RESUMO
BACKGROUND: Acetaminophen and ibuprofen are widely administered to babies due to their presumed safety as over-the-counter drugs. However, no reports exist on the effects of cyclooxygenase inhibitors on undifferentiated spermatogonia and spermatogonial stem cells. Infancy represents a critical period for spermatogonial stem cell formation and disrupting spermatogonial stem cells or their precursors may be associated with infertility and testicular cancer formation. OBJECTIVES: The goal of this study was to examine the molecular and functional impact of cyclooxygenase inhibition and silencing on early steps of undifferentiated spermatogonia (u spg) and spermatogonial stem cell development, to assess the potential reproductive risk of pharmaceutical cyclooxygenase inhibitors. METHODS: The effects of cyclooxygenase inhibition were assessed using the mouse C18-4 undifferentiated juvenile spermatogonial cell line model, previously shown to include cells with spermatogonial stem cell features, by measuring prostaglandins, cell proliferation, and differentiation, using cyclooxygenase 1- and cyclooxygenase 2-selective inhibitors NS398, celecoxib, and FR122047, acetaminophen, and ibuprofen. Cyclooxygenase 1 gene silencing was achieved using a stable short-hairpin RNA approach and clone selection, then assessing gene and protein expression in RNA sequencing, quantitative real-time polymerase chain reaction, and immunofluorescence studies. RESULTS: Cyclooxygenase 2 inhibitors NS398 and celecoxib, as well as acetaminophen, but not ibuprofen, dose-dependently decreased retinoic acid-induced expression of the spg differentiation gene Stra8, while NS398 decreased the spg differentiation marker Kit, suggesting that cyclooxygenase 2 is positively associated with spg differentiation. In contrast, short-hairpin RNA-based cyclooxygenase 1 silencing in C18-4 cells altered cellular morphology and upregulated Stra8 and Kit, implying that cyclooxygenase 1 prevented spg differentiation. Furthermore, RNA sequencing analysis of cyclooxygenase 1 knockdown cells indicated the activation of several signaling pathways including the TGFb, Wnt, and Notch pathways, compared to control C18-4 cells. Notch pathway genes were upregulated by selective cyclooxygenase inhibitors, acetaminophen and ibuprofen. CONCLUSION: We report that cyclooxygenase 1 and 2 differentially regulate undifferentiated spermatogonia/spermatogonial stem cell differentiation. Cyclooxygenases regulate Notch3 expression, with the Notch pathway targeted by PGD2. These data suggest an interaction between the eicosanoid and Notch signaling pathways that may be critical for the development of spermatogonial stem cells and subsequent spermatogenesis, cautioning about using cyclooxygenase inhibitors in infants.
Assuntos
Nitrobenzenos , Espermatogônias , Sulfonamidas , Neoplasias Testiculares , Humanos , Masculino , Animais , Camundongos , Espermatogônias/metabolismo , Neoplasias Testiculares/metabolismo , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 1/farmacologia , Ciclo-Oxigenase 2/metabolismo , Celecoxib/farmacologia , Celecoxib/metabolismo , Ibuprofeno/farmacologia , Acetaminofen , Espermatogênese/fisiologia , Diferenciação Celular/fisiologia , Inibidores de Ciclo-Oxigenase/farmacologia , RNA/metabolismo , Testículo/metabolismoRESUMO
Tyrosine kinase inhibitors (TKIs) are highly effective in treating chronic myelogenous leukemia (CML). However, primary and acquired drug resistance to TKIs have been reported. In this study, we used RNA sequencing followed by RQ-PCR to show that the proto-oncogene EVI1 targets the drug-metabolizing gene PTGS1 in CML. The PTGS1 promoter element had an EVI1 binding site, and CHIP assay confirmed its presence. Data from a publicly available CML microarray dataset and an independent set of CML samples showed a significant positive correlation between EVI1 and PTGS1 expression in CML. Downregulation of EVI1 in K562 cells and subsequent treatment with TKIs resulted in a lower IC50 in the control cells. Furthermore, combined inhibition of BCR-ABL with imatinib and PTGS1 with FR122047 (PTGS1 inhibitor) synergistically reduced the viability of imatinib-resistant K562 cells. We conclude that elevated EVI1 expression contributes to TKIs resistance and that combined inhibition of PTGS1 and BCR-ABL may represent a novel therapeutic approach.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Apoptose , Ciclo-Oxigenase 1/farmacologia , Ciclo-Oxigenase 1/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Las urgencias odontológicas son, quizá, las razones principales de atención en el consultorio, muchas veces el significado de dolor se encuentra acompañado por inflamación; el uso de antiinflamatorios no esteroideos (AINES) es común en el ejercicio de la odontología por la excelente respuesta analgésica y antiinflamatoria que tiene, por lo que es importante conocer la fisiopatología de la inflamación y el dolor y cómo actúan los AINES, ya que algunos de estos fármacos tienen respuestas adversas y sitios de acción importantes. Los factores de riesgo por inflamación y dolor nos obligan a conocer la variedad de fármacos que no entran en la clasificación de AINES y que tenemos a disposición, hay más opciones para la elección ante la presencia de inflamación por un factor en particular, cada uno de éstos tienen indicaciones y contraindicaciones que conoceremos, lo cual nos ampliará el conocimiento para dar una prescripción ante la presencia de eventos inflamatorios. Se realizó un estudio detallado de artículos bibliográficos de cada tema, los fármacos más usados en odontología son los AINES, hay poco uso y conocimiento de antiinflamatorios que podemos usar en urgencias, el porcentaje de uso de los AINES derivados del ácido propiónico es alto por la excelente respuesta en pacientes y otras veces por el desconocimiento de más opciones (AU)
