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(E)-Guggulsterone, the trans-isomer of Guggulsterone which is a naturally occuring phytosteroid derived from resin of the guggul tree, Commiphora mukul, acts as a competitive antagonist of the farnesoid X receptor (FXR) in humans.
| Targets |
Natural product/Steroids; VEGF-VEGF-R2-Akt
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|---|---|
| ln Vitro |
GugguLsterone (0.5 -20 μM; 24 hours) suppresses the production of TREM-1, TLR4 and TNF-α and the phosphorylation of IκBα and NF-κB p65 by LPS [2].
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| ln Vivo |
GugguLsterone (mouse; 100 mg/kg once daily for 8 days) significantly increased the incidence of TNBS-induced cystitis in wild-type mice [2].
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| Enzyme Assay |
Triggering receptor expressed on myeloid cells 1 (TREM-1)-expressing intestinal macrophages are significantly increased in the colons of patients with inflammatory bowel disease (IBD). We focused here on the effects of guggulsterone on macrophage modulation in colitis as a potential therapeutic molecule in human IBD and explore the underlying mechanisms. Gene expression in macrophages was examined and wound-healing assay using HT-29 cells was performed. Colitis in wild-type and IL-10-, Toll-like receptor 4 (TLR4)-, and myeloid differentiation primary response 88 (MyD88)-deficient mice was induced via the administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into the colon. In both in vitro and in vivo experiments, guggulsterone suppressed intestinal inflammation amplified by TREM-1 stimulation, in which the suppression of NF-κB, activating protein-1, and proteasome pathways was involved. In the TNBS-induced colitis model, guggulsterone reduced disease activity index scores and TREM-1 expression, stimulated IL-10 production, and improved survival in wild-type mice. These effects were not observed in IL-10-, TLR4-, and MyD88-deficient mice. Guggulsterone also suppressed M1 polarization, yet induced the M2 phenotype in macrophages from IBD patients as well as from mice. These findings indicate that guggulsterone blocks the hyperactivation of macrophages via TREM-1 suppression and induces M2 polarization via IL-10 mediated by the TLR4 signaling pathway. Furthermore, this study provides a new rationale for the therapeutic potential of guggulsterone in the treatment of IBD. NEW & NOTEWORTHY We found that guggulsterone attenuates triggering receptor expressed on myeloid cells 1 (TREM-1)-mediated hyperactivation of macrophages and polarizes macrophages toward the M2 phenotype. This was mediated by IL-10 and partly Toll-like receptor 4 signaling pathways. Overall, these data support that guggulsterone as a natural plant sterol modulates macrophage phenotypes in colitis, which may be of novel therapeutic importance in inflammatory bowel disease treatment[2].
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| Animal Protocol |
Guggulsterone is an active constituent of guggulipid, an ayurvedic drug derived from Commiphora mukul, and is reported to have hypolipidaemic activity. The pharmacokinetics of Z-guggulsterone (1a) and its metabolite, E-guggulsterone (1b), was studied in rats after oral (50 mg kg−1) and intravenous (18 mg kg−1) administration of 1a. It was observed that 1a was isomerized to 1b in treated rat serum samples.[3]
Serum levels of gugulsterone after intravenous administration showed a biexponential elimination phase with a mean ± s.d. terminal half-life of 10.02 ± 4.74 h and 9.24 ± 3.32 h for 1a and 1b isomers, respectively. The values of systemic clearance and AUC for both 1a and 1b were observed to be 0.71 Lh−1, 4.9 μg h mL−1 and 1.04 Lh−1, 3–65 μg h mL−1, respectively. After oral administration, the concentration-time profile declined in a monoexponential fashion with the value of Cmax, terminal half-life, clearance and AUC for 1a and 1b being 1.07 μg ML−1, 4.48 h, 1.76 Lh−1, 5.95 μg mL−1 and 0.97 μ mL−1, 3.56 h, 2.24 Lh−1 and 4.75 μg h mL−1, respectively. Absolute bioavailability of parent compound (1a) after oral administration was 42.9%.[3] |
| References | |
| Additional Infomation |
E-Guggulsterone is a 3-hydroxy steroid. It has a role as an androgen.
E-Guggulsterone has been reported in Commiphora mukul and Commiphora wightii with data available. |
| Molecular Formula |
C21H28O2
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|---|---|
| Molecular Weight |
312.44582
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| Exact Mass |
312.208
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| Elemental Analysis |
C, 80.73; H, 9.03; O, 10.24
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| CAS # |
39025-24-6
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| PubChem CID |
6439929
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| Appearance |
Typically exists as White to off-white solids at room temperature
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| Density |
1.1±0.1 g/cm3
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| Boiling Point |
463.3±45.0 °C at 760 mmHg
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| Melting Point |
170-171.5°
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| Flash Point |
172.3±25.7 °C
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| Vapour Pressure |
0.0±1.1 mmHg at 25°C
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| Index of Refraction |
1.557
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| LogP |
3.65
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
0
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| Heavy Atom Count |
23
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| Complexity |
640
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| Defined Atom Stereocenter Count |
5
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| SMILES |
C/C=C1/C2(C)C(C3C(CC2)C2(C)C(=CC(=O)CC2)CC3)CC/1=O
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| InChi Key |
WDXRGPWQVHZTQJ-AUKWTSKRSA-N
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| InChi Code |
InChI=1S/C21H28O2/c1-4-16-19(23)12-18-15-6-5-13-11-14(22)7-9-20(13,2)17(15)8-10-21(16,18)3/h4,11,15,17-18H,5-10,12H2,1-3H3/b16-4-/t15-,17+,18+,20+,21-/m1/s1
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| Chemical Name |
(8R,9S,10R,13S,14S,17E)-17-ethylidene-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15-decahydrocyclopenta[a]phenanthrene-3,16-dione
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| Synonyms |
(E)-Guggulsterone; E-Guggulsterone; 39025-24-6; Guggulsterone E; Guggulsterone; trans-Guggulsterone; Guggulsterones E; Guggulsterone, (E)-;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~25 mg/mL (~80.01 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2 mg/mL (6.40 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.2005 mL | 16.0026 mL | 32.0051 mL | |
| 5 mM | 0.6401 mL | 3.2005 mL | 6.4010 mL | |
| 10 mM | 0.3201 mL | 1.6003 mL | 3.2005 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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