Administration Of PGE2 Research Articles

Effect of intrafollicular administration of PGE2 or PGF2α in early estrus on ovulation, hemorrhagic anovulatory follicles formation, progesterone secretion and pregnancy outcome in the mare

This experiment was performed to evaluate whether intrafollicular treatment of PGE2 or PGF2α administered in early estrus would induce normal ovulation, progesterone production (Experiment 1) and pregnancy (Experiment 2). In Experiment 1, mares in estrus after 2 days of endometrial edema were injected in all largest dominant follicles (28–35 mm in diameter) with 0.5 mL of sterile water containing 500 μg PGE2 (n = 6), 125 μg PGF2α (n = 6) or placebo (n = 7) (Hour 0). Ultrasound examinations were performed daily, until ovulation or anovulation was detected, and daily blood samples were taken for 8 days. In Experiment 2, mares with a dominant follicle ≥35 mm after at least three days of slight-to-moderate endometrial edema, were injected with 500 μg PGE2 diluted in 0.5 mL of sterile water for injection in the follicle (PGE2 group; n = 9 mares and 11 dominant follicles). No puncture was performed in the control group (n = 9 mares and 11 dominant follicles). Mares from both groups were inseminated. In Experiment 1, all mares (6/6) in the PGE2 group ovulated within 24 h of treatment. The mean interval from intrafollicular injection to ovulation was shorter (P < 0.001) in PGE2 mares (24 ± 0 h) than in control mares (77 ± 9 h). Mares from the PGF2α group developed hemorrhagic anovulatory follicles (HAF) more often (7/7) than control mares (2/7); P < 0.05). The progesterone concentration in mares from the PGF2α group was lower (P < 0.004) than control mares in the early post-ovulatory period. The first significant increase in post-ovulatory progesterone concentration occurred earlier (P < 0.05) in mares from the control group than in mares from the PGF2α and PGE2 groups. In Experiment 2, more mares from the control group (7/9, 78 %) became pregnant than from the PGE2 group (2/9, 22 %) (P = 0.015). In conclusion, PGE2 alone induced follicle collapse in all treated mares within 24 h of administrations, while PGF2α blocked ovulation and induced formation of HAFs. However, the post-ovulatory rise in progesterone production was delayed and the fertility reduced in mares with ovulation induced by PGE2 compared to control mares.

Mating behaviors in ovoviviparous black rockfish (Sebastes schlegelii): molecular function of prostaglandin E2 as both a hormone and pheromone.

The online version contains supplementary material available at 10.1007/s42995-023-00214-w.

Twice-daily versus once-daily vaginal dinoprostone gel for induction of labor at term: A randomized controlled trial

ObjectiveThe aim of this study was to compare twice-daily versus once-daily administration of intravaginal PGE2 for induction of labor at term. Efficacy, safety, and patient satisfaction were evaluated. Study designFor this single-center, randomized, comparative, open-label, two-arm, and parallel study, pregnant women with term singleton live pregnancies ≥ 37 weeks of gestation, medical indications for induction of labor, and Bishop score ≤ 6 were randomized to either the control group (induction of labor with PGE2 gel with repeat dose after 24 h) or the experimental group (repeat dose after 12 h). The primary outcome was induction-to-delivery interval time. Secondary outcomes were maternal and neonatal outcomes and patient satisfaction. ResultsIn total, 246 women were randomized to the control (n = 121) or experimental groups (n = 125). The mean time for initiation of induction to delivery was 9.4 h shorter in the experimental group compared to controls (p = 0.007). For control vs experimental, there were no differences in tachysystole (19/121, 15.7 % vs 21/124, 16.9 %, respectively; p = 0.79), cesarean section rate (18/121, 14.9 % vs 28/124, 22.6 % respectively; p = 0.12), or other main obstetrical or neonatal outcomes. Patients in the experimental group reported higher satisfaction with their induction (48/96, 50 % with once-daily vs 60/86, 69.8 % with twice-daily; p = 0.010). ConclusionAmong women admitted for induction of labor at term, closer interval of vaginal PGE2 administration was associated with a significantly shorter induction-to-delivery time without increasing maternal or neonatal morbidity. Furthermore, the reduction in induction time was associated with improved patient experience of delivery.

