RESUMO
Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used medications associated with nephrotoxicity, especially when used chronically. Factors such as advanced age and comorbidities, which in themselves already lead to a decrease in glomerular filtration rate, increase the risk of NSAID-related nephrotoxicity. The main mechanism of NSAID action is cyclooxygenase (COX) enzyme inhibition, interfering on arachidonic acid conversion into E2 prostaglandins E2, prostacyclins and thromboxanes. Within the kidneys, prostaglandins act as vasodilators, increasing renal perfusion. This vasodilatation is a counter regulation of mechanisms, such as the renin-angiotensin-aldosterone system works and that of the sympathetic nervous system, culminating with compensation to ensure adequate flow to the organ. NSAIDs inhibit this mechanism and can lead to acute kidney injury (AKI). High doses of NSAIDs have been implicated as causes of AKI, especially in the elderly. The main form of AKI by NSAIDs is hemodynamically mediated. The second form of NSAID-induced AKI is acute interstitial nephritis, which may manifest as nephrotic proteinuria. Long-term NSAID use can lead to chronic kidney disease (CKD). In patients without renal diseases, young and without comorbidities, NSAIDs are not greatly harmful. However, because of its dose-dependent effect, caution should be exercised in chronic use, since it increases the risk of developing nephrotoxicity.
Resumo Os anti-inflamatórios não esteroidais (AINEs) são medicamentos comumente utilizados, associados à nefrotoxicidade, sobretudo quando utilizados cronicamente. Fatores como idade avançada e comorbidades, que por si só já levam à diminuição da taxa de filtração glomerular, aumentam o risco de nefrotoxicidade dos AINEs. O principal mecanismo de ação dos AINEs é a inibição da enzima ciclooxigenase (COX), interferindo na conversão do ácido araquidônico em prostaglandinas E2, prostaciclinas e tromboxanos. Nos rins, as prostaglandinas atuam como vasodilatadoras, aumentando a perfusão renal. Essa vasodilatação atua como uma contrarregulação de mecanismos, como a atuação do sistema renina-angiotensina-aldosterona e do sistema nervoso simpático, culminando com uma compensação para assegurar o fluxo adequado ao órgão. O uso de AINEs inibe esse mecanismo, podendo causar lesão renal aguda (LRA). Altas doses de AINEs têm sido implicadas como causas de LRA, especialmente em idosos. A principal forma de LRA por AINEs é a hemodinamicamente mediada. A segunda forma de apresentação da LRA induzida por AINES é a nefrite intersticial aguda, que pode se manifestar com proteinúria nefrótica. O uso de AINEs em longo prazo pode ocasionar doença renal crônica (DRC). Nos pacientes sem doenças renais, jovens e sem comorbidades, os AINEs não apresentam grandes malefícios. Entretanto, por seu efeito dose-dependente, deve-se ter grande cautela no uso crônico, por aumentar risco de desenvolver nefrotoxicidade.
Assuntos
Humanos , Recém-Nascido , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/efeitos adversos , Inibidores de Ciclo-Oxigenase/efeitos adversos , Insuficiência Renal Crônica/induzido quimicamente , Injúria Renal Aguda/induzido quimicamente , Nefrite Intersticial/induzido quimicamente , Prostaglandinas E/metabolismo , Proteinúria/induzido quimicamente , Anti-Inflamatórios não Esteroides/metabolismo , Fatores de Risco , Inibidores de Ciclo-Oxigenase/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Injúria Renal Aguda/fisiopatologia , Nefrite Intersticial/fisiopatologiaRESUMO
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used medications associated with nephrotoxicity, especially when used chronically. Factors such as advanced age and comorbidities, which in themselves already lead to a decrease in glomerular filtration rate, increase the risk of NSAID-related nephrotoxicity. The main mechanism of NSAID action is cyclooxygenase (COX) enzyme inhibition, interfering on arachidonic acid conversion into E2 prostaglandins E2, prostacyclins and thromboxanes. Within the kidneys, prostaglandins act as vasodilators, increasing renal perfusion. This vasodilatation is a counter regulation of mechanisms, such as the renin-angiotensin-aldosterone system works and that of the sympathetic nervous system, culminating with compensation to ensure adequate flow to the organ. NSAIDs inhibit this mechanism and can lead to acute kidney injury (AKI). High doses of NSAIDs have been implicated as causes of AKI, especially in the elderly. The main form of AKI by NSAIDs is hemodynamically mediated. The second form of NSAID-induced AKI is acute interstitial nephritis, which may manifest as nephrotic proteinuria. Long-term NSAID use can lead to chronic kidney disease (CKD). In patients without renal diseases, young and without comorbidities, NSAIDs are not greatly harmful. However, because of its dose-dependent effect, caution should be exercised in chronic use, since it increases the risk of developing nephrotoxicity.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Anti-Inflamatórios não Esteroides/efeitos adversos , Inibidores de Ciclo-Oxigenase/efeitos adversos , Nefrite Intersticial/induzido quimicamente , Insuficiência Renal Crônica/induzido quimicamente , Injúria Renal Aguda/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/metabolismo , Inibidores de Ciclo-Oxigenase/metabolismo , Humanos , Recém-Nascido , Nefrite Intersticial/fisiopatologia , Prostaglandinas E/metabolismo , Proteinúria/induzido quimicamente , Insuficiência Renal Crônica/fisiopatologia , Fatores de RiscoRESUMO
Mori folium, the leaf of Morus alba L. (Moraceae), has been traditionally used for various medicinal purposes from ancient times to the present. In this study, we examined the effects of water extract of Mori folium (WEMF) on the production of inflammatory mediators, such as nitric oxide (NO) and prostaglandin E2 (PGE2), and reactive oxygen species (ROS) in lipopolysaccharide (LPS)-stimulated murine RAW 264.7 macrophages. Our data indicated that WEMF significantly suppressed the secretion of NO and PGE2 in RAW 264.7 macrophages without any significant cytotoxicity. The protective effects were accompanied by a marked reduction in their regulatory gene expression at the transcription level. WEMF attenuated LPS-induced intracellular ROS production in RAW 264.7 macrophages. It inhibited the nuclear translocation of the nuclear factor-kappa B p65 subunit and the activation of mitogen-activated protein kinases in LPS-treated RAW 264.7 macrophages. Furthermore, WEMF reduced LPS-induced NO production and ROS accumulation in zebrafish. Although more efforts are needed to fully understand the critical role of WEMF in the inhibition of inflammation, the findings of the present study may provide insights into the approaches for Mori folium as a potential therapeutic agent for inflammatory and antioxidant disorders.