Dental emergencies are perhaps the main reasons for care in the office, many times the meaning of pain is accompanied by inflammation, the use of non-steroidal anti-inflammatory drugs is common in the practice of dentistry due to the excellent analgesic and anti-inflammatory response it has, important is knowing the pathophysiology of inflammation and pain, how NSAIDs act, some of these drugs have adverse responses and important sites of action, risk factors for inflammation and pain require us to know the variety of drugs that do not enter the classification of NSAIDs and we have at our disposal, there are more options for choosing in the presence of inflammation due to a particular factor, each of these have indications and contraindications that we will know, it expands our knowledge to give a prescription in the presence of inflammatory events. A detailed study of bibliographic articles on each topic was carried out, the drugs most used in dentistry are NSAIDs, there is little use and knowledge of anti-inflammatories that we can use in the emergency room, the percentage of use of NSAIDs derived from propionic acid is high, due to the excellent response in patients and others due to lack of knowledge of more options (AU)
Assuntos
Humanos , Masculino , Feminino , Odontalgia , Preparações Farmacêuticas , Anti-Inflamatórios não Esteroides , Inflamação , Dor/patologia , Dor Pós-Operatória , Propionatos , Prostaglandinas/fisiologia , Interações Medicamentosas , Ciclo-Oxigenase 1/farmacologia , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , EntorpecentesRESUMO
Mitochondria provide energy for cells via oxidative phosphorylation. Reactive oxygen species, a byproduct of this mitochondrial respiration, can damage mitochondrial DNA (mtDNA), and somatic mtDNA mutations have been found in all colorectal, ovarian, breast, urinary bladder, kidney, lung, and pancreatic tumors studied. The resulting altered mitochondrial proteins or tumor-associated mitochondrial Ags (TAMAs) are potentially immunogenic, suggesting that they may be targetable Ags for cancer immunotherapy. In this article, we show that the RENCA tumor cell line harbors TAMAs that can drive an antitumor immune response. We generated a cellular tumor vaccine by pulsing dendritic cells with enriched mitochondrial proteins from RENCA cells. Our dendritic cell-based RENCA mitochondrial lysate vaccine elicited a cytotoxic T cell response in vivo and conferred durable protection against challenge with RENCA cells when used in a prophylactic or therapeutic setting. By sequencing mtDNA from RENCA cells, we identified two mutated molecules: COX1 and ND5. Peptide vaccines generated from mitochondrial-encoded COX1 but not from ND5 had therapeutic properties similar to RENCA mitochondrial protein preparation. Thus, TAMAs can elicit effective antitumor immune responses, potentially providing a new immunotherapeutic strategy to treat cancer.
Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Carcinoma de Células Renais/prevenção & controle , Ciclo-Oxigenase 1/imunologia , Neoplasias Renais/prevenção & controle , Proteínas de Membrana/imunologia , Proteínas Mitocondriais/imunologia , NADH Desidrogenase/imunologia , Neoplasias Experimentais/prevenção & controle , Animais , Antígenos de Neoplasias/farmacologia , Vacinas Anticâncer/farmacologia , Carcinoma de Células Renais/imunologia , Ciclo-Oxigenase 1/farmacologia , Neoplasias Renais/imunologia , Proteínas de Membrana/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Mitocondriais/farmacologia , NADH Desidrogenase/farmacologia , Neoplasias Experimentais/imunologiaRESUMO
Renal cyclooxygenase (COX) derived eicosanoids are elevated and lipoxygenase (LOX) products are reduced in the Han:SPRD-Cy rat model of polycystic kidney disease (PKD). Selective COX2 inhibition reduces kidney disease progression, but COX1 levels also are elevated in this model. Since the effect of reducing the products of both COX isoforms and the role of LOX products is not known, weanling normal and diseased Han:SPRD-cy littermates were given either low dose acetylsalicylic acid (ASA), nordihydroguaiaretic (NDGA) or no treatment for eight weeks. Renal eicosanoids were altered in the diseased compared to normal cortex, with COX products being higher and LOX products being lower. ASA reduced COX products, cyst growth and kidney water content, while NDGA reduced LOX products without altering disease progression or kidney function. Hence, a human equivalent ASA dose equal to less than one regular strength aspirin per day slowed disease progression, while further reduction of LOX products did not worsen disease progression.