Epithelial presenilin-1 drives colorectal tumour growth by controlling EGFR-COX2 signalling

ObjectivePsen1 was previously characterised as a crucial factor in the pathogenesis of neurodegeneration in patients with Alzheimer’s disease. Little, if any, is known about its function in the gut. Here,...

Mechanical Methods for the Induction of Labour After Previous Caesarean Section - An Updated, Evidence-based Review.

There are currently no up-to-date evidence-based recommendations on the preferred method to induce labour after previous Caesarean section, especially for patients with unripe cervix, as randomised controlled studies are lacking. Intravenous oxytocin and misoprostol are contraindicated in these women because of the high risk of uterine rupture. In women with ripe cervix (Bishop Score > 6), intravenous administration of oxytocin is an effective procedure with comparable rates of uterine rupture to those with spontaneous onset of labour. Vaginal prostaglandin E 2 (PGE 2 ) and mechanical methods (balloon catheters, hygroscopic cervical dilators) are effective methods to induce labour in pregnant women with unripe cervix and previous Caesarean section. According to current guidelines, the administration of PGE 2 is associated with a higher rate of uterine rupture compared to balloon catheters. Balloon catheters are therefore a suitable alternative to PGE 2 to induce labour after previous Caesarean section, even though this is an off-label use. In addition to two meta-analyses published in 2016, 12 mostly retrospective cohort/observational studies with low to moderate levels of evidence have been published on mechanical methods of cervical ripening after previous Caesarean section. But because of the significant heterogeneity of the studies, substantial differences in study design, and insufficient numbers of pregnant women included in the studies, it is not possible to make any evidence-based recommendations based on these studies. According to a recent meta-analysis, the average rate using balloon catheters is approximately 53% and the average rate after spontaneous onset of labour is 72%. The uterine rupture rate was 0.2–0.9% for vaginal PGE 2 and 0.56–0.94% for balloon catheters and is therefore comparable to the uterine rupture rate associated with spontaneous onset of labour. According to the product informations, hygroscopic cervical dilators (Dilapan-S) are currently the only method which is not contraindicated for cervical ripening/induction of labour in women with previous Caesarean section, although data are insufficient. Well-designed, randomised, controlled studies with sufficient case numbers comparing balloon catheters and hygroscopic cervical dilators with mechanical methods and vaginal prostaglandin E 2 /oral misoprostol are therefore necessary to allow proper decision-making.

The Effects of Prostaglandin E2 Treatment on the Secretory Function of Mare Corpus Luteum Depends on the Site of Application: An in vivo Study.

We examined the effect of prostaglandin (PG) E2 on the secretory function of equine corpus luteum (CL), according to the application site: intra-CL injection vs. an intrauterine (intra-U) administration. Moreover, the effect of intra-CL injection vs. intra-U administration of both luteotropic factors: PGE2 and human chorionic gonadotropin (hCG) as a positive control, on CL function was additionally compared. Mares were assigned to the groups (n = 6 per group): (1) an intra-CL saline injection (control); (2) an intra-CL injection of PGE2 (5 mg/ml); (3) an intra-CL injection of hCG (1,500 IU/ml); (4) an intra-U saline administration (control); (5) an intra-U administration of PGE2 (5 mg/5 ml); (6) an intra-U administration of hCG (1,500 IU/5 ml). Progesterone (P4) and PGE2 concentrations were measured in blood plasma samples collected at −2, −1, and 0 (pre-treatment), and at 1, 2, 3, 4, 6, 8, 10, 12, and 24 h after treatments. Moreover, effects of different doses of PGE2 application on the concentration of total PGF2α (PGF2α and its main metabolite 13,14-dihydro-15-keto-prostaglandin F2α– PGFM) was determined. The time point of PGE2, hCG, or saline administration was defined as hour “0” of the experiment. An intra-CL injection of PGE2 increased P4 and PGE2 concentrations between 3 and 4 h or at 3 and 12 h, respectively (p < 0.05). While intra-U administration of PGE2 elevated P4 concentrations between 8 and 24 h, PGE2 was upregulated at 1 h and between 3 and 4 h (p < 0.05). An intra-CL injection of hCG increased P4 concentrations at 1, 6, and 12 h (p < 0.05), while its intra-U administration enhanced P4 and PGE2 concentrations between 1 and 12 h or at 3 h and between 6 and 10 h, respectively (p < 0.05). An application of PGE2, dependently on the dose, supports equine CL function, regardless of the application site, consequently leading to differences in both P4 and PGE2 concentrations in blood plasma.

