208 results on '"Prostanoic Acids"'
Search Results
2. Measurement of prostaglandin metabolites is useful in diagnosis of small bowel ulcerations
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Takanari Kitazono, Motohiro Esaki, Atsushi Hirano, Koichi Kurahara, Naoki Hosoe, Toshiyuki Matsui, Tadakazu Hisamatsu, Yasuharu Okamoto, Tsuneyoshi Yao, Fumihito Hirai, Takayuki Matsumoto, Shunichi Yanai, Junji Umeno, Haruhiko Ogata, Yuta Fuyuno, Shigeyoshi Yasukawa, Kenji Watanabe, Yuichi Matsuno, Takehiro Torisu, Shuhei Hosomi, Shuji Kochi, and Yoichiro Hirakawa
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Adult ,Male ,Crohn’s disease ,medicine.medical_specialty ,Colon ,Urinary system ,Organic Anion Transporters ,Observational Study ,Gastroenterology ,Diagnosis, Differential ,Prostaglandin E major urinary metabolites ,Crohn Disease ,Ileum ,Internal medicine ,medicine ,Humans ,Enteropathy ,Ulcer ,Crohn's disease ,Receiver operating characteristic ,business.industry ,Prostaglandins E ,Prostanoic Acids ,Small intestine ,General Medicine ,Odds ratio ,Middle Aged ,medicine.disease ,digestive system diseases ,Confidence interval ,Chronic nonspecific multiple ulcers of the small intestine ,Intestinal Diseases ,Mutation ,Biomarker (medicine) ,Female ,Chronic enteropathy associated with SLCO2A1 gene ,Differential diagnosis ,business - Abstract
BACKGROUND We recently reported on a hereditary enteropathy associated with a gene encoding a prostaglandin transporter and referred to as chronic enteropathy associated with SLCO2A1 gene (CEAS). Crohn’s disease (CD) is a major differential diagnosis of CEAS, because these diseases share some clinical features. Therefore, there is a need to develop a convenient screening test to distinguish CEAS from CD. AIM To examine whether prostaglandin E major urinary metabolites (PGE-MUM) can serve as a biomarker to distinguish CEAS from CD. METHODS This was a transactional study of 20 patients with CEAS and 98 patients with CD. CEAS was diagnosed by the confirmation of homozygous or compound heterozygous mutation of SLCO2A1. We measured the concentration of PGE-MUM in spot urine by radioimmunoassay, and the concentration was compared between the two groups of patients. We also determined the optimal cut-off value of PGE-MUM to distinguish CEAS from CD by receiver operating characteristic (ROC) curve analysis. RESULTS Twenty Japanese patients with CEAS and 98 patients with CD were enrolled. PGE-MUM concentration in patients with CEAS was significantly higher than that in patients with CD (median 102.7 vs 27.9 μg/g × Cre, P < 0.0001). One log unit increase in PGE-MUM contributed to 7.3 increase in the likelihood for the diagnosis of CEAS [95% confidence interval (CI) 3.2-16.7]. A logistic regression analysis revealed that the association was significant even after adjusting confounding factors (adjusted odds ratio 29.6, 95%CI 4.7-185.7). ROC curve analysis revealed the optimal PGE-MUM cut-off value for the distinction of CEAS from CD to be 48.9 μg/g × Cre with 95.0% sensitivity and 79.6% specificity. CONCLUSION PGE-MUM measurement is a convenient, non-invasive and useful test for the distinction of CEAS from CD.
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- 2019
3. Prostaglandin E-Major Urinary Metabolite Predicts Relapse in Patients With Ulcerative Colitis in Clinical Remission
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Mihoko Yamade, Takahiro Miyazu, Ken Sugimoto, Natsuki Ishida, Satoshi Suzuki, Kiichi Sugiura, Moriya Iwaizumi, Satoshi Tamura, Shinya Tani, Takahisa Furuta, Yasushi Hamaya, and Satoshi Osawa
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Urinary system ,Colonoscopy ,Gastroenterology ,Risk Assessment ,Severity of Illness Index ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Predictive Value of Tests ,Recurrence ,Internal medicine ,Severity of illness ,medicine ,Humans ,Colitis ,Aged ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Inflammatory Bowel Disease ,Prostanoic Acids ,Reproducibility of Results ,Middle Aged ,medicine.disease ,Prognosis ,Ulcerative colitis ,Confidence interval ,ROC Curve ,030220 oncology & carcinogenesis ,Predictive value of tests ,Prostaglandins ,Biomarker (medicine) ,Feasibility Studies ,030211 gastroenterology & hepatology ,Colitis, Ulcerative ,Female ,business ,Biomarkers ,Follow-Up Studies - Abstract
INTRODUCTION: Prostaglandin E-major urinary metabolite (PGE-MUM) is a novel biomarker reflecting endoscopic activity in ulcerative colitis (UC). However, there are no studies investigating the efficacy of PGE-MUM as a biomarker for predicting relapse. We investigated whether PGE-MUM can predict clinical relapse of UC. METHODS: The measurement of PGE-MUM and endoscopic evaluation were performed in 70 patients with UC in clinical remission. The optimal cutoff values predicting relapse and relapse-free rate were analyzed. RESULTS: Sixteen patients (22.9%) relapsed during the 12-month follow-up. The median PGE-MUM value of relapsed patients at entry was significantly higher than that of patients in clinical remission (P = 0.008). The cutoff value of PGE-MUM predicting future relapse was 25.2 μg/g Cr by receiver-operating characteristic (ROC) analysis, and the area under the ROC curve was 0.721 (95% confidence interval: 0.556–0.886). The relapse-free rate of patients with PGE-MUM ≥25.2 μg/g Cr was significantly lower than that in patients with PGE-MUM
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- 2020
4. Identification and quantification of phytoprostanes and phytofurans of coffee and cocoa by- and co-products
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Jean-Marie Galano, Mirna L. Suárez-Quiroz, Maria-Cruz Figueroa-Espinoza, Amandine Rocher, Joseph Vercauteren, Mariana Ruesgas-Ramón, Oscar Gonzalez-Rios, Camille Oger, Thierry Durand, Claire Vigor, Guillaume Reversat, Erwann Durand, Ingénierie des Agro-polymères et Technologies Émergentes (UMR IATE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), UNIDA, Instituto Tecnologico de Veracruz, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Consejo Nacional de Ciencia y Tecnología (CONACyT, Mexico) (grant number 405131), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Anti-inflammatoire ,Ingénierie des aliments ,isoprostane ,Cocoa husk ,Coffee pulp ,Cocoa pod husk ,Isoprostanoids ,Phytoprostanes ,Micro-LC-MS/MS ,Adding-value ,Co-products ,By-products ,Phytofurans ,Q05 - Additifs alimentaires ,Coffee ,Tandem Mass Spectrometry ,[SDV.IDA]Life Sciences [q-bio]/Food engineering ,Food science ,valorisation des sous produits ,Chromatography, High Pressure Liquid ,2. Zero hunger ,valorisation de la biomasse ,Chemistry ,Pulp (paper) ,cosse ,Fatty Acids ,Prostanoic Acids ,General Medicine ,cocoa ,biomarker ,biomarqueur ,Coque de cacao ,sous produit agricole ,engineering.material ,Husk ,03 medical and health sciences ,Dry weight ,Functional food ,coffee pulp ,Food engineering ,Coque de grain ,Q04 - Composition des produits alimentaires ,Furans ,Additif alimentaire ,Cacao ,030109 nutrition & dietetics ,Plant Extracts ,Stress oxydatif ,pulpe de café ,Oxidative Stress ,030104 developmental biology ,engineering ,Biomarkers ,Food Science - Abstract
International audience; Phytoprostanes (PhytoPs) and phytofurans (PhytoFs) are isoprostanoids that result from the peroxidation of α-linolenic acid and are biomarkers of oxidative stress in plants and humans. These compounds exhibit several interesting biological activities (e.g. neuroprotection and anti-inflammatory activities). The aim of this research was to add value to coffee pulp (CP), cocoa husk (CH) and cocoa pod husk (CPH) by identifying and quantifying PhytoPs and PhytoFs by liquid chromatography–tandem mass spectrometry. The contents of PhytoPs and PhytoFs in CP, CH, and CPH were, respectively, 654.6, 474.3 and 179.9, and 543.2, 278.0 and 393.8 ng per g dry weight (dw). The main PhytoP found in CP (171.37 ng per g dw) and CPH (37.12 ng per g dw) was 9-epi-9-F1t-PhytoP, while ent-9-L1t-PhytoP was the most abundant in CH (109.78 ng per g dw). The main PhytoF found in all sources was ent-16(RS)-13-epi-ST-Δ14-9-PhytoF, at 196.56, 126.22, and 207.57 ng per g dw in CP, CH, and CPH, respectively. We provide the first complete profile of PhytoPs and PhytoFs for these agro-residues, which could be used in the functional food industry for enriching food or as nutritional supplements.
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- 2019
5. Oxidized products of α-linolenic acid negatively regulate cellular survival and motility of breast cancer cells
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Philippe G. Frank, Jean-Marie Galano, Jorge L. Gutierrez-Pajares, Camille Oger, Céline Ben Hassen, Thierry Durand, Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), J.L.G.-P. was supported by Le Studium (Région Centre-Val de Loire, France). P.G.F. was supported by grants from INCa PLBio (2018-145), the Lipids ARD2020-Biodrug project (Région Centre-Val de Loire, France), La Ligue contre le Cancer (Indre et Loire, Loir et Cher, and Vienne), by an Academic Research Grant from the Région Centre-Val de Loire (France) and by the Canceropole Grand-Ouest (Mature project)., Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Frank, Philippe
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lcsh:QR1-502 ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,[SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,lcsh:Microbiology ,0302 clinical medicine ,Cell Movement ,[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,Cytotoxic T cell ,[SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,2. Zero hunger ,0303 health sciences ,Chemistry ,Prostanoic Acids ,alpha-Linolenic Acid ,Cell migration ,3. Good health ,030220 oncology & carcinogenesis ,MCF-7 Cells ,Female ,Oxidation-Reduction ,medicine.drug ,Cell Survival ,Antineoplastic Agents ,Breast Neoplasms ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Article ,lipids ,03 medical and health sciences ,Breast cancer ,breast cancer ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Cell Line, Tumor ,medicine ,[SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,Humans ,Doxorubicin ,Viability assay ,phytoprostane ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Furans ,Cell adhesion ,Cell Proliferation ,030304 developmental biology ,Cancer ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,medicine.disease ,[SDV.AEN] Life Sciences [q-bio]/Food and Nutrition ,Cell culture ,Cancer research ,Drug Screening Assays, Antitumor ,[SDV.AEN]Life Sciences [q-bio]/Food and Nutrition - Abstract
Despite recent advances in our understanding of the biological processes leading to the development and progression of cancer, there is still a need for new and effective agents to treat this disease. Phytoprostanes (PhytoPs) and phytofurans (PhytoFs) are non-enzymatically oxidized products of &alpha, linolenic acid that are present in seeds and vegetable oils. They have been shown to possess anti-inflammatory and apoptosis-promoting activities in macrophages and leukemia cells, respectively. In this work, seven PhytoPs (PP1&ndash, PP7) and one PhytoFs (PF1) were evaluated for their cytotoxic, chemosensitization, and anti-migratory activities using the MCF-7 and MDA-MB-231 breast cancer cell lines. Among the tested compounds, only three PhytoPs had a significant effect on cell viability compared to the control group: Ent-9-L1-PhytoP (PP6) decreased cell viability in both cell lines, while 16-F1t-PhytoP (PP1) and 9-L1-PhytoP (PP5) decreased viability of MCF-7 and MDA-MB-231 cells, respectively. When combined with a sub-cytotoxic dose of doxorubicin, these three PhytoPs displayed significantly enhanced cytotoxic effects on MCF-7 cells while the chemotherapeutic drug alone had no effect. In cellular motility assays, Ent-9-(RS)-12-epi-ST-&Delta, 10-13-PhytoF could significantly inhibit cellular migration of MDA-MB-231 cells. In addition, Ent-9-(RS)-12-epi-ST-&Delta, 10-13-PhytoF also enhanced cellular adhesion of MDA-MB-231 cells.
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- 2019
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6. Synthesis of Enantiomerically Pure Stereomers of Rosaprostol
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Beata Łukasik, Wiesława Perlikowska, Remigiusz Żurawiński, and Marian Mikołajczyk
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chemistry.chemical_classification ,Esterification ,Molecular Structure ,Double bond ,Antiulcer drug ,Stereochemistry ,Chemistry ,Hydrolysis ,Organic Chemistry ,Prostanoic Acids ,Diastereomer ,Stereoisomerism ,Prostanoic acid ,Stereocenter ,Enantiopure drug ,Yield (chemistry) - Abstract
Enantiopure stereomers of rosaprostol 1, an antiulcer drug, were synthesized from diastereomeric building blocks (-)-5a and (+)-5b. Conversion of (-)-5a into rosaprostol stereomer (-)-(1S,2R,5R)-1a was accomplished in nine steps in 18% overall yield. In this sequence, fully diastereoselective hydrogeneration of the endocyclic carbon double bond in the cyclopentenone ring was key, generating a new stereogenic center (C-2 in 1a). C-5 epimeric rosaprostol (-)-(1S,2R,5S)-1b was obtained from (-)-1a in 72% yield by a two-reaction sequence involving methylation and one-pot Mitsunobu esterification-hydrolysis.
