Methods of induction of labor in women with obesity: A secondary analysis of two multicenter randomized controlled trials.

INTRODUCTION: Obesity is an increasing public health concern worldwide and can lead to more complications in pregnancy and childbirth. Women with obesity more often require induction of labor for various indications. The aim of this study is to assess which method of induction of labor is safest and most effective in women with obesity. MATERIAL AND METHODS: This is a secondary analysis of two randomized controlled trials about induction of labor. Women with a term singleton pregnancy in cephalic presentation, an unfavorable cervix, intact membranes and without a previous cesarean section were randomly allocated to cervical priming with a Foley catheter or vaginal prostaglandin-E2-gel (PROBAAT-I) or a Foley catheter or oral misoprostol (PROBAAT-II). The inclusion and exclusion criteria for the studies were identical. Induction methods were compared in women with obesity (body mass index ≥30.0). Main outcomes were cesarean section and postpartum hemorrhage (blood loss >1000 mL). RESULTS: A total of 2664 women, were included in the trials, 517 of whom were obese: 254 women with obesity received a Foley catheter, 176 oral misoprostol and 87 prostaglandin E2 (PGE2). A cesarean section was performed in 29.1% of women allocated to Foley vs 22.2% in the misoprostol and 23.0% in the PGE2 groups. Comparisons between groups revealed no statistically significant differences: the relative risk [RR] was 1.31 (95% confidence interval [CI] 0.94-1.84) in the Foley vs misoprostol group and 1.27 (95% CI 0.83-1.95) in the Foley vs PGE2 group. The rates of postpartum hemorrhage were comparable (10.6%, 11.4% and 6.9%, respectively; P = 0.512). In women with obesity, more often a switch to another method occurred in the Foley group, (20.1% vs 6.3% in misoprostol vs 1.1% in the PGE2 group; P < 0.001). The risk of a failed Foley placement was higher in women with obesity than in women without obesity (8.3% vs 3.2%; adjusted odds ratio 3.12, 95% CI 1.65-5.90). CONCLUSIONS: In women with obesity we found a nonsignificant trend towards an increased rate of cesarean sections in the group induced with a Foley catheter compared to oral misoprostol; however, the study lacked power for this subgroup analysis. The finding of a higher risk of failed placement of a Foley catheter in women with obesity can be used in shared decision making.

Documented Reperfusion of the Retina on Fluorescein Angiography after Administration of Intravenous Prostaglandin E1 for Central Retinal Artery Occlusion: A Case Report.

Central retinal artery occlusion (CRAO) can result in devastating permanent vision loss. Presently, there is no evidence-based treatment for CRAO that is widely accepted. In the literature, multiple studies propose intravenous (IV) prostaglandin E1 (IV PGE1) as a potential treatment option for patients with CRAO. We illustrate 2 cases of CRAO successfully treated with IV PGE1. In both cases, our patients with vascular risk factors were diagnosed with CRAO of the left eye. They were started on twice daily IV 40 µg PGE1 in 100 mL normal saline, with each dose administered over 3 h. In the first case, we documented reperfusion of the retina on fluorescein angiography after administration of IV PGE1. In the second case, our patient improved from no light perception visual acuity (VA) to count fingers VA within 48 h of treatment with IV PGE1. Our study highlights the vasodilatory effect of IV PGE1. Due to its mechanism of action and safety profile, it should be considered a potential treatment option for CRAO. Further randomized controlled trials are necessary to determine the overall therapeutic effect of IV PGE1 for CRAO.

The influence of various induction methods on adverse outcomes in small for gestational age neonates: A secondary analysis of the PROBAAT 1 and 2 trials.