Connexin hemichannels with prostaglandin release in anabolic function of bone to mechanical loading.

Mechanical stimulation, such as physical exercise, is essential for bone formation and health. Here, we demonstrate the critical role of osteocytic Cx43 hemichannels in anabolic function of bone in response to mechanical loading. Two transgenic mouse models, R76W and Δ130-136, expressing dominant-negative Cx43 mutants in osteocytes were adopted. Mechanical loading of tibial bone increased cortical bone mass and mechanical properties in wild-type and gap junction-impaired R76W mice through increased PGE2, endosteal osteoblast activity, and decreased sclerostin. These anabolic responses were impeded in gap junction/hemichannel-impaired Δ130-136 mice and accompanied by increased endosteal osteoclast activity. Specific inhibition of Cx43 hemichannels by Cx43(M1) antibody suppressed PGE2 secretion and impeded loading-induced endosteal osteoblast activity, bone formation and anabolic gene expression. PGE2 administration rescued the osteogenic response to mechanical loading impeded by impaired hemichannels. Together, osteocytic Cx43 hemichannels could be a potential new therapeutic target for treating bone loss and osteoporosis.

Total ginsenosides promote the IEC-6 cell proliferation via affecting the regulatory mechanism mediated by polyamines

Epithelial cell proliferation has been demonstrated to be a critical modality for mucosal repair after gastrointestinal mucosal injury. This research aimed to investigate the effect of total ginsenosides upon the proliferation of intestinal epithelial cells (IEC-6), and elucidate its potential mechanisms through polyamine-regulated pathway including the expression of proliferation-related proteins. Total ginsenosides (PGE3) were extracted from Panax ginseng, a Chinese herbal medicine, whose chromatogram was obtained by high performance liquid chromatographic method with evaporative light scattering detection (HPLC-ELSD). The cell proliferation, cell cycle distribution and the level of c-Myc, RhoA, Cdk2 proteins were detected to determine the effects of PGE3 at 25, 50 and100 mg/l doses on IEC-6. Furthermore, rats model of intestinal mucosal injury were induced by the subcutaneous injection of indomethacin, and the effect of Panax ginseng aqueous extracts (PGE1) on intestinal mucosal injury was observed. PGE3 could promote IEC-6 cell proliferation, reduce the proportion of G0/G1 phase cells and elevate the proportion of G2/M + S phase cells, and revert the proliferation and cell cycle arrest induced by DFMO (DL-a-difluoromethylornithine, an inhibitor of polyamines synthesis). PGE3 exposure enhanced the level of c-Myc, RhoA and Cdk2 proteins, and reversed the inhibition of these proteins expression induced by DFMO. The results of gross and pathological scores showed administration of PGE1 significantly alleviated intestinal mucosal injury of rats. Our findings indicate that total ginsenosides promoted the IEC-6 proliferation presumably via its regulation on cell cycle and the expression of proliferation-related proteins regulated by polyamines, and provided a novel perspective for exploring the repair effect of Panax ginseng upon gastrointestinal mucosal injury.

COX2 confers bone marrow stromal cells to promoting TNFα/TNFR1β-mediated myeloma cell growth and adhesion.

