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Prostaglandin E2 (prostaglandin + e2)
Terms modified by Prostaglandin E2 Selected AbstractsCOX-2 inhibits Fas-mediated apoptosis in cholangiocarcinoma cellsHEPATOLOGY, Issue 3 2002Ugochukwu C. Nzeako Fas expression has been shown to negatively regulate the progression of cholangiocarcinoma cells in xenografts. However, many human cholangiocarcinomas express Fas, suggesting these cancers have developed mechanisms to inhibit Fas-mediated apoptosis. Cyclooxygenase-2 (COX-2), which generates prostanoids, is expressed by many cholangiocarcinomas. Therefore, our aim was to determine whether COX-2 expression inhibits death receptor,mediated apoptosis in KMBC cells, a cholangiocarcinoma cell line. These cells express messenger RNA for the death receptors Fas, tumor necrosis factor receptor 1 (TNF-R1), death receptor 4 (DR4), and DR5. Agonists for these death receptors, CH-11, TNF-,, and TRAIL all induced apoptosis. However, COX-2, whether induced by proinflammatory cytokines or transient transfection, only significantly inhibited Fas-mediated apoptosis. The COX-2 inhibitor NS-398 restored Fas-mediated apoptosis in COX-2 transfected cells. Prostaglandin E2 reduced apoptosis and mitochondrial depolarization after treatment with the Fas agonist CH-11. Of a variety of antiapoptotic proteins examined, COX-2/prostaglandin E2 only increased expression of Mcl-1, an antiapoptotic member of the Bcl-2 family. In conclusion, these data suggest that prostanoid generation by COX-2 specifically inhibits Fas-mediated apoptosis, likely by up-regulating Mcl-1 expression. Pharmacologic inhibition of COX-2 may be useful in augmenting Fas-mediated apoptosis of cholangiocarcinoma cells. [source] Identification of prostaglandin E2 receptors mediating perinatal masculinization of adult sex behavior and neuroanatomical correlatesDEVELOPMENTAL NEUROBIOLOGY, Issue 12 2008Christopher L. Wright Abstract Prostaglandin E2 (PGE2) mediates the organization of male rat sexual behavior and medial preoptic area (MPOA) neuroanatomy during a sensitive perinatal window. PGE2 is up-regulated in response to estradiol, and initiates a two-fold increase in dendritic spines densities on neurons. All the four receptors for PGE2 and EP1-4 are present in developing POA, a critical region controlling male sexual behavior. Previous studies explored that EP receptors are involved in PGE2-induction of neonatal levels of spinophilin protein, a surrogate marker for dendritic spine formation, but did not assess behavioral masculinization. Here, we used two approaches, suppression of EP receptor expression with antisense oligonucleotides and activation of EP receptors with selective agonists, to test which receptors are necessary and sufficient, respectively, for the effects of PGE2 on behavior and neuronal morphology. In female rats, neonatal treatment with antisense oligonucleotides against EP2 or EP4 but not EP1 or EP3 completely prevented the expression of adult behavior organized by PGE2 exposure. The effects of ONO-DI-004, ONO-AE-259-01, ONO-AE-248, and ONO-AE1-329 (EP1-4 agonists respectively) were equivalent to PGE2 treatment, which suggests activating any EP receptor neonatally suffices in masculinizing sex behavior. When given alone, not all EP agonists increased neonatal POA spinophilin levels; yet giving each agonist neonatally increased adult levels. Moreover, adult spinophilin levels significantly correlated with two measures of male sexual behavior. The body of evidence suggests that EP2 and EP4 are both necessary and sufficient for PGE2-induced masculinization of sex behavior, whereas EP1 and EP3 provide redundant roles. © 2008 Wiley Periodicals, Inc. Develop Neurobiol, 2008 [source] EP1 and EP4 Receptors Mediate Exocytosis Evoked by Prostaglandin E2 in Guinea-Pig Antral Mucous CellsEXPERIMENTAL PHYSIOLOGY, Issue 4 2001Atsuko Ohnishi Effects of prostaglandin E2 (PGE2) on exocytosis of mucin were studied in mucous cells isolated from guinea-pig antrum using video-microscopy. Stimulation with PGE2 elicited a sustained increase in the frequency of exocytotic events in a dose-dependent manner, which was under regulation by both Ca2+ and cAMP. Stimulation with a selective prostanoid EP4 receptor agonist (ONO-AEI-329, 10 ,M), which activates cAMP signals, elicited a sustained increase in the frequency of exocytotic events (30% of that evoked by 1 ,M PGE2). Stimulation with an EP1 agonist (17-P-T-PGE2, 1 ,M), which activates Ca2+ signals, increased the frequency of exocytotic events to a lesser extent (5% of that evoked by 1 ,M PGE2), while addition of an EP1 antagonist (ONO-8713, 10 ,M) decreased the frequency of exocytotic events (approximately 40% of that evoked by 1 ,M PGE2). However, addition of the EP1 agonist potentiated the frequency of exocytotic events evoked by the EP4 agonist or forskolin (which elevates cAMP levels) and increased the sensitivity of the exocytotic events to forskolin. These results suggest that the Ca2+ signal activated via the EP1 receptor potentiates the cAMP-regulated exocytotic events activated via the EP4 receptor during PGE2 stimulation, by increasing the sensitivity of the exocytotic response to cAMP. In conclusion, exocytotic events in PGE2 -stimulated antral mucous cells were regulated by interactions between EP1 and EP4 receptors. [source] Oncostatin M enhances the expression of prostaglandin E2 and cyclooxygenase-2 in astrocytes: Synergy with interleukin-1,, tumor necrosis factor-,, and bacterial lipopolysaccharideGLIA, Issue 4 2003Pavle Repovic Abstract Oncostatin M (OSM), a cytokine of the interleukin-6 family, is expressed in rheumatoid arthritis, multiple sclerosis, multiple myeloma, and other inflammatory and neoplastic conditions. Prostaglandin E2 (PGE2), an eicosanoid also associated with inflammation and cancer, has recently been shown to induce OSM expression. We report here that OSM in turn induces PGE2 production by astrocytes and astroglioma cells. More importantly, in combination with the inflammatory mediators IL-1,, tumor necrosis factor-,, and lipopolysaccharide, OSM exhibits a striking synergy, resulting in up to 50-fold higher PGE2 production by astrocytes, astroglioma, and neuroblastoma cell lines. Enhanced PGE2 production by OSM and IL-1, treatment is explained by their effect on cyclooxygenase-2 (COX-2), an enzyme that catalyzes the committed step in PGE2 synthesis. Of the enzymes involved in PGE2 biosynthesis, only COX-2 mRNA and protein levels are synergistically amplified by OSM and IL-1,. Nuclear run-on assays demonstrate that OSM and IL-1, synergistically upregulate transcription of the COX-2 gene, and the mRNA stability assay indicates that COX-2 mRNA is posttranscriptionally stabilized by OSM and IL-1,. To effect synergy on the PGE2 level, OSM signals in part through its gp130/OSMR, receptor, since neutralizing antibodies against gp130 and OSMR,, but not LIFR,, decrease PGE2 production in response to OSM plus IL-1,. SB202190 and U0126, inhibitors of p38 MAPK and ERK1/2 activation, respectively, inhibit IL-1, and OSM upregulation of COX-2 and PGE2, indicating that these MAPK cascades are utilized by both stimuli. This mechanism of PGE2 amplification may be active in brain pathologies where both OSM and IL-1, are present, such as glioblastomas and multiple sclerosis. GLIA 42:433,446, 2003. © 2003 Wiley-Liss, Inc. [source] COX-2 inhibits Fas-mediated apoptosis in cholangiocarcinoma cellsHEPATOLOGY, Issue 3 2002Ugochukwu C. Nzeako Fas expression has been shown to negatively regulate the progression of cholangiocarcinoma cells in xenografts. However, many human cholangiocarcinomas express