| This dissertation includes two parts. The first part is about the anti-fatigue mechanism investigation of arctigenin (ATG) as an activator of adenosine5’-monophosphate (AMP)-activated protein kinase (AMPK) to improve endurance in rats via regulation of antioxidant signaling pathway. The second part introduces the discovery of novel activators of glucokinase (GK), one of the most important regulatory enzymes in glucose metabolism.Over-production of reactive oxygen species (ROS) by strenuous exercises can influence contractile function of skeletal muscle, accelerate fatigue and decrease task performance. ROS accumulation damages the biomembrane, proteins and DNA that are correlated with several diseases progression, including type2diabetes and other metabolic diseases. Therefore, amelioration of skeletal muscle antioxidant capacity is beneficial for muscle performance, disease prevention and life-quality improvement. AMPK is an axis of energy metabolism, and its activation can increase the expression of the antioxidant enzymes (proteins) responsible for the reduction of ROS. Therefore, AMPK activator can improve oxidative stress and enhance endurance. Previous study in our lab has demonstrated that arctigenin as an AMPK activator could improve mice treadmill endurance by effectively regulating the synthesis of mitochondria, fatty acid oxidation and transcription of related genes. Here we further evaluated the regulation of ATG on ROS production and clearance, and clarified the corresponding signal pathways on cellular level. The in vitro evidence revealed that artigenin up-regulated the expressions of antioxidant-related genes, such as superoxide dismutase (SOD), glutathione reductase (Gsr), glutathione peroxidase (GPX1), thioredoxin (Txn) and uncoupling protein2(UCP2), through regulation of AMPK/p53/Nrf2and AMPK/pGC-1α/PPARa pathways. Moreover, weight-loaded forced swimming test (WFST) based in vivo assay in rats further confirmed the anti-fatigue effect of ATG. Our results evaluated the anti-fatigue of ATG in rat model and enriched the anti-fatigue mechanism of ATG.The defects of insulin secretion in pancreatic β-cells, insulin resistance in peripheral tissues and glycogen metabolism disorder in liver are the primary causes of type2diabetes. Glucokinase (GK) is the rate-limiting enzyme in glucose utilization and mainly distributes in the liver and pancreatic β-cells. In liver, GK phosphorylates glucose to promote the synthesis of glycogen; in pancreatic β-cells, GK can increase the sensitivity of pancreatic β-cells in response to glucose to stimulate the insulin secretion. Therefore, GK is an ideal target for the treatment of type2diabetes. Increasing the activity of GK may improve hepatic glucose balance and decrease the glucose threshold of insulin secretion. Hence, we screened GK activator from our compound library based on the established screening system. Two new GK activators were discovered. Moreover, in the supplementary materials, we also touched the study on the discovery of dengue virus NS2B-NS3inhibitor. Dengue virus (DENV), a mosquito-borne flavivirus, is the causative agent of dengue fever with high morbidity and mortality. Currently, dengue fever spreads rapidly across the globe, but there still lacks approved vaccine or antiviral drugs for human to date. DENV NS2B-NS3protease plays a vital role in virus replication and has become an important target for anti-dengue. In our work, we constructed the screening platform of DENV NS2B-NS3protease inhibitor, and several small molecule NS2B-NS3protease inhibitors were discovered. These novel active compounds might act as lead compounds for further anti-DENV drug discovery. |
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