Bone marrow stromal cells (BMSCs) have been implicated in multiple myeloma (MM) progression. However, the underlying mechanisms remain largely elusive. Therefore, we aimed to explore key factors in BMSCs that contribute to MM development. RNA-sequencing was used to perform gene expression profiling in BMSCs. Enzyme-linked immunosorbent assays (ELISAs) were performed to determine the concentrations of PGE2 and TNFα in sera and conditioned media (CM). Western blotting, qRT-PCR and IHC were used to examine the expression of cyclooxygenase 2 (COX2) in BMSCs and to analyze the regulation of TNFα by COX2. Cell growth and adhesion assays were employed to explore the function of COX2 in vitro. A 5T33MMvt-KaLwRij mouse model was used to study the effects of COX2 inhibition in vivo. COX2 was found to be upregulated in MM patient-derived BMSCs and to play a critical role in BMSC-induced MM cell proliferation and adhesion. Administration of PGE2 to CM derived from BMSCs promoted MM cell proliferation and adhesion. Conversely, inhibition of COX2 in BMSCs greatly compromised BMSC-induced MM cell proliferation and adhesion. PCR array-based analysis of inflammatory cytokines indicated that COX2 upregulates the expression of TNFα. Subsequent rescue assays showed that an anti-TNFα monoclonal antibody could antagonize COX2-mediated MM cell proliferation and adhesion. Administration of NS398, a specific COX2 inhibitor, inhibited in vivo tumor growth and improved the survival of 5TMM mice. Our results indicate that COX2 contributes to BMSC-induced MM proliferation and adhesion by increasing the secretion of PGE2 and TNFα. Targeting COX2 in BMSCs may serve as a potential therapeutic approach of treating MM.

MAP3K8 Regulates Cox-2-Mediated Prostaglandin E2 Production in the Lung and Suppresses Pulmonary Inflammation and Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by exuberant deposition of extracellular matrix components, leading to the deterioration of lung architecture and respiratory functions. Profibrotic mechanisms are controlled by multiple regulatory molecules, including MAPKs, in turn regulated by multiple phosphorylation cascades. MAP3K8 is an MAPK kinase kinase suggested to pleiotropically regulate multiple pathogenic pathways in the context of inflammation and cancer; however, a possible role in the pathogenesis of IPF has not been investigated. In this report, MAP3K8 mRNA levels were found decreased in the lungs of IPF patients and of mice upon bleomycin-induced pulmonary fibrosis. Ubiquitous genetic deletion of Map3k8 in mice exacerbated the modeled disease, whereas bone marrow transfer experiments indicated that although MAP3K8 regulatory functions are active in both hematopoietic and nonhematopoietic cells, Map3k8 in hematopoietic cells has a more dominant role. Macrophage-specific deletion of Map3k8 was further found to be sufficient for disease exacerbation thus confirming a major role for macrophages in pulmonary fibrotic responses and suggesting a main role for Map3k8 in the homeostasis of their effector functions in the lung. Map3k8 deficiency was further shown to be associated with decreased Cox-2 expression, followed by a decrease in PGE2 production in the lung; accordingly, exogenous administration of PGE2 reduced inflammation and reversed the exacerbated fibrotic profile of Map3k8 -/- mice. Therefore, MAP3K8 has a central role in the regulation of inflammatory responses and Cox-2-mediated PGE2 production in the lung, and the attenuation of its expression is integral to pulmonary fibrosis development.

