Doses Of PGE2 Research Articles

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.

Effects of forskolin and PGE2 on progesterone secretion by goat luteal cells at early and late stages of corpus luteum

The aim of this research was to examine the effects of forskolin and PGE2 on steroid synthesis in goat luteal cells, cultured at early and late corpus luteum. Therefore, the luteal cells removed from both stages of the corpus luteum were cultured with newborn calf serum for the first 18 h. Then the media was changed and different concentrations of forskolin (10, 100 ng/ml) or PGE2 (10, 100 ng/ml) were added to the fresh media for another 96 h. The culture media was replaced every 48 h and the retrieval media was kept frozen at -20 °C, until hormone analysis. Luteal cells treated with forskolin produced between 1.87-13.17 times higher production of progesterone, in a dose-dependent manner, compared to the control at early and late stages of corpus luteum (P<0.05). Lower dose of PGE2 increased the progesterone secretion between 2.19-3.28 times in luteal cells compared to the control groups at the late stage of corpus luteum (P<0.05), but not at early stage. The cells treated with a higher dose of PGE2 had no significant effect (P>0.05) on progesterone synthesis at the early and late phases of goat corpus luteum, in comparison to control groups. As a result, this study in goat luteal cells shows that forskolin promotes progesterone synthesis at the early and late corpus luteum, but PGE2 is only effective in cells treated with a low dose at the late stage.

Cumulative Dose of Prostaglandin E1 Determines Gastrointestinal Adverse Effects in Term and Near-Term Neonates Awaiting Cardiac Surgery: A Retrospective Cohort Study.

This study aimed to assess the association between treatment characteristics of prostaglandin E1 including initiation time and duration, maximal and cumulative doses, and adverse effects. A retrospective cohort study in which medical records of neonates with duct-dependent lesions were studied for treatment parameters and adverse effects. Multivariable logistic regression model was applied for testing the effect PGE1 variables on outcomes. The primary outcomes of this study were association of adverse effects of PGE1 treatment with maximal dose, cumulative dose, and treatment duration. The secondary outcomes included safety of feeding in infants treated with PGE1. Eighty-two infants with duct-dependent lesions receiving PGE1 were included. Several infants who received early PGE1 treatment required ventilation support. Feeds were ceased more often as the cumulative dose and duration of PGE1 treatment increased. Gastrointestinal adverse effects were significantly associated with the cumulative dose of PGE1 and treatment duration. Apneas, hyperthermia, and tachycardia were associated with maximal dose. Our data did not demonstrate a difference in the incidence of NEC associated with characteristics of PGE1 treatment. Cumulative PGE1 dose is associated with gastrointestinal adverse effects in neonates. Lower doses should be considered in neonates expecting prolonged PGE1 treatment.

Inhibition of Nonsense-Mediated Decay Induces Nociceptive Sensitization through Activation of the Integrated Stress Response.

RNA stability is meticulously controlled. Here, we sought to determine whether an essential post-transcriptional regulatory mechanism plays a role in pain. Nonsense-mediated decay (NMD) safeguards against translation of mRNAs that harbor premature termination codons and controls the stability of ∼10% of typical protein-coding mRNAs. It hinges on the activity of the conserved kinase SMG1. Both SMG1 and its target, UPF1, are expressed in murine DRG sensory neurons. SMG1 protein is present in both the DRG and sciatic nerve. Using high-throughput sequencing, we examined changes in mRNA abundance following inhibition of SMG1. We confirmed multiple NMD stability targets in sensory neurons, including ATF4. ATF4 is preferentially translated during the integrated stress response (ISR). This led us to ask whether suspension of NMD induces the ISR. Inhibition of NMD increased eIF2-α phosphorylation and reduced the abundance of the eIF2-α phosphatase constitutive repressor of eIF2-α phosphorylation. Finally, we examined the effects of SMG1 inhibition on pain-associated behaviors. Peripheral inhibition of SMG1 results in mechanical hypersensitivity in males and females that persists for several days and priming to a subthreshold dose of PGE2. Priming was fully rescued by a small-molecule inhibitor of the ISR. Collectively, our results indicate that suspension of NMD promotes pain through stimulation of the ISR.SIGNIFICANCE STATEMENT Nociceptors undergo long-lived changes in their plasticity which may contribute to chronic pain. Translational regulation has emerged as a dominant mechanism in pain. Here, we investigate the role of a major pathway of RNA surveillance called nonsense-mediated decay (NMD). Modulation of NMD is potentially beneficial for a broad array of diseases caused by frameshift or nonsense mutations. Our results suggest that inhibition of the rate-limiting step of NMD drives behaviors associated with pain through activation of the ISR. This work reveals complex interconnectivity between RNA stability and translational regulation and suggests an important consideration in harnessing the salubrious benefits of NMD disruption.

