In vitro combinatory effects of the Alternaria mycotoxins alternariol and altertoxin II and potentially involved miRNAs

Vejdovszky, Katharina; Sack, Matej; Jarolim, Katharina; Aichinger, Georg; Somoza, Mark M.; Marko, Doris

doi:10.1016/j.toxlet.2016.12.011

Cited by 35 publications

(26 citation statements)

References 28 publications

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“…So far, only miRNAs (miR-34 family and miR-29a) potentially involved in AOH-induced cell cycle arrest and p53 induction have been identified (Solhaug et al 2012; Vejdovszky et al 2017b). Thus, in addition to miR-125b, we furthermore determined transcription levels of miR-16, miR-146a and miR-155, which are involved in the regulation of TLR/NF-κB signalling and NF-κB target genes (O’Neill et al 2011).…”

Section: Discussionmentioning

confidence: 99%

“…miRNAs are small, non-coding sequences that exert their main function as post-transcriptional modificators regulating the expression of several proteins (Lee et al 2014). Recent studies suggest a link between AOH-induced increase of the tumor suppressor protein p53 and the involvement of miR-29a and the miR-34 family (Solhaug et al 2012; Vejdovszky et al 2017b). miRNAs have also been reported to modulate immune responses by regulating the expression of receptors and transcription factors involved in TLR/NF-κB signalling leading to modified gene expression of target genes (e.g., cytokines) (O’Neill et al 2011).…”

Section: Introductionmentioning

confidence: 99%

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The mycotoxin alternariol suppresses lipopolysaccharide-induced inflammation in THP-1 derived macrophages targeting the NF-κB signalling pathway

et al. 2018

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Alternariol (AOH) is a secondary metabolite formed by black mold of the genus Alternaria alternata. Due to limited hazard and occurrence data, AOH is still considered as an “emerging mycotoxin” and, as such, not monitored and regulated yet. Recent studies indicate immunosuppressive effects in vitro by altering the expression of CD molecules and proinflammatory cytokines, which are indispensable in mounting an innate immune response. However, the mode of action by which AOH exerts its immunosuppressive effects has not been unraveled yet. The present study aimed to characterise the impact of AOH on the nuclear factor kappa B (NF-κB) pathway, the expression of NF-κB target cytokines and involved regulatory microRNAs (miRNAs). In THP-1 derived macrophages, AOH (1–20 µM) was found to suppress lipopolysaccharide (LPS)-induced NF-κB pathway activation, decrease secretion of the proinflammatory cytokines IL-8, IL-6, TNF-α and to induce secretion of the anti-inflammatory IL-10. Thereby, a distinct pattern of cytokine mRNA levels was monitored, varying between short- and long-term exposure. Concomitantly, AOH (2–20 µM) affected the transcription levels of miR-146a and miR-155 in LPS-stimulated THP-1 derived macrophages dose-dependently by down- and upregulation, respectively. In contrast, transcription of miR-16 and miR-125b, two other immune-related miRNAs, was not modulated. In the absence of a LPS stimulus, AOH (20 µM) did not affect basal NF-κB activity, but increased IL-10 transcription. Collectively, our results indicate, that AOH itself does not induce a proinflammatory immune response in human macrophages; however, in an inflamed environment it possesses the ability to repress inflammation by targeting the NF-κB signalling pathway and regulatory miRNAs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The mycotoxin alternariol suppresses lipopolysaccharide-induced inflammation in THP-1 derived macrophages targeting the NF-κB signalling pathway

et al. 2018

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“…The occurrence of those mycotoxin mixtures has already been linked to stronger adverse impacts and synergistic effects on human and animal health than indicated by a single mycotoxin. Dose-dependent combinatory effects of AOH and ATX-II were demonstrated: low dose combinations revealed additive cytotoxic effects, whereas for the combination of higher concentrations an antagonism was stated ( Vejdovszky et al, 2017b ). As consumers are mainly exposed to low Alternaria toxin amounts ( EFSA, 2011 ), possible additive toxin effects should be of concern.…”

Section: Discussionmentioning

confidence: 99%

Chemotaxonomy of Mycotoxigenic Small-Spored Alternaria Fungi – Do Multitoxin Mixtures Act as an Indicator for Species Differentiation?