OBJECTIVE: To evaluate the safety aspects of different induction methods in pregnancies with small-for-gestational-age neonates. STUDY DESIGN: This was a secondary analysis of two previously reported multicenter, randomized controlled trials conducted in the Netherlands. In the original trials, women were randomized to either a 30 cc Foley catheter, vaginal prostaglandin E2 (PROBAAT-1) or oral misoprostol (PROBAAT-2). A total of 425 patients with a term, singleton pregnancy in cephalic presentation with an indication for labor induction and a small-for-gestational-age neonate were included in this secondary analysis. Our primary outcome was a composed adverse neonatal outcome of Apgar score < 7 after 5 min and/or a pH in the umbilical artery < 7.05 and/or NICU admission. Secondary outcomes were mode of birth, operative birth for fetal distress and pH < 7.10 in the umbilical artery. For these outcome measures, multivariate as well as bivariate analyses were performed. RESULTS: An adverse neonatal outcome occurred in 4.7 % (10/214) induction with a Foley catheter, versus 12.8 % (19/149) after misoprostol (RR 0.36; 95 % CI 0.17-0.76) and 4.7 % (3/64) after Prostaglandin E2 (RR 0.98; 95 %CI 0.28-3.51). For individual components of the composed outcome of adverse events, a difference was found between a Foley catheter and misoprostol for Apgar score < 7 at 5 min (0.5 % versus 3.4; RR 0.14; 95 %CI 0.02-1.16) and NICU admission (1.9 % versus 6.1 %; RR 0.31; 0.10-0.97). No differences were found for mode of birth. CONCLUSIONS: For women who gave birth to a small-for-gestational-age neonate, a Foley catheter is probably a safer induction method compared to oral misoprostol.

Prostaglandins as a Topical Therapy for Erectile Dysfunction: A Comprehensive Review.

INTRODUCTION: Erectile dysfunction (ED) is a substantial cause of dissatisfaction among many men. This discontentment has led to the emergence of various drug treatment options for this problem. OBJECTIVES: Unfortunately, due to various interactions, contraindications, and side effects, systemic therapies such as phosphodiesterase-5 inhibitors (including sildenafil, tadalafil, vardenafil, avanafil, etc.) are not welcomed in many patients. These problems have led researchers to look for other ways to reduce these complications. METHODS: This article holistically reviews the efficacy of topical prostaglandins and their role in treating ED. We sought to provide a comprehensive overview of recent findings on the current topic by using the extensive literature search to identify the latest scientific reports on the topic. RESULTS: In this regard, topical and transdermal treatments can be suitable alternatives. In diverse studies, prostaglandins, remarkably PGE1 (also known as alprostadil), have been suggested to be an acceptable candidate for topical treatment. CONCLUSION: Numerous formulations of PGE1 have been used to treat patients so far. Still, in general, with the evolution of classical formulation methods toward modern techniques (such as using nanocarriers and skin permeability enhancers), the probability of treatment success also increases. Hamzehnejadi M, Tavakoli MR, Homayoun F et al. Prostaglandins as a Topical Therapy for Erectile Dysfunction: A Comprehensive Review. Sex Med Rev 2022;10:764-781.

Novel Hyperspectral imaging approaches allow 3D measurement of cAMP signals in localized subcellular domains of human airway smooth muscle cells.

Studies of the cAMP signaling pathway have led to the hypothesis that localized cAMP signals regulate distinct cellular responses. Much of this work focused on measurement of localized cAMP signals using cAMP sensors based upon FÓ§rster resonance energy transfer (FRET). FRET-based probes are comprised of a cAMP binding domain sandwiched between donor and acceptor fluorophores. Binding of cAMP triggers a conformational change which alters FRET efficiency. In order to study localized cAMP signals, investigators have targeted FRET probes to distinct subcellular domains. This approach allows detection of cAMP signals at distinct subcellular locations. However, these approaches do not measure localized cAMP signals per se, rather they measure cAMP signals at specific locations and typically averaged throughout the cell. To address these concerns, our group implemented hyperspectral imaging approaches for measuring highly multiplexed signals in cells and tissues. We have combined these approaches with custom analysis software implemented in MATLAB and Python. Images were filtered both spatially and temporally, prior to adaptive thresholding (OTSU) to detect cAMP signals. These approaches were used to interrogate the distributions of isoproterenol and prostaglandin-triggered cAMP signals in human airway smooth muscle cells (HASMCs). Results demonstrate that cAMP signals are spatially and temporally complex. We observed that isoproterenol- and prostaglandin-induced cAMP signals are triggered at the plasma membrane and in the cytosolic space. We are currently implementing analysis approaches to better quantify and visualize the complex distributions of cAMP signals. This work was supported by NIH P01HL066299, R01HL058506, and S10RR027535.

