Stereoisomers ginsenosides-20(S)-Rg3 and -20(R)-Rg3 differentially induce angiogenesis through peroxisome proliferator-activated receptor-gamma

Kwok, Hoi‐Hin; Guo, Guanlun; Lau, Justin Kai-Chi; Cheng, Yuen Kit; Wang, Jiangrong; Jiang, Zhihong; Keung, Man-Hong; Mak, Nai‐Ki; Yue, Patrick Ying-Kit; Wong, Ricky N S

doi:10.1016/j.bcp.2011.12.039

Cited by 51 publications

(44 citation statements)

References 47 publications

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“…Among them, Diospyros bipindensis was identified as the most interesting plant for possible activity on PPARs receptors. In fact, some plants of the same family and genus are known to have anti-inflammatory, anti-diabetic and hypoglycaemic properties 24–30 . Diospyros bipindensis has been studied, and some secondary metabolites have been purified and identified including plumbagin, betulinic acid, caniculatin, 4-hydroxy-5-methyl-coumarin and ismailin 22 (Figure S1 of Supplementary Information).…”

Section: Introductionmentioning

confidence: 99%

Betulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis

Brusotti

Montanari

Capelli

et al. 2017

Sci Rep

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PPAR antagonists are ligands that bind their receptor with high affinity without transactivation activity. Recently, they have been demonstrated to maintain insulin-sensitizing and antidiabetic properties, and they serve as an alternative treatment for metabolic diseases. In this work, an affinity-based bioassay was found to be effective for selecting PPAR ligands from the dried extract of an African plant (Diospyros bipindensis). Among the ligands, we identified betulinic acid (BA), a compound already known for its anti-inflammatory, anti-tumour and antidiabetic properties, as a PPARγ and PPARα antagonist. Cell differentiation assays showed that BA inhibits adipogenesis and promotes osteogenesis; either down-regulates or does not affect the expression of a series of adipogenic markers; and up-regulates the expression of osteogenic markers. Moreover, BA increases basal glucose uptake in 3T3-L1 adipocytes. The crystal structure of the complex of BA with PPARγ sheds light, at the molecular level, on the mechanism by which BA antagonizes PPARγ, and indicates a unique binding mode of this antagonist type. The results of this study show that the natural compound BA could be an interesting and safe candidate for the treatment of type 2 diabetes and bone diseases.

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Section: Introductionmentioning

confidence: 99%

Betulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis

Brusotti

Montanari

Capelli

et al. 2017

Sci Rep

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“…Angiogenesis assay found that both Rg3 stereoisomers can induce differential angiogenesis effects via PPARγ, and the PPARγ agonist activity of 20(S)‐Rg3 is 10 times stronger than that of 20(R)‐Rg3 11. A fluorescence polarization and total internal reflection fluorescence (FP‐TIRF) binding study also confirmed that only 20(S)‐Rg3 can quantitatively bind to the PPARγ ligand‐binding domain (PPARγ‐LBD) 12.…”

Section: Introductionmentioning

confidence: 80%

“…The importance of drug stereoselectivity is gaining greater attention in recent years,32 and differential pharmacological effects have been reported between ginsenoside Rg3 stereoisomers 9, 11, 12. It is because although the enantiomers of Rg3 possess the same functional group at C20, the difference in three‐dimensional structure may affect the binding affinity to the receptor binding site.…”

Section: Discussionmentioning

confidence: 99%

“…It is because although the enantiomers of Rg3 possess the same functional group at C20, the difference in three‐dimensional structure may affect the binding affinity to the receptor binding site. Previous computational modelling demonstrated that the hydroxyl group at the C20 chiral centre of 20(S)‐Rg3 could interact with Tyr473 through a hydrogen bond, similar to that of rosiglitazone,33, 34 while the sterically strained binding pocket prevented the optimal interaction of 20(R)‐Rg3 with Tyr473 11. In this report, we further performed MD simulation and EDA to investigate the binding modes of 20(R/S)‐Rg3 stereoisomers in PPARγ‐LBD.…”

Section: Discussionmentioning

confidence: 99%

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Ginsenoside Rg3 stereoisomers differentially inhibit vascular smooth muscle cell proliferation and migration in diabetic atherosclerosis

