RESUMEN
OBJECTIVE: The aim of this study was to determine whether Microdispersed Oxidized Cellulose (MDOC) possesses a hypolipidemic effect in apolipoprotein-E/low-density lipoprotein receptor double-knockout (ApoE/LDLR-deficient) mice and the possible mechanism of this effect in mice. METHODS: Female ApoE/LDLR-deficient mice subdivided into two groups were fed with a Western-type diet for 8 wk, and the experimental group was supplemented with 5% MDOC for 8 wk. Female C57BL/6J mice were fed an atherogenic diet containing 5% MDOC or pectin for the determination of a possible hypolipidemic mechanism of MDOC action. RESULTS: Biochemical analysis showed that 5% MDOC treatment significantly decreased total cholesterol by 20% (P = 0.0338) and very-LDL cholesterol by 21% (P = 0.0110) and significantly increased the level of high-density lipoprotein cholesterol by 62% (P = 0.0172) when compared with non-treated ApoE/LDLR-deficient mice. The results Association of Official Analytical Chemists method 991.43 revealed that MDOC contains 59.78 +/- 5.0% of fiber. Furthermore, it was demonstrated that administration of MDOC did not affect cholesterol absorption in the small intestine. Using C57BL/6J mice, MDOC and pectin treatments decreased cholesterol content in liver and increased fermentation in the gut in vivo. In vitro experiments confirmed that MDOC is fermentable under conditions mimicking those in the large intestine. CONCLUSION: We demonstrated hypolipidemic effects of MDOC in ApoE/LDLR-deficient mice. Moreover, we propose that MDOC is a hypolipidemic soluble fiber acting probably by increased fermentation and production of short-chain fatty acids in the large intestine in mice. We propose that MDOC might be a possible source of soluble fiber for use in dietary supplements.
Asunto(s)
Apolipoproteínas E/deficiencia , Celulosa Oxidada/farmacología , Colesterol/sangre , Fibras de la Dieta/farmacología , Hipolipemiantes/farmacología , Receptores de LDL/deficiencia , Animales , Apolipoproteínas E/genética , HDL-Colesterol/sangre , VLDL-Colesterol/sangre , Fibras de la Dieta/administración & dosificación , Modelos Animales de Enfermedad , Ácidos Grasos Volátiles/análisis , Femenino , Fermentación , Absorción Intestinal/efectos de los fármacos , Absorción Intestinal/fisiología , Intestino Grueso/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Distribución Aleatoria , Receptores de LDL/genética , Resultado del TratamientoRESUMEN
Members of the immunoglobulin superfamily of endothelial adhesion molecules, vascular cell adhesion molecule (VCAM-1) and intercellular cell adhesion molecule (ICAM- 1), strongly participate in leukocyte adhesion to the endothelium and play an important role in all stages of atherogenesis. The aim of this study was to detect and quantify the changes of endothelial expression of VCAM-1, and ICAM-1 in the vessel wall after the short-term administration of simvastatin, atorvastatin, and micro dispersed derivatives of oxidised cellulose (MDOC) in apolipoprotein-E-deficient (apoE(-/-)) mice atherosclerotic model. Hyperlipidemic apoE(-/-) mice (n = 32) received normal chow diet or diet containing simvastatin or atorvastatin 10 mg/kg/day or MDOC 50 mg/kg/day. Total cholesterol, VLDL, LDL, HDL and TAG were measured and the endothelial expression of VCAM-1 and ICAM-1 was visualized and quantified by means of immunohistochemistry and stereology, respectively. Total cholesterol levels was insignificantly lowered only in MDOC treated mice but not in mice treated with statins. ICAM-1 endothelial expression was not affected by neither simvastatin nor MDOC treatment. However, significant diminution of VCAM-1 endothelial expression was observed in both atorvastatin and MDOC treated mice. These results provide new information of potential hypolipidemic substance MDOC and its potential anti-inflammatory effects. Furthermore, we have confirmed anti-inflammatory effects of atorvastatin independent of plasma cholesterol lowering. Thus, the results of this study show potential benefit of both MDOC and atorvastatin treatment in apoE(-/-) mouse model of atherosclerosis suggesting their possible combination might be of interest.
Asunto(s)
Antiinflamatorios/farmacología , Apolipoproteínas E/deficiencia , Aterosclerosis , Celulosa Oxidada/farmacología , Endotelio Vascular/efectos de los fármacos , Ácidos Heptanoicos/farmacología , Pirroles/farmacología , Administración Oral , Animales , Antiinflamatorios/uso terapéutico , Apolipoproteínas E/genética , Aterosclerosis/tratamiento farmacológico , Atorvastatina , Celulosa Oxidada/uso terapéutico , Dieta , Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Ácidos Heptanoicos/uso terapéutico , Hiperlipidemias/tratamiento farmacológico , Molécula 1 de Adhesión Intercelular/metabolismo , Lipoproteínas/sangre , Masculino , Ratones , Ratones Noqueados , Pirroles/uso terapéutico , Simvastatina/farmacología , Triglicéridos/sangre , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
The immune system can be manipulated specifically by vaccination or nonspecifically by immunomodulation. Many of biological response modifiers (BRM) have polysaccharidic structure similar to that of microdispersed oxidized cellulose (MDOC). We have investigated the immunomodulatory activity of different inorganic MDOC salts (H, Na, Ca, Mg, Zn, Al, Co, Ca/Na) and organic MDOC derivatives (urea, gelatine, arginine) both in vitro and in vivo. A dose-dependent stimulation by a number of MDOC derivatives was observed with spontaneous and mitogen-induced proliferation of human peripheral blood leukocytes (PBLs) and mouse splenocytes in vitro. In both primary cultures, the most intensive proliferation was induced by a Ca/Na salt at a concentration of 1 mg/ml. We have also demonstrated stimulatory effects of MDOC Ca/Na salt on the mouse mixed leukocyte reaction (MLR). The stimulatory activity of MDOC towards the immune system was further supported by the fact that in vitro the product stimulates the release of Th1 cytokine TNF-alpha, but not IFN-gamma, IL-4 or IL-6. In vivo MDOC application increases more than 50% the number of colony-forming units spleen (CFU-s), i.e., stimulates the stem cells in bone marrow, and increases relative percentage of monocytes and B lymphocytes in the mouse peripheral blood.