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1
Marquez, Jorge, Jianping Dong, Chun Dong, Changsheng Tian, and Ginette Serrero. "Identification of Prostaglandin F2 Receptor Negative Regulator (PTGFRN) as an internalizable target in cancer cells for antibody-drug conjugate development." PLOS ONE 16, no. 1 (January 27, 2021): e0246197. http://dx.doi.org/10.1371/journal.pone.0246197.
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Antibody-drug conjugates (ADC) are effective antibody-based therapeutics for hematopoietic and lymphoid tumors. However, there is need to identify new targets for ADCs, particularly for solid tumors and cancers with unmet needs. From a hybridoma library developed against cancer cells, we selected the mouse monoclonal antibody 33B7, which was able to bind to, and internalize, cancer cell lines. This antibody was used for identification of the target by immunoprecipitation and mass spectrometric analysis, followed by target validation. After target validation, 33B7 binding and target positivity were tested by flow cytometry and western blot analysis in several cancer cell lines. The ability of 33B7 conjugated to saporin to inhibit in vitro proliferation of PTFRN positive cell lines was investigated, as well as the 33B7 ADC in vivo effect on tumor growth in athymic mice. All flow cytometry and in vitro internalization assays were analyzed for statistical significance using a Welsh’s T-test. Animal studies were analyzed using Two-Way Analysis of Variance (ANOVA) utilizing post-hoc Bonferroni analysis, and/or Mixed Effects analysis. The 33B7 cell surface target was identified as Prostaglandin F2 Receptor Negative Regulator (PTGFRN), a transmembrane protein in the Tetraspanin family. This target was confirmed by showing that PTGFRN-expressing cells bound and internalized 33B7, compared to PTGFRN negative cells. Cells able to bind 33B7 were PTGFRN-positive by Western blot analysis. In vitro treatment PTGFRN-positive cancer cell lines with the 33B7-saporin ADC inhibited their proliferation in a dose-dependent fashion. 33B7 conjugated to saporin was also able to block tumor growth in vivo in mouse xenografts when compared to a control ADC. These findings show that screening antibody libraries for internalizing antibodies in cancer cell lines is a good approach to identify new cancer targets for ADC development. These results suggest PTGFRN is a possible therapeutic target via antibody-based approach for certain cancers.
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Muraoka, Satoshi, Mark P. Jedrychowski, Kiran Yanamandra, Seiko Ikezu, Steven P. Gygi, and Tsuneya Ikezu. "Proteomic Profiling of Extracellular Vesicles Derived from Cerebrospinal Fluid of Alzheimer’s Disease Patients: A Pilot Study." Cells 9, no. 9 (August 25, 2020): 1959. http://dx.doi.org/10.3390/cells9091959.
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Pathological hallmarks of Alzheimer’s disease (AD) are deposits of amyloid beta (Aβ) and hyper-phosphorylated tau aggregates in brain plaques. Recent studies have highlighted the importance of Aβ and tau-containing extracellular vesicles (EVs) in AD. We therefore examined EVs separated from cerebrospinal fluid (CSF) of AD, mild cognitive impairment (MCI), and control (CTRL) patient samples to profile the protein composition of CSF EV. EV fractions were separated from AD (n = 13), MCI (n = 10), and CTRL (n = 10) CSF samples using MagCapture Exosome Isolation kit. The CSF-derived EV proteins were identified and quantified by label-free and tandem mass tag (TMT)-labeled mass spectrometry. Label-free proteomics analysis identified 2546 proteins that were significantly enriched for extracellular exosome ontology by Gene Ontology analysis. Canonical Pathway Analysis revealed glia-related signaling. Quantitative proteomics analysis, moreover, showed that EVs expressed 1284 unique proteins in AD, MCI and CTRL groups. Statistical analysis identified three proteins—HSPA1A, NPEPPS, and PTGFRN—involved in AD progression. In addition, the PTGFRN showed a moderate correlation with amyloid plaque (rho = 0.404, p = 0.027) and tangle scores (rho = 0.500, p = 0.005) in AD, MCI and CTRL. Based on the CSF EV proteomics, these data indicate that three proteins, HSPA1A, NPEPPS and PTGFRN, may be used to monitor the progression of MCI to AD.
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Chandras, C., T. E. Harris, A. López Bernal, D. R. E. Abayasekara, and A. E. Michael. "PTGER1 and PTGER2 receptors mediate regulation of progesterone synthesis and type 1 11β-hydroxysteroid dehydrogenase activity by prostaglandin E2 in human granulosa–lutein cells." Journal of Endocrinology 194, no. 3 (September 2007): 595–602. http://dx.doi.org/10.1677/joe-07-0128.
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In luteinizing granulosa cells, prostaglandin E2 (PGE2) can exert luteotrophic actions, apparently via the cAMP signalling pathway. In addition to stimulating progesterone synthesis, PGE2 can also stimulate oxidation of the physiological glucocorticoid, cortisol, to its inactive metabolite, cortisone, by the type 1 11β-hydroxysteroid dehydrogenase (11βHSD1) enzyme in human granulosa–lutein cells. Having previously shown these human ovarian cells to express functional G-protein coupled, E-series prostaglandin (PTGER)1, PTGER2 and PTGER4 receptors, the aim of this study was to delineate the roles of PTGER1 and PTGER2 receptors in mediating the effects of PGE2 on steroidogenesis and cortisol metabolism in human granulosa–lutein cells. PGE2-stimulated concentration-dependent increases in both progesterone production and cAMP accumulation (by 1.9 ± 0.1- and 18.7 ± 6.8-fold respectively at 3000 nM PGE2). While a selective PTGER1 antagonist, SC19220, could partially inhibit the steroidogenic response to PGE2 (by 55.9 ± 4.1% at 1000 nM PGE2), co-treatment with AH6809, a mixed PTGER1/PTGER2 receptor antagonist, completely abolished the stimulation of progesterone synthesis at all tested concentrations of PGE2 and suppressed the stimulation of cAMP accumulation. Both PGE2 and butaprost (a preferential PTGER2 receptor agonist) stimulated concentration-dependent increases in cortisol oxidation by 11βHSD1 (by 42.5 ± 3.1 and 40.0 ± 3.0% respectively, at PGE2 and butaprost concentrations of 1000 nM). Co-treatment with SC19220 enhanced the ability of both PGE2 and butaprost to stimulate 11βHSD1 activity (by 30.2 ± 0.2 and 30.5 ± 0.6% respectively), whereas co-treatment with AH6809 completely abolished the 11βHSD1 responses to PGE2 and butaprost. These findings implicate the PTGER2 receptor–cAMP signalling pathway in the stimulation of progesterone production and 11βHSD1 activity by PGE2 in human granulosa–lutein cells.
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Kowalewski, Mariusz Pawel, Hakki Bülent Beceriklisoy, Christiane Pfarrer, Selim Aslan, Hans Kindahl, Ibrahim Kücükaslan, and Bernd Hoffmann. "Canine placenta: a source of prepartal prostaglandins during normal and antiprogestin-induced parturition." REPRODUCTION 139, no. 3 (March 2010): 655–64. http://dx.doi.org/10.1530/rep-09-0140.
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Expression of cyclooxygenase 2 (COX2, now known as PTGS2), prostaglandin E2 synthase (PTGES, PGES), and prostaglandin F2α synthase (PGFS), of the respective receptors PTGFR (FP), PTGER2 (EP2), and PTGER4 (EP4) and of the progesterone receptor (PGR, PR) was assessed by real-time PCR, immunohistochemistry (IHC), or in situ hybridization (ISH) in utero/placental tissue samples collected from three to five bitches on days 8–12 (pre-implantation), 18–25 (post-implantation), and 35–40 (mid-gestation) of pregnancy and during the prepartal luteolysis. Additionally, ten mid-pregnant bitches were treated with the antiprogestin aglepristone (10 mg/kg bw (2×/24 h)); ovariohysterectomy was 24 and 72 h after the second treatment. Plasma progesterone and 15-ketodihydro-PGF2α (PGFM) concentrations were determined by RIA. Expression of the PGR was highest before implantation and primarily located to the endometrium; expression in the placenta was restricted to the decidual cells. PTGS2 was constantly low expressed until mid-gestation; a strong upregulation occurred at prepartal luteolysis concomitant with an increase in PGFM. PGFS was upregulated after implantation and significantly elevated through early and mid-gestation. PTGES showed a gradual increase and a strong prepartal upregulation. PTGFR, PTGER2, and PTGER4 were downregulated after implantation; a gradual upregulation of PTGFR and PTGER2 occurred towards parturition. ISH and IHC co-localized PGFS, PTGFR, PTGES, and PTGS2 in the trophoblast and endometrium. The changes following application of aglepristone were in the same direction as those observed from mid-gestation to prepartal luteolysis. These data suggest that the prepartal increase of PGF2α results from a strong upregulation of PTGS2 in the fetal trophoblast with the withdrawal of progesterone having a signalling function and the decidual cells playing a key role in the underlying cell-to-cell crosstalk.
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Aguila, Brittany, Adina Brett Morris, Raffaella Spina, Eli Bar, Julie Schraner, Robert Vinkler, Jason W. Sohn, and Scott M. Welford. "The Ig superfamily protein PTGFRN coordinates survival signaling in glioblastoma multiforme." Cancer Letters 462 (October 2019): 33–42. http://dx.doi.org/10.1016/j.canlet.2019.07.018.
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Kim, Soon Ok, Nune Markosyan, Gerald J. Pepe, and Diane M. Duffy. "Estrogen promotes luteolysis by redistributing prostaglandin F2α receptors within primate luteal cells." REPRODUCTION 149, no. 5 (May 2015): 453–64. http://dx.doi.org/10.1530/rep-14-0412.
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Prostaglandin F2α (PGF2α) has been proposed as a functional luteolysin in primates. However, administration of PGF2α or prostaglandin synthesis inhibitors in vivo both initiate luteolysis. These contradictory findings may reflect changes in PGF2α receptors (PTGFRs) or responsiveness to PGF2α at a critical point during the life span of the corpus luteum. The current study addressed this question using ovarian cells and tissues from female cynomolgus monkeys and luteinizing granulosa cells from healthy women undergoing follicle aspiration. PTGFRs were present in the cytoplasm of monkey granulosa cells, while PTGFRs were localized in the perinuclear region of large, granulosa-derived monkey luteal cells by mid-late luteal phase. A PTGFR agonist decreased progesterone production in luteal cells obtained at mid-late and late luteal phases, but did not decrease progesterone production by granulosa cells or luteal cells from younger corpora lutea. These findings are consistent with a role for perinuclear PTGFRs in functional luteolysis. This concept was explored using human luteinizing granulosa cells maintained in vitro as a model for luteal cell differentiation. In these cells, PTGFRs relocated from the cytoplasm to the perinuclear area in an estrogen- and estrogen receptor-dependent manner. Similar to our findings with monkey luteal cells, human luteinizing granulosa cells with perinuclear PTGFRs responded to a PTGFR agonist with decreased progesterone production. These data support the concept that PTGFR stimulation promotes functional luteolysis only when PTGFRs are located in the perinuclear region. Estrogen receptor-mediated relocation of PTGFRs within luteal cells may be a necessary step in the initiation of luteolysis in primates.
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Zschockelt, Lina, Olga Amelkina, Marta J. Siemieniuch, Mariusz P. Kowalewski, Martin Dehnhard, Katarina Jewgenow, and Beate C. Braun. "Synthesis and reception of prostaglandins in corpora lutea of domestic cat and lynx." Reproduction 152, no. 2 (August 2016): 111–26. http://dx.doi.org/10.1530/rep-16-0180.
