Identification of 20(R, S)-protopanaxadiol and 20(R, S)-protopanaxatriol for potential selective modulation of glucocorticoid receptor

Oxidative Medicine and Cellular Longevity

Zhao

Zou

et al. 2022

Self Cite

As the main active ingredients of Panax ginseng, ginsenosides possess numerous bioactivities. Epidermal growth factor receptor (EGFR) was widely used as a valid target in anticancer therapy. Herein, the EGFR targeting activities of 20(S)-ginsenoside Rh2 (20(S)-Rh2) and the relationship of their structure-activity were investigated. Homogeneous time-resolved fluorescence assay showed that 20(S)-Rh2 significantly inhibited the activity against EGFR kinase. 20(S)-Rh2 was confirmed to effectively inhibited cell proliferation in a dose-dependent manner by MTT assay. Furthermore, quantitative real-time PCR and western blotting analysis revealed that 20(S)-Rh2 inhibited A549 cells growth via the EGFR-MAPK pathway. Meanwhile, 20(S)-Rh2 could promote cell apoptosis, block cell cycle, and reduce cell migration of A549 cells, respectively. In silico, the result suggested that both hydrophobic interactions and hydrogen-bonding interactions could contribute to stabilize their binding. Molecular dynamics simulation showed that the side chain sugar moiety of 20(S)-Rh2 was too flexible to be fixed at the active site of EGFR. Collectively, these findings suggested that 20(S)-Rh2 might serve as a potential EGFR tyrosine kinase inhibitor.

Section: Methodsmentioning

confidence: 99%

Identification of 20(S)-Ginsenoside Rh2 as a Potential EGFR Tyrosine Kinase Inhibitor

Oxidative Medicine and Cellular Longevity

Zhao

Zou

et al. 2022

Self Cite

“…As the main bioactive substances of ginseng, ginsenosides play a significant role in nutritional intervention for multiple diseases (Liang, Zhang, Jing, et al, 2021;Zhang, Liang, et al, 2020). According to the different structures on C-3 and C-6, ginsenosides have been classified into two groups, protopanaxatriol (PPT) and protopanaxadiol (PPD) (Zhang et al, 2019). As belonging to the PPT group, ginsenoside Rh1 is divided into 20(R)-ginsenoside Rh1 [20(R)-Rh1] and 20(S)-ginsenoside Rh1 [20(S)-Rh1] from the different spatial structures on C-20 .…”

Section: Introductionmentioning

confidence: 99%

Complexation mechanism between 20(R, S)‐ginsenoside Rh1 and serum albumin: Multi‐spectroscopy, in vitro cytotoxicity, and in silico investigations

Zhao

Journal of Food Science

Zhu

et al. 2022

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As rare ginsenosides, 20(R, S)-ginsenoside Rh1 [20(R, S)-Rh1] are isomers and have been reported to exhibit multiple biological effects. However, the application of 20(R, S)-Rh1 is still limited due to their poor solubilities and low bioavailabilities. Here, the complexation mechanism between 20(R, S)-Rh1 and serum albumin (SA) was explored by a combination of multi-spectroscopy and in silico investigations. Results of spectra experiments showed that 20(R, S)-Rh1 could form complexes with bovine serum albumin (BSA) and quench its intrinsic fluorescence. In addition, the influence of BSA on the anti-cancer activity of 20(R, S)-Rh1 was also evaluated in A549 cells. The result of the MTT assay indicated that anti-cancer activity of 20(R, S)-Rh1 was enhanced when combined with BSA. The results of molecular docking and dynamics simulation demonstrated that the subtle structural differences of 20(R, S)-Rh1 at the 20-carbon atom may be responsible for their different binding capacities and binding stabilities with human serum albumin. The cytotoxicity assay for 20(R, S)-Rh1 alone and their complexes with BSA demonstrated the enhancement effect of BSA for inhibition of cell proliferation. In conclusion, this work provided insight into the complexation mechanism between 20(R, S)-Rh1 and SA.

“…Unfortunately, a series of glucocorticoid‐associated side effects including osteoporosis, diabetes, depression, and muscle wasting have been observed in clinical practice [17]. It has been reported that the side effects induced by glucocorticoids are attributed to transactivation of GR responsive genes [18,19]. Meanwhile, the clinical effects of glucocorticoids are primarily mediated via transrepression of expression of relevant pro‐inflammatory genes [20].…”

Section: Introductionmentioning

confidence: 99%

In vitro Anti‐Inflammatory Potency of Sanguinarine and Chelerythrine via Interaction with Glucocorticoid Receptor

Zhang

et al. 2020

eFood

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As quaternary benzo[c]phenanthridine alkaloids, sanguinarine and chelerythrine possess multiple biological activities including anti-inflammatory effects. They have been confirmed to regulate gene expression of inflammatory-related cytokines at transcription level. This work aims to investigate the glucocorticoid-like anti-inflammatory effects of sanguinarine and chelerythrine, which may be mediated by Glucocorticoid Receptor (GR). Firstly, the interactions of GR with sanguinarine and chelerythrine were investigated by fluorescence polarization assay and the result showed that these two alkaloids could bind to GR with potent affinities. Luciferase reporter assay showed that sanguinarine was a weak GR agonist but chelerythrine failed to induce GR transcriptional activation in HeLa cells. These two alkaloids at high concentration showed similar tumor necrosis factor-a inhibitory potency to dexamethasone in RAW 264.7 cells, indicating their anti-inflammatory effects in vitro. In addition, the results of molecular docking and dynamics simulations showed that sanguinarine and chelerythrine could bind effectively with GR and might serve as its functional ligands. In conclusion, chelerythrine was speculated to be a selective GR modulator that might exhibit GR-mediated beneficial actions with reduced side effects.