Assuntos
Mediadores da Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Morus/química , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Peixe-Zebra , Animais , Expressão Gênica , Genes Reguladores , Mediadores da Inflamação/antagonistas & inibidores , Lipopolissacarídeos , Macrófagos/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Prostaglandinas E/metabolismo , Células RAW 264.7 , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
ABSTRACT Mori folium, the leaf of Morus alba L. (Moraceae), has been traditionally used for various medicinal purposes from ancient times to the present. In this study, we examined the effects of water extract of Mori folium (WEMF) on the production of inflammatory mediators, such as nitric oxide (NO) and prostaglandin E2 (PGE2), and reactive oxygen species (ROS) in lipopolysaccharide (LPS)-stimulated murine RAW 264.7 macrophages. Our data indicated that WEMF significantly suppressed the secretion of NO and PGE2 in RAW 264.7 macrophages without any significant cytotoxicity. The protective effects were accompanied by a marked reduction in their regulatory gene expression at the transcription level. WEMF attenuated LPS-induced intracellular ROS production in RAW 264.7 macrophages. It inhibited the nuclear translocation of the nuclear factor-kappa B p65 subunit and the activation of mitogen-activated protein kinases in LPS-treated RAW 264.7 macrophages. Furthermore, WEMF reduced LPS-induced NO production and ROS accumulation in zebrafish. Although more efforts are needed to fully understand the critical role of WEMF in the inhibition of inflammation, the findings of the present study may provide insights into the approaches for Mori folium as a potential therapeutic agent for inflammatory and antioxidant disorders.
Assuntos
Animais , Ratos , Peixe-Zebra , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Morus/química , Macrófagos/efeitos dos fármacos , Prostaglandinas E/metabolismo , Expressão Gênica , Genes Reguladores , Lipopolissacarídeos , Mediadores da Inflamação/antagonistas & inibidores , Células RAW 264.7 , Macrófagos/metabolismo , Óxido Nítrico/metabolismoRESUMO
Mast cells are immunoregulatory cells that participate in inflammatory processes. Cross-linking mast cell specific GD1b derived gangliosides by mAbAA4 results in partial activation of mast cells without the release of preformed mediators. The present study examines the release of newly formed and newly synthesized mediators following ganglioside cross-linking. Cross-linking the gangliosides with mAbAA4 released the newly formed lipid mediators, prostaglandins D2 and E2, without release of leukotrienes B4 and C4. The effect of cross-linking these gangliosides on the activation of enzymes in the arachidonate cascade was then investigated. Ganglioside cross-linking resulted in phosphorylation of cytosolic phospholipase A2 and increased expression of cyclooxygenase-2. Translocation of 5-lipoxygenase from the cytosol to the nucleus was not induced by ganglioside cross-linking. Cross-linking of GD1b derived gangliosides also resulted in the release of the newly synthesized mediators, interleukin-4, interleukin-6, and TNF-α. The effect of cross-linking the gangliosides on the MAP kinase pathway was then investigated. Cross-linking the gangliosides induced the phosphorylation of ERK1/2, JNK1/2, and p38 as well as activating both NFκB and NFAT in a Syk-dependent manner. Therefore, cross-linking the mast cell specific GD1b derived gangliosides results in the activation of signaling pathways that culminate with the release of newly formed and newly synthesized mediators.