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Felids show different reproductive strategies related to the luteal phase. Domestic cats exhibit a seasonal polyoestrus and ovulation is followed by formation ofcorpora lutea(CL). Pregnant and non-pregnant cycles are reflected by diverging plasma progesterone (P4) profiles. Eurasian and Iberian lynxes show a seasonal monooestrus, in which physiologically persistent CL (perCL) support constantly elevated plasma P4 levels. Prostaglandins (PGs) represent key regulators of reproduction, and we aimed to characterise PG synthesis in feline CL to identify their contribution to the luteal lifespan. We assessed mRNA and protein expression of PG synthases (PTGS2/COX2, PTGES, PGFS/AKR1C3) and PG receptors (PTGER2, PTGER4, PTGFR), and intra-luteal levels of PGE2and PGF2α. Therefore, CL of pregnant (pre-implantation, post-implantation, regression stages) and non-pregnant (formation, development/maintenance, early regression, late regression stages) domestic cats, and prooestrous Eurasian (perCL, pre-mating) and metoestrous Iberian (perCL, freshCL, post-mating) lynxes were investigated. Expression ofPTGS2/COX2, PTGES and PTGER4 was independent of the luteal stage in the investigated species. High levels of luteotrophic PGE2in perCL might be associated with persistence of luteal function in lynxes. Signals for PGFS/AKR1C3 expression were weak in mid and late luteal stages of cats but were absent in lynxes, concomitant with low PGF2αlevels in these species. Thus, regulation of CL regression by luteal PGF2αseems negligible. In contrast, expression of PTGFR was evident in nearly all investigated CL of cat and lynxes, implying that luteal regression, e.g. at the end of pregnancy, is triggered by extra-luteal PGF2α.
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Waclawik, Agnieszka, Piotr Kaczynski, and Henry N. Jabbour. "Autocrine and Paracrine Mechanisms of Prostaglandin E2 Action on Trophoblast/Conceptus Cells through the Prostaglandin E2 Receptor (PTGER2) during Implantation." Endocrinology 154, no. 10 (October 1, 2013): 3864–76. http://dx.doi.org/10.1210/en.2012-2271.
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The conceptus and endometrium secrete large amounts of prostaglandin E2 (PGE2) into the porcine uterine lumen during the periimplantation period. We hypothesized that PGE2 acts on conceptus/trophoblast cells through auto- and paracrine mechanisms. Real-time RT-PCR analysis revealed that PGE2 receptor (PTGER)2 mRNA was 14-fold greater in conceptuses/trophoblasts on days 14–25 (implantation and early placentation period) vs preimplantation day 10–13 conceptuses (P < .05). Similarly, expression of PTGER2 protein increased during implantation. Conceptus expression of PTGER4 mRNA and protein did not differ on days 10–19. PGE2 stimulated PTGER2 mRNA expression in day 15 trophoblast cells through PTGER2 receptor signaling. PGE2 elevated aromatase expression and estradiol-17β secretion by trophoblast cells. Moreover, PGE2 and the PTGER2 agonist, butaprost, increased the adhesive capacity of both human HTR-8/SVneo trophoblast and primary porcine trophoblast cells to extracellular matrix. This PGE2-induced alteration in trophoblast cell adhesion to extracellular matrix was abolished by incubation of these cells with AH6809 (PTGER2 antagonist), ITGAVB3-directed tetrapeptide arg-gly-asp-ser or integrin ITGAVB3 antibody. PGE2 stimulated adhesion of porcine trophoblast cells via the estrogen receptor and MEK/MAPK signaling pathway. PGE2 induced phosphorylation of MAPK1/MAPK3 through PTGER2 and up-regulated expression of cell adhesion proteins such as focal adhesion kinase and intercellular adhesion molecule-1. Our study indicates that elevated PGE2 in the periimplantation uterine lumen stimulates conceptus PTGER2 expression, which in turn promotes trophoblast adhesion via integrins, and synthesis and secretion of the porcine embryonic signal estradiol-17β. Moreover, the mechanism through which PGE2 increases trophoblast adhesion is not species specific because it is PTGER2- and integrin-dependent in both porcine and human trophoblast cells.
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Kauke, Monique, Nikki Ross, Dalia Burzyn, Shelly Martin, Ke Xu, Nuruddeen Lewis, Charan Leng, et al. "703 Engineered exosomes with altered cellular tropism achieve targeted STING agonist delivery and single-agent tumor control in vivo." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A745. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0703.
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BackgroundExosomes are natural, abundant extracellular vesicles capable of transferring complex molecules between neighboring and distant cell types. Translational research efforts have focused on co-opting this communication mechanism to deliver exogenous payloads to treat a variety of diseases. Important strategies to maximize the therapeutic potential of exosomes therefore include payload loading, functionalization of the exosome surface with pharmacologically active proteins, and delivery to target cells of interest.MethodsThrough comparative proteomic analysis of purified exosomes, we identified several highly enriched and exosome-specific proteins, including a transmembrane glycoprotein (PTGFRN) belonging to the immunoglobulin superfamily. Leveraging PTGFRN as a scaffold for exosome surface display, we developed our engExTM platform to generate engineered exosomes functionalized with a variety of structurally and biologically diverse proteins.Systemically administered exosomes are primarily taken up by macrophages in the liver and spleen. To redirect exosome uptake to other cell types, we employed our engineering platform to display functional targeting ligands, including single domain antibodies, single chain variable fragments, single chain Fabs (scFabs), and receptor ligands, on the exosome surface at high density. To demonstrate that exosome surface modifications can alter cellular tropism, we generated exosomes displaying anti-Clec9A scFabs to target conventional type 1 dendritic cells (cDC1s), anti-CD3 scFabs to target T cells, and CD40 ligand to target B cells. The engineered exosomes exhibited functional antigen binding that led to greater association with the cell types expressing the cognate receptor both in vitro and in vivo.ResultsIn mice, systemic administration of exosomes engineered to display scFabs targeting Clec9A resulted in a 4-fold increase in the percentage of cDC1 cells in the blood that had taken up exosomes over controls, and a 6-fold increase in the number of exosomes taken up per cell. We further showed that compared to untargeted exosomes, those with altered tropism achieved increased functional payload delivery to the target cell of interest. In primary mouse dendritic cells, anti-Clec9A exosomes loaded with a cyclic dinucleotide STING agonist achieved greater pathway induction, 2.3-fold greater as measured by IFNβ production, 2-fold by IFNα, and 15-fold by IL-12, when compared to an untargeted control. Preliminary in vivo data show that intra-tumorally administered anti-Clec9A exosomes reduce the required STING agonist dose 10-fold to achieve single-agent tumor control and induce immune responses against tumor-associated antigen, compared to controls.ConclusionsThese results demonstrate the potential of our engExTM platform to generate targeted exosome therapeutics capable of immune cell stimulation and tumor growth inhibition in vivo.Ethics ApprovalAll experimental animal studies were performed according to Codiak BioSciences IACUC approved AUP CB2020-001.
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Przygrodzka, E., M. M. Kaczmarek, P. Kaczynski, and A. J. Ziecik. "Steroid hormones, prostanoids, and angiogenic systems during rescue of the corpus luteum in pigs." REPRODUCTION 151, no. 2 (February 2016): 135–47. http://dx.doi.org/10.1530/rep-15-0332.
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In order to characterize the transition of the corpora lutea (CL) from acquisition of luteolytic sensitivity to rescue of luteal function: i) the expression of 38 factors associated with steroids, prostanoids, and angiogenic systems and ii) concentrations of the main hormones responsible for maintenance of CL function in cyclic and pregnant pigs were examined. Additionally, the effect of prostaglandin (PG) E2 and F2α on luteal function during the estrous cycle and pregnancy was evaluated in vitro. Significantly up-regulated gene expression was revealed in CL collected on day 14 of the estrous cycle (CYP19A1, ESR2, PTGS2, HIF1A, and EDN1) and on days 12–14 of pregnancy (SCARB1, PGRMC1, STAR, HSD3B1, NR5A1, PTGFR, PTGER4, and VEGFA). Elevated concentrations of estradiol-17β and PGE2 occurred in CL on days 12 and 14 of pregnancy respectively, while an increased intraluteal PGF2α content was noted on day 14 of the estrous cycle. Both PGs increased the synthesis of progesterone by cultured luteal slices obtained on day 14 of pregnancy, in contrast to the action of PGF2α on the corresponding day of the estrous cycle. PGE2 stimulated cAMP production via PTGER2 and PTGER4, while PGF2α elevated the content of CREB in cultured luteal slices from CL of pregnant pigs. In silico analysis showed that infiltration of lymphocytes and apoptosis of microvascular endothelium were activated in CL on day 12 of the estrous cycle vs pregnancy. Summarizing, an abundance of E2 and PGE2 during pregnancy regulates specific pathways responsible for steroidogenesis, the prostanoid signaling system and angiogenesis during rescue from luteolysis in porcine CL.
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Karaky, Mohamad, Gabrielle Boucher, Saraï Mola, Sylvain Foisy, Claudine Beauchamp, Marie-Eve Rivard, Melanie Burnette, et al. "Prostaglandins and calprotectin are genetically and functionally linked to the Inflammatory Bowel Diseases." PLOS Genetics 18, no. 9 (September 26, 2022): e1010189. http://dx.doi.org/10.1371/journal.pgen.1010189.
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Background Genome wide association studies (GWAS) have identified and validated more than 200 genomic loci associated with the inflammatory bowel disease (IBD), although for most the causal gene remains unknown. Given the importance of myeloid cells in IBD pathogenesis, the current study aimed to uncover the role of genes within IBD genetic loci that are endogenously expressed in this cell lineage. Methods The open reading frames (ORF) of 42 genes from IBD-associated loci were expressed via lentiviral transfer in the THP-1 model of human monocytes and the impact of each of these on the cell’s transcriptome was analyzed using a RNA sequencing-based approach. We used a combination of genetic and pharmacologic approaches to validate our findings in the THP-1 line with further validation in human induced pluripotent stem cell (hiPSC)-derived-monocytes. Results This functional genomics screen provided evidence that genes in four IBD GWAS loci (PTGIR, ZBTB40, SLC39A11 and NFKB1) are involved in controlling S100A8 and S100A9 genes expression, which encode the two subunits of calprotectin (CP). We demonstrated that increasing PTGIR expression and/or stimulating PTGIR signaling resulted in increased CP expression in THP-1. This was further validated in hiPSC-derived monocytes. Conversely, knocking-down PTGIR endogenous expression and/or inhibiting PTGIR signaling led to decreased CP expression. These analyses were extended to the known IBD gene PTGER4, whereby its specific agonist also led to increased CP expression. Furthermore, we demonstrated that the PTGIR and PTGER4 mediated control of CP expression was dependent on signaling via adenylate cyclase and STAT3. Finally, we demonstrated that LPS-mediated increases in CP expression could be potentiated by agonists of PTGIR and PTGER4, and diminished by their antagonists. Conclusion Our results support a causal role for the PTGIR, PTGER4, ZBTB40, SLC39A11 and NFKB1 genes in IBD, with all five genes regulating the expression of CP in myeloid cells, as well as potential roles for the prostacyclin/prostaglandin biogenesis and signaling pathways in IBD susceptibility and pathogenesis.
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Kirwin, Katherine, Su Chul Jang, Christine Sia, Kevin Dooley, Tong Zi, Kelvin Zhang, Yanyan Liu, Kyriakos Economides, Shil Patel, and Sriram Sathyanaryanan. "572 Combination therapy of exoSTING, exoIL-12 activates systemic anti-tumor immunity." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A601. http://dx.doi.org/10.1136/jitc-2021-sitc2021.572.