Green Synthesis and Characterization of Silver Nanoparticles of Psidium guajava Leaf Extract and Evaluation for Its Antidiabetic Activity.

Diabetes mellitus (DM) and its complications are a severe public health concern due to the high incidence, morbidity, and mortality rates. The present study aims to synthesize and characterize silver nanoparticles (AgNPs) using the aqueous leaf extract of Psidium guajava (PGE) for investigating its antidiabetic activity. Psidium guajava silver nanoparticles (PGAg NPs) were prepared and characterized by various parameters. The in vivo study was conducted using PGE and PGAg NPs in Streptozotocin (STZ)-induced diabetic rats to assess their antidiabetic properties. STZ of 55 mg/kg was injected to induce diabetes. The PGE, PGAg NPs at a dose of 200 and 400 mg/kg and standard drug Metformin (100 mg/kg) were administered daily to diabetic rats for 21 days through the oral route. Blood glucose level, body weight changes, lipid profiles, and histopathology of the rats’ liver and pancreas were examined. In the diabetic rats, PGE and PGAg NPs produced a drastic decrease in the blood glucose level, preventing subsequent weight loss and ameliorating lipid profile parameters. The histopathological findings revealed the improvements in pancreas and liver cells due to the repercussion of PGE and PGAg NPs. A compelling effect was observed in all doses of PGE and PGAg NPs; however, PGAg NPs exhibited a more promising result. Thus, from the results, it is concluded that the synthesized PGAg NPs has potent antidiabetic activity due to its enhanced surface area and smaller particle size of nanoparticles.

Outcome of Induction of Labour in Nulliparous Women

Objective: To determine the outcomes following induction of labor in nulliparous women presenting to tertiary care facility. Study Design: Case Series Place and Duration: Department of Obstetrics & Gynaecology, Aga Khan University & Hospital Karachi. Duration was Six months from 15thJanuary 2016 - 15th June 2016. Methadology: Admitted women was selected, women were induced with PGE2 3mg vaginal tablet, inserted in the posterior vaginal fornix. This was repeated at 4-hour intervals, if contractions are not initiated. Maximum 6 mg was given. Decision was taken for cesarean section 4 hours post second dose by the consultant having more than 2 years of post-fellowship experience. Results: 100 women enrolled in this study, mean age of the patients was 26.9±3.9 years. BMI of the patient were 30.4±4.5 kg/m2. Stratification analysis was performed and observed that statistically significant association in MOD in nulliparous women with age and dose of PGE2. MOD of delivery in nulliparous women was not associated with height weight BMI gestational age and baby NICU admission. Conclusion: Elective induction of labour at term gestation can reduce perinatal mortality and morbidity in Pakistan with increasing the risk of operative delivery. Keywords: Induction of labour, Nulliparous women, Unfavorable cervix.

Effect of vaginal pH on efficacy of dinoprostone gel for labour induction: a cross-sectional study

The purpose of this study was to assess the effect of vaginal pH on efficacy of intracervical dinoprostone gel (PGE2) for labour induction, progression and induction delivery interval. A cross-sectional study was done among 150 term pregnant women planned for induction with unfavourable Bishop’s score ≤5. Women were categorised into two groups based on vaginal pH >4.5 and ≤4.5. Induction was done with maximum of three doses of PGE2 based on Bishop’s score, followed by oxytocin administration. Failed induction rate was 14.5%. There was no significant association between vaginal pH and Bishop’s score change after first gel application. There was no significant difference in failed induction rates, time from induction to active labour as well as induction delivery interval between two groups. Similarly, there was no significant association between oxytocin requirement and mode of delivery with vaginal pH. Intracervical PGE2 is an ideal route, unaffected by vaginal pH. Impact Statement What is already known on this subject? Prostaglandins are organic acids that have diminished solubility in aqueous solution with a low pH. The release of the drug could be altered by the acidity of vagina and this could result in variable clinical response. Vaginal pH may alter the efficacy of intravaginally administered prostaglandins through several potential mechanisms. What the results of this study add? There was no significant effect of change in vaginal pH on effectiveness of intracervical administered PGE2. There was no significant association between vaginal pH and time from induction to time women is entering into active labour as well as time from induction to delivery. Similarly, there was no significant association between mode of delivery and oxytocin usage with vaginal pH in labour. Intracervical PGE2 is an ideal route, unaffected by vaginal pH. What the implications are of these findings for clinical practice and/or further research? Further randomised studies are required comparing both vaginally administered PG inserts and intracervical PGE2 gels with vaginal and cervical pH, to directly compare their effectiveness in labour induction.