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- 2015
7. Prostaglandin E-major Urinary Metabolite as a Biomarker for Pediatric Ulcerative Colitis Activity
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Ryusuke Nambu, Shin-ichiro Hagiwara, Isao Okayasu, Hiromitsu Ohnishi, Hiroshi Kishimoto, Satoru Ito, Masaaki Matsuura, Seiichi Kagimoto, and Mutsunori Fujiwara
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Male ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Metabolite ,Urinary system ,Prostaglandin ,Gastroenterology ,Sensitivity and Specificity ,Severity of Illness Index ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Colitis ,Child ,business.industry ,Case-control study ,Prostanoic Acids ,Infant ,Colonoscopy ,medicine.disease ,Ulcerative colitis ,chemistry ,030220 oncology & carcinogenesis ,Case-Control Studies ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Biomarker (medicine) ,Regression Analysis ,lipids (amino acids, peptides, and proteins) ,030211 gastroenterology & hepatology ,Colitis, Ulcerative ,Female ,business ,Biomarkers ,Prostaglandin E - Abstract
Prostaglandin E-major urinary metabolite (PGE-MUM) is a useful biomarker for adult ulcerative colitis (UC) activity. In the present study, we evaluated whether PGE-MUM can also be a biomarker of pediatric UC activity and compared its efficacy in predicting UC activity with that of C-reactive protein and erythrocyte sedimentation rate.Twenty-nine pediatric patients with UC (8-18 years) and 29 healthy age- and sex-matched subjects were enrolled. UC activity was evaluated using the Pediatric Ulcerative Colitis Activity Index, highest Mayo endoscopic scoring (Mayo), and Matts grading (Matts) for histologic scoring, and the sum of Mayo (total of 6 segments) and Matts in all patients with UC. PGE-MUM levels were measured using a radioimmunoassay.PGE-MUM levels were elevated in endoscopically and histologically active UC patients, but not in patients with endoscopic and histologic remission or controls. PGE-MUM levels positively and significantly correlated with UC activity. PGE-MUM levels were positively correlated with Pediatric Ulcerative Colitis Activity Index (r = 0.594), highest Mayo (r = 0.462), the sum of Mayo (r = 0.694), and the sum of Matts (r = 0.613), but not with highest Matt (r = 0.352). The sum of Mayo and the sum of Matts, which reflect total colon inflammation, showed highest correlation with PGE-MUM. C-reactive protein levels did not correlate with any UC activity scores. Erythrocyte sedimentation rate exhibited correlation (r = 0.490) with the sum of Mayo only.PGE-MUM is a reliable biomarker that reflects both the endoscopic and histologic activity of the entire colon in pediatric UC.
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- 2016
8. GC-ECNICI-MS/MS of eicosanoids as pentafluorobenzyl-trimethylsilyl (TMS) derivatives: Evidence of CAD-induced intramolecular TMS ether-to-ester rearrangement using carboxy
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Dimitrios, Tsikas
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Fluorobenzenes ,Trimethylsilyl Compounds ,Tandem Mass Spectrometry ,Prostanoic Acids ,Eicosanoids ,Humans ,Esters ,Oxygen Isotopes ,Gas Chromatography-Mass Spectrometry - Abstract
GC-MS and GC-MS/MS of pentafluorobenzyl (PFB) ester trimethylsilyl (TMS) ether (PFB-TMS) derivatives of hydroxylated long-chain fatty acids including arachidonic acid metabolites, the eicosanoids, in the electron-capture negative-ion chemical ionization (ECNICI) mode are the most sensitive and accurate approaches to quantify carboxyl groups-containing compounds in complex biological fluids such as plasma and urine. Under ECNICI conditions, PFB-TMS derivatives of eicosanoids ionize to form very few ions, with the carboxylates [M-PFB]
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- 2016
9. Prostaglandin E-Major Urinary Metabolite as a Biomarker for Inflammation in Ulcerative Colitis: Prostaglandins Revisited
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Mutsunori Fujiwara, Satoru Ito, Isao Okayasu, Seiji Arihiro, Masaaki Matsuura, Tomokazu Matsuura, and Yoshinori Arai
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medicine.medical_specialty ,Carcinogenesis ,medicine.medical_treatment ,Biopsy ,Prostaglandin ,Prostanoic acid ,Gastroenterology ,Dinoprostone ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Intestinal mucosa ,Internal medicine ,medicine ,Humans ,Prostaglandin E2 ,Colitis ,Intestinal Mucosa ,business.industry ,Carcinoma ,Prostanoic Acids ,Colonoscopy ,medicine.disease ,Ulcerative colitis ,Enteritis ,chemistry ,030220 oncology & carcinogenesis ,Immunology ,Colonic Neoplasms ,Biomarker (medicine) ,030211 gastroenterology & hepatology ,Colitis, Ulcerative ,business ,Biomarkers ,medicine.drug ,Prostaglandin E - Abstract
With the development of new therapeutic approaches, the ultimate goal of ulcerative colitis (UC) treatment is not only clinical remission but also mucosal healing. Successful mucosal healing has been associated with a dramatic risk reduction in UC recurrence and colitis-associated cancer development, which are the most critical complications of UC. However, invasive tests such as colonoscopy and biopsy are required to evaluate mucosal healing. Therefore, frequent examinations are unsuitable for UC patients. Mucosal inflammation of the colon and prostaglandin E2 production are assumed to be correlated; therefore, we considered that prostaglandin E-major urinary metabolite (PGE-MUM; 7-hydroxy-5,11-diketotetranor-prosta-1,16-dioic acid) may be a surrogate biomarker of UC activity. In this review, we propose that PGE-MUM levels reflect the colonoscopic and histological appearance of UC, suggesting that it is a more sensitive biomarker than those previously utilized for UC-related mucosal inflammation. According to the ‘organ-specific chronic inflammation-carcinoma sequence' theory, by measuring PGE-MUM periodically, it would be possible to control inflammation, with subsequent prevention of UC recurrence and colitis-associated cancer development. The measurement of urine samples for PGE-MUM - a simple, noninvasive method - can reduce the patient burden as well as medical costs, suggesting its potential for application in routine practice.
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- 2016
10. Amyloid precursor protein promotes endoplasmic reticulum stress-induced cell death via C/EBP homologous protein-mediated pathway
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Takeshi Kihara, Hachiro Sugimoto, Tetsuhiro Niidome, Akinori Akaike, and Keita Takahashi
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Chromatin Immunoprecipitation ,Programmed cell death ,Time Factors ,CHOP ,Endoplasmic Reticulum ,Transfection ,Biochemistry ,Cell Line ,Amyloid beta-Protein Precursor ,Neuroblastoma ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Stress, Physiological ,mental disorders ,Amyloid precursor protein ,Humans ,RNA, Messenger ,Enzyme Inhibitors ,RNA, Small Interfering ,Gene knockdown ,Amyloid beta-Peptides ,Cell Death ,L-Lactate Dehydrogenase ,biology ,Tunicamycin ,Endoplasmic reticulum ,Prostanoic Acids ,Dipeptides ,Molecular biology ,Protein Structure, Tertiary ,Dithiothreitol ,chemistry ,Apoptosis ,Unfolded protein response ,biology.protein ,Tyrosine ,Transcription Factor CHOP ,Signal Transduction - Abstract
The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) is known to activate the ER, which is termed ER stress. Here, we demonstrated that amyloid precursor protein (APP) is a novel mediator of ER stress-induced apoptosis through the C/EBP homologous protein (CHOP) pathway. Expression of APP mRNA was elevated by tunicamycin- or dithiothreitol-induced ER stress. The levels of C83 and APP intracellular domain (AICD) fragments, which are cleaved from APP, were significantly increased under ER stress, although the protein level of full-length APP was decreased. Cellular viability was reduced in APP-over-expressing cells, which was attenuated by treatment with a gamma-secretase inhibitor, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). Cellular viability was also reduced in AICD-FLAG-over-expressing cells. The mRNA and protein levels of CHOP, an ER stress-responsive gene, were remarkably increased by APP over-expression, which was attenuated by treatment with DAPT. CHOP mRNA induction was also found in AICD-FLAG-over-expressing cells. Cell death and CHOP up-regulation by ER stress were attenuated by APP knockdown. Data obtained with a luciferase assay and chromatin immunoprecipitation assay indicated that AICD associates with the promoter region of the CHOP gene. In conclusion, ER stress-induced APP undergoes alpha- and gamma-secretase cleavage and subsequently induces CHOP-mediated cell death.
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- 2009
11. RNA interference silencing of DRAL affects processing of amyloid precursor protein
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Hiroshi Tanahashi and Katsuji Yoshioka
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Small interfering RNA ,ADAM-17/TACE ,LIM-Homeodomain Proteins ,Muscle Proteins ,ADAM17 Protein ,Biology ,Transfection ,ADAM10 Protein ,Amyloid beta-Protein Precursor ,DRAL/FHL2/SLIM3 ,RNA interference ,Cricetinae ,Chlorocebus aethiops ,Phorbol Esters ,mental disorders ,Amyloid precursor protein ,Animals ,Humans ,Gene silencing ,RNA, Small Interfering ,Amyloid precursor protein (APP) ,Cell Line, Transformed ,Homeodomain Proteins ,Gene knockdown ,General Neuroscience ,Prostanoic Acids ,Membrane Proteins ,RNA ,ADAM-10/Kuzbanian ,α-Secretase ,Alzheimer's disease ,Molecular biology ,ADAM Proteins ,biology.protein ,Amyloid Precursor Protein Secretases ,Transcription Factors - Abstract
金沢大学医薬保健研究域医学系, In a previous study, we reported that Alzheimer's disease-associated presenilin-2 interacts with a LIM-domain protein, namely, DRAL/FHL2/SLIM3. In this study, we investigated whether DRAL modifies the metabolism of the amyloid precursor protein (APP). We used small interfering RNA (siRNA) to knockdown DRAL in COS7 and HEK293 cells that stably overexpress APP695. We found that the knockdown was accompanied by a decrease in the amount of secreted α-secretase-cleaved APP and the membrane-bound C-terminal fragment C83 and an increase in the amount of secreted β-amyloid peptide (Aβ) from the cells. We also found that in addition to a disintegrin and metalloprotease (ADAM)-17, DRAL binds to ADAM-10. Thus, DRAL may be involved in the processing of APP through the α-secretase pathway. © 2008 Elsevier Ireland Ltd. All rights reserved.
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- 2008
12. Stimulation of cannabinoid (CB1) and prostanoid (EP2) receptors opens BKCa channels and relaxes ocular trabecular meshwork
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Friederike Stumpff, Lars Choritz, Hagen Thieme, Rita Rosenthal, Susann Meissner, Marianne Boxberger, Michael Wiederholt, and Achim H.-P. Krauss
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Patch-Clamp Techniques ,medicine.medical_treatment ,8-Bromo Cyclic Adenosine Monophosphate ,Potassium Channels, Calcium-Activated ,Piperidines ,Receptor, Cannabinoid, CB1 ,Cyclic AMP ,Cells, Cultured ,Endothelin-1 ,Chemistry ,Prostanoic Acids ,Middle Aged ,Iberiotoxin ,Calcium Channel Blockers ,Stimulation, Chemical ,Sensory Systems ,Potassium channel ,medicine.anatomical_structure ,Ion Channel Gating ,medicine.drug ,Adult ,AM251 ,Agonist ,medicine.medical_specialty ,Carbachol ,medicine.drug_class ,Morpholines ,Cholinergic Agonists ,In Vitro Techniques ,Naphthalenes ,Contractility ,Cellular and Molecular Neuroscience ,Trabecular Meshwork ,Internal medicine ,medicine ,Animals ,Humans ,Receptors, Prostaglandin E ,Aged ,Cannabinoids ,Cyclohexanols ,Benzoxazines ,Ophthalmology ,Endocrinology ,15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ,Pyrazoles ,Calcium ,Cattle ,Trabecular meshwork ,Cannabinoid ,Peptides - Abstract
Prostanoids and cannabinoids have ocular hypotensive and neuroprotective properties. The effect of the prostanoid AH13205 (EP2), the thromboxane-mimetic U46619, the cannabinoid (CB) agonists WIN55212-2 and CP 55,940, endothelin-1 (ET-1) and 8-bromo-cAMP on the membrane currents of trabecular meshwork (TM) cells were measured using the patch-clamp technique and compared to their effects on TM contractility. Previous studies show relaxation of TM to AH 13205 and other substances that elevate cAMP, while U46619 and endothelin-1 contract TM. This study shows that after contraction (100%) with carbachol (10−6 m ), the CB agonist CP 55,940 dose-dependently reduced contractility to 83±4% (n=9) (10−6 m ) and 61±10%, (n=7) (10−5 m ). In the presence of both the CB1 antagonist AM251 (10−6 m ) and CP 55,940 (10−5 m ), the contractile response to carbachol reached 84±3% (n=6) of the original level. In patch-clamp experiments, membrane permeable 8-bromo-cAMP (10−4 m ) had no effect on currents of TM cells. In contrast, AH 13205 and two cannabinoids reversibly enhanced outward current through high-conductance Ca2+-activated K+ channels (BKCa, BK, maxi-K) to the following values (in % of the initial value at 100 mV): AH 13205 (10−5 m ): 200±28% (n=6), CP 55,940 (10−6 m ): 196±33% (n=7), CP 55,940 (10−5 m ): 484±113% (n=7), WIN55212-2 (10−5 m ): 205±41% (n=10). Iberiotoxin (10−7 m ) completely blocked these responses. The current response to CP 55,940 (10−5 m ) could be partially blocked by the CB1 antagonist AM251 (10−6 m ). Conversely, the contractile agents in this study either caused a transient reduction in outward current (ET-1(5×10−8 m )) or had no effect (U46619 (10−6 m )). We conclude that stimulation of EP2 and CB1 receptors in TM is coupled to the activation of BKCa channels via a non-diffusible second messenger cascade. This effect may contribute to the relaxant activity of EP2 and CB1 agonists in isolated TM strips, modulating ocular outflow.
