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].
参考文献:
[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.
Z-Guggulsterone 是阿育吠陀药用植物 Commiphora mukul 的一种成分，在体外和体内抑制血管生成，IC50 值为 1740、1000、220 和 >； 50000 nM 用于糖皮质激素、盐皮质激素、雄激素和法尼醇 X 受体 [1]。
在与 z-guggulsterone 孵育的 SGC-7901 细胞中，Bcl-2 蛋白表达显着降低，活性 caspase-3 和 Bax 蛋白表达增加。 z-guggulsterone[3]培养的SGC-7901细胞TNF-α含量显着升高，VEGF和TGF-β1含量显着降低。在人脐静脉内皮细胞 (HUVEC) 和 DU145 细胞中，z-guggulsterone（5、10 和 20 μM）以浓度和时间依赖性方式显着降低细胞迁移，抑制毛细管样管形成[4] 。 Z-guggulsterone (30 μM) 在 24 小时时同时抑制人脑微血管内皮细胞 (hBDMEC) 中 PXR 和 MDR1 的表达[5]。Z-guggulsterone 减弱 TREM-1 介导的巨噬细胞通过抑制 TREM-1 表达和 NF-κB 和 AP-1 激活来过度激活[2]。
程序性死亡配体 1 (PD-L1) 是一种免疫检查点分子，在非小细胞肺癌 (NSCLC) 中过度表达，并且与抗 PD-1/PD-L1 免疫疗法的反应有关.在体内，Z-Guggulsterone 剂量依赖性地增加了小鼠 LLC 肿瘤模型中的 PD-L1 表达水平[6]。 Z-Guggulsterone 显着减轻 MCAO 大鼠的神经功能缺损、梗塞体积和组织病理学损伤。 Z-Guggulsterone 成功抑制氧-葡萄糖剥夺 (OGD) 处理的神经元中的氧化应激和炎症反应。 Z-Guggulsterone 通过抑制 TXNIP/NLRP3 轴来减轻氧化应激和炎症，发挥神经保护作用[7]。
| Cell experiment [1]: | |
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Cell lines |
Bone marrow-derived macrophage (BMDM) |
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Preparation Method |
Cells were incubated with Z-Guggulsterone at increasing concentrations (0, 0.5, 5, and 20 M) for 1 h and then simulated with LPS in the presence or absence of TREM-1 agonist antibody for the indicated time. |
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Reaction Conditions |
0.5-20uM Z-Guggulsterone for 1h |
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Applications |
Z-Guggulsterone attenuates TREM-1-mediated hyperactivation of macrophages through inhibition of TREM-1 expression and NF-κB and AP-1 activation. |
| Animal experiment [2]: | |
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Animal models |
IL-10, TLR4, and MyD88 deficient mice |
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Preparation Method |
Z-Guggulsterone were administered orally at 100 mg/kg once daily after TNBS administration for 4 days or throughout the experiment. The mice were monitored for weight loss, fecal consistency, presence of crude blood in the feces or anus, and overall mortality |
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Dosage form |
100 mg/kg Z-Guggulsterone orally administered once daily for 4 days |
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Applications |
Z-Guggulsterone improves colitis in mice by regulating macrophage phenotype through IL-10 and TLR4/MyD88 pathways. |
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参考文献: [1]: 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. | |
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