title: PTP1B inhibitory and anti-inflammatory effects of secondary metabolites isolated from the marine-derived fungus Penicillium sp. JF-55.
abstract: Protein tyrosine phosphatase 1B (PTP1B) plays a major role in the negative regulation of insulin signaling, and is thus considered as an attractive therapeutic target for the treatment of diabetes. Bioassay-guided investigation of the methylethylketone extract of marine-derived fungus Penicillium sp. JF-55 cultures afforded a new PTP1B inhibitory styrylpyrone-type metabolite named penstyrylpyrone (1), and two known metabolites, anhydrofulvic acid (2) and citromycetin (3). Compounds 1 and 2 inhibited PTP1B activity in a dose-dependent manner, and kinetic analyses of PTP1B inhibition suggested that these compounds inhibited PTP1B activity in a competitive manner. In an effort to gain more biological potential of the isolated compounds, the anti-inflammatory effects of compounds 1-3 were also evaluated. Among the tested compounds, only compound 1 inhibited the production of NO and PGE2, due to the inhibition of the expression of iNOS and COX-2. Penstyrylpyrone (1) also reduced TNF-α and IL-1β production, and these anti-inflammatory effects were shown to be correlated with the suppression of the phosphorylation and degradation of IκB-α, NF-κB nuclear translocation, and NF-κB DNA binding activity. In addition, using inhibitor tin protoporphyrin (SnPP), an inhibitor of HO-1, it was verified that the inhibitory effects of penstyrylpyrone (1) on the pro-inflammatory mediators and NF-κB DNA binding activity were associated with the HO-1 expression. Therefore, these results suggest that penstyrylpyrone (1) suppresses PTP1B activity, as well as the production of pro-inflammatory mediators via NF-κB pathway, through expression of anti-inflammatory HO-1.
authors.affiliation: Hanbang Body-Fluid Research Center, Wonkwang University, Iksan 570-749, Korea. hsds@wku.ac.kr
authors.forename: Dong-Sung
authors.initials: DS
authors.lastname: Lee
authors.forename: Jae-Hyuk
authors.initials: JH
authors.lastname: Jang
authors.forename: Wonmin
authors.initials: W
authors.lastname: Ko
authors.forename: Kyoung-Su
authors.initials: KS
authors.lastname: Kim
authors.forename: Jae Hak
authors.initials: JH
authors.lastname: Sohn
authors.forename: Myeong-Suk
authors.initials: MS
authors.lastname: Kang
authors.forename: Jong Seog
authors.initials: JS
authors.lastname: Ahn
authors.forename: Youn-Chul
authors.initials: YC
authors.lastname: Kim
authors.forename: Hyuncheol
authors.initials: H
authors.lastname: Oh
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D002867:Chromones / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010407:Penicillium / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D011753:Pyrones / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D002867:Chromones; D018836:Inflammation Mediators; D016328:NF-kappa B; D011753:Pyrones; C121904:anhydrofulvic acid; C585610:penstyrylpyrone; C013444:citromycetin; D051547:Heme Oxygenase-1; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1