Assuntos
Citocinas/metabolismo , Gangliosídeos/metabolismo , Mastócitos/metabolismo , Animais , Linhagem Celular , Fosfolipases A2 do Grupo IV/metabolismo , Immunoblotting , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Leucotrienos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Fosforilação , Prostaglandinas D/metabolismo , Prostaglandinas E/metabolismo , Ratos , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
RESUMO: Objetivo: Descrever as principais doenças crônicas não transmissíveis (DCNT) no país segundo as informações coletadas em indivíduos de 18 anos ou mais de idade. Métodos: Foram utilizados dados da Pesquisa Nacional de Saúde (PNS), 2013, estudo transversal de base populacional. As proporções de cada DCNT foram calculadas e apresentadas segundo sexo, com intervalo de confiança de 95% (IC95%), com os valores absolutos. Resultados: Do total de entrevistados, 45,1% referiram ter pelo menos uma DCNT. A Região com maior prevalência de DCNT foi a Sul (52,1%). A hipertensão arterial apresentou a maior prevalência dentre as DCNT, com 21,4%, seguida por problema crônico de coluna (18,5%), depressão (7,6%), artrite (6,4%) e diabetes (6,2%). O grau de limitação intenso/muito intenso apresentou maiores prevalências para outra doença mental (37,6%) e acidente vascular cerebral (AVC) (25,5%). Conclusão: A melhoria dos serviços de saúde é indispensável para uma resposta efetiva à dupla carga de adoecimento de países de média e baixa renda.
ABSTRACT: Objective: To describe the major noncommunicable diseases (NCDs) in Brazil, according to the information collected from individuals aged 18 years or older. Methods: Data from the National Health Survey (PNS), 2013, a transversal population-based study, were used. The proportions of each NCD were calculated and presented according to sex, with a 95% confidence interval (95%CI), with the absolute values. Results: Of the total respondents, 45.1% reported presenting at least one NCD. The region with the highest prevalence of NCDs was the South (52.1%). Hypertension showed the highest prevalence among NCDs, with 21.4%, followed by chronic back problem (18.5%), depression (7.6%), arthritis (6.4%), and diabetes (6.2%). The intense/very intense degree of limitation showed a higher prevalence of other mental illnesses (37.6%) and cerebrovascular accident (25.5%). Conclusion: The improvement of health services is essential for an effective response to the double burden of illness in the middle- and low-income countries.
Assuntos
Humanos , Antivirais/farmacologia , /metabolismo , Enterovirus Humano A/efeitos dos fármacos , Infecções por Enterovirus/genética , Isoflavonas/farmacologia , Prostaglandinas E/metabolismo , Replicação Viral/efeitos dos fármacos , /genética , Enterovirus Humano A/fisiologia , Infecções por Enterovirus/enzimologia , Infecções por Enterovirus/metabolismo , Infecções por Enterovirus/virologiaRESUMO
This study analyzed the effect of in utero exposure to maternal diabetes on contraction to noradrenaline in mesenteric resistance arteries (MRA) from adult offspring, focusing on the role of cyclooxygenase (COX)-derived prostanoids. Diabetes in the maternal rat was induced by a single injection of streptozotocin (50 mg/kg body weight) on day 7 of pregnancy. Contraction to noradrenaline was analyzed in isolated MRA from offspring of diabetic (O-DR) and non-diabetic (O-CR) rats at 3, 6 and 12 months of age. Release of thromboxane A(2) (TxA(2)) and prostaglandins E(2) (PGE(2)) and F(2α) (PGF(2α)), was measured by specific enzyme immunoassay kits. O-DR developed hypertension from 6 months of age compared with O-CR. Arteries from O-DR were hyperactive to noradrenaline only at 6 and 12 months of age. Endothelial removal abolished this hyperreactivity to noradrenaline between O-CR and O-DR. Preincubation with either the COX-1/2 (indomethacin) or COX-2 inhibitor (NS-398) decreased noradrenaline contraction only in 6- and 12-month-old O-DR, while it remained unmodified by COX-1 inhibitor SC-560. In vessels from 6-month-old O-DR, a similar reduction in the contraction to noradrenaline produced by NS-398 was observed when TP and EP receptors were blocked (SQ29548+AH6809). In 12-month-old O-DR, this effect was only achieved when TP, EP and FP were blocked (SQ29548+AH6809+AL8810). Noradrenaline-stimulated TxB(2) and PGE(2) release was higher in 6- and 12-month-old O-DR, whereas PGF(2α) was increased only in 12-month-old O-DR. Our results demonstrated that in utero exposure to maternal hyperglycaemia in rats increases the participation of COX-2-derived prostanoids on contraction to noradrenaline, which might help to explain the greater response to this agonist in MRA from 6- and 12-month-old offspring. As increased contractile response in resistance vessels may contribute to hypertension, our results suggest a role for these COX-2-derived prostanoids in elevating vascular resistance and blood pressure in offspring of diabetic rats.
