Danshen extract 15,16-dihydrotanshinone I functions as a potential modulator against metabolic syndrome through multi-target pathways.
Hypertension is a common complication of type 2 diabetes mellitus (T2DM), and is the main cause for T2DM-associated mortality. Although the stringent control of blood pressure is known to be beneficial in reducing the cardiovascular mortality of T2DM patients, drugs with both anti-hypertensive and anti-hyperglycemic effects are seldom reported. The traditional Chinese medicine danshen has long been used for lowering both blood pressure and blood glucose in T2DM patients, shedding lights on the development of such medication. However, the molecular mechanism and active component remain unclear. Here, we report that the lipophilic component, 15,16-dihydrotanshinone I (DHTH) from danshen potently antagonized both mineralocorticoid and glucocorticoid receptors, and efficiently inhibited the expression of their target genes like Na(+)/K(+) ATPase, glucose 6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK). In addition, DHTH increased AMPKalpha phosphorylation and regulated its downstream pathways, including increasing acetyl-CoA carboxylase (ACC) phosphorylation, inhibiting transducer of regulated CREB activity 2 (TORC2) translocation and promoting glucose uptake. Such discovered multi-target effects of DHTH are expected to have provided additional understandings on the molecular basis of the therapeutic effects of danshen against the metabolic syndrome.
Liu
Qiong
Q
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Zhang
Yu
Y
Lin
Zhonghui
Z
Shen
Hong
H
Chen
Lili
L
Hu
Lihong
L
Jiang
Hualiang
H
Shen
Xu
X
D016475:3T3 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D002262:Carboxy-Lyases / Q000235:genetics; D002460:Cell Line; D005663:Furans; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000235:genetics; D006801:Humans; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists; D010616:Phenanthrenes / Q000302:isolation & purification / Q000494:pharmacology*; D011809:Quinones; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism
C493245:CRTC2 protein, human; D005663:Furans; D000451:Mineralocorticoid Receptor Antagonists; D010616:Phenanthrenes; D011809:Quinones; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D014157:Transcription Factors; C000713095:dihydrotanshinone I; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; D005952:Glucose-6-Phosphatase; D002262:Carboxy-Lyases; D000103:Acetyl-CoA Carboxylase; D000254:Sodium-Potassium-Exchanging ATPase; D005947:Glucose