Protein contain in Cyprinus carpio (Ham.) of experimental and control fishes due to administration of ovaprim, ovatide and pituitary gland extract at Fish Seed Production Centre, Paithan, Aurangabad, Maharashtra State, India

Protein contain is a cornerstone mechanism and form part and parcel of nutritive value in particular rely on season, food intake, breeding and spawning capacity. The protein contain in the fish body constitute as a firsthand source of energy for physiological functions incorporating reproduction. Present investigation display that variations in the protein is observed from the mature fishes of Indian major carps such as Cyprinus carpio comprises 20 to 50cm selected for the estimation of protein study considered as experimental and control fishes upon administration of PGE, ovaprim and ovatide synthetic hormonal doses to the male and female sex ratio separately. Protein in the liver of female major carps may be because of vitellogenin, a lipoprotein which is synthesized in the liver and is transported to the ovary (Wallace, 1985). Moreover, gonadal protein enhanced with maturation amongst these fishes. Protein estimation represents the variations throughout the study period amongst the muscle, gonad and liver. After hormonal injections are given then fishes are kept in the breeding pool at the Fish Seed Production Centres (FSPC) located near Paithan barrage. The protein is estimated upon satisfactory administration of hormonal doses Pituitary Gland Extract and by other two synthetic hormonal doses viz. Ovaprim and Ovatide. Study is conducted during 2013 to 2014.

8-iso prostaglandin E2 causes nasal congestion in allergic rhinitis of mice

Abstract Allergic rhinitis (AR) is a complex nasal disease accompanied with mast cell and eosinophils infiltration into nasal cavity. Nasal congestion is a typical symptom of allergic rhinitis that is difficult to treat. Thromboxane A2 (TXA2)-TP receptor axis is reported to be involved in nasal congestion; however, its detailed mechanism is unknown. Here, we assessed the involvement of TP-mediated signaling in nasal congestion of mice. Intraperitoneal sensitization and intranasal administration of ovalbumin induced rhinitis with nasal congestion in mice. Pharmacological TP blockade but not TXA2 synthase inhibition abolished the nasal congestion accompanied with vascular hyper-permeability. These data suggest the presence of some other TP ligand than TXA2 in nasal cavity. LC-MS/MS based comprehensive analysis identified 15 types of lipid metabolites in nasal lavage fluid (NALF) of AR. The levels of almost all metabolites were higher in the NALF of AR than that in non-AR. Among these, we detected a possible TP ligand, 8-iso PGE2 in the AR NALF. Both in vitro and in vivo experiments showed that treatment of 8-iso PGE2 caused vascular hyper-permeability which was inhibited by pharmacological TP blockade. In addition, intranasal administration of 8-iso PGE2 induced nasal congestion which was significantly inhibited by TP blockade. We identified 8-iso PGE2 as a novel TP ligand which exacerbate nasal congestion in rhinitis mice.

PO-01-028 Two cases of penile arterial leak detected by color Doppler ultrasound

Among the anatomical variations in penile vascularization, dorso-cavernosal anastomosis is relatively frequent (18.5-80%). We present two cases of patients with caverno-dorsal anastomosis detected by penile ultrasound. We have called this entity "Penile arterial leak". Case 1 is an 80-year-old male with long-term erectile dysfunction without response to PDE5-Is. Case 2 is a 48-year-old patient with penile curvature without erectile dysfunction. Both color and power Doppler were performed (General Electrics® LOGIQe or LOGICS8, utilizing multifrequency 6-12 MHz linear probe) following genital stimulation after administration of intracavernosal PGE1 of 20 and 10 mcg, respectively. In Case 1, a right caverno-dorsal anastomosis was observed in the central third of the penis. The peak systolic velocity (PSV) in the right cavernous prior to anastomosis was 26 cm/s, and the end diastolic velocity (EDV) was 5.4 cm/s. The PSV at anastomosis, with inverted flow (caverno-dorsal) was 10 cm/s and EDV was 0 cm/s. Case 2 presented a predominantly fibrous Peyronie's disease in the form of a dorsal plaque, affecting the proximal and middle third of the penis. A right caverno-dorsal anastomosis was found in the proximal third of the penis. Ten minutes after administration of PGE1, the PSV in the native right cavernous was 69 cm/s, and the EDV was 13 cm/s. Eighteen minutes after administration, the cavernosal-dorsal (with inverted flow) anastomosis PSV was 20 cm/s and EDV was 4 cm/s; while the native right cavernous PSV has decreased to 54 cm/s and EDV was 14 cm/s.

