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1.
Genet Mol Res ; 14(3): 10877-87, 2015 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-26400315

RESUMO

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


Assuntos
Dinoprostona/uso terapêutico , Trabalho de Parto Induzido/métodos , RNA Mensageiro/biossíntese , Receptores de Prostaglandina E Subtipo EP1/genética , Contração Uterina/efeitos dos fármacos , Adulto , Estudos de Casos e Controles , Colo do Útero/efeitos dos fármacos , Colo do Útero/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Miométrio/efeitos dos fármacos , Miométrio/metabolismo , Gravidez , RNA Mensageiro/genética , Receptores de Prostaglandina E Subtipo EP1/biossíntese , Receptores de Prostaglandina E Subtipo EP2/biossíntese , Receptores de Prostaglandina E Subtipo EP2/genética , Receptores de Prostaglandina E Subtipo EP3/biossíntese , Receptores de Prostaglandina E Subtipo EP3/genética , Falha de Tratamento
2.
Oncol Rep ; 34(2): 715-26, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26058972

RESUMO

Prostaglandin E2 (PGE2) is involved in cholangiocarcinoma cell proliferation, migration and invasion through E prostanoid receptors, including EP1, EP2 and EP4. However, the functions and the mechanisms of those splice variants of EP3 receptors in promoting liver cancer cell growth and invasion remain to be elucidated. In our previous studies, four isoforms of EP3 receptors, EP3-4, EP3-5, EP3-6 and EP3-7 receptors, were detected in CCLP1 and HuCCT1 cells. However, the functions of these receptors in these cells have yet to be determined. It was reported that ß-catenin is closely correlated with malignancy, including cholangiocarcinoma. The present study was designed to examine the effects of 4-7 isoforms of EP3 in promoting cholangiocarcinoma progression and the mechanisms by which PGE2 increases ß-catenin protein via EP3 receptors. The results showed that PGE2 promotes cholangiocarcinoma progression via the upregulation of ß-catenin protein, and the EP3-4 receptor pathway is mainly responsible for this regulation. These findings reveal that PGE2 upregulated the cholangiocarcinoma cell ß-catenin protein through the EP3-4R/Src/EGFR/PI3K/AKT/GSK-3ß pathway. The present study identified the functions of EP3 and the mechanisms by which PGE2 regulates ß-catenin expression and promoted cholangiocarcinoma cell growth and invasion.


Assuntos
Colangiocarcinoma/genética , Dinoprostona/biossíntese , Receptores de Prostaglandina E Subtipo EP3/biossíntese , beta Catenina/biossíntese , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Colangiocarcinoma/patologia , Ciclo-Oxigenase 2/genética , Dinoprostona/genética , Regulação Neoplásica da Expressão Gênica , Quinase 3 da Glicogênio Sintase/genética , Glicogênio Sintase Quinase 3 beta , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Fosfatidilinositol 3-Quinases/genética , Receptores de Prostaglandina E Subtipo EP3/genética , beta Catenina/genética
3.
PLoS One ; 9(10): e110828, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25333975

RESUMO

EP3, one of four prostaglandin E2 (PGE2) receptors, is significantly lower in atherosclerotic plaques than in normal arteries and is localized predominantly in macrophages of the plaque shoulder region. However, mechanisms behind this EP3 expression pattern are still unknown. We investigated the underlying mechanism of EP3 expression in phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 macrophages with oxidized low-density lipoprotein (oxLDL) treatment. We found that oxLDL decreased EP3 expression, in a dose-dependent manner, at both the mRNA and protein levels. Moreover, oxLDL inhibited nuclear factor-κB (NF-κB)-dependent transcription of the EP3 gene by the activation of peroxisome proliferator-activated receptor-γ (PPAR-γ). Finally, chromatin immunoprecipitation revealed decreased binding of NF-κB to the EP3 promoter with oxLDL and PPAR-γ agonist treatment. Our results show that oxLDL suppresses EP3 expression by activation of PPAR-γ and subsequent inhibition of NF-κB in macrophages. These results suggest that down-regulation of EP3 expression by oxLDL is associated with impairment of EP3-mediated anti-inflammatory effects, and that EP3 receptor activity may exert a beneficial effect on atherosclerosis.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Lipoproteínas LDL/administração & dosagem , PPAR gama/biossíntese , Receptores de Prostaglandina E Subtipo EP3/biossíntese , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipoproteínas LDL/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , NF-kappa B/biossíntese , PPAR gama/genética , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , RNA Mensageiro/biossíntese , Receptores de Prostaglandina E Subtipo EP3/genética , Acetato de Tetradecanoilforbol/administração & dosagem , Acetato de Tetradecanoilforbol/análogos & derivados
4.
Mol Cancer Res ; 11(4): 427-39, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23364535