Regular use of ibuprofen reduces rat penile prostaglandins and induces cavernosal fibrosis.

Ibuprofen is a commonly used non-steroidal anti-inflammatory drug that is noted for its favorable safety profile. It exerts its therapeutic effect through inhibition of prostaglandin (PG) production at inflammatory sites. However, the inhibition of PG synthesis at other sites is responsible for the occurrence of adverse events. Evidence regarding the effect of regular ibuprofen intake on penile PG homeostasis or penile histopathologic changes is lacking. The aim of this study was to examine the effect of regular administration of analgesic therapeutic doses of ibuprofen on penile PG E1 and F2α and penile microscopic changes of the treated rats. This study included four groups of adult male Wistar rats; a control group (I) injected intraperitoneally with saline (2 ml/kg/day) for 30 days and 3 ibuprofen-treated groups (IIa, IIb, and IIc) injected intraperitoneally with 6 mg/kg/day, 12 mg/kg/day, and 18 mg/kg/day ibuprofen, respectively, for 30 days, respectively. Mean levels of penile PGE1 and PGF2α in the control group were significantly higher than ibuprofen-treated groups IIa, IIb, and IIc. The percentage area of collagen around cavernous tissue was significantly higher in ibuprofen-treated groups IIa, IIb, and IIc than control rats. Our findings suggest that despite ibuprofen's safety profile, regular use of ibuprofen is associated with reduced penile PG and increased cavernosal fibrosis.

[Efficacy and safety of oral misoprostol 25µg vs. vaginal dinoprostone in induction of labor at term]. / Efficacité et tolérance du misoprostol oral 25µg vs dinoprostone vaginale dans le déclenchement du travail à terme.

OBJECTIVE: To compare the efficacy and safety of oral misoprostol 25µg compared to vaginal dinoprostone in the induction of labor at term. METHODS: Analytic, retrospective study of patients induced at term by prostaglandins with an unfavorable cervix, over two consecutive periods from 01/01/2019 to 19/02/2020 and from 20/02/2020 to 07/04/2021, within a regional level III university hospital center. We compared the safety and the efficacy between the oral misoprostol Angusta® used since 20/02/2020 and the vaginal dinoprostone previously used in gel or diffuser. The primary endpoint was the rate of vaginal deliveries within 24h. Secondary endpoints were cesarean section rate, indications for cesarean section, uterine contractility abnormalities and neonatal outcomes. RESULTS: Our study found no difference in terms of efficacy with similar rates of vaginal deliveries within 24h (51.88% vs. 51.25%; P=0.87) and caesarean sections (misoprostol group: 19.42% vs. dinoprostone group: 16.62%; P=0.33). However, the tolerance criteria revealed in the dinoprostone group an increase in tachysystole (misoprostol group: 9.28% vs. dinoprostone group: 16.90%; P=0.003) and acidosis (arterial pH<7.10, misoprostol group: 3.83% vs. dinoprostone group: 9.29%; P=0.006). CONCLUSION: No difference in efficacy was found between the two induction techniques. Oral misoprostol 25µg seems to be better tolerated from a maternal and fetal point of view.

Prostaglandins as a Topical Therapy for Erectile Dysfunction: A Comprehensive Review.

