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1.
Pharmacol Res ; 57(5): 344-50, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18456507

RESUMO

15-Deoxy-delta12,14-prostaglandin-J(2) (15d-PGJ(2)) has potent anti-inflammatory effects including the inhibition of interleukin-1beta (IL-1beta)-induced expression of cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)) production in several cell types. 15d-PGJ(2) contains an alpha,beta-unsaturated electrophilic ketone and several evidences suggest that thiol reducing agents prevent or revert the cellular effects of 15d-PGJ(2). The present study was devoted to analyze the effect of 15d-PGJ(2) on COX-2 expression in cultured human mesangial cells (HMC). 15d-PGJ(2) induced an increase in the reduced glutathione (GSH) content and up-regulated COX-2 protein expression, but not COX-1, in a manner which was unaffected by selective peroxisome proliferator-activated receptor gamma (PPARgamma) blockade nor mimicked by ciglitazone, a PPARgamma agonist. N-acetylcysteine (NAC), a thiol reducing agent, but not reactive oxygen species scavengers, prevented 15d-PGJ(2)-induced COX-2 up-regulation. Depletion of GSH by buthionine sulfoximine, which diminishes thiol antioxidant activity, cooperated with 15d-PGJ(2) to accumulate COX-2. Therefore, 15d-PGJ(2) up-regulated COX-2 through a thiol antioxidant-sensitive mechanism. Interestingly, NAC did not inhibit the COX-2 expression induced by the electrophilic alpha,beta-unsaturated compound PGA(2). Up-regulation of COX-2 by 15d-PGJ(2) did not result in increased PGE(2) production. Furthermore, preincubation with 15d-PGJ(2) inhibited IL-1beta-induced PGE(2) production although IL-1beta-induced COX-2 expression remained unaffected by the treatment with 15d-PGJ(2). On the contrary, PGA(2) elicited an increase in PGE(2) production and it acted synergistically with IL-1beta to enhance PGE(2) production. These results indicate for the first time that 15d-PGJ(2) inhibits PGE(2) production independently of its effect on COX-2 expression.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Dinoprostona/biossíntese , Prostaglandina D2/análogos & derivados , Acetilcisteína/farmacologia , Antioxidantes/metabolismo , Butionina Sulfoximina/farmacologia , Células Cultivadas , Sequestradores de Radicais Livres/farmacologia , Glutationa/metabolismo , Humanos , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , PPAR gama/metabolismo , Prostaglandina D2/farmacologia , Prostaglandinas A/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Compostos de Sulfidrila/metabolismo , Regulação para Cima/efeitos dos fármacos
2.
Pharmacol Res ; 55(4): 295-302, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17291778

RESUMO

The stress response of the distal tubule to oxidative attack may be relevant to recovery from acute renal failure. In distal tubular Madin-Darby cells (MDCK), H(2)O(2) induced up-regulation of cyclooxygenases (COX-1 and COX-2), prostaglandin-E(2) production and caspase-independent cell death. Cell death was inhibited by S-ketoprofen, but not by the much weaker COX inhibitor R-ketoprofen. Interestingly, we identified 15-deoxy-Delta(12,14)-prostaglandin-J(2) (15d-PGJ(2)), a peroxisome-proliferator activated receptor-gamma agonist, as a lethal prostaglandin whose effect was reproduced by the PPAR-gamma agonist ciglitazone. Nevertheless, H(2)O(2)-induced cell death was unaffected by other non-steroidal anti-inflammatory drugs (NSAIDs) or all-trans-retinoic acid. Moreover, c-Jun-N-terminal kinase inhibitor SP600125 prevented 15-deoxy-Delta(12,14)-PGJ(2)-induced cell death, but not H(2)O(2)-induced cell death. PPAR-gamma antagonist GW9662 showed no affect on the cell death. These results indicated that protection by S-ketoprofen was COX-independent and PPARgamma independent. Moreover, the IC(50) value of the action of S-ketoprofen for the inhibition of H(2)O(2)-induced MDCK cell death ( approximately equal 140microM) was much higher than the IC(50) value for the inhibition of COX-1 and COX-2 activities ( approximately equal 1microM). Further design of S-ketoprofen derivatives devoid of COX inhibitory activity will give opportunity to protect the kidney against oxidative attack while avoiding unwanted effects of NSAID.


Assuntos
Apoptose/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Peróxido de Hidrogênio/toxicidade , Cetoprofeno/farmacologia , Células Mesangiais/efeitos dos fármacos , Oxidantes/toxicidade , Prostaglandina-Endoperóxido Sintases/biossíntese , Substâncias Protetoras/farmacologia , Animais , Inibidores de Ciclo-Oxigenase/farmacologia , Dinoprostona/metabolismo , Cães , Relação Dose-Resposta a Droga , Indução Enzimática/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Cetoprofeno/química , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Células LLC-PK1 , Células Mesangiais/metabolismo , Células Mesangiais/patologia , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/agonistas , PPAR gama/metabolismo , Prostaglandina D2/análogos & derivados , Prostaglandina D2/farmacologia , Substâncias Protetoras/química , Ratos , Estereoisomerismo , Suínos
3.
Int J Vitam Nutr Res ; 75(1): 47-53, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15830921

RESUMO

UNLABELLED: All-trans-retinoic acid (tRA) modulates in human mesangial cells (MC) antioxidant defenses, the expression of interleukin-1beta-induced vascular cell-adhesion molecule-1 (VCAM-1), cyclooxygenase-2 (COX-2), and the retinoic acid-receptor-beta (RAR-beta). The correlation of the serum levels of glycated hemoglobin A1c with tRA in type 2 diabetes mellitus patients led us to hypothesize that tRA and glycated albumin (GA), the main circulating glycated protein, might mutually interact in MC. We studied 1) the influence of tRA on GA effects in cultured MC: an assessment was made on how pre-incubation with tRA modified the effects of GA on intracellular oxidation and on the expression of mRNA and protein of COX-2 and VCAM-1; and 2) the influence of GA on tRA effects in MC: we studied how the induction of RARbeta expression by tRA was modified by GA. RESULTS: GA dose-dependently increased intracellular oxidation and the expression of the molecules involved in leukocyte infiltration, namely COX-2 and VCAM-1 . Pre-incubation with tRA exacerbated GA effects by up to a three- to four-fold additional increase. In turn, induction by tRA of RAR-beta was fully inhibited by GA. Thus tRA and GA reciprocally influence their effects in MC. It is possible that this interaction may have a pathophysiological or pharmacological role in diabetic nephropathy.


Assuntos
Antineoplásicos/farmacologia , Mesângio Glomerular/efeitos dos fármacos , Albumina Sérica/farmacologia , Tretinoína/farmacologia , Western Blotting/métodos , Ciclo-Oxigenase 2 , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Produtos Finais de Glicação Avançada , Humanos , Técnicas In Vitro , Proteínas de Membrana , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , RNA Mensageiro/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Estatísticas não Paramétricas , Molécula 1 de Adesão de Célula Vascular/efeitos dos fármacos , Albumina Sérica Glicada
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