Assuntos
Aspirina/farmacologia , Ciclo-Oxigenase 1/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Lipoxigenase/metabolismo , Masoprocol/farmacologia , Proteínas de Membrana/farmacologia , Doenças Renais Policísticas , Animais , Modelos Animais de Doenças , Humanos , Rim/metabolismo , Rim/patologia , Masculino , Doenças Renais Policísticas/induzido quimicamente , Doenças Renais Policísticas/metabolismo , Doenças Renais Policísticas/patologia , RatosRESUMO
The objective of this study was to determine the effect of eight 5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-carboxyamidepyrazoles (TFDPs) on rat body temperature and baker's yeast-induced fever. TFDPs or vehicle (5% Tween 80 in 0.9% NaCl, 5 mL/kg) were injected subcutaneously and rectal temperature was measured as a function of time in 28-day-old male Wistar rats (N = 5-12 per group). Antipyretic activity was determined in feverish animals injected with baker's yeast (Saccharomyces cerevisiae suspension, 0.135 mg/kg, 10 mL/kg, ip). 3-Ethyl- and 3-propyl-TFDP (140 and 200 µmol/kg, respectively, 4 h after yeast injection) attenuated baker's yeast-induced fever by 61 and 82%, respectively. These two effective antipyretics were selected for subsequent analysis of putative mechanisms of action. We then determined the effects on cyclooxygenase-1 and -2 (COX-1 and COX-2) activities on 1,1-diphenyl-2-picrylhydrazyl (DPPH) oxidation in vitro, on tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) levels and on leukocyte counts in the washes of peritoneal cavities of rats injected with baker's yeast. While 3-ethyl- and 3-propyl-TFDP did not reduce baker's yeast-induced increases of IL-1ß or TNF-α levels, 3-ethyl-TFDP caused a 42% reduction in peritoneal leukocyte count. 3-Ethyl- and 3-propyl-TFDP did not alter COX-1 or COX-2 activities in vitro, but presented antioxidant activity in the DPPH assay with an IC50 of 39 mM (25-62) and 163 mM (136-196), respectively. The data indicate that mechanisms of action of these two novel antipyretic pyrazole derivatives do not involve the classic inhibition of the COX pathway or pyrogenic cytokine release.
Assuntos
Antioxidantes/farmacologia , Antipiréticos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Pirazóis/farmacologia , Animais , Antipiréticos/química , Ciclo-Oxigenase 1/farmacologia , Ciclo-Oxigenase 2/farmacologia , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/metabolismo , Masculino , Pirazóis/química , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Prostaglandins control osteoblastic and osteoclastic function under physiological or pathological conditions and are important modulators of the bone healing process. The non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity and consequently prostaglandins synthesis. Experimental and clinical evidence has indicated a risk for reparative bone formation related to the use of non-selective (COX-1 and COX-2) and COX-2 selective NSAIDs. Ketorolac is a non-selective NSAID which, at low doses, has a preferential COX-1 inhibitory effect and etoricoxib is a new selective COX-2 inhibitor. Although literature data have suggested that ketorolac can interfere negatively with long bone fracture healing, there seems to be no study associating etoricoxib with reparative bone formation. Paracetamol/acetaminophen, one of the first choices for pain control in clinical dentistry, has been considered a weak anti-inflammatory drug, although supposedly capable of inhibiting COX-2 activity in inflammatory sites. OBJECTIVE: The purpose of the present study was to investigate whether paracetamol, ketorolac and etoricoxib can hinder alveolar bone formation, taking the filling of rat extraction socket with newly formed bone as experimental model. MATERIAL AND METHODS: The degree of new bone formation inside the alveolar socket was estimated two weeks after tooth extraction by a differential point-counting method, using an optical microscopy with a digital camera for image capture and histometry software. Differences between groups were analyzed by ANOVA after confirming a normal distribution of sample data. RESULTS AND CONCLUSIONS: Histometric results confirmed that none of the tested drugs had a detrimental effect in the volume fraction of bone trabeculae formed inside the alveolar socket.