Assuntos
Ciclo-Oxigenase 2/metabolismo , Diabetes Mellitus Experimental/metabolismo , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Norepinefrina/farmacologia , Prostaglandinas/metabolismo , Animais , Células Cultivadas , Dinoprosta/análogos & derivados , Dinoprosta/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Técnicas Imunoenzimáticas , Indometacina/farmacologia , Masculino , Nitrobenzenos/farmacologia , Gravidez , Prostaglandinas E/metabolismo , Prostaglandinas F/metabolismo , Ratos , Sulfonamidas/farmacologia , Tromboxano A2/metabolismo , Xantonas/farmacologiaRESUMO
OBJECTIVE: Periodontitis is an infectious disease leading to inflammation and destruction of tissue surrounding and supporting the tooth. The progress of the inflammatory response depends on the host's immune system and risk factors such as stress. The aim of the present study was to investigate the role of the endocannabinoid anandamide (AEA) in experimental periodontitis with restraint stress, since the endocannabinoid system is known to modulate the hypothalamo-pituitary-adrenal axis as well as immune functions and has been found in human gingival tissues. METHODS: Experimental periodontitis was induced by ligature around first inferior molars and immobilization stress for 2 h twice daily for 7 days in a rat model. RESULTS: Corticosterone plasma levels, locomotor activity, adrenal gland weight and bone loss were increased in periodontitis and stress groups, and there was also less weight gain. The inflammatory parameters such as prostaglandin E(2) (radioimmunoassay), nitric oxide (radioconversion of (14)C-arginine), tumor necrosis factor (TNF)-α (ELISA) and interleukin (IL)-1ß (Western blot) measured in the gingival tissue were significantly increased in the periodontitis groups compared to the control group. Local injection of AEA (10(-8)M, 30 µl) decreased corticosterone plasma levels and the content of the cytokines TNF-α and IL-1ß in gingival tissue in periodontitis-stress groups. These AEA-induced inhibitions were mediated by CB(1) and CB(2) cannabinoid receptors since the injection of both antagonists together, AM251 (10(-6)M) and AM630 (10(-6)M) in 30 µl, prevented these effects. CONCLUSION: The endocannabinoid AEA diminishes the inflammatory response in periodontitis even during a stressful situation.
Assuntos
Anti-Inflamatórios/uso terapêutico , Ácidos Araquidônicos/uso terapêutico , Agonistas de Receptores de Canabinoides/uso terapêutico , Endocanabinoides/uso terapêutico , Periodontite/tratamento farmacológico , Alcamidas Poli-Insaturadas/uso terapêutico , Estresse Psicológico/tratamento farmacológico , Perda do Osso Alveolar/etiologia , Perda do Osso Alveolar/patologia , Animais , Peso Corporal/efeitos dos fármacos , Corticosterona/sangue , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Comportamento Exploratório/efeitos dos fármacos , Indóis/uso terapêutico , Interleucina-1beta/metabolismo , Masculino , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Periodontite/sangue , Periodontite/fisiopatologia , Piperidinas/uso terapêutico , Prostaglandinas E/metabolismo , Pirazóis/uso terapêutico , Ratos , Ratos Wistar , Estatísticas não Paramétricas , Estresse Psicológico/sangue , Estresse Psicológico/fisiopatologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
All forms of stress, including restraint stress (RS) and lipopolysaccharide (LPS) administration, activate the hypothalamic-pituitary-adrenal (HPA) axis. LPS binds to a recognition protein (CD14) and toll-like receptor 2/4 in different cells and tissues, including the adrenal gland, to induce the production of cytokines and cause upregulation of cyclooxygenase and nitric oxide synthase (NOS) enzymes. Acute ethanol exposure activates the HPA axis, but in some conditions prolonged administration can dampen this activation as well as decrease the inflammatory responses to LPS. Therefore, this study was designed to evaluate the adrenal response to a challenge dose of LPS (50 µg/kg) injected i.p., after submitting male rats to RS, twice a day (2 h each time) for 5 days and/or ethanol administration (3 g/kg) by gavage also for 5 days, twice daily. At the end of the experiment, plasma corticosterone concentrations and adrenal gland content of prostaglandin E (PGE) and NOS activity were measured as stress mediators. The results showed that repetitive ethanol administration attenuated the adrenal stress response to LPS challenge alone and after RS, by preventing the increase in plasma corticosterone concentrations and by decreasing the PGE content and NOS activity in the adrenal gland. Therefore, we conclude that moderate alcohol consumption could attenuate the effects of psychophysical stress and impair an inflammatory response.
Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/fisiologia , Etanol/farmacologia , Lipopolissacarídeos/farmacologia , Animais , Corticosterona/sangue , Ciclo-Oxigenase 1/biossíntese , Ciclo-Oxigenase 2/biossíntese , Inflamação/prevenção & controle , Receptores de Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Masculino , Proteínas de Membrana/biossíntese , Óxido Nítrico Sintase/metabolismo , Prostaglandinas E/metabolismo , Ratos , Ratos Sprague-Dawley , Restrição Física , Estresse Psicológico/tratamento farmacológico , Receptor 4 Toll-Like/metabolismoRESUMO
OBJECTIVE: To evaluate the effect of aromatase inhibitors on ectopic endometrial growth and on the release of proangiogenic and proinflammatory factors in peritoneal fluid (PF). DESIGN: Prospective experimental study. SETTING: Animal research and laboratory facility. ANIMAL(S): Female Balb/c mice 2 months of age. INTERVENTION(S): Mice had surgery performed to induce endometriosis-like lesions. Treatment with anastrozole or letrozole was started on either postoperative day 1 or 28 and continued for 4 weeks. MAIN OUTCOME MEASURE(S): Endometriotic lesions were counted and measured and aromatase expression, cell proliferation, and apoptosis were assessed. Vascular endothelial growth factor (VEGF) and prostaglandin E (PGE) levels were evaluated in the PF. RESULT(S): Endometriosis-like lesions express aromatase P-450. Treatment with either anastrozole or letrozole did not prevent lesion establishment; however, it significantly decreased the size of the endometriotic lesion. When treatment was initiated on postoperative day 1, letrozole and anastrozole decreased cell proliferation and increased apoptosis. When treatment was started on postoperative day 28, both aromatase inhibitors decreased cell proliferation, but only anastrozole augmented apoptosis levels. In addition, letrozole reduced VEGF and PGE levels in PF. Anastrozole diminished VEGF content but did not cause any significant change in PGE levels. CONCLUSION(S): These findings support the further investigation of aromatase inhibition as a treatment option for endometriosis.
