Polyphenolic compounds from Artemisia dracunculus L. inhibit PEPCK gene expression and gluconeogenesis in an H4IIE hepatoma cell line.
An ethanolic extract of Russian tarragon, Artemisia dracunculus L., with antihyperglycemic activity in animal models was reported to decrease phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression in STZ-induced diabetic rats. A quantitative polymerase chain reaction (qPCR) assay was developed for the bioactivity-guided purification of the compounds within the extract that decrease PEPCK expression. The assay was based on the inhibition of dexamethasone-stimulated PEPCK upregulation in an H4IIE hepatoma cell line. Two polyphenolic compounds that inhibited PEPCK mRNA levels were isolated and identified as 6-demethoxycapillarisin and 2',4'-dihydroxy-4-methoxydihydrochalcone with IC(50) values of 43 and 61 muM, respectively. The phosphoinositide-3 kinase (PI3K) inhibitor LY-294002 showed that 6-demethoxycapillarisin exerts its effect through the activation of the PI3K pathway, similarly to insulin. The effect of 2',4'-dihydroxy-4-methoxydihydrochalcone is not regulated by PI3K and dependent on activation of AMPK pathway. These results indicate that the isolated compounds may be responsible for much of the glucose-lowering activity of the Artemisia dracunculus extract.
Govorko
Dmitry
D
Rutgers University, Biotech Center, 59 Dudley Road, New Brunswick, NJ 08901, USA. govorko@aesop.rutgers.edu
Logendra
Sithes
S
Wang
Yanxin
Y
Esposito
Debora
D
Komarnytsky
Slavko
S
Ribnicky
David
D
Poulev
Alexander
A
Wang
Zhong
Z
Cefalu
William T
WT
Raskin
Ilya
I
D000818:Animals; D019306:Artemisia / Q000737:chemistry*; D045744:Cell Line, Tumor; D047188:Chalcones / Q000032:analysis / Q000302:isolation & purification / Q000494:pharmacology*; D002867:Chromones / Q000032:analysis / Q000302:isolation & purification / Q000494:pharmacology*; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000032:analysis / Q000302:isolation & purification / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000032:analysis / Q000302:isolation & purification / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D010636:Phenols / Q000032:analysis / Q000302:isolation & purification / Q000494:pharmacology; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology; D018520:Plant Shoots / Q000737:chemistry; D059808:Polyphenols; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013873:Thionucleotides / Q000494:pharmacology
C514624:2',4'-dihydroxy-4-methoxydihydrochalcone; C514569:6-demethoxycapillarisin; D047188:Chalcones; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007004:Hypoglycemic Agents; D007328:Insulin; D009025:Morpholines; D010636:Phenols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010936:Plant Extracts; D059808:Polyphenols; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D013873:Thionucleotides; C516138:dorsomorphin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D003907:Dexamethasone; D000242:Cyclic AMP; C494923:Akt2 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose