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1.
《Prostaglandins & other lipid mediators》1986,32(4):517-525
To study the precise mechanism of cytotoxic activity of PGD2 or Δ12-PGJ2 (a biological active metabolite of PGD2), we examined the effect of various compounds on PGD2 or Δ12-PGJ2 cytottoxic, using a human neuroblastoma cell line (NCG). Cycloheximide (CHM) specifically protected PGD2 cytotoxicity on NCG cells. When Δ12-PGJ2 was tested, CHM exhibited a similar rescue effect. Puromycin, mitomycin C, and α-amanitin did not affect PGD2 or Δ12-PGJ2 cytotoxicity. Emetine showed a variable and no consistent rescue effect CHM may have been active at the primary site where PGD2 or Δ12-PGJ2 exerts its cytotoxicity. This is the first report indicating that CHM reduces the cytotoxicity induced by PGD2 or Δ12-PGJ2. 相似文献
2.
We studied the effect of intracellular glutathione (GSH), which was known to conjugate readily with an α, β-unsaturated carbonyl of 9-deoxy-Δ9,12-13,14-dihydro PGD2 (Δ12-PGJ2), on the cytotoxicity of Δ12-PGJ2. Δ12-PGJ2 caused DNA fragmentation in human hepatocellular carcinoma Hep 3B cells, which was blocked by cycloheximide (CHX). The Δ12-PGJ2-induced apoptosis was augmented by GSH depletion resulted from pretreatment with buthioninine sulfoximine (BSO), an inhibitor of γ-glutamylcysteine synthetase. On the contrary, N-acetyl-cysteine (NAC), a precursor of cysteine, elevated the GSH level and protected cells from initiating apoptosis by Δ12-PGJ2. Sodium arsenite, a thiol-reactive agent, also induced apoptosis, which was potentiated or attenuated by BSO or NAC treatment respectively. These results suggest that the apoptosis-inducing activity of Δ12-PGJ2 is due to thiol-reactivity and intracellular GSH modulates the Δ12-PGJ2-induced apoptosis by regulating the accessibility of Δ12-PGJ2 to target proteins containing thiol groups. 相似文献
3.
We investigate the effect of the prostaglandin D2 metabolite Δ12−PGD2 (9−Deoxy−Δ9, Δ12−13,14-dihydroprostaglandin D2) on collagen synthesis in human osteoblast. Δ12-PGJ2 at 10−5M enhanced collagen synthesis in the presence of 2 mM α-glycerophosphate-2Na. The stimulative effect appeared as early as 3 days after addition and continued until 22 days. The enhancement of type I collagen synthesis was confirmed by polyacrylamide gel electrophoresis. The potency was the same as 101t-8M 1 α, 25 dihydroxy vitamine D3 (1,25(OH)2D3). Northern blot analysis showed that 10−5M Δ 12-PGD2 and 10−8M 1,25(OH)2D3 enhanced the transcribtion of type 1 procollagen (α1) mRNA levels in osteoblasts. 相似文献
4.
《Prostaglandins & other lipid mediators》1987,34(6):769-781
δ12-prostaglandin(PG)J2 (7.5μg/ml) significantly inhibited protein synthesis and cell growth in a human neuroblastoma cell line (NCG), decreasing these factors by 31.5% and 78.2% of the control values, respectively. Two protein synthesis inhibitors, cycloheximide (CHM)_and emetine, exhibited a dose-dependent protective effect for neuroblastoma cells against δ12-PCJ2 cytotoxicity. At a concentration of 15μ/ml CHM, the number of viable cells increased from 21.8% to 36.7% of the control value (p<0.01). The sodium dodecyl sulfate-polyacrylamide gel analysis of [35S]methionine-incorporated proteins revealed an increased synthesis of 86k, 70k and 66k proteins in the δ12-PGJ2-treated NCG cells under the condition that δ12-PGJ2 exerts cytotoxicity. Of these proteins, the amount of 66k protein was particularly increased in cell cytosol; however, its synthesis did not occur when CHM prohibited the δ12-PGJ2 cytotoxic effect. When emetine was used instead of CHM, similar results were obtained.These results strongly suggest that the 66k protein plays a critical role in the °12-PGJ2 cytotoxicity. 相似文献
5.