Assuntos
Animais , Masculino , Ratos , Acetaminofen/efeitos adversos , Analgésicos não Narcóticos/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Regeneração Óssea/efeitos dos fármacos , /efeitos adversos , Cetorolaco/efeitos adversos , Piridinas/efeitos adversos , Sulfonas/efeitos adversos , Análise de Variância , Acetaminofen/farmacologia , Analgésicos não Narcóticos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 1/efeitos adversos , Ciclo-Oxigenase 1/farmacologia , /farmacologia , Modelos Animais de Doenças , Consolidação da Fratura/efeitos dos fármacos , Cetorolaco/farmacologia , Piridinas/farmacologia , Ratos Wistar , Sulfonas/farmacologia , Fatores de TempoRESUMO
The objective of this study was to determine the effect of eight 5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-carboxyamidepyrazoles (TFDPs) on rat body temperature and baker’s yeast-induced fever. TFDPs or vehicle (5 percent Tween 80 in 0.9 percent NaCl, 5 mL/kg) were injected subcutaneously and rectal temperature was measured as a function of time in 28-day-old male Wistar rats (N = 5-12 per group). Antipyretic activity was determined in feverish animals injected with baker’s yeast (Saccharomyces cerevisiae suspension, 0.135 mg/kg, 10 mL/kg, ip). 3-Ethyl- and 3-propyl-TFDP (140 and 200 μmol/kg, respectively, 4 h after yeast injection) attenuated baker’s yeast-induced fever by 61 and 82 percent, respectively. These two effective antipyretics were selected for subsequent analysis of putative mechanisms of action. We then determined the effects on cyclooxygenase-1 and -2 (COX-1 and COX-2) activities on 1,1-diphenyl-2-picrylhydrazyl (DPPH) oxidation in vitro, on tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels and on leukocyte counts in the washes of peritoneal cavities of rats injected with baker’s yeast. While 3-ethyl- and 3-propyl-TFDP did not reduce baker’s yeast-induced increases of IL-1β or TNF-α levels, 3-ethyl-TFDP caused a 42 percent reduction in peritoneal leukocyte count. 3-Ethyl- and 3-propyl-TFDP did not alter COX-1 or COX-2 activities in vitro, but presented antioxidant activity in the DPPH assay with an IC50 of 39 mM (25-62) and 163 mM (136-196), respectively. The data indicate that mechanisms of action of these two novel antipyretic pyrazole derivatives do not involve the classic inhibition of the COX pathway or pyrogenic cytokine release.
Assuntos
Animais , Masculino , Ratos , Antioxidantes/farmacologia , Antipiréticos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Pirazóis/farmacologia , Antipiréticos/química , Ciclo-Oxigenase 1/farmacologia , /farmacologia , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/metabolismo , Pirazóis/química , Ratos Wistar , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The synthesis and the pharmacological activity of a series of 1-aroyl derivatives of kynurenic acid methyl ester (4-oxo-quinolin-2-carboxy methyl (KYNA) esters), structurally related to NSAID indomethacin are described. The derivatives were screened in vivo for anti-inflammatory and analgesic activities. Most of the compounds exhibited good anti-inflammatory and analgesic activities. An automatic docking of the synthesized compounds was performed using X-ray structures of COX-1 and COX-2. Docking results are in good accordance with the experimental biological data.
Assuntos
Analgésicos/síntese química , Analgésicos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Ácido Cinurênico/análogos & derivados , Ácido Cinurênico/síntese química , Ácido Cinurênico/farmacologia , Analgésicos/química , Analgésicos/metabolismo , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Carragenina/química , Carragenina/metabolismo , Ciclo-Oxigenase 1/farmacologia , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/farmacologia , Avaliação Pré-Clínica de Medicamentos , Indometacina/farmacologia , Ácido Cinurênico/química , Modelos Moleculares , Ratos , Relação Estrutura-AtividadeRESUMO
In the kidney, prostaglandin (PG) E2 is the main PG, playing important roles in maintaining homeostasis or development of pathological settings. Roles of PGE2 in renal lesions remain to be clarified. The expression patterns of PGE2 synthesis enzymes such as cyclooxygenase (COX)-1, COX-2 and microsomal PGE synthase (mPGES)-1, and PGE2 receptors (EP2 and EP4) were examined in cisplatin-induced rat renal failure. The immunoexpressions for COX-1, mPGES-1 and EP4 receptor were increased exclusively in the affected renal tubules, but those of COX-2 and EP2 receptor were not detected; increased expression of COX-1 was confirmed at mRNA level. Using rat renal epithelial cell line (NRK-52E), the effects of PGE2 on cell proliferation were investigated. The addition of PGE2 or 11-deoxy-PGE1 (EP4 receptor agonist) to NRK-52E increased the cell number, indicating the effects of PGE2 via EP4 receptor. Furthermore, 11-deoxy-PGE1-treated NRK-52E cells underwent the G0/G1 arrest and decreased apoptosis. NRK-52E treated with transforming growth factor (TGF)-beta1, an inducer of epithelial-mesenchymal transition (EMT), in the presence of 11-deoxy-PGE1 decreased the mRNA expression of alpha-smooth muscle actin (a marker of myofibroblasts). Collectively, the present study shows that COX-1 plays more important roles than dose COX-2 in cisplatin-induced rat renal failure; the product, PGE2, may regulate renal epithelial regeneration via EP4 receptor through inhibition of apoptosis and EMT.
