RESUMEN
Our previous study indicated that the interleukin (IL)-6/STAT-3 signal was up-regulated in inflammatory bowel disease (IBD) in both humans and animal models. We also discovered phosphorylated STAT-3 in the nucleus of the colonic epithelial cells in IBD mice. Intestinal epithelial cells (IEC) have been shown to secrete IL-6. Therefore, the secretion of IL-6 from IEC may be one of the mechanisms of STAT-3 phosphorylation in IEC during the pathogenesis of IBD, and inhibition of IL-6 production by IEC may be beneficial in preventing IBD. We examined the preventative effect of various types of fucoidans on IL-6 production in a lipopolysaccharide (LPS)-stimulated murine colonic epithelial cells line, CMT-93, in vitro. We also determined in vivo the effect of fucoidans on murine chronic colitis induced with dextran sodium sulphate. Among fucoidans, those from Cladosiphon okamuranus Tokida and Kjellmaniella crassifolia inhibited IL-6 production in CMT-93 cells with the down-regulation of NF-kappaB nuclear translocation. Analysis of the effect of fucoidan on murine colitis in vivo showed that the disease activity index and myeloperoxidase activity decreased in mice fed Cladosiphon fucoidan, but not Fucus fucoidan. Cytokine profiles in colonic lamina propria indicated that the synthesis of interferon (IFN)-gamma and IL-6 decreased and that of IL-10 and transforming growth factor (TGF)-beta increased in mice fed Cladosiphon fucoidan, compared with mice fed a standard diet or Fucus fucoidan. The levels of IL-6 mRNA in colonic epithelial cells was lower in colitis-induced Balb/c mice fed Cladosiphon fucoidan than those fed a standard diet. Fucoidan improves murine chronic colitis by down-regulating the synthesis of IL-6 in the colonic epithelial cells. Fucoidan derived from C. o. Tokida may be useful as a dietary substance for the patients with inflammatory bowel disease.
Asunto(s)
Colitis/tratamiento farmacológico , Interleucina-6/biosíntesis , Mucosa Intestinal/inmunología , Fitoterapia/métodos , Polisacáridos/uso terapéutico , Algas Marinas , Animales , Enfermedad Crónica , Colon , Depresión Química , Células Epiteliales/inmunología , Femenino , Citometría de Flujo , Interleucina-6/análisis , Interleucina-6/genética , Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
To elucidate the anti-ulcer potential of Cladosiphon fucoidan, anti-peptic activity, bFGF stabilizing activity and inflammatory properties of this and related substances were investigated. Anti-peptic activity was observed with this and other sulfated polysaccharides such as dextran sulfate, carrageenan, and Fucus fucoidan. However, non-sulfated polysaccharides such as mannan and dextran did not exert the anti-peptic activity. The loss of bFGF bioactivity was prevented by all sulfated polysaccharides tested except chondroitin sulfate, at pH 7.4 and at pH 4.0. At pH 2.0, only heparin protected the bFGF activity. The generation of superoxide by macrophages and PMNs was stimulated by dextran sulfate, carrageenan, and Fucus fucoidan, whereas Cladosiphon fucoidan, heparin and chondroitin did not. Dextran sulfate, carrageenan, and Fucus fucoidan also stimulated the secretion of TNFalpha from macrophages, while Cladosiphon fucoidan did not. Thus, Cladosiphon fucoidan is a sulfated polysaccharide without inflammatory action. These results suggest that Cladosiphon fucoidan is a safe substance with potential for gastric protection.
Asunto(s)
Antiulcerosos/uso terapéutico , Mucosa Gástrica/efectos de los fármacos , Polisacáridos/uso terapéutico , Algas Marinas/química , Animales , Carragenina/farmacología , Sulfatos de Condroitina/farmacología , Sulfato de Dextran/farmacología , Inhibidores Enzimáticos/farmacología , Factor 2 de Crecimiento de Fibroblastos/farmacología , Heparina/farmacología , Concentración de Iones de Hidrógeno , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Pepsina A/antagonistas & inhibidores , Pepsina A/metabolismo , Ratas , Superóxidos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoAsunto(s)
Antiulcerosos/farmacología , Eucariontes/química , Polisacáridos/farmacología , Agar/química , Agar/farmacología , Alginatos/química , Alginatos/farmacología , Animales , Antiulcerosos/química , Carragenina/química , Carragenina/farmacología , Desoxiazúcares/química , Desoxiazúcares/farmacología , Aditivos Alimentarios , Glucanos , Ácido Glucurónico , Ácidos Hexurónicos , Humanos , Mananos/química , Mananos/farmacología , Estructura Molecular , Polisacáridos/química , Polisacáridos/uso terapéutico , Úlcera Gástrica/tratamiento farmacológicoRESUMEN
A structural study was carried out on a fucoidan isolated from the brown seaweed Cladosiphon okamuranus. The polysaccharide contained fucose, glucuronic acid and sulfate in a molar ratio of about 6.1 : 1.0 : 2.9. The results of Smith degradation showed that this polysaccharide has a linear backbone of 1-->3-linked alpha-fucopyranose with a half sulfate substitution at the 4-positions, and a portion of the fucose residues was O-acetylated. The data obtained from partial acid hydrolysis, a methylation analysis and NMR spectra indicated that the alpha-glucuronic acid residue is linked to the 2-positions of the fucose residues, which were not substituted by a sulfate group. These results indicated that the average structure of this fucoidan is as follows: -[(-->3Fuc-4(+/-OSO3-)alpha1-)5-->3[GlcA alpha1-->2]Fuc alpha1-]n-. (Half of each fucose residue was sulfated. One O-acetyl ester was present in every 6 fucose residues.)
