Natural product/Steroids; VEGF-VEGF-R2-Akt

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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Guggulsterone suppressed LX-2 cell growth in a dose- and activation-dependent manner. This growth suppression was due to the induction of HSC apoptosis, which was mediated by the activation of c-Jun N-terminal kinase and mitochondrial apoptotic signaling. Additionally, guggulsterone regulated phosphorylation of Akt and adenosine monophosphate-activated protein kinase, which were subsequently proven responsible for the guggulsterone-induced HSC growth suppression. Guggulsterone inhibited NF-κB activation in LX-2 cells, which is one of the major mediators in HSC activation. Indeed, guggulsterone decreased collagen α1 synthesis and α-smooth muscle actin expression in these cells. [3]

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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Compared with the control mice or mice treated with a low dose of guggulsterone , high dose of guggulsterone significantly decreased the extent of collagen deposition and the percentage of activated HSCs undergoing apoptosis. Conclusions: These results demonstrate that guggulsterone suppressed HSC activation and survival by inhibiting NF-κB activation and inducing apoptosis. Therefore, guggulsterone may be useful as an antifibrotic agent in chronic liver diseases.[3]

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].

Thirty-five white male mice of six weeks’ old were used. Their weights ranged between 20-30 gm. The animals were housed in well-ventilated plastic cages, and were maintained under conditions of relatively controlled temperature, humidity, and 12 hrs. light / dark cycle. With a free access to a standard commercial diet that was purchased from the local market and tap water ad libitum. The animals randomly were divided into five groups of 7 animals in each group, as the following: Group I: mice utilized in this group were fed standard commercial diet and considered to be the control group. Group II: mice utilized in this group were fed a specially formulated high-fat diet (HFD) for 12 weeks to induce nonalcoholic liver disease. Group III: mice utilized in this group were fed a high-fat diet that contains Guggulsterone at a concentration of 500 ppm for 12 weeks. Group IV: mice utilized in this group were fed a high-fat diet that contains guggulsterone at a concentration of 1000 ppm for 12 weeks. Group V: mice utilized in this group were fed a high-fat diet that contains Guggulsterone at a concentration of 2000 ppm for 12 weeks. The animal’s weight of all groups was measured routinely once weekly and at zero time. The animals of each group at the end of the experiment after overnight fasting were anesthetized using diethyl ether, and blood was collected from the heart by cardiac puncture, then the animals were sacrificed and the liver were obtained and weighed for calculating liver index (by dividing liver weight in mg by the last body weight. [4]

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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]

[1]. Guggulsterone for Chemoprevention of Cancer. Curr Pharm Des. 2016;22(3):294-306.
[2]. 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.
[3]. Guggulsterone attenuates activation and survival of hepatic stellate cell by inhibiting nuclear factor kappa B activation and inducing apoptosis. J Gastroenterol Hepatol. 2013 Dec;28(12):1859-68.
[4]. Possible Amelioration of the Severity of Nutritional Steatohepatitis by Guggulsterone in Mice. Iraqi J Pharm Sci, Vol.28(1) 2019. DOI: https://doi.org/10.31351/vol28iss1pp17-23; https://bijps.uobaghdad.edu.iq/index.php/bijps/article/view/801; https://pdfs.semanticscholar.org/fed5/b2b899b009d9a009406450b1d111bb67f233.pdf

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.

C21H28O2

312.44582

312.208

C, 80.73; H, 9.03; O, 10.24

39025-24-6

6439929

Typically exists as White to off-white solids at room temperature

1.1±0.1 g/cm3

463.3±45.0 °C at 760 mmHg

170-171.5°

172.3±25.7 °C

0.0±1.1 mmHg at 25°C

1.557

3.65

0

2

0

23

640

5

C/C=C1/C2(C)C(C3C(CC2)C2(C)C(=CC(=O)CC2)CC3)CC/1=O

WDXRGPWQVHZTQJ-AUKWTSKRSA-N

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

(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

(E)-Guggulsterone; E-Guggulsterone; 39025-24-6; Guggulsterone E; Guggulsterone; trans-Guggulsterone; Guggulsterones E; Guggulsterone, (E)-;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~25 mg/mL (~80.01 mM)

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.

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 (Please use freshly prepared in vivo formulations for optimal results.)