To study the precise mechanism of cytotoxic activity of PGD2 or delta 12-PGJ2 (a biologically active metabolite of PGD2), we examined the effect of various compounds on PGD2 or delta 12-PGJ2 cytotoxicity, using a human neuroblastoma cell line (NCG). Cycloheximide (CHM) specifically protected PGD2 cytotoxicity on NCG cells. When delta 12-PGJ2 was tested, CHM exhibited a similar rescue effect. Puromycin, mitomycin C, and alpha-amanitin did not affect PGD2 or delta 12-PGJ2 cytotoxicity. Emetine showed a variable and no consistent rescue effect CHM may have been active at the primary site where PGD2 or delta 12-PGJ2 exerts its cytotoxicity. This is the first report indicating that CHM reduces the cytotoxicity induced by PGD2 or delta 12-PGJ2. 相似文献
6.
A. Richard Whorton Jeffrey D. Lazar Murray D. Smigel John A. Oates 《Prostaglandins & other lipid mediators》1981,22(3):455-468
We have investigated the direct effects of prostaglandins E1, E2, F2α and D2 on renin release from rabbit renal cortical slices. Prostaglandin E1 (PGE1) was the most potent stimulant of renin release, while PGE2 was 20–30 fold less active. PGF2α was found not to be an inhibitor of renin release as reported by others, but rather a weak agonist. PGD2 up to a concentration of 10 μg/ml had no activity in this system. That the stimulation of renin release by PGE1 is a direct effect is supported by the finding that PGE1-induced release is not blocked by L-propranolol or by Δ5,8,11,14-eicosatetraynoic acid (ETYA), a prostaglandin synthesis is inhibitor. The fatty acid precursor of PGE1, Δ8,11,14-eicosatrienoic acid, also stimulated renin release, an effect which was blocked by ETYA. In addition to the above findings, ethanol, a compound frequently used to dissolve prostaglandins, was shown to inhibit renin release. 相似文献
7.
PGJ2 and Δ12PGJ2 (1 μM to 30 μm) inhibited the growth of human astrocytoma cells (1321N1) in a time-dependent manner within 48 hrs, determined by [3H]thymidine incorporation into acid-insoluble fraction or amounts of protein. The EC50 values for PGJ2 and Δ12PGJ2 were approximately 8 μM and 6 μM, respectively. [3H]Thymidine incorporation to acid insoluble fraction was inhibited by these PGs within 1 hr, indicating that these PGs rapidly affect cell functions. Although it has been reported that an increase in cyclic AMP inhibits cell growth, PGJ2 and Δ12PGJ2, but not PGE1, reduced isoproterenol (10 μM)-induced accumulation of cyclic AMP, suggesting that PGJ2 and Δ12PGJ2 may disturb adenylate cyclase system, which might be independent on cell growth. On the other hand, these PGs inhibited the incorporation of [3H]inositol into phospholipid fraction within 6 hrs. Furthermore, PGJ2 and Δ12PGJ2 inhibited carbachol- and/or histamine-induced accumulation of inositol phosphates with a similar dose-dependency to their inhibitions of cell growth. In membrane preparations, however, PGJ2 and Δ12PGJ2 failed to inhibit GTPγS (10 μM)- nor Ca2+ (1mM)-induced accumulation of inositol phosphate. The site of PGJ2 or Δ12PGJ2 in inhibition of inositol phosphate accumulation would not be phospholipase C nor a putative GTP binding protein involved in activation of phospholipase C. The present results indicate that PGJ2 and Δ12PGJ2 inhibit cell growth in human astrocytoma cells and the inhibition of phosphoinositide turnover by these PGs might be involved in the inhibition of cell growth. 相似文献
8.