RESUMO

PGE2 has been implicated in prostate cancer tumorigenesis. We hypothesized that abnormal prostaglandin receptor (EPR) expression may contribute to prostate cancer growth. Twenty-six archived radical prostatectomy specimens were evaluated by immunohistochemistry (IHC) and Western blotting for the expression of EP1, EP2, EP3, and EP4. As a corollary, EPR expression in one normal (PZ-HPV7) and four prostate cancer cell lines (CA-HPV10, LNCaP, PC3, and Du145) were assessed by Western blotting. Prostate cancer and normal cell growth were compared in vitro after EPR blockade, siRNA EPR knockdown, or overexpression. EP1, EP2, EP3, and EP4 receptors were detected by IHC in all areas of benign tissue within the clinical prostate cancer specimens. In areas of prostate cancer, EP4 and EP2 were overexpressed in 85% (22 of 26) and 75% (18 of 24) and EP3 expression was reduced in all (26 of 26, 100%) specimens (P < 0.05 vs. benign tissue). EP1 showed no specific differential expression pattern. Increased EP4 and reduced EP3 was confirmed by Western blotting in fresh clinical specimens and in prostate cancer cell lines (CA-HPV10, LNCaP, PC3, and Du145) compared with the normal prostate cell line (PZ-HPV7). EP2 and EP4 siRNA knockdown resulted in reduced in vitro growth and metastasis-related gene expression (MMP9 and Runx2) of prostate cancer lines, and in vitro migration was inhibited by EP4 antagonists. As a corollary, EP3-overexpressing PC3 cells displayed impaired growth in vitro. Human prostate cancer is associated with EP4 and EP2 overexpression and reduced EP3 expression. These data suggest that targeting specific EPR may represent a novel therapeutic approach for prostate cancer.


Assuntos
Neoplasias da Próstata/metabolismo , Receptores de Prostaglandina E Subtipo EP3/biossíntese , Receptores de Prostaglandina E Subtipo EP4/biossíntese , Idoso , Movimento Celular/fisiologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Fosforilação , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
5.
PLoS One ; 7(8): e40222, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22870195

RESUMO

The use of the lipid lowering agent niacin is hampered by a frequent flush response which is largely mediated by prostaglandin (PG) D(2). Therefore, concomitant administration of the D-type prostanoid (DP) receptor antagonist laropiprant has been proposed to be a useful approach in preventing niacin-induced flush. However, antagonizing PGD(2), which is a potent inhibitor of platelet aggregation, might pose the risk of atherothrombotic events in cardiovascular disease. In fact, we found that in vitro treatment of platelets with laropiprant prevented the inhibitory effects of PGD(2) on platelet function, i.e. platelet aggregation, Ca(2+) flux, P-selectin expression, activation of glycoprotein IIb/IIIa and thrombus formation. In contrast, laropiprant did not prevent the inhibitory effects of acetylsalicylic acid or niacin on thrombus formation. At higher concentrations, laropiprant by itself attenuated platelet activation induced by thromboxane (TP) and E-type prostanoid (EP)-3 receptor stimulation, as demonstrated in assays of platelet aggregation, Ca(2+) flux, P-selectin expression, and activation of glycoprotein IIb/IIIa. Inhibition of platelet function exerted by EP4 or I-type prostanoid (IP) receptors was not affected by laropiprant. These in vitro data suggest that niacin/laropiprant for the treatment of dyslipidemias might have a beneficial profile with respect to platelet function and thrombotic events in vascular disease.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Indóis/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Receptores de Prostaglandina E Subtipo EP3/biossíntese , Plaquetas/citologia , Cálcio/metabolismo , Dislipidemias/tratamento farmacológico , Dislipidemias/metabolismo , Feminino , Humanos , Hipolipemiantes/uso terapêutico , Indóis/uso terapêutico , Masculino , Niacina/uso terapêutico , Selectina-P/biossíntese , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/biossíntese , Prostaglandina D2/metabolismo , Trombose/metabolismo , Trombose/prevenção & controle
6.
Biol Reprod ; 86(5): 159, 1-10, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22402965