Fas, suggesting these cancers have developed mechanisms to inhibit Fas-mediated apoptosis. Cyclooxygenase-2 (COX-2), which generates prostanoids, is expressed by many cholangiocarcinomas. Therefore, our aim was to determine whether COX-2 expression inhibits death receptor,mediated apoptosis in KMBC cells, a cholangiocarcinoma cell line. These cells express messenger RNA for the death receptors Fas, tumor necrosis factor receptor 1 (TNF-R1), death receptor 4 (DR4), and DR5. Agonists for these death receptors, CH-11, TNF-,, and TRAIL all induced apoptosis. However, COX-2, whether induced by proinflammatory cytokines or transient transfection, only significantly inhibited Fas-mediated apoptosis. The COX-2 inhibitor NS-398 restored Fas-mediated apoptosis in COX-2 transfected cells. Prostaglandin E2 reduced apoptosis and mitochondrial depolarization after treatment with the Fas agonist CH-11. Of a variety of antiapoptotic proteins examined, COX-2/prostaglandin E2 only increased expression of Mcl-1, an antiapoptotic member of the Bcl-2 family. In conclusion, these data suggest that prostanoid generation by COX-2 specifically inhibits Fas-mediated apoptosis, likely by up-regulating Mcl-1 expression. Pharmacologic inhibition of COX-2 may be useful in augmenting Fas-mediated apoptosis of cholangiocarcinoma cells. [source] Prostaglandin E2 is a negative regulator on human plasmacytoid dendritic cellsIMMUNOLOGY, Issue 1 2006Yonsu Son Summary Prostaglandin E2 (PGE2), a major lipid derived from the metabolism of arachidonic acid, is an environmentally bioactive substance produced by inflammatory processes and acts as a cAMP up-regulator that plays an important role in immune responses. It has been reported that PGE2 has the ability to inhibit the production of interleukin-12 by myeloid dendritic cells (MDCs) and macrophages, and then induce preferential T helper type 2 (Th2) cell responses. However, little is known of the function of PGE2 for plasmacytoid dendritic cells (PDCs), which may contribute to the innate and adaptive immune response to viral infection, allergy and autoimmune diseases. In the present study, we compared the biological effect of PGE2 on human PDCs and MDCs. PGE2 caused the death of PDCs but MDCs survived. Furthermore, we found that, whereas PGE2 inhibited interferon-, production by PDCs in response to virus or cytosine,phosphate,guanosine, it inhibited interelukin-12 production by MDCs in response to lipopolysaccharide (LPS) or poly(I:C). Although both virus-stimulated PDCs and LPS-stimulated MDCs preferentially induced the development of interferon-,-producing Th1 cells, pretreatment with PGE2 led both DC subsets to attenuate their Th1-inducing capacity. These findings suggest that PGE2 represents a negative regulator on not only MDCs but also PDCs. [source] Prostaglandin E2 promotes cell proliferation via protein kinase C/extracellular signal regulated kinase pathway-dependent induction of c-Myc expression in human esophageal squamous cell carcinoma cellsINTERNATIONAL JOURNAL OF CANCER, Issue 11 2009Le Yu Abstract Overexpression of cyclooxygenase-2 (COX-2) and elevation of its derivative prostaglandin E2 (PGE2) are implicated in human esophageal squamous cell carcinoma. The expression of c-Myc, an oncogenic transcription factor, is also upregulated in this malignant disease. This study sought to elucidate whether a functional connection exists between COX-2/PGE2 and c-Myc in esophageal squamous cell carcinoma. Results showed that PGE2 substantially increased the proliferation of cultured esophageal squamous cell carcinoma cells. In this regard, PGE2 substantially increased the mRNA and protein expression of c-Myc and its association with the binding partner Max. Knockdown of c-Myc by RNA interference also significantly attenuated PGE2 -induced cell proliferation. Further, mechanistic study revealed that PGE2 increased the protein stability and nuclear accumulation of c-Myc via phosphorylation on serine 62 in an extracellular signal regulated kinase (ERK)-dependent manner. To this end, ERK activation by PGE2 was completely abolished by protein kinase C (PKC) inhibitors. Moreover, the effect of PGE2 on c-Myc expression was mimicked by EP2 receptor agonist. In addition, knockdown of EP2 receptor by EP2 siRNA attenuated PGE2 -induced c-Myc expression. Collectively, our findings suggest that PGE2 upregulates c-Myc via the EP2/PKC/ERK pathway. This study sheds new light on the carcinogenic mechanism of PGE2 in esophageal squamous cell carcinoma. © 2009 UICC [source] Prostaglandin E2 -Mediated Anabolic Effect of a Novel Inhibitor of Phosphodiesterase 4, XT-611, in the In Vitro Bone Marrow Culture,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2003Ken-Ichi Miyamoto Abstract The mechanism of osteoblast formation by a novel PDE4 inhibitor, XT-611, was studied in the in vitro bone marrow culture system. The compound potentiated the osteoblast differentiation through accumulation of cyclic AMP after autocrine stimulation of EP4 receptor by PGE2 in pro-osteoblastic cells. Introduction: We previously reported that inhibitors of phosphodiesterase (PDE)4 isoenzyme increase osteoblast formation in an in vitro bone marrow culture system and inhibit bone loss in animal osteoporosis models. Here we investigated the mechanism of the effect of a novel PDE4 inhibitor, 3,4-dipropyl-4,5,7,8-tetrahydro-3H -imidazo[1,2- i]-purin-5-one (XT-611), on osteoblast formation in the in vitro bone marrow culture system. Materials and Methods: Rodent bone marrow cells were cultured in the presence of 0.2 mM ascorbic acid phosphate ester, 1 mM ,-glycerophosphate, and 10 nM dexamethasone for 10 days. Drug treatments were done for 24 h on day 3 of culture. Results: PDE4 inhibitors, including XT-611, but not PDE3 and PDE5 inhibitors, increased mineralized nodule formation in rat and mouse bone marrow cell cultures. During culture of the bone marrow cells, prostaglandin E2 (PGE2) production increased with a peak on day 4, but the increase was completely inhibited by indomethacin, an unselective cyclo-oxygenase (COX) inhibitor. Spontaneous and XT-611-induced mineralized-nodule formation was also inhibited by indomethacin and COX-2 inhibitors, in a similar potential. Alkaline phosphatase-positive nodule formation in the absence or presence of XT-611 was inhibited by an antagonist of EP4 receptor, AH23848B, and synergistically potentiated by 11-deoxy-PGE1, but it was not influenced by other EP antagonists and agonists examined. The expression of PDE4 and EP4 mRNAs was observed in bone marrow cells. The effect of XT-611 was also confirmed to involve an increase of cyclic AMP and the cyclic AMP-dependent protein kinase pathway. Conclusion: These results suggest that PGE2 stimulates differentiation of osteoblast progenitor cells through the EP4 receptor in an autocrine manner, and the PDE4 inhibitor potentiates the differentiation by inhibiting hydrolysis of cyclic AMP in the cells. [source] Prostaglandin E2 inhibits the proliferation of human gingival fibroblasts via the EP2 receptor and EpacJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2009Evgeny Weinberg Abstract Elevated levels of prostaglandins such as PGE2 in inflamed gingiva play a significant role in the tissue destruction caused by periodontitis, partly by targeting local fibroblasts. Only very few studies have shown that PGE2 inhibits the proliferation of a gingival fibroblast (GF) cell line, and we expanded this research by using primary human GFs (hGFs) and looking into the mechanisms of the PGE2 effect. GFs derived from healthy human gingiva were treated with PGE2 and proliferation was assessed by