Prostaglandins In Regulation Research Articles

Interleukin-1 beta treatment alters prostaglandin-related mRNA expression and cytokine abundance in equine endometrial culture

Interleukin-1β (IL-1β) is a proinflammatory cytokine that modulates the immunoinflammatory response and induces prostaglandin synthesis. IL-1β has a variety of roles in the endometrium during inflammation, decidualization, pregnancy, and post-partum. It can cause changes in endometrial gene expression and may affect cytokine, chemokine, and prostaglandin-related pathways. The relationship between IL-1β, prostaglandins, and downstream inflammatory responses in the equine uterine environment is not fully known. Our objective was to determine the effect that IL-1β has on prostaglandin-related gene expression, as well as cytokine and chemokine abundance, in endometrial cell culture. Light breed mares (n=8) were examined daily by transrectal ultrasound until ovulation. An endometrial biopsy was collected at day 11 post ovulation, and used for primary endometrial cell culture. Cells were cultured in DMEM with 10% FBS. At 80% confluence, cells were either not supplemented or supplemented with: 100 nM Progesterone (Prog); 1 nM Estradiol-17β (Est); or 100 nM Prog and 1 nM Est (P+E). After 24 hours, cells were treated with recombinant equine IL-1β at either 10 ng/mL (Low) or 1000 ng/mL (High), or 0.2% DMSO as an untreated control. Twenty-four hours post-treatment, supernatant was collected, and a bead-based multiplex assay was used to quantify concentration of twelve cytokines and chemokines. Total RNA was extracted from the cells and mRNA expression was evaluatedfor 10 prostaglandin-related genes, using the ΔCT method with ACTB as the reference gene. Data analysis was performed using JMP Pro 16, using a restricted maximum likelihood model with treatment and supplementation as factors, and mare as a random factor. Treatment with IL-1β High resulted in increased levels of CCL2, CCL5, and CCL11 (p<0.001) in cell culture supernatant, as well as increased mRNA expression of PTGS2 (p<0.02), regardless of supplementation. Cells supplemented with Prog or P+E and treated with IL-1β High had increased expression of IL1R1, IL1RAP, PTGS1, and PTGES compared to non-supplemented cells (p<0.05). IL-1β High treatment increased LiF expression in cells supplemented with Prog or P+E compared to untreated cells (p<0.05). IL-1β likely acts to modulate inflammatory pathways in the endometrium, altering chemokine levels and activating expression of PTGS2, leading to changes in downstream prostaglandin synthesis and other related pathways. Progesterone appears to increase expression of several target genes when compared to non-supplemented cells. Progesterone has been shown to be involved in the suppression of several inflammatory pathways, and investigation into the ovarian steroid regulation of genes and proteins in the equine endometrium is warranted. Further studies on the effect of IL-1β on molecular pathways and prostaglandin regulation could lead to a greater understanding of the uterine environment in the pregnant and non-pregnant mare.

Differential gene expression in the equine endometrium and conceptus from Day 11 to 16 post-ovulation