RESUMO

The mechanisms of cervical ripening and dilation in mammals remain obscure. Information is lacking about the localization of prostaglandin E(2) (PGE(2))-producing cells and PGE(2) receptors (EP) in intrapartum cervix and whether cervical dilation at parturition is an active process. To reveal these mechanisms, immunolocalization of EP1-EP4 (official gene symbols PTGER1-PTGER4) and PGE(2)-producing cells in caprine cervix during nonpregnancy, pregnancy, and parturition was assayed by immunohistochemistry (IHC); the mRNA expression levels of PTGS2, PTGER2 (EP2), and PTGER4 (EP4) were determined using quantitative PCR; and the existence of adipocytes in the cervix at various stages was demonstrated with Oil Red O staining and IHC of perilipin A. The results suggested that in intrapartum caprine cervix staining of the PGE(2) was observed in the overall tissues, for example, blood vessels, canal or glandular epithelia, serosa, circular and longitudinal muscles, and stroma in addition to adipocytes; EP2 was detectable in all the tissues other than glandular epithelia; EP4 was strongly expressed in all the tissues other than serosa; EP1 was detected mainly in arterioles and canal or glandular epithelia; and EP3 was poorly expressed only in stroma, canal epithelia, and circular muscles. Little or no expression of EP2, EP3, and EP4 as well as PGE(2) in all cervical tissues was observed during nonpregnancy and pregnancy except for the strong expression of EP1 in canal or glandular epithelia during pregnancy. The mRNA expression levels of PTGS2, PTGER2, and PTGER4 were significantly higher in intrapartum than nonpregnant and midpregnant cervices (P < 0.01). Adipocytes appear only in the intrapartum cervix. These results support the concept that PGE(2) modulates specific functions in various anatomical structures of the caprine cervix at labor and the appearance of adipocytes at labor is likely related to caprine cervical dilation.


Assuntos
Dinoprostona/biossíntese , Receptores de Prostaglandina E Subtipo EP1/biossíntese , Receptores de Prostaglandina E Subtipo EP2/biossíntese , Receptores de Prostaglandina E Subtipo EP3/biossíntese , Receptores de Prostaglandina E Subtipo EP4/biossíntese , Adipócitos/citologia , Adipócitos/fisiologia , Animais , Proteínas de Transporte/análise , Maturidade Cervical/metabolismo , Colo do Útero/citologia , Colo do Útero/metabolismo , Dinoprostona/fisiologia , Feminino , Cabras/fisiologia , Trabalho de Parto/fisiologia , Perilipina-1 , Fosfoproteínas/análise , Gravidez , Receptores de Prostaglandina E Subtipo EP1/fisiologia , Receptores de Prostaglandina E Subtipo EP2/fisiologia , Receptores de Prostaglandina E Subtipo EP3/fisiologia , Receptores de Prostaglandina E Subtipo EP4/fisiologia
7.
Neurosci Lett ; 504(3): 185-90, 2011 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-21939736

RESUMO

Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of severe and permanent neurologic disability after birth. The inducible cyclooxygenase COX-2, which along with COX-1 catalyzes the first committed step in prostaglandin (PG) synthesis, elicits significant brain injury in models of cerebral ischemia; however its downstream PG receptor pathways trigger both toxic and paradoxically protective effects. Here, we investigated the function of PGE(2) E-prostanoid (EP) receptors in the acute outcome of hypoxic-ischemic (HI) injury in the neonatal rat. We determined the temporal and cellular expression patterns of the EP1-4 receptors before and after HIE and tested whether modulation of EP1-4 receptor function could protect against cerebral injury acutely after HIE. All four EP receptors were expressed in forebrain neurons and were induced in endothelial cells after HIE. Inhibition of EP1 signaling with the selective antagonist SC-51089 or co-activation of EP2-4 receptors with the agonist misoprostol significantly reduced HIE cerebral injury 24 h after injury. These receptor ligands also protected brain endothelial cells subjected to oxygen glucose deprivation, suggesting that activation of EP receptor signaling is directly cytoprotective. These data indicate that the G-protein coupled EP receptors may be amenable to pharmacologic targeting in the acute setting of neonatal HIE.


