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1.
Dev Neurosci ; 28(3): 196-208, 2006.
Article in English | MEDLINE | ID: mdl-16679766

ABSTRACT

Dietary polyunsaturated fatty acids (PUFAs) have been postulated as alternative supportive treatment for multiple sclerosis, since they may promote myelin repair. We set out to study the effect of supplementation with n-3 and n-6 PUFAs on OLN-93 oligodendroglia and rat primary oligodendrocyte differentiation in vitro. It appeared that OLN-93 cells actively incorporate and metabolise the supplemented PUFAs in their cell membrane. The effect of PUFAs on OLN-93 differentiation was further assessed by morphological and Western blot evaluation of markers of oligodendroglia differentiation: 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), zonula occludens-1 (ZO-1) and myelin-associated glycoprotein (MAG). Supplementation of the OLN-93 cells with n-3 and n-6 PUFAs increased the degree of differentiation determined by morphological analysis. Moreover, CNP protein expression was significantly increased by gamma-linolenic acid (GLA, 18:3n-6) supplementation. In accordance with the OLN-93 results, studies with rat primary oligodendrocytes, a more advanced model of cell differentiation, showed GLA supplementation to promote oligodendrocyte differentiation. Following GLA supplementation, increased numbers of proteolipid protein (PLP)-positive oligodendrocytes and increased myelin sheet formation was observed during differentiation of primary oligodendrocytes. Moreover, increased CNP, and enhanced PLP and myelin basic protein expression were found after GLA administration. These studies provide support for the dietary supplementation of specific PUFAs to support oligodendrocyte differentiation and function.


Subject(s)
Cell Differentiation/drug effects , Fatty Acids, Unsaturated/pharmacology , Oligodendroglia/cytology , Oligodendroglia/drug effects , 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase , Animals , Blotting, Western , Cell Membrane/chemistry , Cells, Cultured , Fluorescent Antibody Technique , In Vitro Techniques , Membrane Proteins/drug effects , Membrane Proteins/metabolism , Myelin-Associated Glycoprotein/drug effects , Myelin-Associated Glycoprotein/metabolism , Phosphoproteins/drug effects , Phosphoproteins/metabolism , Phosphoric Diester Hydrolases/drug effects , Phosphoric Diester Hydrolases/metabolism , Rats , Reverse Transcriptase Polymerase Chain Reaction , Zonula Occludens-1 Protein
2.
Eur J Clin Nutr ; 59(12): 1347-61, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16118655

ABSTRACT

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Oligodendrocyte damage and subsequent axonal demyelination is a hallmark of this disease. Different pathomechanisms, for example, immune-mediated inflammation, oxidative stress and excitotoxicity, are involved in the immunopathology of MS. The risk of developing MS is associated with increased dietary intake of saturated fatty acids. Polyunsaturated fatty acid (PUFA) and antioxidant deficiencies along with decreased cellular antioxidant defence mechanisms have been observed in MS patients. Furthermore, antioxidant and PUFA treatment in experimental allergic encephalomyelitis, an animal model of MS, decreased the clinical signs of disease. Low-molecular-weight antioxidants may support cellular antioxidant defences in various ways, including radical scavenging, interfering with gene transcription, protein expression, enzyme activity and by metal chelation. PUFAs may not only exert immunosuppressive actions through their incorporation in immune cells but also may affect cell function within the CNS. Both dietary antioxidants and PUFAs have the potential to diminish disease symptoms by targeting specific pathomechanisms and supporting recovery in MS.


Subject(s)
Antioxidants/administration & dosage , Dietary Fats, Unsaturated/administration & dosage , Multiple Sclerosis/diet therapy , Oxidative Stress/drug effects , Animals , Antioxidants/therapeutic use , Dietary Fats, Unsaturated/therapeutic use , Dietary Supplements , Disease Models, Animal , Fatty Acids, Unsaturated/administration & dosage , Fatty Acids, Unsaturated/deficiency , Fatty Acids, Unsaturated/therapeutic use , Humans , Multiple Sclerosis/immunology , Multiple Sclerosis/metabolism , Oxidative Stress/immunology , Reactive Oxygen Species
3.
Dig Dis Sci ; 47(3): 503-10, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11913411

