scholarly journals Stimulation of Hepatic Apolipoprotein A-I Production by Novel Thieno-Triazolodiazepines: Roles of the Classical Benzodiazepine Receptor, PAF Receptor, and Bromodomain Binding

2013 ◽  
Vol 6 ◽  
pp. LPI.S13258 ◽  
Author(s):  
Herman J. Kempen ◽  
Daniel Bellus ◽  
Oleg Fedorov ◽  
Silke Nicklisch ◽  
Panagis Filippakopoulos ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Platelet Activating Factor ◽  
Benzodiazepine Receptor ◽  
Considerable Effect ◽  
Bet Inhibitor ◽  
Apolipoprotein A ◽  
Cultured Liver Cells ◽  
Paf Receptor ◽  
High Doses

Expression and secretion of apolipoprotein A-I (apoA-I) by cultured liver cells can be markedly stimulated by triazolodiazepines (TZDs). It has been shown previously that the thieno-TZD Ro 11-1464 increases plasma levels of apoA-I and in vivomacrophage reverse cholesterol transport in mice. However, these effects were only seen at high doses, at which the compound could act on central benzodiazepine (BZD) receptors or platelet activating factor (PAF) receptors, interfering with its potential utility. In this work, we describe 2 new thieno-TZDs MDCO-3770 and MDCO-3783, both derived from Ro 11-1464. These compounds display the same high efficacy on apoA-I production, metabolic stability, and lack of cytotoxicity in cultured hepatocytes as Ro 11-1464, but they do not bind to the central BZD receptor and PAF receptor. The quinazoline RVX-208 was less efficacious in stimulating apoA-I production and displayed signs of cytotoxicity. Certain TZDs stimulating apoA-I production are now known to be inhibitors of bromodomain (BRD) extra-terminal (BET) proteins BRDT, BRD2, BRD3, and BRD4, and this inhibition was inferred as a main molecular mechanism for their effect on apoA-I expression. We show here that the thieno-TZD (+)-JQ1, a potent BET inhibitor, strongly stimulated apoA-I production in Hep-G2 cells, but that its enantiomer (-)-JQ1, which has no BET inhibitor activity, also showed considerable effect on apoA-I production. MDCO-3770 and MDCO-3783 also inhibited BRD3 and BRD4 in vitro, with potency somewhat below that of (+)-JQ1. We conclude that the effect of thieno-TZDs on apoA-I expression is not due to inhibition of the BZD or PAF receptors and is not completely explained by transcriptional repression by BET proteins.

scholarly journals An Antagonistic Activity of Etizolam on Platelet-Activating Factor (PAF) In Vitro Effects on Platelet Aggregation and PAF Receptor Binding

1987 ◽  
Vol 44 (4) ◽  
pp. 387-391
Author(s):  
Hiroshi MIKASHIMA ◽  
Shüzö TAKEHARA ◽  
Yoshito MURAMOTO ◽  
Takako KHOMARU ◽  
Michio TERASAWA ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Receptor Binding ◽  
Platelet Activating Factor ◽  
Antagonistic Activity ◽  
Paf Receptor ◽  
In Vitro Effects

scholarly journals Metabolic effects of platelet-activating factor in rats in vivo. Stimulation of hepatic glycogenolysis and lipogenesis

1990 ◽  
Vol 269 (1) ◽  
pp. 269-272 ◽  
Author(s):  
R D Evans ◽  
V Ilic ◽  
D H Williamson
Keyword(s):  
Platelet Activating Factor ◽  
Hepatic Metabolism ◽  
Isolated Hepatocytes ◽  
Metabolic Effects ◽  
Hepatic Glycogen ◽  
Dose Dependent Fashion ◽  
Paf Receptor ◽  
High Doses ◽  
Stimulation Of

1. The effects of platelet-activating factor (1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphocholine; PAF) on hepatic metabolism in vivo in rats were studied. 2. PAF stimulated synthesis of hepatic lipid (saponified and non-saponified) in a dose-dependent fashion and caused hypertriglyceridaemia. There was no effect of PAF on lipogenesis in isolated hepatocytes. 3. High doses of PAF also decreased hepatic glycogen. 4. All doses of PAF decreased plasma insulin, and this was accompanied by hyperglycaemia, except at the lowest dose. 5. The selective PAF-receptor antagonist L659.989 prevented the stimulation of lipogenesis, but indomethacin did not.