A Study on Pre-Induction Cervical Ripening with PGE2 Vaginal Tablet One (3 mg) vs. Half (1.5 mg) in Low Risk Multi Parous Mothers at 40 Weeks of Gestation

Backgrounds: Induction of labor is a common practice. In women with immature cervix, PGE2 is commonly used for pre-induction. We hypothesized that PGE2 1.5 mg may be equally effective to PGE2 3 mg in multiparous women for labor induction. The present effort was an attempt to compare the efficacy and effects of pre-induction cervical ripening with PGE2 3 mg vs. 1.5 mg in multi-parous mothers (2nd and 3rd Pregnancy) at 40 weeks. Methods: A double-blind randomized controlled trial was carried out at Castle Street Hospital for Women, Colombo, Sri Lanka. Study subjects consisted of women with singleton pregnancy (no cesarean history) admitted for delivery at 40 weeks of their 2nd or 3rd pregnancy. PGE2 1.5 mg vs. 3 mg PGE2 vaginal tablet were used for treatment (n = 173) and control (n = 170) groups, respectively. Cervical ripening and maternal, fetal complications were observed. Unfavorable cervices were induced with the same PGE2 dose in the following day. Results: Study group, compared with the control group, achieved the same rate of favorable cervices in 1st and 2nd cycles (63.5% vs. 64%, respectively). Both groups showed the same rate of cervical dilatation achievement, and admissions to Special Care Baby Unit. Study group showed significantly less maternal complications (4% and 11%, respectively: p = 0.01). Conclusion: PGE2 of 1.5 mg is equally effective in achieving favorable cervices, adequate cervical dilatation with minimum maternal complications compared to the usual 3 mg dose in multiparous low-risk women.

Safety and Effectiveness of a Shortened Regimen of Alprostadil (PGE1) with Large Infusion Dose, for Ischemic Manifestations of the Extremities in Real?World Clinical Practice

Objective: To analyse historical indications, tolerance, secondary effects and effectiveness of a treatment regimen with short interrupted cycles of large doses of PGE1 as well as possible factors that may influence the results in real world clinical practice in a tertiary hospital. Material and Methods: This is an observational, descriptive, retrospective study of all patients treated from 2013 to 2020 with high-doses of PGE1 in our hospital. Results: Forty five patients from 27 to 91 years old were treated for ischemic diseases, grouped into 6 types. Treatment caused side effects in 14 patients (31%) and has to be discontinued in 6 of them for intolerance (13% of total). Intolerance was associated with heart disease and advanced age. No short or long term complications were observed in these patients after discontinuation of treatment. Effectiveness was considered in 53.3% in mean, decreasing with age, more abruptly from 80 years old. Neither heart disease nor kidney disease, decreased effectiveness. Conclusion: Although side effects are relatively common, there is no morbidity associated with the high-dose in short cycles of alprostadil, with a considerable effectiveness in not elderly patients and thus, could be considered a useful tool in the treatment of severe non-surgical vascular pathology.

The association between repeated doses of vaginal PGE2 (Dinoprostone, Prostin®) and both maternal and neonatal outcomes among women in the north of Jordan

