Pseudolaric acid analogs as a new class of peroxisome proliferator-activated receptor agonists.
Extracts of the root and trunk barks of the Chinese tree Pseudolarix kaempferi, which contain pseudolaric acids, are used in Chinese medicine for treatment of fungal infections. Pseudolaric acid B (PLAB) is the major constituent that exhibits anti-fungal activity. The nuclear peroxisome proliferator-activator receptors (PPAR) were proposed as a cellular target for the action of PLAB and its analogs. PLAB and two derivatives were tested for the activation of PPAR isoforms in two mammalian cell lines. CV-1 and H4IIEC3 cells were transfected with phorbol ester response element or PPAR response element reporter constructs, and CV-1 cells were co-transfected with the individual PPAR isoform expression plasmids. PLAB showed similar concentration-dependent effects for the activation of PPAR alpha, gamma and delta isoforms in CV-1 and H4IIEC3 cells. O-Deacetylation of PLAB (PLAC) or esterification of the free carboxy group of PLAB with beta-D-O-glucopyranoside (PLAG) markedly reduced or abolished the activation of these PPAR isoforms. In H4IIEC3 cells, PLAB increased the activation of endogenous PPARalpha and the phospholipase C signaling pathway; and stimulated peroxisomal fatty acyl-CoA oxidase activity. These effects of PLAB on the activation of endogenous PPARalpha and phospholipase C-dependent pathway were blocked by staurosporine. These results suggest that the action of PLAB on PPARalpha in H4IIEC3 cells is mediated by a protein kinase C dependent phosphorylation. Based upon these findings, the chemical class of biologically active diterpene acids related to PLAB may have promise for the treatment of metabolic and pathophysiological disorders that are regulated by these nuclear receptor isoforms.
Jaradat
Maisa S
MS
Department of Pharmacology and National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677-1848, USA.
Noonan
Daniel J
DJ
Wu
Baogen
B
Avery
Mitchell A
MA
Feller
Dennis R
DR
Jardat
Maisa S
MS
D000818:Animals; D002460:Cell Line; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes; D015394:Molecular Structure; D028201:Pinaceae / Q000737:chemistry*; D024301:Plant Bark / Q000737:chemistry; D018517:Plant Roots / Q000737:chemistry; D010946:Plants, Medicinal / Q000737:chemistry; D020033:Protein Isoforms / Q000819:agonists / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism
D004224:Diterpenes; D004365:Drugs, Chinese Herbal; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C058391:pseudolaric acid B