Gypenoside XLIX isolated from Gynostemma pentaphyllum inhibits nuclear factor-kappaB activation via a PPAR-alpha-dependent pathway.
Nuclear factor (NF)-kappaB is important in the generation of inflammation. Besides regulating lipid metabolism, peroxisome proliferator-activated receptor (PPAR)-alpha activators also reduce NF-kappaB activation to terminate activation of inflammatory pathways. Gynostemma pentaphyllum (GP) has been used to treat various inflammatory diseases and hyperlipidemia. Here, we demonstrate that GP extract and one of its main components, Gypenoside XLIX (Gyp-XLIX) inhibited LPS-induced NF-kappaB activation in murine macrophages. Furthermore, Gyp-XLIX restored the LPS- and TNF-alpha-induced decrease in cytosolic I-kappaBalpha protein expression and inhibited the translocation of NF-kappaB(p65) to the nucleus in THP-1 monocyte and HUVEC cells. The inhibition of LPS- and TNF-alpha-induced NF-kappaB luciferase activity in macrophages was abolished by MK-886, a selective PPAR-alpha antagonist. GP extract and Gyp-XLIX (EC(50): 10.1 microM) enhanced PPAR-alpha luciferase activity in HEK293 cells transfected with the tK-PPREx3-Luc reporter plasmid and expression vectors for PPAR-alpha. Additionally, Gyp-XLIX specifically enhanced PPAR-alpha mRNA and protein expression in THP-1-derived macrophage cells. The selectivity of Gyp-XLIX for PPAR-alpha was demonstrated by the activation of only PPAR-alpha in HEK293 cells transfected with expression vectors for PPAR-alpha, PPAR-beta/delta or PPAR-gamma1 plasmids and in THP-1-derived macrophage naturally expressing all three PPAR isoforms. The present study demonstrates that Gyp-XLIX, a naturally occurring gynosaponin, inhibits NF-kappaB activation via a PPAR-alpha-dependent pathway.
Huang
Tom Hsun-Wei
TH
Pharmaceutical Chemistry Discipline and Herbal Medicines Research and Education Centre, Faculty of Pharmacy, University of Sydney, A15 S322, Sydney, NSW 2006, Australia.
Li
Yuhao
Y
Razmovski-Naumovski
Valentina
V
Tran
Van Hoan
VH
Li
George Qian
GQ
Duke
Colin C
CC
Roufogalis
Basil D
BD
D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000187:drug effects*; D029774:Gynostemma / Q000737:chemistry*; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D002722:Chlorobenzenes
D017931:DNA Primers; D007211:Indoles; D008156:Luciferases; D016328:NF-kappa B; D047493:PPAR alpha; D010936:Plant Extracts; C474918:gypenoside; C060893:MK-886; D002722:Chlorobenzenes