Assuntos
Dinoprostona/metabolismo , Alprostadil/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Cisplatino/metabolismo , Cisplatino/farmacologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 1/farmacologia , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/farmacologia , Dinoprostona/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Oxirredutases Intramoleculares , Rim/metabolismo , Túbulos Renais/metabolismo , Masculino , Prostaglandina-E Sintases , Ratos , Ratos Endogâmicos F344 , Receptores de Prostaglandina E/metabolismo , Receptores de Prostaglandina E/fisiologia , Receptores de Prostaglandina E Subtipo EP2 , Receptores de Prostaglandina E Subtipo EP4 , Regeneração/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologiaRESUMO
Prostaglandins, generated within the fetal brain, are integral components of the mechanism controlling the fetal hypothalamus-pituitary-adrenal (HPA) axis. Previous studies in this laboratory demonstrated that prostaglandin G/H synthase isozyme 2 (PGHS-2) inhibition reduces the fetal HPA axis response to cerebral hypoperfusion, blocks the preparturient rise in fetal plasma ACTH concentration, and delays parturition. We also discovered that blockade of N-methyl-d-aspartate (NMDA) receptors reduces the fetal ACTH response to cerebral hypoperfusion. The present study was designed to test the hypothesis that PGHS-2 action and the downstream effect of HPA axis stimulation are stimulated by NMDA-mediated glutamatergic neurotransmission. Chronically catheterized late-gestation fetal sheep (n = 8) were injected with NMDA (1 mg iv). All responded with increases in fetal plasma ACTH and cortisol concentrations. Pretreatment with resveratrol (100 mg iv, n = 5), a specific inhibitor of PGHS-1, did not alter the magnitude of the HPA axis response to NMDA. Pretreatment with nimesulide (10 mg iv, n = 6), a specific inhibitor of PGHS-2, significantly reduced the HPA axis response to NMDA. To further explore this interaction, we injected NMDA in six chronically catheterized fetal sheep that were chronically infused with nimesulide (n = 6) at a rate of 1 mg/day into the lateral cerebral ventricle for 5-7 days. In this group, there was no significant ACTH response to NMDA. Finally, we tested whether the HPA axis response to prostaglandin E(2) (PGE(2)) is mediated by NMDA receptors. Seven chronically catheterized late-gestation fetal sheep were injected with 100 ng of PGE(2), which significantly increased fetal plasma ACTH and cortisol concentrations. Pretreatment with ketamine (10 mg iv), an NMDA antagonist, did not alter the ACTH or cortisol response to PGE(2). We conclude that generation of prostanoids via the action of PGHS-2 in the fetal brain augments the fetal HPA axis response to NMDA-mediated glutamatergic stimulation.
Assuntos
Ciclo-Oxigenase 2/metabolismo , Sistema Hipófise-Suprarrenal/fisiologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Animais , Ciclo-Oxigenase 1/farmacologia , Ciclo-Oxigenase 2/farmacologia , Ácido D-Aspártico/farmacologia , Feminino , Feto/metabolismo , Hidrocortisona/sangue , Hipotálamo/metabolismo , Isoenzimas/metabolismo , Isoenzimas/farmacologia , N-Metilaspartato/farmacologia , Sistemas Neurossecretores/metabolismo , Parto , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Gravidez , Prostaglandina-Endoperóxido Sintases/farmacologia , Prostaglandinas/farmacologia , Resveratrol , Ovinos , Estilbenos , SulfonamidasRESUMO
BACKGROUND AND PURPOSE: The aim of the current study was to investigate the role of arachidonic acid (AA) metabolism via cyclooxygenase (COX) in the endothelial dysfunction of penile arteries from pre-diabetic, obese Zucker rats (OZR). EXPERIMENTAL APPROACH: Penile arteries from OZR and from lean Zucker rats (LZR) were mounted in microvascular myographs to assess vascular function and COX expression was determined by immunohistochemistry. KEY RESULTS: Acetylcholine (ACh) and AA elicited relaxations that were impaired in arteries from OZR. Inhibition of both COX-1 and COX-2 reduced the relaxant effects of ACh and AA in LZR but not in OZR. Inhibitors of COX-1 and of the TXA(2)/PGH(2) (TP) receptor enhanced the relaxations induced by AA in both LZR and OZR, whereas COX-2 inhibition enhanced these responses only in OZR. TP receptor blockade did not restore ACh relaxant responses in arteries from OZR. Inhibition of COX-1 increased basal tension in OZR and this contraction was blunted by TP receptor blockade. The vasoconstrictor responses to noradrenaline were augmented by indomethacin and by COX-2 inhibition in LZR but not in OZR. Immunohistochemical staining showed that both COX-1 and COX-2 are expressed in the endothelium of penile arteries from both LZR and OZR. CONCLUSIONS AND IMPLICATIONS: Vasoactive prostanoids were formed via constitutively active COX-1 and COX-2 pathways in normal rat penile arteries. Under conditions of insulin resistance, the release and/or effects of vasodilator prostanoids were impaired, contributing to the blunted endothelium-dependent vasodilatation and to the enhanced vasoconstriction.