Objective: To evaluate the association between repeated doses of vaginal PGE2 and the maternal and neonatal outcomes for primigravid and multiparous women. Study design: A retrospective descriptive study was conducted at a teaching university hospital in Jordan. The study involved 885 women with singleton live fetuses; these women had been admitted to the labor ward for an induction of labor by vaginal PGE2 (Dinoprostone, Prostin®) for different indications from January 2015 to December 2016. The women were classified according to parity into two main groups, namely, primigravid and multiparous. In the primigravid group, the women who had received two or fewer doses of a vaginal PGE2 tablet (3 mg Dinoprostone) were compared with those who had received a PGE2 tablet three times. In the multiparous group, the women who had received one or two doses of half the usual vaginal PGE2 tablet (1.5 mg Dinoprostone) were compared with those who had received the same dose three times. The main outcomes studied were the cesarean section rate and the APGAR score. Results: There was a statistically significant association, namely, X2 (1) = 13.96, P = 0.001, between the repeated doses of PGE2 and the mode of delivery. This indicates that primigravid women who received more than two doses of PGE2 were more likely to have a cesarean section (65.5%, n = 57 out of 87) compared with primigravid women who received two or fewer doses of PGE2 (42.9%, n = 132 out of 308). There was no significant association between repeated doses of PGE2 insertion and admission either to the nursery or the neonatal intensive care unit (NICU) X2 (1) = 2.11, P = 0.14. Moreover, the results also showed that there was no significant association between repeated doses of PGE2 insertion and the APGAR score X2 (1) = 0.06, P = 0.88. For multiparous women, there was no statistically significant association X2 (1) = 2.15, P = 0.14 between repeated doses of PGE2 insertion and the mode of delivery. Conclusion: In both groups of primigravid and multiparous women, the third dose of vaginal PGE2 was not associated with a significant increase in maternal or neonatal morbidity. In the primigravid group, despite the third dose of PGE2 being associated with a higher rate of cesarean section in comparison with two or fewer doses of it, nearly a third of the women nevertheless achieved vaginal delivery. In the multiparous group, the third dose of PGE2 was not associated with a higher rate of cesarean sections.

Diagnostic categorization of erectile dysfunction using duplex color doppler ultrasonography and significance of phentolamine redosing in abolishing false diagnosis of venous leak impotence: A single center experience.

Background and Aims:Erectile dysfunction (ED) is an inability to achieve and maintain erectile rigidity sufficient for satisfactory sexual performance. It is either organic or psychogenic in origin. This study was aimed at establishing vasculogenic causes among patients being evaluated for ED using Penile Doppler Ultrasound.Methods:Fifty-two consecutive patients with the clinical diagnosis of ED were evaluated with color Doppler ultrasound scan using a 7.5 MHz high-frequency linear transducer between July 2016 and June 2019. The examination was commenced 3 min after an intracavernosal injection with 10-20 μg of PGE1 and continued for 30 min. The measurements were obtained alternately from both deep penile arteries. The variables analyzed were the peak systolic velocity (PSV), end-diastolic velocity (EDV) and resistive index (RI), calculated as (PSV-EDV)/PSV. Erection Hardness was evaluated subjectively using the EH Score (EHS), a 5-point response score denoting how the patient would rate his erection. ED was subjectively assessed using the International Index of Erectile Function (IIEF-5) questionnaire. In patients with a diagnosis of vasculogenic ED, intracavernosal PGE1 injection was started with a 5 μg dose and then increased in 5 μg increments until the final dose of 20 μg was reached.Results:PSV of cavernosal arteries (CA) varied between 19.2 and 106.2 cm/s (mean: 43.8 ± 18.2) among the entire patients and between 19.7 and 80.2 cm/s (mean: 42.6 ± 11.3) among patients with arteriogenic ED. Arteriogenic ED was found in 8 patients (15.3%), while venogenic ED was observed in 12 patients, which constituted 23% of the entire study population and mixed arteriogenic-venogenic ED was found in 6 patients (11.5%) of the study population. DICC performed on patients diagnosed with venogenic ED on color Doppler ultrasonography revealed venous leakage and no statistically significant differences between results of DICC and color Doppler ultrasonography were found in EDV, RI, and PI measurements (P< 0.005). Among patients with venogenic ED and mixed arteriogenic-venogenic ED,2 patients had a normal erectile response and the remaining 16 received 2 mg phentolamine. A significant increase in PSV between baseline and 20 mg PGE1 (P < 0.001) was observed in all cases. Following phentolamine, there was a significant increase in grade of erection (P = 0.0001) and a significant reduction in the EDV (P = 0.0001). A reduction of the EDV to below 0.0 cm/s was observed in 12 patients. In patients with arteriogenic erectile dysfunction, mean (±standard deviation) duration of erection for consecutive doses of PGE15 μg, 10 μg, 15 μg, and 20 μg were 42.2±18.4, 55.4±24.1, 66.1 ± 31.1, and 83.3±36.7 minutes, respectively, with significant increase for each dose. In patients with veno-occlusive dysfunction, mean durations of erection significantly increased from 9.1±8.0 minutes at 10 μg to 19.2±9.8 minutes at 20 μg.Conclusion:In the current study, 50% of patients had vasculogenic ED and “false-positive’’ diagnosis of venous leakage was unmasked by phentolamine re-dosing. It is therefore imperative that patients with ED benefit from duplex color Doppler ultrasonography which is safe, cheap and non-ionizing diagnostic modality before initiating therapy as ED treatment is cause specific.