INTRODUCTION: Erectile dysfunction (ED) is a substantial cause of dissatisfaction among many men. This discontentment has led to the emergence of various drug treatment options for this problem. OBJECTIVES: Unfortunately, due to various interactions, contraindications, and side effects, systemic therapies such as phosphodiesterase-5 inhibitors (including sildenafil, tadalafil, vardenafil, avanafil, etc.) are not welcomed in many patients. These problems have led researchers to look for other ways to reduce these complications. METHODS: This article holistically reviews the efficacy of topical prostaglandins and their role in treating ED. We sought to provide a comprehensive overview of recent findings on the current topic by using the extensive literature search to identify the latest scientific reports on the topic. RESULTS: In this regard, topical and transdermal treatments can be suitable alternatives. In diverse studies, prostaglandins, remarkably PGE1 (also known as alprostadil), have been suggested to be an acceptable candidate for topical treatment. CONCLUSION: Numerous formulations of PGE1 have been used to treat patients so far. Still, in general, with the evolution of classical formulation methods toward modern techniques (such as using nanocarriers and skin permeability enhancers), the probability of treatment success also increases.

The Role of Prostaglandin E1 as a Pain Mediator through Facilitation of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 2 via the EP2 Receptor in Trigeminal Ganglion Neurons of Mice.

Cyclooxygenase metabolizes dihomo-γ-linolenic acid and arachidonic acid to form prostaglandin (PG) E, including PGE1 and PGE2, respectively. Although PGE2 is well known to play an important role in the development and maintenance of hyperalgesia and allodynia, the role of PGE1 in pain is unknown. We confirm whether PGE1 induced pain using orofacial pain behavioral test in mice and determine the target molecule of PGE1 in TG neurons with whole-cell patch-clamp and immunohistochemistry. Intradermal injection of PGE1 to the whisker pads of mice induced a reduced threshold, enhancing the excitability of HCN channel-expressing trigeminal ganglion (TG) neurons. The HCN channel-generated inward current (Ih) was increased by 135.3 ± 4.8% at 100 nM of PGE1 in small- or medium-sized TG, and the action of PGE1 on Ih showed a concentration-dependent effect, with a median effective dose (ED50) of 29.3 nM. Adenylyl cyclase inhibitor (MDL12330A), 8-bromo-cAMP, and the EP2 receptor antagonist AH6809 inhibited PGE1-induced Ih. Additionally, PGE1-induced mechanical allodynia was blocked by CsCl and AH6809. PGE1 plays a role in mechanical allodynia through HCN2 channel facilitation via the EP2 receptor in nociceptive neurons, suggesting a potential therapeutic target in that PGE1 could be involved in pain as endogenous substances under inflammatory conditions.

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.

Prenatal Pericardiocentesis and Postnatal Sirolimus for a Giant Inoperable Cardiac Rhabdomyoma.

We describe the case of an antenatally diagnosed massive cardiac tumor in a fetus requiring cardiorespiratory support immediately following birth. We further discuss the successful management of this case and highlight the importance of a multidisciplinary team in managing such complicated cases. (Level of Difficulty: Advanced.).

Histomorphometry evaluation of bone anabolism promoted by prostaglandin E1 and its relation to hypercalcemia / Evaluación histomorfométrica del anabolismo óseo en la reparación promovida por la prostaglandina E1 y su relación con la hipercalcemia

Abstract Background: At present, parathyroid hormone is the only existing anabolic bone therapy but produces hypercalcemia. Prostaglandin E1 (PGE1) has been suggested as a bone anabolic agent that allows bone modeling formation without producing hypercalcemia. This study aimed to corroborate these PGE1 properties. Methods: For 22 days, rabbits (n = 30) were divided into three groups (n = 10 each group) and received intravenous solutions: vehicle (control group), palate disjunction + vehicle (sham group), and palate disjunction + 50 mg of PGE1 (PGE1 group). On days 1, 3, and 22, palatine suture X-rays were taken. On day 22, bone formation markers were analyzed, and the rabbits were sacrificed. Bone palate undecalcified samples were processed. Histomorphometry software was used to analyze bone parameters, and the mineralization front was stained with toluidine blue. Scalloped lines reflect remodeling-based bone formation (RBF), and smooth lines reflect modeling-based formation (MBF). Results: X-rays showed more significant palatal disjunction in the PGE1 group; this group exhibited significant calcitriol serum increments. Hypercalciuria was observed in the PGE1 group, and resorption markers (N-telopeptides) remained stable. Sutural bones in the PGE1 group exhibited significant anabolism in structural parameters. RBF was 20%, and MBF was 6% in the sham group; in the PGE1 group, RBF was 8.6%, and MBF was 17%. In the PGE1 group, mineralization was significantly accelerated, but resorption remained stable. Conclusions: This model suggests that PGE1 favors palate disjunction, calcitriol synthesis, and shortens the mineralization. Therefore, PGE1 is an important bone anabolic molecule predominantly of modeling-based form and no hypercalcemia.