Assuntos
Artérias/fisiologia , Artérias/fisiopatologia , Obesidade , Vasoconstrição/fisiologia , Vasodilatação/fisiologia , Acetilcolina/metabolismo , Acetilcolina/farmacologia , Animais , Ácido Araquidônico/metabolismo , Ácido Araquidônico/farmacologia , Artérias/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 1/farmacologia , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/farmacologia , Hiperemia/metabolismo , Hiperemia/fisiopatologia , Resistência à Insulina , Masculino , Óxido Nítrico Sintase Tipo III , Norepinefrina/metabolismo , Norepinefrina/farmacologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Pênis/metabolismo , Pênis/fisiopatologia , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/fisiopatologia , Ratos , Ratos Zucker , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/metabolismo , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/metabolismo , Vasodilatadores/farmacologiaRESUMO
BACKGROUND AND PURPOSE: Although resveratrol is currently being evaluated in pre-clinical studies as a potential cancer chemopreventive agent and cardiovascular stress-releasing compound, treatment with resveratrol severely delays healing of pre-existing gastric ulcers. Resveratrol treatment can also induce endothelial NOS (eNOS) expression. Here, we have attempted to modulate NO production via eNOS in order to alleviate the pro-ulcer effects of resveratrol. EXPERIMENTAL APPROACH: Gastric ulcers were induced in mice with a single dose of indomethacin. The effects of pretreatment with l-arginine on the pro-ulcer effects of resveratrol in these mice were then assessed. We measured ulcer damage scores (DS), myeloperoxidase (MPO) activity, generation of prostaglandin E(2) (PGE(2)) and NO, along with a gene expression study. KEY RESULTS: Resveratrol significantly aggravated damage from indomethacin-induced gastric ulcers, and delayed healing, as shown by increased DS and MPO activity. The mRNA for cyclooxygenase (COX)-1, but not that for COX-2, was inhibited by resveratrol treatment, with reduced synthesis of PGE(2) by gastric tissue. However, resveratrol treatment induced eNOS gene expression and shifted the eNOS/iNOS balance. l-Arginine given before resveratrol in mice with indomethacin-induced ulcers significantly increased tissue NO synthesis and improved ulcer healing. CONCLUSIONS AND IMPLICATIONS: Exogenous l-arginine increased NO formation via raised levels of eNOS induced by resveratrol and protected against the pro-ulcer effects of resveratrol. Therefore, l-arginine might be useful for alleviation of the pro-ulcer side effects of resveratrol in patients.
Assuntos
Indometacina/farmacologia , Úlcera Gástrica/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Arginina/metabolismo , Arginina/farmacologia , Arginina/uso terapêutico , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 1/farmacologia , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/farmacologia , Indometacina/efeitos adversos , Indometacina/uso terapêutico , Masculino , Camundongos , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , RNA Mensageiro/metabolismo , RNA Mensageiro/farmacologia , Resveratrol , Estilbenos , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismo , Úlcera/tratamento farmacológico , Úlcera/metabolismo , Cicatrização/efeitos dos fármacosRESUMO
UNLABELLED: Prostaglandins control osteoblastic and osteoclastic function under physiological or pathological conditions and are important modulators of the bone healing process. The non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity and consequently prostaglandins synthesis. Experimental and clinical evidence has indicated a risk for reparative bone formation related to the use of non-selective (COX-1 and COX-2) and COX-2 selective NSAIDs. Ketorolac is a non-selective NSAID which, at low doses, has a preferential COX-1 inhibitory effect and etoricoxib is a new selective COX-2 inhibitor. Although literature data have suggested that ketorolac can interfere negatively with long bone fracture healing, there seems to be no study associating etoricoxib with reparative bone formation. Paracetamol/acetaminophen, one of the first choices for pain control in clinical dentistry, has been considered a weak anti-inflammatory drug, although supposedly capable of inhibiting COX-2 activity in inflammatory sites. OBJECTIVE: The purpose of the present study was to investigate whether paracetamol, ketorolac and etoricoxib can hinder alveolar bone formation, taking the filling of rat extraction socket with newly formed bone as experimental model. MATERIAL AND METHODS: The degree of new bone formation inside the alveolar socket was estimated two weeks after tooth extraction by a differential point-counting method, using an optical microscopy with a digital camera for image capture and histometry software. Differences between groups were analyzed by ANOVA after confirming a normal distribution of sample data. RESULTS AND CONCLUSIONS: Histometric results confirmed that none of the tested drugs had a detrimental effect in the volume fraction of bone trabeculae formed inside the alveolar socket.
Assuntos
Acetaminofen/efeitos adversos , Analgésicos não Narcóticos/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Regeneração Óssea/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Cetorolaco/efeitos adversos , Piridinas/efeitos adversos , Sulfonas/efeitos adversos , Acetaminofen/farmacologia , Analgésicos não Narcóticos/farmacologia , Análise de Variância , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 1/efeitos adversos , Ciclo-Oxigenase 1/farmacologia , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2/farmacologia , Modelos Animais de Doenças , Etoricoxib , Consolidação da Fratura/efeitos dos fármacos , Cetorolaco/farmacologia , Masculino , Piridinas/farmacologia , Ratos , Ratos Wistar , Sulfonas/farmacologia , Fatores de TempoRESUMO
A range of activation processes and confirmatory and metabolic changes take place in blood platelets following their activation. The paper discusses some of the blood platelet activation steps and describes the specific processes that take place on this level. Furthermore, the points at which it is possible to actively interfere with the blood platelet metabolism or activation processes are described. Antiplatelet treatment focuses on these points and there are efforts to identify active substances that either inhibit access to certain receptors or targets or, alternatively, inhibit the enzymes participating in these processes.