MPGES-1-derived prostaglandin E2 stimulates Stat3 to promote podocyte apoptosis

We previously reported that microsomal prostaglandin E synthase-1 (mPGES-1) contributed to adriamycin (Adr)-induced podocyte apoptosis. However, the molecular mechanism remains unclear. Here we studied the role of mPGES-1/PGE2 cascade in activating Stat3 signaling and the contribution of Stat3 in PGE2- and Adr-induced podocyte apoptosis. In murine podocytes, PGE2 dose- and time-dependently increased the phosphorylation of Stat3 in line with the enhanced cell apoptosis and reduced podocyte protein podocin. In agreement with the increased Stat3 phosphorylation, Stat3-derived cytokines including IL-6, IL-17, MCP-1, and ICAM-1 were significantly upregulated following PGE2 treatment. By application of a specific Stat3 inhibitor S3I-201, PGE2-induced podocyte apoptosis was largely abolished in parallel with a blockade of podocin reduction. Next, we observed that Adr treatment also enhanced p-Stat3 and activated mPGES-1/PGE2 cascade. Blockade of Stat3 by S3I-201 significantly ameliorated Adr-induced cell apoptosis and podocin reduction. More interestingly, silencing mPGES-1 in podocytes by mPGES-1 siRNA blocked Adr-induced increments of Stat-3 phosphorylation, PGE2 production, and Stat3-derived inflammatory cytokines. Taken together, this study suggested that mPGES-1-derived PGE2 could activate Stat3 signaling to promote podocyte apoptosis. Targeting mPGES-1/PGE2/Stat3 signaling might be a potential strategy for the treatment of podocytopathy.

A dose response study of the effect of prostaglandin E2 on thermal nociceptive sensitivity

Inhibition of prostaglandin (PG) biosynthesis has been used to relieve pain for thousands of years. Today non-steroidal anti-inflammatory drugs (which largely inhibit PG synthesis) are widely used to treat pain. Four main types of PGs (PGD2, PGE2, PGF2 and PGI2) are synthesized from arachidonic acid during inflammation and have been demonstrated to impact nociception. PGE2 has been the most studied and utilized for its pain producing properties and has been demonstrated to increase hypersensitivity in rodent nociceptive behavioral models when applied centrally and/or peripherally. Surprisingly, there are no published reports that use withdrawal from radiant light beam (Hargreaves apparatus) to examine the dose response effect of peripherally applied PGE2 on thermal nociceptive hypersensitivity. To address this gap in the literature, we performed a dose response study examining the effect of PGE2 on thermal hypersensitivity (assessed using a Hargreaves apparatus) where rats were injected with 0.003–30μg of PGE2, intradermally into the hindpaw. Thermal hypersensitivity was assessed by measuring withdraw latency from a radiant light beam (Hargreaves test) and our primary objective was to determine the dose of PGE2 causing the most pronounced increase in thermal hypersensitivity (i.e. lowest withdraw latency). A secondary objective was to determine the minimum dose of PGE2 required to cause statistically significant decreases in thermal withdrawal latency as compared to rats injected with vehicle. We found that rats injected with the 30μg dose of PGE2 exhibited the most pronounced thermal nociceptive hypersensitivity though secondary analysis showed that rats injected with PGE2 doses of 0.03–30μg had lower withdrawal latencies as compared to rats injected with vehicle. This work fills an evidence gap and provides context to guide dose selection in future rodent pain behavior studies.

Effects of prostaglandin E2 on clonogenicity, proliferation and expression of pluripotent markers in human periodontal ligament cells

Background and objectiveBased on our earlier work on the response of periodontal ligament (PDL) cells to mechanical stress by induction of cyclooxygenase expression and production of prostaglandin PGE2 that could regulate mineralization of PDL cells, it was hypothesized that PGE2 had potential effects on PDL stemness. In this study, we aimed to investigate clonogenicity, proliferation and expression of certain pluripotent markers, considered to be characteristics of PDL stemness, in response to treatment with exogenously-added PGE2. Material and methodsHuman PDL cells were cultured and treated with various doses of PGE2, and the aforementioned characteristics of PDL stemness were analyzed. ResultsThe clonogenicity and proliferation were significantly enhanced by PGE2 at low concentrations (0.01, 0.1 and 1ng/ml; P<0.05), but only the proliferation was significantly diminished by PGE2 at a high concentration (100ng/ml; P<0.05). Expression of NANOG and OCT4 mRNA and protein was increased by PGE2 treatment at 0.1 and 1ng/ml. Consistently, expression of stage-specific embryonic antigen 4, a putative stem cell marker, was significantly augmented by PGE2 treatment at 1ng/ml (P<0.05). ConclusionOur findings suggest that although a high dose of PGE2 (100ng/ml) inhibits proliferation of PDL cells, PGE2 at low doses appears to play a role in the maintenance of PDL stemness.