measuring cell number and DNA synthesis and potential signaling pathways were investigated using selective activators or inhibitors. PGE2 inhibited the proliferation of hGFs dose-dependently. The effect was mimicked by forskolin (adenylate cyclase stimulator) and augmented by IBMX (a cAMP-breakdown inhibitor), pointing to involvement of cAMP. Indeed, PGE2 and forskolin induced cAMP generation in these cells. Using selective EP receptor agonists we found that the anti-proliferative effect of PGE2 is mediated via the EP2 receptor (which is coupled to adenylate cyclase activation). We also found that the effect of PGE2 involved activation of Epac (exchange protein directly activated by cAMP), an intracellular cAMP sensor, and not PKA. While serum increased the amount of phospho-ERK in hGFs by ,300%, PGE2 decreased it by ,50%. Finally, the PGE2 effect does not require endogenous production of prostaglandins since it was not abrogated by two COX-inhibitors. In conclusion, in human gingival fibroblasts PGE2 activates the EP2,cAMP,Epac pathway, reducing ERK phosphorylation and inhibiting proliferation. This effect could hamper periodontal healing and provide further insights into the pathogenesis of inflammatory periodontal disease. J. Cell. Biochem. 108: 207,215, 2009. © 2009 Wiley-Liss, Inc. [source] Cytokine levels in crevicular fluid are less responsive to orthodontic force in adults than in juvenilesJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 8 2002Yijin Ren Abstract Objectives:, Bone remodelling during orthodontic tooth movement is related to the expression of mediators in gingival crevicular fluid (GCF). No information is available concerning the effect of age on the levels of these mediators in GCF. The purpose of this study was to quantify three mediators (prostaglandin E2, interleukin-6 and granulocyte-Macrophage Colony-Stimulating Factor) in GCF during orthodontic tooth movement in juveniles and adults. Material and methods:, A total of 43 juvenile patients (mean age 11 ± 0.7 year), and 41 adult patients (mean age 24 ± 1.6 year) took part in the study. One of the lateral incisors of each patient was tipped labially, the other served as control. GCF samples were taken before force activation (t0) and 24 h later (t24). Mediator levels were determined by radioimmunoassay (RIA). Results: PGE2 concentrations were significantly elevated at t24 in juveniles and adults, while concentrations of IL-6 and GM-CSF were significantly elevated only in juveniles. Total amounts of all three mediators in GCF significantly increased at t24 in both groups. Conclusions:, In early tooth movement, mediator levels in juveniles are more responsive than levels in adults, which agrees with the finding that the initial tooth movement in juveniles is faster than in adults and starts without delay. Zusammenfassung Cytokinlevel in der krevikulären Flüssigkeit sind weniger veränderbar bei Erwachsenen als bei Jugendlichen infolge orthodontischer Kräfte Ziele: Knochenremodellation während orthodontischer Zahnbewegung steht in Beziehung zur Expression von Mediatoren in der gingivalen Sulkusflüssigkeit (GCF). Es gibt keine Informationen bezüglich des Effektes von Alter auf die Level dieser Mediatoren in der GCF. Der Zweck dieser Studie war die Quantifizierung von drei Mediatoren (Prostaglandin E2, Interleukin-6 und Granulozyten-Makrophagen-Kolonien-stimulierender Faktor) in der GCF während orthodontischer Zahnbewegung bei Jugendlichen und Erwachsenen. Material und Methoden: Insgesamt 43 jugendliche Patienten (mittleres Alter 11±0.7 Jahre) und 41 erwachsene Patienten (mittleres Alter 24±1.6 Jahre) nahmen an der Studie teil. Einer der lateralen Schneidezähne jedes Patienten wurde nach labial gekippt, der andere diente als Kontrolle. GCF Proben wurden vor der Aktivation (t0) und 24 h später (t24) gewonnen. Die Mediatorenlevel wurden mit Radioimmunoassay (RIA) bestimmt. Ergebnisse: Die PGE2 Konzentrationen waren signifikant zum Zeitpunkt t24 bei Jugendlichen und Erwachsenen erhöht, während die Konzentrationen von IL-6 und GM-CSF nur bei Jugendlichen signifikant erhöht waren. Die totale Menge der drei Mediatoren in der GCF nahmen signifikant zum Zeitpunkt t24 in beiden Gruppen zu. Schlussfolgerungen: In der frühen Zahnbewegung sind die Mediatorenlevel bei Jugendlichen mehr veränderbar als bei Erwachsenen. Dies stimmt überein mit der Beobachtung, dass die initiale Zahnbewegung bei Jugendlichen schneller als bei Erwachsenen ist und ohne Verspätung beginnt. Résumé Les niveaux de cytokine dans le fluide gingival répondent moins aux forces orthodontiques chez l'adulte que chez les jeunes. Objectifs: Le remodelage osseux lors des mouvements dentaires orthodontiques est en relation avec l'expression des médiateurs dans le fluide gingival (GCF). Aucune information n'est disponible sur les effets de l'âge sur les niveaux de ces médiateurs dans le GCF. Le but de cette étude était de quantifier 3 médiateurs (la prostaglandine E-2, L'interleukine-6 et le facteur de stimulation des colonies de macrophage et de granulocyte) dans le GCF pendant un mouvement orthodontique chez des jeunes et chez des adultes. Matériels et méthodes: 43 jeunes patients (en moyenne âgés de 11±0.7 ans) et 41 patients adultes (en moyenne âgés de 24±1.6 ans) prirent part à cette étude. Une des incisives latérale de chaque patient fut versée vestibulairement, l'autre servant de contrôle. Des échantillons de GCF furent prélevés avant l'activation de la force (t0) et 24 heures plus tard (t24). Le niveau de cytokine fut déterminé par radioimmunoassay. Résultats: Les concentrations de PgE-2 étaient significativement élevées à t24 chez les jeunes et les adultes, alors que les concentrations de IL-6 et de GM-CSF étaient significativement augmentées seulement chez les jeunes. La quantité totale des 3 médiateurs dans le GCF augmentait significativement à t24 dans chaque groupe. Conclusions: Rapidement après l'application des mouvements dentaires, les niveaux de médiateurs chez les jeunes répondent plus que chez l'adulte, ce qui est en accord avec les résultats qui montrent que le mouvement initial dentaire chez les jeunes est plus rapide que chez les adultes et débute sans délai. [source] Granulocyte elastase, matrix metalloproteinase-8 and prostaglandin E2 in gingival crevicular fluid in matched clinical sites in smokers and non-smokers with persistent periodontitisJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 5 2002B. Söder Abstract Background/aims: Smokers with persistent periodontitis may have granulocytes with impaired function. This study aimed to determine the levels of granulocyte elastase, matrix metalloproteinase-8 (MMP-8) and prostaglandin E2 (PGE2) in gingival crevicular fluid (GCF) in smokers and non-smokers with persistent periodontitis. Methods: We analyzed GCF from 70 matched sites in 29 periodontitis and 6 gingivitis sites in 34 subjects, 17 smokers, and 17 non-smokers. We also analyzed separately GCF from 28 of these subjects, 14 smokers and 14 non-smokers in 14 matched periodontitis sites. The following measurements were made: elastase complexed to ,1 -antitrypsin (EA-,1AT) and MMP-8 with ELISA, functional elastase with a chromogenic substrate, and PGE2 with radioimmunoassay (125I RIA). The significance of the findings was determined with Mann-Whitney test. Results: In the 29 matched periodontitis sites, smokers had significantly more functional elastase (p<0.005) and more EA-,1AT (p<0.05) than non-smokers. In the 14 matched periodontitis sites in 14 smokers and 14 non-smokers, the former had significantly more functional elastase than the latter (p<0.001). A significant correlation was found between