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- 2005
13. New Reagent System for Attaining High Regio- and Stereoselectivities in Allylic Displacement of 4-Cyclopentene-1,3-diol Monoacetate with Aryl- and Alkenylmagnesium Bromides
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Yuichi Kobayashi, Takayuki Ainai, and Kenya Nakata
- Subjects
Allylic rearrangement ,Molecular Structure ,Aryl ,Organic Chemistry ,Diol ,Prostanoic Acids ,Regioselectivity ,Stereoisomerism ,General Medicine ,Cyclopentanes ,Acetates ,Alkenes ,Medicinal chemistry ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Present method ,Reagent ,Organometallic Compounds ,Organic chemistry ,Cyclopentene ,Displacement (orthopedic surgery) ,Physical and Theoretical Chemistry - Abstract
[Reaction: see text] Low regioselectivity of RMgBr (R = aryl, alkenyl) in the CuCN-catalyzed reaction with 4-cyclopentene-1,3-diol monoacetate is improved by addition of LiCl or MgCl2 to a similar extent as previously obtained with RMgCl (90:10). The limitation encountered in the preparation of RMgCl no longer exists in the present method using RMgBr. The method is utilized in the synthesis of AH-13205, a selective EP2-receptor agonist.
- Published
- 2004
14. A Functional Study on Prostanoid Receptors Involved in Cultured Human Iridal Melanocyte Stimulation
- Author
-
Dan-Ning Hu, David F. Woodward, and Steven A. McCormick
- Subjects
Adult ,Agonist ,medicine.medical_specialty ,Prostaglandin Antagonists ,medicine.drug_class ,medicine.medical_treatment ,Receptors, Prostaglandin ,Basic fibroblast growth factor ,Iris ,Prostaglandin ,Cell Count ,Prostanoic acid ,Biology ,Melanocyte ,Dinoprostone ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Internal medicine ,Cyclic AMP ,medicine ,Humans ,Receptor ,Cells, Cultured ,Melanins ,Hydantoins ,Prostanoic Acids ,Prostaglandin antagonist ,Epoprostenol ,Sensory Systems ,Ophthalmology ,Endocrinology ,medicine.anatomical_structure ,chemistry ,15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ,Melanocytes ,Fibroblast Growth Factor 2 ,Prostaglandin E - Abstract
The effects of various prostanoids on the growth, melanogenesis and dendrification of cultured iridal melanocytes were studied. Iridal melanocytes were isolated and cultured with medium supplemented with cAMP elevating agents and basic fibroblast growth factor (bFGF) (complete medium). The iridal melanocytes were plated into multiple well plates and cultured with complete medium or various deleted media with or without various prostanoids at different concentrations. After 6 days, the numbers of cells and dendrites were counted and melanin content was measured and compared with controls. Prostaglandin E(2), an EP(2)receptor agonist (AH 13205) and AGN 192093 (thromboxane mimetic) stimulated growth, melanogenesis and dendrification of cultured iridal melanocytes in cAMP-deleted medium. A mixed EP(1)and EP(3)receptor agonist (sulprostone), a EP(4)receptor agonist (ONO-AE1-329), IP receptor agonists (cicaprost or iloprost) and a TP receptor agonist (U-46619) showed no effect. Prostaglandin D(2)showed stimulating effects. However, these stimulating effects could not be blocked by the addition of a DP receptor antagonist (BW A868C). Furthermore, a DP receptor agonist (BW 245C) showed no effects, indicating that the effect of prostaglandin D(2)may involve receptors other than the DP receptor subtype. The present study indicates that: (1) among various EP receptor agonists, only an EP(2)receptor agonist has stimulating effects on iridal melanocytes; (2) DP, IP and TP receptor agonists do not have stimulating effects; and (3) the mechanisms of action of prostaglandin D(2)and AGN 192093 need further study.
- Published
- 2001
15. Significant Increase in Prostaglandin E-Main Urinary Metabolite by Laxative Administration: Comparison with Ulcerative Colitis
- Author
-
Junko Komatsu, Takafumi Bandoh, Jun Kanno, Masae Oritsu, Yoshihisa Katoh, Michiyasu Yoshitsugu, Kunio Sugihara, Mutsunori Fujiwara, Hiroshi Toyoshima, Isao Okayasu, Yuzo Hayashi, and Yoshio Kase
- Subjects
Male ,Sennosides ,medicine.medical_specialty ,Urinary system ,medicine.medical_treatment ,Metabolite ,Laxative ,Prostaglandin ,Anthraquinones ,Pharmacology ,Citric Acid ,Statistics, Nonparametric ,chemistry.chemical_compound ,Internal medicine ,Organometallic Compounds ,medicine ,Humans ,Prostaglandin E2 ,Aged ,Cathartics ,business.industry ,Senna Extract ,Prostanoic Acids ,Gastroenterology ,Middle Aged ,medicine.disease ,Ulcerative colitis ,Diarrhea ,Endocrinology ,chemistry ,Colitis, Ulcerative ,Female ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,business ,medicine.drug ,Prostaglandin E - Abstract
Objective: To assess the production of prostaglandin E2, an important chemical mediator in diarrhea induced by laxative administration, a prostaglandin E-main urinary metabolite (7α-hydroxy-5,11-diketotetranor-prosta-1,16-dioic acid, PGE-MUM) was measured in healthy volunteers and compared with the values of patients with ulcerative colitis. Methods: PGE-MUM was determined by a simplified immunoassay of bicyclic PGE-MUM and analyzed for the influence of laxative administration and active/remission phases of ulcerative colitis. Results: Administration of laxatives induced a significant increase in PGE-MUM in healthy volunteers. A significant elevation was also found in the active as compared with the remission phase of ulcerative colitis. The PGE-MUM levels were significantly correlated with our modified Talstad scores, clinical disease activity indices in ulcerative colitis. It was confirmed by time course studies of individual patients that changes in PGE-MUM correlated well with colitis activity. Conclusion: Laxative administration induces production of prostaglandin E2 as one of the chemical mediators, although its production grade is relatively low as compared with ulcerative colitis in the active phase.
- Published
- 2000
16. Enhancement of cell proliferation and prostaglandin biosynthesis by 1,8- dihydroxyanthraquinone in the rat large intestine
- Author
-
Y Kase, A Nishikawa, Jun Kanno, T Hayakawa, T Yanagisawa, and Yuzo Hayashi
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Prostaglandin ,Anthraquinones ,Biology ,Dinoprostone ,Excretion ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Large intestine ,Intestine, Large ,Intestinal Mucosa ,Prostaglandin E2 ,Gastrointestinal tract ,Cathartics ,Body Weight ,Dantron ,Prostanoic Acids ,General Medicine ,Rats, Inbred F344 ,Small intestine ,Rats ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Toxicity ,lipids (amino acids, peptides, and proteins) ,Cell Division ,medicine.drug - Abstract
The effects of 1,8-dihydroxyanthraquinone (DHAQ), a stimulant laxative named danthron, on cell kinetics and prostaglandin (PG) biosynthesis in the gastrointestinal tract were investigated in male 8-week-old F344 rats divided into three groups, each consisting of 10 animals. The animals in groups one, two and three were respectively given diets supplemented with 0%, 0.1% and 0.2% DHAQ for 24 days. PGE 2 levels in the colorectal mucosa were significantly (P < 0.05 and 0.001) elevated after DHAQ treatment and showed some evidence of a dependence of DHAQ dose, consistent with the plasma PGE 2 levels. BrdU-labeling indices in the large intestinal epithelium were also significantly (P < 0.01) increased, although the other portions of the gut such as the stomach and small intestine were not significantly affected. Excretion of the main urinary metabolite of PGE (PGE-MUM) was significantly (P < 0.001 or 0.01) increased whereas the urinary PGE 2 concentration and total PGE 2 excretion were not changed. Thus the results of the present study clearly indicate enhancement of cell proliferation by DHAQ in the large intestine epithelia, correlated with increased PGE 2 levels in the large intestinal mucosa as well as the plasma, and possible support for the conclusion that quantitative analysis of urinary PGE-MUM, but not PGE 2 itself, offer a useful approach for biomonitoring exposure to such stimulant laxatives.
- Published
- 1997
17. Kinetics of the Interaction of Nonsteroidal Antiinflammatory Drugs with Prostaglandin Endoperoxide Synthase-1 Studied by Limited Proteolysis
- Author
-
Amit S. Kalgutkar, Brenda C. Crews, and Lawrence J. Marnett
- Subjects
Conformational change ,Protein Conformation ,Stereochemistry ,Proteolysis ,Kinetics ,Ibuprofen ,Cleavage (embryo) ,Biochemistry ,chemistry.chemical_compound ,Prostaglandin-Endoperoxide Synthase ,medicine ,Cyclooxygenase Inhibitors ,Trypsin ,skin and connective tissue diseases ,Nitrobenzenes ,Sulfonamides ,Arachidonic Acid ,Nonsteroidal ,Molecular Structure ,medicine.diagnostic_test ,Anti-Inflammatory Agents, Non-Steroidal ,Prostanoic Acids ,Thiazoles ,chemistry ,Prostaglandin-Endoperoxide Synthases ,Hemin ,lipids (amino acids, peptides, and proteins) ,sense organs ,Protein Binding - Abstract
Many nonsteroidal antiinflammatory agents (NSAIDs) bind to prostaglandin endoperoxide synthase (PGHS) and induce a conformational change in the PGHS apoprotein that renders it resistant to cleavage by trypsin at Arg277. In the present study, the trypsin protection assay was modified to permit detection of conformational changes at times as short as 5 s after the addition of inhibitor. The kinetics of the induction and reversal of trypsin resistance in apoPGHS-1 by a series of NSAIDs and isozyme-specific PGHS-1 and PGHS-2 inhibitors were determined. All compounds induced resistance to trypsin cleavage at a rapid rate. The conformational change induced by competitive inhibitors was reversed on prolonged incubation with trypsin (approximately 5 min). In contrast, the resistance induced by irreversible inhibitors was not lost during a 5 min incubation with trypsin. All of the selective PGHS-2 inhibitors protected against tryptic cleavage of apoPGHS-1 but did not inhibit the protein's cyclooxygenase activity. The results suggest that induction of trypsin resistance is a reflection of the initial association of reversible as well as irreversible inhibitors with the apoprotein.
- Published
- 1996
18. Comparison of the EP receptor subtypes mediating relaxation of the rabbit jugular and pig saphenous veins
- Author
-
S A Milne, D.F. Woodward, and Roma A. Armstrong
- Subjects
Male ,Prostaglandins F ,medicine.medical_specialty ,Swine ,Muscle Relaxation ,Prostaglandin E2 receptor ,EP4 Receptor ,Stimulation ,Biology ,Biochemistry ,Cyclase ,Muscle, Smooth, Vascular ,Endocrinology ,16,16-Dimethylprostaglandin E2 ,Jugular vein ,Internal medicine ,medicine ,Animals ,Receptors, Prostaglandin E ,Saphenous Vein ,Alprostadil ,Receptor ,Biphenyl Compounds ,Prostanoic Acids ,Antagonist ,Prostaglandins F, Synthetic ,lipids (amino acids, peptides, and proteins) ,Endothelium, Vascular ,Rabbits ,Jugular Veins - Abstract
A fourth PGE receptor subtype, the EP4 receptor, has recently been described in the pig saphenous vein (PSV). Similar to the EP2 receptor, it mediates relaxation and is linked to stimulation of adenylate cyclase. The aim of this study was to determine whether or not the EP receptor present in the rabbit jugular vein (RJV), currently classified as an atypical EP2 receptor, is of the EP4 subtype. The relaxant activities of four EP2 agonists, 11-deoxy PGE1, 16,16-dimethyl PGE2, butaprost, and AH 13205, on the RJV and PSV have been examined, and the effect of the EP4 receptor antagonist AH 23,848B studied. The EP2 agonists showed a similar order of potency on the two preparations. 11-Deoxy PGE1 and 16,16-dimethyl PGE2 were potent agonists on the EP4 receptors of the PSV and on the RJV giving approximately equi-effective concentration ratios (EECs) of 2.0-6.6 and 2.8-9.9, respectively, compared to PGE2 (EEC = 1), and so do not discriminate between EP2 and EP4 receptors. Butaprost was less active on these preparations (EEC 42-43) than on classical EP2 receptors, and AH 13205 was much less active (EEC 3100-2780). While these results suggest that the EP receptors on the RJV are of the EP4 subtype, this was not confirmed using the EP4 receptors antagonist AH 23,848B.
