Dietary Polyphenols and Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD), which is emerging as a major public health issue worldwide, is characterized by a wide spectrum of liver disorders, ranging from simple fat accumulation in hepatocytes, also known as steatosis, to non-alcoholic steatohepatitis (NASH) and cirrhosis. At present, the pharmacological treatment of NAFLD is still debated and dietary strategies for the prevention and the treatment of this condition are strongly considered. Polyphenols are a group of plant-derived compounds whose anti-inflammatory and antioxidant properties are associated with a low prevalence of metabolic diseases, including obesity, hypertension, and insulin resistance. Since inflammation and oxidative stress are the main risk factors involved in the pathogenesis of NAFLD, recent studies suggest that the consumption of polyphenol-rich diets is involved in the prevention and treatment of NAFLD. However, few clinical trials are available on human subjects with NAFLD. Here, we reviewed the emerging existing evidence on the potential use of polyphenols to treat NAFLD. After introducing the physiopathology of NAFLD, we focused on the most investigated phenolic compounds in the setting of NAFLD and described their potential benefits, starting from basic science studies to animal models and human trials.

Regorafenib in combination with silybin as a novel potential strategy for the treatment of metastatic colorectal cancer.

PURPOSE: Regorafenib, an oral multikinase inhibitor, has demonstrated survival benefit in metastatic colorectal cancer (mCRC) patients that have progressed after all standard therapies. However, novel strategies to improve tolerability and enhance anti-cancer efficacy are needed. EXPERIMENTAL DESIGN: We have evaluated in vitro the effects of regorafenib in combination with silybin, a biologically active component extracted from the seeds of Silybum marianum, in a panel of human colon cancer cells. Furthermore, we have prospectively treated a cohort of 22 refractory mCRC patients with regorafenib plus silybin. RESULTS: Treatment with regorafenib determined a dose-dependent growth inhibition whereas treatment with silybin had no anti-proliferative effects among all cancer cells tested. The combined treatment with regorafenib and silybin induced synergistic anti-proliferative and apoptotic effects by blocking PI3K/AKT/mTOR intracellular pathway. Moreover, combined treatment with regorafenib and silybin increased the production of reactive oxygen species levels within cells. In an exploratory proof of concept clinical study in a cohort of 22 mCRC patients after failure of all standard therapies, the clinical activity of regorafenib in combination with silybin was assessed. A median progression-free survival of 10.0 months and a median overall survival of 17.6 months were observed in these patients. These results suggest that the combined treatment potentially increases the clinical efficacy of regorafenib. Moreover, due to its anti-oxidative properties, silybin could protect patients from drug-induced liver damages, allowing to continue an effective anti-cancer therapy. CONCLUSIONS: The present study suggests that silybin in combination with regorafenib is a promising strategy for treatment of metastatic colorectal patients.

A Long-term Treatment with Silybin in Patients with Non-alcoholic Steatohepatitis Stimulates Catalase Activity in Human Endothelial Cells.

AIM: To compare levels of oxidative stress markers in patients' sera with non-alcoholic steatohepatitis (NASH) treated for 12 months (T12) with silybin conjugated with phosphatidylcholine (Realsil®) (R) or placebo (P) and investigate oxidative stress responses in human endothelial cells conditioned with patients' sera. PATIENTS AND METHODS: We recruited twenty-seven patients with histological NASH. We measured thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD) and catalase (CAT) activities in human endothelial cells conditioned with patients' sera exposed or not to H2O2 Results: We found in decreased-TBARS patients' sera, at T12, a decrease of alanine aminotransferase (p=0.038), transforming growth factor-beta (p=0.009) and procollagen I (p=0.001). By dividing patients into two groups, increased (P-I/R-I) and decreased TBARS (P-II/R-II) at T12 compared to T0, we found an increased CAT activity in conditioned endothelial cells at T12 in both groups (p=0.05 and p=0.001, respectively). CONCLUSION: Realsil® may be effective against endothelial dysfunction by stimulating the cellular antioxidant defense.