EA-,1AT and MMP-8 in smokers (p<0.05) and non-smokers (p<0.001) and a positive correlation between levels of functional elastase and MMP-8 in non-smokers (r2=0.98; p<0.001). Conclusions: Granulocyte function seems to be impaired in smokers with persistent periodontitis. The cells react to the bacterial challenge by releasing serine proteases, which reflect the degradation of connective tissue. The risk of progression of the disease is therefore higher in smokers with persistent periodontitis than in non-smokers. Zusammenfassung Hintergrund, Ziele: Raucher mit bestehender Parodontitis haben möglicherweise Granulozyten mit beeinträchtigter Funktion. Diese Studie zielt auf die Bestimmung der Levels von Granulozytenelastase, Matrix-Metalloproteinase-8 (MMP-8) und Prostaglandin E2 (PGE2) in der krevikulären gingivalen Flüssigkeit (GCF) bei Rauchern und Nichtrauchern mit bestehender Parodontitis. Methoden: Wir analysierten GCF von 70 entsprechenden Flächen bei 29 Parodontitis und 6 Gingivitisflächen von 34 Personen, 17 Rauchern und 17 Nichtrauchern. Wir analysierten zusätzlich getrennt die GCF von 28 dieser Personen: 14 Raucher und 14 Nichtraucher von 14 entsprechenden parodontalen Flächen. Die folgenden Messungen wurden vorgenommen: Elastasekomplex zu ,1 -Antitrypsin (EA-,1AT) und MMP-8 mit ELISA, funktionelle Elastase mit chromogenem Substrat und PGE2 mit Radioimmunoassay (125I RIA). Die Signifikanz der Ergebnisse wurde mit dem Mann-Whitney Test bestimmt. Ergebnisse: In den 29 entsprechenden parodontalen Flächen hatten die Raucher signifikant mehr funktionelle Elastase (p<0.005) und mehr EA-,1At (p<0.05) als Nichtraucher. Bei den 14 entsprechenden parodontalen Flächen der 14 Raucher und 14 Nichtraucher hatten die ersten signifikant mehr funktionelle Elastase als die letzteren (p<0.001). Eine signifikante Korrelation wurde zwischen EA-,1AT und MMP-8 bei Rauchern (p<0.05) und Nichtrauchern (p<0.001) gefunden und eine positive Korrelation zwischen den Levels der funktionellen Elastase und MMP-8 bei Nichtrauchern (r2=0.98; p<0.001) festgestellt. Schlussfolgerungen: Die Granulozytenfunktion scheint bei Rauchern mit bestehender Parodontitis beeinträchtigt zu sein. Die Zellen reagieren auf die bakterielle Herausforderung durch Freisetzung von Serinproteasen, die die Degradation von Bindegewebe reflektiert. Das Risiko einer Progression dieser Erkrankung ist deshalb bei Rauchern mit bestehender Parodontitis höher als bei Nichtrauchern. Résumé Origine, but: Les fumeurs avec parodontite persistante pourraient avoir des granulocytes ayant des fonctions déréglées. Cette étude a eu pour but de déterminer les niveaux d'élastase granulocytaire, de la métallo-protéinase-8 de la matrice (MMP-8) et de la prostaglandine E2 (PGE2) dans le fluide créviculaire gingival (GCF) chez les fumeurs et les non-fumeurs avec parodontite persistante. Méthodes: Le GCF a été prélevé de 70 sites équivalents dans 29 parodontites et 6 sites avec gingivite chez 34 sujets, 17 fumeurs et 17 non-fumeurs. Le GCF de 28 de ces sujets a été analysé séparément, 14 fumeurs et 14 non-fumeurs dans 14 sites équivalents du point de vue parodontite. Les mesures suivantes ont été relevées: l'élastase avec ,1 -antitrypsine (EA-,1AT) et MMP-8 par ELISA, l'élastase fonctionnelle avec un substrat chromogénique, et PGE2 avec un essai radio-immunitaire (125I RIA). La signification de ces découvertes a été par l'utilisation du test de Mann-Whitney. Résultats: Dans les 29 sites équivalents, les fumeurs avaient significativement plus d'élastase functionnelle (p<0.005) et plus de EA-,1AT (p<0.05) que les non-fumeurs. Dans les 14 sites équivalents du point de vue parodontite, les 14 fumeurs avaient significativement plus d'élastase fonctionnelle que les 14 non-fumeurs (p<0.001). Une relation significative a étéétablie entre EA-,1AT et MMP-8 chez les fumeurs (p<0.05) et les non-fumeurs (p<0.001) et une relation positive entre les niveaux d'élastase fonctionnelle et de MMP-8 chez les non-fumeurs (r2=0.98; p<0.001). Conclusions: La fonction granulocytaire semble être altérée chez les fumeurs avec parodontite persistante. Les cellules réagissent à l'attaque bactérienne en relâchant des protéases sérine, ce qui démontre une dégradation du tissu conjonctif. Le risque de progression de la maladie est ainsi plus élevé chez les fumeurs avec parodontite persistante que chez les non-fumeurs. [source] PGE2 receptor EP1 renders dopaminergic neurons selectively vulnerable to low-level oxidative stress and direct PGE2 neurotoxicityJOURNAL OF NEUROSCIENCE RESEARCH, Issue 14 2007Emilce Carrasco Abstract Oxidative stress and increased cyclooxygenase-2 (COX-2) activity are both implicated in the loss of dopaminergic neurons from the substantia nigra (SN) in idiopathic Parkinson's disease (PD). Prostaglandin E2 (PGE2) is one of the key products of COX-2 activity and PGE2 production is increased in PD. However, little is known about its role in the selective death of dopaminergic neurons. Previously, we showed that oxidative stress evoked by low concentrations of 6-hydroxydopamine (6-OHDA) was selective for dopaminergic neurons in culture and fully dependent on COX-2 activity. We postulated that this loss was mediated by PGE2 acting through its receptors, EP1, EP2, EP3, and EP4. Using double-label immunohistochemistry for specific EP receptors and tyrosine hydroxylase (TH), we identified EP1 and EP2 receptors on dopaminergic neurons in rat SN. EP2 receptors were also found in non-dopaminergic neurons of this nucleus, as were EP3 receptors, whereas the EP4 receptor was absent. PGE2, 16-phenyl tetranor PGE2 (a stable synthetic analogue), and 17-phenyl trinor PGE2 (an EP1 receptor,selective agonist) were significantly toxic to dopaminergic cells at nanomolar concentrations; EP2- and EP3-selective agonists were not. We challenged dopaminergic neurons in embryonic rat mesencephalic primary neuronal cultures and tested whether these receptors mediate selective 6-OHDA toxicity. The nonselective EP1,3 receptor antagonist AH-6809 and two selective EP1 antagonists, SC-19220 and SC-51089, completely prevented the 40%,50% loss of dopaminergic neurons caused by exposure to 5 ,M 6-OHDA. Together, these results strongly implicate PGE2 activation of EP1 receptors as a mediator of selective toxicity in this model of dopaminergic cell loss. © 2007 Wiley-Liss, Inc. [source] Comparative study of induction of labor in nulliparous women with premature rupture of membranes at term compared to those with intact membranes: Duration of labor and mode of deliveryJOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH (ELECTRONIC), Issue 5 2006Kyo Hoon Park Abstract Aim:, To evaluate the effect of premature rupture of membranes (PROM) at term on the duration of labor and mode of delivery in comparison with intact membranes in nulliparous women with an unfavorable cervix whose labor was induced. Methods:, This retrospective cohort study included all term nulliparous women with an unfavorable cervix requiring labor induction over a 2-year period. Prostaglandin E2 (dinoprostone) and oxytocin were used for labor induction. Criteria for enrolment included (i) singleton pregnancy; (ii) term nulliparous women; or (iii) Bishop score below 6. Statistics were analyzed with Student's t -test, ,2 -test, Fisher's exact test, and multiple logistic regression. Results:, Our study subjects were 82 women whose labor was induced for PROM and 219 women with intact membranes whose labor was induced for social or fetal reasons. The mean durations of active phase of labor were not significantly different between women with PROM and those with intact membranes. However, the women