Disease relevance of Guggulsterones E

• Guggulsterone, derived from Commiphora mukul and used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, has been recently shown to antagonize the farnesoid X receptor and decrease the expression of bile acid-activated genes [1].
• Finally, differentiation to osteoclasts induced by coincubating human breast tumor cells (MDA-MB-468) or human multiple myeloma (U266) cells with monocytes was also completely suppressed by guggulsterone [2].
• Guggulsterone (GS) is the active substance in guggulipid, an extract of the guggul tree, Commiphora mukul, used to treat a variety of disorders in humans, including dyslipidemia, obesity, and inflammation [3].
• The combination of antioxidant and lipid-lowering properties of C. mukul and guggulsterone makes them especially beneficial against atherogenesis [4].
• The present study was undertaken to gain insights into the molecular mechanism of cell death (apoptosis) by guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, using PC-3 human prostate cancer cells as a model [5].
• The present study reveals that the guggulsterone-induced cell death in human prostate cancer cells is regulated by ROI-dependent activation of JNK and guggulsterone inhibits promoter activity of androgen receptor [6].

High impact information on Guggulsterones E

• Guggulsterone suppressed DNA binding of NF-kappaB induced by tumor necrosis factor (TNF), phorbol ester, okadaic acid, cigarette smoke condensate, hydrogen peroxide, and interleukin-1 [1].
• Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis [1].
• Guggulsterone is a farnesoid X receptor antagonist in coactivator association assays but acts to enhance transcription of bile salt export pump [7].
• Collectively, our results indicate that guggulsterone suppresses RANKL and tumor cell-induced osteoclastogenesis by suppressing the activation of NF-kappaB [2].
• Guggulsterone also suppressed the differentiation of monocytes to osteoclasts in a dose-dependent and time-dependent manner [2].

Biological context of Guggulsterones E

• We found that treatment of monocytes with guggulsterone suppressed RANKL-activated NF-kappaB activation (as indicated by gel-shift assay) and that this suppression correlated with inhibition of IkappaBalpha kinase and phosphorylation and degradation of IkappaBalpha, an inhibitor of NF-kappaB [2].
• We also show that PXR-CAR cross-talk determines the net activity of guggulsterone treatment toward Cyp2b10 gene expression [8].
• Moreover, the induction of ICAM-1 by GW4064 was inhibited by the FXR antagonist guggulsterone or with transfection of FXR siRNA [9].
• To determine whether guggulsterone has the ability to function as an agonist of other nuclear receptor family members, we screened a panel of these proteins for their ability to transactivate reporter genes [10].
• The present study describes degradation of guggulsterone under different ICH prescribed stress conditions (acid and base hydrolysis, oxidation, dry and wet heat degradation and photodegradation) and establishment of a stability indicating HPTLC assay [11].

Anatomical context of Guggulsterones E

• Furthermore, we show that guggulsterone-mediated activation of the pregnane X receptor induces the expression of CYP3A genes in both rodent and human hepatocytes [10].
• Thyroid stimulatory action of (Z)-guggulsterone: mechanism of action [12].
• Stress degradation studies were carried out on guggulsterone (the hypolipidemic agent in the gum-resin exudates of Commiphora mukul) following the conditions prescribed in the parent drug stability testing guideline (Q1AR) issued by International Conference on Harmonization (ICH) [11].
• Chronic feeding of guggulsterone to rats showed hypolipidaemic activity in blood serum and liver membrane lipids [13].
• The viability of PC-3 cells, but not a normal prostate epithelial cell line (PrEC), was reduced significantly on treatment with guggulsterone in a concentration-dependent manner [5].

Associations of Guggulsterones E with other chemical compounds

• The active ingredient in gugulipid is guggulsterone, a plant sterol compound recently identified as a pregnane X receptor (PXR; NR1I2) ligand [8].
• Examples of some natural product ligands for NHRs include genestein (estrogen receptors NR3A1 and NR3A2), guggulsterone (farnesoid X receptor NR1H4), and St [14].
• Thus, we propose that inhibition of FXR activation is the basis for the cholesterol-lowering activity of guggulsterone [15].

Gene context of Guggulsterones E

• Guggulsterone activates multiple nuclear receptors and induces CYP3A gene expression through the pregnane X receptor [10].
• In conclusion, the present study indicates that caspase-dependent apoptosis by guggulsterone is mediated in part by Bax and Bak [5].
• Guggulsterone-induced apoptosis was associated with induction of multidomain proapoptotic Bcl-2 family members Bax and Bak [5].
• The ratio of constitutive androstane receptor to pregnane X receptor determines the activity of guggulsterone against the Cyp2b10 promoter [8].
• Stimulation of low density lipoprotein receptor activity in liver membrane of guggulsterone treated rats [13].

Analytical, diagnostic and therapeutic context of Guggulsterones E

• Using mammalian two-hybrid assays, we show that treatment with guggulsterone differentially affects protein cofactor recruitment to these two nuclear receptors [8].
• Simultaneous determination of the stereoisomers of guggulsterone in serum by high-performance liquid chromatography [16].

References