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- Kumar Jeengar, Manish, et al.
(författare)
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Local administration of 4-Thiouridine, a novel molecule with potent antiinflammatory properties, protects against experimental colitis and arthritis
- 2020
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Ingår i: International Immunopharmacology. - : ELSEVIER. - 1567-5769 .- 1878-1705. ; 85
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies in a rat model of Sephadex induced lung inflammation showed that 4-Thiouridine (4SU), a thiol substituted nucleoside, was very effective in reducing edema, leukocyte influx and TNF levels in bronchoalvelolar lavage fluid. However, little is known about the factors and mechanisms underlying these effects. In the present study, we have used two separate mouse models of chronic inflammation, a model of dextran sulphate sodium (DSS) induced colitis and a model of antigen induced arthritis, to evaluate the anti-inflammatory effect of 4-thiouridine. We have analyzed a broad spectrum of inflammatory mediators in order to delineate the mechanisms behind a potential anti-inflammatory effect of 4SU. Colitis was induced in C57BL/6 mice by administration of 3.5% DSS in drinking water for 5 days and the potential anti-colitic effect of 4SU was assessed by monitoring the disease activity index (DAI), measurement of colon length and histopathological analysis of colon tissue. We analyzed tissue myeloperoxidase (MPO) activity, serum pro-inflammatory cytokines (IL-1 beta, IL-6 and TNF), mRNA and protein expression of pro-inflammatory cytokines, COX-2, and NF-kappa B activity in colitis tissue. Intracolonic administration of 4SU (5 mg/kg & 10 mg/kg.) significantly inhibited MPO activity and reduced the levels of pro-inflammatory cytokines (IL-1 beta, IL-6 and TNF) as well as COX-2. Further, NF-kappa B activation was also blocked by attenuating the phosphorylation of IkB kinase (IKK alpha/beta) in DSS-induced colitis tissues. Arthritis was induced by intra-articular injection of mBSA in the knee of NMRI mice pre-immunized with mBSA and 4SU was administered locally by direct injection into the knee joint. The antiarthritic potential of 4SU was calculated by histopathological scores and histochemical analysis of joint tissue. Further, immunohistochemistry was used to study inflammatory cell infiltration and expression of cytokines and adhesion molecules in the synovium. Local administration of 50-100 mg/kg 4SU at the time of arthritis onset clearly prevented development of joint inflammation and efficiently inhibited synovial expression of CD18, local cytokine production and recruitment of leukocytes to the synovium. Taken together, our data clearly demonstrates a potent anti-inflammatory effect of 4SU in two experimental models. In conclusion 4SU could be a new promising candidate for therapeutic modulation of chronic inflammatory diseases like ulcerative colitis and arthritis.
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| 2. |
- Kumar Jeengar, Manish, et al.
(författare)
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Uridine Ameliorates Dextran Sulfate Sodium (DSS)-Induced Colitis in Mice
- 2017
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Uridine, one of the four components that comprise RNA, has attracted attention as a novel therapeutic modulator of inflammation. However, very little is known about its effect on intestinal inflammation. The aim of the present study was to investigate the potential protective effect of intracolonic administered uridine against DSS induced colitis in male C57BL/6 mice. Intracolonic instillation of 3 doses of uridine 1 mg/Kg (lower dose), 5 mg/Kg (medium dose), and 10 mg/Kg (higher dose) in saline was performed daily. Uridine at medium and high dose significantly reduced the severity of colitis (DAI score) and alleviated the macroscopic and microscopic signs of the disease. The levels of proinflammatory cytokines IL-6, IL-1 beta and TNF in serum as well as mRNA expression in colon were significantly reduced in the uridine treated groups. Moreover, colon tissue myloperoxidase activities, protein expression of IL-6, TNF-alpha, COX-2, P-NFkB and P-Ikk-alpha beta in the colon tissues were significantly reduced in medium and high dose groups. These findings demonstrated that local administration of uridine alleviated experimental colitis in male C57BL/6 mice accompanied by the inhibition of neutrophil infiltration and NF-kappa B signaling. Thus, Uridine may be a promising candidate for future use in the treatment of inflammatory bowel disease.
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