with PROM had a significantly longer mean duration of second stage and a higher rate of cesarean delivery for failure to progress than those with intact membranes. Multiple logistic regression demonstrated that only PROM and fetal macrosomia were significantly associated with an increased risk of cesarean delivery for failure to progress after other confounding variables were adjusted. Conclusions:, Labor induction for PROM at term in nulliparous women with an unfavorable cervix is associated with longer duration of the second stage and a higher risk of cesarean delivery for failure to progress in comparison to those with intact membranes. [source] Detection of fascin and CCR-7 positive mature dendritic cells in oral lichen planusJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 4 2009Shotaro Mukae Background:, Dendritic cells (DC) play a crucial role in the pathogenesis of oral lichen planus (OLP) with respect to antigens presented to T cells. We performed immunohistochemical analysis to elucidate the process of activation of DC in OLP. Methods:, Thirty biopsy specimens were obtained from the patients with OLP. The expressions of CD1a, Langerin, S-100, fascin, chemokine receptor-7 (CCR-7), D2-40, cyclooxygenase-2 (COX-2), and microsomal prostaglandin E synthase-1 (mPGES-1) in DC from OLP and disease free control were investigated using specific antibodies. The distribution and number (1 mm2) of DC were assessed in the intra-epithelium and the submucosa specimens. Correlation between the number of DC and epithelium thickness was also determined. Result:, Immature DC (Langerin+, CD1a+, and S-100+) were identified in the epithelia from OLP patients and control, though the numbers of Langerin+ and CD1a+ positive cells were decreased in the OLP samples as compared to the control. Mature DC (fascin+) were identified in the submucosa specimens, not found in the epithelium from OLP or control. Double immunostaining revealed DC positive for fascin and CCR-7 in the submucosa, which had migrated into D2-40+ lymph vessels. Furthermore, keratinocytes expressed both Prostaglandin E2 (PGE2) converting enzymes, COX-2, and mPGES-1, indicating PGE2 synthesis in the epithelial layer of the OLP specimens. Conclusion:, Our results indicate that DC change from immature to mature in the epithelium and are then drawn out to the submucosa. We demonstrate that mature DC localized in the submucosa, it consequently migrates into lymph vessels. This maturation process of DC is an important immunopathological feature of OLP. [source] Prostaglandin E2 inhibits BMP signaling and delays chondrocyte maturationJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2009Christine A. Clark Abstract While cyclooxygenases are important in endochondral bone formation during fracture healing, mechanisms involved in prostaglandin E2 (PGE2) regulation of chondrocyte maturation are incompletely understood. The present study was undertaken to determine if PGE2 effects on chondrocyte differentiation are related to modulation of the bone morphogenetic protein (BMP) signaling pathway. In primary murine sternal chondrocytes, PGE2 differentially regulated genes involved in differentiation. PGE2 induced type II collagen and MMP-13, had minimal effects on alkaline phosphatase, and inhibited the expression of the maturational marker, type X collagen. In BMP-2,treated cultures, PGE2 blocked the induction of type X collagen. All four EP receptors were expressed in chondrocytes and tended to be inhibited by BMP-2 treatment. RCJ3.1C5.18 chondrocytes transfected with the protein kinase A (PKA) responsive reporter, CRE-luciferase, showed luciferase induction following exposure to PGE2, consistent with activation of PKA signaling and the presence of the EP2 and EP4 receptors. Both PGE2 and the PKA agonist, dibutyryl cAMP, blocked the induction of the BMP-responsive reporter, 12XSBE, by BMP-2 in RCJ3.1C5.18 chondrocytes. In contrast, PGE2 increased the ability of TGF-, to activate the TGF-,-responsive reporter, 4XSBE. Finally, PGE2 down-regulated BMP-mediated phosphorylation of Smads 1, 5, and 8 in RCJ3.1C5.18 cells and in primary murine sternal chondrocytes. Altogether, the findings show that PGE2 regulates chondrocyte maturation in part by targeting BMP/Smad signaling and suggest an important role for PGE2 in endochondral bone formation. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 785,792, 2009 [source] Prostanoids induce egr1 gene expression in cementoblastic OCCM cellsJOURNAL OF PERIODONTAL RESEARCH, Issue 5 2007L. Pham Background and Objective:, Prostanoids that activate protein kinase C signaling are potent anabolic stimulators of cementoblastic OCCM cells. Using cDNA subtractive hybridization, we identified early growth response gene-1 (egr1) as a prostanoid-induced gene. Egr1, a zinc-finger transcription factor expressed during tooth development, regulates cell growth and differentiation. We hypothesize that Egr1 may mediate part of the prostanoid-induced anabolic effect in cementoblasts. Our objective was to characterize prostanoid-induced egr1 gene expression in OCCM cells. Material and Methods:, Total RNA and proteins were assayed by northern blot and western immunoblot assays. Results:, Prostaglandin E2 -, prostaglandin F2, - and fluprostenol-induced egr1 mRNA levels peaked at 0.5 h and returned to baseline by 4 h. Prostaglandin F2, and fluprostenol more potently induced egr1 compared with prostaglandin E2. The phorbol ester, phorbol 12-myristate 13-acetate, which activates protein kinase C signaling, induced egr1 mRNA levels 66-fold over the control, whereas forskolin (a cAMP-protein kinase A activator) and ionomycin (a calcium activator) had no effect. Protein kinase C inhibition significantly inhibited prostaglandin E2 -, prostaglandin F2, - and fluprostenol-induced egr1 mRNA levels. Finally, prostanoids maximally induced Egr1 protein at 1 h. Conclusion:,egr1 is a primary response gene induced by prostaglandin E2, prostaglandin F2, and fluprostenol in OCCM cells through protein kinase C signaling, suggesting that Egr1 may be a key mediator of anabolic responses in cementoblasts. Cementum is vital for periodontal organ maintenance and regeneration. Periodontal ligament fibers (Sharpey's fibers) insert into bone and cementum, thereby supporting the tooth in the alveolus (1). If the periodontal organ is lost, its regeneration requires cementoblast differentiation in order to form new cementum for periodontal ligament fiber insertion. Early attempts to regenerate cementum have proven difficult and rarely generate sufficient tissue (2). A better understanding of the molecular and cellular regulators that promote cementoblast differentiation is critical for developing targeted periodontal regeneration. [source] Prostaglandin E2 induces vascular endothelial growth factor secretion in prostate cancer cells through EP2 receptor-mediated cAMP pathwayMOLECULAR CARCINOGENESIS, Issue 11 2007Xingya Wang Abstract Prostaglandin E2 (PGE2) has been shown to induce expression of vascular endothelial growth factor (VEGF) and other signaling molecules in several cancers. PGE2 elicits its functions though four G-protein coupled membrane receptors (EP1,4). In this study, we investigated the role of EP receptors in PGE2 -induced molecular events in prostate cancer cells. qRT-PCR analysis revealed that PC-3 cells express a substantially higher level of EP2 and moderately higher EP4 than DU145 and LNCaP cells. LNCaP cells had virtually no detectable EP2 mRNA. EP1 and EP3 mRNAs were not detected in these cells. Treatment of prostate cancer cells with PGE2 (1 nM,10 µM) increased both VEGF secretion and cyclic