The mycotoxin penicillic acid inhibits Fas ligand-induced apoptosis by blocking self-processing of caspase-8 in death-inducing signaling complex.
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Upon engagement with Fas ligand (FasL), Fas rapidly induces recruitment and self-processing of caspase-8 via the adaptor protein Fas-associated death domain (FADD), and activated caspase-8 cleaves downstream substrates such as caspase-3. We have found that penicillic acid (PCA) inhibits FasL-induced apoptosis and concomitant loss of cell viability in Burkitt's lymphoma Raji cells. PCA prevented activation of caspase-8 and caspase-3 upon treatment with FasL. However, PCA did not affect active caspase-3 in FasL-treated cells, suggesting that PCA primarily blocks early signaling events upstream of caspase-8 activation. FasL-induced processing of caspase-8 was severely impaired in the death-inducing signaling complex, although FasL-induced recruitment of FADD and caspase-8 occurred normally in PCA-treated cells. Although PCA inhibited the enzymatic activities of active recombinant caspase-3, caspase-8, and caspase-9 at similar concentrations, PCA exerted weak inhibitory effects on activation of caspase-9 and caspase-3 in staurosporine-treated cells but strongly inhibited caspase-8 activation in FasL-treated cells. Glutathione and cysteine neutralized an inhibitory effect of PCA on caspase-8, and PCA bound directly to the active center cysteine in the large subunit of caspase-8. Thus, our present results demonstrate that PCA inhibits FasL-induced apoptosis by targeting self-processing of caspase-8. (+info)
Three new chlorine containing antibiotics from a marine-derived fungus Aspergillus ostianus collected in Pohnpei.
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A marine bacterium Ruegeria atlantica (designated as strain TUF-D) was isolated from a glass plate submerged in the coastal water. Three new chlorine containing compounds (1 to approximately 3), together with penicillic acid (4) were obtained from a marine-derived fungus Aspergillus ostianus strain TUF 01F313 isolated from a marine sponge at Pohnpei as antibacterial components against R. atlantica. The structures of three new antibiotics were determined based on their spectral data as 8-chloro-9-hydroxy-8,9-deoxyasperlactone (1), 9-chloro-8-hydroxy-8,9-deoxyasperlactone (2), and 9-chloro-8-hydroxy-8,9-deoxyaspyrone (3). Compound 1 inhibited the growth of R. atlantica at 5 microg/disc (inhibition zone: 12.7 mm), while 2 and 3 were active at 25 microg/disc (10.1 and 10.5 mm, respectively). (+info)
Identity and effects of quorum-sensing inhibitors produced by Penicillium species.
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Quorum sensing (QS) communication systems are thought to afford bacteria with a mechanism to strategically cause disease. One example is Pseudomonas aeruginosa, which infects immunocompromised individuals such as cystic fibrosis patients. The authors have previously documented that blockage of the QS systems not only attenuates Ps. aeruginosa but also renders biofilms highly susceptible to treatment with conventional antibiotics. Filamentous fungi produce a battery of secondary metabolites, some of which are already in clinical use as antimicrobial drugs. Fungi coexist with bacteria but lack active immune systems, so instead rely on chemical defence mechanisms. It was speculated that some of these secondary metabolites could interfere with bacterial QS communication. During a screening of 100 extracts from 50 Penicillium species, 33 were found to produce QS inhibitory (QSI) compounds. In two cases, patulin and penicillic acid were identified as being biologically active QSI compounds. Their effect on QS-controlled gene expression in Ps. aeruginosa was verified by DNA microarray transcriptomics. Similar to previously investigated QSI compounds, patulin was found to enhance biofilm susceptibility to tobramycin treatment. Ps. aeruginosa has developed QS-dependent mechanisms that block development of the oxidative burst in PMN neutrophils. Accordingly, when the bacteria were treated with either patulin or penicillic acid, the neutrophils became activated. In a mouse pulmonary infection model, Ps. aeruginosa was more rapidly cleared from the mice that were treated with patulin compared with the placebo group. (+info)
Penicillic acid production in submerged culture.
