RESUMEN
CONTEXT: Metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) are the emerging co-morbidities of skin inflammation. Occurrence of skin inflammation such as psoriasis is substantially higher in NAFLD patients than normal. Currently, there are no animal models to study the interaction between these co-morbidities. OBJECTIVE: The present study seeks to develop a simple mouse model of NAFLD-enhanced skin inflammation and to study the effect of NAFLD on different parameters of skin inflammation. MATERIALS AND METHOD: Metabolic syndrome and NAFLD were induced in C57BL/6 mice by feeding high-fat diet (HFD, 60% kcal) and high fructose liquid (HFL, 40% kcal) in drinking water. Skin inflammation was induced by repeated application of oxazolone (1% sensitization and repeated 0.5% challenge) in both normal and NAFLD mice and various parameters of skin inflammation and NAFLD were measured. RESULTS: HFD and HFL diet induced obesity, hyperglycemia, hyperinsulinemia, and histological features of NAFLD in mice. Oxazolone challenge significantly increased ear thickness, ear weight, MPO activity, NF-κB activity, and histological features of skin inflammation in NAFLD mice as compared with normal mice. Overall, induction of oxazolone-induced skin inflammation was more prominent in NAFLD mice than normal mice. Hence, HFD and HFL diet followed by topical oxazolone application develops metabolic syndrome, NAFLD, and enhanced skin inflammation in mice. DISCUSSION AND CONCLUSION: This simple model can be utilized to evaluate a therapeutic strategy for the treatment of metabolic syndrome and NAFLD with skin inflammation and also to understand the nexus between these co-morbidities.
Asunto(s)
Dermatitis/metabolismo , Modelos Animales de Enfermedad , Síndrome Metabólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Dermatitis/etiología , Dermatitis/patología , Dieta Alta en Grasa/efectos adversos , Masculino , Síndrome Metabólico/etiología , Síndrome Metabólico/patología , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/patologíaRESUMEN
Atorvastatin is a 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor used in the treatment of atherosclerosis and dyslipidemia. Studies have evaluated the utility of statins in the treatment of skin inflammation but with varied results. In the present study, we investigated the effect of atorvastatin on TNF-α release and keratinocyte proliferation in vitro and in acute and chronic 12-O-tetradecanoylphorbol-13-acetate (TPA) induced skin inflammation in vivo. Atorvastatin significantly inhibited lipopolysacharide induced TNF-α release in THP-1 cells and keratinocyte proliferation in HaCaT cells. In an acute study, topical atorvastatin showed dose dependent reduction in TPA induced skin inflammation with highest efficacy observed at 500 µg/ear dose. In chronic study, topical atorvastatin significantly reduced TPA induced ear thickness, ear weight, cutaneous cytokines, MPO activity and improved histopathological features comparable to that of dexamethasone. Atorvastatin also inhibited TPA stimulated NF-κB activation in mouse ear. In conclusion, our results suggest that atorvastatin ameliorates TPA induced skin inflammation in mice at least in part, due to inhibition of cytokine release and NF-κB activation and may be beneficial for the treatment skin inflammation like psoriasis.
Asunto(s)
Atorvastatina/farmacología , Citocinas/metabolismo , Dermatitis/prevención & control , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , FN-kappa B/metabolismo , Piel/metabolismo , Acetato de Tetradecanoilforbol/antagonistas & inhibidores , Acetato de Tetradecanoilforbol/toxicidad , Animales , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Oído Externo/efectos de los fármacos , Femenino , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Peroxidasa/metabolismo , Psoriasis/tratamiento farmacológico , Piel/efectos de los fármacosRESUMEN
OBJECTIVES: To evaluate the effect of vildagliptin alone and in combination with metformin or rosiglitazone on murine hepatic steatosis in diet-induced nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: Male C57BL/6 mice were fed with high fat diet (60 Kcal %) and fructose (40%) in drinking water for 60 days to induce NAFLD. After the induction period, animals were divided into different groups and treated with vildagliptin (10 mg/kg), metformin (350 mg/kg), rosiglitazone (10 mg/kg), vildagliptin (10 mg/kg) + metformin (350 mg/kg), or vildagliptin (10 mg/kg) + rosiglitazone (10 mg/kg) orally for 28 days. Following parameters were measured: body weight, food intake, plasma glucose, triglyceride (TG), total cholesterol, liver function tests, and liver TG. Liver histopathology was also examined. RESULTS: Oral administration of vildagliptin and rosiglitazone in combination showed a significant reduction in fasting plasma glucose, hepatic steatosis, and liver TGs. While other treatments showed less or no improvement in the measured parameters. CONCLUSIONS: These preliminary results demonstrate that administration of vildagliptin in combination with rosiglitazone could be a promising therapeutic strategy for the treatment of NAFLD.
Asunto(s)
Adamantano/análogos & derivados , Hígado Graso/tratamiento farmacológico , Nitrilos/uso terapéutico , Pirrolidinas/uso terapéutico , Tiazolidinedionas/uso terapéutico , Adamantano/administración & dosificación , Adamantano/farmacología , Adamantano/uso terapéutico , Animales , Quimioterapia Combinada , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Nitrilos/administración & dosificación , Nitrilos/farmacología , Enfermedad del Hígado Graso no Alcohólico , Tamaño de los Órganos/efectos de los fármacos , Pirrolidinas/administración & dosificación , Pirrolidinas/farmacología , Rosiglitazona , Tiazolidinedionas/administración & dosificación , Tiazolidinedionas/farmacología , Triglicéridos/metabolismo , VildagliptinaRESUMEN
A series of bezafibrate ester prodrugs 1-7 were synthesized and evaluated for hypolipidemic activity in Swiss Albino mice (SAM). Bezafibrate (1a), a hypolipidemic drug was used as a reference compound for data comparison. Among the synthesized compounds, prodrug 7 showed superior activities in decreasing triglyceride up to 30% in mice plasma after oral administration of 50mg/kg/day for 8 days. Prodrugs 2, 3, 5, 6, and 7 were found to be more lipophilic than bezafibrate (1a), indicated by partition coefficients measured in octanol-buffer system at pH 7.4. On the basis of in vivo studies, prodrug 7 emerged as new potent hypolipidemic agent.
Asunto(s)
Bezafibrato/análogos & derivados , Bezafibrato/síntesis química , Hipolipemiantes/síntesis química , Profármacos/síntesis química , Administración Oral , Animales , Bezafibrato/farmacología , Esquema de Medicación , Estabilidad de Medicamentos , Ésteres , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Hipolipemiantes/farmacología , Masculino , Ratones , Octanoles , Profármacos/farmacología , Relación Estructura-Actividad , Triglicéridos/sangre , AguaRESUMEN
A series of novel fenofibric acid ester prodrugs 1c-1h were synthesized and evaluated with the aim of obtaining potent hypolipidemic agents. Prodrugs 1c and 1d exhibited potent hypochlolesterolemic activity, lowering the mice plasma triglyceride level up to 47% in Swiss albino mice after oral administration of 50 mg/kg/day for 8 days. Fenofibric acid ester prodrugs 1c-1h were found lipophilic like fenofibrate (1b), indicated by partition coefficients measured in octanol-buffer system at pH 7.4. On the basis of in vivo studies, prodrugs 1c and 1d emerged as potent hypolipidemic agents.