Resumen Introducción: La hormona paratiroidea es la única molécula anabólica ósea, pero ocasiona hipercalcemia. La prostaglandina E1 (PGE1) sugiere ser un anabólico óseo con formación por modelación predominante y generalmente no ocasiona hipercalcemia. El objetivo de este estudio fue corroborar estas propiedades de la PGE1. Métodos: Por 22 días, 30 conejos divididos en tres grupos (n = 10 cada grupo) recibieron una solución por vía intravenosa: vehículo (grupo control), disyunción palatina más vehículo (grupo sham) y disyunción palatina más 50 mg de PGE1 (grupo PGE1). A los días 1, 3 y 22 se obtuvieron radiografías de la sutura palatina. En el día 22 se analizaron los marcadores bioquímicos de formación ósea y se sacrificó a los conejos. Las suturas y los huesos suturales se procesaron sin descalcificar. La evaluación histomorfométrica fue digitalizada y el frente de mineralización ósea se tiñó con azul de toluidina. Las líneas irregulares reflejan resorción (remodelación) y las líneas rectas no resorción (modelación). Resultados: Radiográficamente, la disyunción palatina fue mayor en el grupo PGE1. Este grupo mostró una hipercalcitonemia significativa, pero la calcemia y los marcadores resortivos (N-telopéptidos) se mantuvieron estables. Por histomorfometría, los huesos suturales del grupo PGE1 mostraron anabolismo significativo en parámetros estructurales. En el grupo sham, la remodelación ósea fue del 20% y la modelación fue del 6%; en el grupo PGE1, la remodelación fue del 8.6% y la modelación fue del 17%. En este mismo grupo, la mineralización fue significativamente acelerada, pero la resorción se mantuvo igual. Conclusiones: Este modelo sugiere que la PGE1 favorece la disyunción palatina y el aumento del calcitriol, y acelera la mineralización y el anabolismo óseo por modelación predominante sin hipercalcemia.

PGE1 triggers Nrf2/HO-1 signal pathway to resist hemin-induced toxicity in mouse cortical neurons.

BACKGROUND: Prostaglandin E1 (PGE1) exerts various pharmacological effects such as membrane stabilization, anti-inflammatory functions, vasodilation, and platelet aggregation inhibition. We have previously demonstrated that PGE1 has a beneficial impact on patients suffering from intracerebral hemorrhage (ICH). The related mechanism underlying PGE1's beneficial effect on ICH treatment needs further exploration. METHODS: The present study elucidates the mechanism of PGE1 on ICH treatment using a neuronal apoptosis model in vitro. The mouse primary cortical neurons were pretreated with different concentrations of PGE1, followed by the treatment with hemin, the main catabolite in whole blood, to mimic the clinical ICH. RESULTS: Comparing with the vehicle-treated group, PGE1 prevented cultured cortical neurons from the accumulation of inhibited intracellular levels of reactive oxygen species (ROS), amelioration of mitochondrial membrane potential, and hemin-induced apoptosis. The reduction of ROS and apoptosis were associated with the up-regulation of Heme oxygenase-1 (HO-1) expression. Knockdown of nuclear transcription factor erythroid 2-related factor (Nrf2) by siRNA attenuated the upregulation of HO-1 as well as the protective effect of PGE1. CONCLUSIONS: Our work suggests that the Nrf2/HO-1 molecular pathway may play a crucial role in treating ICH patients with PGE1 and may represent novel molecular targets, resulting in discovering new drugs for ICH treatment.