Predictors of mode of birth and duration of labour following induction using prostaglandin vaginal gel.

Using data from a randomised controlled trial (RCT) comparing two policies of prostaglandin (PGE2) vaginal gel induction of labour (IOL) at term, this study aimed to determine: (i) demographic/clinical factors that predict IOL outcomes; and (ii) clinical characteristic(s) of women who would benefit from a policy of amniotomy once technically possible as opposed to giving more PGE2. Following an initial PGE2 dose, women were randomised to amniotomy or repeat-PGE2. Using RCT data, two multivariate models were developed, assessing the relationship between demographic/clinical characteristics and the outcomes of caesarean section (CS), and vaginal delivery within 24h (VD<24h). Regression-equations were used to predict the likelihood of CS and VD<24h, varying independent predictors from the multivariate analyses. Of 245 term women undergoing IOL, 90 had a CS, 155 delivered vaginally and 79 had a VD<24h. Controlling for confounders, nulliparity [adjusted odds ratio (aOR)=3.71 (1.55, 8.88)] and modified Bishop's score (MBS) at first review [aOR=0.78 (0.66, 0.92)] were independently associated with CS. Nulliparity [aOR=0.06 (0.02, 0.15)], MBS at first review [aOR=1.66 (1.35, 2.05)], and a policy of early amniotomy [aOR=2.28 (1.04, 5.00)] were associated with VD<24h. Modelling using regression equations, and varying both MBS at first review and parity, there was no scenario where repeat PGE2 was predicted to be superior to an earlier amniotomy. Following IOL using PGE2 vaginal gel at term, both parity and cervical favourability at first review are associated with CS and VD<24h. All combinations of parity and MBS at first review predicted fewer CS and greater likelihood of VD<24h with a policy of amniotomy once technically possible.

Salidroside attenuates inflammatory response via suppressing JAK2-STAT3 pathway activation and preventing STAT3 transfer into nucleus

Salidroside (SAL) is an active ingredient isolated from the Rhodiola rosea, has potent anti-inflammatory effect, but the mechanism is still elusive. The purpose of this study is to verify the effects of SAL on LPS-induced inflammatory response and investigate the possible underlying molecular mechanism. RAW264.7 cells were pre-incubated with SAL for 2h, then stimulated with or without LPS for another 16h. The levels of TNF-α, MCP-1, IL-6, and PGE2 were detected by ELISA, and the production of NO was determined by nitrite analysis. The expression levels of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were detected by Western blotting. In RAW264.7 cells and murine peritoneal macrophages, the activation of signal molecules was also measured by Western blot. The nuclear translocation of STAT3 was determined by Laser confocal and nucleocytoplasmic separation experiments. Our results showed that SAL attenuated the productions of TNF-α, IL-6, MCP-1, PGE2 and NO dose dependently. SAL also suppressed LPS-induced expressions of iNOS and COX-2 significantly. Further studies revealed that SAL down-regulated the phosphorylation of JAK2-STAT3 signaling pathway and reduced the nuclear translocation of STAT3 induced by LPS in RAW264.7 cells and primary peritoneal macrophages. In addition, consistent with the results in vitro, in the model of mice acute lung injury (ALI) induced by LPS, SAL reduced the infiltration of inflammatory cells and decreased the levels of serum TNF-α and IL-6 obviously. Taken together, these data indicated that SAL exerted anti-inflammatory action via down-regulating LPS-induced activation of JAK2-STAT3 pathway and suppressing STAT3 transfer into the nucleus at least in part.