ABSTRACT

Mice deficient in interleukin-2 (IL-2-/-) develop inflammatory bowel disease resembling human ulcerative colitis. After death, macroscopic and microscopic scores were used to determine colonic inflammation. Both scores were significantly increased in the colon of IL-2-/- mice as compared to wild types mice. The level of IL-1beta 24-week-old was increased in IL-2-/- mice produced by the colon as compared with IL-2+/+ controls. However, the concentrations of IL-6 and IL-10 were not changed. The spleen weight of IL-2-/- mice was significantly increased compared with IL-2+/+ controls. We used immunochemical techniques in low-temperature paraffin-embedded spleen of IL-2-/- mice to examine pathological changes of CD4+ T cells, CD8' T cells, and CD11b+ cells. The tissue was successfully stained and was well preserved. The percentage CD4+ T cells was not significantly changed, while the percentage CD8+ T cells was significantly decreased in IL-2-/- mice compared with IL-2+/+ controls. On the other hand, the percentage CD11b+ cells was significantly increased in the spleen of IL-2-/- mice compared with IL-2+/- controls. As well as the marked difference in CD8+ and CD11b+ cells in the spleen, the increased level of IL-1beta in colonic tissue might indicate that cytotoxic T cells as well as macrophages are involved in the development and/or perpetuation of the inflammatory reactions in IL-2-/- mice.


Subject(s)
Colitis/metabolism , Colon/chemistry , Cytokines/metabolism , Interleukin-2/deficiency , Animals , CD4 Lymphocyte Count , CD8-Positive T-Lymphocytes , Colitis/immunology , Colitis/pathology , Colon/pathology , Immunohistochemistry , Interleukin-1/metabolism , Interleukin-10/metabolism , Interleukin-2/physiology , Interleukin-6/metabolism , Macrophage-1 Antigen/analysis , Mice , Mice, Knockout , Organ Size , Proteins/analysis , Spleen/chemistry , Spleen/immunology , Spleen/pathology
4.
Scand J Gastroenterol ; 35(5): 517-21, 2000 May.
Article in English | MEDLINE | ID: mdl-10868455

ABSTRACT

BACKGROUND: Corticosteroids are used as anti-inflammatory drugs in the treatment of inflammatory bowel disease. We wanted to know whether dexamethasone (DEX) treatment could prevent dextran sulphate sodium (DSS)-induced colitis in mice. METHODS: Acute colitis was induced after oral administration of 10% DSS for 2 days. Controls received normal tap water. Five days before and during DSS or tap water exposure half the group was treated with 0.06 mg/day DEX, and the other half received saline. After the mice had been killed, macroscopic observation and histologic evaluation were used to determine the degree of colonic inflammation. RESULTS: The macroscopic score was significantly increased in untreated DSS mice (P < 0.001). The induction of colitis was not prevented by DEX pretreatment (5.9 +/- 0.9 versus 4.2 +/- 0.6; NS). In addition, the macroscopic scores of DEX-treated controls were significantly increased (1.8 +/- 0.2 versus 0.7 +/- 0.2; P = 0.007), which suggests that DEX has a stimulating effect on colitis induction. The histology score was significantly increased in untreated DSS mice compared with controls (P = 0.016). Analogous to the macroscopic scoring results, the histology score of DEX-treated controls was significantly increased compared with untreated controls (P = 0.046). CONCLUSIONS: Pretreatment with dexamethasone did not prevent the induction of acute DSS colitis, reflected by both aggravated macroscopic and histologic inflammation scores.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Colitis/drug therapy , Dexamethasone/therapeutic use , Glucocorticoids/therapeutic use , Acute Disease , Animals , Anti-Inflammatory Agents/administration & dosage , Colitis/chemically induced , Colitis/pathology , Dexamethasone/administration & dosage , Dextran Sulfate , Disease Models, Animal , Mice , Mice, Inbred BALB C
5.
Chem Res Toxicol ; 11(9): 1075-81, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9760282

ABSTRACT

Earlier studies in our laboratory showed that hydroxylated metabolites of polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), and dibenzofurans (PCDFs) competitively inhibit thyroxine (T4) binding to transthyretin (TTR) and type I deiodinase (D1) activity. In this study, we investigated the possible inhibitory effects of hydroxylated metabolites of polyhalogenated aromatic hydrocarbons (PHAHs) on iodothyronine sulfotransferase activity. Rat liver cytosol was used as a source of sulfotransferase enzyme in an in vitro assay with 125I-labeled 3,3'-diiodothyronine (T2) as a model substrate. Increasing amounts of hydroxylated PCBs, PCDDs, or PCDFs or extracts from incubation mixtures of PHAHs and induced liver microsomes were added as potential inhibitors of T2 sulfotransferase activity. Hydroxylated metabolites of PCBs, PCDDs, and PCDFs were found to be potent inhibitors of T2 sulfotransferase activity in vitro with IC50 values in the low micromolar range (0.2-3.8 microM). The most potent inhibitor of T2 sulfotransferase activity in our experiments was the PCB metabolite 3-hydroxy-2,3',4, 4',5-pentachlorobiphenyl with an IC50 value of 0.2 microM. A hydroxyl group in the para or meta position appeared to be an important structural requirement for T2 sulfotransferase inhibition by PCB metabolites. Ortho hydroxy PCBs were much less potent, and none of the parent PHAHs was capable of inhibiting T2 sulfotransferase activity. In addition, the formation of T2 sulfotransferase-inhibiting metabolites of individual brominated diphenyl ethers and nitrofen as well as from some commercial PHAH mixtures (e.g., Bromkal, Clophen A50, and Aroclor 1254) was also demonstrated. These results indicate that hydroxylated PHAHs are potent inhibitors of thyroid hormone sulfation. Since thyroid hormone sulfation may play an important role in regulating free hormone levels in the fetus, and PCB metabolites are known to accumulate in fetal tissues after maternal exposure to PCBs, these observations may have implications for fetal thyroid hormone homeostasis and development.


