Cyclogalegigenin

The root of Astragalus membranaceus (Fisch.) Bunge

Cycloastragenol, a natural tetracyclic triterpenoid, was first identified when screening Astragalus membranaceus extracts for active ingredients with antiaging properties. IC50 value: Target: In vitro: In the study of Cycloastragenolon the treatment of degenerative diseases, the result showed that first-pass intestinal metabolism of cycloastragenol might occur upon passage through the intestinal epithelium. Cycloastragenol underwent extensive metabolism in rat and human liver microsomes with only 17.4% and 8.2%, respectively, of the starting amount of Cycloastragenol remaining after 30 min of incubation [1]. The present study demonstrates that cycloastragenol stimulates telomerase activity and cell proliferation in human neonatal keratinocytes. In particular, cycloastragenol promotes scratch wound closure of human neonatal keratinocyte monolayers in vitro [3]. In vivo: Rats were treated with Cycloastragenol (40 mg·kg- 1·d- 1) for 7 days to induce hepatic microsomal enzyme. The result showed that compared with the control, cycloastragenol obviously activated CYP2E1, and remarkably inhibited CYP3A4 [2].

References:
[1]. Jing Zhu, et al. In vitro Intestinal Absorption and First-pass Intestinal and Hepatic Metabolism of Cycloastragenol, a Potent Small Molecule Telomerase Activator. Drug Metabolism and Pharmacokinetics Volume 25, Issue 5, 2010, Pages 477-486 [2]. WEI Bao-hong, et al. Effect of continuous oral cycloastragenol on the activity of cytochrome P450 enzymes in rats. Chinese New Drugs Journal, 2014 -04 [3]. Ip FC, et al. Cycloastragenol is a potent telomerase activator in neuronal cells: implications for depression management. Neurosignals. 2014;22(1):52-63.

Astragaloside IV and cycloastragenol are equally effective in inhibition of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation in the endothelium.[Pubmed:25922268]

J Ethnopharmacol. 2015 Jul 1;169:210-8.

ETHNOPHARMACOLOGICAL RELEVANCE: Astragaloside IV and cycloastragenol are present together in Astragalus membranaceus Moench (Fabaceae) and this study aims to simultaneously investigate their regulation of endothelial homeostasis in the setting of endoplasmic reticulum stress (ER stress). MATERIAL AND METHODS: We stimulated endothelial cells with palmitate (PA 100muM) to evoked ROS-associated ER stress and observed the effects of astragaloside IV and cycloastragenol on thioredoxin-interacting protein (TXNIP) expression, NLRP3 inflammasome activation and mitochondrion-dependent apoptosis. RESULTS: Astragaloside IV and cycloastragenol inhibited ROS generation and attenuated ER stress inducer IRE1alpha phosphorylation, indicating the inhibition of ROS-associated ER stress. In response to ER stress, TXNIP expression increased, accompanied with NLRP3 induction and increased IL-1beta and IL-6 production, but these alternations were reversed by treatment with astragaloside IV and cycloastragenol, demonstrating the inhibitory effects of astragaloside IV and cycloastragenol on TXNIP/NLRP3 inflammasome activation. Inflammasome activation led to mitochondrial cell death in endothelial cells, whereas astragaloside IV and cycloastragenol restored the loss of the mitochondrial membrane potential with inhibition of caspase-3 activity, and thereby protected cells from ER stress-induced apoptosis. Astragaloside IV and cycloastragenol enhanced AMPK phosphorylation and AMPK inhibitor compound C diminished their beneficial effects, indicative of the potential role of AMPK in their regulation. CONCLUSIONS: Astragaloside IV and cycloastragenol suppressed ROS-associated ER stress and then inhibited TXNIP/NLRP3 inflammasome activation with regulation of AMPK activity, and thereby ameliorated endothelial dysfunction by inhibiting inflammation and reducing cell apoptosis. Simultaneous investigations further showed that astragaloside IV and cycloastragenol were equally effective in regulation of endothelial homeostasis.