Assuntos
Inibidores da Aromatase/farmacologia , Endometriose/metabolismo , Nitrilas/farmacologia , Triazóis/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Anastrozol , Animais , Apoptose/efeitos dos fármacos , Aromatase/biossíntese , Líquido Ascítico/metabolismo , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Endometriose/patologia , Endométrio/efeitos dos fármacos , Feminino , Letrozol , Camundongos , Prostaglandinas E/metabolismoRESUMO
Residency in cities with high air pollution is associated with neuroinflammation and neurodegeneration in healthy children, young adults, and dogs. Nonsteroidal anti-inflammatory drugs may offer neuroprotection. The authors measured the plasma concentrations of 3-nitrotyrosine and the cerebro-spinal-fluid concentrations of prostaglandin E2 metabolite and the oligomeric form of amyloid derived diffusible ligand; measured the mRNA expression of cyclooxygenase-2, interleukin 1beta, CD14, and Aquaporin-4 in target brain areas; and evaluated brain MRI, cognition, and neuropathology in 8 dogs treated with a preferential cyclooxygenase-2 inhibitor (Nimesulide) versus 7 untreated litter-matched Mexico City dogs. Nimesulide significantly decreased nitrotyrosine in plasma (p < .0001), frontal gray IL1beta (p = .03), and heart IL1beta (p = .02). No effect was seen in mRNA COX2, amyloid, and PGE2 in CSF or the MRI white matter lesions. All exposed dogs exhibited olfactory bulb and frontal accumulation of Abeta(42) in neurons and blood vessels and frontal vascular subcortical pathology. White matter hyperintense MRI frontal lesions were seen in 4/6 non-treated and 6/8 treated dogs. Nonsteroidal anti-inflammatory drugs may offer limited neuroprotection in the setting of severe air pollution exposures. The search for potentially beneficial drugs useful to ameliorate the brain effects of pollution represents an enormous clinical challenge.
Assuntos
Poluição do Ar/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Cães/metabolismo , Sulfonamidas/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Aquaporina 4/metabolismo , Encéfalo/anatomia & histologia , Encéfalo/patologia , Distribuição de Qui-Quadrado , Ciclo-Oxigenase 2/genética , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Lobo Frontal/metabolismo , Imuno-Histoquímica , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Imageamento por Ressonância Magnética , México , Mucosa Nasal/metabolismo , Ozônio/efeitos adversos , Projetos Piloto , Prostaglandinas E/metabolismo , Estatísticas não Paramétricas , Sulfonamidas/farmacocinética , Tirosina/metabolismoRESUMO
We evaluated the effect of hyperandrogenism in ovaries with functional and regressing corpora lutea (CL) and the action of metformin in preventing these possible alterations using a mouse model. To obtain a CL functional for 9+/-1 days, immature female mice of the BALB/c strain were injected i.p. with 10 IU/mouse of pregnant mare's serum gonadotropin (PMSG). DHEA (60 mg/kg body weight s.c., 24 and 48 h prior to kill) decreased both serum progesterone (P) and estradiol (E(2)) levels and increased the activity of superoxide dismutase (SOD) from ovaries with functional CL (on day 5 after PMSG). It increased P and E(2) and the activities of SOD and catalase (CAT) and decreased lipoperoxidation of ovaries with regressing CL (on day 9 after PMSG). Treatment with DHEA did not affect the production of prostaglandin F(2alpha) (PGF(2alpha)) or PGE by ovaries with functional CL, whereas DHEA decreased PGF(2alpha) and increased PGE production by ovaries with regressing CL. Metformin (50 mg/kg body weight, orally) given together with DHEA restored E(2) levels from mice with ovaries with functional CL and serum P, PGF(2alpha) and PGE levels, and oxidative balance in mice with ovaries with regressing CL. Metformin alone was able to modulate serum P and E(2) levels, lipoperoxidation, SOD and CAT, and the 5,5-dimethyl-1-pyrroline N-oxide/(*)OH signal. These findings suggest that hyperandrogenism is able to induce or to rescue CL from luteolysis and metformin treatment is able to prevent these effects.
Assuntos
Corpo Lúteo/efeitos dos fármacos , Desidroepiandrosterona/farmacologia , Metformina/farmacologia , Animais , Corpo Lúteo/fisiologia , Dinoprosta/análise , Dinoprosta/metabolismo , Feminino , Hiperandrogenismo/patologia , Hiperandrogenismo/fisiopatologia , Hipoglicemiantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologia , Ovário/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Gravidez , Prostaglandinas E/análise , Prostaglandinas E/metabolismoRESUMO
This report addressed the question whether ExoU stimulation of airway epithelial cells may contribute to the inflammatory response detected in the course of Pseudomonas aeruginosa respiratory infections. Infection with PA103 P. aeruginosa elicited a potent release of IL-6 and IL-8, as well as of arachidonic acid (AA) and PGE(2) that was reduced by the bacterial treatment with MAFP, a cPLA(2) inhibitor. Airway cells from the BEAS-2B line and in primary culture were shown to be enriched in lipid bodies (LBs), that are cytoplasmic domains implicated in AA transformation into eicosanoids. However, cells infected with PA103 and with a mutant deficient in exoU but complemented with a functional gene exhibited reduced contents of LBs, and this reduction was inhibited by MAFP. FACS analysis showed that the decrease in the LB content correlated with the presence of intracellular PGE(2). Also, in PA103-infected cells, PGE(2) was immunolocalized in LBs, suggesting that the reduction in the cell content of the organelles was due to consumption of their glycerolipids, resulting in local synthesis of the prostanoid. In conclusion, we showed the ExoU ability to induce airway epithelial cells to overproduce PGE(2) and we speculate that LB may represent intracellular loci involved in ExoU-induced eicosanoid synthesis.
Assuntos
Proteínas de Bactérias/metabolismo , Brônquios/metabolismo , Células Epiteliais/metabolismo , Corpos de Inclusão/metabolismo , Mediadores da Inflamação/metabolismo , Infecções por Pseudomonas/metabolismo , Pseudomonas aeruginosa/metabolismo , Ácido Araquidônico/metabolismo , Ácidos Araquidônicos/farmacologia , Proteínas de Bactérias/genética , Brônquios/citologia , Brônquios/efeitos dos fármacos , Brônquios/microbiologia , Linhagem Celular , Citocinas/metabolismo , Inibidores Enzimáticos/farmacologia , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/microbiologia , Humanos , Metabolismo dos Lipídeos , Organofosfonatos/farmacologia , Prostaglandinas E/metabolismo , Pseudomonas aeruginosa/efeitos dos fármacosRESUMO
The mechanisms of the teratogenic effects of maternal alcohol consumption remain unclear. The aim of the present work was to study the organogenic PGE(2) levels and the modulation of PGE(2) levels by NO after periconceptional alcohol ingestion. Female mice were intoxicated with a 10% ethanol in drinking water before pregnancy and up to day 10 of gestation. The PGE(2) released from organogenic embryos was measured by radio immunoassay following incubation with or without the addition of either a NO donor or a NO synthase (NOS) inhibitor. In the ethanol-treated females, we found increased percentages of retarded embryos, associated with a significantly elevated resorption rate (p<0.05), very high quantities of morphologically abnormal E.10 embryos (p<0.001) and significantly increased PGE(2) release, as compared to the embryo parameters of control females. While in the control-derived E.10 embryos the NO donor produced significantly increased PGE(2) release, in the ethanol-derived embryos decreased quantities of PGE(2) were observed. L-NMMA inhibited PGE(2) release in both control and ethanol-derived embryos at different concentrations, whereas it decreased PGE(2) content in controls but not in ethanol-derived embryos. The periconceptional alcohol ingestion produced excessive PGE(2) release, decreased PGE(2) content and disruption of the regulatory NO-PGE(2) pathways. These PGs alterations may be related to delayed organogenesis and abnormal neural tube development after chronic periconceptional consumption of alcohol.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Etanol/farmacologia , Prostaglandinas E/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/farmacologia , Implantação do Embrião/efeitos dos fármacos , Embrião de Mamíferos/efeitos dos fármacos , Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Etanol/administração & dosagem , Etanol/sangue , Feminino , Camundongos , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Organogênese/efeitos dos fármacos , Gravidez , Radioimunoensaio , ômega-N-Metilarginina/farmacologiaRESUMO
The aim of this study was to investigate the mechanisms by which N,N'-dimethylbiguanide metformin (50 mg/100 g body weight (BW) in 0.05 ml of water, given orally with a cannula) prevents the ovarian disorders provoked by the hyperandrogenization with dehydroepiandrosterone (DHEA) in prepuberal BALB/c mice. The injection of DHEA (6 mg/100 g BW in 0.1 ml of oil) for 20 consecutive days re-creates a mouse model that resembles some aspects of the human polycystic ovary syndrome (PCOS). The treatment with DHEA increased ovarian oxidative stress because it enhanced lipid peroxidation (LPO) and diminished both catalase (CAT) activity and glutathione (GSH) content. Therefore, the treatment with DHEA diminished both ovarian nitric oxide synthase (NOS) activity and prostaglandin E (PGE) production. When metformin was administered together with DHEA, the ovarian GSH content, NOS activity and PGE production did not differ when compared with controls. However, metformin was not able to prevent the effect of DHEA on ovarian LPO or CAT activity. Finally, DHEA increased the ovarian protein expressions of inducible NOS (iNOS), inducible cyclooxygenase (COX2) and the phosphorylated AMP-dependent kinase alpha (AMPK-alpha) (Thr172). Metformin administered together with DHEA was able to prevent the increase of ovarian iNOS and COX2 expressions and to enhance the activation of phosphorylated AMPK-alpha expression.
