(E)-Guggulsterone

(E)-Guggulsterone is an orally active farnesoid X receptor (FXR) antagonist that modulates cholesterol/bile acid metabolism, with an IC₅₀ of 24.06μM^[1]. FXR is a bile acid-activated transcription factor that plays a crucial role in maintaining the homeostasis of bile acids, lipids, and glucose^[2]. (E)-Guggulsterone is commonly used in the study and treatment of conditions such as hyperlipidemia, atherosclerosis, and chronic inflammation^[3,4,5].

In vitro, treatment of dengue virus (DENV)-infected Huh-7 cells with (E)-Guggulsterone (2.5-20μM) for 3 days inhibited DENV protein synthesis and RNA replication in a dose-dependent manner, with an EC₅₀ of 8.7 ± 1.5μM, and showed no cytotoxicity within this concentration range^[6]. Treatment of lamina propria CD4+ T cells isolated from 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis mice (co-cultured with anti-CD3/CD28 antibodies) with (E)-Guggulsterone (100μM) for 6-24h induced apoptosis in a time-dependent manner and was accompanied by a decrease in mitochondrial membrane potential^[7].

In vivo, intraperitoneal administration of (E)-Guggulsterone (5, 10mg/kg) to DENV-infected 6-day-old ICR suckling mice on days 1, 3, and 5 post-infection significantly improved survival rates (by 20% and 60%, respectively) and promoted body weight recovery^[6]. Intraperitoneal administration of (E)-Guggulsterone (30mg/kg) for 5 days, starting concurrently with colitis induction, significantly alleviated TNBS-induced colitis symptoms in BALB/c mice, including reduced weight loss, improved stool scores, and downregulated gene expression of IFN-γ, IL-2, IL-6, TNF-α, and TGF-β1 in the colon^[7].

References:
[1] HSU C W, ZHAO J, HUANG R, et al. Quantitative high-throughput profiling of environmental chemicals and drugs that modulate farnesoid X receptor[J]. Scientific reports, 2014, 4(1): 6437.
[2] CLAUDEL T, STAELS B, KUIPERS F. The Farnesoid X receptor: a molecular link between bile acid and lipid and glucose metabolism[J]. Arteriosclerosis, thrombosis, and vascular biology, 2005, 25(10): 2020-2030.
[3] DENG R. Therapeutic effects of guggul and its constituent guggulsterone: cardiovascular benefits[J]. Cardiovascular drug reviews, 2007, 25(4): 375-390.
[4] GEBHARD C, STÄMPFLI S F, GEBHARD C E, et al. Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis[J]. Basic research in cardiology, 2009, 104(3): 285-294.
[5] CHHONKER Y S, CHANDASANA H, BALA V, et al. In-vitro metabolism, CYP profiling and metabolite identification of E-and Z-guggulsterone, a potent hypolipidmic agent[J]. Journal of Pharmaceutical and Biomedical Analysis, 2018, 160: 202-211.
[6] CHEN W C, WEI C K, HOSSEN M, et al. (E)-Guggulsterone inhibits dengue virus replication by upregulating antiviral interferon responses through the induction of heme oxygenase-1 expression[J]. Viruses, 2021, 13(4): 712.
[7] MENCARELLI A, RENGA B, PALLADINO G, et al. The plant sterol guggulsterone attenuates inflammation and immune dysfunction in murine models of inflammatory bowel disease[J]. Biochemical pharmacology, 2009, 78(9): 1214-1223.

(E)-Guggulsterone是一种具有口服活性，能够调节胆固醇/胆汁酸代谢的法尼醇X受体（FXR）拮抗剂，IC₅₀值为24.06μM^[1]。FXR是一种胆汁酸激活的转录因子，在维持胆汁酸、脂质和葡萄糖的稳态中起着至关重要的作用^[2]。(E)-Guggulsterone通常用于高脂血症、动脉粥样硬化和慢性炎症等疾病的研究和治疗^[3,4,5]。

在体外，(E)-Guggulsterone（2.5-20μM）处理登革病毒（DENV）感染的Huh-7细胞3天，以剂量依赖方式抑制了DENV蛋白合成和RNA复制，EC₅₀值为8.7 ± 1.5μM，且在该浓度范围内未表现出细胞毒性^[6]。(E)-Guggulsterone（100μM）处理从2 4 6-三硝基苯磺酸（TNBS）诱导结肠炎小鼠分离的肠道固有层CD4+ T细胞（与抗CD3/CD28抗体共培养）6-24h，能以时间依赖性方式诱导细胞凋亡，并伴随线粒体膜电位的下降^[7]。

在体内，(E)-Guggulsterone（5, 10mg/kg）在感染后第1、3、5天腹腔注射给药于DENV感染的6日龄ICR乳鼠，能显著提高小鼠存活率（分别提高20%和60%），并促进体重恢复^[6]。于诱导结肠炎同时开始，腹腔注射给予(E)-Guggulsterone（30mg/kg）5天，能显著减轻TNBS诱导的BALB/c小鼠结肠炎症状，包括减少体重下降，改善粪便评分，并下调结肠中IFN-γ、IL-2、IL-6、TNF-α和TGF-β1的基因表达^[7]。