Astragaloside IV and cycloastragenol stimulate the phosphorylation of extracellular signal-regulated protein kinase in multiple cell types.[Pubmed:22083896]

Planta Med. 2012 Jan;78(2):115-21.

Two Chinese herb-derived small molecule telomerase activators, astragaloside IV (AG-IV) and cycloastragenol (CAG), have recently been shown to improve the proliferative response of CD8+ T lymphocytes from HIV-infected patients by upregulating telomerase activity. Here, we examined the signaling mechanism of AG-IV and CAG. Telomerase activity in human embryonic kidney HEK293 fibroblasts was increased upon treatment with increasing concentrations of AG-IV or CAG. Both compounds induced the phosphorylation of extracellular signal-regulated protein kinase (ERK) in a time- and dose-dependent manner in HEK293 cells and HEK-neo keratinocytes. AG-IV and CAG also stimulated ERK phosphorylation in other cell lines of lung, brain, mammary, endothelial, and hematopoietic origins. Use of selective inhibitors and dominant negative mutants revealed the involvement of c-Src, MEK (ERK kinase), and epidermal growth factor receptor in CAG-induced ERK phosphorylation. Our data indicate that AG-IV and CAG may exert their cellular effects through the activation of the Src/MEK/ERK pathway.

Cycloastragenol, a triterpene aglycone derived from Radix astragali, suppresses the accumulation of cytoplasmic lipid droplet in 3T3-L1 adipocytes.[Pubmed:24942874]

Biochem Biophys Res Commun. 2014 Jul 18;450(1):306-11.

Cycloastragenol (CAG), a bioactive triterpenoid sapogenin isolated from the Chinese herbal medicine Radix astragali, was reported to promote the phosphorylation of extracellular signal-regulated protein kinase (ERK). Here we investigated the effect of CAG on adipogenesis. The image-based Nile red staining analyses revealed that CAG dose dependently reduced cytoplasmic lipid droplet in 3T3-L1 adipocytes with the IC50 value of 13.0 muM. Meanwhile, cytotoxicity assay provided evidence that CAG was free of injury on HepG2 cells up to 60 muM. In addition, using calcium mobilization assay, we observed that CAG stimulated calcium influx in 3T3-L1 preadipocytes with a dose dependent trend, the EC50 value was determined as 21.9 muM. There were proofs that elevated intracellular calcium played a vital role in suppressing adipocyte differentiation. The current findings demonstrated that CAG was a potential therapeutic candidate for alleviating obesity and hyperlipidemia.

Cycloastragenol is a potent telomerase activator in neuronal cells: implications for depression management.[Pubmed:25095809]

Neurosignals. 2014;22(1):52-63.

Cycloastragenol (CAG) is an aglycone of astragaloside IV. It was first identified when screening Astragalus membranaceus extracts for active ingredients with antiaging properties. The present study demonstrates that CAG stimulates telomerase activity and cell proliferation in human neonatal keratinocytes. In particular, CAG promotes scratch wound closure of human neonatal keratinocyte monolayers in vitro. The distinct telomerase-activating property of CAG prompted evaluation of its potential application in the treatment of neurological disorders. Accordingly, CAG induced telomerase activity and cAMP response element binding (CREB) activation in PC12 cells and primary neurons. Blockade of CREB expression in neuronal cells by RNA interference reduced basal telomerase activity, and CAG was no longer efficacious in increasing telomerase activity. CAG treatment not only induced the expression of bcl2, a CREB-regulated gene, but also the expression of telomerase reverse transcriptase in primary cortical neurons. Interestingly, oral administration of CAG for 7 days attenuated depression-like behavior in experimental mice. In conclusion, CAG stimulates telomerase activity in human neonatal keratinocytes and rat neuronal cells, and induces CREB activation followed by tert and bcl2 expression. Furthermore, CAG may have a novel therapeutic role in depression.

Cycloastragenol, a natural tetracyclic triterpenoid, was first identified when screening Astragalus membranaceus extracts for active ingredients with antiaging properties.

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