Hiroya Tanaka Takao Yamamuro Manabu Matsumoto Yoshihiko Kotoura Chiaki Tanaka 《Prostaglandins & other lipid mediators》1985,30(1)
Effects of antineoplastic prostaglandins (PG), PGD2 and 9-deoxy-Δ9-PGD2, on colony formation of cloned Dunn osteosarcoma (TA 102), normal Swiss 3T3 and V-79 cell lines were evaluated. PGD2 significantly inhibited the colony formation of TA 102 cells in a dose-dependent manner at concentrations between 0.5 and 5 ug/ml. The IC50 value was calculated to be 0.72 ug/ml. A dose-dependent inhibition of TA 102 colony formation was also observed with 9-deoxy-Δ9-PGD2 between 0.01 to 1 ug/ml, the IC50 value being 0.22 ug/ml. These prostaglandins did not exert cytocidal effects in vitro on Swiss 3T3 cells at concentrations between 0.01 to 1 ug/ml. The two agents had no significant cytocidal effects on V-79 cells except for 9-deoxy-Δ9-PGD2 at a concentration of 5 ug/ml. These results suggest that PGD2 and 9-deoxy-Δ9-PGD2 are considered to have cytocidal activity on Dunn osteosarcoma cells in dosages which do not affect non-malignant cells. 相似文献
9.
Darhl Foreman Lydia Zuk Donald B. Miller Robert G. Salomon 《Prostaglandins & other lipid mediators》1987,34(1)
The effects of E2 levuglandins on the contractile activity of rat uterine horns were studied. LGE2, AnLGE2, Δ9-LGE2 and the synthetic epimer, 8-epi-Δ9-LGE2 all induced contractions in a dose-response fashion. AnLGE2 gave decreased response with increased bath concentrations. Paired comparision showed potent and selective inhibitory effects of AnLGE2 on the uterotonic activity of prostaglandins. An LGE2 inhibited the uterotonic activity of PGe2 at a 0.1:1 ratio, of PGD2 at 1:1 ratio, but did not inhibit the activity of PGF2α. Exposure of sponteneously contracting uteri to high concentrations of AnLGE2, or prolonged exposure to lower concentrations, suppressed contractions. 相似文献
10.
We studied the effect of intracellular glutathione (GSH), which was known to conjugate readily with an α, β-unsaturated carbonyl of 9-deoxy-Δ9,12-13,14-dihydro PGD2 (Δ12-PGJ2), on the cytotoxicity of Δ12-PGJ2. Δ12-PGJ2 caused DNA fragmentation in human hepatocellular carcinoma Hep 3B cells, which was blocked by cycloheximide (CHX). The Δ12-PGJ2-induced apoptosis was augmented by GSH depletion resulted from pretreatment with buthioninine sulfoximine (BSO), an inhibitor of γ-glutamylcysteine synthetase. On the contrary, N-acetyl-cysteine (NAC), a precursor of cysteine, elevated the GSH level and protected cells from initiating apoptosis by Δ12-PGJ2. Sodium arsenite, a thiol-reactive agent, also induced apoptosis, which was potentiated or attenuated by BSO or NAC treatment respectively. These results suggest that the apoptosis-inducing activity of Δ12-PGJ2 is due to thiol-reactivity and intracellular GSH modulates the Δ12-PGJ2-induced apoptosis by regulating the accessibility of Δ12-PGJ2 to target proteins containing thiol groups. 相似文献
11.