- Published
- 1995
19. Characterization of the prostaglandin E2 sensitive (EP)-receptor in the rat isolated trachea
- Author
-
K. McKechnie and S.J. Lydford
- Subjects
Male ,Prostaglandins E, Synthetic ,Agonist ,medicine.medical_specialty ,medicine.drug_class ,Muscle Relaxation ,In Vitro Techniques ,Dinoprostone ,Rats, Sprague-Dawley ,Thromboxane A2 ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Receptors, Prostaglandin E ,Prostaglandin E2 ,Receptor ,Prostaglandin receptor ,Pharmacology ,Biphenyl Compounds ,Prostanoic Acids ,Antagonist ,Muscle, Smooth ,Receptor antagonist ,Prostaglandin Endoperoxides, Synthetic ,Rats ,Trachea ,Endocrinology ,Muscle relaxation ,chemistry ,Heptanoic Acids ,15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ,lipids (amino acids, peptides, and proteins) ,Prostaglandin D2 ,Research Article ,Muscle Contraction ,medicine.drug - Abstract
1. Using a range of natural and synthetic prostanoid receptor agonists and antagonists, we have shown that the rat isolated trachea contains a heterogeneous population of prostaglandin receptor sub-types mediating both relaxation and contraction of the smooth muscle. Prostaglandin E2 (PGE2) elicits smooth muscle relaxation of pre-contracted preparations, the responses being well defined, with a mean potency (p[A50]) of 7.81 +/- 0.05. 2. 11-deoxy PGE1 16,16-dimethyl PGE2 and misoprostol were all full agonists at this receptor, whilst AH13205 was a low potency agonist, and sulprostone was inactive. 3. The EP1 receptor antagonist, AH6809 (5 microM), and the selective DP receptor antagonist, BW A868C (0.1 microM), had no significant effect on the concentration-effect (E/[A]) curves to PGE2. 4. The putative EP4-receptor antagonist, AH23848B, produced non-competitive antagonism of the PGE2 response curves; pA2 values of 5.07 +/- 0.15 and 5.24 +/- 0.19 were obtained at concentrations of 30 microM and 100 microM respectively. 5. The synthetic thromboxane A2 mimetic, U46619, caused smooth muscle contractions, with a mean p[A50] of 6.90 +/- 0.11. This response was antagonized by the TP receptor antagonist, GR32191B, yielding a mean pA2 of 8.31. 6. At concentrations of 1 microM and above, prostaglandin D2 (PGD2) and the IP-receptor agonist, cicaprost, generally elicited concentration-dependent relaxations of the rat trachea. Prostaglandin F2 alpha (PGF2 alpha) was without affinity or efficacy. 7. These data suggest that the rat isolated trachea contains EP-receptors, TP-receptors, and few, if any DP, IP or FP-receptors. The inactivity of sulprostone (EP3/EPj receptor selective) and the low potency of AH1 3205 (EP2-receptor selective) suggest that the rat trachea contains an atypical EP-receptor that does not conform to the current classification system.
- Published
- 1994
20. The contractile mechanism of beraprost sodium, a stable prostacyclin analog, in the isolated canine femoral vein
- Author
-
Michiro Ishikawa and Atsushi Namiki
- Subjects
Male ,medicine.medical_specialty ,Contraction (grammar) ,Femoral vein ,Prostaglandin ,Prostacyclin ,In Vitro Techniques ,Dinoprost ,urologic and male genital diseases ,Norepinephrine ,Thromboxane A2 ,chemistry.chemical_compound ,Dogs ,Internal medicine ,medicine ,Animals ,Vasoconstrictor Agents ,Dose-Response Relationship, Drug ,biology ,business.industry ,Fissipedia ,Prostanoic Acids ,Femoral Vein ,biology.organism_classification ,Epoprostenol ,Acetylcholine ,Prostaglandin Endoperoxides, Synthetic ,Beraprost ,Femoral Artery ,Schild regression ,Endocrinology ,chemistry ,Vasoconstriction ,15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ,Potassium ,cardiovascular system ,Female ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine ,business ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
The vascular contractile mechanism of prostacyclin (PGI2) was investigated using beraprost sodium (BPS), a stable PGI2 analog. Ring strips without endothelium isolated from canine femoral veins and arteries were used. BPS induced a dose-dependent contraction without precontraction and after precontraction with norepinephrine (NE) or 60 mM K+ in the veins. In contrast, BPS induced a dose-dependent relaxation after precontraction with U46619, a thromboxane A2 (TXA2) analog, or prostaglandin F2 alpha (PGF2 alpha) in the veins. In the arteries, BPS induced contraction at higher concentrations after precontraction with NE. However, BPS relaxed arteries dose-dependently after precontraction with PGF2 alpha. By pretreatment with 13-azaprostanoic acid (13-APA), a TXA2/endoperoxide receptor antagonist, the dose-response curve of BPS in the veins was shifted to the right. Schild plot analysis resulted in a linear regression with a slope of 0.86 +/- 0.13, which was not significantly different from unity, and the pA2 value for 13-APA against BPS was 7.10 +/- 0.06. By pretreatment with BPS, the dose-response curve of U46619 in the veins was shifted to the right. Kaumann plot analysis resulted in a linear regression with a slope of 0.89 +/- 0.09, which was not significantly different from unity, and the pA2 value for BPS against U46619 was 5.68 +/- 0.04. These findings indicate that BPS is a partial agonist for the TXA2/endoperoxide receptors.
- Published
- 1994
21. EP4 receptor as a new target for bronchodilator therapy
- Author
-
Deborah L. Clarke, James Buckley, Sarah A. Maher, Mark A. Birrell, Anthony T. Nials, and Maria G. Belvisi
- Subjects
Relaxation ,respiratory muscles ,asthma pharmacology ,Pharmacology ,Rats, Sprague-Dawley ,Mice ,Pulmonary Disease, Chronic Obstructive ,0302 clinical medicine ,Bronchodilator ,Medicine ,Receptor ,0303 health sciences ,Prostanoic Acids ,prostanoid receptors ,airway smooth muscle ,Phenylbutyrates ,Bronchodilator Agents ,3. Good health ,Trachea ,Hydrazines ,Fatty Acids, Unsaturated ,Airway Biology ,Regression Analysis ,lipids (amino acids, peptides, and proteins) ,Methyl Ethers ,Pulmonary and Respiratory Medicine ,Agonist ,medicine.drug_class ,Xanthones ,Prostaglandin E2 receptor ,Guinea Pigs ,EP4 Receptor ,Prostanoic acid ,Naphthalenes ,Phenylbutyrate ,Dinoprostone ,Guinea pig ,03 medical and health sciences ,Species Specificity ,Animals ,Humans ,Receptors, Prostaglandin E ,Alprostadil ,prostanoids ,030304 developmental biology ,business.industry ,Bridged Bicyclo Compounds, Heterocyclic ,Asthma ,Rats ,Mice, Inbred C57BL ,Macaca fascicularis ,030228 respiratory system ,Immunology ,business - Abstract
Background Asthma and chronic obstructive pulmonary disease are airway inflammatory diseases characterised by airflow obstruction. Currently approved bronchodilators such as long-acting β 2 adrenoceptor agonists are the mainstay treatments but often fail to relieve symptoms of chronic obstructive pulmonary disease and severe asthma and safety concerns have been raised over long-term use. The aim of the study was to identify the receptor involved in prostaglandin E 2 (PGE 2 )-induced relaxation in guinea pig, murine, monkey, rat and human airways in vitro . Methods Using an extensive range of pharmacological tools, the relaxant potential of PGE 2 and selective agonists for the EP 1–4 receptors in the presence and absence of selective antagonists in guinea pig, murine, monkey, rat and human isolated airways was investigated. Results In agreement with previous studies, it was found that the EP 2 receptor mediates PGE 2 -induced relaxation of guinea pig, murine and monkey trachea and that the EP 4 receptor mediates PGE 2 -induced relaxation of the rat trachea. These data have been confirmed in murine airways from EP 2 receptor-deficient mice ( Ptger2 ). In contrast to previous publications, a role for the EP 4 receptor in relaxant responses in human airways in vitro was found. Relaxant activity of AH13205 (EP 2 agonist) was also demonstrated in guinea pig but not human airway tissue, which may explain its failure in clinical studies. Conclusion Identification of the receptor mediating PGE 2 -induced relaxation represents a key step in developing a novel bronchodilator therapy. These data explain the lack of bronchodilator activity observed with selective EP 2 receptor agonists in clinical studies.
- Published
- 2011
22. Characterization of the inhibitory prostanoid receptors on human neutrophils
- Author
-
Alan Wheeldon and C.J. Vardey
- Subjects
Agonist ,Prostaglandin Antagonists ,Neutrophils ,Leukotriene B4 ,medicine.drug_class ,Xanthones ,Prostaglandin E2 receptor ,Receptors, Prostaglandin ,Prostanoic acid ,In Vitro Techniques ,Pharmacology ,chemistry.chemical_compound ,Oxygen Consumption ,Superoxides ,medicine ,Humans ,Prostaglandin E2 ,Receptor ,Hydantoins ,Zymosan ,Prostanoic Acids ,Prostanoid ,N-Formylmethionine Leucyl-Phenylalanine ,Xanthenes ,chemistry ,Biochemistry ,Prostaglandins ,lipids (amino acids, peptides, and proteins) ,Misoprostol ,Research Article ,medicine.drug - Abstract
1. We have evaluated the effects of various prostanoid agonists on the release of leukotriene B4 (LTB4) and superoxide anions (O2-) from human neutrophils stimulated with opsonized zymosan (OZ) and formyl-methionyl-leucyl-phenylalanine (FMLP), respectively. 2. Prostaglandin E2 (PGE2) and PGD2 inhibited both OZ-induced LTB4 release (EC50 0.72 microM and 0.91 microM respectively), and FMLP-induced O2- release (EC50 0.42 microM and 0.50 microM respectively). PGF2 alpha, the TP-receptor agonist, U46619, and the IP-receptor agonist, iloprost, were also active, but were all at least an order of magnitude less potent than PGE2 and PGD2. 3. The EP2/EP3-receptor agonist, misoprostol, and the selective EP2-agonist, AH13205, were both effective inhibitors of LTB4 release, being approximately equipotent with and 16-times less potent than PGE2, respectively. In contrast, the EP1/EP3-receptor agonist, sulprostone, had no inhibitory activity at concentrations of up to 10 microM. 4. The selective DP-receptor agonist, BW245C, inhibited LTB4 release, (EC50 0.006 microM) being approximately 50 times more potent than PGD2. BW245C also inhibited O2- release, and this inhibition was antagonized competitively by the DP-receptor blocking drug, AH6809 (pA2 6.6). 5. These data indicate the presence of both inhibitory EP- and DP-receptors on the human neutrophil. The rank order of potency of EP-receptor agonists suggest that the EP-receptors are of the EP2-subtype.
- Published
- 1993
23. Inhibition of ovulation in the gonadotropin-primed immature rat by exogenous prostaglandin E2
- Author
-
N. Tanaka, H. Okamura, S. Stacy, and Lawrence L. Espey
- Subjects
Male ,Ovulation ,medicine.medical_specialty ,medicine.drug_class ,media_common.quotation_subject ,medicine.medical_treatment ,Indomethacin ,Prostaglandin ,Alpha (ethology) ,Ovary ,Prostanoic acid ,Biology ,Biochemistry ,Dinoprostone ,chemistry.chemical_compound ,Endocrinology ,Ovulation Induction ,Internal medicine ,medicine ,Animals ,Prostaglandin E2 ,media_common ,Prostanoic Acids ,Rats, Inbred Strains ,Rats ,medicine.anatomical_structure ,chemistry ,Female ,lipids (amino acids, peptides, and proteins) ,Ovulation induction ,Gonadotropin ,medicine.drug - Abstract
In the past two decades there have been innumerable reports that prostaglandins (PGs) are essential for mammalian ovulation. However, we have recently found that a relatively low dose of 0.03 mg indomethacin (INDO) sc to PMSG/hCG-primed immature Wistar rats can significantly reduce ovarian PG levels without inhibiting the control ovulation rate of 60+ ova/rat (1-3). In view of this information, the present study was an effort to duplicate the earlier reports that PGs can reverse the "inhibitory" effect of INDO on ovulation. In control animals, which received PMSG and hCG only, the ovulation rate was 63.8 +/- 4.5 ova/rat. This rate was reduced to 4.1 +/- 1.1 ova/rat when the animals were injected with 1.0 mg INDO at 3 h after hCG. In no instance was this inhibition reversed when the animals were treated with 1.0 mg of PGE2 or PGF2 alpha, or a combination of both prostanoids in either a single dose at 3 h after hCG, or in 4x doses at 2-h intervals beginning at 3 h after hCG. Furthermore, in animals that did not receive INDO, the ovulation rate in PGE2-treated animals was reduced to 20.0 +/- 6.7 ova/rat, and in animals treated with PGE2 and PGF2 alpha (combined) it was reduced to 19.4 +/- 6.5 ova/rat. In summary, not only did the PGs fail to reverse the anti-ovulatory effect of INDO, PGE2 actually suppressed the ovulation rate.
