Z-Guggulsterone

Z-Guggulsterone, a component of the Ayurvedic medicinal plant Commiphora mukul, suppresses angiogenesis in vitro and in vivo with IC50 values of 1740, 1000, 220 and > 50000 nM for glucocorticoid, mineralocorticoid, androgen and farnesoid X receptors ^[1].

Bcl-2 protein expression was significantly decreased, and active caspase-3 and Bax protein expression was increased in SGC-7901 cells incubated with z-guggulsterone. The content of TNF-α was significantly increased, and the contents of VEGF and TGF-β1 were decreased in SGC-7901 cells incubated with z-guggulsterone^[3]. In human umbilical vein endothelial cells (HUVEC) and DU145 cells, z-guggulsterone (5, 10 and 20 µM) significantly decrease cell migration in a concentration- and time-dependent manner, inhibiting capillary-like tube formation^[4]. Z-guggulsterone (30 µM) simultaneously inhibited the expression of PXR and MDR1 at 24 h in human brain-derived microvessel endothelial cells (hBDMECs)^[5].Z-guggulsterone attenuated TREM-1-mediated macrophage hyperactivation by suppressing TREM-1 expression and NF-κB and AP-1 activation^[2].

Programmed death-ligand 1 (PD-L1) is an immune checkpoint molecule, that is overexpressed in non-small cell lung cancer (NSCLC) and has been associated with the response to anti-PD-1/PD-L1 immunotherapy.In vivo, Z-Guggulsterone treatment dose-dependently increased PD-L1 expression levels in mouse LLC tumor models^[6]. Z-Guggulsterone significantly alleviated neurological deficits, infarct volume and histopathological damage in MCAO rats. Z-Guggulsterone successfully inhibited oxidative stress and inflammatory response in oxygen-glucose deprivation (OGD) treated neurons. Z-Guggulsterone exerted neuroprotective property through alleviated oxidative stress and inflammation via inhibiting the TXNIP/NLRP3 axis^[7].

References:
[1]: Burris TP, Montrose C, et,al. The hypolipidemic natural product guggulsterone is a promiscuous steroid receptor ligand. Mol Pharmacol. 2005 Mar;67(3):948-54. doi: 10.1124/mol.104.007054. Epub 2004 Dec 15. PMID: 15602004.
[2]: Che X, Park KC, et,al.Protective effects of guggulsterone against colitis are associated with the suppression of TREM-1 and modulation of macrophages. Am J Physiol Gastrointest Liver Physiol. 2018 Jul 1;315(1):G128-G139. doi: 10.1152/ajpgi.00027.2018. Epub 2018 Mar 15. PMID: 29543509.
[3]: Lv R, Zhu M, et,al. Z-Guggulsterone Induces Apoptosis in Gastric Cancer Cells through the Intrinsic Mitochondria-Dependent Pathway. ScientificWorldJournal. 2021 Jan 4;2021:3152304. doi: 10.1155/2021/3152304. PMID: 33488300; PMCID: PMC7801056.
[4]: Xiao D, Singh SV. z-Guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, inhibits angiogenesis in vitro and in vivo. Mol Cancer Ther. 2008 Jan;7(1):171-80. doi: 10.1158/1535-7163.MCT-07-0491. PMID: 18202020.
[5]: Xu HB, Tang ZQ, et,al. Z-guggulsterone regulates MDR1 expression mainly through the pregnane X receptor-dependent manner in human brain microvessel endothelial cells. Eur J Pharmacol. 2020 May 5;874:173023. doi: 10.1016/j.ejphar.2020.173023. Epub 2020 Feb 19. PMID: 32087256.
[6]: Tian H, Gui Y, et,al. Z-guggulsterone induces PD-L1 upregulation partly mediated by FXR, Akt and Erk1/2 signaling pathways in non-small cell lung cancer. Int Immunopharmacol. 2021 Apr;93:107395. doi: 10.1016/j.intimp.2021.107395. Epub 2021 Jan 30. PMID: 33529916.
[7]: Liu T, Wang W, et,al. Z-Guggulsterone alleviated oxidative stress and inflammation through inhibiting the TXNIP/NLRP3 axis in ischemic stroke. Int Immunopharmacol. 2020 Dec;89(Pt B):107094. doi: 10.1016/j.intimp.2020.107094. Epub 2020 Oct 28. PMID: 33129097.