RESUMO
Prostaglandin E2 (PGE2) has a central role in inflammation and both cyclooxygenase-2 (COX-2) and prostaglandin E synthases are critical enzymes in its synthesis. In inflammation, bacterial products and cytokines enhance the expression of COX-2 and inducible microsomal prostaglandin E synthase-1 (mPGES-1) which are functionally coupled to result in increased PGE2 formation in macrophages and tissue cells. In the present study, we systematically investigated the effects of 26 naturally occurring flavonoids on PGE2 production and on COX-2 and mPGES-1 expression in activated macrophages. Twelve flavonoids, i.e., flavone, luteolin-7-glucoside, kaempferol, isorhamnetin, morin, quercetin, naringenin, taxifolin, pelargonidin, daidzein, genistein, and genistin effectively inhibited lipopolysaccharide (LPS)-induced PGE2 production. Four flavonoids (flavone, isorhamnetin, daidzein, and genistein) inhibited significantly LPS-induced COX-2 expression, while mPGES-1 expression was downregulated by kaempferol and isorhamnetin. The present study characterizes the effects of flavonoids on PGE2 production and on COX-2 and mPGES-1 expression in activated macrophages. The results add to our knowledge of the anti-inflammatory actions of flavonoids and introduce kaempferol and isorhamnetin as compounds capable of downregulating the expression of mPGES-1.
Assuntos
Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Dinoprostona/biossíntese , Flavonoides/farmacologia , Oxirredutases Intramoleculares/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/análise , Regulação para Baixo/efeitos dos fármacos , Flavonoides/química , Regulação da Expressão Gênica/efeitos dos fármacos , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Macrófagos/metabolismo , Camundongos , Prostaglandina-E SintasesRESUMO
There has been an enormous interest in the development of alternative medicines for type 2 diabetes, specifically screening for phytochemicals with the ability to delay or prevent glucose absorption. The goal of the present study was to provide in vitro evidence for potential inhibition of alpha-glucosidase and alpha-amylase enzymes, followed by a confirmatory in vivo study on rats to generate a stronger biochemical rationale for further studies on the ethanolic extract of Andrographis paniculata and andrographolide. The extract showed appreciable alpha-glucosidase inhibitory effect in a concentration-dependent manner (IC(50)=17.2+/-0.15 mg/ml) and a weak alpha-amylase inhibitory activity (IC(50)=50.9+/-0.17 mg/ml). Andrographolide demonstrated a similar (IC(50)=11.0+/-0.28 mg/ml) alpha-glucosidase and alpha-amylase inhibitory activity (IC(50)=11.3+/-0.29 mg/ml). The positive in vitro enzyme inhibition tests paved way for confirmatory in vivo studies. The in vivo studies demonstrated that A. paniculata extract significantly (P<0.05) reduced peak blood glucose and area under curve in diabetic rats when challenged with oral administration of starch and sucrose. Further, andrographolide also caused a significant (P<0.05) reduction in peak blood glucose and area under the curve in diabetic rats. Hence alpha-glucosidase inhibition may possibly be one of the mechanisms for the A. paniculata extract to exert antidiabetic activity and indicates that AP extract can be considered as a potential candidate for the management of type 2 diabetes mellitus.
Assuntos
Andrographis/química , Diterpenos/farmacologia , Inibidores de Glicosídeo Hidrolases , alfa-Amilases/antagonistas & inibidores , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacologia , Feminino , Teste de Tolerância a Glucose , Hipoglicemiantes/farmacologia , Técnicas In Vitro , Fitoterapia , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Amido/administração & dosagemRESUMO
A new sesquiterpenoid, 1α,4ß,7ß-eudesmanetriol (1), was isolated together with the known compounds 1ß,4ß,7ß-eudesmanetriol (2) and oplopanone (3) from the rhizomes of Homalomena sagittifolia. The structures of these compounds were determined by extensive spectral analyses. The compounds 1 and 2 inhibited growth of Pseudomonas stutzeri with a MIC value of 117 µM when evaluated for antibacterial activity using the minimum concentration assay. Both these compounds showed remarkable activities against acetylcholinesterase enzyme with IC(50) values ranging between 25 and 26 µM. The isolation of these sesquiterpenoids and their biological activities observed in this study support the reported traditional uses of H. sagittifolia for the treatment of microbial related diseases and central nervous system disorders.
Assuntos
Araceae/química , Sesquiterpenos/isolamento & purificação , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Inibidores da Colinesterase/isolamento & purificação , Inibidores da Colinesterase/farmacologia , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Pseudomonas stutzeri/efeitos dos fármacos , Sesquiterpenos/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria InfravermelhoRESUMO
The present study was undertaken to evaluate the sensitivity of the plethysmometer and micrometer, which are the most commonly employed methods to measure the paw oedema for screening anti-inflammatory agents. Acute paw swelling was induced by s.c. injection of 0.02 ml carrageenan in mice. The maximum paw oedema (59.4%) was found to be at 3.5 h after injection of carrageenan in the hind paw of mice. Oral indomethacin treatment in the dose of 5 mg/kg 1 h prior to the induction of paw oedema, caused a significant (P < 0.05) reduction in paw swelling, when the plethysmometer method was used. When the micrometer method was used to measure the paw swelling, oral indomethacin at the dose of 1 mg/kg resulted in a significant reduction in paw oedema. These findings suggest that micrometer method is more sensitive to detect the lowest antiinflammatory dose of indomethacin when compared with the plethysmometer method. The possible significance of these findings is discussed.