- Published
- 1992
24. Differences between in vivo and in vitro production of eicosanoids following long-term dietary fish oil supplementation in the rat
- Author
-
Mahinda Y. Abeywardena, Peter L McLennan, and John S. Charnock
- Subjects
medicine.medical_specialty ,Clinical Biochemistry ,Dietary lipid ,Endogeny ,In Vitro Techniques ,Biology ,Kidney ,Thromboxane A2 ,Fish Oils ,Internal medicine ,medicine ,Animals ,Vitamin E ,Phospholipids ,chemistry.chemical_classification ,Myocardium ,Prostanoic Acids ,Kidney metabolism ,Fatty acid ,Rats, Inbred Strains ,Cell Biology ,Fish oil ,Dietary Fats ,Epoprostenol ,Rats ,Endocrinology ,Eicosanoid ,chemistry ,Eicosanoids ,lipids (amino acids, peptides, and proteins) ,Polyunsaturated fatty acid ,Eicosanoid Production - Abstract
The effects of different lipid supplements on endogenous and exogenous production of eicosanoids were investigated in the rat following a 12-month pre-feeding period. The urinary excretion of tetranorprostanemonoic (TPM) and tetranorprostanedioic (TPD) acids was measured as an index of endogenous production whilst myocardial release of PGI2 and TXA2 was estimated under in vitro conditions. Compared to the reference group, n-3 PUFA rich tuna fish oil (TFO) fed rats displayed a near doubling of endogenous (TPM + TPD) synthesis; however, myocardial production was reduced by 32% (PGI2) and 55% (TXA2). Sheep fat supplementation also caused a 62% rise in urinary tetranor metabolites but in contrast to TFO feeding, myocardial production in vitro also showed a significant increase (P less than 0.05). Considerable changes in PUFA profile of plasma, heart and kidney occurred as a result of dietary lipid treatment and in addition a high tissue specificity was also noted with regard to the incorporation and conversion of dietary n-3 PUFA. For example, the heart showed a low EPA (1.2%) and high DHA (28.0%), whereas their proportions in the kidney were near equal (6-7%). As only the TFO diet exerted a significant effect on the proportion of AA, the changes in eicosanoid production cannot be fully explained on the basis of precursor/inhibitor availability. The results probably reflect the complex interactions between fatty acid substrates, release mechanisms and biosynthetic enzymes.
- Published
- 1991
25. Endothelium-dependent and -independent relaxations to adenosine in guinea pig aorta
- Author
-
Robert M. Berne and J. P. Headrick
- Subjects
Male ,Adenosine ,Physiology ,Muscle Relaxation ,Guinea Pigs ,Aorta, Thoracic ,Coronary Disease ,Endothelium dependent ,Pharmacology ,Nitric Oxide ,Muscle, Smooth, Vascular ,Physiology (medical) ,medicine ,Animals ,Hypoxia ,Chemistry ,Guinea pig aorta ,Prostanoic Acids ,Hypoxia (medical) ,Endothelium, Vascular ,Sodium nitroprusside ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Muscle Contraction ,medicine.drug - Abstract
Effects of endothelial removal and hypoxia on responses to adenosine, 5'-(N-ethylcarboxamido)-adenosine (NECA), 2-chloroadenosine, N6-cyclohexyladenosine (CHA), sodium nitroprusside, and acetylcholine were examined in guinea pig aortic rings. Rings contracted with 2 microM prostaglandin F2 alpha (PGF2 alpha) relaxed in a dose-dependent manner in response to all drugs. The order of potency of adenosine compounds was NECA greater than 2-chloroadenosine greater than adenosine greater than CHA. Endothelial rubbing potentiated the PGF2 alpha response by 11 +/- 3%, eliminated the acetylcholine (ACh) response, but had no effect on nitroprusside and CHA responses. Responses to adenosine, NECA, and 2-chloroadenosine were significantly depressed by rubbing (P less than 0.05). Oxyhemoglobin (5 microM) and metyrapone (0.1 mM) reduced ACh responses in intact rings but had no effect on the adenosine and nitroprusside responses. Indomethacin treatment (10 microM) did not alter ACh, nitroprusside, or adenosine responses in intact rings. Hypoxia (10% O2) potentiated maximal responses to adenosine (+26 +/- 3%) and nitroprusside (+28 +/- 4%) in intact and rubbed rings and reduced the maximal response to ACh in intact rings (-28 +/- 3%). It is concluded that 1) adenosine mediates relaxation in guinea pig aorta by endothelial-dependent and -independent mechanisms, 2) receptors involved in both endothelial-dependent and -independent relaxations are characteristic of the A2 adenosine subtype, 3) the endothelial response appears unrelated to EDRF or prostanoid release, and 4) the adenosine response is significantly potentiated by hypoxia.
- Published
- 1990
26. Tetranor PGDM, an abundant urinary metabolite reflects biosynthesis of prostaglandin D2 in mice and humans
- Author
-
Muredach P. Reilly, Emanuela Ricciotti, Garret A. FitzGerald, Ying Yu, Miao Wang, Wen-Liang Song, Susanne Fries, Tilo Grosser, and John A. Lawson
- Subjects
Male ,medicine.medical_specialty ,Lipopolysaccharide ,Metabolite ,Biochemistry ,Mass Spectrometry ,chemistry.chemical_compound ,Lactones ,Mice ,Internal medicine ,medicine ,Animals ,Humans ,Cyclooxygenase Inhibitors ,Sulfones ,Receptor ,Molecular Biology ,Chromatography, High Pressure Liquid ,Mice, Knockout ,biology ,Prostaglandin D2 ,Prostanoic Acids ,Prostanoid ,Cell Biology ,Lipocalins ,Intramolecular Oxidoreductases ,Mice, Inbred C57BL ,Endocrinology ,chemistry ,biology.protein ,Arachidonic acid ,Cyclooxygenase ,Dimerization ,Niacin - Abstract
Prostaglandin D(2) (PGD(2)) is a cyclooxygenase (COX) product of arachidonic acid that activates D prostanoid receptors to modulate vascular, platelet, and leukocyte function in vitro. However, little is known about its enzymatic origin or its formation in vivo in cardiovascular or inflammatory disease. 11,15-dioxo-9alpha-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acid (tetranor PGDM) was identified by mass spectrometry as a metabolite of infused PGD(2) that is detectable in mouse and human urine. Using liquid chromatography-tandem mass spectrometry, tetranor PGDM was much more abundant than the PGD(2) metabolites, 11beta-PGF(2alpha) and 2,3-dinor-11beta-PGF(2alpha), in human urine and was the only endogenous metabolite detectable in mouse urine. Infusion of PGD(2) dose dependently increased urinary tetranor PGDM2,3-dinor-11beta-PGF(2alpha)11beta-PGF(2alpha) in mice. Deletion of either lipocalin-type or hemopoietic PGD synthase enzymes decreased urinary tetranor PGDM. Deletion or knockdown of COX-1, but not deletion of COX-2, decreased urinary tetranor PGDM in mice. Correspondingly, both PGDM and 2,3-dinor-11beta-PGF(2alpha) were suppressed by inhibition of COX-1 and COX-2, but not by selective inhibition of COX-2 in humans. PGD(2) has been implicated in both the development and resolution of inflammation. Administration of bacterial lipopolysaccharide coordinately elevated tetranor PGDM and 2,3-dinor-11beta-PGF(2alpha) in volunteers, coincident with a pyrexial and systemic inflammatory response, but both metabolites fell during the resolution phase. Niacin increased tetranor PGDM and 2,3-dinor-11beta-PGF(2alpha) in humans coincident with facial flushing. Tetranor PGDM is an abundant metabolite in urine that reflects modulated biosynthesis of PGD(2) in humans and mice.
- Published
- 2007
27. Effects of anoxia and hypoxia on amyloid precursor protein processing in cerebral microvascular smooth muscle cells
- Author
-
Harry V. Vinters and Ilene D. Auerbach
- Subjects
medicine.medical_specialty ,Time Factors ,ADAM10 ,Blotting, Western ,Myocytes, Smooth Muscle ,Biology ,ADAM17 Protein ,Muscle, Smooth, Vascular ,Pathology and Forensic Medicine ,Cellular and Molecular Neuroscience ,ADAM10 Protein ,Amyloid beta-Protein Precursor ,Internal medicine ,mental disorders ,medicine ,Amyloid precursor protein ,Myocyte ,Humans ,Immunoprecipitation ,RNA, Messenger ,Hypoxia ,Cells, Cultured ,Cerebral Cortex ,Metalloproteinase ,Reverse Transcriptase Polymerase Chain Reaction ,Prostanoic Acids ,Membrane Proteins ,General Medicine ,Hypoxia (medical) ,medicine.disease ,ADAM Proteins ,Endocrinology ,Neurology ,Biochemistry ,Gene Expression Regulation ,biology.protein ,Neurology (clinical) ,Cerebral amyloid angiopathy ,medicine.symptom ,Amyloid Precursor Protein Secretases ,Amyloid precursor protein secretase - Abstract
Cerebral amyloid angiopathy (CAA) is characterized by the degeneration of cerebral microvascular smooth muscle cells (MV-SMC) and the replacement of normal vessel wall components by beta-amyloid (Abeta) protein. Little is known regarding the mechanisms of SMC degeneration in CAA. The effects of anoxia on the metabolism of the amyloid precursor protein (APP) were studied to investigate the MV-SMC response to anoxic stress and its possible role in the pathogenesis of CAA. MV-SMC exposed to chronic anoxia (24-48 hours) showed a decrease in expression of the 2 putative alpha-secretase enzymes, mature TACE (TNFalpha-converting enzyme) and ADAM10 (a disintegrin and metalloprotease). A concomitant decrease in the alpha-secretase cleavage products sAPPalpha and C83 was observed. Investigation of mRNA expression showed an increase in TACE and a sharp decrease in ADAM10 at 24 hours. Exposing MV-SMC to hypoxia (1% O2) revealed a different pattern of expression with no significant change in TACE protein, but an increase in TACE mRNA occurring at a later time point (48 hours). There was no change in ADAM10 mRNA expression, but a reduction in mature ADAM10 with a parallel increase in immature ADAM10 protein. These results demonstrate a requirement for oxygen in the regulation of the alpha-secretase pathway during APP metabolism.
- Published
- 2006
28. Cobalt(diamine)-Catalyzed Cross-Coupling Reaction of Alkyl Halides with Arylmagnesium Reagents: Stereoselective Constructions of Arylated Asymmetric Carbons and Application to Total Synthesis of AH13205
- Author
-
Koichiro Oshima, Hirohisa Ohmiya, and Hideki Yorimitsu
- Subjects
chemistry.chemical_element ,Biochemistry ,Medicinal chemistry ,Radical cyclization ,Catalysis ,Coupling reaction ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Organometallic Compounds ,Organic chemistry ,Magnesium ,Alkyl ,chemistry.chemical_classification ,Hydrocarbons, Halogenated ,Aryl ,Prostanoic Acids ,Total synthesis ,Stereoisomerism ,General Chemistry ,Cobalt ,General Medicine ,Oxidative addition ,chemistry ,Cyclization - Abstract
A cobalt-diamine complex catalyzes the cross-coupling reactions of primary and secondary alkyl halides with aryl Grignard reagents. It is confirmed that oxidative addition of alkyl halide to cobalt proceeds via a radical process. Optically pure Ueno-Stork halo acetals undergo diastereoselective cross-coupling reactions, the products of which are transformed into optically active THF derivatives. A sequential radical cyclization/arylation reaction under cobalt catalysis provides extremely short access to a synthetic prostaglandin AH13205.
- Published
- 2006
29. Synthesis, immunomodulating activity and (1)H NMR studies of 7-oxo-9,11-ethano-13-azaprostanoids
- Author
-
Natalia F. Bondar, M. B. Golubeva, Boleslav Kuzmitsky, Gennadi S. Lyubin, Lyudmila P. Isaenya, and Nicolay A. Konoplya
- Subjects
Magnetic Resonance Spectroscopy ,medicine.drug_class ,Stereochemistry ,Prostaglandin Endoperoxides ,Chemical synthesis ,Aminoketone ,Bridged Bicyclo Compounds ,Mice ,Immune system ,In vivo ,Drug Discovery ,medicine ,Animals ,Pharmacology ,B-Lymphocytes ,Bicyclic molecule ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,Prostanoic Acids ,General Medicine ,In vitro ,Proton NMR ,Mice, Inbred CBA ,Female ,Aliphatic compound ,Spleen ,Hydrogen - Abstract
Novel 9,11-ethano analogues of prostaglandin endoperoxides with a nitrogen in position 13 were synthesized. (1)H NMR spectra of the obtained compounds were studied. All prostanoids administered perorally at doses of 2.5-10.0 microg x kg(-1) had specific dose-dependent effects on the B-cellular immunity estimated under in vivo conditions on the model of the B-cellular immune response. In terms of the direction of their activities, eight of the studied compounds were found to be immunostimulators, whereas other three compounds displayed immunosuppressing effect. Two of the compounds increased the amount of antibody-forming cells (AFC) per 10(6) spleen cells by 1.9 times in comparison with the respective parameter of control group.
