Immunosuppressive effects of the mycotoxin patulin in macrophages.

Patulin (PAT) is a fungi-derived secondary metabolite produced by numerous fungal species, especially within Aspergillus, Byssochlamys, and Penicillium genera, amongst which P. expansum is the foremost producer. Similar to other fungi-derived metabolites, PAT has been shown to have diverse biological features. Initially, PAT was used as an effective antimicrobial agent against Gram-negative and Gram-positive bacteria. Then, PAT has been shown to possess immunosuppressive properties encompassing humoral and cellular immune response, immune cell function and activation, phagocytosis, nitric oxide and reactive oxygen species production, cytokine release, and nuclear factor-κB and mitogen-activated protein kinases activation. Macrophages are a heterogeneous population of immune cells widely distributed throughout organs and connective tissue. The chief function of macrophages is to engulf and destroy foreign bodies through phagocytosis; this ability was fundamental to his discovery. However, macrophages play other well-established roles in immunity. Thus, considering the central role of macrophages in the immune response, we review the immunosuppressive effects of PAT in macrophages and provide the possible mechanisms of action.

Patulin inhibits LPS-induced nitric oxide production by suppressing MAPKs signaling pathway.

Patulin (PAT) is a natural product isolated from several species of fungi. Here, we evaluated the effect of PAT (62.5-4,000 ng/ml) in lipopolysaccharide (LPS)-activated murine peritoneal macrophages. Cell viability assay showed that PAT at concentrations up to 250 ng/ml did not affect macrophage viability. PAT (250 ng/ml) significantly reduced LPS-induced nitric oxide production (by 98.4%), inducible nitric oxide synthase (iNOS) expression (by 83.5%), and iNOS messenger ribonucleic acid expression (by 100.0%). Moreover, PAT significantly reduced LPS-induced interleukin-1ß (by 80.6%), cluster of differentiation (CD) 69 (by 63.1%), and Toll-like receptor (TLR) 4 (by 91.9%) protein expression. Finally, PAT significantly reduced LPS-triggered phosphorylation of all mitogen-activated protein kinases (MAPK) assessed: extracellular signal-regulated kinase (ERK; by 89.5%), c-Jun N-terminal kinase (JNK; by 77.5%), and p38 (by 72.3%). Taken together, these data suggest that PAT downregulates acute inflammatory response, inhibiting nitric oxide production by suppressing CD69-TLR4/ERK-JNK-p38 MAPKs/Nos2/iNOS signaling pathway.

Effects of patulin and ascladiol on porcine intestinal mucosa: An ex vivo approach.

Patulin (PAT) is a secondary metabolite mainly produced by Aspergillus and Penicillium that is frequently found contaminating apples and rotten fruits. Patulin can be transformed in potencially less toxic compounds such as ascladiol (ASC). Toxic effects of patulin were described in rats and in in vitro models, however concerning ascladiol, data are restricted to metabolic pathways. The aim of the present study was to evaluate the effects of different concentrations of PAT (10 µM, 30 µM, 100 µM) and ASC (30 µM, 100 µM) on intestinal tissue using the jejunal explant model. Explants from pigs were exposed for 4 h to PAT and ASC and after this period were processed for histological, morphometrical and immunohistochemical analysis. Mild histological changes were observed in jejunal explants exposed to PAT and ASC, however no significant difference in the lesional score or villi height was observed between the PAT/ASC-groups and the control. Also, explants exposed to 100 µM of PAT showed a significant decrease in goblet cells density and a significant increase in cell apoptosis. These results indicate that high levels of patulin can induce mild toxic effects on intestinal mucosa whereas ascladiol apparently is non-toxic to intestinal tissue.

Effect of the combination of crude extracts of Penicillium griseofulvum and Fusarium graminearum containing patulin and zearalenone on rumen microbial fermentation and on their metabolism in continuous culture fermenters.

Six single-flow continuous cultures were used to study the effects of the mycotoxins patulin (PAT) and zearalenone (ZEN) alone or in combination on rumen microbial fermentation. In each of the four 7-d periods, the fermenters were supplemented in a 2 × 3 factorial arrangement with two levels of PAT (0 and 20 mg/l) and three levels of ZEN (0, 5 and 10 mg/l). The treatments did not affect the apparent and true digestibility of organic matter. PAT alone decreased the digestibility of neutral detergent fibre (NDF) and acid detergent fibre (ADF) (p < 0.01), but in the presence of 5 or 10 mg/l of ZEN, there were no effects of PAT. In contrast, the digestibility of NDF and ADF was decreased at 10 mg/l of ZEN in the absence of PAT (p < 0.05). The pH of the fermenters increased after 2 and 3 d of PAT treatment (p < 0.01). PAT decreased the concentration of total volatile acids (VFA), the molar proportion of acetate and the acetate:proportionate ratio (p < 0.01). The molar concentrations of other VFA were unchanged. Ammonia N (NH3-N) flow increased (p < 0.05) and there was a tendency to a higher NH3-N concentration (p < 0.1) in fermenters with PAT. Total N, non-ammonia N and bacterial N as well as efficiency of microbial protein synthesis and efficiency of N utilisation were not affected by treatments. PAT was nearly completely degraded during incubation. The mean recovery of ZEN, α-zearalenol and ß-zearalenol expressed as a proportion of administered ZEN was less than 50% in effluents from fermenters receiving only ZEN and ZEN plus PAT, respectively. With exception of fibre digestion, the co-administration of PAT and ZEN did not elicit interaction effects on most measured parameters of rumen metabolism.