Mobility of the equine conceptus is essential for maternal recognition of pregnancy (MRP) and is regulated by the conceptus's own derived prostaglandin secretion. Our objective was to compare prostaglandin-related genes and other genes of interest during the expected MRP time. Light breed mares were examined daily by transrectal ultrasound when in estrus until the day (D) of ovulation. Mares in the pregnant (P) group were bred by artificial insemination with >500 million progressively motile normal sperm from one fertile stallion until D0. Conceptuses were detected and measured via transrectal ultrasound and collected via uterine lavage using 0.9% NaCl through a transcervical bivona catheter. Endometrium was collected via a transcervical biopsy punch following conceptus retrieval. Endometrium of non-pregnant (NP) mares was collected at: D11 (NP11; n=6) and D13 (NP13; n=7), while endometrium from the pregnant horn and conceptuses was collected at D11 (P11; n=7), D13 (P13; n=8), and D16 (P16; n=6). Total RNA from trophoblast and endometrial samples was isolated and evaluated for expression of PTGS2, PTGES, mPGES2, PTGER4, PTGER2, PTGIS, PTGIR, HPGD, SLCO2A1, CRTC2, NR3C1, CBR1, CREB, NF-Kβ, SPP1, IGFBP1, ESR1 and DNTTIP2 using Real-time PCR. Mean threshold cycle was determined and normalized to the reference gene (GAPDH and ACTB) (ΔCT). Statistical analyses were performed using JMP Pro 16, and data was ranked, transformed if necessary, followed by a restricted maximum likelihood model with mare as arandom factor to test differences between Groups and Day. Regarding endometrial mRNA, NP11 had higher expression for NF-Kβ, PTGIS, PTGIR and CBR1 compared to NP13 (p<0.007). ESR1, mPGES2, PTGIS, and CBR1 mRNA were higher in P11 compared to P16 (p<0.05), while CRTC2 was higher in P16 compared to P11 (p<0.06). Lastly, NF-Kβ, PTGIR and CBR1 were higher in P11 compared to P13 (p<0.01), but NF-Kβ P13 was lower compared to P16 (p<0.04). Regarding the conceptuses, CREB and PTGFR expressions were higher in D16 compared to D11 (p<0.003), while CRTC2, NR3C1, NF-Kβ and SPP1 were higher in D16 compared to D11 and 13 (p<0.02). D13 conceptuses had lower expression of HPGD compared to D11 and 16 (p<0.02). Lastly, D11 conceptuses had higher expression of mPGES2, PTGIS and PTGER4 compared to D13 and D16 (p<0.03). Higher expression of D11 PTGIS from both tissues may increase nutrient and blood flow to the endometrium in support of the early conceptus. The upregulation of endometrial NF-Kβ at D11 may be a result of endometrial receptivity through the regulation of inflammation, and the up-regulation of HPGD may function to regulate PGE2 during early pregnancy. Understanding embryonic and endometrial prostaglandin regulation during MRP may help to develop future therapies to ameliorate pregnancy loss in the horse.

PPARγ/mTOR Regulates the Synthesis and Release of Prostaglandins in Ovine Trophoblast Cells in Early Pregnancy.

Trophoblast cells synthesize and secrete prostaglandins (PGs), which are essential for ruminants in early gestation to recognize pregnancy. Hormones in the intrauterine environment play an important role in regulating PGs synthesis during implantation, but the underlying mechanism remains unclear. In this study, co-treatment of sheep trophoblast cells (STCs) with progesterone (P4), estradiol (E2), and interferon-tau (IFN-τ) increased the ratio of prostaglandin E2 (PGE2) to prostaglandin F2α (PGF2α) and upregulated peroxisome proliferator-activated receptor γ (PPARγ) expression, while inhibiting the mechanistic target of rapamycin (mTOR) pathway and activating cellular autophagy. Under hormone treatment, inhibition of PPARγ activity decreased the ratio of PGE2/PGF2α and cellular activity, while activating expression of the mTOR downstream marker-the phosphorylation of p70S6K (p-p70S6K). We also found that the PPARγ/mTOR pathway played an important role in regulating trophoblast cell function. Inhibition of the mTOR pathway by rapamycin increased the ratio of PGE2/PGF2α and decreased the expression of apoptosis-related proteins after inhibiting PPARγ activity. In conclusion, our findings provide new insights into the molecular mechanism of prostaglandin regulation of trophoblast cells in sheep during early pregnancy, indicating that the PPARγ/mTOR pathway plays an important role in PGs secretion and cell viability.

Expression of Oxytocin/Neurophysin I and Oxytocinase in the Equine Conceptus from Day 8 to Day 21 Post-Ovulation.

Simple SummaryOxytocinase is an enzyme that breaks down oxytocin in serum and tissues. The presence of oxytocin and oxytocinase mRNA and protein and their relationship to other genes in the horse embryo/conceptus that regulate pregnancy recognition and embryo/conceptus fixation have not been investigated. Our objective was to characterize the expression of oxytocin, oxytocinase and other related genes in horse embryos. Oxytocinase was increased at D15 compared to D10 and was identified in the horse embryo membranes. Oxytocin expression was highest at D21, and lowest on D12 and D14; no protein was identified, while its receptor (OXTR) was highest on D14 and D21. Oxytocinase was highest at D15 compared to D10 and high expression of prostaglandin E synthase was found on D14, D15 and D21. Oxytocinase may have a role in embryonic fixation. Further investigation of the role of oxytocinase during pregnancy is warranted.Leucyl and cystinyl aminopeptidase (LNPEP/oxytocinase) is an enzyme that metabolizes oxytocin in serum and tissues. The presence of oxytocin/neurophysin I (OXT), oxytocin and LNPEP and their relationship to other genes is unknown in the equine conceptus. Our objective was to characterize gene expression of LNPEP and OXT on D8, 10, 12, 14, 15, 16 and 21 conceptuses in relationship to other genes. Immunohistochemistry, western blot and liquid chromatography with tandem mass spectrometry (LC-MS/MS) were used for identification of oxytocin and LNPEP in D15, 16 and 18 conceptuses. LNPEP was increased at D15 compared to D10, was immunolocalized in the equine trophectoderm and endoderm, and protein was confirmed by LC-MS/MS. Maximal abundance of OXT was at D21, and lowest on D12 and D14, but no protein was identified. OXTR abundance was highest on D14 and D21. LNPEP was correlated with PTGFR and PTGES on D12 and D14–D15, and high expression of PTGES, PTGS2 was found on D14, D15 and D21; PTGFR was found on D8 and D12–21. LNPEP may have a role in prostaglandin regulation and conceptus fixation by decreasing the availability of oxytocin. Further investigation on the role embryonic LNPEP during pregnancy is warranted.