Avinash K. Kudva Naveen Kaushal Sonia Mohinta Mary J. Kennett Avery August Robert F. Paulson K. Sandeep Prabhu 《PloS one》2013,8(12)
Previous studies have demonstrated the ability of an eicosapentaenoic acid (EPA)-derived endogenous cyclopentenone prostaglandin (CyPG) metabolite, Δ12-PGJ3, to selectively target leukemic stem cells, but not the normal hematopoietic stems cells, in in vitro and in vivo models of chronic myelogenous leukemia (CML). Here we evaluated the stability, bioavailability, and hypersensitivity of Δ12-PGJ3. The stability of Δ12-PGJ3 was evaluated under simulated conditions using artificial gastric and intestinal juice. The bioavailability of Δ12-PGJ3 in systemic circulation was demonstrated upon intraperitoneal injection into mice by LC-MS/MS. Δ12-PGJ3 being a downstream metabolite of PGD3 was tested in vitro using primary mouse bone marrow-derived mast cells (BMMCs) and in vivo mouse models for airway hypersensitivity. ZK118182, a synthetic PG analog with potent PGD2 receptor (DP)-agonist activity and a drug candidate in current clinical trials, was used for toxicological comparison. Δ12-PGJ3 was relatively more stable in simulated gastric juice than in simulated intestinal juice that followed first-order kinetics of degradation. Intraperitoneal injection into mice revealed that Δ12-PGJ3 was bioavailable and well absorbed into systemic circulation with a Cmax of 263 µg/L at 12 h. Treatment of BMMCs with ZK118182 for 12 h resulted in increased production of histamine, while Δ12-PGJ3 did not induce degranulation in BMMCs nor increase histamine. In addition, in vivo testing for hypersensitivity in mice showed that ZK118182 induces higher airways hyperresponsiveness when compared Δ12-PGJ3 and/or PBS control. Based on the stability studies, our data indicates that intraperitoneal route of administration of Δ12-PGJ3 was favorable than oral administration to achieve effective pharmacological levels in the plasma against leukemia. Δ12-PGJ3 failed to increase histamine and IL-4 in BMMCs, which is in agreement with reduced airway hyperresponsiveness in mice. In summary, our studies suggest Δ12-PGJ3 to be a promising bioactive metabolite for further evaluation as a potential drug candidate for treating CML. 相似文献
12.
Treatment with prostaglandin (PG) D2 in concentrations (10−8 to 10−7 M) insufficient to alter the basal tone potentiated the contractile response of helical strips of dog mesenteric arteries to transmural electrical stimulation but did not influence the response to norepinephrine. The potentiating effect of PGD2 was not prevented by treatment with diphloretin phosphate, a PG antagonist, whereas contractions of dog cerebral arteries induced by PGD2 were suppressed. The 3H-overflow evoked by transmural stimulation in superfused mesenteric arterial strips previously soaked in 3H-norepinephrine containing media was significantly increased by PGD2. It is concluded that PGD2 increases the stimulation-evoked release of norepinephrine from adrenergic nerves innervating the arterial wall. PGD2 appears to act differently on receptive sites responsible for increasing the release of norepinephrine and for producing arterial contraction. 相似文献
13.
A method for the preparation of a highly purified sample of rabbit blood monocytes is described. The metabolism of arachidonic acid (AA) in these cells was studied. Mononuclear cells were prepared by centrifugation on Ficoll-Paque gradients and the monocytes were obtained by further centrifugation and adherence onto plastic culture dishes. These procedures provided a preparation which contained 95% monocytes (non-specific esterase positive). Incubation of [1-14C]-AA with these cells produced four major metabolites which were separated by TLC; these corresponded to prostaglandin (PG) D2, thromboxane (TX) B2, 12-hydroxyheptadecatrienoic acid (HHT) and 12-/15- hydroxyeicosatetraenoic acid (HETE). A minor product which co-migrated with PGE2 was also detected but neither 6-keto-PGF1α nor PGF2α were detected. Also, there was no evidence of the formation of 5-lipoxygenase products (5-HETE and LTB4) by rabbit monocytes with or without calcium-ionophore A23187-stimulation. The production of PGD2, TXB2 and PGE2 was further confirmed by analyzing [3H]-AA metabolites using high-performance liquid chromatography (HPLC) with tritiated standards as references. The biosynthesis of these compounds from endogenous substrate in A23187-stimulated monocytes was confirmed by specific radioimmunoassays with or without prior HPLC separation. The synthesis of immunoreactive LTB4 and LTC4 by A23187-stimulated cells was also monitored and found to be relatively low. The synthesis of PGD2, TXB2 and PGE2 from both exogenous and endogenous substrate was suppressed by treatment of the monocytes with indomethacin (10−6 M). 相似文献
14.