Platelet-activating factor stimulates lung pericyte growth in vitro

1996 ◽  
Vol 270 (2) ◽  
pp. L298-L304 ◽  
Author(s):  
J. Khoury ◽  
D. Langleben
Keyword(s):  
Distress Syndrome ◽  
Thymidine Incorporation ◽  
Platelet Activating Factor ◽  
In Vitro Growth ◽  
Rat Lung ◽  
Pulmonary Vessel ◽  
Control Growth ◽  
Paf Receptor

Platelet-activating factor (PAF) is released from activated leukocytes and endothelial cells in sepsis, lung injury, and the adult respiratory distress syndrome. With these disorders, pulmonary hypertension develops, partly due to muscularization of the microvasculature by proliferation of pericytes. PAF may be a mediator of this process. Therefore, we examined the effects of PAF on in vitro growth of rat lung pericytes. Compared with control growth, semisynthetic PAF (10(-9) M) stimulated the 7-day mean growth of proliferating pericytes by 31% in medium with serum and 29% without serum and of previously growth-arrested pericytes by 12% with serum and 23% without serum. These effects were blocked by the PAF-receptor blocker CV-3988. PAF also increased [3H]thymidine incorporation into pericytes by 79%. Synthetic 16:0 PAF stimulated pericyte growth, but 18:0 PAF did not. PAF exposure did not induce apoptosis in pericytes. Thus PAF compounds, similar to those found in vivo, stimulate lung pericyte growth in vitro. PAF may act as a direct cytokine on cells involved in muscularization of the pulmonary vessel walls.

Hydroxysafflor yellow A (HSYA) targets the platelet-activating factor (PAF) receptor and inhibits human bronchial smooth muscle activation induced by PAF

2019 ◽  
Vol 10 (8) ◽  
pp. 4661-4673 ◽  
Author(s):  
Xinjing Guo ◽  
Meng Zheng ◽  
Ruiyan Pan ◽  
Baoxia Zang ◽  
Jianwei Gao ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Activation ◽  
Platelet Activating Factor ◽  
Muscle Cells ◽  
Hydroxysafflor Yellow A ◽  
Bronchial Smooth Muscle ◽  
Paf Receptor ◽  
Bronchial Smooth Muscle Cells

HSYA suppressed the activation of human bronchial smooth muscle cells induced by platelet activating factor (PAF) in vitro by targeting the PAFR.

scholarly journals Paf receptor expression in the marsupial embryo and endometrium during embryonic diapause

Reproduction ◽  
2014 ◽  
Vol 147 (1) ◽  
pp. 21-31 ◽  
Author(s):  
Jane C Fenelon ◽  
Geoff Shaw ◽  
Chris O'Neill ◽  
Stephen Frankenberg ◽  
Marilyn B Renfree
Keyword(s):  
Platelet Activating Factor ◽  
Tammar Wallaby ◽  
Receptor Expression ◽  
Limiting Factor ◽  
Embryonic Diapause ◽  
Paf Receptor ◽  
Sequential Activation ◽  
Uterine Environment ◽  
Low Levels

The control of reactivation from embryonic diapause in the tammar wallaby (Macropus eugenii) involves sequential activation of the corpus luteum, secretion of progesterone that stimulates endometrial secretion and subsequent changes in the uterine environment that activate the embryo. However, the precise signals between the endometrium and the blastocyst are currently unknown. In eutherians, both the phospholipid Paf and its receptor, platelet-activating factor receptor (PTAFR), are present in the embryo and the endometrium. In the tammar, endometrial Paf releasein vitroincreases around the time of the early progesterone pulse that occurs around the time of reactivation, but whether Paf can reactivate the blastocyst is unknown. We cloned and characterised the expression of PTAFR in the tammar embryo and endometrium at entry into embryonic diapause, during its maintenance and after reactivation. Tammar PTAFR sequence and protein were highly conserved with mammalian orthologues. In the endometrium, PTAFR was expressed at a constant level in the glandular epithelium across all stages and in the luminal epithelium during both diapause and reactivation. Thus, the presence of the receptor appears not to be a limiting factor for Paf actions in the endometrium. However, the low levels of PTAFR in the embryo during diapause, together with its up-regulation and subsequent internalisation at reactivation, supports earlier results suggesting that endometrial Paf could be involved in reactivation of the tammar blastocyst from embryonic diapause.

Exogenous platelet-activating factor stimulates cell proliferation in mouse pre-implantation embryos prior to the fourth cell cycle and shows isoform-specific stimulatory effects

Zygote ◽  
2001 ◽  
Vol 9 (3) ◽  
pp. 261-268 ◽  
Author(s):  
Neil R. Stoddart ◽  
William E. Roudebush ◽  
Steven D. Fleming
Keyword(s):  
Cell Proliferation ◽  
Biological Activities ◽  
Platelet Activating Factor ◽  
Cell Number ◽  
Blastocyst Stage ◽  
Embryonic Cell ◽  
Cell Stage ◽  
Cell Numbers ◽  
Paf Receptor