Prostaglandin regulation of type 2 inflammation: From basic biology to therapeutic interventions.

Type 2 immunity is critical for the protective and repair responses that mediate resistance to parasitic helminth infection. This immune response also drives aberrant inflammation during atopic diseases. Prostaglandins are a class of critical lipid mediators that are released during type 2 inflammation and are integral in controlling the initiation, activation, maintenance, effector functions, and resolution of Type 2 inflammation. In this review, we explore the roles of the different prostaglandin family members and the receptors they bind to during allergen‐ and helminth‐induced Type 2 inflammation and the mechanism through which prostaglandins promote or suppress Type 2 inflammation. Furthermore, we discuss the potential role of prostaglandins produced by helminth parasites in the regulation of host–pathogen interactions, and how prostaglandins may regulate the inverse relationship between helminth infection and allergy. Finally, we discuss opportunities to capitalize on our understanding of prostaglandin pathways to develop new therapeutic options for humans experiencing Type 2 inflammatory disorders that have a significant prostaglandin‐driven component including allergic rhinitis and asthma.

Gene expression profiling of brain endothelial cells after experimental subarachnoid haemorrhage

Subarachnoid haemorrhage (SAH) is a type of hemorrhagic stroke that is associated with high morbidity and mortality. New effective treatments are needed to improve outcomes. The pathophysiology of SAH is complex and includes early brain injury and delayed cerebral ischemia, both of which are characterized by blood–brain barrier (BBB) impairment. We isolated brain endothelial cells (BECs) from mice subjected to SAH by injection of blood into the prechiasmatic cistern. We used gene expression profiling to identify 707 unique genes (2.8% of transcripts, 403 upregulated, 304 downregulated, 24,865 interrogated probe sets) that were significantly differentially expressed in mouse BECs after SAH. The pathway involving prostaglandin synthesis and regulation was significantly upregulated after SAH, including increased expression of the Ptgs2 gene and its corresponding COX-2 protein. Celecoxib, a selective COX-2 inhibitor, limited upregulation of Ptgs2 in BECs. In this study, we have defined the gene expression profiling of BECs after experimental SAH and provide further insight into BBB pathophysiology, which may be relevant to other neurological diseases such as traumatic brain injury, brain tumours, ischaemic stroke, multiple sclerosis, and neurodegenerative disorders.

Maternal Recognition of Pregnancy in the Horse: Are MicroRNAs the Secret Messengers?

The signal for maternal recognition of pregnancy (MRP) has still not been identified in the horse. High-throughput molecular biology at the embryo–maternal interface has substantially contributed to the knowledge on pathways affected during MRP, but an integrated study in which proteomics, transcriptomics and miRNA expression can be linked directly is currently lacking. The aim of this study was to provide such analysis. Endometrial biopsies, uterine fluid, embryonic tissues, and yolk sac fluid were collected 13 days after ovulation during pregnant and control cycles from the same mares. Micro-RNA-Sequencing was performed on all collected samples, mRNA-Sequencing on the same tissue samples and mass spectrometry was conducted previously on the same fluid samples. Differential expression of miRNA, mRNA and proteins showed high conformity with literature and confirmed involvement in pregnancy establishment, embryo quality, steroid synthesis and prostaglandin regulation, but the link between differential miRNAs and their targets was limited and did not indicate the identity of an unequivocal signal for MRP in the horse. Differential expression at the embryo–maternal interface was prominent, highlighting a potential role of miRNAs in embryo–maternal communication during early pregnancy in the horse. These data provide a strong basis for future targeted studies.