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BackgroundEngineered exosomes are emerging as a novel therapeutic modality for cancer immunotherapy. Leveraging cell type specific delivery, tumor restricted pharmacology and compartmental dosing, exosome-based immunotherapy can elicit a tumor specific immune response that may not be achievable with other traditional drugging modalities. Pre-clinical studies have shown that exosomes loaded with a STING agonist (exoSTINGTM) or engineered to express the cytokine interleukin-12 (exoIL-12TM) can substantially improve potency and selectivity resulting in improved therapeutic window [1,2]. Both exoSTING and exoIL-12 are currently in clinical trials in cancer patients. Utilizing a combination strategy involving exoSTING and exoIL-12, we demonstrate the development of potent systemic anti-tumor responses in both injected and non-injected tumors.Methods exoSTING exosomes are engineered to overexpress PTGFRN, an abundant exosome surface protein, and loaded ex vivo with a proprietary STING agonist. exoIL-12 exosomes are engineered to overexpress functional IL-12 attached via fusion to PTGFRN. In these studies, exoSTING and exoIL-12 were dosed intratumorally into one flank tumor into mice bearing dual flank subcutaneous MC38 or B16F10 tumors, or B16F10 single flank subcutaneous tumors with B16F10 lung metastases. T-cell infiltration in the non-injected tumor was monitored by histopathology.ResultsIn the checkpoint therapy refractory B16F10 melanoma dual flank tumor model, exoSTING/exoIL-12 combination provided 93% and 78% tumor growth inhibition (TGI) in both the injected and non-injected tumors, respectively, whereas monotherapy of exoSTING or exoIL-12 provided modest anti-tumor activity (44% and 48% TGI) in the non-injected tumors, respectively. In a MC38 subcutaneous CRC model, the addition of anti-PD-1 checkpoint inhibitor further enhanced anti-tumor activity with 100% TGI (7/7 CR) in injected and non-injected tumors. The tumor free animals were refractory to tumor re-challenge demonstrating immunological memory. A dosing schedule optimization experiment showed that same day dosing of exoSTING and exoIL-12 significantly inhibited the tumor growth in the non-injected tumors. In a lung metastasis model, the triple combination also showed potent anti-tumor effect in decreasing distal lung metastases when dosed intratumorally into the subcutaneous tumors. Subsequent imaging and histology studies demonstrated enhanced T cell infiltration in the non-injected subcutaneous tumor with the combination therapy.ConclusionsBy combining both exosome immunotherapies with a checkpoint blockade, we are able to elicit systemic anti-tumor immune immunity in both injected and non-injected tumors.ReferencesJang SC, Economides KD, Moniz RJ, et al. ExoSTING, an extracellular vesicle loaded with STING agonists, promotes tumor immune surveillance. Commun Biol. 2021;4(1):497.Lewis ND, Sia CL, Kirwin K, et al. Exosome surface display of IL12 results in tumor-retained pharmacology with superior potency and limited systemic exposure compared with recombinant IL12. Mol Cancer Ther. 2020;20(3):523-534.Ethics ApprovalAll animals were maintained and treated at the animal care facility of Codiak Biosciences in accordance with the regulations and guidelines of the Institutional Animal Care and Use Committee (CB2020-001).
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Walusimbi, S. S., L. M. Wetzel, D. H. Townson, and J. L. Pate. "Isolation of luteal endothelial cells and functional interactions with T lymphocytes." Reproduction 153, no. 5 (May 2017): 519–33. http://dx.doi.org/10.1530/rep-16-0578.
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The objectives of this study were to optimize the isolation of luteal endothelial cells (LEC) and examine their functional interactions with autologous T lymphocytes. Analysis by flow cytometry showed that the purity of LEC isolated by filtration was nearly 90% as indicated byBandeiraea simplicifolia(BS)-1 lectin binding. LEC expressed mRNA for progesterone receptor (PGR), prostaglandin receptors (PTGFR, PTGER2 and 4, and PTGIR), tumor necrosis factor receptors (TNFRSF1A&B) and interleukin (IL) 1B receptors (IL1R1&2). LEC were pretreated with either vehicle, progesterone (P4; 0–20 µM), prostaglandin (PG) E2or PGF2α(0–0.2 µM), and further treated with or without TNF and IL1B (50 ng/mL each). LEC were then incubated with autologous T lymphocytes in an adhesion assay. Fewer lymphocytes adhered to LEC after exposure to high compared to low P4concentrations (cubic response;P < 0.05). In contrast, 0.2 µM PGE2and PGF2αeach increased T lymphocyte adhesion in the absence of cytokines (P < 0.05). LEC induced IL2 receptor alpha (CD25) expression and proliferation of T lymphocytes. In conclusion, filtration is an effective way of isolating large numbers of viable LEC. It is proposed that PGs and P4modulate the ability of endothelial cells to bind T lymphocytes, potentially regulating extravasation, and that LEC activate T lymphocytes migrating into or resident in the CL.
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Waclawik, Agnieszka, Agnieszka Blitek, and Adam J. Ziecik. "Oxytocin and tumor necrosis factor α stimulate expression of prostaglandin E2 synthase and secretion of prostaglandin E2 by luminal epithelial cells of the porcine endometrium during early pregnancy." REPRODUCTION 140, no. 4 (October 2010): 613–22. http://dx.doi.org/10.1530/rep-10-0092.
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Oxytocin (OXT) and tumor necrosis factor α (TNF) have been implicated in the control of luteolysis by stimulating endometrial secretion of luteolytic prostaglandin F2α(PGF2α). Nevertheless, OXT concentration in porcine uterine lumen increases markedly on days 11–12 of pregnancy, and TNF is expressed in endometrium during pregnancy. The objective of the study was to determine the effect of OXT and TNF on expression of the enzymes involved in PG synthesis: PG-endoperoxide synthase 2 (PTGS2), PGE2synthase (mPGES-1) and PGF synthase, and PGE2receptor (PTGER2), as well as on PG secretion by endometrial luminal epithelial cells (LECs) on days 11–12 of the estrous cycle and pregnancy. LECs isolated from gilts on days 11–12 of the estrous cycle (n=8) and pregnancy (n=7) were treated with OXT (100 nmol/l) and TNF (0.6 nmol/l) for 24 h. OXT increasedPTGS2mRNA and mPGES-1 protein contents, as well as PGE2secretion but only on days 11–12 of pregnancy. TNF stimulatedPTGS2andmPGES-1mRNA, as well as mPGES-1 protein expression and PGE2release on days 11–12 of pregnancy and the estrous cycle. In addition, expressions of PTGER2 and PTGER4 were determined in corpus luteum (CL). Abundance ofPTGER2mRNA and PTGER4 protein in CL was upregulated on day 14 of pregnancy versus day 14 of the estrous cycle. This study indicates that TNF and OXT regulate PGE2synthesis in LECs during early pregnancy. PGE2secreted by LECs, after reaching ovaries, could have a luteoprotective effect through luteal PTGER2 and PTGER4, or may directly promote uterine function and conceptus development.
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González, Luz María, Nicolás Roberto Robles, Sonia Mota-Zamorano, José Manuel Valdivielso, Juan López-Gómez, and Guillermo Gervasini. "Genetic Variants in PGE2 Receptors Modulate the Risk of Nephrosclerosis and Clinical Outcomes in These Patients." Journal of Personalized Medicine 11, no. 8 (August 6, 2021): 772. http://dx.doi.org/10.3390/jpm11080772.
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Prostaglandin E2 (PGE2) is a major actor mediating renal injury. We aimed to determine genetic variability in the genes coding for its receptors (PTGER1-4) and study associations with nephrosclerosis risk and clinical outcomes. We identified 96 tag-SNPs capturing global variability in PTGER1-4 and screened 1209 nephrosclerosis patients and controls. The effect of these variants was evaluated by multivariate regression analyses. Two PTGER3 SNPs, rs11209730 and rs10399704, remained significant in a backward elimination regression model with other non-genetic variables (OR = 1.45 (1.07–1.95), p = 0.016 and OR = 0.71 (0.51–0.99), p = 0.041, respectively). In the nephrosclerosis patients, a proximal region of PTGER3 was tagged as relevant for eGFR (p values for identified SNPs ranged from 0.0003 to 0.038). Two consecutive PTGER3 SNPs, rs2284362 and rs2284363, significantly decreased systolic (p = 0.005 and p = 0.0005), diastolic (p = 0.039 and p = 0.005), and pulse pressure values (p = 0.038 and 0.014). Patients were followed for a median of 47 months (7–54) to evaluate cardiovascular (CV) risk. Cox regression analysis showed that carriers of the PTGER1rs2241360 T variant had better CV event-free survival than wild-type individuals (p = 0.029). In addition, PTGER3rs7533733 GG carriers had lower event-free survival than AA/AG patients (p = 0.011). Our results indicate that genetic variability in PGE2 receptors, particularly EP3, may be clinically relevant for nephrosclerosis and its associated CV risk.
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Misawa, Kiyoshi, Atsushi Imai, Takeharu Kanazawa, Masato Mima, Satoshi Yamada, Daiki Mochizuki, Taiki Yamada, et al. "G Protein-Coupled Receptor Genes, PTGDR1, PTGDR2, and PTGIR, Are Candidate Epigenetic Biomarkers and Predictors for Treated Patients with HPV-Associated Oropharyngeal Cancer." Microorganisms 8, no. 10 (September 29, 2020): 1504. http://dx.doi.org/10.3390/microorganisms8101504.
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Differences in the biology of human papillomavirus (HPV)-associated oropharyngeal cancers (OPCs) and HPV-negative OPCs may have implications in patient management. Early detection is imperative to reduce HPV-associated OPC mortality. Circulating tumor DNA (ctDNA) can potentially serve as a biomarker for monitoring clinically relevant cancer-related genetic and epigenetic modifications. We analyzed the methylation status of 24 G protein-coupled receptor (GPCR) genes in verification (85 OPC primary samples) and validation (8 OPC ctDNA samples) studies using quantitative methylation-specific polymerase chain reaction (Q-MSP). The Q-MSP-based verification study with 85 OPC primary samples revealed the GPCR genes that were significantly associated with recurrence in high methylation groups (≥14 methylated genes) with OPC and HPV-associated OPC (p < 0.001). In the Kaplan–Meier estimate and multivariate Cox proportional hazard analyses, 13 GPCR genes were significantly related to increased recurrence in the methylation group. Furthermore, the validation study on ctDNA showed that three of these genes (Prostaglandin D2 receptor 1: PTGDR1, Prostaglandin D2 receptor 2: PTGDR2, and Prostaglandin I2 Receptor: PTGIR) had a prediction performance as emerging biomarkers. We characterized the relationship between the methylation status of GPCR genes and outcomes in HPV-associated OPC. Our results highlight the potential utility of ctDNA methylation-based detection for the clinical management of HPV-associated OPC.
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Nakayama, Akiyoshi, Masahiro Nakatochi, Yusuke Kawamura, Ken Yamamoto, Hirofumi Nakaoka, Seiko Shimizu, Toshihide Higashino, et al. "Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients." Annals of the Rheumatic Diseases 79, no. 5 (April 1, 2020): 657–65. http://dx.doi.org/10.1136/annrheumdis-2019-216644.
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ObjectivesGenome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000–3000 years.MethodsTwo genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype.ResultsIn addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10–8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients’ gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout.ConclusionsOur findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.
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Mangelsen, Eva, Michael Rothe, Angela Schulz, Aikaterini Kourpa, Daniela Panáková, Reinhold Kreutz, and Juliane Bolbrinker. "Concerted EP2 and EP4 Receptor Signaling Stimulates Autocrine Prostaglandin E2 Activation in Human Podocytes." Cells 9, no. 5 (May 19, 2020): 1256. http://dx.doi.org/10.3390/cells9051256.
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Glomerular hyperfiltration is an important mechanism in the development of albuminuria. During hyperfiltration, podocytes are exposed to increased fluid flow shear stress (FFSS) in Bowman’s space. Elevated Prostaglandin E2 (PGE2) synthesis and upregulated cyclooxygenase 2 (Cox2) are associated with podocyte injury by FFSS. We aimed to elucidate a PGE2 autocrine/paracrine pathway in human podocytes (hPC). We developed a modified liquid chromatography tandem mass spectrometry (LC/ESI-MS/MS) protocol to quantify cellular PGE2, 15-keto-PGE2, and 13,14-dihydro-15-keto-PGE2 levels. hPC were treated with PGE2 with or without separate or combined blockade of prostaglandin E receptors (EP), EP2, and EP4. Furthermore, the effect of FFSS on COX2, PTGER2, and PTGER4 expression in hPC was quantified. In hPC, stimulation with PGE2 led to an EP2- and EP4-dependent increase in cyclic adenosine monophosphate (cAMP) and COX2, and induced cellular PGE2. PTGER4 was downregulated after PGE2 stimulation in hPC. In the corresponding LC/ESI-MS/MS in vivo analysis at the tissue level, increased PGE2 and 15-keto-PGE2 levels were observed in isolated glomeruli obtained from a well-established rat model with glomerular hyperfiltration, the Munich Wistar Frömter rat. COX2 and PTGER2 were upregulated by FFSS. Our data thus support an autocrine/paracrine COX2/PGE2 pathway in hPC linked to concerted EP2 and EP4 signaling.