- Published
- 2003
30. Influence of dietary linoleic acid intake with different fat intakes on arachidonic acid concentrations in plasma and platelet lipids and eicosanoid biosynthesis in female volunteers
- Author
-
O. Adam, Günther Wolfram, and N. Zöllner
- Subjects
Adult ,Blood Platelets ,medicine.medical_specialty ,Time Factors ,Platelet Aggregation ,Linolenic acid ,Linoleic acid ,Medicine (miscellaneous) ,Prostaglandin ,Statistics, Nonparametric ,Linoleic Acid ,chemistry.chemical_compound ,Dietary Fats, Unsaturated ,Reference Values ,Internal medicine ,medicine ,Humans ,Platelet ,Phospholipids ,Nutrition and Dietetics ,Arachidonic Acid ,Linoleic acid intake ,Healthy subjects ,Prostanoic Acids ,Thromboxanes ,Endocrinology ,chemistry ,Biochemistry ,Prostaglandins ,Eicosanoids ,lipids (amino acids, peptides, and proteins) ,Arachidonic acid ,Female ,Eicosanoid biosynthesis - Abstract
Background/Aim: N-6 fatty acids are considered to promote diseases prevalent in industrialized countries and characterized by an increased eicosanoid biosynthesis from arachidonic acid (AA). We investigated the impact of the linoleic acid (LA) intake on AA levels in humans. Methods: Six healthy female volunteers (age range 23–34 years) were given liquid formula diets (LFD) devoid of AA for 6 weeks, providing a constant intake of zero energy% (LFD 0: protein 15%, carbohydrates 85%) or 20 energy% (LFD 20: protein 15%, carbohydrates 55%, fat 30%) LA, for 3 weeks each. Fatty acids of plasma cholesteryl esters and platelet lipids were determined each week, and the prostaglandin biosynthesis was measured in 24-hour urine samples. Results: LFD 0 increased (+31% of initial value) and LFD 20 lowered (–30% of initial value) the percentage of AA in plasma cholesteryl esters and platelet lipids. Moreover, absence of dietary AA lowered the percentages of AA in plasma (–31% week 0 vs. week 6) and platelet (–11%) lipids, indicating a low transformation of LA. LFD 0 reduced urinary metabolite levels of prostaglandins D, E, and F in 24-hour urine samples (–48%, p < 0.001) within 24 h, but did not significantly affect platelet aggregation (–10%) and thromboxane formation (–25%). LFD 20 significantly lowered platelet aggregation (–25%) and thromboxane formation (–43%). The prostaglandin metabolite levels increased during the first 10 days, declined thereafter, and were lower than the preexperimental values at the end of the 3-week period. Conclusions: The results show that dietary LA does not increase the AA levels in plasma or platelet lipids and does not persistently contribute to prostaglandin biosynthesis which is increased by AA intake with Western diets.
- Published
- 2001
31. 7-Oxabicycloheptylprostanoic acids: potent, time-dependent cyclooxygenase inhibitors that induce a conformational change in the prostaglandin endoperoxide synthase protein
- Author
-
Indrani Pal, Rebecca Odenwaller, and Lawrence J. Marnett
- Subjects
Male ,Conformational change ,Protein Conformation ,Prostaglandin ,Prostanoic acid ,chemistry.chemical_compound ,Protein structure ,Drug Discovery ,medicine ,Animals ,Cyclooxygenase Inhibitors ,chemistry.chemical_classification ,Sheep ,biology ,Chemistry ,Prostanoic Acids ,Seminal Vesicles ,Enzyme ,Biochemistry ,Mechanism of action ,Prostaglandin-Endoperoxide Synthases ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Cyclooxygenase ,medicine.symptom - Published
- 1992
32. Synthesis of (±)-Homosarkomycin and (±)-Rosaprostol
- Author
-
Tsutomu kainuki, Mitsuru Nakayama, and Shinji Tanimori
- Subjects
Cyclopropanes ,Magnetic Resonance Spectroscopy ,Stereochemistry ,Carboxylic acid ,Cyclopentanes ,Ring (chemistry) ,Applied Microbiology and Biotechnology ,Biochemistry ,Analytical Chemistry ,Cyclopropane ,chemistry.chemical_compound ,Nucleophile ,Prostaglandins, Synthetic ,Methods ,Homosarkomycin ,Molecular Biology ,chemistry.chemical_classification ,Addition reaction ,Organic Chemistry ,Prostanoic Acids ,Stereoisomerism ,General Medicine ,Rosaprostol ,chemistry ,Indicators and Reagents ,Enone ,Biotechnology - Abstract
(±)-Homosarkomycin (2) and (±)-rosaprostol (3) were synthesized from (±)-methyl 2-oxo-bicyclo[3.1.0]hexane-1-carboxylate (1) by using the nucleophilic ring opening reaction on the double-activated cyclopropane ring as the key step.
- Published
- 1992
33. A new strategy for cyclopentenone synthesis
- Author
-
Barry M. Trost and Anthony B. Pinkerton
- Subjects
chemistry.chemical_classification ,Cyclopentenone ,Ketone ,Organic Chemistry ,Tetrahydrodicranenone B ,Prostanoic Acids ,Alkyne ,Esters ,Cyclopentanes ,Anti-Ulcer Agents ,Biochemistry ,Bryopsida ,Rosaprostol ,chemistry.chemical_compound ,chemistry ,Anti-Infective Agents ,Gastrointestinal Agents ,Prostaglandins, Synthetic ,Organic chemistry ,Physical and Theoretical Chemistry ,Antihypertensive Agents ,Expectorants - Abstract
[reaction--see text] A new strategy for the synthesis of 2,3-disubstituted cyclopentenones emerges from two key reactions-the ruthenium-catalyzed three-component coupling of an equivalent of HBr, an alkyne, and a vinyl ketone and the Ni-Cr Barbier type reaction. As a result, these important structures are readily accessed from an alkyne and a vinyl ketone (which derive directly from carboxylic acids). Syntheses of tetrahydrodicranenone B and rosaprostol illustrate the new strategy.
- Published
- 2000
34. Adrenaline potentiates type 2B von Willebrand factor-induced activation of human platelets by enhancing both the formation and action of thromboxanes
- Author
-
M. Francesconi, Renzo Deana, Margherita Scapin, Antonio Girolami, and Alessandra Casonato
- Subjects
Blood Platelets ,Serotonin ,medicine.medical_specialty ,Epinephrine ,Platelet Aggregation ,Thromboxane ,Lipoxygenase ,Prostanoic acid ,Serotonin secretion ,chemistry.chemical_compound ,Internal medicine ,von Willebrand Factor ,medicine ,Humans ,Vasoconstrictor Agents ,Platelet ,Platelet activation ,Phosphorylation ,Sympathomimetics ,Adrenergic alpha-Antagonists ,Arachidonic Acid ,Aspirin ,Chemistry ,Prostanoic Acids ,Thromboxanes ,Yohimbine ,Drug Synergism ,Hematology ,Platelet Activation ,Kinetics ,Endocrinology ,Prostaglandin-Endoperoxide Synthases ,15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ,Tyrosine ,Platelet aggregation inhibitor ,Calcium ,Arachidonic acid ,Platelet Aggregation Inhibitors - Abstract
Von Willebrand factor (vWF) is a large plasma glycoprotein that mediates platelet adhesion at sites of vascular injury. We have previously reported that the pathological type 2B (formerly named type IIB) variant of vWF promotes platelet activation through phospholipase A(2)-mediated release of arachidonic acid. The present report shows that adrenaline (1 microM) potentiates type 2B vWF-induced platelet aggregation, serotonin secretion, rise in cytosolic Ca(2+) concentration, and pleckstrin phosphorylation, as well as thromboxane B(2) production. The hormone also increases the partially inhibited release of serotonin observed in platelets pretreated with the anti-GPIIb-IIIa antibody LJCP8 but does remove the total inhibition on the secretion caused by the anti-GPIb antibody LJIB1. Adrenaline also increases type 2B vWF-elicited tyrosine phosphorylation of proteins with apparent molecular masses of 60 and 80 kDa. Furthermore, adrenaline potentiates the rise in cytosolic Ca(2+) and the release of thromboxane B(2) in platelets stimulated with arachidonic acid (2 microM) as well as the increase in Ca(2+) induced by the thromboxane mimetic U46619 (0.3 microM). Platelet pretreatment with yohimbine or 13-azaprostanoic acid, which are antagonists of the alpha(2)-adrenergic and thromboxane receptors, respectively, or with acetylsalicylate and indomethacin, both of which act as inhibitors of thromboxane formation, abolishes the potentiating effect of adrenaline. These observations lead to the conclusion that the potentiating action of adrenaline on type 2B vWF-promoted platelet responses is due to an increase in both the formation and activating action of thromboxanes.
- Published
- 2000
35. The isoprostanes: novel prostaglandin-like products of the free radical-catalyzed peroxidation of arachidonic acid
- Author
-
Arnold Stern, Jason D. Morrow, L. Jackson Roberts, and Tsan Liu
- Subjects
Isoprostane ,Free Radicals ,Arteriosclerosis ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Hypercholesterolemia ,Prostaglandin ,medicine.disease_cause ,Chemistry Techniques, Analytical ,Lipid peroxidation ,chemistry.chemical_compound ,Isomerism ,In vivo ,medicine ,Diabetes Mellitus ,Animals ,Humans ,Pharmacology (medical) ,Molecular Biology ,Homocysteine ,Arachidonic Acid ,Biochemistry (medical) ,Smoking ,Prostanoic Acids ,Thromboxanes ,Cell Biology ,General Medicine ,Isoprostanes ,Oxidative Stress ,chemistry ,Biochemistry ,Eicosanoid ,Prostaglandins ,Arachidonic acid ,Lipid Peroxidation ,Oxidative stress - Abstract
The isoprostanes (IsoPs) are a unique series of prostaglandin-like compounds formed in vivo from the free radical-catalyzed peroxidation of arachidonic acid. This review summarizes our current knowledge regarding these compounds. Novel aspects of the biochemistry and bioactivity of IsoPs are detailed and methods by which these compounds are analyzed are discussed. A considerable portion of this review deals with the utility of measuring IsoPs as markers of oxidant injury in human diseases particularly in association with risk factors that predispose to atherosclerosis, a condition in which excessive oxidative stress has been causally implicated.
- Published
- 1999
36. Cyclosporine-induced coronary artery constriction--dissociation between thromboxane release and coronary vasospasm
- Author
-
Gerhard Walker, Hans-Joachim Kraemer, Harald Tillmanns, Werner Haberbosch, Markus Feussner, Ruediger C. Braun-Dullaeus, Heike Hopmann, and Friedrich Grimminger
- Subjects
Male ,Thromboxane ,Vasodilator Agents ,Receptors, Thromboxane ,Coronary Vasospasm ,Blood Pressure ,Polyethylene Glycols ,Thromboxane receptor ,Thromboxane A2 ,chemistry.chemical_compound ,Nitroglycerin ,Heart Rate ,Vasoconstrictor Agents ,Prostanoic Acids ,Heart ,Calcium Channel Blockers ,Coronary Vessels ,medicine.anatomical_structure ,Anesthesia ,Cardiology ,Cyclosporine ,Pharmaceutical Vehicles ,Cardiology and Cardiovascular Medicine ,Perfusion ,Immunosuppressive Agents ,medicine.drug ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Nifedipine ,6-Ketoprostaglandin F1 alpha ,Internal medicine ,Coronary Circulation ,medicine ,Animals ,Cyclooxygenase Inhibitors ,Nitric Oxide Donors ,Rats, Wistar ,Transplantation ,Aspirin ,business.industry ,Myocardium ,Prostanoid ,medicine.disease ,Myocardial Contraction ,Rats ,Coronary arteries ,Thromboxane B2 ,chemistry ,Coronary vasospasm ,Surgery ,Endothelium, Vascular ,business - Abstract
Cyclosporine influences vascular tone, including that of coronary arteries. But its effect on myocardial prostanoid release, which may contribute to a drug-induced coronary and/or myocardial dysfunction, remains unknown. We used the isolated perfused rat heart to study the effect of cyclosporine on both the mechanical function parameters and myocardial prostanoid release into the effluent by ELISA. Cyclosporine (5 microM) induced an increase of perfusion pressure from 40 +/- 3 to 73 +/- 4 mm Hg within 60 minutes (p0.001), reflecting an increase of coronary tone. Cyclosporine did not affect heart rate but contractility (+dp/dtmax) tended to decrease, although not significantly. The drug's effect on coronary tone was rapidly reversible upon withdrawal. Cyclosporine perfusion resulted in an increase of thromboxane B2 liberation from 236 +/- 150 to 1321 +/- 354 pg/ml effluent (p0.001), whereas the 6-keto-prostaglandin F1 alpha release was unaffected. The vehicle cremophor did not change any of these parameters. Neither inhibition of myocardial prostanoid formation with acetylsalicylic acid nor thromboxane receptor blockade prevented the cyclosporine-induced increase of perfusion pressure. However, perfusion with nitroglycerin or the voltage-sensitive calcium channel antagonist nifedipine in addition to cyclosporine were able to prevent the increase of perfusion pressure. This is the first time it has been demonstrated that cyclosporine induces an acute release of the prostanoid thromboxane within the myocardium. Despite the resulting imbalance in favor of the vasoconstrictive prostanoid, a dependency of the cyclosporine-induced increase of coronary tone on this imbalance was excluded. Conversely, nitric oxide donation or calcium channel blockade were able to prevent the negative effect of the drug on coronary tone, supporting the concept of endothelium-dependent and/or myogenic mechanism of cyclosporine toxicity on the coronary vascular bed.