Adipocyte mTORC1 Suppresses Treg Cell Development and Browning of White Adipose Tissue through CRTC2/COX-2/PGs Pathway

Adipose tissue (AT) contains abundant CD4+Foxp3+ regulatory T (Treg) cells; however, the physiological signals that control AT Treg cell and the role of AT Treg cell in thermogenesis have not been defined. Here we show that obesity activated mTORC1 signaling while decreased frequency of Treg cells in white adipose tissue (WAT), and adipose-specific inhibition of mTORC1 by raptor deficiency promoted development of Treg cells and beige adipocytes and protected mice against diet-induced reduction of Treg cells and beige adipocytes in WAT and diet-induced obesity. Mechanistically, mTORC1 signaling phosphorylated CREB regulated transcription coactivator 2 (CRTC2) and subsequently suppressed expression of cyclooxygenase 2 (COX-2) and secretion of prostaglandins (PGs) including PGI2, PGD2 and PGE2 in vivo and in adipocytes. Treatment of PGE2 but not PGI2 and PGD2 promoted differentiation and activation of Treg cells in vitro and in vivo. Pharmacological inhibition of COX-2 or blocking Treg cell by neutralization of CD25 attenuated mTORC1 inhibition-induced browning of white fat. Further, deficiency of Treg cell suppressed the inducing effect of PGE2 administration on thermogenic gene expression and oxygen consumption in inguinal and epididymal WAT. Taken together, these results uncover that adipocyte mTORC1 is a key regulator of Treg cell and beige adipocyte development in adipose tissue via CRTC2/COX-2/PGs pathway-dependent mechanisms. Disclosure X. Zhang: None. Y. Luo: None. X. Ding: None. C. Wang: None. X. Yang: None. M. Liu: None.

Piecemeal Mechanism Combining Sprouting and Intussusceptive Angiogenesis in Intravenous Papillary Formation Induced by PGE2 and Glycerol.

Recently, we demonstrated that in human intravascular papillary endothelial hyperplasia (IPEH), vein wall vascularization occurs in association with myriad papillae, a large part of which formed in the vascularized vein wall. Previously, using an animal model, we observed that PGE2 and glycerol administration around the femoral vein originates intense vascularization of the vein wall from its intimal endothelial cells (ECs). This vascularization is similar to that in IPEH. The aim of this study is to assess the mechanism of papillary formation, using this model after demonstrating papillary development in neo-vascularized femoral vein walls. In semithin and ultrathin sections, the sequential vascular and papillary development was as follows: (a) activation of vein intimal ECs, (b) sprouting of intimal ECs towards the vein media layer and microvessel development, (c) interconnection between neighboring microvessels originated elementary loops, which encircled vein wall components and formed papillae. The encircling ECs formed the papillary cover, and the encircled component formed the core. The papillae showed a similar structure to that of folds and pillars in intussusceptive angiogenesis, and (d) origin of secondary and complex loop systems by interconnection of neighboring elementary loops and by splitting of papillae by new loops, with abundant papillary development. In conclusion, the results support a piecemeal angiogenic mechanism in papillary formation, with association of sprouting and intussusceptive types of angiogenesis. Further studies are needed to assess whether the intravascular papillae described in several pathologic processes, including vessel tumors, such as Dabska's tumor, retiform hemangioendothelioma, and angiosarcoma, follow a similar mechanism. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc. Anat Rec, 300:1781-1792, 2017. © 2017 Wiley Periodicals, Inc.