Mouse embryos secrete molecules homologous to platelet-activating factor (PAF), termed embryo-derived PAF (EPAF), which act in an autocrine/paracrine fashion to stimulate embryonic development in vitro. Mouse EPAF is thought to consist predominantly of hexadecyl (C16) and octadecyl (C18) PAF-like components. Mouse pre-implantation embryos cultured with exogenous PAF from the early cleavage stages exhibit increased blastocyst cell numbers and rates of mitosis around the 8-cell stage. We investigated whether exogenous PAF could specifically stimulate embryonic cell proliferation prior to the blastocyst stage in the mouse and also compared the biological activities of the C16 and C18 PAF isoforms as follows. Embryos were cultured for either 24 h or 120 h from the 2-cell stage and their total cell numbers were determined or their development assessed in terms of their incidence of successful zona-hatching respectively. In each case, embryos were cultured in unsupplemented medium or in medium supplemented with either C16 or C18 PAF (0.5 μM). Compared with controls, culture with C16 PAF produced a significant stimulation of mean total per number per embryo and a significant increase in the incidence of successful zona-hatching, whilst culture with C18 PAF had no significant effect. We then cultured 1-cell zygotes for 48 h in unsupplemented medium or medium supplemented with either an equimolar mixture of C16 and C18 PF or with either C16 or C18 PF alone (each at 0.2 μM). Embryos were also scored for cell number at 4 h and 30 h of culture. Although no significant effect on mean cell number per embryo was seen following 4 h or 30 h of culture with a mixed C16/C18 PAF preparation, culture for 48 h with a mixed C16/C18 PAF preparation or with C16 PAF alone produced a significant increase in mean cell number per embryo compared with controls - an effect that is likely to be receptor-mediated, since culture with an equivalent concentration of C18 PAF had no significant effect compared with controls. We have demonstrated that mouse zygotes/embryos can respond in a specific manner to exogenous hexadecyl PAF in terms of increased rates of cell proliferation prior to cavitation, and must be capable of doing so at some time between the first and third, and also between the second and fourth, cell cycles. Such embryos presumably express one or more classes of functional PAF-receptor molecule during this period (i.e. as early as during the 1-, 2- or 4-cell stages). We have also demonstrated that embryonic response to exogenous PAF is significantly isoform-specific, which may reflect differences between the two isoforms either in affinity for binding to putative embyronic PAF-receptor molecules or in their ability to elicit a stimulatory response following binding. This observation calls into question the use of preparations containing a mixture of hexadecyl and octadecyl PAF isoforms, particularly in dose-response studies, in the mouse.

scholarly journals An antagonistic activity of etizolam on platelet-activating factor(PAF). In vitro effects on platelet aggregation and PAF receptor binding.

1987 ◽  
Vol 44 (4) ◽  
pp. 387-391 ◽  
Author(s):  
Hiroshi MIKASHIMA ◽  
Shuzo TAKEHARA ◽  
Yoshito MURAMOTO ◽  
Takako KHOMARU ◽  
Michio TERASAWA ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Receptor Binding ◽  
Platelet Activating Factor ◽  
Antagonistic Activity ◽  
Paf Receptor ◽  
In Vitro Effects

scholarly journals Platelet-Activating Factor Receptor Blockade Ameliorates Aggregatibacter actinomycetemcomitans-Induced Periodontal Disease in Mice

2013 ◽  
Vol 81 (11) ◽  
pp. 4244-4251 ◽  
Author(s):  
Mila Fernandes Moreira Madeira ◽  
Celso Martins Queiroz-Junior ◽  
Graciela Mitre Costa ◽  
Silvia Maria Cordeiro Werneck ◽  
Daniel Cisalpino ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Periodontal Disease ◽  
Alveolar Bone ◽  
Platelet Activating Factor ◽  
Aggregatibacter Actinomycetemcomitans ◽  
Content Type ◽  
Periodontal Tissues ◽  
Oral Inoculation ◽  
Paf Receptor

ABSTRACTPeriodontal disease (PD) is a chronic inflammatory and alveolar bone destructive disease triggered by oral biofilm-producing microorganisms, such asAggregatibacter actinomycetemcomitans. The levels of the phospholipid platelet-activating factor (PAF) in the saliva, gingival crevicular fluid, and periodontal tissues are significantly increased during inflammatory conditions, such as PD, but the exact mechanism that links PAF to alveolar bone resorption is not well understood. In the current study, alveolar bone resorption was induced by experimental PD through the oral inoculation ofA. actinomycetemcomitansin wild-type (WT) and PAF receptor knockout (Pafr−/−) mice.In vitroexperiments usingA. actinomycetemcomitanslipopolysaccharide (LPS)-stimulated RAW 264.7 cells treated with a PAF receptor antagonist (UK74505) were also performed. The expression of lyso-PAF acetyltransferase in periodontal tissues was significantly increased 3 h afterA. actinomycetemcomitansLPS injection in mice. WT andPafr−/−mice that were subjected to oral inoculation ofA. actinomycetemcomitanspresented neutrophil accumulation and increased levels of CXCL-1 and tumor necrosis factor alpha (TNF-α) in periodontal tissues. However,Pafr−/−mice presented less alveolar bone loss than WT mice. Thein vitroblockade of the PAF receptor impaired the resorptive activity ofA. actinomycetemcomitansLPS-activated osteoclasts. In conclusion, this study shows for the first time that the blockade of PAF receptor may contribute to the progression of PD triggered byA. actinomycetemcomitansby directly affecting the differentiation and activity of osteoclasts.

Sign in / Sign up

Export Citation Format

Share Document