Ilexgenin A

Eur J Pharmacol. 2017 Oct 15;813:84-93.

Inhibition of lipolysis by ilexgenin A via AMPK activation contributes to the prevention of hepatic insulin resistance.[Pubmed: 28739087 ]

Adipose dysfunction links tightly to hepatic insulin resistance and gluconeogenesis. Ilexgenin A is reported with the ability to regulate lipid profile and protect the liver against high fat diet (HFD) -induced impairment.
METHODS AND RESULTS:
Here, we propose that Ilexgenin A ameliorates hepatic insulin signaling and gluconeogenesis by regulating lipolysis in white adipose tissue (WAT). Pyruvate tolerance test and biochemical analysis coupled with the ex vivo siRNA knockdown and co-culture studies demonstrate that Ilexgenin A suppresses inflammation-associated lipolysis in epididymal fat pad via 5'-AMP-activated protein kinase (AMPK) activation, thus inhibits diacylglycerol (DAG) accumulation and protein kinase C ε (PKCε) translocation in liver, leading to the improvement of insulin sensitivity and hepatic glucose production.
CONCLUSIONS:
These findings suggest that the relationship between adipose function and hepatic insulin action may be targeted by natural bioactive components for the potential treatment of hepatic insulin resistance related disorders.

Eur J Pharmacol. 2017 Feb 15;797:94-105.

Ilexgenin A, a novel pentacyclic triterpenoid extracted from Aquifoliaceae shows reduction of LPS-induced peritonitis in mice.[Pubmed: 28104349]

Ilexgenin A (IA) is a novel pentacyclic triterpenoid, which extracted from leaves of Ilex hainanensis Merr.
METHODS AND RESULTS:
In the present study, we aim to explore anti-inflammatory activity of IA on LPS-induced peritonitis and its underlying molecular mechanism. The results determined that IA was capable of suppressing peritonitis in mice induced by intraperitoneal (i.p.) injection of lipopolysaccaride (LPS). Furthermore, the results showed that IA dramatically inhibited levels of inflammatory cells infiltration in peritoneal cavity and serum in LPS-induced mice peritonitis model. Besides, IA could dramatically inhibit levels of inflammatory cytokines (IL-1β, IL-6 and TNF-α) in peritoneal cavity in LPS-induced mice peritonitis model. In vitro study, the results showed that IA inhibited production of IL-1β, IL-6 and TNF-α at transcriptional and translational levels in RAW 264.7 cells induced by LPS. Furthermore, IA could suppress the LPS-induced activation of Akt and downstream degradation and phosphorylation of kappa B-α (IκB-α). Moreover, IA could significantly inhibit ERK 1/2 phosphorylation in RAW 264.7 cells induced by LPS.
CONCLUSIONS:
These results were concurrent with molecular docking which revealed ERK1/2 inhibition. These results demonstrated that IA might as an anti-inflammatory agent candidate for inflammatory disease therapy.

Pharmacol Res. 2015 Sep;99:101-15.

Ilexgenin A inhibits endoplasmic reticulum stress and ameliorates endothelial dysfunction via suppression of TXNIP/NLRP3 inflammasome activation in an AMPK dependent manner.[Pubmed: 26054569 ]

Ilexgenin A is a natural triterpenoid with beneficial effects on lipid disorders. This study aimed to investigate the effects of Ilexgenin A on endothelial homeostasis and its mechanisms.
METHODS AND RESULTS:
Palmitate (PA) stimulation induced endoplasmic reticulum stress (ER stress) and subsequent thioredoxin-interacting protein (TXNIP)/NLRP3 inflammasome activation in endothelial cells, leading to endothelial dysfunction. Ilexgenin A enhanced LKB1-dependent AMPK activity and improved ER stress by suppression of ROS-associated TXNIP induction. However, these effects were blocked by knockdown of AMPKα, indicating AMPK is essential for its action in suppression of ER stress. Meanwhile, Ilexgenin A inhibited NLRP3 inflammasome activation by down-regulation of NLRP3 and cleaved caspase-1 induction, and thereby reduced IL-1β secretion. It also inhibited inflammation and apoptosis exposed to PA insult. Consistent with these results in endothelial cells, Ilexgenin A attenuated ER stress and restored the loss of eNOS activity in vascular endothelium, and thereby improved endothelium-dependent vasodilation in rat aorta. A further analysis in high-fat fed mice showed that oral administration of Ilexgenin A blocked ER stress/NLRP3 activation with reduced ROS generation and increased NO production in vascular endothelium, well confirming the beneficial effect of Ilexgenin A on endothelial homeostasis in vivo.
CONCLUSIONS:
Taken together, these results show ER stress-associated TXNIP/NLRP3 inflammasome activation was responsible for endothelial dysfunction and Ilexgenin A ameliorated endothelial dysfunction by suppressing ER-stress and TXNIP/NLRP3 inflammasome activation with a regulation of AMPK. This finding suggests that the application of Ilexgenin A is useful in the management of cardiovascular diseases in obesity.