PGE2/EP4 receptor attenuated mucosal injury via β‐arrestin1/Src/EGFR‐mediated proliferation in portal hypertensive gastropathy

Background and PurposePortal hypertensive gastropathy (PHG) is a serious complication of liver cirrhosis and a potential cause of bleeding in patients with cirrhosis. Suppressed mucosal epithelial proliferation is a crucial pathological characteristic of PHG. Our studies demonstrated an important role for PGE2 and its EP4 receptor in the promotion of mucosal proliferation. However, whether β‐arrestin1 (β‐arr1), a well‐established mediator of GPCRs, is involved in the PGE2/EP4 receptor‐mediated mucosal proliferation complex in PHG remains unclear. The aim of the study was to investigate whether β‐arr1 participated in PGE2/EP4 receptor‐mediated mucosal proliferation by recruiting the Src/EGF receptor (EGFR) complex to activate Akt/proliferating cell nuclear antigen (PCNA) signalling in PHG.Experimental ApproachGastric mucosal proliferation was examined in patients with PHG and the PHG model of β‐arr1‐knockout (β‐arr1‐KO) and β‐arr1‐wild type (β‐arr1‐WT) mice. The induction of β‐arr1 and EP4 receptor expression and the Src/EGFR signalling elements was investigated, and the mechanisms underlying PGE2‐regulated gastric mucosal proliferation were analysed.Key ResultsPortal hypertension suppressed COX‐1 but not COX‐2, which was accompanied by a down‐regulation of PGE2 generation and EP4 receptor levels in the mucosa of patients with PHG. PGE2 administration markedly promoted mucosal proliferation in a mouse model of PHG. Targeted deletion of β‐arr1 abolished PGE2/EP4 receptor‐mediated gastric proliferation in PHG by repressing the Src/EGFR/Akt/PCNA signalling network.Conclusions and ImplicationsThese results indicate that β‐arr1 regulates PGE2/EP4 receptor‐mediated mucosal proliferation by promoting activation of the Src/EGFR/Akt/PCNA signalling pathway, and thus, this network is a potential therapeutic target for PHG.

Prostaglandin E2 Inhibition of IL-27 Production in Murine Dendritic Cells: A Novel Mechanism That Involves IRF1

IL-27, a multifunctional cytokine produced by APCs, antagonizes inflammation by affecting conventional dendritic cells (cDC), inducing IL-10, and promoting development of regulatory Tr1 cells. Although the mechanisms involved in IL-27 induction are well studied, much less is known about the factors that negatively impact IL-27 expression. PGE2, a major immunomodulatory prostanoid, acts as a proinflammatory agent in several models of inflammatory/autoimmune disease, promoting primarily Th17 development and function. In this study, we report on a novel mechanism that promotes the proinflammatory function of PGE2 We showed previously that PGE2 inhibits IL-27 production in murine bone marrow-derived DCs. In this study, we show that, in addition to bone marrow-derived DCs, PGE2 inhibits IL-27 production in macrophages and in splenic cDC, and we identify a novel pathway consisting of signaling through EP2/EP4→induction of cAMP→downregulation of IFN regulatory factor 1 expression and binding to the p28 IFN-stimulated response element site. The inhibitory effect of PGE2 on p28 and irf1 expression does not involve endogenous IFN-β, STAT1, or STAT2, and inhibition of IL-27 does not appear to be mediated through PKA, exchange protein activated by cAMP, PI3K, or MAPKs. We observed similar inhibition of il27p28 expression in vivo in splenic DC following administration of dimethyl PGE2 in conjunction with LPS. Based on the anti-inflammatory role of IL-27 in cDC and through the generation of Tr1 cells, we propose that the PGE2-induced inhibition of IL-27 in activated cDC represents an important additional mechanism for its in vivo proinflammatory functions.

Induction of labor: does indication matter?