Subject(s)
Hydrocarbons, Halogenated/pharmacology , Sulfotransferases/antagonists & inhibitors , Sulfur/metabolism , Triiodothyronine/metabolism , Animals , Benzofurans/pharmacokinetics , Benzofurans/pharmacology , Biotransformation , Cytochrome P-450 Enzyme System/biosynthesis , Cytochrome P-450 Enzyme System/metabolism , Diiodothyronines/metabolism , Dioxins/pharmacokinetics , Dioxins/pharmacology , Hydrocarbons, Halogenated/pharmacokinetics , Hydroxylation , Isoenzymes/biosynthesis , Isoenzymes/metabolism , Male , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Phenobarbital/pharmacology , Polychlorinated Biphenyls/pharmacology , Rats , Rats, Wistar , Structure-Activity Relationship , Sulfotransferases/metabolism , beta-Naphthoflavone/pharmacology
6.
Mediators Inflamm ; 7(3): 163-8, 1998.
Article in English | MEDLINE | ID: mdl-9705603

ABSTRACT

We developed an in vitro organ bath method to measure permeability and contractility simultaneously in murine intestinal segments. To investigate whether permeability and contractility are correlated and influenced by mucosal damage owing to inflammation, BALB/c mice were exposed to a 10% dextran sulphate sodium (DSS) solution for 8 days to induce colitis. The effect of pharmacologically induced smooth muscle relaxation and contraction on permeability was tested in vitro. Regional permeability differences were observed in both control and 10% DSS-treated mice. Distal colon segments were less permeable to 3H-mannitol and 14C-PEG 400 molecules compared with proximal colon and ileum. Intestinal permeability in control vs. 10% DSS mice was not altered, although histologic inflammation score and IFN-gamma pro-inflammatory cytokine levels were significantly increased in proximal and distal colon. IL-1beta levels were enhanced in these proximal and distal segments, but not significantly different from controls. Any effect of pharmacologically induced contractility on intestinal permeability could not be observed. In conclusion, intestinal permeability and contractility are not correlated in this model of experimentally induced colitis in mice. Although simultaneous measurement in a physiological set-up is possible, this method has to be further validated.


Subject(s)
Colitis/physiopathology , Gastrointestinal Motility , Intestinal Mucosa/metabolism , Animals , Female , In Vitro Techniques , Interferon-gamma/biosynthesis , Mice , Mice, Inbred BALB C , Muscle Contraction , Permeability
7.
Mediators Inflamm ; 7(3): 169-73, 1998.
Article in English | MEDLINE | ID: mdl-9705604

ABSTRACT

FRom several in vitro and in vivo studies involvement of somatostatin (SMS) in intestinal inflammation emerge. Acute colitis induced in rats is attenuated by the long-acting SMS analogue octreotide. We studied the potential beneficial effect of SMS on non-acute experimental colitis. BALB/c mice received either saline, SMS-14 (36 or 120 microg daily) or octreotide (3 microg daily) subcutaneously delivered by implant osmotic pumps. A non-acute colitis was induced by administration of dextran sodium sulphate (DSS) 10% in drinking water during 7 days. DSS evoked a mild, superficial pancolitis, most characterized by mucosal ulceration and submucosal influx of neutrophils. Neither SMS-14 nor octreotide reduced mucosal inflammatory score or macroscopical disease activity, although reduction of intestinal levels of interleukin-1beta (IL-1beta), IL-6 and IL-10 during DSS was augmented both by SMS and octreotide. A slight increase of neutrophil influx was seen during SMS administration in animals not exposed to DSS. In conclusion, SMS or its long-acting analogue did not reduce intestinal inflammation in non-acute DSS-induced colitis. According to the cytokine profile observed, SMS-14 and octreotide further diminished the reduction of intestinal macrophage and Th2 lymphocyte activity.


Subject(s)
Colitis/drug therapy , Intestinal Mucosa/drug effects , Somatostatin/therapeutic use , Animals , Colitis/immunology , Colitis/pathology , Dextran Sulfate/toxicity , Female , Interleukin-1/analysis , Interleukin-10/analysis , Interleukin-6/analysis , Intestinal Mucosa/pathology , Mice , Mice, Inbred BALB C
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