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Twenty known penicillic acid (PA)-producing Aspergillus and Penicillium cultures were grown under various conditions in shaken flasks to determine the highest yielding strains and their requirements for maximum toxin production. Abilities of the cultures to utilize eight different carbon sources in Raulin-Thom medium for mycotoxin synthesis were determined at four different incubation temperatures: 15, 20, 25, and 28 degrees C. Of the 20 cultures, P. cyclopium NRRL 1888 was superior, yielding up to 4 mg of PG per ml, with mannitol as the carbon source and 25 degrees C as the incubation temperature. Fifteen of the cultures elaborated lesser amounts of PA, whereas four strains yielded none under the test conditions. Whey from the manufacture of cottage cheese by the cultured process was also a satisfactory medium for PA production. In whey medium, yields up to 3 mg/ml were obtained with P. cyclopium NRRL 1888. (+info)
6-Methyl-1,2,4-benzenetriol, a new intermediate in penicillic acid biosynthesis in Penicillium cyclopium.
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Penicillic acid-negative mutants were obtained from a color mutant derived from Penicillium cyclopium NRRL 1888 through N-methyl-N'-nitro-N-nitrosoguanidine treatment. One mutant (SK2N6) accumulated 6-methyl-1,2,4-benzenetriol, which was not previously known to be a metabolite of P. cyclopium, in addition to orsellinic acid and orcinol. The radioactivity of [1-14C]acetic acid was rapidly incorporated into 6-methyl-1,2,4-benzenetriol in a culture of P. cyclopium SK2N6. Moreover, the radioactivity of [14C]6-methyl-1,2,4-benzenetriol was efficiently incorporated into penicillic acid in a culture of P. cyclopium NRRL 1888. These data indicate that 6-methyl-1,2,4-benzenetriol is a precursor for penicillic acid biosynthesis. The results on the addition of 1,4-dihydroxy-6-methoxy-2-methylbenzene, 6-methoxy-2-methylbenzoquinone(1,4), and 1-O-methylorcinol to a culture of P. cyclopium SK2N6 indicated that only the former two compounds are converted to penicillic acid. Thus, a new portion of the penicillic acid biosynthetic pathway is proposed. (+info)
Production of penicillic acid and patulin by an atypical Penicillium roqueforti isolate.
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Simultaneous production of penicillic acid and patulin by an atypical strain of Penicillium roqueforti isolated from cheddar cheese is reported. Mycotoxin production was confirmed by thin-layer and gas-liquid chromatography and by ultraviolet, infrared, and mass spectral analyses. Culture extracts were toxic to Bacillus megaterium and chicken embryos. Commercial strains of P. roqueoforti used in production of blue-veined cheeses were shown not to produce penicillic acid and patulin. (+info)
Wild rice as fermentation substrate for mycotoxin production.
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Many cereal grains have been studied for their suitability as substrates for the fermentative production of mycotoxins. However, except for aflatoxin, wild rice has not been investigated. Hence, five mold cultures known to produce the mycotoxins ochratoxin-A, penicillic acid, patulin, vomitoxin, and zearalenone were grown on wild rice under varying conditions of moisture and temperature to determine whether this grain would serve as a suitable substrate for toxin production. Under appropriate fermentation conditions, good yields of ochratoxin-A and moderate amounts of patulin were obtained, but only small amounts of penicillic acid, vomitoxin, and zearalenone were elaborated. An extract from a sample of naturally molded wild rice contained 0.8 microgram of patulin per g of rice. The predominating mold was identified as Aspergillus clavatus. Under identical cultural conditions, this isolate and a known patulin-producing strain of A. clavatus yielded approximately equivalent amounts of the mycotoxin. (+info)
DNA-attacking ability of carcinogenic mycotoxins in recombination-deficient mutant cells of Bacillus subtilis.
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Thirty mycotoxins and 5 chemically modified toxins were tested for DNA-attacking ability in the rec assay using the recombination-deficient mutant of Bacillus subtilis M45 (rec-) and the parent strain H17 (rec+). Six Penicillium toxins (citrinin, penicillic acid, patulin, (-)-luteoskyrin, (+)-rugulosin, and PR-toxin), 5 Aspergillus toxins (aflatoxins B1 and G1, sterigmatocystin, O-acetylsterigmatocystin, and O-acetyldihydrosterigmatocystin), and 2 Fusarium toxins (zearalenone and zearalenol-b) were positive. Among these 13 compounds, the following 8 mycotoxins have been reported to be carcinogenic in animals: citrinin, penicillic acid, patulin, (-)-luteoskyrin, (+)-rugulosin, aflatoxins B1, and G1, sterigmatocystin. Correlation between the rec effect and in vivo carcinogenicity of mycotoxins is discussed. (+info)