- Published
- 1999
37. Characterization of the prostanoid receptor(s) on human blood monocytes at which prostaglandin E2 inhibits lipopolysaccharide-induced tumour necrosis factor-alpha generation
- Author
-
K K, Meja, P J, Barnes, and M A, Giembycz
- Subjects
Lipopolysaccharides ,Prostaglandin Antagonists ,Tumor Necrosis Factor-alpha ,Xanthones ,Biphenyl Compounds ,Receptors, Prostaglandin ,Prostanoic Acids ,Epoprostenol ,Dinoprostone ,Prostaglandin Endoperoxides, Synthetic ,Thromboxane A2 ,Xanthenes ,15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ,Papers ,Leukocytes, Mononuclear ,Humans ,lipids (amino acids, peptides, and proteins) ,Drug Interactions - Abstract
1. The prostanoid receptor(s) that mediates inhibition of bacterial lipopolysaccharide (LPS)-induced tumour necrosis factor-alpha (TNF-alpha) generation from human peripheral blood monocytes was classified by use of naturally occurring and synthetic prostanoid agonists and antagonists. 2. In human monocytes that were adherent to plastic, neither prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), prostaglandin F(2 alpha) (PGF(2 alpha)) nor the stable prostacyclin and thromboxane mimetics, cicaprost and U-46619, respectively, promoted the elaboration of TNF alpha-like immunoreactivity, as assessed with a specific ELISA, indicating the absence of excitatory prostanoid receptors on these cells. 3. Exposure of human monocytes to LPS (3 ng ml-1, approximately EC84) resulted in a time-dependent elaboration to TNF alpha which was suppressed in cells pretreated with prostaglandin E1 (PGe1), PGE2 and cicaprost. This effect was concentration-dependent with mean pIC50 values of 7.14, 7.34 and 8.00 for PGE1, PGE2 and cicaprost, respectively. PGD2, PGF(2 alpha) and U-46619 failed to inhibit the generation of TNF alpha at concentrations up to 10 microM. 4. With respect to PGE2, the EP-receptor agonists, 16,16-dimethyl PGE2 (non-selective), misoprostol (EP2/EP3-selective), 11-deoxy PGE1 (EP2-selective) and butaprost (EP2-selective) were essentially full agonists as inhibitors of LPS-induced TNF alpha generation with mean pIC50 values of 6.21, 6.02, 5.67 and 5.59, respectively. In contrast to the results obtained with butaprost and 11-deoxy PGE1, another EP2-selective agonist, AH 13205, inhibited TNF alpha generation by only 21% at the highest concentration (10 microM) examined. EP-receptor agonists which have selectively for the EP1- (17-phenyl-omega-trinor PGE2) and EP3-receptor (MB 28,767, sulprostone) were inactive or only weakly active as inhibitors of TNF alpha generation. 5. Pretreatment of human monocytes with the TP/EP4-receptor antagonist, AH 23848B, at 10, 30 and 100 microM suppressed LPS-induced TNF alpha generation by 10%, 28% and 77%, respectively, but failed to shift significantly the location of the PGE2 concentration-response curves. 6. Given that AH 13205 was a poor inhibitor of TNF alpha generation, studies were performed to determine if it was a partial agonist and whether it could antagonize the inhibitory effect of PGE2. Pretreatment of human monocytes with 10 and 30 microM AH 13205 inhibited the generation of TNF alpha by 31% and 53%, respectively, but failed to shift significantly the location of the PGE2 concentration-response curves at either concentration examined. 7. Since PGD2 and 17-phenyl-omega-trinor PGE2 (EP1-agonist) did not suppress TNF alpha generation, the EP1/EP2/DP-receptor antagonist, AH 6809, was employed to assess if EP2-receptors mediated the inhibitory effect of PGE2. Pretreatment of human monocytes with 10 microM AH 6809 did not affect LPS-induced TNF alpha generation but produced a parallel 3.5 fold rightwards shift of the PGE2 concentration-response curve. 8. Collectively, these data suggest that human peripheral blood monocytes express at least two distinct populations of inhibitory prostanoid receptors that mediate inhibition of LPS-induced TNF alpha generation. One of these probably represents i.p. receptors based upon the selectivity of cicaprost for this subtype. The other population has the pharmacology of EP-receptors, but the rank of potency for a range of synthetic EP-receptor agonists was inconsistent with an interaction with any of the currently defined subtypes. Given the pharmacological behaviour of butaprost, AH 6809 and AH 23848B in these cells, we propose that multiple (EP2- and/or EP-4- and/or i.p.) or novel EP-receptors mediate the inhibitory effect of PGE2 on TNF alpha generation.
- Published
- 1997
38. Functional characterization of the prostanoid DP receptor in human myometrium
- Author
-
Bernadette Fernandes and Denis J. Crankshaw
- Subjects
Agonist ,Adult ,medicine.medical_specialty ,medicine.drug_class ,Receptors, Prostaglandin ,Dinoprost ,Hysterectomy ,Partial agonist ,chemistry.chemical_compound ,Internal medicine ,medicine ,Humans ,Receptor ,Pharmacology ,Dose-Response Relationship, Drug ,Chemistry ,Prostaglandin D2 ,Hydantoins ,Myometrium ,Antagonist ,Prostanoic Acids ,Prostanoid ,Muscle, Smooth ,Middle Aged ,Receptor antagonist ,Endocrinology ,Female ,Muscle Contraction - Abstract
Spontaneous contractile activity of strips of human myometrium obtained from non-pregnant donors at the time of hysterectomy was inhibited by the selective prostanoid DP receptor agonists BW 245C (5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin) and ZK110841 ((5Z,13E)-(9R,11R,15S)-9 beta-chlor-15-cyclohexyl-11,15-dihydroxy-16,17,18,19, 20-pentanor-5,13-prostadienoic acid) with pEC50 values of 8.4 and 7.3 respectively but prostaglandin D2 produced a biphasic effect. In the presence of the TP receptor antagonist L670596 ((-)-6,8-difluoro-9-p-methylsulfonyl benzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid), contractile activity induced by the FP receptor agonist, cloprostenol ([1R-[1 alpha(Z),2 beta(1E,3R),3 alpha,5 alpha]]-7-[2-[4-(3- chlorophenoxy)-3-hydroxy-7-butenyl]-3,5-dihydroxycyclopentyl]-5-he ptenoic acid), was inhibited by BW 245C (pEC50 = 7.5), ZK110841 (pEC50 = 6.7) and prostaglandin D2 (pEC50 = 6.3). Under these conditions both prostaglandin J2 and 9 alpha,11 beta-prostaglandin F2 were inhibitory partial agonists. All compounds were antagonized by the selective DP receptor antagonist BW A868C (3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2-hydroxyethylamino)h ydantoin), but the pKB values were both concentration-dependent (pKB versus BW 245C at 10 nM = 9.1, at 50 nM = 8.3) and agonist-dependent (pKB at 10 nM versus BW 245C = 9.1, versus ZK110841 = 7.4). Both agonist and antagonist potencies support the existence of DP receptors in human myometrium. The concentration and agonist dependence of the action of BW A868C suggests that putative DP receptor agonists relax human myometrium by more than one mechanism. These observations may be explained by the existence of subtypes of DP receptor in human myometrium.
- Published
- 1995
39. Molecular characterization and ocular hypotensive properties of the prostanoid EP2 receptor
- Author
-
John E. Donello, Steven W. Andrews, A.M. Bogardus, E. Runde, Alexander B. Kharlamb, D.F. Woodward, J. W. Regan, J.A. Burke, D. W. Gil, Kristen L. Pierce, Karen M. Kedzie, and C.E. Fairbairn
- Subjects
Agonist ,Prostaglandins E, Synthetic ,medicine.drug_class ,Prostaglandin E2 receptor ,Clone (cell biology) ,Ocular Hypotension ,Prostanoic acid ,Biology ,Transfection ,Cyclase ,Binding, Competitive ,Fluorophotometry ,Cell Line ,Aqueous Humor ,Radioligand Assay ,Complementary DNA ,medicine ,Cyclic AMP ,Animals ,Humans ,Receptors, Prostaglandin E ,Pharmacology (medical) ,Alprostadil ,Cloning, Molecular ,Receptor ,Intraocular Pressure ,Pharmacology ,Prostanoic Acids ,Ophthalmology ,Macaca fascicularis ,Biochemistry ,lipids (amino acids, peptides, and proteins) ,Female ,DNA Probes - Abstract
The cloning of the genes that encode for prostaglandin (PG) receptors has resolved much of the complexity and controversy in this area by confirming the classification proposed by Coleman, et al. Two issues that remained unresolved were (1) the inability of the EP2 agonist butaprost to interact with the cloned putative EP2 receptor and (2) molecular biological confirmation of a fourth PGE2-sensitive receptor, which was pharmacologically designated EP4. In order to provide clarification, we attempted to clone further PGE2-sensitive receptors. By using a cDNA probe that encodes for the human EP3A receptor, a cDNA clone that encoded for a novel PGE2-sensitive receptor was obtained by screening a human placenta library. This cDNA clone was transfected into COS-7 cells for pharmacological studies. The cDNA clone obtained from human placenta had only about 30% amino acid identity with cDNAs for other PG receptors, including those that encode for the previously proposed murine and human EP2 receptors. Radioligand binding studies on the novel EP receptor expressed in COS-7 cells revealed that selective EP2 agonists such as butaprost, AH 13205, AY 23626 and 19(R)-OH PGE2 all competed with 3H-PGE2 for its binding sites, whereas selective agonists for other PG receptor subtypes had minimal or no effect. This receptor was coupled to adenylate cyclase and EP2 agonists caused dose-related increases in cAMP. It appears that the cDNA described herein encodes for the pharmacologically defined EP2 receptor. Ocular studies revealed that AH 13205 decreased intraocular pressure in normal and ocular hypertensive monkeys by a mechanism that does not appear to involve inhibition of aqueous humor secretion.
- Published
- 1995
40. Evidence for the presence of AH 13205-sensitive EP2-prostanoid receptors in the pregnant baboon but not in the pregnant sheep myometrium near term
- Author
-
R, Garcia-Villar, L R, Green, S L, Jenkins, R A, Wentworth, R A, Coleman, and P W, Nathanielsz
- Subjects
Sheep ,Prostanoic Acids ,Gestational Age ,In Vitro Techniques ,Dinoprost ,Oxytocin ,Dinoprostone ,Kinetics ,Uterine Contraction ,Species Specificity ,Pregnancy ,Myometrium ,Animals ,Humans ,Pregnancy, Animal ,Receptors, Prostaglandin E ,Female ,Papio - Abstract
Our purposes were to assess the effects of prostaglandin (PG) E2 and PGF2 alpha on myometrial contractility in pregnant sheep and baboons in an in vitro superfusion study, and to characterize further the PGE-sensitive (EP) receptor subtype involved in the myometrial response to PGE2 by using the selective prostanoid EP2 agonist AH 13205.Strip preparations of uterine muscle from 15 sheep (107-145 days' gestational age) and ten baboons (158-185 days' gestation) were studied. Cumulative concentration-response curves (CRC) were constructed to oxytocin (4.2 pmol/L to 0.42 mumol/L, PGE2 (0.1 nmol/L to 1 mumol/L), and PGF2 alpha (1 nmol/L to 100 mumol/L), and 50% effective concentration (EC50) values (mean and 95% confidence interval) were calculated. We also tested the hypothesis that PGE2-induced myometrial relaxation in pregnant baboons could be mediated by EP2-prostanoid receptors. Myometrial strips were stimulated by oxytocin (0.42 nmol/L), and CRCs to the EP2-agonist AH 13205 (0.1 nmol/L to 10 mumol/L) were constructed.Prostaglandin F2 alpha stimulated myometrial activity in a concentration-related fashion in all preparations from both sheep and baboons. The EC50 in the sheep myometrium for PGF2 alpha (52 nmol/L, 95% confidence interval [CI] 25-110) was significantly (P.05) lower than that in baboon myometrium (183 nmol/L, 95% CI 93-355). Oxytocin stimulated myometrial activity in preparations of both sheep (EC50 = 0.29 nmol/L, 95% CI 0.11-0.71) and baboon (EC50 = 0.31 nmol/L, 95% CI 0.18-0.52). In contrast, responses to PGE2 were species-related: PGE2 caused concentration-related stimulation of myometrial activity in sheep tissue (EC50 = 3.2 nmol/L, 95% CI 2.0-5.0), but induced concentration-related inhibition of activity in baboon myometrium (50% inhibitory concentration [IC50] = 21 nmol/L, 95% CI 2.2-203). A concentration-related inhibitory response to AH 13205 (IC50 = 3.56 nmol/L, 95% CI 1.28-5.99) was obtained in the baboon. In contrast, AH 13205 failed to inhibit comparable myometrial strip preparations from pregnant sheep.The present studies suggest that both sheep and baboon myometrium contain prostanoid receptors that mediate stimulation. In addition, baboon myometrium, like that from the human, contains AH 13205-sensitive EP receptors (EP2 receptors), which mediate inhibition. The pregnant baboon may therefore represent a suitable animal model for investigations into the use of EP2 agonists for the prevention of premature labor in humans.