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Nelis, H. M., K. Goossens, B. Leemans, L. Peelman, and A. Van Soom. "220 STEROID-REGULATED mRNA EXPRESSION IN OVIDUCT EPITHELIAL CELLS IN THE MARE." Reproduction, Fertility and Development 25, no. 1 (2013): 258. http://dx.doi.org/10.1071/rdv25n1ab220.
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It is well known that oviducal physiology undergoes cyclical changes under the influence of steroid hormones associated with the establishment of an optimal microenvironment for fertilization and early embryonic development. Genes associated with the preovulatory phase are likely to be involved in modulation of gamete function and sperm storage, whereas those in the post-ovulatory phase are involved in embryonic development. So far, in the horse, no genes that change activity during the oestrous cycle, which may be important in fertilization, gamete and embryo passage, and early embryonic development, have been identified. Therefore, to identify steroid-regulated genes, we compared the mRNA expression of PAI-1, uPA, TGFA, TIMP-1, MMP-1, CSF, PTGER2, and PTGER4 in oviducal explants from mares in the pre- and the post-ovulatory early luteal stages. The cycle stage of healthy warmblood mares was determined in the slaughterhouse by assessment of ovarian morphology and uterine oedema. Oviducal explants were isolated by scraping the epithelium of oviducts ipsilateral to a preovulatory follicle or a recent corpus luteum and frozen in lysis buffer at –80°C until RNA extraction. The genes were quantified by RT-qPCR and normalized against the geometric mean of 6 validated reference genes (UBB, SDHA, 18S, TUB, ACTB, HPRT) according to the MIQE-guidelines (Bustin et al., 2009). Data were analysed using the independent samples t-test or the Mann–Whitney U-test. The mRNA expression of PAI-1, MMP-1, TGFA (0.01 < P < 0.05), and uPA (P = 0.007) was downregulated in the post-ovulatory phase, whereas no significant change in TIMP-1, CSF, PTGER2, and PTGER4 expression was observed. The results show that mRNA of components of the extracellular matrix turnover, such as PAI-1, uPA, MMP-1, and TIMP-1 as well as growth factors, such as TFGA and CSF and prostaglandin E2 receptors (PTGER2 and PTGER4), are produced. Moreover, down-regulation of PAI-1, MMP-1, TGFA, and uPA in the early luteal stage indicates that mRNA expression of these genes is steroid regulated. In other species, all these components are likely to protect gametes and the early embryo against proteolytic degradation and to stimulate embryonic development. Further transcriptome and proteome analyses are necessary to unravel changes in the oviducal epithelium during the oestrous cycle and early pregnancy in the mare.
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Williams, Joseph H., and Paulo E. Oliveira. "For things to stay the same, things must change: polyploidy and pollen tube growth rates." Annals of Botany 125, no. 6 (January 20, 2020): 925–35. http://dx.doi.org/10.1093/aob/mcaa007.
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Abstract Background and Aims Pollen tube growth rate (PTGR) is an important single-cell performance trait that may evolve rapidly under haploid selection. Angiosperms have experienced repeated cycles of polyploidy (whole genome duplication), and polyploidy has cell-level phenotypic consequences arising from increased bulk DNA amount and numbers of genes and their interactions. We sought to understand potential effects of polyploidy on several underlying determinants of PTGR – pollen tube dimensions and construction rates – by comparing diploid–polyploid near-relatives in Betula (Betulaceae) and Handroanthus (Bignoniaceae). Methods We performed intraspecific, outcrossed hand-pollinations on pairs of flowers. In one flower, PTGR was calculated from the longest pollen tube per time of tube elongation. In the other, styles were embedded in glycol methacrylate, serial-sectioned in transverse orientation, stained and viewed at 1000× to measure tube wall thicknesses (W) and circumferences (C). Volumetric growth rate (VGR) and wall production rate (WPR) were then calculated for each tube by multiplying cross-sectional tube area (πr2) or wall area (W × C), by the mean PTGR of each maternal replicate respectively. Key Results In Betula and Handroanthus, the hexaploid species had significantly wider pollen tubes (13 and 25 %, respectively) and significantly higher WPRs (22 and 18 %, respectively) than their diploid congeners. PTGRs were not significantly different in both pairs, even though wider polyploid tubes were predicted to decrease PTGRs by 16 and 20 %, respectively. Conclusions The larger tube sizes of polyploids imposed a substantial materials cost on PTGR, but polyploids also exhibited higher VGRs and WPRs, probably reflecting the evolution of increased metabolic activity. Recurrent cycles of polyploidy followed by genome reorganization may have been important for the evolution of fast PTGRs in angiosperms, involving a complex interplay between correlated changes in ploidy level, genome size, cell size and pollen tube energetics.
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Lewis, Nuruddeen, Chang Ling Sia, Katherine Kirwin, Sonya Haupt, Gauri Mahimkar, Tong Zi, Ke Xu, et al. "709 Exosome surface display of IL-12 results in tumor-retained pharmacology with superior potency and limited systemic exposure." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A751. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0709.
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BackgroundThe promise of Interleukin-12 as a cancer treatment has yet to be fulfilled with multiple tested approaches being limited by unwanted systemic exposure and unpredictable pharmacology. To address these limitations, we generated exoIL-12™, a novel, engineered-exosome therapeutic that displays functional IL-12 on the surface of an exosome.MethodsIL-12 exosomal surface expression was achieved via fusion to the abundant exosomal surface protein PTGFRN. Potency was assessed in vitro using human PBMCs or murine splenocytes and in vivo using mouse subcutaneous tumor models. Local versus systemic pharmacology was determined with intratumoral injection in mice and subcutaneous injection in monkeys. All studies were benchmarked against recombinant IL-12 (rIL-12).ResultsExosomes engineered to express either murine or human IL-12 had equivalent potency in vitro to rIL-12 as demonstrated by IFNγ production. Following intratumoral injection, exoIL-12 exhibited prolonged tumor retention and greater antitumor activity than rIL-12. Moreover, exoIL-12 was 100-fold more potent than rIL-12 in tumor growth inhibition. In the MC38 tumor model, complete responses were observed in 63% of mice treated with exoIL-12; in contrast, rIL-12 resulted in 0% complete responses at an equivalent IL-12 dose. This correlated with dose-dependent increases in tumor antigen-specific CD8+ T cells. Re-challenge studies of exoIL-12 in complete responder mice showed no tumor regrowth. Moreover, depletion of CD8+ T cells completely abrogated the antitumor activity of exoIL-12. Following intratumoral administration, exoIL-12 exhibited 10-fold higher intratumoral exposure than rIL-12 and prolonged IFNγ production up to 48 hr. Retained, local pharmacology of exoIL-12 was further confirmed using subcutaneous injections in non-human primates.ConclusionsThis work demonstrates that tumor-restricted pharmacology of exoIL-12 results in superior in vivo efficacy and immune memory without systemic IL-12 exposure and related toxicity. exoIL-12 is a novel cancer therapeutic candidate that has the potential to overcome key limitations of rIL-12 and thereby create a therapeutic window for this potent cytokine.Ethics ApprovalAll animals were maintained and treated at the animal care facility of Codiak Biosciences in accordance with the regulations and guidelines of the Institutional Animal Care and Use Committee (CB2017-001).
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Yoshida, Masahide, Yuki Takayanagi, Azusa Ichino-Yamashita, Kei Sato, Yukihiko Sugimoto, Tadashi Kimura, and Katsuhiko Nishimori. "Functional Hierarchy of Uterotonics Required for Successful Parturition in Mice." Endocrinology 160, no. 12 (September 13, 2019): 2800–2810. http://dx.doi.org/10.1210/en.2019-00499.
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Abstract Parturition is an essential process in placental mammals for giving birth to offspring. However, the molecular machineries of parturition are not fully understood. We investigated whether oxytocin plays a crucial role in the progress of parturition in cooperation with the prostaglandin F2α (PGF2α) receptor. We first examined alterations in the expression of uterine contraction-associated genes in uteri of oxytocin receptor–deficient mice (Oxtr−/−) during parturition. We found that induction of cyclooxygenase (COX)-2 and connexin 43 expression was impaired in Oxtr−/−, whereas that of PGF2α receptor expression was not. We next generated mice with double knockout of genes for the oxytocin receptor/oxytocin and PGF2α receptor (Oxtr−/−;Ptgfr−/− and Oxt−/−;Ptgfr−/−) and evaluated their parturition with Oxtr−/−, Oxt−/−, Ptgfr−/−, and wild-type mice. In Oxtr−/−;Ptgfr−/− and Oxt−/−;Ptgfr−/−, pregnancy rates were similar to those of other genotypes. However, normal parturition was not observed in Oxtr−/−;Ptgfr−/− or Oxt−/−;Ptgfr−/− because of persistent progesterone from the corpus luteum, as observed in Ptgfr−/−. We administered RU486, a progesterone antagonist, to Ptgfr−/−, Oxtr−/−;Ptgfr−/−, and Oxt−/−;Ptgfr−/− on gestation day 19. These mice were able to deliver a living first pup and the parturition onset was similar to that in Ptgfr−/−. Meanwhile, unlike Ptgfr−/−, ∼75% of Oxtr−/−;Ptgfr−/− and Oxt−/−;Ptgfr−/− administered RU486 remained in labor at 24 hours after the onset of parturition. All of the pups that experienced prolonged labor died. We thus revealed that the oxytocin receptor is an upstream regulator of COX-2 and connexin 43 in the uterus during parturition and that both oxytocin/oxytocin receptor and PGF2α receptor are major components for successful parturition.
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Lee, Jia Ming, Jemma R. Mayall, Anne Chevalier, Huw McCarthy, Dirk Van Helden, Philip M. Hansbro, Jay C. Horvat, and Phillip Jobling. "Chlamydia muridarum infection differentially alters smooth muscle function in mouse uterine horn and cervix." American Journal of Physiology-Endocrinology and Metabolism 318, no. 6 (June 1, 2020): E981—E994. http://dx.doi.org/10.1152/ajpendo.00513.2019.
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Chlamydia trachomatis infection is a primary cause of reproductive tract diseases including infertility. Previous studies showed that this infection alters physiological activities in mouse oviducts. Whether this occurs in the uterus and cervix has never been investigated. This study characterized the physiological activities of the uterine horn and the cervix in a Chlamydia muridarum ( Cmu)-infected mouse model at three infection time points of 7, 14, and 21 days postinfection (dpi). Cmu infection significantly decreased contractile force of spontaneous contraction in the cervix (7 and 14 dpi; P < 0.001 and P < 0.05, respectively), but this effect was not observed in the uterine horn. The responses of the uterine horn and cervix to oxytocin were significantly altered by Cmu infection at 7 dpi ( P < 0.0001), but such responses were attenuated at 14 and 21 dpi. Cmu infection increased contractile force to prostaglandin (PGF2α) by 53–83% in the uterine horn. This corresponded with the increased messenger ribonucleic acid (mRNA) expression of Ptgfr that encodes for its receptor. However, Cmu infection did not affect contractions of the uterine horn and cervix to PGE2 and histamine. The mRNA expression of Otr and Ptger4 was inversely correlated with the mRNA expression of Il1b, Il6 in the uterine horn of Cmu-inoculated mice ( P < 0.01 to P < 0.001), suggesting that the changes in the Otr and Ptger4 mRNA expression might be linked to the changes in inflammatory cytokines. Lastly, this study also showed a novel physiological finding of the differential response to PGE2 in mouse uterine horn and cervix.