et al. 2018

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Necrotrophic as well as saprophytic small-spored Alternaria (A.) species are annually responsible for major losses of agricultural products, such as cereal crops, associated with the contamination of food and feedstuff with potential health-endangering Alternaria toxins. Knowledge of the metabolic capabilities of different species-groups to form mycotoxins is of importance for a reliable risk assessment. 93 Alternaria strains belonging to the four species groups Alternaria tenuissima, A. arborescens, A. alternata, and A. infectoria were isolated from winter wheat kernels harvested from fields in Germany and Russia and incubated under equal conditions. Chemical analysis by means of an HPLC-MS/MS multi-Alternaria-toxin-method showed that 95% of all strains were able to form at least one of the targeted 17 non-host specific Alternaria toxins. Simultaneous production of up to 15 (modified) Alternaria toxins by members of the A. tenuissima, A. arborescens, A. alternata species-groups and up to seven toxins by A. infectoria strains was demonstrated. Overall tenuazonic acid was the most extensively formed mycotoxin followed by alternariol and alternariol mono methylether, whereas altertoxin I was the most frequently detected toxin. Sulfoconjugated modifications of alternariol, alternariol mono methylether, altenuisol and altenuene were frequently determined. Unknown perylene quinone derivatives were additionally detected. Strains of the species-group A. infectoria could be segregated from strains of the other three species-groups due to significantly lower toxin levels and the specific production of infectopyrone. Apart from infectopyrone, alterperylenol was also frequently produced by 95% of the A. infectoria strains. Neither by the concentration nor by the composition of the targeted Alternaria toxins a differentiation between the species-groups A. alternata, A. tenuissima and A. arborescens was possible.

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“…miR-6720 has been reported to be upregulated in hepatocellular carcinoma cells following treatment with alternariol, a mycotoxin ( 39 ). However, not much evidence is available concerning its functions in TGF-β regulated signaling transduction.…”

Section: Discussionmentioning

confidence: 99%

microRNA expression profiles of scar and normal tissue from patients with posterior urethral stricture caused by pelvic fracture urethral distraction defects

et al. 2018

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Pelvic fracture urethral distraction defect (PFUDD) seriously affects the quality of life of patients. At present, there are few effective drug treatments available for PFUDD-induced urethral stricture, which is associated with fibrosis and scar formation in urethra lumen. Emerging evidence suggests that microRNAs (miRNAs/miRs) may be involved in the regulation of fibrosis, and analysis of miRNA expression profiles in urethral scar and normal urethra tissues may therefore benefit the discovery of novel treatments for urethral stricture with micro invasive procedures. In the present study, miRNA sequencing and quantitative polymerase chain reaction (qPCR) validation using paired scar and normal tissues from patients with PFUDD, and functional analysis of the miRNAs involved in the fibrosis associated signaling pathway was performed. A total of 94 differentially expressed miRNAs were identified in the scar tissue of patients with PFUDD. Among them, 26 miRNAs had significantly altered expression in the scar tissue compared with the normal tissue from the same patient. qPCR validation confirmed that miR-129-5p was overexpressed in scar tissue. The TGF-β pathway-associated functions of a total of 5 miRNAs (hsa-miR-129-5p, hsa-miR-135a-5p, hsa-miR-363-3p, hsa-miR-6720-3p and hsa-miR-9-5p) were further analyzed, as well as their key molecular targets and functional mechanisms in signaling regulation. To conclude the miRNA sequencing indicated a significantly altered expression of hsa-miR-129-5p, hsa-miR-135a-5p, hsa-miR-363-3p, hsa-miR-6720-3p and hsa-miR-9-5p in patients with PFUDD. These miRNAs and their potential target genes were associated with fibrosis in several diseases, and the data from the present study may help explore potential miRNA targets for future precision treatments for urethral stricture.

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In vitro combinatory effects of the Alternaria mycotoxins alternariol and altertoxin II and potentially involved miRNAs

Cited by 35 publications

References 28 publications

The mycotoxin alternariol suppresses lipopolysaccharide-induced inflammation in THP-1 derived macrophages targeting the NF-κB signalling pathway

The mycotoxin alternariol suppresses lipopolysaccharide-induced inflammation in THP-1 derived macrophages targeting the NF-κB signalling pathway

Chemotaxonomy of Mycotoxigenic Small-Spored Alternaria Fungi – Do Multitoxin Mixtures Act as an Indicator for Species Differentiation?

microRNA expression profiles of scar and normal tissue from patients with posterior urethral stricture caused by pelvic fracture urethral distraction defects

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