adenosine monophosphate (cAMP) production. Levels of induction in PC-3 cells were greater than in DU145 and LNCaP cells. The selective EP2 agonist CAY10399 also significantly increased VEGF secretion and cAMP production in PC-3 cells, but not in DU145 and LNCaP cells. Moreover, PGE2 and CAY10399 increased mitogen activated protein kinase/extracellular signal regulated kinase (MAPK/Erk) and Akt phosphorylation in PC-3 and DU145 cells, but not in LNCaP cells. However, neither the MAPK/Erk inhibitor U0126 nor the PI3K/Akt inhibitor LY294002 abolished PGE2 -induced VEGF secretion in PC-3 cells. We further demonstrated that the adenylate cyclase activator forskolin and the cAMP anologue 8-bromo-cAMP mimicked the effects of PGE2 on VEGF secretion in PC-3 cells. Meanwhile, the adenylate cyclase inhibitor 2,5,-dideoxyadenosine, at concentrations that inhibited PGE2 -induced cAMP, significantly blocked PGE2 -induced VEGF secretion in PC-3 cells. We conclude that PGE2 -induced VEGF secretion in prostate cancer cells is mediated through EP2-, and possibly EP4-, dependent cAMP signaling pathways. © 2007 Wiley-Liss, Inc. [source] Leishmania donovani -induced macrophages cyclooxygenase-2 and prostaglandin E2 synthesisPARASITE IMMUNOLOGY, Issue 4 2001Claudine Matte Prostaglandin E2 (PGE2) secretion during Leishmania infection has been reported. However, the signalling mechanisms mediating this response are not well understood. Since cyclooxygenase-2 (COX-2) and cytosolic phospholipase A2 (cPLA2) are involved in PGE2 synthesis in response to various stimuli, the implication of these enzymes was evaluated in Leishmania -infected phorbol myristate acetate-differentiated U937 human monocytic cell line. Time-course experiments showed that PGE2 synthesis increased significantly in parallel with COX-2 expression when cells were incubated in the presence of Leishmania donovani promastigotes or lipopolysaccharides (LPS). Increase in cPLA2 mRNA expression was only detected when cells were stimulated with LPS. Indomethacin, genistein, and H7, which are antagonists of COX-2, protein tyrosine kinase (PTK) and protein kinase C (PKC), respectively, inhibited PGE2 production induced by L. donovani and LPS. However, only H7 inhibited COX-2 mRNA synthesis, and there was a significant correlation between PGE2 inhibition and reduced COX-2 expression. Collectively, our results indicate that infection of U937 by L. donovani leads to the generation of PGE2 in part through a PKC-dependent signalling pathway involving COX-2 expression. They further reveal that PTK-dependent events are necessary for Leishmania -induced PGE2 generation, but not for COX-2 expression. A better understanding of the mechanisms by which Leishmania can induce PGE2 production could provide insight into the pathophysiology of leishmaniasis and may help to improve therapeutic approaches. [source] A new role for bicarbonate secretion in cervico-uterine mucus releaseTHE JOURNAL OF PHYSIOLOGY, Issue 13 2010Ruth W. Muchekehu Cervical mucus thinning and release during the female reproductive cycle is thought to rely mainly on fluid secretion. However, we now find that mucus released from the murine reproductive tract critically depends upon concurrent bicarbonate (HCO3,) secretion. Prostaglandin E2 (PGE2)- and carbachol-stimulated mucus release was severely inhibited in the absence of serosal HCO3,, HCO3, transport, or functional cystic fibrosis transmembrane conductance regulator (CFTR). In contrast to mucus release, PGE2 - and carbachol-stimulated fluid secretion was not dependent on bicarbonate or on CFTR, but was completely blocked by niflumic acid. We found stimulated mucus release was severely impaired in the cystic fibrosis ,F508 reproductive tract, even though stimulated fluid secretion was preserved. Thus, CFTR mutations and/or poor bicarbonate secretion may be associated with reduced female fertility associated with abnormal mucus and specifically, may account for the increased viscosity and lack of cyclical changes in cervical mucus long noted in women with cystic fibrosis. [source] Prostaglandin E2 is activated by airway injury and regulates fibroblast cytoskeletal dynamics,THE LARYNGOSCOPE, Issue 7 2009Vlad C. Sandulache MD Abstract Objectives/Hypothesis: To characterize the activation of cyclooxygenase (COX)-2/prostaglandin (PG) E2 signaling during airway mucosal repair and its subsequent role during the wound healing process. Study Design: Prospective animal study. Methods: The subglottis was approached via cricothyroidotomy. Sham airways were closed, and wounded airways were subjected to laser injury and closed. Subglottic tissue was harvested at 12 hours, 24 hours, 48 hours, and 72 hours postinjury. Secretions were collected preoperatively and at time of sacrifice. Inflammatory gene expression was analyzed using quantitative reverse transcriptase polymerase chain reaction. Subglottic/tracheal explants were exposed to exogenous IL-1, in the presence or absence of COX inhibitors. Explant-produced PGE2 levels were assayed using enzyme linked immunoassays. Human airway fibroblast migration and collagen contraction were assayed in the presence or absence of prostaglandin E2. Results: Laser injury triggers a rapid, dose-dependent increase in mucosal IL-1, and COX-2 gene expression, with an anatomical distribution proportional to the distance from the site of injury. Gene upregulation correlates with dose-dependent increases in PGE2 mucosal secretion levels. Ex vivo analysis indicates IL-1, is responsible for the activation of the COX-2 / PGE2 pathway. Prostaglandin E2 differentially inhibits airway fibroblast migration and contraction in a specific, dose-dependent manner. Conclusions: PGE2 is activated during mucosal inflammation and acts to decrease fibroplastic activity in the mucosal wound bed. During subglottic stenosis (SGS) development, the levels of PGE2 generated in response to injury may be insufficient to blunt the intrinsically fibroplastic phenotype of SGS fibroblasts, resulting in excessive scarring. Laryngoscope, 2009 [source] Prostaglandin E2 modulates the expression of antimicrobial peptides in the fat body and midgut of Anopheles albimanusARCHIVES OF INSECT BIOCHEMISTRY AND PHYSIOLOGY (ELECTRONIC), Issue 1 2008F.L. García Gil de Muñoz Abstract Prostaglandins (PGs) participate in the regulation of vertebrate and in at least six insect orders' immune responses. We identified PGE2 in midgut, fat body, Malpighian tubules, and ovarioles of Anopheles albimanus (Aa) mosquitoes. Our data indicate that PGE2 synthesis in cultured midguts responds to the presence of two bacterial species, Micrococcus luteus and Klebsiella pneumoniae. The production of mRNA coding for antimicrobial peptides Aa -Attacin, Aa -Cecropin, and Aa -Gambicin was observed in cultured fat bodies and midguts. The production of these messengers was reduced in the presence of dexamethasone, and this effect was reversed by arachidonic acid. Adding PGE2 to cultures resulted in increased Aa -cecropin mRNA and decreased Aa -attacin and Aa -gambicin mRNAs. Arch. Insect Biochem. Physiol. 