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Robertson, Sarah A., Inge Christiaens, Camilla L. Dorian, Dean B. Zaragoza, Alison S. Care, Anke M. Banks, and David M. Olson. "Interleukin-6 Is an Essential Determinant of On-Time Parturition in the Mouse." Endocrinology 151, no. 8 (June 7, 2010): 3996–4006. http://dx.doi.org/10.1210/en.2010-0063.
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IL-6 abundance in amniotic fluid and uterine tissues increases in late gestation or with infection-associated preterm labor. A role in regulation of labor onset is suggested by observations that IL-6 increases expression of genes controlling prostaglandin synthesis and signaling in isolated uterine cells, but whether IL-6 is essential for normal parturition is unknown. To evaluate the physiological role of IL-6 in parturition in mice, we investigated the effect of Il6 null mutation on the timing of parturition and expression of genes associated with uterine activation. Il6 null mutant mice delivered 24 h later than wild-type mice, although circulating progesterone fell similarly in both genotypes during the prepartal period. Il6 null mutant mice were also refractory to low doses of lipopolysaccharide sufficient to induce preterm delivery in wild-type mice. The characteristic late-gestation elevation in uterine expression of Oxtr mRNA encoding oxytocin receptor, and peripartal increases in Ptgfr and Ptgs2 mRNAs regulating prostaglandin synthesis and signaling were delayed by 24 h in Il6 null mutant mice. Conversely, Ptger4 mRNA encoding the prostaglandin E receptor-4 was abnormally elevated in late-gestation in Il6 null mutant mice. Administration of recombinant IL-6 from d 11.5 postcoitum until term restored the normal timing of delivery and normalized Ptger4 mRNA expression in late gestation. We conclude that IL-6 has a key role in controlling the progression of events culminating in parturition and that it acts downstream of luteolysis in the uterus to regulate genes involved in the prostaglandin-mediated uterine activation cascade.
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Rebordão, Maria Rosa, Ana Amaral, Carina Fernandes, Elisabete Silva, Karolina Lukasik, Anna Szóstek-Mioduchowska, Pedro Pinto-Bravo, António Galvão, Dariusz J. Skarzynski, and Graça Ferreira-Dias. "Enzymes Present in Neutrophil Extracellular Traps May Stimulate the Fibrogenic PGF2α Pathway in the Mare Endometrium." Animals 11, no. 9 (September 6, 2021): 2615. http://dx.doi.org/10.3390/ani11092615.
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Endometrosis, a fibrotic disease of mare endometrium, impairs uterine function. Prostaglandins (PG), despite modulating reproductive physiological functions, may also cause local pathological collagen deposition (fibrogenesis). We have previously shown that neutrophil extracellular traps (NETs) may also favor mare endometrosis. The aim of this study was to investigate the effect of enzymes present in NETs on PGF2α-pathway activation. Kenney and Doig’s type I/IIA and IIB/III mare endometria, from follicular phase (FLP) and mid-luteal (MLP) phase, were cultured in vitro in the presence of NETs enzymes (elastase, cathepsin-G or myeloperoxidase). Production of PGF2α (EIA) and transcription (qPCR) of its synthases (PTGS2, AKR1C3) and receptor (PTGFR) genes were evaluated. PGF2α and PTGFR were influenced by endometrial category and estrous cycle phase. In FLP endometrium, NETs enzymes induced both high PGF2α production and/or PTGFR transcription. In MLP type I/IIA tissues, down-regulation of PTGFR transcripts occurred. However, in MLP type IIB/III endometrium, high levels of PTGFR transcripts were induced by NETs enzymes. As PGF2α-pathway activation facilitates fibrogenesis in other tissues, PGF2α may be involved in endometrosis pathogenesis. In the mare, the endocrine microenvironment of healthy and pathological endometrium might modulate the PGF2α pathway, as well as fibrosis outcome on endometrium challenged by NETs enzymes.
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Jamshed, Laiba, Genevieve A. Perono, Shanza Jamshed, Kim Ann Cheung, Philippe J. Thomas, and Alison Holloway. "The Effects of Naphthenic Acids on Tryptophan Metabolism and Peripheral Serotonin Signalling." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A493. http://dx.doi.org/10.1210/jendso/bvab048.1008.
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Abstract Introduction: Serotonin produced in the periphery has been shown to affect glucose and lipid homeostasis. The availability of the amino acid tryptophan, the precursor of serotonin, affects serotonin availability. In addition, the metabolism of tryptophan via the kynurenine pathway produces physiologically active metabolites which have been shown to be altered under conditions of increased adiposity and dysglycemia. There is now evidence demonstrating some environmental xenobiotics, known to affect glucose and lipid homeostasis, can also alter serotonin production and key components of the kynurenine pathway. Recent evidence suggests that exposure to compounds present in petroleum and wastewaters from oil and gas extraction sites can impact endocrine signaling and result in aberrant lipid accumulation and altered glycemic control. However, whether any of these changes can be causally ascribed to altered serotonin synthesis/signaling or tryptophan metabolism remains unknown. The goal of this study was to determine the effects of exposure to naphthenic acid (NA), a key toxicant found in wastewater from bitumen (thick crude oil present in oil sands deposits) extraction on the enzymes involved in tryptophan metabolism and serotonin production. Methods: McA-RH7777 rat hepatoma cells, were exposed to a technical NA mixture for 48 hours at concentrations within the reported range of NA found in wastewaters from oil extraction. We assessed mRNA expression for key rate-limiting enzymes involved in tryptophan metabolism that lead to either serotonin [Tph1] and/or kynurenine [Ido2 and Tdo2] production, as well as downstream enzymes in the kynurenine pathway [Afmid, Kyat1, Aadat, Kyat3, Kmo, Haao, Acmsd, Qprt]. We also examined the effects of NA on prostaglandin synthesis [Ptgs1, Ptgs2, Ptges] and signalling [Ptger2, Ptger4] as prostaglandins have been shown to be induced by serotonin and are linked to hepatic fat accumulation. Results: NA treatment significantly increased Tph1 and Ido2 expression; this occurred in association with a significant increase in the expression of the inducible prostaglandin synthase Ptgs2 (COX-2), prostaglandin E synthase Ptges, and prostaglandin receptors Ptger2 and Ptger4. Acmsd was the only downstream enzyme in the kynurenine pathway that was significantly altered by NA treatment. Conclusion: These results provide proof-of-concept that compounds associated with oil sands extraction have the potential to perturb key components of serotonin synthesis (Tph1) and tryptophan metabolism (Ido2, Acmsd). Furthermore, we found that the increase in Tph1 expression paralleled expression of Ptgs2. As increased prostaglandin production has been reported in association with nonalcoholic steatohepatitis, these data provide a potential mechanism by which exposure to NA and other petroleum-based compounds may increase the risk of metabolic disease.
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Rempel, Lea Magdalena, Karina Tietgen Andresen Lillevang, Ann-Kirstine thor Straten, Sólrún Barbara Friðriksdóttir, Hanna Körber, Axel Wehrend, Mariusz P. Kowalewski, Iris Margaret Reichler, Orsolya Balogh, and Sandra Goericke-Pesch. "Do uterine PTGS2, PGFS, and PTGFR expression play a role in canine uterine inertia?" Cell and Tissue Research 385, no. 1 (April 8, 2021): 251–64. http://dx.doi.org/10.1007/s00441-021-03427-6.
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AbstractThe aetiology of primary uterine inertia (PUI), which is the most common cause of canine dystocia, is still not elucidated. Prostaglandins (PGs) play a crucial role in parturition. We hypothesized that the expression of prostaglandin endoperoxidase synthase 2 (PTGS2), PGF2α synthase (PGFS), and corresponding receptor (PTGFR) is altered in PUI. We investigated PTGS2, PGFS, and PTGFR mRNA expression, and PTGS2 and PGFS protein expression in interplacental (IP) and uteroplacental sites (UP) in bitches with PUI, obstructive dystocia (OD), and prepartum (PC). PTGS2, PGFS, and PTGFR mRNA expression did not differ significantly between PUI and OD (IP/UP). PTGFR ratio in UP was higher in PC than in OD (p = 0.014). PTGS2 immunopositivity was noted in foetal trophoblasts, luminal and superficial glandular epithelial cells, smooth muscle cells of both myometrial layers, and weakly and sporadically in deep uterine glands. PGFS was localized in luminal epithelial cells and in the epithelium of superficial uterine glands. PTGS2 and PGFS staining was similar between PUI and OD, while PGFS protein expression differed between OD and PC (p = 0.0215). For PTGS2, the longitudinal myometrial layer of IP stained significantly stronger than the circular layer, independent of groups. These results do not support a role for PTGS2, PGFS, and PTGFR in PUI. Reduced PGFS expression in IP during parturition compared with PC and the overall lack of placental PGFS expression confirm that PGFS is not the main source of prepartal PGF2alpha increase. The difference in PTGS2 expression between IP myometrial layers warrants further investigation into its physiological relevance.
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Jamioł, Monika, Magdalena Sozoniuk, Jacek Wawrzykowski, and Marta Kankofer. "Effect of Sex Steroids and PGF2α on the Expression of Their Receptors and Decorin in Bovine Caruncular Epithelial Cells in Early–Mid Pregnancy." Molecules 27, no. 21 (November 1, 2022): 7420. http://dx.doi.org/10.3390/molecules27217420.
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Changes in the expression of various genes, including pregnancy-associated hormone receptors and extracellular matrix proteins, have been suggested to play a significant role in bovine placental development. This study aimed to examine the influence of sex steroids and PGF2α on decorin (DCN) expression in the epithelial cells of bovine caruncle in early–mid pregnancy in cows. The expression patterns of DCN, PTGFR, PGR and ESR1 were analyzed by RT-qPCR and Western blotting in primary caruncular epithelial cell cultures (PCECC) and placental tissue homogenates derived from the 2nd and 4th months of pregnancy. PCECC were found to express DCN, PTGFR, PGR and ESR1. The intensity of PGR staining was higher in cells derived from the 4th month of pregnancy (p < 0.05). The 17β-estradiol, progesterone and PGF2α have not been shown to affect DCN expression. PGF2α decreased PTGFR expression in cells derived from the 4th month of gestation (p < 0.05). In conclusion, the results of the present preliminary study showed that the expression of the PTGFR, ESR1, PGR and DCN in PCECC does not vary throughout early–mid pregnancy. Further studies should be carried out to observe the relationship between hormonal status and cellular adhesion to determine their importance for properly developing placentation and pregnancy in cows.
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ZHANG, Nan, Wei MAO, Ying ZHANG, Na HUANG, Bo LIU, Long GAO, Shuangyi ZHANG, and Jinshan CAO. "The prostaglandin E2 receptor PTGER2 and prostaglandin F2α receptor PTGFR mediate oviductal glycoprotein 1 expression in bovine oviductal epithelial cells." Journal of Reproduction and Development 64, no. 2 (2018): 101–8. http://dx.doi.org/10.1262/jrd.2017-076.
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Miyoshi, Moe, Masayuki Sato, Kenji Saito, Lila Otani, Katsuhiko Shirahige, Fumihito Miura, Takashi Ito, Huijuan Jia, and Hisanori Kato. "Maternal Protein Restriction Alters the Renal Ptger1 DNA Methylation State in SHRSP Offspring." Nutrients 10, no. 10 (October 5, 2018): 1436. http://dx.doi.org/10.3390/nu10101436.
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We previously reported that maternal protein restriction (LP) during pregnancy increases salt sensitivity in offspring using the Stroke-Prone Spontaneously Hypertensive Rat (SHRSP). In the present study, we focus on DNA methylation profiles of prostaglandin E receptor 1 gene (ptger1), which is known to be associated with hypertension. We evaluated the ptger1 DNA methylation status via bisulfite sequencing, and analyzed the expression of ptger1-related genes. The results of these analyses showed that, compared to controls, the LP-S offspring exhibited both marked ptger1 hypermethylation, and significantly increased ptger1 expression. Moreover, they also exhibited significantly decreased expression of the downstream gene epithelial Na+ channel alpha (enacα). Interestingly, LP offspring that were provided with a standard water drinking supply (W) also exhibited increased ptger1 methylation and expression. Together, these results suggest that maternal protein restriction during pregnancy modulates the renal ptger1 DNA methylation state in SHRSP offspring, and thereby likely mediates ptger1 and enacα gene expression to induce salt sensitivity.