ASSOCIATION OF PLASMA COX-2 LEVELS AND ITS GENETIC VARIANTS WITH SALT SENSITIVITY OF BLOOD PRESSURE, BLOOD PRESSURE CHANGES AND HYPERTENSION INCIDENCE IN CHINESE ADULTS

Objective: Cyclooxygenase (COX)-2, inducible isoform of a major rate-limiting enzyme, contributes to the regulation of prostaglandins, which associates with injury, inflammation and proliferation. We sought to examine the associations of serum COX-2 levels and its genetic variants with salt sensitivity, BP changes and hypertension incidence in humans. Design and method: 1. 80 subjects (18–65 years old) were sequentially maintained on a normal diet for 3 days at baseline, a low-salt diet for 7 days (3.0 g/day), and a high-salt diet for an additional 7 days (18.0 g/day). Serum COX-2 levels were measured by ELISA kits. 2. A total of 539 subjects from 124 families were recruited from rural areas of Northern China in 2004. All subjects were given salt intake intervention, which was similar to protocol 1. We followed up this cohort in 2009, 2012 and 2018, respectively. 13 SNPs in COX-2 gene were genotyped to investigate the associations with BP responses to strict dietary salt intervention, and with BP changes during the follow-ups and incident hypertension. Results: 1. Plasma COX-2 levels significantly decreased with the change from baseline to low-salt diet (9.07 ± 0.30 vs. 7.47 ± 0.32 ng/mL, P < 0.001) and further decreased from the low-salt to high-salt one (7.47 ± 0.32 vs. 6.51 ± 0.19 ng/mL, P < 0.001). 24 h urinary sodium excretions were inversely correlated with plasma COX-2 (r = −0.185, P = 0.019) during both low-salt and high-salt diet intervention periods. 2. SNPs rs20417 and 1119231 of the COX-2 gene were significantly associated with systolic BP (SBP) and mean arterial pressure (MAP) responses to high-salt intervention. In addition, COX-2 SNP rs689466 were significantly associated with longitudinal changes in SBP after adjustment for multiple testing (P = 0.008). SNPs rs2066826 and rs689466 in COX-2 were associated with increased risk of developing hypertension (P = 0.023 and 0.037, respectively).Conclusions: The current study suggests that variations in dietary salt intake affect plasma COX-2 levels, and COX-2 may be involved in pathophysiological process of salt sensitivity, BP progression and hypertension incidence in the Chinese population.

NF-κB targeting for overcoming tumor resistance and normal tissues toxicity.

Radiotherapy andchemotherapy are two famous modalities in tumor-targeted therapy that lead to systemic and local toxicities for normal tissues. Moreover, several studies have confirmed that exposure of the tumor to radiation or chemotherapy drugs stimulate some signaling pathways in the tumor microenvironment (TME), leading to resistance of cancer cells to apoptosis, as well as promoting angiogenesis and tumor growth. Nuclear factor kappa B (NF-κB) plays a central role in the regulation of inflammatory responses in both normal tissues and tumors via the release of several cytokines, regulation of prostaglandins, reduction/oxidation (redox) reactions, angiogenesis, and cell death. Upregulation of NF-κB in normal tissues causes an appearance of inflammatory reactions and oxidative stress, whereas it regulates angiogenesis and suppresses apoptosis, leading to resistance to subsequent doses of radiation or chemotherapy. Selective inhibition of NF-κB in experimental studies has shown promising results for tumor sensitization via apoptosis induction, inhibition of angiogenesis, and increasing delay of tumor growth. The use of some agents for NF-κB inhibition has been shown to alleviate radiation/chemotherapy toxicities in normal cells/ tissues. In this current review, we explained the pivotal role of NF-κB in both normal tissue toxicity and tumor resistance. We also discussed the promising strategies for overcoming these problems with regard to chemotherapy and radiotherapy.