68:14,25, 2008. © 2008 Wiley-Liss, Inc. [source] Prostaglandin E2 and its cognate EP receptors control human adult articular cartilage homeostasis and are linked to the pathophysiology of osteoarthritisARTHRITIS & RHEUMATISM, Issue 2 2009Xin Li Objective To elucidate the pathophysiologic links between prostaglandin E2 (PGE2) and osteoarthritis (OA) by characterizing the catabolic effects of PGE2 and its unique receptors in human adult articular chondrocytes. Methods Human adult articular chondrocytes were cultured in monolayer or alginate beads with and without PGE2 and/or agonists of EP receptors, antagonists of EP receptors, and cytokines. Cell survival, proliferation, and total proteoglycan synthesis and accumulation were measured in alginate beads. Chondrocyte-related gene expression and phosphatidylinositol 3-kinase/Akt signaling were assessed by real-time reverse transcription,polymerase chain reaction and Western blotting, respectively, using a monolayer cell culture model. Results Stimulation of human articular chondrocytes with PGE2 through the EP2 receptor suppressed proteoglycan accumulation and synthesis, suppressed aggrecan gene expression, did not appreciably affect expression of matrix-degrading enzymes, and decreased the type II collagen:type I collagen ratio. EP2 and EP4 receptors were expressed at higher levels in knee cartilage than in ankle cartilage and in a grade-dependent manner. PGE2 titration combined with interleukin-1 (IL-1) synergistically accelerated expression of pain-associated molecules such as inducible nitric oxide synthase and IL-6. Finally, stimulation with exogenous PGE2 or an EP2 receptor,specific agonist inhibited activation of Akt that was induced by insulin-like growth factor 1. Conclusion PGE2 exerts an antianabolic effect on human adult articular cartilage in vitro, and EP2 and EP4 receptor antagonists may represent effective therapeutic agents for the treatment of OA. [source] Possible association between amniotic fluid micro-organism infection and microflora in the mouthBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 5 2002Caroline Bearfield Objective To determine whether oral bacteria are found in the amniotic cavity. Design Laboratory based analysis of clinical samples. Setting Royal London Hospital, Whitechapel. Population Forty-eight women attending for elective caesarean section. Methods Dental plaque, a high vaginal swab, amniotic fluid and chorioamnion tissue were taken from women with intact membranes. Main outcome measures Samples were investigated using culture and microscopy for the presence of micro-organisms. Amniotic fluid was analysed by polymerase chain reaction (PCR) for the presence of the ubiquitous 16S rRNA gene specific to most eubacteria. Samples were analysed using PCR genus and species specific primers directed to bacterial taxa found as part of the normal oral microflora (Streptococcus spp. and Fusobacterium nucleatum). Levels of prostaglandin E2 and cytokines were measured in amniotic fluid. Results Amniotic fluid was positive for universal bacteria PCR, Streptococcus spp. PCR and F. nucleatum PCR in 34/48, 20/48 and 7/48 of cases, respectively. Streptococcus spp. and F. nucleatum were cultured from the dental plaque, vagina and amniotic fluid of 48/48, 14/48, 0/48 and 29/48, 6/48, 0/48 subjects, respectively. A significant association was found between detection of microbial DNA (universal and F. nucletum) and complications in previous pregnancies including miscarriage, intrauterine death, neonatal death, preterm delivery and premature rupture of membranes (P < 0.05 and P < 0.01, respectively). Prostaglandin E2 and cytokine levels, with the exception of IL-1,, were not significantly different between women with and without evidence of infection. Conclusions The results indicate that Streptococcus spp. and F. nucleatum in the amniotic fluid may have an oral origin. [source] Prostaglandin E2, Wnt, and BMP in gastric tumor mouse modelsCANCER SCIENCE, Issue 10 2009Hiroko Oshima The development of gastric cancer is closely associated with Helicobacter pylori (H. pylori) infection. The expression of cylooxigenase-2 (COX-2), a rate-limiting enzyme for prostaglandin biosynthesis, is induced in H. pylori -associated chronic gastritis, which thus results in the induction of proinflammatory prostaglandin, PGE2. The COX-2/PGE2 pathway plays a key role in gastric tumorigenesis. On the other hand, several oncogenic pathways have been shown to trigger gastric tumorigenesis. The activation of Wnt/,-catenin signaling is found in 30,50% of gastric cancers, thus suggesting that Wnt signaling plays a causal role in gastric cancer development. Mutations in the bone morphogenetic protein (BMP) signaling pathway are responsible for the subset of juvenile polyposis syndrome (JPS) that develops hamartomas in the gastrointestinal tract. BMP suppression appears to contribute to gastric cancer development because gastric cancer risk is increased in JPS. Wnt signaling is important for the maintenance of gastrointestinal stem cells, while BMP promotes epithelial cell differentiation. Accordingly, it is possible that both Wnt activation and BMP suppression can cause gastric tumorigenesis through enhancement of the undifferentiated status of epithelial cells. Recent mouse model studies have indicated that induction of the PGE2 pathway is required for the development of both gastric adenocarcinoma and hamartoma in the Wnt-activated and BMP-suppressed gastric mucosa, respectively. This article reviews the involvement of the PGE2, Wnt, and BMP pathways in the development of gastric cancer, and gastric phenotypes that are found in transgenic mouse models of PGE2 induction, Wnt activation, BMP suppression, or a combination of these pathways. (Cancer Sci 2009; 100: 1779,1785) [source] Effects of short-term food deprivation on orexin-A-induced intestinal bicarbonate secretion in comparison with related secretagoguesACTA PHYSIOLOGICA, Issue 3 2010G. Flemström Abstract Studies of gastrointestinal physiology in humans and intact animals are usually conducted after overnight fast. We compared the effects of orexin-A, vasoactive intestinal polypeptide (VIP), melatonin, serotonin, uroguanylin, ghrelin and prostaglandin E2 (PGE2) on duodenal bicarbonate secretion in fed and overnight fasted animals. This review is a summary of our findings. Secretagogues were administered by intra-arterial infusion or luminally (PGE2). Enterocyte intracellular calcium ([Ca2+]i) signalling was studied by fluorescence imaging. Total RNA was extracted, reverse transcripted to cDNA and expression of orexin receptors measured by quantitative real-time PCR. Orexin-A stimulates the duodenal secretion in continuously fed animals but not in food-deprived animals. Similarly, short-term fasting causes a 100-fold decrease in the amount of the muscarinic agonist bethanechol required for stimulation of secretion. In contrast, fasting does not affect secretory responses to intra-arterial VIP, melatonin, serotonin, uroguanylin and ghrelin, or that to luminal PGE2. Orexin-A induces [Ca2+]i signalling in enterocytes from fed rats but no significant [Ca2+]i responses occur in enterocytes from fasted animals. In addition, overnight fasting decreases the expression of mucosal orexin receptors. Short-term food deprivation thus decreases duodenal expression of orexin receptors and abolishes the secretory response to orexin-A as well as orexin-A-induced [Ca2+]i signalling. Fasting, furthermore, decreases mucosal sensitivity to bethanechol. The absence of declines in secretory responses to other secretagogues tested strongly suggests that short-term fasting does not affect the secretory capacity of the duodenal mucosa in general. Studies of intestinal secretion require particular evaluation with respect to feeding status. [source] Suppression of inflammatory responses by celastrol, a quinone methide triterpenoid isolated from Celastrus regeliiEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 9 2009D. H. Kim Abstract Background, Celastrol, a quinone methide triterpenoid isolated from the Celastraceae family, exhibits various biological properties, including chemopreventive, antioxidant and neuroprotective