Toxicol Appl Pharmacol. 2017 Jan 15;315:90-101.

Ilexgenin A exerts anti-inflammation and anti-angiogenesis effects through inhibition of STAT3 and PI3K pathways and exhibits synergistic effects with Sorafenib on hepatoma growth.[Pubmed: 27986624]

Recently, we reported that Ilexgenin A exhibits anti-cancer activities and induces cell arrest. Here, we investigated the effect of Ilexgenin A on the inflammation, angiogenesis and tumor growth of hepatocellular carcinoma (HCC).
METHODS AND RESULTS:
Our current study revealed that Ilexgenin A significantly inhibited the inflammatory cytokines TNF-α and IL-6 levels and downregulated pro-angiogenic factor VEGF production and transcription in HepG2 cells. The underlying mechanism for Ilexgenin A effects appears to be through inhibiting STAT3 and PI3K pathways. Furthermore, we found that not only Ilexgenin A inhibited STAT3 and PI3K pathways in HepG2 cells but also blocked these signaling pathways in HUVECs. Most importantly, by employing two HCC xenografts models - HepG2 and H22, we showed that Ilexgenin A reduced tumor growth and exhibited synergy effect with Sorafenib. ELISA assay, histological analysis and immunohistochemistry examination revealed that the expression of VEGF and MVD was significantly decreased after the treatment with Ilexgenin A and the combination. Moreover, Ilexgenin A could enhance caspase-3/7 activity in vitro and transmission electron microscope indicated that the combination induced evident apoptosis of tumor cells and caused the structural changes of mitochondria in vivo. Although no apparent adverse effects occurred during the treatment period, Sorafenib monotherapy elicited hepatotoxicity for specific expression in the increased level of AST and the ratio of AST/ALT. However, the combination could remedy this adverse effect.
CONCLUSIONS:
In conclusion, the results described in the present study identifies Ilexgenin A as a promising therapeutic candidate that modulates inflammation, angiogenesis, and HCC growth.

Int Immunopharmacol. 2016 Nov;40:115-124.

A novel pentacyclic triterpenoid, Ilexgenin A, shows reduction of atherosclerosis in apolipoprotein E deficient mice.[Pubmed: 27588911 ]

Ilexgenin A (IA), a novel pentacyclic triterpenoid, is a compound extracted from leaves of Ilex hainanensis Merr. In this study, we explored the efficacy of IA on atherosclerosis and its underlying mechanism.
METHODS AND RESULTS:
We determined that treatment with IA attenuated atherosclerosis in high-fat diet-induced apolipoprotein E deficient mice via a series of effects involving regulation of lipid parameters, decrease of atherosclerosis-related indexes, inhibition of inflammatory cytokines secretion and pathological changes of main organs. Furthermore, the underlying mechanism of IA was investigated on oxidized low-density lipoprotein (Ox-LDL)-induced THP-1 cells. We showed that pre-treatment with IA decreased active inflammation cytokines involving interleukin-6 (IL-6), IL-1 and tumor necrosis factor-α (TNF-α) expression in a concentration-dependent manner. In addition, we confirmed that IA inhibited the phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), IKKα phosphorylation and NF-κB activity induced by Ox-LDL.
CONCLUSIONS:
Overall, these findings define IA as a novel drug candidate for anti-atherosclerotic therapy.

Int Immunopharmacol. 2015 Feb;24(2):423-431.

Ilexgenin A induces B16-F10 melanoma cell G1/S arrest in vitro and reduces tumor growth in vivo.[Pubmed: 25596038 ]

The present study aimed to investigate the anti-tumor activity of Ilexgenin A in B16-F10 murine melanoma and to evaluate its effect on the production of tumor-associated inflammatory cytokines.
METHODS AND RESULTS:
In vitro, our study showed that Ilexgenin A inhibited the proliferation of B16-F10 murine melanoma cells in a dose- and time-dependent manner, and this effect could be ascribed to the arrest of the cell cycle at G0/G1. In vivo, we evaluated the anti-tumor activity of Ilexgenin A in a tumor-bearing mouse model. The results showed that Ilexgenin A reduced the tumor weight by 51.13% (p<0.01). The Ilexgenin A treatment groups showed no apparent side effects during the treatment period. In addition, a histological analysis revealed that Ilexgenin A changed the cell morphology, and induced large areas of necrosis that correlated with a reduction in tumor size. The detection of inflammatory cytokines indicated that the IL-6 level decreased (p<0.001) and the TNF-α level increased (p<0.01) in mice treated with Ilexgenin A. Ilexgenin A also inhibited the IL-6 production of macrophages stimulated by melanoma conditioned medium (MCM) significantly (p<0.001). Importantly, Ilexgenin A dramatically prolonged survival time (p<0.001).
CONCLUSIONS:
In conclusion, Ilexgenin A could be regarded as a promising agent for the treatment of melanoma; it exerts anti-melanoma activity by arresting the cell cycle at G0/G1 and regulating IL-6 and TNF-α production.