15.
Potential interactions between PGD2 and PGF2α in the mesenteric and renal vascular beds were investigated in the anesthetized dog. Regional blood flows were measured with electromagnetic flow probes. PGD2, PGF2α and Norepinephrine (NE) were injected as a bolus directly into the appropriate artery, and responses to these agents were obtained before, during and after infusion of either PGD2 or PGF2α into the left ventricle. In each case, the infused prostaglandin caused vascular effects of its own. Left ventricular infusion of PGD2 reduced responses to local injections of PGD2 in the intestine, and a similar effect was observed for PGF2α, suggesting significant receptor or receptor-like interactions for each of the prostanoids. However, systemic infusion of prostaglandin F2α (20–100 ng/kg/min) had no effect on renal or mesenteric vascular responses to local injection of prostaglandin D2. Similarly, PGD2 administration (100 ng/kg/min) did not affect responses to PGF2α in the intestine. The present results therefore suggest that these prostaglandins, i.e., D2 and F2α, act through separate receptors in the mesenteric and renal vascular beds. In addition, increased prostaglandin F2α levels produced by infusion of F2α reduced mesenteric but not renal blood flow, suggesting that redistribution of cardiac output might participate in side effects often observed with clinical use of this prostaglandin, such as nausea and abdominal pain. 相似文献
16.
Prostaglandin (PG) D3 has been identified as an inhibitor of human platelet aggregation, but little is known of the hemodynamic activity of this material. In morphine pretreated, chloralose-urethan anesthetized dogs, bolus intravenous injections (1, 3.2 and 10 μg/kg) of PGD3 and also PGD2 were associated with marked, dose-related increases in pulmonary arterial pressure. Cardiac index and rate increased, while peripheral vascular resistance decreased in response to injections of PGD3. A biphasic (depressor followed by a pressor phase) effect on systemic arterial pressure was observed after PGD2, while PGD3 was associated with dose-related depressor responses. Graded intravenous infusions (0.25, 0.50 and 1.0 μg/kg/min) of PGD3 and PGD2 were associated with qualitatively similar cardiovascular responses. Quantitatively, PGD3 infusions were associated with greater decreases in peripheral vascular resistance and greater increases in cardiac output, heart rate, and peak left ventricular dp/dt than were infusions of PGD2. In contrast, PGD3 was less potent than PGD2 as a pulmonary pressor material. Systemic arterial pressure responses to infusions of the prostaglandins were variable. In these experiments, PGD3 and PGD2 were associated with qualitatively similar cardiovascular responses characterized by peripheral vasodilatation. 相似文献
17.