effects. In this study, we showed that celastrol inhibits inflammatory reactions in macrophages and protects mice from skin inflammation. Materials and methods, Anti-inflammatory effects of celastrol (0,1 ,M) were examined in lipopolysaccharide (LPS)-stimulated RAW 264·7 macrophages. To investigate the effects of celastrol (0,50 ,g per mice) in vivo, activation of myeloperoxidase (MPO) and histological assessment were examined in the 12- O -tetradecanoyl-phorbol-13-acetate (TPA)-induced mouse ear oedema model. Results, Our in vitro experiments showed that celastrol suppressed not only LPS-stimulated generation of nitric oxide and prostaglandin E2, but also expression of inducible nitric oxide synthase and cyclooxygenase-2 in RAW264·7 cells. Similarly, celastrol inhibited LPS-induced production of inflammatory cytokines, including tumour necrosis factor-, and interleukin-6. In an animal model, celastrol protected mice from TPA-induced ear oedema, possibly by inhibiting MPO activity and production of inflammatory cytokines. Conclusions, Our data suggest that celastrol inhibits the production of inflammatory mediators and is a potential target for the treatment of various inflammatory diseases. [source] Pulmonary stromal cells induce the generation of regulatory DC attenuating T-cell-mediated lung inflammationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2008Qian Li Abstract The tissue microenvironment may affect the development and function of immune cells such as DC. Whether and how the pulmonary stromal microenvironment can affect the development and function of lung DC need to be investigated. Regulatory DC (DCreg) can regulate T-cell response. We wondered whether such regulatory DC exist in the lung and what is the effect of the pulmonary stromal microenvironment on the generation of DCreg. Here we demonstrate that murine pulmonary stromal cells can drive immature DC, which are regarded as being widely distributed in the lung, to proliferate and differentiate into a distinct subset of DCreg, which express high levels of CD11b but low levels of MHC class II (I-A), CD11c, secrete high amounts of IL-10, NO and prostaglandin E2 (PGE2) and suppress T-cell proliferation. The natural counterpart of DCreg in the lung with similar phenotype and regulatory function has been identified. Pulmonary stroma-derived TGF-, is responsible for the differentiation of immature DC to DCreg, and DCreg-derived PGE2 contributes to their suppression of T-cell proliferation. Moreover, DCreg can induce the generation of CD4+CD25+Foxp3+ Treg. Importantly, infusion with DCreg attenuates T-cell-mediated eosinophilic airway inflammation in vivo. Therefore, the pulmonary microenvironment may drive the generation of DCreg, thus contributing to the maintenance of immune homoeostasis and the control of inflammation in the lung. [source] Induction of prolonged tenderness in patients with tension-type headache by means of a new experimental model of myofascial painEUROPEAN JOURNAL OF NEUROLOGY, Issue 3 2003H. Mørk Tenderness is the most prominent abnormal finding in patients with tension-type headache (TTH). Recently we developed a model of myofascial tenderness using intramuscular infusion of a combination of bradykinin, serotonin, histamine and prostaglandin E2. We aimed to examine tenderness after this combination in patients with episodic TTH (ETTH). Fifteen patients and 15 healthy controls completed the study. Participants received the combination into the non-dominant trapezius muscle in a randomized, double-blinded and placebo-controlled design. Local tenderness and stimulus,response functions, mechanical pain thresholds (PPDT) in the temporal region and on the finger, and total tenderness score (TTS) were recorded. A local, prolonged, and mild to moderate tenderness was reported both in patients (P = 0.001) and in controls (P = 0.001) after the combination compared with the placebo. The response to the combination tended to be increased in patients. The stimulus,response function was leftward shifted after the combination, compared with baseline in both groups. No changes in PPDT or TTS were found after the infusions, whereas baseline PPDTs were decreased in ETTH compared with controls (PPDTfinger: P = 0.033; PPDTtemporal: P = 0.015). Intramuscular infusion of a combination of endogenous substances induced prolonged tenderness in both patients with episodic TTH and healthy subjects. The present results suggest an increased excitability of peripheral muscle afferents in TTH. [source] Transient receptor potential A1 mediates acetaldehyde-evoked pain sensationEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2007Sangsu Bang Abstract Six transient receptor potential (TRP) ion channels expressed in the sensory afferents play an important role as body thermosensors and also as peripheral pain detectors. It is known that a number of natural compounds specifically activate those sensory neuronal TRP channels, and a well-known example is cinnamaldehyde for TRPA1. Here we show that human and mouse TRPA1 are activated by acetaldehyde, an intermediate substance of ethanol metabolism, in the HEK293T cell heterologous expression system and in cultured mouse trigeminal neurons. Acetaldehyde failed to activate other temperature-sensitive TRP channels expressed in sensory neurons. TRPA1 antagonists camphor and gadolinium, and a general TRP blocker ruthenium red inhibited TRPA1 activation by acetaldehyde. Camphor, gadolinium and ruthenium red also suppressed the acute nociceptive behaviors induced by the intradermal administration of acetaldehyde into the mouse footpads. Intradermal co-application of prostaglandin E2 and acetaldehyde greatly potentiated the acetaldehyde-induced nociceptive responses, and this effect was reversed by treatment with the TRPA1 antagonist camphor. These results suggest that acetaldehyde causes nociception via TRPA1 activation. Our data may also help elucidate the mechanisms underlying acetaldehyde-related pathological symptoms such as hangover pain. [source] Peripheral antinociceptive effect of pertussis toxin: activation of the arginine/NO/cGMP/PKG/ ATP-sensitive K+ channel pathwayEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2006Gerly A. C. Brito Abstract The aim of the present study was to determine the effect of pertussis toxin (PTX) on inflammatory hypernociception measured by the rat paw pressure test and to elucidate the mechanism involved in this effect. In this test, prostaglandin E2 (PGE2) administered subcutaneously induces hypernociception via a mechanism associated with neuronal cAMP increase. Local intraplantar pre-treatment (30 min before), and post-treatment (5 min after) with PTX (600 ng/paw1, in 100 µL) reduced hypernociception induced by prostaglandin E2 (100 ng/paw, in 100 µL, intraplantar). Furthermore, local intraplantar pre-treatment (30 min before) with PTX (600 ng/paw, in 100 µL) reduced hypernociception induced by DbcAMP, a stable analogue of cAMP (100 µg/paw, in 100 µL, intraplantar), which indicates that PTX may have an effect other than just Gi/G0 inhibition. PTX-induced analgesia was blocked by selective inhibitors of nitric oxide synthase (L-NMMA), guanylyl cyclase (ODQ), protein kinase G (KT5823) and ATP-sensitive K+ channel (Kir6) blockers (glybenclamide and tolbutamide). In addition, PTX was shown to induce nitric oxide (NO) production in cultured neurons of the dorsal root ganglia. In conclusion, this study shows a peripheral antinociceptive effect of pertussis toxin, resulting from the activation of the arginine/NO/cGMP/PKG/ATP-sensitive K+ channel pathway. [source] | |||||||||||||||||||||||||||||||||||||