Oral administration of oat beta-glucan preparations of different molecular weight results in regulation of genes connected with immune response in peripheral blood of rats with LPS-induced enteritis

PurposeBeta-glucans are biologically active polysaccharides having antioxidant, immunomodulatory, and antiinflammatory properties. This study investigated the transcriptomic profile in peripheral blood of rats with LPS-induced enteritis, which were fed a diet supplemented with high- (G1) and low- (G2) molecular-weight oat beta-glucans.MethodsTwo-color rat gene expression microarrays were applied and the analysis was performed using a common reference design to provide easy means of comparing samples from various experimental conditions against one another. Common reference sample was labeled with cyanine 3 (Cy3) and investigated samples from each experimental group: C-G0 (control group fed semi-synthetic diet), LPS-G0 (LPS-challenged group fed semi-synthetic diet), LPS-G1 (LPS-challenged group fed G1 beta-glucan enriched diet), and LPS-G2 (LPS-challenged group fed G2 beta-glucan enriched diet) were labeled with cyanine 5 (Cy5). Each microarray was performed in quadruplicate. Statistical analysis was performed using one-way ANOVA and Tukey’s HSD post-hoc test (p < 0.05). A multiple testing correction was performed using Benjamini and Hochberg False Discovery Rate < 5%. A quantitative real-time RT-PCR was performed to verify the expression of chosen transcripts.ResultsThe microarray analyses revealed differentially expressed transcripts between: the LPS-G0 and the control groups: C-G0 (138 genes), the LPS-G1 and LPS-G0 groups (533 genes), and the LPS-G2 and LPS-G0 groups (97 genes). Several differentially expressed genes in the beta-glucan-supplemented groups encoded proteins belonging to TLR and NLR signaling pathways, as well as prostaglandin synthesis and regulation pathways. Both beta-glucans up-regulated the expression of Atg10, which belongs to the family of autophagy-related genes, suggesting a possible link between autophagy induction and beta-glucan supplementation.ConclusionThe changes in gene expression observed in the peripheral blood indicate that oat beta-glucans exerted a protective effect in rats with an induced inflammatory state caused by LPS challenge. The greater number of differentially expressed genes was observed in group supplemented with G1 beta-glucan, pointing at the differences in the mode of action of high- and low-molecular-weight beta-glucans in the organism.

Effect of fish meal supplementation on luteal sensitivity to intrauterine infusions of prostaglandin F2α in the bovine.

Progesterone is a steroid hormone secreted from the corpus luteum (CL), which is responsible for establishment and maintenance of pregnancy. Early embryonic mortality often occurs due to inadequate regulation of uterine prostaglandin (PG) F2α secretion, leading to a decrease in progesterone and loss of pregnancy. The objective of the current study was to determine the effects of fish meal supplementation on luteal sensitivity to intrauterine infusions of PGF2α. Nonlactating beef cows received corn gluten meal or fish meal supplementation for 60 days. Cows were administered four intrauterine infusions of 0.25 mL saline at 6-h intervals (n=6 corn gluten meal; n=5 fish meal) or two doses of 0.5 mg PGF2α in 0.25 mL saline at 12-h intervals (n=11 corn gluten meal; n=11 fish meal) commencing on days 10 to 12 of the estrous cycle. At time of each infusion, luteal biopsies were collected to determine the effects of supplementation on expression of immediate early and steroidogenic genes involved in cholesterol transport and progesterone biosynthesis. Transrectal ultrasonography was performed to measure diameter of CL, and blood samples were collected to determine serum progesterone. Intrauterine infusion of PGF2α resulted in upregulation or no change in FOS, NR4A1, and 3BHSD and downregulation in LDLR, STARD1, and CYP11A1. Although CL diameter decreased, infusion of PGF2α resulted in functional regression in 91% of cows supplemented with corn gluten meal, and only 46% for fish meal supplemented animals. Results demonstrate that fish meal supplementation alters luteal sensitivity to PGF2α, which may affect fertility.

Update on COX-2 Selective Inhibitors: Chemical Classification, Side Effects and their Use in Cancers and Neuronal Diseases.

Inflammation is a complex phenomenon necessary in human defense mechanisms but also involved in the development of some human diseases. The discovery of cyclooxygenase-2 (COX- 2) improved the pharmacology of nonsteroidal anti-inflammatory drugs (NSAID) giving a clear mechanism for prostaglandin regulation in vivo and providing a new target for the development of COX-2-selective drugs without gastrointestinal side-effects. Keeping in view the importance of this pharmacological class, several literature reports have underlined the impact of these antiinflammatory compounds in therapeutics. The present review considers the most recently published literature concerning COX-2 inhibitors until 2016. Through a wide chemical classification, the last developments concerning this therapeutic family by highlighting structure-activity relationships insights and mechanisms are presented. A summary of the principal adverse effects observed and an overview of the new potential therapeutic indications for COX-2 inhibitors are also reported.