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Hryciuk, Michał M., Katarina Jewgenow, and Beate C. Braun. "Cloprostenol, a synthetic analog of prostaglandin F2α induces functional regression in cultured luteal cells of felids." Biology of Reproduction 105, no. 1 (April 16, 2021): 137–47. http://dx.doi.org/10.1093/biolre/ioab070.
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Abstract In the present study, we investigated the effect of the synthetic analog of prostaglandin F2α (PGF2α)—cloprostenol—on cultured steroidogenic luteal cells of selected felid species over a 2-day culture period. The changes induced by cloprostenol were measured based on progesterone concentration and mRNA expression analysis of selected genes. Cloprostenol significantly reduced concentration of progesterone in cell culture medium of small luteal cells isolated from domestic cat corpora lutea (CL) at the development/maintenance stage (P < 0.05), but did not influence progesterone production in cultured cells from the regression stage. A decrease or complete silencing of progesterone production was also measured in cultured luteal cells of African lion (formation stage) and Javan leopard (development/maintenance stage). Gene-expression analysis by real-time PCR revealed that treatment with cloprostenol did not have an influence on expression of selected genes coding for enzymes of steroidogenesis (StAR, HSD3B, CYP11A1) or prostaglandin synthesis (PTGS2, PGES), nor did it effect hormone receptors (AR, ESR1, PGR, PTGER2), an anti-oxidative enzyme (SOD1) or factors of cell apoptosis (FAS, CASP3, TNFRSF1B, BCL2) over the studied period. Significant changes were measured only for expressions of luteinizing hormone (P < 0.05), prolactin (P < 0.05) and PGF2α receptors (P < 0.005) (LHCGR, PRLR, and PTGFR). The obtained results confirm that PGF2α/cloprostenol is a luteolytic agent in CL of felids and its impact on progesterone production depends on the developmental stage of the CL. Cloprostenol short-term treatment on luteal cells was associated only with functional but not structural changes related to luteal regression.
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Camargos, A., S. Wohlres-Viana, I. F. Costa, L. S. Camargo, J. C. Ferreira, A. A. Ramos, and E. Oba. "Cloprostenol administration in the first week postpartum reduces expression of oxytocin receptors in the endometrium in Holstein-Zebu cows." Arquivo Brasileiro de Medicina Veterinária e Zootecnia 69, no. 4 (August 2017): 821–29. http://dx.doi.org/10.1590/1678-4162-9318.
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ABSTRACT The present study investigated the hormonal profile and expression of prostaglandin F2α (PGF2α), oxytocin and estrogen receptors in uterine tissues of postpartum cows treated with cloprostenol. Twenty Holstein-Zebu crossbred cows were treated with saline solution (treatment CONT) or cloprostenol (treatment CLO), both administered two and five days postpartum. Blood samples were collected on days two, seven, 14, 21 and 28 postpartum for progesterone, PGF2α metabolite (PGFM) and estradiol determination, and endometrial biopsy was performed in order to quantify the expression of oxytocin receptor (OXTR), prostaglandin F receptor (PTGFR) and estrogen receptor 1 (ERS1) genes. In the CLO treatment, expression of OXTR was reduced (P<0.05) but no difference (P>0.05) between treatments was found for PTGFR and ERS1 expression. Estrogen concentrations increased progressively until day 14 (P<0.05) and the highest OXTR expression and lowest PTGFR expression were observed on day 14 (P<0.05) in both treatments. Serum PGFM concentrations were high throughout the experiment. In conclusion, cloprostenol administration at days two and five of postpartum seems to reduce OXTR expression in the endometrium in crossbred cows.
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Chen, Dongjiang, Son Le, Tarun Hutchinson, and David Tran. "DDRE-13. PROSTAGLANDIN E RECEPTOR 3 (PTGER3) REGULATES RESISTANCE TO TUMOR TREATING FIELDS (TTFields) IN GLIOBLASTOMA CELLS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi77. http://dx.doi.org/10.1093/neuonc/noab196.297.
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Abstract INTRODUCTION TTFields, a novel approved therapy for GBM, employ alternating intermediate-frequency electric fields to disrupt mitotic macromolecules leading to chromosome mis-segregation and apoptosis. The addition of TTFields significantly improves survival. However, most patients eventually develop resistance to TTFields through an unknown mechanism. METHODS Multiple human GBM cell lines were treated with TTFields continuously using Inovitro, an in vitro TTFields system, until cells with relative resistance to killing by TTFields emerged. Temporal gene expression profiles were analyzed using NETZEN, an innovative deep-learning and gene network-based ranking computational algorithm, to identify resistance pathways, followed by experimental validation. RESULTS PTGER3, a Gαi-protein-coupled cell surface receptor, is the top ranked master regulator in the predicted resistance program, which is upregulated in GBM cells within 24 hrs of exposure to TTFields and further reinforced as resistance sets in. Forced expression of PTGER3 in sensitive GBM cells confers relative resistance to TTFields, while PTGER3 depletion in resistant cells re-sensitizes them to TTFields. Most importantly, pharmacological inhibition of PTGER3 using either aspirin to reduce prostaglandin E production or PTGER3-specific inhibitors effectively prevent resistance from developing. Mechanistically, PTGER3 is rapidly translocated from the plasma membrane to the nucleus after TTFields exposure, where it interacts with ZNF488, a stemness transcription factor tightly linked to PTGER3 in our predicted network to initiate and maintain the resistance program. Indeed, TTFields resistance is associated with a transition to glioma stem cells (GSCs) as determined by increased neurosphere formation and orthotopic tumorigenesis in immunocompromised mice, and PTGER3 inhibition alone reverses the GSC transition leading to improved tumor control and survival. CONCLUSIONS PTGER3 is at the apex of a novel pathway that indispensably regulates TTFields resistance through a unique mechanism involving the physical nuclear translocation of this 7-transmembrane receptor. PTGER3 and its pathway are thus potential therapeutic targets to enhance therapeutic efficacy of TTFields.
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Murn, Jernej, Olivier Alibert, Ning Wu, Simon Tendil, and Xavier Gidrol. "Prostaglandin E2 regulates B cell proliferation through a candidate tumor suppressor, Ptger4." Journal of Experimental Medicine 205, no. 13 (December 15, 2008): 3091–103. http://dx.doi.org/10.1084/jem.20081163.
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B cell receptor (BCR) signaling contributes to the pathogenesis of B cell malignancies, and most B cell lymphomas depend on BCR signals for survival. Identification of genes that restrain BCR-mediated proliferation is therefore an important goal toward improving the therapy of B cell lymphoma. Here, we identify Ptger4 as a negative feedback regulator of proliferation in response to BCR signals and show that its encoded EP4 receptor is a principal molecule conveying the growth-suppressive effect of prostaglandin E2 (PGE2). Stable knockdown of Ptger4 in B cell lymphoma markedly accelerated tumor spread in mice, whereas Ptger4 overexpression yielded significant protection. Mechanistically, we show that the intrinsic activity of Ptger4 and PGE2–EP4 signaling target a similar set of activating genes, and find Ptger4 to be significantly down-regulated in human B cell lymphoma. We postulate that Ptger4 functions in B cells as a candidate tumor suppressor whose activity is regulated by PGE2 in the microenvironment. These findings suggest that targeting EP4 receptor for prostaglandin may present a novel strategy for treatment of B cell malignancies.
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Kaczynski, Piotr, Mariusz P. Kowalewski, and Agnieszka Waclawik. "Prostaglandin F2α promotes angiogenesis and embryo–maternal interactions during implantation." Reproduction 151, no. 5 (May 2016): 539–52. http://dx.doi.org/10.1530/rep-15-0496.
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AbstractImplantation in humans and other mammals is a critical period during which high embryonic mortality rates occur. Prostaglandins (PGs) are key mediators regulating interactions between the reproductive tract and the conceptus (embryo with extraembryonic membranes). Although the significance of PGF2α as a regulator of corpus luteum regression is well established, the role of its high amounts in the uterine lumen in most mammals, regardless of placentation type, during the implantation period remains unresolved. We hypothesized that PGF2α acting as an embryonic signal mediator contributes to pregnancy establishment. Using a porcine model, we demonstrated that the conceptus and its signal (estradiol-17β) elevated endometrial expression of PGF2α receptor (PTGFR)invivoandin vitro. PTGFR protein was expressed mainly in luminal epithelial (LE) and glandular epithelial cells and blood vessels in the endometrium. PGF2α stimulated the MAPK1/3 pathway in endometrial LE cells that coincided with elevated gene expression and secretion of endometrial vascular endothelial growth factor A (VEGFA) protein. PGF2α–PTGFR and adenylyl cyclase signaling were involved in this process. PGF2α-induced VEGFA acting through its receptors stimulated proliferation of endometrial endothelial cells. Moreover, PGF2α elevated gene expression of biglycan, matrix metalloproteinase 9, transforming growth factor β3, and interleukin 1α in the endometrium. In summary, our study indicates that PGF2α participates in pregnancy establishment by promoting angiogenesis and expression of genes involved in tissue remodeling and conceptus–maternal interactions in porcine endometrium during early pregnancy.
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Zhang, Shuangyi, Bo Liu, Long Gao, Wei Mao, Changqi Fu, Duritahala, Nan Zhang, Ying Zhang, Yuan Shen, and Jinshan Cao. "Prostaglandin F2α–PTGFR signalling activation, growth factor expression and cell proliferation in bovine endometrial explants." Reproduction, Fertility and Development 29, no. 11 (2017): 2195. http://dx.doi.org/10.1071/rd16144.
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The endometrium of domestic animals undergoes regular periods of regeneration and degeneration and exhibits a remarkable capacity for self-repair during the oestrous cycle. The endometrial growth pattern is also observed during in the implantation period and early pregnancy, but the mechanism underlying endometrial growth in these processes remains unclear. A positive correlation between endometrial growth in these processes and prostaglandin (PG) F2α secretion has been reported, but the roles that PGF2α plays in endometrial growth is less studied. In the present study, cell proliferation and the responses of a series of growth factors essential for endometrial growth to PGF2α receptor (PTGFR) activation were investigated in bovine endometrial explants in vitro. Using real-time reverse transcription–polymerase chain reaction and western blotting, mRNA and protein expression of connective tissue growth factor, fibroblast growth factor2, interleukin8, matrix metalloproteinase2, transforming growth factor β1 and vascular endothelial growth factor A was increased (P < 0.05) and cell proliferation, including epithelial and fibroblast proliferation, was induced in response to increased levels of proliferating cell nuclear antigen, cytokeratin-18 and fibroblast-specific protein-1 (P < 0.05) following PTGFR activation by adding fluprostenol (10−9–10−5 M) into culture medium of bovine endometrial explants. However, caspase-3 protein expression was reduced following treatment of explants with fluprostenol (10−9–10−5 M, P < 0.05). These results may help define the possible roles the PGF2α–PTGFR signalling pathway plays in endometrial growth.
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Kamyshna, Iryna, and Aleksandr Kamyshnyi. "Transcriptional Activity of Neurotrophins Genes and Their Receptors in the Peripheral Blood in Patients with Thyroid Diseases in Bukovinian Population of Ukraine." Open Access Macedonian Journal of Medical Sciences 9, A (May 2, 2021): 208–16. http://dx.doi.org/10.3889/oamjms.2021.6037.
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Objective. Thyroid hormone has an especially strong impact on central nervous system development, and thyroid hormone deficiency has been shown to result in severe mental retardation. It is crucial to identify compensatory mechanisms that can be involved in improving cognitive function and the quality of life of patients with hypothyroidism.