Assuntos
Dinoprostona/fisiologia , Hipóxia-Isquemia Encefálica/fisiopatologia , Receptores de Prostaglandina E Subtipo EP1/fisiologia , Receptores de Prostaglandina E Subtipo EP2/fisiologia , Receptores de Prostaglandina E Subtipo EP3/fisiologia , Receptores de Prostaglandina E Subtipo EP4/fisiologia , Animais , Animais Recém-Nascidos , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , Células Endoteliais/metabolismo , Glucose/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Hidrazinas/farmacologia , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Misoprostol/farmacologia , Neurônios/metabolismo , Oxazepinas/farmacologia , Oxigênio/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E Subtipo EP1/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP1/biossíntese , Receptores de Prostaglandina E Subtipo EP1/genética , Receptores de Prostaglandina E Subtipo EP2/biossíntese , Receptores de Prostaglandina E Subtipo EP2/genética , Receptores de Prostaglandina E Subtipo EP3/biossíntese , Receptores de Prostaglandina E Subtipo EP3/genética , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP4/biossíntese , Receptores de Prostaglandina E Subtipo EP4/genética , Transdução de Sinais
8.
J Pediatr Surg ; 46(3): 489-95, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21376198

RESUMO

BACKGROUND: Necrotizing enterocolitis (NEC) is a devastating intestinal disease of premature infants. Although ω-3 fatty acids are known to have antiinflammatory effects, their effect against NEC remains unclear. METHODS: Mother rats fed a soybean-based, docosahexaenoic acid (DHA)- or eicosapentaenoic acid (EPA)-enriched diet from days 7 to 20 of gestation were examined. On day 20, the rat pups were delivered by abdominal incision, their intestines were removed, and messenger RNA was extracted. A rat NEC model was used to confirm the effects of ω-3 fatty acids on the inflamed intestine (n = 20-28). The expression of inflammatory molecules was analyzed by real-time polymerase chain reaction (n = 11-14). RESULTS: The concentrations of DHA and EPA in the intestine were significantly increased in the DHA and EPA groups (P < .01). The expression of the antiinflammatory prostaglandin E2 receptor EP3 was increased in the DHA (P < .05) and EPA groups (P < .01). In the NEC model, the reduced incidence of colitis was confirmed in the DHA and EPA groups. The expression of peroxisome proliferator-activated receptor γ was increased (P < .05), and the inhibitor of nuclear factor-κB α/ß decreased in both the DHA (P < .01) and EPA groups (P < .05). CONCLUSION: Our findings indicate that ω-3 fatty acids are beneficial for protecting the premature intestine from inflammation by regulating eicosanoid- and nuclear factor-κB-related metabolite expression.


Assuntos
Anti-Inflamatórios/uso terapêutico , Gorduras Insaturadas na Dieta/uso terapêutico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/uso terapêutico , Enterocolite Necrosante/prevenção & controle , Animais , Animais Recém-Nascidos , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Gorduras Insaturadas na Dieta/administração & dosagem , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Ácido Eicosapentaenoico/administração & dosagem , Ácido Eicosapentaenoico/farmacologia , Enterocolite Necrosante/induzido quimicamente , Ácidos Graxos/análise , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Íleo/química , Íleo/efeitos dos fármacos , Íleo/embriologia , Alimentos Infantis/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Troca Materno-Fetal , Modelos Animais , NF-kappa B/efeitos dos fármacos , PPAR gama/biossíntese , PPAR gama/genética , Gravidez , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E Subtipo EP3/biossíntese , Receptores de Prostaglandina E Subtipo EP3/genética , Óleo de Soja , Organismos Livres de Patógenos Específicos
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