Assuntos
Hiperandrogenismo/fisiopatologia , Metformina/farmacologia , Ovário/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP , Adjuvantes Imunológicos/farmacologia , Administração Oral , Animais , Catalase/metabolismo , Ciclo-Oxigenase 2/metabolismo , Desidroepiandrosterona/farmacologia , Ativação Enzimática/efeitos dos fármacos , Feminino , Glutationa/metabolismo , Hiperandrogenismo/induzido quimicamente , Hiperandrogenismo/metabolismo , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Metformina/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Complexos Multienzimáticos/metabolismo , Óxido Nítrico Sintase/metabolismo , Ovário/metabolismo , Ovário/fisiopatologia , Fosforilação/efeitos dos fármacos , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/fisiopatologia , Prostaglandinas E/metabolismo , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
The present study investigated the role of the N, N{'}-dimethylbiguanide metformin (50 mg/100 g body weight in 0.05 ml water, given orally with a canulla) in the prevention of endocrine and immune disorders provoked by the hyperandrogenization with dehydroepiandrosterone (DHEA) in prepuberal BALB/c mice. The treatment with DHEA (6 mg/100 g body weight in 0.1 ml oil) for 20 consecutive days, recreates a mouse model that resembles some aspects of the human polycystic ovary syndrome (PCOS). The treatment with DHEA did not modify either body mass index (BMI) or blood glucose levels, but did increase fasting insulin levels when compared with controls. Markers of ovarian function - serum estradiol (E), progesterone (P) and ovarian prostaglandin E (PGE) - were evaluated. The treatment with DHEA increased serum E and P levels while ovarian PGE diminished. When metformin was administered together with DHEA, serum insulin, E and P levels, and ovarian PGE values did not differ when compared with controls. Using flow cytometry assays we found that the treatment with DHEA diminished the percentage of the CD4 + T lymphocyte population and increased the percentage of the CD8 + T lymphocyte population from both ovarian tissue and retroperitoneal lymph nodes. However, when metformin was administered together with DHEA, the percentages of CD4 + and CD8 + T lymphocyte populations from both ovarian tissue and retroperitoneal lymph nodes were similar to those observed in controls. Finally, when DHEA was administered alone it increased the serum tumor necrosis factor-alpha (TNF-alpha ) levels when compared with controls; however, when metformin was administered together with DHEA, serum TNF-alpha levels were similar to controls. These results indicate that metformin is able, directly or indirectly, to avoid the endocrine and immune alterations produced when mice are hyperandrogenized with DHEA.
Assuntos
Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Androgênios , Animais , Glicemia/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Desidroepiandrosterona , Estradiol/sangue , Jejum , Feminino , Citometria de Fluxo , Insulina/sangue , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Ovário/imunologia , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/imunologia , Progesterona/sangue , Prostaglandinas E/metabolismo , Espaço Retroperitoneal , Maturidade Sexual , Fator de Necrose Tumoral alfa/análiseRESUMO
Inducible (calcium-independent) nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are important in the regulation of the function of different organs during infection. A single dose of lipopolysaccharide (LPS; 5 mg/kg ip) within 6 h increased NOS activity (20%) and prostaglandin E (PGE) content (100%) in submandibular glands (SMG) and blocked stimulated salivary secretion in adult male rats. The administration of an iNOS synthesis inhibitor, aminoguanidine (AG), with LPS decreased NOS activity and PGE content. Furthermore, the administration of meloxicam (MLX), an inhibitor of COX-2, blocked the increase in PGE and the production of NO. The incubation of slices of SMG in the presence of 3-morpholinosydnonimine, a donor of NO, increased the release of PGE highly significantly. The incubation of SMG in the presence of a PGE(1) analog (alprostadil) increased the production of NO. These results indicate that LPS activates NOS, leading to NO release, which activates COX, generating PGEs that act back to further activate NOS, causing further generation of PGEs by activation of COX. Because the alprostadil administration inhibited stimulated salivation, LPS-induced inhibition of salivation appears to be caused by increased PGE production. Diminished salivary secretion produces poor oral health; thus the use of COX-2 inhibitors to counteract the effects of inhibited salivation should be considered.
