Therapeutic role of niacin in the prevention and regression of hepatic steatosis in rat model of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), a leading cause of liver damage, comprises a spectrum of liver abnormalities including the early fat deposition in the liver (hepatic steatosis) and advanced nonalcoholic steatohepatitis. Niacin decreases plasma triglycerides, but its effect on hepatic steatosis is elusive. To examine the effect of niacin on steatosis, rats were fed either a rodent normal chow, chow containing high fat (HF), or HF containing 0.5% or 1.0% niacin in the diet for 4 wk. For regression studies, rats were first fed the HF diet for 6 wk to induce hepatic steatosis and were then treated with niacin (0.5% in the diet) while on the HF diet for 6 wk. The findings indicated that inclusion of niacin at 0.5% and 1.0% doses in the HF diet significantly decreased liver fat content, liver weight, hepatic oxidative products, and prevented hepatic steatosis. Niacin treatment to rats with preexisting hepatic steatosis induced by the HF diet significantly regressed steatosis. Niacin had no effect on the mRNA expression of fatty acid synthesis or oxidation genes (including sterol-regulatory element-binding protein 1, acetyl-CoA carboxylase 1, fatty acid synthase, and carnitine palmitoyltransferase 1) but significantly inhibited mRNA levels, protein expression, and activity of diacylglycerol acyltrasferase 2, a key enzyme in triglyceride synthesis. These novel findings suggest that niacin effectively prevents and causes the regression of experimental hepatic steatosis. Approved niacin formulation(s) for other indications or niacin analogs may offer a very cost-effective opportunity for the clinical development of niacin for treating NAFLD and fatty liver disease.

Intrapleural injection of transforming growth factor-beta antibody inhibits pleural fibrosis in empyema.

STUDY OBJECTIVES: Transforming growth factor (TGF)-beta is a cytokine that has been demonstrated to be an important modulator of inflammation and angiogenesis, as well as a potent stimulator of pleural fluid production and fibrosis. We previously demonstrated that rising levels of pleural fluid TGF-beta(1) correlate with pleural fibrosis in experimental empyema in rabbits. In this study, our hypothesis is that neutralization of TGF-beta with an intrapleural injection of a monoclonal antibody to TGF-beta will decrease pleural fibrosis in empyema. DESIGN: Prospective, randomized, blinded study. SETTING: Animal research laboratory. SUBJECTS: Nineteen rabbits. INTERVENTIONS: An empyema was induced in 19 rabbits by intrapleural injection of Pasteurella multocida. A panspecific monoclonal antibody to TGF-beta was injected into the pleural space on 2 subsequent concurrent days in nine rabbits. Ten rabbits received intrapleural injections of bacteria alone and served as controls. All animals were then killed on day 6. Immunohistochemistry, using the antibody to TGF-beta, was performed on pleural tissue specimens from the control rabbits. MEASUREMENTS AND RESULTS: Immunohistochemistry revealed localization of TGF-beta to macrophages in the exudative material and the visceral pleura. After injection of the antibody to TGF-beta, the amount of purulent, exudative material in the pleural space of the nine experimental animals was markedly decreased at autopsy on day 6, relative to control animals. All markers of empyema and pleural fibrosis were also significantly decreased in the rabbits receiving intrapleural anti-TGF-beta. CONCLUSIONS: TGF-beta localizes to macrophages in experimental empyema. Early intrapleural injection of an antibody to TGF-beta inhibits empyema formation and significantly decreases pleural fibrosis in experimental empyema.

Pleural fluid transforming growth factor-beta1 correlates with pleural fibrosis in experimental empyema.

Transforming growth factor-beta1 (TGF-beta1) is a growth factor that is implicated in fibrosis of many organs. The purpose of this study was to determine the sequential levels of TGF-beta1 in the pleural fluid of rabbits that had undergone empyema induction, as fibrosis of the pleural space develops. Thirty-seven rabbits underwent empyema induction. Rabbits were sacrificed on Days 1, 2, 3, 4, 5, 6, and 8. Pleural fluid and viscera pleura specimens were collected at autopsy. TGF-beta1 levels were measured in pleural fluid using a commercially available ELISA kit, and pathologic specimens were scored for evidence of fibrosis (pleural thickness and number of fibroblasts). The median levels of pleural fluid TGF-beta1 increased from 8,100 pg/ml (Days 1 and 2) to 39,600 pg/ml (Day 8). Pleural fluid TGF-beta1 levels closely correlated with microscopic pleural thickness (r = 0.7, p < 0.001) and number of fibroblasts present in the visceral pleura (r = 0.68, p < 0.001). The first increase in pleural fluid levels of TGF-beta1 (Day 3) occurred before the increase in pleural thickness (Day 4) and before the increase in number of fibroblasts (Day 4). In conclusion, pleural fluid levels of TGF-beta1 rise in experimental empyema as pleural fibrosis develops. The rise in empyemic pleural fluid TGF-beta1 levels correlates with markers of pleural space fibrosis.

Differences of creatine kinase MB and cardiac troponin I concentrations in normal and diseased human myocardium.

The diagnosis of myocardial infarction (MI) is established in patients with chest pain and equivocal electrocardiogram changes by demonstrating a rise in blood levels of creatine kinase MB (CK-MB) and/or an increase in cardiac troponin I (cTnI) or cardiac troponin T (cTnT). Previous studies have shown that levels of CK-MB are increased in the left ventricle of individuals with heart disease; however, it has not been established whether there are differences in the ventricular myocardium concentrations of cTnI in diseased compared to healthy hearts. Using a simple extraction technique, concentrations of CK-MB and cTnI were measured in the left ventricle (LV) of six hearts obtained at autopsy from individuals ranging in age from 25 to 79 yr, with and without evidence of cardiac disease. The results show an 86-fold higher concentration of CK-MB and 7.7-fold lower concentration of cTnI in left ventricular myocardium of older men with and without cardiac disease, compared to that of younger men (< age 35 yr) without heart disease. These data suggest that age may need to be considered when setting cutoff limits for these markers for the diagnosis of myocardial infarction.