Labor induction is performed in 20% of pregnancies. However, the impact of the indications for induction on its failure rate has hardly been investigated. We aimed to evaluate the association of indications for labor induction with failure rate. Background and delivery-related data were retrospectively collected for all women with a viable term singleton pregnancy, who underwent labor induction with a PGE2 vaginal insert in 2013-2014. Reasons for induction were categorized as maternal indications, hypertensive disorders, premature rupture of membranes, and fetal indications. Induction failure was defined as Bishop score ≤7 at 24h after PGE2 administration, cesarean delivery due to latent phase dystocia or removal of the insert due to non-reassuring fetal heart rate followed by emergency cesarean delivery. Outcome measures were rate of induction failure (primary) and rate of cesarean delivery (secondary). The cohort included 1066 women. Those who failed induction (n=213, 20%) were more likely to be nulliparous (69.5 vs. 45.7%, p<0.0001), older (31 vs. 30years, p=0.047), and at an earlier gestational age (39.4 vs. 40.0weeks, p<0.0001). Among nulliparous women, maternal indications were significantly associated with induction failure (aOR 2.52, 95% CI 1.28-4.95, p=0.007) and cesarean delivery (aOR 2.36, 95% CI 0.40-2.29, p=0.019). Among multiparous women, hypertensive disorders (aOR 7.26, 95% CI 1.89-27.87, p=0.004) and maternal indications (aOR 4.22, 95%CI 1.14-15.58, p=0.031) were significantly associated with induction failure but not cesarean delivery. The indication for induction of labor may impact its failure rate.

Cyp2aa9 regulates haematopoietic stem cell development in zebrafish.

Definitive haematopoiesis occurs during the lifetime of an individual, which continuously replenishes all blood and immune cells. During embryonic development, haematopoietic stem cell (HSC) formation is tightly controlled by growth factors, signalling molecules and transcription factors. But little is known about roles of the cytochrome P450 (CYP) 2 family member in the haematopoiesis. Here we report characterization and functional studies of Cyp2aa9, a novel zebrafish Cyp2 family member. And demonstrate that the cyp2aa9 is required for the HSC formation and homeostasis. Knockdown of cyp2aa9 by antisense morpholino oligos resulted the definitive HSC development is defective and the Wnt/β-catenin activity becomes reduced. The impaired HSC formation caused by cyp2aa9 morpholino can be rescued by administration of PGE2 through the cAMP/PKA pathway. Furthermore, the in vivo PGE2 level decreases in the cyp2aa9 morphants, and none of the PGE2 precursors is able to rescue phenotypes in the Cyp2aa9-deficient embryos. Taken together, these data indicate that Cyp2aa9 is functional in the step of PGE2 synthesis from PGH2, thus promoting Wnt activation and definitive HSC development.

Novel concepts on the role of prostaglandins on luteal maintenance and maternal recognition and establishment of pregnancy in ruminants

In ruminants, the corpus luteum (CL) of early pregnancy is resistant to luteolysis. Prostaglandin (PG)E2 is considered a luteoprotective mediator. Early studies indicate that during maternal recognition of pregnancy (MRP) in ruminants, a factor(s) from the conceptus or gravid uterus reaches the ovary locally through the utero-ovarian plexus (UOP) and protects the CL from luteolysis. The local nature of the embryonic antiluteolytic or luteoprotective effect precludes any direct effect of a protein transported or acting between the gravid uterus and CL in ruminants. During MRP, interferon tau (IFNT) secreted by the trophoblast of the conceptus inhibits endometrial pulsatile release of PGF2α and increases endometrial PGE2. Our recent studies indicate that (1) luteal PG biosynthesis is selectively directed toward PGF2α at the time of luteolysis and toward PGE2 at the time of establishment of pregnancy (ESP); (2) the ability of the CL of early pregnancy to resist luteolysis is likely due to increased intraluteal biosynthesis and signaling of PGE2; and (3) endometrial PGE2 is transported from the uterus to the CL through the UOP vascular route during ESP in sheep. Intrauterine co-administration of IFNT and prostaglandin E2 synthase 1 (PGES-1) inhibitor reestablishes endometrial PGF2α pulses and regresses the CL. In contrast, intrauterine co-administration of IFNT and PGES-1 inhibitor along with intraovarian administration of PGE2 rescues the CL. Together, the accumulating information provides compelling evidence that PGE2 produced by the CL in response to endometrial PGE2 induced by pregnancy may counteract the luteolytic effect of PGF2α as an additional luteoprotective mechanism during MRP or ESP in ruminants. Targeting PGE2 biosynthesis and signaling selectively in the endometrium or CL may provide luteoprotective therapy to improve reproductive efficiency in ruminants.