Assuntos
Lipopolissacarídeos/administração & dosagem , Prostaglandinas E/metabolismo , Saliva/metabolismo , Glândula Submandibular/efeitos dos fármacos , Glândula Submandibular/fisiologia , Alprostadil/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Ácido Araquidônico/metabolismo , Fármacos do Sistema Nervoso Autônomo/farmacologia , Ciclo-Oxigenase 2 , Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Técnicas In Vitro , Injeções Intraperitoneais , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Masculino , Meloxicam , Cloreto de Metacolina/farmacologia , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Norepinefrina/farmacologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Ratos , Tiazinas/farmacologia , Tiazóis/farmacologiaRESUMO
Despite the evidence for a functional role of nitric oxide (NO) in the regulation of uterine contractility in several species, there is little information about the effects of this gas on the mouse uterus. The aims of this study were to investigate if the NO relaxation pathway is present in mouse pregnant uterus and the relationship with the uterotonic prostaglandins (PGs E and F2alpha) production. We evaluated the effect of the treatment with a competitive nitric oxide synthase (NOs) inhibitor: N(G)-monomethyl-L-arginine on the spontaneous contractile activity and prostaglandin production on two different days of pregnancy: second day of pregnancy (preimplantation stage) and on the afternoon of the fifth day of pregnancy (postimplantation stage). We found that only on the fifth day of pregnancy did the inhibitor induce a highly significant isometric developed tension (IDT) and that this effect was maintained throughout the experiment. In order to evaluate if the generation of NO was also different between the two days of pregnancy, NOs activity was measured. Total NOs activity was significantly elevated during the postimplantation stage. We studied the interaction between the NO and cyclooxygenase (COX) pathways on the fifth day of pregnancy, and the data show no stimulation of PGs production by endogenous NO. In summary, we found that NO participates in the control of uterine contractility on the fifth day (a postimplantation stage) and that in this condition the NO was not able to elicit an increase in PGs production.
Assuntos
Contração Muscular/efeitos dos fármacos , Óxido Nítrico/fisiologia , Prostaglandinas/metabolismo , Útero/fisiologia , Animais , Arginina/metabolismo , Citrulina/metabolismo , Dinoprosta/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Gravidez , Prostaglandina-Endoperóxido Sintases/metabolismo , Prostaglandinas E/metabolismo , ômega-N-Metilarginina/farmacologiaRESUMO
Embryo prostaglandin (PG) synthesis plays a role in the modulation of embryo metabolism and viability, and in the beginning of the implantation. The effects of ethanol consumption seem to be mediated at least in part by PGs. Increased PG production of postimplantation embryos is associated with retardation and abnormalities in the gestational period. The aim of this study was to find out the effects of low chronic ethanol ingestion by mice, previous to pregnancy, on the PGE released by in vitro and in vivo derived embryos. Immature females or adult males were treated with 5% ethanol for 30 days. After fertilization and mating, two-cell embryos, morulae and blastocysts were collected. The PGE synthesis and release were measured by radioimmunoassay. PGE production by in vitro derived two-cell embryos from ethanol-treated females was lower than in the control group (P < 0.01). Also, PGE production was reduced when two-cell embryos came from ethanol-treated males (P < 0.01). There were no differences in PGE synthesis by in vitro derived morulae and blastocysts in these groups. Two-cell embryos derived from mating produced lower quantities of PGE when they came from ethanol-treated females mated with control males, as compared to the control group. PGE release by in vivo derived blastocysts from ethanol-treated females was reduced significantly, as compared to the control group (P < 0.01). We conclude that a low concentration of ethanol administered chronically to immature females reduces PGE synthesis and release by two-cell embryos from culture in vitro, and by embryos of days 2 and 4 from in vivo development.
Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Embrião de Mamíferos/efeitos dos fármacos , Embrião de Mamíferos/metabolismo , Etanol/farmacologia , Prostaglandinas E/biossíntese , Animais , Blastômeros/efeitos dos fármacos , Blastômeros/metabolismo , Técnicas de Cultura , Desenvolvimento Embrionário , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Gravidez , Prostaglandinas E/metabolismoRESUMO
Embryonic implantation is a complex process in which both maternal and embryonic signals are involved. In the present study, we evaluated changes in uterine prostaglandins production and nitric oxide synthase (NOS) activity during the course of early pregnancy and their interaction during implantation in rats. Uterine phospholipase A2 (PLA2) activity is increased on days 5 (day of ovoimplantation) and 6, compared to preimplantation days (3 and 4). This enhanced activity might be responsible for the observed increase in uterine PGE and PGF2 alpha production observed on day 5 of pregnancy, which induces endometrial vascular permeability and decidualization. When embryo access to the uterus is impaired, the increase of PG production is suppressed. During postimplantation, PGE levels return to preimplantation values, while PGF2 alpha decreased with respect to preimplantation values. Uterine NOS activity is also increased on day 4 and reaches a maximum on day 5, with a profile similar to PGE and PGF2 alpha. Dexamethasone administered in vivo decreased uterine NOS activity on day 4 of pregnancy but not on day 5, suggesting the presence of at least two types of NOS enzymes in the early days of pregnancy. A competitive inhibitor of NOS, L-NAME (600 and 1000 microM) induced a decrease in PGE and PGF2 alpha production in uterine tissue on day 5 of pregnancy. These results suggest the existence of a physiologically relevant nitridergic system which modulates prostaglandin production in the rat uterus during embryonic implantation.