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Objective: No effective drugs have been developed to date to prevent or treat non-alcoholic fatty liver disease (NAFLD), although diet modification and exercise to improve obesity have been attempted. Therefore, development of a novel drug/strategy to treat NAFLD is urgently needed. In the present study, a novel concept is proposed for the treatment of NAFLD. Methods: Fisher 344 male rats were given a cholinedeficient, L-amino acid-defined (CDAA) diet or a high-fat high-calorie (HF/HC) diet with or without the antiplatelet agents, aspirin, ticlopidine or cilostazol for 16 weeks. Liver steatosis, inflammation and fibrosis, and the possible mechanisms involved were investigated. Results: All three antiplatelet drugs, namely aspirin, ticlopidine and cilostazol, significantly attenuated liver steatosis, inflammation and fibrosis in the CDAA diet group. Of the three agents, cilostazol was the most effective, and the drug also suppressed HF/HC dietinduced liver steatosis. Cilostazol appeared to exert its beneficial effect against NAFLO by suppressing mitogenactivated protein kinase activation induced by oxidative stress and platelet-derived growth factor via intercepting signal transduction from Akt to c-Raf. Conclusion: Antiplatelet agents, especially cilostazol, offer the promise of becoming key agents for the treatment of NAFLD. [ABSTRACT FROM AUTHOR]

Background: A number of recent studies have demonstrated a protective effect of renin-angiotensin system (RAS) antagonism against immune mediated diseases such as myocarditis, chronic allograft rejection, and antiglomerular basement membrane nephritis. To our knowledge, there has been no report on the immunological contribution of the RAS in colonic tissue. Aims: We evaluated the direct effect of angiotensin II (All) on the pathogenesis of immune mediated colitis using angiotensinogen deficient homozygous (Atg-/-) mice. Subjects: 2,4,6-Trinitrobenzene sulphonic acid (TNBS) colitis was induced in Atg-/- and wild-type (Atg+/+) mice. Methods: Levels of proinflammatory cytokines in the colon were determined by enzyme linked immunosorbent assay. Histological analysis was performed simultaneously. Results: Although Atg-/- mice developed colitis, the degree was much milder than that in Atg+/+ mice (p<0.05). Colonic cytokine analysis showed that the production of proinflammatory cytokines (interleukin (IL)-1 β, interferon γ (IFN-γ)) was impaired in Atg-/- mice. Furthermore, expression of cytokines such as lL-4 and IL-10 in the colon was predominant in Atg-/-- compared with Atg+/+ mice after TNBS instillation (p<0.005, p<0.01, respectively). Similarly, subcutaneous infusion of losartan suppressed colitis (p<0.05) and the production of proinflammatory cytokines (IL-1 β, IFN-γ). These results indicate that the RAS is directly involved in the pathogenesis of TNBS colitis through regulation of proinflammatory and anti-inflammatory cytokines in the colon. Conclusions: This study revealed that the RAS is involved in the immune system in the colon. Antagonism of the RAS is a potential prophylactic strategy for the treatment of human inflammatory bowel disease. [ABSTRACT FROM AUTHOR]