Activation of phospholipase A2 by prostaglandin in vitro.

Prostaglandins are a diverse family of biological active molecules that are synthesized after liberation of arachnidonic or linolenic acid from the plasma membrane by phospholipase A2 (PLA2). Specific prostaglandins may be pro-inflammatory or anti-inflammatory due to a poorly understood biochemical equilibrium. Some of the anti-inflammatory prostaglandins namely, prostaglandin A1 (PGA1) and prostaglandin E1 (PGE1) have a cyclopentenone moiety that can react and modify a protein's activity. These two prostaglandins are electrophilic reactive lipid species and are formed as a result of the reaction cascade initiated by PLA2. It was of interest to study the interaction with these prostaglandins as they could either amplify or block this enzyme's activity. We found that the former is true initially as there is a shorter time to activate the protein on the lipid membrane and an overall increase in hydrolysis was observed when PGA1 and PGE1 prostaglandin was added with PLA2 and liposomes. The interfacial activation model was further explored in which there is a modification of the enzyme rather than a modifcation of the substrate. However, after a time the protein was shown to form amyloid like fibrils thereby blocking further hydrolysis. The fibrillization kinetics in the presence of the one of the prostaglandins was monitored using thioflavin T (ThT) and the resulting fibrils were characterized using transmission electron microscopy (TEM) and atomic force microscopy (AFM). Modification of PLA2 by these prostaglandins leading to amyloid like fibrils gives an additional perspective of control of the interfacial activation mechanism of this enzyme.

DUSP-1 Induced by PGE2 and PGE1 Attenuates IL-1ß-Activated MAPK Signaling, Leading to Suppression of NGF Expression in Human Intervertebral Disc Cells.

The molecular mechanism of discogenic low back pain (LBP) involves nonphysiological nerve invasion into a degenerated intervertebral disc (IVD), induced by nerve growth factor (NGF). Selective cyclooxygenase (COX)-2 inhibitors are mainly used in the treatment of LBP, and act by suppressing the inflammatory mediator prostaglandin E2 (PGE2), which is induced by inflammatory stimuli, such as interleukin-1ß (IL-1ß). However, in our previous in vitro study using cultured human IVD cells, we demonstrated that the induction of NGF by IL-1ß is augmented by a selective COX-2 inhibitor, and that PGE2 and PGE1 suppress NGF expression. Therefore, in this study, to elucidate the mechanism of NGF suppression by PGE2 and PGE1, we focused on mitogen-activated protein kinases (MAPKs) and its phosphatase, dual-specificity phosphatase (DUSP)-1. IL-1ß-induced NGF expression was altered in human IVD cells by MAPK pathway inhibitors. PGE2 and PGE1 enhanced IL-1ß-induced DUSP-1 expression, and suppressed the phosphorylation of MAPKs in human IVD cells. In DUSP-1 knockdown cells established using small interfering RNA, IL-1ß-induced phosphorylation of MAPKs was enhanced and prolonged, and NGF expression was significantly enhanced. These results suggest that PGE2 and PGE1 suppress IL-1ß-induced NGF expression by suppression of the MAPK signaling pathway, accompanied by increased DUSP-1 expression.

Duloxetine strengthens osteoblast activation by prostaglandin E1: Upregulation of p38 MAP kinase.

