μM). Agonists of nAChRs α7 (choline, acetylcholine, and PNU 282987), or an inhibitor of voltage-dependent
anion channels, DIDS, prevented the release of cytochrome c from the intermembrane mitochondrial space under the action of H2O2. In contrast, an antagonist of nAChRs α7, methyllycaconitine, promoted the release of cytochrome c and prevented the effects of agonists. The obtained data confirm the active involvement of nAChRs α7 and voltage-dependent
anion channels in the process of formation of mitochondrial pores. In this case, agonists of mitochondrial nAChRs α7 subunits
exert an antiapoptotic effect, while antagonists of mitochondrial nAChRs α7 subunits manifest a proapoptotic action. 相似文献
17.
Niels H. Andersen Thomas L. Eggerman L. A. Harker Cynthia H. Wilson Biswanath De 《Prostaglandins & other lipid mediators》1980,19(5):711-735
Methods for the evaluation of competitive interactions at receptors associated with platelet activation and inhibition using aggregometry of human PRP have been developed. The evidence supports the suggestion that PGE1 and PGI2 share a common receptor for inhibition of platelet reactivity, but only a portion (if any) of the aggregation stimulation associated with PGE2 is the result of PGE2 binding (without efficacy) to this receptor. PGE2 (@.3–20 μ
) is an effective antagonist of PGE1, PGI2,
producing a shift of about one order of magnitude in the IC50-values obtained from complete aggregation inhibition dose response curves. The antagonism of PGD2 inhibition is particularly notable, 80 n
PGE2 levels are detectable. This and other actions of PGE2 indicate another platelet receptor for PGE2. PGE1 acts at both the PGE2 and PGI2 receptor. Other substances showing PGI2-like actions only at high doses (1–30 μ
), display additive responses with PGI2 indicative of decreased affinity for the I2/E1 receptor and the absence of PGE2-like aggregation stimulation activity.PGI2 methyl ester has intrinsic inhibitory action not associated with in situ ester hydrolysis. The methyl ester is dissaggregatory showing particular specificity for inhibition of release and second wave aggregation. 相似文献
18.
Xiao-Ming Bai Hui Jiang Jing-Xian Ding Tao Peng Juan Ma Yao-Hui Wang Li Zhang Hai Zhang Jing Leng 《Life sciences》2010,86(5-6):214-223
AimsCyclooxygenase-2 (COX-2)-controlled production of prostaglandin E2 (PGE2) has been implicated in cell growth and metastasis in many cancers. Recent studies have found that COX-2 is co-expressed with survivin in many cancers. Survivin is a member of the inhibitor-of-apoptosis protein family. Some COX-2 inhibitors (e.g., celecoxib) can reduce the expression of survivin. However, little is known about the mechanism of PGE2-mediated expression of survivin. This study was designed to uncover the effect of PGE2 on survivin expression in hepatocellular carcinoma cells.Main methodsThe effects of PGE2 and EP1 agonist on survivin expression were examined in HUH-7 and HepG2 cells. Plasmid transfection and EP1 siRNA were used to regulate the expression of COX-2 and the EP1 receptor protein.Key findingsPGE2 treatment increased survivin expression 2.3-fold. COX-2 overexpression resulted in a similar level of survivin upregulation. However, this effect was suppressed by treatment with celecoxib. EP1 receptor transfection or treatment with a selective EP1 agonist mimicked the effect of PGE2 treatment. Conversely, the PGE2-induced upregulation of survivin was blocked by treatment with a selective EP1 antagonist or siRNA against the EP1 receptor. The phosphorylation of EGFR and Akt were elevated in EP1 agonist-treated cells, and both EGFR and PI3K inhibitors suppressed the upregulation of survivin induced by PGE2 or EP1 agonist.SignificancePGE2 regulates survivin expression in hepatocellular carcinoma cells through the EP1 receptor by activating the EGFR/PI3K pathway. Targeting the PGE2/EP1/survivin signaling pathway may aid the development of new therapeutic strategies for both the prevention and treatment of this cancer. 相似文献
19.
Yutaka Shimizu Shizuka Mita Takashi Takeuchi Tatsuto Notsu Kiyoshi Mizuguchi Satoru Kyo 《Steroids》2011,76(1-2):60-67
Prostaglandin E2 (PGE2) is a major mediator in the pathophysiology, and pathogenesis of gynecological diseases associated with abnormal endometrial disease with proliferation and inflammation, such as endometriosis. In this study, we investigated the effect of dienogest, a selective progesterone receptor agonist, on PGE2 production and the expression of aromatase, an estrogen synthase, in human immortalized endometrial epithelial cells. Compared with monolayer culture, the cells showed enhanced PGE2 production and expression of the PGE2 synthases cyclooxygenase-2 (COX-2), and microsomal prostaglandin E2 synthase-1 (mPGES-1) in a spheroid culture system. Dienogest inhibited PGE2 production and this effect was reversed by RU486, a progesterone receptor antagonist. Dienogest inhibited the PGE2 synthases mRNA and protein expression, and the nuclear factor-κB activation. Moreover, the suppressive effect of dienogest on PGE2 production was sustained 24 h after the drug was withdrawn. Dienogest but not COX inhibitors inhibited aromatase expression. These results suggest that progesterone receptor activation reduces the gene expressions of COX-2, mPGES-1, and aromatase. Our findings suggest that the pharmacological mechanism of dienogest includes the direct inhibition of PGE2 synthase and aromatase expression and may contribute to the therapeutic effect on the progression of endometriosis. 相似文献
20.
Jia-Huey Yu Herbert Wells William J. Ryan Jr. Weldon S. Lloyd 《Prostaglandins & other lipid mediators》1976,12(4):501-513
Prostaglandins of the E-series (PGE1 and PGE2) may be involved in disease-related, localized loss of bone. E-prostaglandins increase the cyclic AMP content of many cells; and, to determine if their effects on bone are mediated by cyclic AMP, we examined the effects of E-prostaglandins and of other agents on the cyclic AMP content of cultured bone cells. PGE2 produced a rapid, marked and dose-related increase in the cyclic AMP content of confluent monolayers of bone cells isolated from newborn rat calvaria. At 2.8 × 10−6 M, PGE1 and PGE2 had approximately the same effect, while the effect of PGF2α was much less pronounced. In the presence of theophylline, PGE2 had a more marked effect than parathyroid hormone (PTH) and the combination of PGE2 and PTH had a synergistic effect. The divalent, cationic, ionophore, A23187, produced an increase in cellular cyclic AMP and had an additive effect in combination with PGE2. Synthetic salmon calcitonin (CT), which inhibits the bone resorptive effect of PGE2, increased cellular cyclic AMP and had an additive effect in combination with PGE2. A prostaglandin antagonist, SC-19220, partially inhibited the resorptive effect of PGE2 and reduced its effect on cellular cyclic AMP. The calcium antagonist, D600, inhibited the bone resorptive effects of PGE2 but had no effect on increased cellular cyclic AMP produced by PGE2.The marked effect of PGE2 on bone cell cyclic AMP suggests that this action is involved in the mechanism of PGE2-related bone loss. The fact that agents with different effects on PGE2-induced increases in cellular cyclic AMP can inhibit its resorptive actions, suggests that PGE2-induced changes in cyclic AMP may be related less to its resorptive actions than to its inhibitory effect on bone formation. 相似文献