MPGES-1-Derived PGE2 Contributes to Indoxyl Sulfate-Induced Mesangial Cell Proliferation

Background/Aims: We previously reported that indoxyl sulfate (IS) could cause mesangial cell (MC) proliferation via a cyclooxygenase (COX)-2-dependent mechanism. However, the specific prostaglandin contributing to COX-2 effect on IS-induced MC proliferation remained unknown. Thus, the present study was undertaken to examine the role of microsomal prostaglandin E synthase-1 (mPGES-1)-derived Prostaglandin E2 (PGE₂) in IS-induced MC proliferation. Methods: IS was administered to the MCs with or without mPGES-1 siRNA pretreatment to induce the MC proliferation which was determined by cell cycle analysis, DNA synthesis, and the expressions of cyclins. In another experimental setting, PGE₂ was applied to the MCs to examine its direct effect on MC proliferation, as well as the regulation of prostaglandin E receptors (EPs) by qRT-PCR. Results: With the administration of IS, mPGES-1(not mPGES-2 and cytosolic PGES) was significantly upregulated at both protein and mRNA levels in line with a promoted MC proliferation. Interestingly, silencing mPGES-1 reduced cell number in S and G2 phases and blocked the upregulation of cyclin A2 and cyclin D1 in parallel with blunted PGE₂ release after IS treatment, indicating that mPGES-1-derived PGE₂ could contribute to MC proliferation. Furthermore, we confirmed that exogenous PGE₂ could directly trigger the proliferative response in MCs. Lastly, we observed a selective upregulation of EP2 after PGE2 treatment and enhanced phosphorylation of NF-κB following IS administration in MCs, suggesting the potential involvements of EP2 and NF-κB in this pathological process. Conclusion: mPGES-1-derived PGE₂ contributed to IS-induced mesangial cell proliferation.

Mutation Burden in Multiple Myeloma Is Captured By Gene Expression Profiles

Mutation Burden in Multiple Myeloma Is Captured By Gene Expression Profiles

Transcriptional regulation of microsomal prostaglandin E synthase 1 by the proto-oncogene, c-myc, in the pathogenesis of inflammation and cancer

Pro-inflammatory molecules play a key role in the progression of various types of cancers highlighting the importance of studying the pathways that regulate the inflammatory cytokine production. To this end, prostaglandins have been reported to correlate with exacerbated cancer phenotypes that may be prevented by using anti-inflammatory drugs in humans. To understand how the prostaglandin E synthase 1 (mPGES1) may be regulated we analyzed its promoter sequence and identified myc-binding sites. Functional validation was performed by mutating the sites that led to attenuated promoter activation of mPGES1. The known c-myc inhibitor (10058-F4) also blocked PGE2 activity, indicating the importance of c-Myc in PGE2 synthesis. Isocoumarin analogs were able to reduce the expressions of both c-myc as well as mPGES1 and also inhibit the production of PGE2. Based on these data and the well-established role of c-myc in oncogenesis, we have demonstrated an additional role of c-myc in exacerbating cancers via PGE2 production, which may provide a therapeutic opportunity to treat these diseases.

Regulation of inducible prostaglandin E synthase-1 (mPGES-1) expression in human OA chondrocytes

Regulation of inducible prostaglandin E synthase-1 (mPGES-1) expression in human OA chondrocytes

Peroxisome proliferator-activated receptors in the regulation of female reproductive functions.

Peroxisome proliferator-activated receptors (PPARs) belong to a ligand-dependent nuclear receptor family. In the past decade, numerous studies have revealed the presence and significance of PPARs in the reproductive system. PPARs are expressed at different levels of hypothalamic-pituitary-gonadal (HPG) axis. They are also present in the uterus as well as in the placenta and embryonic tissues of different species. PPARs significance has been reported during the estrous/menstrual cycle and pregnancy with the gamma isoform studied most frequently. Several studies indicate that PPARs regulate proliferation of ovarian cells, tissue remodeling and steroidogenesis. In the endometrium, PPARs are engaged in the regulation of prostaglandins, steroids and cytokines synthesis. The role of PPARs in the trophoblast differentiation, maturation and invasion as well as in the embryo development has also been demonstrated. In this review, we summarize current findings concerning the role of PPARs in the regulation of reproductive functions at different levels of the HPG axis during various physiological statuses of females. In addition, the role of PPARs in the modulation of uterine functions as well as the placenta and embryo development has also been discussed.