Duloxetine, a serotonin-norepinephrine reuptake inhibitor, is currently recommended as a useful medicine to chronic pain including low back pain. However, as the analogy of classical selective serotonin reuptake inhibitors, there is a concern to deteriorate osteoporosis with remaining to clarify the exact mechanism of duloxetine in bone metabolism. We have previously reported that prostaglandin E1 (PGE1) induces the synthesis of both osteoprotegerin (OPG) and interleukin-6 (IL-6), essential regulators of bone metabolism, in osteoblast-like MC3T3-E1 cells. Based upon them, we herein investigated the mechanism whereby the effect of duloxetine on the synthesis of OPG and IL-6 induced by PGE1 in these cells. Duloxetine enhanced the release from MC3T3-E1 cells of both OPG and IL-6 stimulated by PGE1. However, reboxetine, a selective and specific inhibitor of norepinephrine reuptake, failed to affect the PGE1-induced release of OPG or IL-6. Oppositely, fluvoxamine and sertraline, agents belonging to the class of selective serotonin reuptake inhibitor, upregulated the PGE1-stimulated release of both OPG and IL-6. Duloxetine amplified the expression of OPG mRNA and IL-6 mRNA stimulated by PGE1. Duloxetine strengthened the PGE1-induced p38 MAP kinase phosphorylation, which was amplified by fluvoxamine as well. SB203880, an inhibitor of p38 MAP kinase, suppressed the amplifying effects by duloxetine or fluvoxamine on the PGE1-stimulated release of OPG and IL-6. These results strongly suggest that duloxetine could strengthen osteoblast activation by PGE1 through the upregulation of p38 MAP kinase, leading to increasing the synthesis of OPG and IL-6.

Prostaglandin E1 Improves Cerebral Microcirculation Through Activation of Endothelial NOS and GRPCH1.

Endothelial dysfunction greatly contributes to microcirculation disorder. The role of prostaglandin E1 (PGE1) in cerebral microcirculation was explored in vitro. LPS (0.5 or 1 µg/ml) was added to induce injury in human brain microvascular endothelial cells (HCMEC/D3). CCK-8 was applied to check viabilities of HCMEC/D3 before and after LPS treatment. Western blot witnessed the changes in protein expressions of inflammatory cytokines, IL-6 and TNF-α. Caspase-3/7 activity was analyzed and so were the protein expressions of pro-apoptotic gene BAX and anti-apoptotic gene Bcl-2. mRNA expressions of eNOS and GTPCH1 were evaluated by RT-qPCR. After overexpressing eNOS or GTPCH1 in LPS-induced HCMEC/D3 cells, viabilities, inflammatory cytokines, caspase-3/7 activity, and apoptosis-related genes were detected. The modulation of PGE1 in eNOS and GTPCH1 production, viability, inflammation, and apoptosis was investigated. The inhibitor of eNOS or GTPCH1 was introduced to examine impacts of eNOS or GTPCH1 could have on the PGE1 function. LPS decreased cell viabilities, eNOS and GTPCH1 expression, and promoted inflammation and apoptosis in HCMEC/D3 cells. Overexpressed eNOS or GTPCH1 promoted cell viabilities and suppressed inflammation and apoptosis. PGE1 enhanced viability and decreased inflammation and apoptosis in cells treated by LPS. PGE1 activated eNOS and GTPCH1 and inhibition of eNOS or GTPCH1 led to the attenuation of the protective functions of PGE1 in LPS-induced cells. PGE1 protected HCMEC/D3 cells from injuries induced by LPS by activation of eNOS and GTPCH1, suggesting that PGE1 might be used to help maintain cerebral microcirculation in future.

Multiparametric MRI Evaluation of Liposomal Prostaglandins E1 Intervention on Hepatic Warm Ischemia-Reperfusion Injury in Rabbits.

