Nifedipine prevents hepatic fibrosis in a non-alcoholic steatohepatitis model induced by an L-methionine-and choline-deficient diet.

Recent reports have shown that nifedipine, a calcium channel blocker, increases peroxisome proliferator-activated receptor-γ (PPARγ) activity. Since PPARγ agonists, such as pioglitazone and rosiglitazone, are effective in reducing non-alcoholic steatohepatitis (NASH) and cirrhosis in animal models, we examined the protective effects of nifedipine, as compared with bezafibrate, a PPARα agonist, in a NASH model induced by an L-methionine- and choline-deficient (MCD) diet. An MCD diet for 20 weeks changed the color of the rat liver to yellow with an irregular surface, whereas the color of the liver in both the bezafibrate and nifedipine treatment groups was markedly changed to yellow-brown with a smooth surface. Furthermore, nifedipine, as well as bezafibrate, significantly prevented liver fibrosis induced by an MCD diet, as assessed by Masson's trichrome staining, accompanied by a significant decrease in serum AST. Overall, nifedipine treatment resulted in an improvement in NASH, similar to bezafibrate, in a rat model. In hypertensive patients with metabolic syndrome, nifedipine may provide additional benefits, beyond its blood pressure-lowering effects, to prevent NASH and fatty liver disease.

Prevention and regression of non-alcoholic steatohepatitis (NASH) in a rat model by metabosartan, telmisartan.

The favorable metabolic effects of telmisartan have been attributed to its angiotensin II receptor blockade and action as a partial agonist of peroxisome proliferator-activated receptor (PPAR)-gamma. We previously reported that administration of telmisartan markedly inhibited lipid accumulation in the liver in mice fed a high-fat diet. In the present study, we further examined the protective effect of telmisartan in a non-alcoholic steatohepatitis (NASH) model induced by feeding Wistar rats an L-methionine- and choline-deficient (MCA) diet. In the first experiment, rats were fed an MCA diet for 8 weeks with or without telmisartan (3 mg/kg/day). Liver fibrosis was observed by Masson trichrome staining, and co-treatment was shown to attenuate liver fibrosis. In the second experiment, Wistar rats were fed an MCA diet for 20 weeks, and telmisartan (3 mg/kg/day) was administered during weeks 0-20 as a preventive model or weeks 8-20 as a therapeutic model. As a result, telmisartan administration in both models significantly attenuated liver fibrosis and an increase in serum AST. Of importance, the HGF concentration in the liver was significantly increased in the telmisartan-treated group. Overall, telmisartan showed a potential action to improve NASH induced by an MCA diet, possibly due to increased HGF production through partial agonist of PPAR-gamma. These favorable characteristics of telmisartan as a partial agonist of PPAR-gamma may provide a benefit in the treatment of metabolic syndrome beyond its blood pressure-lowering effect.

New treatment of periodontal diseases by using NF-kappaB decoy oligodeoxynucleotides via prevention of bone resorption and promotion of wound healing.

Nuclear factor-kappa B (NF-kappaB) is involved in osteoclast differentiation and activation. Thus, the blockade of the NF-kappaB pathway might be a novel therapeutic strategy for treating bone metabolic diseases. Periodontitis is subgingival inflammation caused by bacterial infection; this disease also is thought to be a chronic focal point responsible for systemic diseases. In this study, NF-kappaB decoy oligodeoxynucleotides (ODNs) were topically applied for experimental periodontitis in a debris-accumulation model and wound healing in a bone-defect model of beagle dogs to investigate the effect of decoy ODN on bone metabolism. Application of NF-kappaB decoy ODN significantly reduced interleukin-6 activity in crevicular fluid and improved alveolar bone loss in the analysis of dental radiographs and DEXA. Direct measurement of exposed root that lost alveolar bone support revealed that NF-kappaB decoy treatment dramatically protected bone from loss. In a bone-defect model, NF-kappaB decoy ODN promoted the healing process as compared with control scrambled decoy in micro-CT analysis. Overall, inhibition of NF-kappaB by decoy strategy prevented the progression of bone loss in periodontitis and promoted the wound healing in bone defects through the inhibition of osteoclastic bone resorption. Targeting of NF-kappaB might be a potential therapy in various bone metabolic diseases.