Assuntos
Plaquetas/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Animais , Ácido Araquidônico/farmacologia , Ciclo-Oxigenase 1/farmacologia , Humanos , Ativação Plaquetária/fisiologiaRESUMO
Non-steroidal anti-inflammatory drugs (NSAIDs) are known to increase the risk of gastrointestinal injury including gastric ulcer. Topical injury under low pH environment and cyclooxygenase-1 (COX-1) inhibition resulting in gastric prostaglandin (PG) suppression are two main mechanisms of gastric damage. Topical injury can be avoided by prodrug which is activated after absorption or alter drug administration route such as suppository. But, gastric injury by PG suppression cannot be avoided even by such contrivances. Use of selective COX-2 inhibitor is another way to reduce gastric injury and certain effect is already established. However, least expected side effect of cardiovascular damage was identified by selective COX-2 inhibitor. Still NSAIDs are effective and applicable for many diseases. Numbers of prescription for aged patients are increasing. Physicians should percept the mechanism of effect and side effect of NSAIDs, and exert their best to avoid side effects of NSAIDs.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Trato Gastrointestinal/efeitos dos fármacos , Úlcera Péptica/induzido quimicamente , Idoso , Anti-Inflamatórios não Esteroides/administração & dosagem , Ciclo-Oxigenase 1/farmacologia , Ciclo-Oxigenase 2/farmacologia , Quimioterapia Combinada , HumanosRESUMO
OBJECTIVE: There are extensive data on roles of cyclooxygenase 1 (COX 1) and cyclooxygenase 2 (COX 2) enzymes in temperature, coagulation, and inflammatory modulation. There is little known of the function of these enzymes in regulating tone in pulmonary vasculature. The purpose of this investigation was to elucidate the roles of COX 1 and 2 enzymes in the feline pulmonary vascular bed. DESIGN: Prospective vehicle controlled study. SETTING: University research laboratory. SUBJECTS: Intact chest preparation; adult mongrel cats. INTERVENTIONS: The effects of intravascular administration of U46619, angiotensin II, prostaglandin E1 (PGE1), arachidonic acid, and norepinephrine, were analyzed before and after intravascular administration of selective COX enzyme inhibitors. MEASUREMENTS AND MAIN RESULTS: Because lobar arterial flow is constant in these experiments, changes in lobar pressure represent changes in pulmonary arterial resistance. Under constant flow conditions, lobar arterial and systemic pressures were continuously monitored, electronically averaged, and recorded. In the isolated left lower lobe of the feline lung bed, U46619, angiotensin II, arachidonic acid, and norepinephrine induced a dose-dependent vasoconstrictor response. PGE1 induced a dose-dependent vasodepressor response. After administration of the COX 1 inhibitor SC 560, the arachidonic acid-induced vasopressor responses were significantly attenuated while U46619, angiotensin II, and norepinephrine-induced vasopressor, and PGE1-induced vasodepressor responses were not significantly altered. After administration of the COX 2 inhibitor nimesulide, both the PGE 1 vasodepressor responses and arachidonic acid-induced vasopressor responses were significantly decreased while the U46619, angiotensin II, and norepinephrine-induced vasopressor responses were not significantly attenuated. CONCLUSIONS: The results of the study indicate that PGE1 has potent vasodepressor effects in the feline lung bed and this response is mediated by COX 2 pathways. The data also suggest that arachidonic acid has potent vasopressor activity in the feline pulmonary vascular bed and this response is mediated by both COX 1 and COX 2 sensitive pathways.