BACKGROUND: Liposomal prostaglandin E1 (Lipo-PGE1) treatment should protect against hepatic warm ischemia-reperfusion injury (WIRI). Improved methods are needed for the noninvasive evaluation of hepatic responses to prophylactic Lipo-PGE1 pretreatment approaches. PURPOSE: To demonstrate that multiparametric MRI measurements permit noninvasive differentiation of Lipo-PGE1 treatment outcomes in a hepatic WIRI animal model. STUDY TYPE: Animal study. ANIMAL MODEL: Seventy rabbits were randomly divided into a sham-operated group (A0), warm ischemia groups experiencing increasing periods of ischemia (A1-A3), and corresponding intervention groups (I1-I3) (n = 10 for each group). FIELD STRENGTH/SEQUENCE: Imaging was performed at 3T using a multiecho gradient echo (GRE) sequence (repetition time / echo time [TR/TE], 75/2.57-24.25 msec) for R2* blood oxygenation level-dependent (BOLD) measurements, free-breathing single-shot echo-planar imaging (ss-EPI) sequence with two b-values (0 and 500 s/mm2 ) in 12 diffusion directions for diffusion tensor imaging (DTI), and a free-breathing ss-EPI sequence with eight b-values (0 to 800 s/mm2 ) for intravoxel incoherent motion (IVIM) measurements. ASSESSMENT: The BOLD-derived parameter (R2*), DTI-derived parameters (ADC, FA), and IVIM-derived parameters (Dslow, Dfast, and PF) were calculated for comparisons between treatment groups and correlation to ALT, AST, and LDH levels. STATISTICAL TESTS: One-way analysis of variance (ANOVA), independent sample t-test, Spearman correlation, and receiver operating characteristic (ROC) analysis were performed. RESULTS: Histopathology confirmed the validity of the WIRI model and the efficacy of intervention with clear structure and morphology differences between the different ischemia times and between the Lipo-PGE1 treatment and control groups. Prolonged warm ischemia times resulted in higher R2* and FA values and gradually lower ADC, Dslow, Dfast, and PF values (all P < 0.05). The R2* and FA values were lower, and the ADC, Dslow, Dfast, and PF values were higher in the Lipo-PGE1 intervention groups compared with those in the warm ischemia group for each paired time. However, none of the parameters reached the levels of the A0 group (all P < 0.05). As the warm ischemia time increased, additional parameters demonstrated significant differences between warm ischemia time groups and corresponding intervention groups. At the shortest (30 min), middle (40 min), and longest (60 min) ischemia times, three, four, and five parameters were significantly different between the WIRI and intervention groups, respectively (all P < 0.05). ADC, Dslow, Dfast, and PF values were negatively correlated, while R2* and FA values were positively correlated with serum ALT (|r| = 0.312-0.606) and AST (|r| = 0.432-0.602) (all P < 0.05). ADC and Dfast values showed negative correlations, and R2* showed positive correlations with serum LDH (|r| = 0.323-0.542, all P < 0.05). ROC analysis showed that DTI yielded the strongest diagnostic performance for evaluating the improvement of WIRI. DATA CONCLUSION: Multiparametric MRI can serve as a noninvasive radiologic evaluation for monitoring the protective impact of Lipo-PGE1 therapy on hepatic WIRI. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;52:217-228.

PGE1-Containing Protocols Generate Mature (Leukemia-Derived) Dendritic Cells Directly from Leukemic Whole Blood.

Dendritic cells (DCs) and leukemia-derived DC (DCleu) are potent stimulators of various immunoreactive cells and they play a pivotal role in the (re-) activation of the immune system. As a potential treatment tool for patients with acute myeloid leukemia, we developed and analyzed two new PGE1-containing protocols (Pici-PGE1, Kit M) to generate DC/DCleu ex vivo from leukemic peripheral blood mononuclear cells (PBMCs) or directly from leukemic whole blood (WB) to simulate physiological conditions. Pici-PGE1 generated significantly higher amounts of DCs from leukemic and healthy PBMCs when compared to control and comparable amounts as the already established protocol Pici-PGE2. The proportions of sufficient DC-generation were even higher after DC/DCleu-generation with Pici-PGE1. With Kits, it was possible to generate DCs and DCleu directly from leukemic and healthy WB without induction of blast proliferation. The average amounts of generated DCs and DCleu-subgroups were comparable with all Kits. The PGE1 containing Kit M generated significantly higher amounts of mature DCs when compared to the PGE2-containing Kit K and increased the anti-leukemic-activity. In summary PGE1-containing protocols were suitable for generating DC/DCleu from PBMCs as well as from WB, which reliably (re-) activated immunoreactive cells, improved the overall ex vivo anti-leukemic activity, and influenced cytokine-release-profiles.