pregna-4-17-diene-3-16-dione--(17z)-isomer and pregna-4-17-diene-3-16-dione

Guggulsterone is a bioactive plant sterol naturally found in migratory plants. It exists in various forms, and its active compounds include the isomers cis-guggulsterone (E-GS) and trans-guggulsterone (Z-GS). In this study, the anti-inflammatory effects of these two isomeric pregnadienedione steroids were investigated against lipopolysaccharide-induced inflammatory reaction in RAW264.7 mouse macrophages. Our results showed that both guggulsterones inhibited the production of NO in macrophages treated with lipopolysaccharide, with IC50 values ranging from 3.0 to 6.7 μM. E-GS exerted higher efficacy than Z-GS, and its anti-inflammatory effects was mediated through inhibition of iNOS and COX-2 expression.

Topics: Animals; Anti-Inflammatory Agents; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Down-Regulation; Escherichia coli; Lipopolysaccharides; Macrophages; Mice; Nitric Oxide; Nitric Oxide Synthase Type II; Pregnenediones; RAW 264.7 Cells; Stereoisomerism

E- and Z-guggulsterones and nine guggulsterone derivatives (GSDs) were synthesized and evaluated for their preferential cytotoxicity against human PANC-1 cell in nutrient deprived medium utilizing antiausterity strategy. Among the synthesized compounds, GSD-1 and GSD-7 showed potent cytotoxicity against PANC-1 cells under nutrient-deprived conditions in a concentration dependent manner, with a PC

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Survival; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Pancreatic Neoplasms; Pregnenediones; Structure-Activity Relationship

Guggulsterone (7) and cembranoids (8-12) from Commiphora mukul stem bark resin guggul were shown to be specific modulators of two independent sites that are also modulated by bile salts (1-6) to control cholesterol absorption and catabolism. Guggulsterone (7) antagonized the chenodeoxycholic acid (3)-activated nuclear farnesoid X receptor (FXR), which regulates cholesterol metabolism in the liver. The cembranoids did not show a noticeable effect on FXR, but lowered the cholate (1)-activated rate of human pancreatic IB phospholipase A2 (hPLA2), which controls gastrointestinal absorption of fat and cholesterol. Analysis of the data using a kinetic model has suggested an allosteric mechanism for the rate increase of hPLA2 by cholate and also for the rate-lowering effect by certain bile salts or cembranoids on the cholate-activated hPLA2 hydrolysis of phosphatidylcholine vesicles. The allosteric inhibition of PLA2 by certain bile salts and cembranoids showed some structural specificity. Biophysical studies also showed specific interaction of the bile salts with the interface-bound cholate-activated PLA2. Since cholesterol homeostasis in mammals is regulated by FXR in the liver for metabolism and by PLA2 in the intestine for absorption, modulation of PLA2 and FXR by bile acids and selected guggul components suggests novel possibilities for hypolipidemic and hypocholesterolemic therapies.

Topics: Animals; Anticholesteremic Agents; Bile Acids and Salts; Cholesterol; Commiphora; Diterpenes; DNA-Binding Proteins; Humans; Models, Molecular; Molecular Structure; Pancreas; Phospholipase A2 Inhibitors; Phospholipases A2; Plant Extracts; Plant Gums; Pregnenediones; Receptors, Cytoplasmic and Nuclear; Swine; Transcription Factors

Guggulsterone 1, the active principle of guggulipid, has been used in ethnic medicine for thousands of years for its antinflammatory and antilipidemic activities. The activities of 1 are apparently mediated by its interaction with an array of nuclear receptors, including endocrine steroid receptors and metabolic lipid receptors. Although relatively weak, the activity at the metabolic farnesoid X receptor (FXR) is particularly intriguing, as 1 is, so far, the only antagonist known for this receptor, with a peculiar ability of gene selective modulation. We report here a systematic study aimed at identifying the potential binding pocket of 1 at FXR. Although 1 could be docked into the canonical binding site, we identified a novel, so far undescribed binding pocket, localized near the loop region between helix 1 and helix 2. This novel binding pocket may explain some of the peculiar characteristics of 1 when acting at FXR.

Topics: Binding Sites; Commiphora; DNA-Binding Proteins; Ligands; Models, Molecular; Pregnenediones; Protein Conformation; Receptors, Cytoplasmic and Nuclear; Stereoisomerism; Transcription Factors