W941, a new PI3K inhibitor, exhibits preferable anti-proliferative activities against nonsmall cell lung cancer with autophagy inhibitors.

The PI3K pathway is aberrantly activated in many cancers and plays a critical role in tumour cell proliferation and survival, making it a rational therapeutic target. In the present study, the effects and the underlying mechanism of a new PI3K inhibitor, W941, were investigated in non-small-cell lung cancer (NSCLC). The results of this study showed that W941 inhibited the growth of A549 and Hcc827 cells with IC50 values of 0.12 and 0.23 µM, respectively, and that W941 markedly inhibited the growth of A549 xenograft tumours in a nude mouse model without decreasing body weight. Western blotting assays showed that W941 inhibited the phosphorylation of downstream proteins in the PI3K pathway (AKT, mTOR, p70S6K and 4EBP1) in both A549 and Hcc827 cells. In addition, after W941 treatment, a dose-dependent increase in the ratio of the LC3-II/I ratio was observed. When cells were pre-treated with chloroquine or bafilomycin A1, W941 increased the LC3-II/I ratio, suggesting that W941 acted as an autophagy inducer. Moreover, autophagy blockers enhanced apoptosis after W941 treatment, indicating that W941-induced autophagy actually protected the cells against its cytotoxicity. Our findings suggest that the combination of a PI3K inhibitor with an autophagy inhibitor might be a novel option for NSCLC treatment.

Ginsenoside Re inhibits vascular neointimal hyperplasia in balloon-injured carotid arteries through activating the eNOS/NO/cGMP pathway in rats.

Ginsenoside Re (GS-Re) is one of the main ingredients of ginseng, a widely known Chinese traditional medicine, and has a variety of beneficial effects, including vasorelaxation, antioxidative, anti-inflammatory, and anticancer properties. The aims of the present study were to observe the effect of GS-Re on balloon injury-induced neointimal hyperplasia in the arteries and to investigate the mechanisms underlying this effect. A rat vascular neointimal hyperplasia model was generated by rubbing the endothelium of the common carotid artery (CCA) with a balloon, and GS-Re (12.5, 25 or 50 mg/kg/d) were subsequently continuously administered to the rats by gavage for 14 days. After GS-Re treatment, the vessel lumen of injured vessels showed significant increases in the GS-Re 25.0 and 50.0 mg/kg/d (intermediate- and high-dose) groups according to H.E. staining. Additionally, a reduced percentage of proliferating cell nuclear antigen (PCNA)-positive cells and an increased number of SM α-actin-positive cells were detected, and the levels of NO, cyclic guanosine monophosphate (cGMP), and eNOS mRNA as well as the phos-eNOSser1177/eNOS protein ratio were obviously upregulated in the intermediate- and high-dose groups. Moreover, the promotive effects of GS-Re on NO and eNOS expression were blocked by L-NAME treatment to different degrees. These results suggested that GS-Re can suppress balloon injury-induced vascular neointimal hyperplasia by inhibiting VSMC proliferation, which is closely related to the activation of the eNOS/NO/cGMP pathway.

Involvement of growth factors in diabetes mellitus and its complications: A general review.

Diabetes mellitus (DM) is a major endocrine metabolic disease and is marked by a lack of insulin. The complication of DM is one of the most difficult problems in medicine. The initial translational studies revealed that growth factors have a major role in integrating tissue physiology and in embryology as well as in growth, maturation and tissue repair. In some tissues affected by diabetes, growth factors are induced by a relative deficit or excess. Fibroblast growth factor 21 (FGF21) is a promising regulator of glucose and lipid metabolism with multiple beneficial effects including hypoglycemic and lipid-lowering. Vascular endothelial growth factor (VEGF) is a potent angiogenic and vascular permeability factor and is implicated in both of these complications in diabetes. Increase or decrease in the production of transforming growth factor-ß1 (TGF-ß1) has been associated with diabetic nephropathy and retinopathy. The insulin-like growth factor-I (IGF-I) is a naturally-occurring single chain polypeptide which has been widely used in the treatment of diabetic glomerular and renal tubular injuries. This review summarizes the recent evidences for an involvement of growth factors in diabetic complications, focusing on their emergence in sequence of events leading to vascular complications or their potential therapeutic role in these diseases. Growth factor therapy in diabetic foot ulcers is already a clinical reality. As methods to finely regulate growth factors in a tissue and time-specific manner are further developed and tested, regulation of the growth factor to normal level in vivo may well become a therapy to prevent and treat diabetic complications.