Prostaglandin vaginal gel induction of labor comparing amniotomy with repeat prostaglandin gel

The purpose of this study was to compare 2 inductions of labor protocols. Women with live singleton pregnancies at ≥37 + 0 weeks gestation who were booked for prostaglandins 2 (PGE2) vaginal gel induction with a modified Bishop's score of <7 were eligible for inclusion. After an evening dose of PGE2 vaginal gel, women were assigned randomly the next morning into the amniotomy or repeat-PGE2 group. The amniotomy group underwent artificial rupture of membranes (ARM), regardless of modified Bishop's score, and received further PGE2 doses only if ARM was not technically possible. The repeat-PGE2 group received further PGE2 (to a maximum of 3 doses) until a modified Bishop's score ≥7 occurred, when an ARM was performed. In both groups, Syntocinon was commenced once membranes were ruptured. The primary outcome measure was time from commencement of induction until birth. Two hundred forty-five women were assigned randomly into either the amniotomy (n = 121) or repeat-PGE2 group (n = 124). The time for induction of labor-to-birth was >5 hours shorter in the amniotomy group (24.8 vs 30.0 hours; mean difference, 5.2 h; 95% confidence interval, -2.5 to -7.8). Fewer women in the amniotomy group remained undelivered after 24 hours (47.1% vs 67.7%; P < .01). However, the likelihood of an in-hours birth and the length of hospital stay were no different between the groups. There was no difference in the mode of birth or any of the secondary outcomes. After an initial dose of PGE2 vaginal gel, an amniotomy (once technically possible) is associated with a shorter induction of labor-to-birth time compared with the use of repeat doses of PGE2. Administering more PGE2 with the aim of starting contractions or making the cervix "more favorable," appears to have no clinical advantage.

Failure to attain stretched penile length after intracavernosal injection of a vasodilator agent is predictive of veno-occlusive dysfunction on penile duplex Doppler ultrasonography.

Penile duplex Doppler ultrasound (PDDU) assesses the etiology of erectile dysfunction. Peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) are common PDDU parameters. We assessed whether stretched penile length (SPL) in the flaccid state and measured penile length at peak erection after intracavernosal injection (ICI) of a vasodilator during PDDU correlated with the etiology of erectile dysfunction. We performed a retrospective review of 93 patients who underwent PDDU for erectile dysfunction. Normal and stretched penile length were measured, both at a flaccid state prior to ICI and at peak erection during PDDU. Collected data included patient demographics, vascular, and anatomic parameters. The mean age was 52years. SPL was equivalent to peak penile length after ICI in 60 patients (65%, group 1) and did not match in 33 (35%, group 2). There were no significant differences between the two groups in terms of flaccid, stretched, and post-ICI erect penile lengths, IIEF score, PSV, percent rigidity or tumescence, and vasodilator dose used. Patients in group 2 had less of a change in penile length from flaccid to erect state (36% vs. 44%, p=0.02), higher EDV (12.0 vs. 8.5, p=0.041), lower RI (0.6 vs. 1.0, p=0.046), and more veno-occlusive dysfunction (82% vs. 53%, p=0.001). On multivariate analysis, failure to reach maximum SPL at peak ICI erection (OR 2.255, CI 1.191-4.271, p=0.0126), EDV (OR 1.281, CI 1.115-1.471, p<0.001) and RI (OR 0.694, CI 0.573-0.723, p=0.009) predicted veno-occlusive dysfunction. Failure to reach maximal SPL during PDDU using ICI with a vasodilator agent predicted veno-occlusive dysfunction, which is independent of both penile rigidity and tumescence. This measurement could serve as another diagnostic tool for predicting veno-occlusive dysfunction when PDDU is not readily available. Limitations include the subjective nature of penile measurements and different PGE1 doses used.

