Induction of tolerogenic lung CD4+ T cells by local treatment with a pSTAT-3 and pSTAT-5 inhibitor ameliorated experimental allergic asthma.

Signal transducer and activator of transcription (STAT)-3 inhibitors play an important role in regulating immune responses. Galiellalactone (GL) is a fungal secondary metabolite known to interfere with the binding of phosphorylated signal transducer and activator of transcription (pSTAT)-3 as well of pSTAT-6 dimers to their target DNA in vitro. Intra nasal delivery of 50 μg GL into the lung of naive Balb/c mice induced FoxP3 expression locally and IL-10 production and IL-12p40 in RNA expression in the airways in vivo. In a murine model of allergic asthma, GL significantly suppressed the cardinal features of asthma, such as airway hyperresponsiveness, eosinophilia and mucus production, after…

Isolactarane and Sterpurane Sesquiterpenoids from the Basidiomycete Phlebia uda

Three new sesquiterpenoids, named udasterpurenol A, udalactarane A, and udalactarane B, as well as the known compounds hyphodontal and sterpuric acid have been isolated from the basidiomycete Phlebia uda. These compounds represent the first natural products described from this species. The structures were elucidated by NMR spectroscopy and mass spectrometry. Udalactaranes A and B were isolated as mixtures with their respective epimeric acetals. These mixtures inhibited the spore germination of the plant pathogenic fungus Fusarium graminearum at 10 and 5 μg/mL, respectively, and were active against Jurkat cells with IC(50) values of 101 and 42 μM, respectively.

Elucidation of the biosynthesis and degradation of allantofuranone by isotopic labelling and fermentation of modified precursors.

Feeding experiments with the ascomycete Allantophomopsis lycopodina indicated that the potent fungistatic allantofuranone is biosynthesized from phenylalanine. Further experiments with synthetic precursors gave evidence that the naturally occurring polyporic acid serves as a key intermediate in the biosynthesis. In addition to the formation of allantofuranone, its abiotic and metabolic degradation were investigated.

Hirsutane-Type Sesquiterpenes with Uncommon Modifications from Three Basidiomycetes

From three basidiomycetes, Xeromphalina sp., Stereum sp., and Pleurocybella porrigens, six triquinane sesquiterpenes with unprecendented modifications and a rearranged sesquiterpene related to coriolin C have been isolated. Their isolation, structure elucidation, and biological evaluation are described.

Sporogen, S14-95, and S-curvularin, three inhibitors of human inducible nitric-oxide synthase expression isolated from fungi.

The induction of human inducible nitric-oxide synthase (iNOS) expression depends (among other factors) on activation of the signal transducer and activator of transcription 1 (STAT1) pathway. Therefore, the STAT1 pathway may be an appropriate target for the development of inhibitors of iNOS expression. HeLa S3 cells transiently transfected with a gamma-activated site (GAS)/interferon-stimulated response element-driven reporter gene construct were used as the primary screening system. Using this system, three novel inhibitors of interferon-gamma-dependent gene expression, namely, sporogen, S14-95, and S-curvularin, were isolated from different Penicillium species. These three compounds also …

Oxacyclododecindione, a Novel Inhibitor of IL-4 Signaling from Exserohilum rostratum

In a screening program for new metabolites from fungi inhibiting the IL-4 mediated signal transduction, a novel chlorinated macrocyclic lactone, designated as oxacyclododecindione, was isolated from fermentations of the imperfect fungus Exserohilum rostratum. The structure was determined by a combination of spectroscopic techniques. Oxacyclododecindione inhibits the IL-4 induced expression of the reporter gene secreted alkaline phosphatase (SEAP) in transiently transfected HepG2 cells with IC50 values of 20-25 ng/ml (54-67.5 nM). Studies on the mode of action of the compound revealed that the inhibition of the IL-4 dependent signaling pathway is caused by blocking the binding of the activat…

Inhibitors of inducible NO synthase expression: total synthesis of (S)-curvularin and its ring homologues.

(S)-Curvularin and its 13-, 14-, and 16-membered lactone homologues were synthesized through a uniform strategy in which a Kochi oxidative decarboxylation and ring-closing metathesis reactions constitute the key processes. In the evaluation of the anti-inflammatory effects of the synthesized compounds in assays using cells stably transfected with a human iNOS promoter-luciferase reporter gene construct, the 14- and 16-membered homologues showed a slightly higher inhibitory effect towards iNOS promoter activity than curvularin itself. However, the larger ring homologues also exhibited higher cytotoxicity, manifest in downregulated eNOS promoter activity. In contrast, the di-O-acetyl and 4-ch…

ChemInform Abstract: Inhibitors of Inducible NO Synthase Expression: Total Synthesis of (S)-Curvularin (Ia) and Its Ring Homologues.

The Creolophins: A Family of Linear Triquinanes fromCreolophus cirrhatus (Basidiomycete)

Complicatic acid and five novel linear triquinanes were isolated from mycelial cultures of Creolophus cirrhatus. The creolophins A, C, D, and E represent a novel type of highly oxidized triquinane sesquiterpenoids. Whereas those compounds with a secondary alcohol moiety in ring A are stable, the exomethylene ketone creolophin E (5) partly dimerized during workup to form the decacyclic 1,4-dioxepin-6-one neocreolophin (6). Compounds 5 and 6 display cytotoxic activities against several tumor cell lines.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)