Involvement of the glucocorticoid receptor in pro-inflammatory transcription factor inhibition by daucane esters from Laserpitium zernyi

Autor: Arne Heyerick, Višnja Popović, Sven Eyckerman, Johan Van der Eycken, Karolien De Bosscher, Nadia Bougarne, Jan Goeman
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Transcriptional Activation
0301 basic medicine
Magnetic Resonance Spectroscopy
food.ingredient
Anti-Inflammatory Agents
Pharmaceutical Science
KAPPA-B
CYTOTOXIC ACTIVITY
Dexamethasone
Analytical Chemistry
Bridged Bicyclo Compounds
03 medical and health sciences
Transactivation
Receptors
Glucocorticoid
Glucocorticoid receptor
food
CAROTANE SESQUITERPENES
LINKII
Drug Discovery
PROTEIN-1
Humans
Ferula communis
Receptor
Transcription factor
Pharmacology
Hormone response element
Reporter gene
Molecular Structure
biology
LACTONES
Organic Chemistry
REPRESSION
NF-kappa B
ARRIGONII
Biology and Life Sciences
Esters
biology.organism_classification
GENE
Transcription Factor AP-1
Laserpitium
030104 developmental biology
Complementary and alternative medicine
Biochemistry
Molecular Medicine
CONSTITUENTS
Sesquiterpenes
FERULA-COMMUNIS
Apiaceae
Zdroj: JOURNAL OF NATURAL PRODUCTS
ISSN: 0163-3864
1520-6025
Popis: Species of the genus Laserpitium have been used traditionally to treat inflammation and infection. From the herb of Laserpitium zernyi, six new compounds were isolated and their structures elucidated (using IR, NMR, HRMS data) a derivatives of 8-daucene,2,4,10-triol (1, 2, and 4), 7-daucene-2,4,10-triol (3), a lapiferin derivative featuring a C-2 ester moiety (5), and a daucane featuring an exomethylene group at C-8 (6). Also isolated were the rare daucanes vaginatin (7) and laserpitin (8). In a search for selective glucocorticoid receptor (GR) modulators, the compounds were tested for their capacity to inhibit NF-kappa B and AP-1 pro-inflammatory factors and for a potential competitive effect on a dexamethasone (Dex)-induced GR-driven glucocorticoid response element (GRE) reporter gene. The new 2 beta-angeloyloxy-10 alpha-acetoxy-8-daucene-2,4,10-triol (2) significantly inhibited transactivation of both NF-kappa B and AP-1, while vaginatin (7) was the most active of the compounds tested in blocking AP-1, Both compounds competitively repressed Dex-induced GRE-driven promoter activities, indicative of a potential role for GR. In addition, a decreased potential to inhibit NF-kappa B was apparent in GR knockout A549 cells. In line with the transcriptional assays, compounds 2 and 7 also significantly lowered CCL-2 chemokine production, albeit to a lesser extent than Dex. The results suggest that daucanes may be interesting candidates in the search for compounds with GR-modulating activities.
Databáze: OpenAIRE
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