Guo

Xiao

et al. 2018

J Cellular Molecular Medi

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Ginsenoside 20(R/S)‐Rg3, as a natural peroxisome proliferator‐activated receptor gamma (PPARγ) ligand, has been reported to exhibit differential biological effects. It is of great interest to understand the stereochemical selectivity of 20(R/S)‐Rg3 and explore whether differential PPARγ activation by Rg3 stereoisomers, if it exists, could lead to differential physiological outcome and therapeutic effects in diabetic atherosclerosis. Here, we investigated the binding modes of 20(R/S)‐Rg3 stereoisomers in the PPARγ ligand‐binding domain (PPARγ‐LBD) using molecular modelling and their effects on smooth muscle cell proliferation and migration induced by advanced glycation end products (AGEs). The results revealed that 20(S)‐Rg3 exhibited stronger antiproliferative and antimigratory effects due to stronger PPARγ activation. To validate the in vitro results, we used a mice model with diabetic atherosclerosis and obtained that 20(S)‐Rg3 markedly reduced the plaque size secondary to reducing the proliferation and migration of VSMCs, while the plaques were more stable due to improvements in other plaque compositions. The results shed light on the structural difference between Rg3 stereoisomers that can lead to significant differential physiological outcome, and the (S)‐isomer seems to be the more potent isomer to be developed as a promising drug for diabetic atherosclerosis.

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“…The peroxisome proliferator activated receptor-γ activity of 20(S)-Rg3 is 10-fold higher than that of 20(R)-Rg3 [18]. 20(R)-Rg3 has more potent activity than 20(S)-Rg3 in stimulating the immune response [19].…”

Section: Introductionmentioning

confidence: 96%

Stereoselective Property of 20(S)-Protopanaxadiol Ocotillol Type Epimers Affects Its Absorption and Also the Inhibition of P-Glycoprotein

Wang

et al. 2014

PLoS ONE

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Stereoselectivity has been proved to be tightly related to drug action including pharmacodynamics and pharmacokinetics. (20S,24R)-epoxy-dammarane-3,12,25-triol (24R-epimer) and (20S,24S)-epoxy-dammarane-3,12,25-triol (24S-epimer), a pair of 20(S)-protopanaxadiol (PPD) ocotillol type epimers, were the main metabolites of PPD. Previous studies have shown that 24R-epimer and 24S-epimer had stereoselectivity in pharmacological action and pharmacokinetics. In the present study, the aim was to further study the pharmacokinetic characteristics of both epimers, investigate their absorption mechanism and analyze the selectivity effects of ocotillol type side chain and C24 stereo-configuration on P-glycoprotein (P-gp) in vivo and in vitro. Results showed that the absolute bioavailability of 24R-epimer was about 14-fold higher than that of 24S-epimer, and a linear kinetic characteristic was acquired in doses of 5–20 mg/kg for both epimers after oral administration. Furthermore, the apparent permeability coefficients of 24R-epimer were 5–7 folds higher than that of 24S-epimer having lower efflux ratios in Caco-2 cell models. Moreover, both 24R-epimer and 24S-epimer had similar inhibitory effects on P-gp by increasing cellular retention of rhodamine 123 in Caco-2 cells and decreasing efflux of digoxin across Caco-2 cell monolayers. In situ in vivo experiments showed that the inhibition of 24R-epimer on P-gp was stronger than that of 24S-epimer by single-pass intestinal perfusion of rhodamine 123 in rats. Western blot analyses demonstrated that both epimers had no action on P-gp expression in Caco-2 cells. In conclusion, with respect to the stereoselectivity, C24 S-configuration of the ocotillol type epimers processed a poor transmembrane permeability and could be distinguished by P-gp. Sharing a dammarane skeleton, both 24R-epimer and 24S-epimer were potent inhibitors of P-gp. This study provides a new case of stereoselective pharmacokinetics of chiral compounds which contributes to know the chiral characteristics of P-gp and structure-action relationship of PPD type and ocotillol type ginsenosides as a P-gp inhibitor.

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Stereoisomers ginsenosides-20(S)-Rg3 and -20(R)-Rg3 differentially induce angiogenesis through peroxisome proliferator-activated receptor-gamma

Cited by 51 publications

References 47 publications

Betulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis

Betulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis

Ginsenoside Rg3 stereoisomers differentially inhibit vascular smooth muscle cell proliferation and migration in diabetic atherosclerosis

Stereoselective Property of 20(S)-Protopanaxadiol Ocotillol Type Epimers Affects Its Absorption and Also the Inhibition of P-Glycoprotein

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