Methods: We used the pathway-specific PCR array (Neurotrophins and Receptors RT2 Profiler PCR Array, QIAGEN, Germany) to identify and validate neurotrophins genes and their receptor expression in patients with thyroid pathology and control group.
Results: The analysis of gene expression of neurotrophins and their receptors showed that CRHBP, FRS2, FRS3, GFRA1, GFRA2, GMFB, NGF, NRG2, NRG4, NTF4, TRO, and VGF significantly decreased their expression in Group 3, which includes the patients with postoperative hypothyroidism. The patients with primary hypothyroidism stemming from AIT had significantly reduced expression of CRHBP, GFRA1, GFRA2, GMFB, NGF, PTGER2, and VGF, while the expression of NRG4 and TRO increased. In Group 3, which includes the patients with AIT and elevated serum anti-Tg and anti-TPO autoantibodies, the mRNA levels of GFRA2, NGF, NRG2, NTF4, NGF, PTGER were reduced, and the expression of CRHBP, FRS2, FRS3 GFRA1, GMFB, NRG4, TRO, and VGF significantly increased.
Conclusion: These results indicate significant variability in the transcriptional activity of the genes of encoding neurotrophins and their receptors in the peripheral blood in people with thyroid diseases.
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Kautz, E., A. Gram, S. Aslan, S. S. Ay, M. Selçuk, H. Kanca, E. Koldaş, et al. "Expression of genes involved in the embryo–maternal interaction in the early-pregnant canine uterus." REPRODUCTION 147, no. 5 (May 2014): 703–17. http://dx.doi.org/10.1530/rep-13-0648.
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Although there is no acute luteolytic mechanism in the absence of pregnancy in the bitch, a precise and well-timed embryo–maternal interaction seems to be required for the initiation and maintenance of gestation. As only limited information is available about these processes in dogs, in this study, the uterine expression of possible decidualization markers was investigated during the pre-implantation stage (days 10–12) of pregnancy and in the corresponding nonpregnant controls. In addition, the expression of selected genes associated with blastocyst development and/or implantation was investigated in embryos flushed from the uteri of bitches used for this study (unhatched and hatched blastocysts). There was an upregulated expression of prolactin receptor (PRLR) and IGF2 observed pre-implantation. The expression of PRL and of IGF1 was unaffected, and neither was the expression of progesterone- or estrogen receptor β (ESR2). In contrast, (ESR1) levels were elevated during early pregnancy. Prostaglandin (PG)-system revealed upregulated expression of PGE2-synthase and its receptors, PTGER2 and PTGER4, and of the PG-transporter. Elevated levels of AKR1C3 mRNA, but not the protein itself, were noted. Expression of prostaglandin-endoperoxide synthase 2 (PTGS2) remained unaffected. Most of the transcripts were predominantly localized to the uterine epithelial cells, myometrium and, to a lesser extent, to the uterine stroma. PGES (PTGES) mRNA was abundantly expressed in both groups of embryos and appeared higher in the hatched ones. The expression level of IGF2 mRNA appeared higher than that of IGF1 mRNA in hatched embryos. In unhatched embryos IGF1, IGF2, and PTGS2 mRNA levels were below the detection limit.
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Wu, Victoria H., Alexander Wenzel, Bryan Yung, Zhiyong Wang, Jill P. Mesirov, and J. Silvio Gutkind. "Illuminating the onco-GPCRome: targeting the prostaglandin receptor-Gαs signaling axis as a novel immune checkpoint in cancer." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 165.37. http://dx.doi.org/10.4049/jimmunol.204.supp.165.37.
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Abstract Recent advances in checkpoint blockade immunotherapy (CBI) have revolutionized cancer treatment, but the limited response rates in most cancers suggest that new approaches and targets are clearly needed to fully elucidate the underlying biology of dysfunctional CD8 T cells and achieve durable responses. G-protein coupled receptors (GPCRs) are the most intensively studied drug targets as they play key roles in many physiological processes, and they have remained longstanding favorable pharmacological targets. Using novel computational approaches integrating multiple single cell RNAseq databases, we first deconvoluted tumor-infiltrating T cell heterogeneity to generate a transcriptomic GPCR signature based on coupling specificity and receptor family. Preliminary data shows an upregulation of prostaglandin receptors, PTGER2 and PTGER4, on exhausted T cells, suggesting that these GPCRs, coupled to the Gαs G protein α subunit, may contribute to diminishing anti-tumor cytotoxicity. Expression and stimulation of EP2 and EP4 on highly activated CD8 T cells and subsequent Gαs signaling decreases cytokine secretion and CXCR3-mediated migration. Additionally, blockade of EP2 and EP4 significantly decreases tumor growth in multiple immune competent, syngeneic tumor models. Altogether, we hypothesize that activation of Gαs downstream signaling cascades may be dampening the anti-tumor cytotoxicity of CD8 T cells, thereby limiting the effectiveness of PD-1 and CTLA-4 blockade. EP2 and EP4 and Gαs signaling may represent promising candidates as immune checkpoints that can be targeted in combination with CBI as part of novel multimodality precision immunotherapy approaches to reactivate the immune system to destroy tumors.
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Akison, Lisa K., Michael J. Boden, David J. Kennaway, Darryl L. Russell, and Rebecca L. Robker. "Progesterone receptor-dependent regulation of genes in the oviducts of female mice." Physiological Genomics 46, no. 16 (August 15, 2014): 583–92. http://dx.doi.org/10.1152/physiolgenomics.00044.2014.
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Oviducts play a critical role in gamete and embryo transport, as well as supporting early embryo development. Progesterone receptor (PGR) is a transcription factor highly expressed in oviductal cells, while its activating ligand, progesterone, surges to peak levels as ovulation approaches. Progesterone is known to regulate oviduct cilia beating and muscular contractions in vitro, but how PGR may mediate this in vivo is poorly understood. We used PGR null mice to identify genes potentially regulated by PGR in the oviducts during the periovulatory period. Histologically, oviducts from PGR null mice showed no gross structural or morphological defects compared with normal littermates. However, microarray analysis of oviducts at 8 h posthuman chorionic gonadotropin revealed >1,000 PGR-dependent genes. Using reverse-transcription polymerase chain reaction (RT-PCR) we selected 10 genes for validation based on their potential roles in oocyte/embryo transport and support. Eight genes were confirmed to be downregulated ( Adamts1, Itga8, Edn3, Prlr, Ptgfr, Des, Myocd, and Actg2) and one upregulated ( Agtr2) in PGR null oviducts. Expression of these genes was also assessed in oviducts of naturally cycling mice during ovulation and day 1 and day 4 of pregnancy. Adamts1, Itga8, Edn3, Prlr, and Ptgfr were significantly upregulated in oviducts at ovulation/mating. However, most genes showed basal levels of expression at other times. The exceptions were Prlr and Ptgfr, which showed pulsatile increases on day 1 and/or day 4 of pregnancy. This is the first, comprehensive study to elucidate putative PGR-regulated genes in the oviduct and reveals key downstream targets potentially mediating oocyte and embryo transport.
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García-Sánchez, Asunción, Miguel Estravís, Maria J. Martin, Jacqueline Pérez-Pazos, Cristina Martín-García, María Gil-Melcón, Jacinto Ramos-González, et al. "PTGDR2 Expression in Peripheral Blood as a Potential Biomarker in Adult Patients with Asthma." Journal of Personalized Medicine 11, no. 9 (August 24, 2021): 827. http://dx.doi.org/10.3390/jpm11090827.
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Background: Precision medicine is a promising strategy to identify biomarkers, stratify asthmatic patients according to different endotypes, and match them with the appropriate therapy. This proof-of-concept study aimed to investigate whether gene expression in peripheral blood could provide a valuable noninvasive approach for the molecular phenotyping of asthma. Methods: We performed whole-transcriptome RNA sequencing on peripheral blood of 30 non-atopic non-asthmatic controls and 30 asthmatic patients. A quantitative PCR (qPCR) validation study of PTGDR2 that encodes for CRTH2 receptor, expressed in cells involved in T2 inflammation, was developed in a cohort of 361 independent subjects: 94 non-asthmatic non-atopic controls, 187 asthmatic patients [including 82 with chronic rhinosinusitis with nasal polyposis (CRSwNP) and 24 with aspirin-exacerbated respiratory disease (AERD)], 52 with allergic rhinitis, and 28 with CRSwNP without asthma. Results: PTGDR2 was one of the most differentially overexpressed genes in asthmatic patients’ peripheral blood (p-value 2.64 × 106). These results were confirmed by qPCR in the validation study, where PTGDR2 transcripts were significantly upregulated in asthmatic patients (p < 0.001). This upregulation was mainly detected in some subgroups such as allergic asthma, asthma with CRSwNP, AERD, eosinophilic asthma, and severe persistent asthma. PTGDR2 expression was detected in different blood cell types, and its correlation with eosinophil counts showed differences in some groups of asthmatic patients. Conclusions: We found that PTGDR2 expression levels could identify asthma patients, introduce a minimally invasive biomarker for adult asthma molecular phenotyping, and add additional information to blood eosinophils. Although further studies are required, analyzing PTGDR2 expression levels in peripheral blood of asthmatics might assist in selecting patients for treatment with specific antagonists.
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Hay, A., S. Wood, D. Olson, and D. M. Slater. "Labour is associated with decreased expression of the PGF2 receptor (PTGFR) and a novel PTGFR splice variant in human myometrium but not decidua." Molecular Human Reproduction 16, no. 10 (June 2, 2010): 752–60. http://dx.doi.org/10.1093/molehr/gaq046.
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Chen, Dongjiang, Son Le, Tarun Hutchinson, and David Tran. "CSIG-15. INNOVATIVE COMPUTATIONAL PLATFORM ADDRESSES PROSTAGLANDIN E RECEPTOR 3 AS THE MASTER REGULATOR MEDIATING RESISTANCE TO TUMOR TREATING FIELDS IN GLIOBLASTOMA CELLS." Neuro-Oncology 22, Supplement_2 (November 2020): ii30—ii31. http://dx.doi.org/10.1093/neuonc/noaa215.127.
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Abstract OBJECTIVES Tumor Treating Fields (TTFields) are approved in combination with temozolomide for newly diagnosed glioblastoma (GBM). TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly. The addition of TTFields resulted in a significant improvement in overall survival. However, most GBM patients eventually develop resistance to TTFields and the mechanism remains unexplored. METHODS Multiple GBM cell lines were treated continuously at clinically approved frequency of 200 kHz using an in vitro TTFields system until cells with relative resistance to the cytotoxic effects of TTFields. A systems approach aided by innovative network ranking computational algorithms were utilized to analyze global gene expression profiles and identify resistance pathways, which were subsequently validated experimentally. RESULTS TTFields-induced chromosomal instability is preserved in resistant cells, indicating that TTFields resistance is mediated through a non-biophysical mechanism. This acquired TTFields resistance phenotype is associated with a transition of GBM cells to a stem-like state as determined by a neurosphere assay, stemness markers such as CD44 and increased tumorigenesis when implanted into mouse brain. Using an innovative computational platform-NETZEN, we methodically dissected this stemness program in resistant cells. 3 networks were found disrupted and all play critical roles in GBM stemness. Mechanistically, Prostaglandin E Receptor 3 (PTGER3) is the top ranked regulator responsible for resistance. PTGER3 is rapidly upregulated both in vitro and in vivo upon exposure to TTFields and further increases with prolonged treatment as resistance sets in. Immunofluorescence staining shows PTGER3’s nuclear translocation along with Lamin A/C disruption in response to TTFields. Pharmacological inhibition of PTGER3 using aspirin or PTGER3-specific inhibitors resensitized or prevent cells becoming resistance to TTFields. CONCLUSIONS We have identified a novel regulator PTGER3 at the apex that plays a critical role in TTFields resistance. This is a potential therapeutic target to reduce resistance to TTFields therapy in GBM.
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Rahman, M. Jubayer, Kameron Rodrigues, Yi Liu, Yongge Zhao, Juan A. Quiel, and Kristin V. Tarbell. "PTGER4 inhibition in non-obese diabetic mice restores impaired IFNAR signaling, decreases chronic inflammatory signals and inhibits autoimmunity." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 222.18. http://dx.doi.org/10.4049/jimmunol.198.supp.222.18.