Martin A. Wasserman Donald W. DuCharme Robert L. Griffin Gary L. DeGraaf Franklin G. Robinson 《Prostaglandins & other lipid mediators》1977,13(2):255-269
The effects of intravenously administered prostaglandin D2 (PGD2) on bronchopulmonary and cardiovascular functions were examined in the dog. PGD2 (0.03–1.0 μg/kg) was shown to be more active than PGF2α, a known bronchoconstrictor, in decreasing dynamic lung compliance, tidal volume, and expiratory airflow rate, as well as in elevating lung resistance. PGD2 demonstrated a potency approximately 4–6 times that of PGF2α on pulmonary mechanics. Atropine sulfate infusions reduced significantly the resistance and compliance responses to PGF2α, but only the resistance responses to PGD2, thereby suggesting that part of the bronchoconstrictor activities of these agents involved a cholinergic component.In another series of anesthetized dogs, PGD2 (0.1–10.0 μg/kg) increased pulmonary arterial pressure (comparable to PGF2α) and heart rate (greater than PGF2α, but less than PGE2), while concomitantly decreasing systemic arterial pressure in a dose-related manner (
that of PGE2). Qualitatively similar alterations in cardiovascular parameters were obtained for PGD2 in conscious dogs.Therefore, potent biologica activity of PGD2 has been shown in the dog. No physiologic or pathologic role for PGD2 has yet been demonstrated, but nonetheless, since it is a naturally occurring PG derived from arachidonic acid, further studies are warranted. 相似文献
18.
Effects of PGD2 and PGF2α on longitudinal and circular muscles of guinea-pig isolated proximal colon
The mechanical effects of PGD2 and PGF2α on longitudinal and circular muscles of the guinea-pig isolated proximal colon were investigated. PGD2 and PGF2α (1 nM – 10 μM) produced a dose-dependent contraction in longitudinal and circular muscles. The contractile action of PGD2 was more potent than that of PGF2α in circular muscle and was less potent in longitudinal muscle.Contractions induced by PGD2 or PGF2α(1 μM) were unaffected by atropine (1 μM) in both muscles, but tetrodotoxin (1 μM) slightly inhibited these contractions in longitudinal muscle.The results suggest that in longitudinal muscle PGD2 and PGF2α have largely a direct action on the muscle cells and a partial neuronal action on the non-cholinergic intrinsic nerves, whereas in circular muscle these PGs have only a direct action on the muscle cells. 相似文献
19.
John G. Gerber Robert A. Branch Alan S. Nies John F. Gerkens David G. Shand John Hollifield John A. Oates 《Prostaglandins & other lipid mediators》1978,15(1):81-88
The influence of intra-renal infusions of prostaglandin (PG) I2, PGE2 and PGD2 on renin secretion and renal blood flow was investigated in renally denervated, beta-adrenergic blocked, indomethacin treated dogs with unilateral nephrectomy. All three prostaglandins when infused at doses of 10−8 g/kg/min and 10−7 g/kg/min resulted in marked renal vasodilation. Renin secretory rates increased significantly with both PGI2 and PGE2 at the 10−8 g/kg/min and 10−7 g/kg/min infusion rates in a dose dependent manner. However, PGD2 was inactive. At 10−7 g/kg/min, PGI2 infusions resulted in systemic hypotension indicating recirculation of this prostaglandin. These findings suggest that PGI2 should be included among the cyclooxygenase derived metabolites of arachidonic acid to be considered as possible mediators of renin release. 相似文献
20.
J.L. Black C.L. Armour K.S. Vincenc P.R.A. Johnson 《Prostaglandins & other lipid mediators》1986,32(1)
Prostaglandins may be implicated in the bronchoconstriction which occurs in asthma. Prostaglandins F2α (PGF2α and D2 (PGD2) have been reported to produce bronchoconstriction in asthmatic subjects in vivo and PGF2α cotnracts human isolated airway smooth muscle. We examined the relative efficacy and potency of PGF2α and PGD2 on human bronchial spiral strips taken from 6 patients at thoracotomy. PGF2α had greater efficacy than PGD2. The mean % Tmax (percentage of maximal contractile response) ± s.e. mean were 84 ± 7 and 54 ±7 respectively (P < 0.05). PGF2α (mean pD2 ± s.e. mean = 6.39 ± 0.6) tended to be more potent than PGD2 (5.68 ± 0.2). Since, in vivo, PGD2 has greater efficacy and potency than PGF2α, our results suggest that the in vivo effect of these prostaglandins does not result solely from an action on airway muscle. 相似文献