Abstract IA18: Obesity, inflammation, and pancreatic cancer

Abstract There is epidemiologic evidence that obesity increases the risk of cancers including pancreatic cancer. Several underlying mechanisms, e.g. inflammation and insulin resistance, are proposed. However, the driving mechanisms in pancreatic cancer are poorly understood. We developed a model of diet-induced obesity and pancreatic cancer development in a state-of-the-art mouse model, which resembles important clinical features of human obesity, e.g. weight gain and metabolic disturbances. Offspring of Pdx-1-Cre (or p48-cre) and LSL-KrasG12D crosses were allocated to either a diet high in fats and calories (HFCD; ~4,535 kcal/kg; 40% of calories from fats) or control diet (CD; ~3,725 kcal/kg; 12% of calories from fats) for various time periods. Compared to control animals, mice fed the HFCD significantly gained more weight and developed hyperinsulinemia, hyperglycemia, hyperleptinemia, and elevated levels of IGF-1. Mice fed the HFCD had a substantial increase in visceral fat as measured by micro-CT. The white visceral adipose tissue in mice fed the HFCD showed signs of marked inflammation, which was more pronounced in the peri-pancreatic fat depot. In addition, the pancreas of HFCD-fed animals showed robust signs of inflammation with increased numbers of infiltrating inflammatory cells. Detailed flow cytometry analysis showed a marked elevation of infiltrating natural killer cells, myeloid-derived suppressor cells, T-regulatory cells, and tumor-infiltrating macrophages into the pancreas of mice fed the HFCD. Multiplex analysis demonstrated a significant change in the pancreatic cytokine profile in HFCD-fed mice compared to CD-fed animals. Importantly, the HFCD led to an acceleration of PanIN development in conditional KrasG12D mice. These results demonstrate that a diet high in fats and calories leads to obesity and metabolic disturbances similar to humans and accelerates early pancreatic neoplasia in the conditional KrasG12D mouse model. Based on the notion that obesity is associated with an increase in inflammatory mediators and insulin-resistance and our previous finding that non-steroidal anti-inflammatory drugs inhibit the progression of PanIN lesions in the conditional KrasG12D mouse model, we investigated a potential crosstalk between the PGE2/EP/cAMP and IGF-1/Akt/mTORC1 signaling pathways in pancreatic cancer. In multiple cell lines PGE2 increased intracellular cAMP levels, indicating the activation of Gsα-coupled EP receptors (EP2 and/or EP4). PGE2 dose- and time-dependently increased the phosphorylation of S6 ribosomal protein downstream of mTORC1, suggesting a crosstalk between PGE2/cAMP and mTORC1. In addition, the effect of PGE2 on phospho-S6rp was mimicked by Forskolin, a pharmacological cAMP stimulator. Importantly, PGE2 enhanced the effect of IGF-1 on S6rp phosphorylation, supporting the existence of a positive reinforcement. Interestingly, PGE2 and forskolin had no effect on Akt phosphorylation, suggesting a link downstream of Akt. In the presence of the PKA inhibitor H89, baseline phosphorylation of S6rp and PGE2-activated S6rp phosphorylation were reduced, indicating a role of PKA in the crosstalk. In summary, these data provide evidence of a crosstalk between the PGE2/EP/cAMP and IGF-1/Akt/mTORC1 signaling pathways. Since both pathways are over-activated in obesity-associated cancers, this interaction may be of great importance in elucidating the tumor-promoting effects of obesity in pancreatic cancer. Citation Format: Guido Eibl. Obesity, inflammation, and pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA18.

Prostaglandin E2 Inhibits NLRP3 Inflammasome Activation through EP4 Receptor and Intracellular Cyclic AMP in Human Macrophages.

PGE2 is a potent lipid mediator involved in maintaining homeostasis but also promotion of acute inflammation or immune suppression in chronic inflammation and cancer. Nucleotide-binding domain, leucine-rich repeat-containing protein (NLR)P3 inflammasome plays an important role in host defense. Uncontrolled activation of the NLRP3 inflammasome, owing to mutations in the NLRP3 gene, causes cryopyrin-associated periodic syndromes. In this study, we showed that NLRP3 inflammasome activation is inhibited by PGE2 in human primary monocyte-derived macrophages. This effect was mediated through PGE2 receptor subtype 4 (EP4) and an increase in intracellular cAMP, independently of protein kinase A or exchange protein directly activated by cAMP. A specific agonist of EP4 mimicked, whereas its antagonist or EP4 knockdown reversed, PGE2-mediated NLRP3 inhibition. PGE2 caused an increase in intracellular cAMP. Blockade of adenylate cyclase by its inhibitor reversed PGE2-mediated NLRP3 inhibition. Increase of intracellular cAMP by an activator of adenylate cyclase or an analog of cAMP, or a blockade of cAMP degradation by phosphodiesterase inhibitor decreased NLRP3 activation. Protein kinase A or exchange protein directly activated by cAMP agonists did not mimic, and their antagonists did not reverse, PGE2-mediated NLRP3 inhibition. Additionally, constitutive IL-1β secretion from LPS-primed PBMCs of cryopyrin-associated periodic fever syndromes patients was substantially reduced by high doses of PGE2. Moreover, blocking cytosolic phospholipase A2α by its inhibitor or small interfering RNA or inhibiting cyclooxygenase 2, resulting in inhibition of endogenous PGE2 production, caused an increase in NLRP3 inflammasome activation. Our results suggest that PGE2 might play a role in maintaining homeostasis during the resolution phase of inflammation and might serve as an autocrine and paracrine regulator.