- Published
- 1995
41. Characterization of dilator prostanoid receptors in the fetal rabbit ductus arteriosus
- Author
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G C, Smith, R A, Coleman, and J C, McGrath
- Subjects
Dose-Response Relationship, Drug ,Pregnancy ,Receptors, Prostaglandin ,Receptors, Thromboxane ,Prostaglandins ,Prostanoic Acids ,Animals ,Female ,Ductus Arteriosus ,Rabbits ,In Vitro Techniques ,Epoprostenol ,Dinoprostone - Abstract
The purpose of this study was to determine which receptors mediate the dilator effects of prostaglandins (PGs) on the ductus arteriosus of the fetal rabbit. Isolated rings of the vessel from fetal New Zealand White rabbits were precontracted with indomethacin (1 microM) and potassium (25 mM) in 100 to 110 mmHg oxygen, and the dilator effects of a range of synthetic prostanoids were quantified by cumulative relaxant concentration-effect curves. The potencies of agonists were quantified with reference to PGE2 by the equieffective molar ratio (EMR): EC50 test agonist/EC50 PGE2. The effects on these responses of available antagonists were also studied. None of a range of synthetic prostanoids with selective agonism of EP1, EP2 or EP3 receptors was as potent as PGE2. The rank order of potency was as follows: PGE2 (EC50 = 0.36 nM [95% confidence intervals [CI] = 0.32-0.41, n = 44], EMR = unity)misoprostol (EMR 145, 95% CI 73-217)[1R-[1 alpha (Z),2 beta (R*),3 alpha]]-4-(benzoyl-amino)phenyl 7-[3 hydroxy-2(2-hydroxy-3-phenoxypropoxy)-5- oxocyclopentyl]-4-heptenoate, single enantiomer (GR 63799K) (EMR 685, 95% CI 427-944)((+/-)-trans-2-[4[(1-hydroxphenyl) phenyl]-5-oxocylopentaneheptanoic acid (AH13205) (EMR100,000)or = sulprostone (EMR10,000)or = 0. The EP1 antagonists, 6-isopropoxy-9-oxoxanthine-2-carboxylic acid (AH6809) (10 microM) and 8-clorodi-benz[b,f][1,4]oxazepine-10 (11H)-carboxylic acid, 2-acetylhydrazide (SC19220) (30 microM), had no significant effect on the sensitivity of the ductus to PGE2.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1994
42. [Hypercholesterolemic effect of unsaturated fatty acids]
- Author
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M J, Santi, A, Barba, and J, Millán
- Subjects
Lipoproteins, LDL ,Cholesterol ,Fatty Acids, Unsaturated ,Prostanoic Acids ,Humans ,Lipoproteins, HDL - Published
- 1993
43. [The gastroprotective and antiaggregant activities of 13-azaprostanoids]
- Author
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B B, Kuz'mitskiĭ, N A, Mizulo, V N, Romanova, L P, Malaeva, T S, Khlebnikova, and F A, Lakhvich
- Subjects
Male ,Structure-Activity Relationship ,Ethanol ,Platelet Aggregation ,Gastric Mucosa ,Drug Evaluation, Preclinical ,Prostanoic Acids ,Animals ,Rabbits ,Stomach Ulcer ,Platelet Aggregation Inhibitors ,Rats - Abstract
Some 13-azaprostanoic acid derivatives were shown to have a high cytoprotective activity against the damaging effect of ethanol on the gastric mucosa in non-strain rats and affect ATP- and arachidonate-induced platelet aggregation in the whole blood of rabbits and rats in a different way. The gastroprotective activity that is common to natural and synthetic prostanoids is not closely related to the chemical structure of the compounds. On the contrary, the trends of these compounds to affect the induced platelet aggregation depend on the modification of both the cyclic moiety and both chains of a prostanoid molecule.
- Published
- 1992
44. [How does short-term ischemia protect the heart?]
- Author
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Peuhkurinen K and Kai Kiviluoma
- Subjects
Myocardial Stunning ,Adenosine ,Time Factors ,Myocardial Ischemia ,Prostanoic Acids ,Humans ,Myocardial Reperfusion - Published
- 1992
45. Mass spectrometric identification of urinary and plasma metabolites of 6-(6'-carboxyhexyl)-7-n-hexyl-1,3-diazaspiro-[4-4]-nonan-2,4-dione, a new cytoprotective agent
- Author
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E, Benfenati, R, Fanelli, E, Bosone, C, Biffi, R, Caponi, M, Cianetti, and P, Farina
- Subjects
Dogs ,Species Specificity ,Prostanoic Acids ,Animals ,Female ,Spiro Compounds ,Mass Spectrometry ,Rats - Abstract
The compound IBI-P-01028, or R,S-cis-6-(6'-carboxyhexyl)-7-trans-n-hexyl-1,3-diazaspiro-[4-4]-nona n-2,4- dione, is a new cytoprotective agent under development. To study the metabolites of this compound in laboratory animals, we administered it to dogs and rats, and analyzed extracts from dog and rat urine, and from dog plasma, by GC-MS. The metabolic profiles were different in the rat and dog. In the dog (plasma and urine), one metabolite was found, and in the rat urine two other metabolites were found. The unmetabolized drug was found only in the dog plasma and urine.
- Published
- 1991
46. Endogenous vasoconstrictor prostanoids: role in serotonin and vasopressin-induced coronary vasoconstriction
- Author
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S L, Lee, S, Levitsky, and H, Feinberg
- Subjects
Male ,Vasopressins ,Prostanoic Acids ,Rats, Inbred Strains ,Bridged Bicyclo Compounds, Heterocyclic ,Coronary Vessels ,Rats ,Thromboxane A2 ,Hydrazines ,Vasoconstriction ,Fatty Acids, Unsaturated ,Prostaglandins ,Animals ,Drug Interactions ,Serotonin Antagonists - Abstract
A vasoconstrictor-induced prostacyclin (PGI2) production in a perfused rat heart was found, suggesting a mitigating role of PGI2 on coronary vasoconstriction. Treatment of the heart with cyclooxygenase inhibitors (aspirin or indomethacin) decreased PGI2 production by more than 90% and paradoxically reduced the vasoconstriction response. The attenuating effect of cyclooxygenase blockade suggested that endogenous prostanoids contribute to serotonin-, vasopressin- or U46619-induced vasoconstriction. Two prostaglandin (PG) H2/thromboxane A2 (TXA2) receptor antagonists, i.e., 13-azaprostanoic acid (13-APA) and SQ 29,548 were used to investigate putative endogenous vasoconstrictor prostanoids on the exogenously induced vasoconstriction. Retrogradely perfused (5-6 ml/min) rat hearts were rendered guiescent, yet responsive to stimuli, by local injection of lidocaine to the atrioventricular node. Changes in coronary vascular resistance (i.e., perfusion pressure at constant flow) were monitored and the cardiac effluent was collected for analysis of 6-keto PGF1 alpha (the stable metabolite of PGI2) as well as PGF2 alpha by radioimmunoassay. Three vasoconstrictors, i.e., serotonin, vasopressin and the TXA2/PGH2 analog U46619, as well as authentic PGD2, PGE2 and PGF2 alpha were infused. PGD2, PGE2 and PGF2 alpha exerted a dose-related coronary vasoconstriction, as did U46619, serotonin and vasopressin. Treatment with 13-APA (100 microM) or SQ 29,548 (100 nM) almost abolished U46619-induced vasoconstriction. The addition of PGH2/TXA2 receptor antagonists also significantly reduced the pressor effect of exogenously administered PGs, serotonin and vasopressin, with the exception that SQ 29,548 did not significantly antagonize PGE2-induced vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1991
47. A double blind randomized placebo-controlled study demonstrates the protective efficacy of rosaprostol on aspirin-induced gastrointestinal bleeding in man
- Author
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G, Calcamuggi, G, Babini, C, Arduino, M, Lanzio, G, Anfossi, D, Ciani, and G, Emanuelli
- Subjects
Adult ,Male ,Aspirin ,Double-Blind Method ,Occult Blood ,Prostanoic Acids ,Humans ,Prospective Studies ,Anti-Ulcer Agents ,Gastrointestinal Hemorrhage - Published
- 1991
48. Determination of 11 alpha-hydroxy-9,15-dioxo-2,3,4,5,20-pentanor-19-carboxyprostan oic acid and 9 alpha,11 alpha-dihydroxy-15-oxo-2,3,4,5,20-pentanor-19-carboxyprostanoi c acid by gas chromatography/negative ion chemical ionization triple-stage quadrupole mass spectrometry
- Author
-
H, Schweer, C O, Meese, and H W, Seyberth
- Subjects
Oximes ,Prostaglandins F ,Prostanoic Acids ,Reference Standards ,Deuterium ,Gas Chromatography-Mass Spectrometry - Abstract
11 alpha-Hydroxy-9,15-dioxo-2,3,4,5,20-pentanor-19-carboxyprostano ic acid (PGE-M) and 9 alpha,11 alpha-dihydroxy-15-oxo-2,3,4,5,20-pentanor-19-carboxyprostanoic acid (PGF-M) in urine were determined in an isotope dilution assay by gas chromatography/triple-stage quadrupole mass spectrometry. After addition of the 2H7-labeled internal standard, O-methylhydroxylamine hydrochloride in acetate buffer was added either directly (PGE-M) or after standing overnight at pH 10 (PGF-M) to form the methoxime. The sample was acidified to pH 2.5 and PGE-M and PGF-M were extracted with ethyl acetate/hexane. Then the prostanoids were derivatized to the pentafluorobenzyl ester and purified by thin-layer chromatography and the trimethylsilyl ether was formed. The products were quantified by gas chromatography/triple-stage quadrupole mass spectrometry. For PGE-M, the fragment ions m/z 349 and m/z 356 (2H7 standard) (daughter ions of m/z 637 and m/z 644 (2H7 standard] were used. The results of the PGE-M assay were compared with those of an assay using the [2H3]methoxime as the internal standard. For determination of PGF-M, the daughter ions m/z 484 and m/z 491 (2H7 standard) with the parent ions m/z 682 and m/z 689 (2H7 standard) were chosen.
- Published
- 1990
49. Effects of acetylsalicylic acid and paracetamol alone and in combination on prostanoid synthesis in man
- Author
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H Bippi and Jürgen C. Frölich
- Subjects
Adult ,Male ,Urinary system ,Metabolite ,Analgesic ,Urine ,Pharmacology ,Kidney ,Dinoprostone ,Gas Chromatography-Mass Spectrometry ,Excretion ,chemistry.chemical_compound ,Random Allocation ,Oral administration ,medicine ,Humans ,Pharmacology (medical) ,Drug Interactions ,Antipyretic ,Acetaminophen ,Aspirin ,Chemistry ,Prostanoic Acids ,Kidney metabolism ,Creatinine ,Prostaglandins ,medicine.drug ,Research Article - Abstract
1. The present study was designed to investigate the effects of acetylsalicylic acid and paracetamol given separately and in combination on total body and renal PGE2 synthesis in healthy volunteers. 2. In a randomized four-way cross-over study eleven female volunteers received for two consecutive days 3 g day-1 acetylsalicylic acid or 3 g day-1 paracetamol or a combination of 1.5 g day-1 acetylsalicylic acid and 1.5 g day-1 paracetamol, or 1.5 g day-1 acetylsalicylic acid separated by washout phases of at least 5 days. Urinary excretion of the major urinary metabolite of PGE2 (PGE-MUM), PGE2 and creatinine clearance were measured before and on day 2 of each treatment period. Compliance was tested by measuring metabolites of the two drugs in urine. 3. Paracetamol did not reduce urinary excretion of PGE2 whereas both dosages of acetylsalicylic acid caused a significant reduction. 4. The combination of both drugs did not reduce PGE2 excretion more than acetylsalicylic acid alone. 5. All four drug schedules reduced urinary excretion of PGE-MUM significantly.
- Published
- 1990
50. Influence of an alpha-1-adrenoceptor antagonist, nicergoline, on placental prostanoid production in streptozotocin-induced diabetic pregnant rats
- Author
-
Schrub Jc, N. Chartrel, M. Clabaut, and F. Boismare
- Subjects
medicine.medical_specialty ,medicine.medical_treatment ,Placenta ,Pregnancy in Diabetics ,Prostacyclin ,Prostanoic acid ,6-Ketoprostaglandin F1 alpha ,Dinoprostone ,Diabetes Mellitus, Experimental ,chemistry.chemical_compound ,Thromboxane A2 ,Pregnancy ,Internal medicine ,medicine ,Animals ,Insulin ,Prostaglandin E2 ,Ergolines ,Adrenergic alpha-Antagonists ,Nicergoline ,business.industry ,Fatty Acids ,Prostanoic Acids ,Prostanoid ,Rats, Inbred Strains ,Rats ,Thromboxane B2 ,Endocrinology ,chemistry ,Pediatrics, Perinatology and Child Health ,Female ,business ,Developmental Biology ,medicine.drug - Abstract
The aim of this study was to determine if placental prostanoids could mediate the vasodilating action of an alpha- 1-adrenoceptor antagonist, nicergoline (400 μg/kg i.p.), during late pregnancy in streptozotocin-induced diabetic rats (40 mg/kg i.v.). Placental prostanoid concentrations were evaluated by radioimmunoassay. Prostaglandin E2 levels showed a highly significant increase in diabetic and nondiabetic rats treated with nicergoline (p < 0.001). 6-Keto-PGF1α concentrations were slightly increased in diabetic rats compared to controls, and this increase was reversed by both nicergoline and insulin treatments. In all groups studied thromboxane B2 levels were comparable. It is concluded that prostaglandin E2 could mediate the vasodilating action of nicergoline on the placental irrigation and, therefore, improved the hemodynamic state of this organ in diabetic rats.
- Published
- 1990
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