Endothelial dysfunction contributes to the initiation and development of hypertension. We previously found that simvastatin moderately decreases blood pressure in 2-kidney-2-clip (2k2c) renal hypertension, but the precise mechanisms are still unclear. The present study was designed to examine the protective actions of simvastatin in 2k2c-evoked endothelial dysfunction and also delineate the underlying mechanisms. Here we show that 2k2c-induced elevation in plasma angiotensin II impaired acetylcholine-induced endothelium-dependent vascular relaxation, suppressed endothelial NO synthase (eNOS) activity and reduced nitric oxide (NO) production. Additionally, the levels of tetrahydrobiopterin (BH4), an essential cofactor of eNOS, as well as the activity of GTP cyclohydrolase I (GTPCH I), the rate-limiting enzyme for BH4 synthesis, were markedly reduced. Administration of simvastatin significantly improved acetylcholine-induced endothelium-dependent carotid arteries relaxation at 9 weeks in reno-hypertensive rats. Notably, GTPCH I activity, BH4 production, p-eNOS expression and NO levels in the vascular endothelium were elevated as a result of simvastatin administration. In cultured rat arterial endothelial cells, simvastatin restored BH4, GTPCH I activity and NO release impaired by angiotensin II, and pretreatment with mevalonate (MVA) or geranylgeranyl pyrophosphate (GGPP) abolished the beneficial effects exerted by simvastatin. Moreover, RhoA inhibitor C3 exoenzyme, Rho kinase inhibitor Y-27632 and dominant negative mutant of RhoA prevented BH4 and NO loss due to Ang II treatment. Taken together, normalization of BH4-eNOS-NO pathway at least in part accounts for the beneficial actions of simvastatin on vascular endothelium during 2k2c hypertension, and RhoA-Rho kinase pathway is involved in regulation of BH4 production.

Vinpocetine is a clinically used drug for cerebrovascular disorders as well as age-related memory impairment. Of note, vinpocetine has been recently identified as a novel anti-inflammatory agent; however, its effects on cancer cells remain to be investigated. In the present study, we found that vinpocetine potently inhibited proliferation of multiple types of human breast cancer cells by arresting cell cycle at G(0)/G(1) phase. It was also revealed that vinpocetine induced cell apoptosis via mitochondria-dependent pathway. Moreover, vinpocetine impaired the migration of the strongly metastatic cell MDA-MB-231. In xenograft model of human breast cancer in nude mice, both systemic and local administration of vinpocetine significantly suppressed the tumor growth without observed toxicity. Interestingly, vinpocetine markedly attenuated the activation of Akt and signal transducer and activator of transcription factor 3 (STAT3), but had no effects on MAP kinases pathways. Collectively, the data suggest that vinpocetine possesses significant yet previously unknown antitumor properties that may be utilized for the treatment of breast cancer.

Background: Ginkgo biloba extract 50 (GBE50) has a variety of pharmacological functions such as anti-inflammatory, antioxidant and maintenance of glucose and lipid metabolism homeostasis. However, the therapeutic effects and mechanisms of GBE50 on non-alcoholic fatty liver disease (NAFLD) remain unknown. Therefore, in this study, we evaluated the therapeutic effects of GBE50 in NAFLD by using a high-fat diet (HFD) mice model. Methods: C57BL/6J mice were fed a HFD diet for 15 weeks and were given respectively 25, 50, and 100 mg/kg GBE50 daily by gavage from 3 to 15 weeks. After the administration, blood samples and liver tissues were collected for biochemical detection, histological measurement, immunohistochemistry and Western blot, respectively. Results: We found that GBE50 treatment could ameliorate insulin resistance (IR), glucose intolerance, lipid accumulation, hepatic steatosis and liver injury in HFD-fed mice. Further mechanism exploration discovered that the hepatoprotective effects of GBE50 on NAFLD may be related to the strengthening of IRS-1 signal activation and the weakening of NF-κB, Akt and endoplasmic reticulum stress signals activation. Conclusion: GBE50 is a potentially powerful therapeutic agent for the treatment of NAFLD.