COX-2 regulation and TUNEL-positive cell death differ between genders in the secondary inflammatory response following experimental penetrating focal brain injury in rats.

Traumatic brain injury is followed by secondary neuronal degeneration, largely dependent on an inflammatory response. This response is probably gender specific, since females are better protected than males in experimental models. The reasons are not fully known. We examined aspects of the inflammatory response following experimental TBI in male and female rats to explore possible gender differences at 24 h and 72 h after trauma, times of peak histological inflammation and neuronal degeneration. A penetrating brain injury model was used to produce penetrating focal TBI in 20 Sprague-Dawley rats, 5 males and 5 females for each time point. After 24 and 72 h the brains were removed and subjected to in situ hybridization and immunohistochemical analyses for COX-2, iNOS, osteopontin, glial fibrillary acidic protein, 3-nitrotyrosine, TUNEL and Fluoro-Jade. COX-2 mRNA and protein levels were increased in the perilesional area compared to the uninjured contralateral side and significantly higher in males at 24 h and 72 h (p < 0.05). iNOS mRNA was significantly increased in females at 24 h (p < 0.05) although protein was not. TUNEL was increased in male rats after 24 h (p < 0.05). Glial fibrillary acidic protein, osteopontin, 3-nitrotyrosine and Fluoro-Jade stained degenerating neurons were increased in the perilesional area, showing no difference between genders. COX-2 regulation differed between genders after TBI. The increased COX-2 expression in male rats correlated with increased apoptotic cell death detected by increased TUNEL staining at 24 h, but not with neuronal necrosis measured by Flouro-Jade. Astrogliosis and microgliosis did not differ, confirming a comparable level of trauma. The gender-specific trait of the secondary inflammatory response may be connected to prostaglandin regulation, which may partially explain gender variances in outcome after TBI.

Responsivity to PGE2 labor induction involves concomitant differential prostaglandin E receptor gene expression in cervix and myometrium.

Prostaglandin E2 (dinoprostone) is largely used for labor induction. However, one-third of patients do not respond to treatment. One cause of this poor response may be associated with changes in regulation of prostaglandin E receptors (EP1-4). In this study, we investigated EP mRNA expression in the uterine cervix and lower uterine segment myometrium for term births. Biopsies were obtained from women with successful (responders) and failed (non-responders) dinoprostone labor induction, while women that underwent spontaneous labor were included as controls. EP1 mRNA was upregulated in the cervical tissue of women who did not respond to dinoprostone induction. In addition, in the myometrium, significantly higher levels of EP3 mRNA were observed in women treated with dinoprostone, independent of their responsiveness. Dinoprostone-responders presented 3.6-fold higher levels of EP3 mRNA expression than the spontaneous labor group. Significantly higher levels of EP3 mRNA in the myometrium of the dinoprostone-treated group indicated that dinoprostone may regulate the EP3 gene on the transcriptional level. These results highlight the relationship between EP gene expression and delivery and indicate that understanding the regulation of prostaglandin E receptors may lead to improved labor induction.

Effects of estrogen and estrogenic compounds, 4-tert-octylphenol, and bisphenol A on the uterine contraction and contraction-associated proteins in rats

We examined the effects of estradiol (E2), 4-tert-octylphenol (OP), and bisphenol A (BPA) on uterine contractions in immature rats. The expression and localization of contraction-associated proteins (CAPs), and contractility of rat uterus with a collagen gel contraction assay were analyzed. E2, OP, and BPA all increased oxytocin (OT)-related pathway, while the prostaglandin-related signaling was reduced. Interestingly, E2 and estrogenic compounds showed distinct effects on the contractile activity of uterine cells. E2 enhanced the contractility, while OP and BPA significantly decreased it. Immunohistochemical analysis of CAPs showed distinct regulation of prostaglandin F receptor localization by E2 and estrogenic compounds, which may explain the different contractile activities of those reagents. In summary, we demonstrate that E2, OP, and BPA regulate CAP expression in a similar manner in the immature rat uterus, however, the effects on contractile activity were modulated differently. These findings suggest that OP and BPA interfere with uterine contractility.