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Abstract We recently demonstrated that dendritic cells (DCs) from autoimmune-prone non-obese diabetic (NOD) mice at prediabetic age (8–10 week) have a diminished IFN-alpha Receptor (IFNAR) response despite increased production of type 1 IFN. This impaired IFN response may result from chronic activation of inflammatory pathways that contribute to dysregulated innate activation. qPCR of innate targets showed that younger NOD mice (3 week old) did not yet display impaired IFNAR signaling, but already had higher IL-1. To understand the interplay between different innate signals, we compared gene expression of 5 key DC populations from prediabetic NOD mice and diabetes-resistant B6.g7 mice. Several inflammatory pathways including IL-1, Eicosanoids, and NFκB were higher in NOD DCs whereas type 1 IFN-response genes, especially those associated with tonic signal, were lower in prediabetic NOD mice. Analysis of potential upstream regulators of these changes identified increased PTGER4 signal and decreased IRF7. PTGER4 binds prostaglandin E2 (PGE2) and mediates specific aspects of both inflammatory and regulatory eicosanoid signaling. Interestingly, NOD mice treated with an inhibitor of PTGER4 displayed increased IFNAR signaling in DCs, but decreased IL-1, Nlrp3 and IFN-gamma production. These changes suggest restoration of cross-talk between key inflammatory mediators, namely that IFN-gamma and IL-1 can inhibit type 1 IFN and vice versa. Furthermore, mice treated with the PTGER4 antagonist display reduced autoimmune pathology, namely an increase in the number and percentage of healthy islets. These findings highlight PTGER4 as a potential target in type 1 diabetes, affecting several inflammatory pathways including IFNAR signaling.
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Huang, Xianping, Weihe Zhou, Yuefeng Zhang, and Yong Liu. "High Expression of PTGR1 Promotes NSCLC Cell Growth via Positive Regulation of Cyclin-Dependent Protein Kinase Complex." BioMed Research International 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/5230642.
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Lung cancer has been the most common cancer and the main cause of cancer-related deaths worldwide for several decades. PTGR1 (prostaglandin reductase 1), as a bifunctional enzyme, has been involved in the occurrence and progression of cancer. However, its impact on human lung cancer is rarely reported. In this study, we found that PTGR1 was overexpressed in lung cancer based on the analyses of Oncomine. Moreover, lentivirus-mediated shRNA knockdown of PTGR1 reduced cell viability in human lung carcinoma cells 95D and A549 by MTT and colony formation assay. PTGR1 depletion led to G2/M phase cell cycle arrest and increased the proportion of apoptotic cells in 95D cells by flow cytometry. Furthermore, silencing PTGR1 in 95D cells resulted in decreased levels of cyclin-dependent protein kinase complex (CDK1, CDK2, cyclin A2, and cyclin B1) by western blotting and then PTGR1 is positively correlated with cyclin-dependent protein by using the data mining of the Oncomine database. Therefore, our findings suggest that PTGR1 may play a role in lung carcinogenesis through regulating cell proliferation and is a potential new therapeutic strategy for lung cancer.
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Huang, Wenhai, Hao Huang, Shuishen Zhang, Xueping Wang, Juan Ouyang, Zhichao Lin, and Peisong Chen. "A Novel Diagnosis Method Based on Methylation Analysis of SHOX2 and Serum Biomarker for Early Stage Lung Cancer." Cancer Control 27, no. 1 (January 1, 2020): 107327482096970. http://dx.doi.org/10.1177/1073274820969703.
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Objectives: Lung cancer (LC) is often accompanied by significant methylation abnormalities. This study aimed to develop a decision tree (DT) accompanied the stature homeobox 2 gene (SHOX2) / prostaglandin E receptor 4 (PTGER4) gene DNA methylation with traditional tumor marker in the differential diagnosis of benign and malignant lung nodule. Methods: We performed a study with 104 patients enrolled in the LC group and 36 patients in the benign lung diseases group. All the clinical data of these patients were collected through electronic medical record. Total Methylation (TM) status of both SHOX2 and PTGER4 was defined as methylation levels of SHOX2 plus methylation levels of PTGER4. One-way analysis was used to compare the concentrations of serum samples and t-test was used to compare pairwise mean values between groups. Receiver operating curve (ROC) was used to evaluate the diagnostic value. Furthermore, the strategy was validated in 19 LC patients and 11 patients with benign lung diseases. Results: There were significant differences between the concentration of neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), cytokeratin 19 fragments (CYFRA21 -1) and the methylation levels of SHOX2, PTGER4 and TM in lung benign diseases and cancer group. The AUCs of NSE, CEA, CYFRA21 -1, Methylation SHOX2, Methylation PTGER4 and TM were 0.721 (95% CI: 0.627–0.816), 0.753 (95% CI: 0.673–0.833) and 0.778(95% CI: 0.700–0.856), 0.851(0.786-0.916), 0.847(0.780-0.913) and 0.861(0.800-0.922) respectively. We developed a DT model with TM and CYFRA21 -1 used in this study, and the area under the curve (AUC) of DT was 0.921 and the sensitivity up to 0.856. In the validation cohort, the AUC of SHOX2, PTGER4 and TM was also much higher than traditional serum markers. Conclusions: Our results indicated that the DT model calculated from the TM and CYFRA21 -1 can accurately classify LC and benign diseases, which showed better diagnostic performance than traditional serum parameter.
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Prager, Matthias, Janine Büttner, and Carsten Büning. "PTGER4 modulating variants in Crohn’s disease." International Journal of Colorectal Disease 29, no. 8 (May 3, 2014): 909–15. http://dx.doi.org/10.1007/s00384-014-1881-3.
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Zhang, Long, Changfan Zhou, Xiaoyu Jiang, Shuntao Huang, Yiheng Li, Tao Su, Guowei Wang, You Zhou, Min Liu, and Dequan Xu. "Circ0001470 Acts as a miR-140-3p Sponge to Facilitate the Progression of Embryonic Development through Regulating PTGFR Expression." Cells 11, no. 11 (May 25, 2022): 1746. http://dx.doi.org/10.3390/cells11111746.
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Embryonic implantation and development are vital in early pregnancy and assisted reproduction. Circular RNAs (circRNAs) are involved in the two physiological processes and thus regulate animal reproduction. However, their specific regulatory functions and mechanisms remain unclear. Here, a novel circ0001470, originating from the porcine GRN gene, differentially expressed on day 18 versus day 32 of gestation in Meishan and Yorkshire pigs was screened. The circularization characteristic of circ0001470 was identified based on divergent primer amplification, Sanger sequencing, RNase digestion, and RNA nuclear-cytoplasmic fractionation. Functionally, circ0001470 can promote cell proliferation and cycle progression of endometrial epithelial cells (EECs) and also inhibit apoptosis of EECs using CCK-8 assays and flow cytometry analyses. Mechanistically, bioinformatics database prediction, luciferase screening, RNA immunoprecipitation (RIP), RNA-pull down, and FISH co-localization experiments revealed that the circ0001470 acted as a competing endogenous RNA (ceRNA) through sponging miR-140-3p to regulate downstream PTGFR expression. Moreover, in vivo assays revealed that mmu_circGRN promoted embryonic development by affecting the expression of PTGFR, which can activate the MAPK reproduction pathway and facilitate pregnancy maintenance. This study enriched our understanding of circRNAs in embryo implantation and development by deciding the fate of EECs.
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Sun, Li-Qun, Gong-Liang Guo, Sai Zhang, and Li-Li Yang. "Effects of MicroRNA-592-5p on Hippocampal Neuron Injury Following Hypoxic-Ischemic Brain Damage in Neonatal Mice - Involvement of PGD2/DP and PTGDR." Cellular Physiology and Biochemistry 45, no. 2 (2018): 458–73. http://dx.doi.org/10.1159/000486923.
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Background/Aims: This study aimed to explore the effect of microRNA-592-5p (miR-592-5p) on hypoxic-ischemic brain damage (HIBD)-induced hippocampal neuronal injury in a neonatal mouse model relative to the involvement of one target gene, PTGDR, and the PGD2/ DP signaling pathway. Methods: A total of 30 neonatal mice aged 7 days were randomly selected to establish an HIBD mouse model. Hippocampal neuronal cells were transfected into a control group, a blank group, a negative control (NC) group, an miR-592-5p mimics group, an miR-592-5p inhibitors group, an siRNA-PTGDR group and an miR-592-5p inhibitors + siRNA-PTGDR group. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analyses were performed to detect the expression levels of miR-592-5p, PTGDR, DP2, Bcl-2 and Bax in tissues and cells. Cell proliferation, cell cycle and apoptosis were detected by MTT assay and flow cytometry, respectively. Results: The expression levels of miR-592-5p and Bcl-2 decreased, while the expression levels of PTGDR, DP2 and Bax increased in the HIBD group. PTGDR is a target gene of miR-592-2p. Compared with the NC and blank groups, the expression levels of PTGDR, DP2 and Bax decreased, while the expression levels of miR-592-5p and Bcl-2 increased in the miR-592-5p mimics group. The siRNA-PTGDR group showed the same trend as that observed in the miR-592-5p mimics group, except with no difference in miR-592-5p expression. The miR-592-5p inhibitors group showed an opposite gene expression trend compared to that in the miR-592-5p mimics group. The S phase of the cell cycle was prolonged, the G1 phase was reduced, proliferation was increased, and the apoptosis rate was decreased in the siRNA-PTGDR and miR-592-5p mimics groups. Opposite trends for cell cycle, proliferation and apoptosis were observed in the miR-592-5p inhibitors group. Conclusions: Our study suggests that miR-592-5p upregulation protects against hippocampal neuronal injury caused by HIBD by targeting PTGDR and inhibiting the PGD2/DP signaling pathway.
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Chen, Dongjiang, Son Le, Nagheme Thomas, and David Tran. "DRES-06. PROSTAGLANDIN E RECEPTOR 3 MEDIATES RESISTANCE TO TUMOR TREATING FIELDS IN GLIOBLASTOMA CELLS." Neuro-Oncology 21, Supplement_6 (November 2019): vi72. http://dx.doi.org/10.1093/neuonc/noz175.294.
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Abstract OBJECTIVES Tumor Treating Fields (TTFields) are approved in combination with temozolomide for newly diagnosed glioblastoma (GBM). The addition of TTFields resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly. However, most GBM patients eventually develop resistance to TTFields. The mechanism of TTFields resistance remains largely unexplored. Understanding how GBM cells circumvent the biophysical forces of TTFields and their downstream effects will improve therapeutic efficacy of this novel anti-cancer treatment modality. METHODS A panel of GBM cell lines were treated continuously with TTFields at the clinically approved frequency of 200 kHz using an in vitro TTFields system until cells with relative resistance to the cytotoxic effects of TTFields. A systems approach aided by innovative network ranking computational algorithms were utilized to analyze global gene expression profiles and identify resistance pathways, which were subsequently validated experimentally. RESULTS TTFields-induced chromosomal instability such as the formation of cytoplasmic micronuclei is preserved in resistant cells, indicating that TTFields resistance is mediated through a non-biophysical mechanism. This acquired TTFields resistance phenotype is associated with a transition of GBM cells to a stem-like state as determined by a neurosphere assay. Using an innovative computational platform, we methodically dissected this stemness program in resistant cells. Mechanistically, Prostaglandin E Receptor 3 (PTGER3) is the top ranked master regulator responsible for resistance. PTGER3 is rapidly upregulated in GBM cells upon exposure to TTFields and further increases with prolonged treatment as resistance sets in. Pharmacological inhibition of PTGER3 either using aspirin to reduce prostaglandin E production or PTGER3-specific inhibitors resensitized cells to TTFields. CONCLUSIONS We have identified a novel pathway with PTGER3 at the apex that plays a critical role in TTFields resistance. This pathway is a potential therapeutic target to reduce resistance to TTFields therapy in GBM.