title: Anti-diabetic effect of three new norditerpenoid alkaloids in vitro and potential mechanism via PI3K/Akt signaling pathway.
abstract: Diabetes is a metabolic disease with the characteristic of high blood glucose (hyperglycemia). In our previous study, we found that nigelladines A-C (compounds A-C), three norditerpenoid alkaloids from the seeds of Nigella glandulifera Freyn (Ranunculaceae) exhibited protein of tyrosine phosphatase 1B (PTP1B) inhibitory activity in vitro. In the present study, we further investigated their anti-diabetes activities in L6 moytubes and illuminated the mechanisms of action of compounds A-C. Several parameters of glucose metabolism such as glucose consumption, glycogen content and hexokinase activity were increased by compounds A-C. The results suggested that compounds A-C improved glucose metabolism through promoting synthesis of glycogen. Expression of PTP1B protein was inhibited by compounds A-C in L6 moytubes. PI3K-dependent Akt phosphorylation was found to be activated by compounds A-C and completely blocked by wortmannin (a PI3K inhibitor). Moreover, the insulin-mediated induction of insulin receptor substrate-1 (IRS-1) and glycogen synthase kinase-3β (GSK-3β) were also suppressed by wortmannin. Western blot results indicated that compounds A-C-induced IRS-1/Akt activation was likely a consequence of PTP1B inhibition. Compounds A-C promoted glycogen synthesis through Akt-mediated GSK3 phosphorylation. Therefore, activation of PI3K/Akt insulin signaling pathway and suppression of PTP1B is the molecular mechanism that contributes to the anti-diabetic effect of compounds A-C in cellular models. The three alkaloids potentially serve as lead compounds for the development of antidiabetic drugs.
authors.affiliation: The Key Laboratory of Plant Resources and Chemistry of Arid Zone and State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Tang
authors.affiliation: The Key Laboratory of Plant Resources and Chemistry of Arid Zone and State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, People's Republic of China; University of Chinese Academy of Sciences, Beijing 100039, People's Republic of China.
authors.forename: Qi-Bin
authors.initials: QB
authors.lastname: Chen
authors.affiliation: The Key Laboratory of Plant Resources and Chemistry of Arid Zone and State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, People's Republic of China. Electronic address: xinxl@ms.xjb.ac.cn.
authors.forename: Xue-Lei
authors.initials: XL
authors.lastname: Xin
authors.affiliation: The Key Laboratory of Plant Resources and Chemistry of Arid Zone and State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, People's Republic of China. Electronic address: haji@ms.xjb.ac.cn.
authors.forename: Haji-Akber
authors.initials: HA
authors.lastname: Aisa
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004224:Diterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D005947:Glucose / Q000819:agonists / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D031844:Nigella; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D012639:Seeds; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D004224:Diterpenes; D007004:Hypoglycemic Agents; D010936:Plant Extracts; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
keywords: Anti-diabetic activity; Diabetes; Glucose metabolism; Norditerpenoid alkaloids; PI3K/Akt signaling pathway; Protein tyrosine phosphatase 1B