Assuntos
Ciclo-Oxigenase 1/fisiologia , Ciclo-Oxigenase 2/fisiologia , Inibidores de Ciclo-Oxigenase/farmacologia , Pulmão/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Alprostadil/farmacologia , Animais , Ácido Araquidônico/farmacologia , Gatos , Ciclo-Oxigenase 1/farmacologia , Ciclo-Oxigenase 2/farmacologia , Interações Medicamentosas , Pulmão/irrigação sanguínea , Norepinefrina/farmacologia , Vasoconstritores/antagonistas & inibidoresRESUMO
CONTEXT: Recent randomized trials suggest that women may not accrue the same cardioprotective benefits as men do from low-dose aspirin therapy used in primary prevention. Failure of aspirin to suppress platelet aggregation in women is one hypothesized mechanism. OBJECTIVE: To examine differential platelet reactivity to low-dose aspirin therapy by sex. DESIGN, SETTING, AND PARTICIPANTS: A clinical trial of aspirin at 81 mg/d for 14 days was conducted in 571 men and 711 women. Baseline and post-aspirin therapy measures included platelet aggregation to arachidonic acid, adenosine diphosphate, epinephrine, and platelet function analyzer closure time. MAIN OUTCOME MEASURE: Sex differences in cyclooxygenase 1 (COX-1) direct and indirect platelet activation pathways before and after administration of aspirin. RESULTS: In 10 of the 12 platelet agonist exposures, women's platelets were significantly more reactive at baseline. However, after aspirin therapy, the percent aggregation to arachidonic acid (the direct COX-1 pathway) decreased more in women than in men (P<.001) and demonstrated near total suppression of residual platelet reactivity in both men and women. In COX-1 indirect pathways, women experienced the same or more platelet inhibition than men in 8 of the 9 assays yet retained modestly greater platelet reactivity after aspirin therapy. In multivariable analysis, female sex significantly predicted aggregation to 2 muM and 10 muM of adenosine diphosphate (P = .02 and <.001, respectively) and collagen at 5 mug/mL (P<.001) independent of risk factors, age, race, menopausal status, and hormone therapy. CONCLUSIONS: Women experienced the same or greater decreases in platelet reactivity after aspirin therapy, retaining modestly more platelet reactivity compared with men. However, most women achieved total suppression of aggregation in the direct COX-1 pathway, the putative mechanism for aspirin's cardioprotection.
Assuntos
Aspirina/uso terapêutico , Inibidores de Ciclo-Oxigenase/uso terapêutico , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/uso terapêutico , Difosfato de Adenosina/farmacologia , Ácido Araquidônico/farmacologia , Aspirina/farmacologia , Doenças Cardiovasculares/prevenção & controle , Colágeno/farmacologia , Ciclo-Oxigenase 1/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Epinefrina/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/farmacologia , Testes de Função Plaquetária , Análise de Regressão , Fatores SexuaisRESUMO
Typically, small lizards rely heavily on behavioral thermoregulation rather than physiological mechanisms to control their rates of warming and cooling. We tested the hypothesis that prostaglandins participate in mediating the cardiovascular response to heating and cooling and temperature regulating neurons in the hypothalamus of the small lizard Phrynocephalus przewalskii. In vivo and in vitro treatments, heart rates (HRs) were all found to be higher during heating than during cooling, hysteresis was distinct below 30 and 26 degrees Celsius, respectively. In vivo, as administration of COX inhibitor, there were no differences in HR between heating and cooling at any body temperature and administration of agonist prostaglandins only produced a significant effect on HR below 25 degrees Celsius. Single-unit activity was recorded extracellularly in vitro with microelectrodes, found the firing rate of the continuous unit increased 23% when the temperature of the artificial cerebrospinal fluid dropped from 30-20 degrees Celsius. We conclude that prostaglandins appear to play only a limited role in modulating heart activity in Phrynocephalus przewalskii and suggest that cold-sensitive neurons in the preoptic and anterior hypothalamus (PO/AH) are involved in thermoregulatory control during heating or cooling.
Assuntos
Regulação da Temperatura Corporal , Frequência Cardíaca/efeitos dos fármacos , Hipotálamo/irrigação sanguínea , Lagartos/fisiologia , Prostaglandinas/farmacologia , Animais , Temperatura Corporal , Ciclo-Oxigenase 1/farmacologia , Ciclo-Oxigenase 2/farmacologia , Hipotálamo/fisiologia , Técnicas In Vitro , Masculino , Microeletrodos , Fluxo Sanguíneo Regional , Cloreto de Sódio/farmacologiaRESUMO
Non-steroidal anti-inflammatory drugs (NSAIDs) and inhibitors of the cyclooxygenase (COX) pathways are currently recommended for the prevention and treatment of several inflammatory diseases, including neurodegenerative disorders. However non-selective blockade of COX was found to have pro-inflammatory properties, because they have the ability to alter the plasma glucocorticoid levels that play a critical role in the control of the innate immune response. The present study investigated the role of non-selective (ketorolac or indomethacin) or specific inhibitors of COX-1 (SC-560) and COX-2 (NS-398) in these effects. Mice challenged systemically with the endotoxin lipopolysaccharide (LPS) exhibited a robust hybridization signal for numerous inflammatory genes in vascular-associated cells of the brain and microglia across the cerebral tissue. Ketorolac, indomethacin and NS-398 significantly increased the ability of LPS to trigger such an innate immune response at time 3 h post challenge, whereas SC-560 failed to change gene expression in the brain of animals treated with the endotoxin. These data together with the crucial role of COX-2-derived prostaglandin E2 (PGE2) in the increase of glucocorticoids during systemic immune stimuli provide evidence that inhibition of this pathway results in an exacerbated early innate immune reaction. This may have a major impact on the use of these drugs in diseases where inflammation is believed to be a contributing and detrimental factor.