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Keratin is important and needed for the growth of dermatophytes in the host tissue. In turn, the ability to invade keratinised tissues is defined as a pivotal virulence attribute of this group of medically important fungi. The host–dermatophyte interaction is accompanied by an adaptation of fungal metabolism that allows them to adhere to the host tissue as well as utilize the available nutrients necessary for their survival and growth. Dermatophyte infections pose a significant epidemiological and clinical problem. Trichophyton rubrum is the most common anthropophilic dermatophyte worldwide and its typical infection areas include skin of hands or feet and nail plate. In turn, Microsporum canis is a zoophilic pathogen, and mostly well known for ringworm in pets, it is also known to infect humans. The aim of the study was to compare the intracellular metabolite content in the T. rubrum and M. canis during keratin degradation using liquid chromatography system coupled with tandem mass spectrometer (LC-MS/MS). The metabolite “fingerprints” revealed compounds associated with amino acids metabolism, carbohydrate metabolism related to the glycolysis and the tricarboxylic acid cycle (TCA), as well as nucleotide and energy metabolism. The metabolites such as kynurenic acid, l-alanine and cysteine in case of T. rubrum as well as cysteine and riboflavin in case of M. canis were detected only during keratin degradation what may suggest that these compounds may play a key role in the interactions of T. rubrum and M. canis with the host tissue. The metabolomic results were completed by qPCR gene expression assay. Our findings suggest that metabolomic analysis of T. rubrum and M. canis growing in culture media that mimic the dermatophyte infection could allow the understanding of processes involved in the pathogenesis of dermatophytes.

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Valproic acid (VPA) is a known teratogen. In the present study, the effects of VPA and seven VPA derivatives with different teratogenic potencies were investigated in L929 cells in vitro. Evaluated end-points included changes in cell proliferation, growth, cell cycle distribution, morphology, speed, glycogen synthase kinase-3b (GSK-3b) and Erk1 ⁄ 2 phosphorylation, and histone H3 acetylation. Changes in proliferation, growth, speed, Erk1 ⁄ 2 and GSK-3b-Tyr216 phosphorylation, and H3 acetylation were significantly associated with the teratogenic potencies of the VPA derivatives. However, in contrast to changes in Erk1 ⁄ 2 phosphorylation and H3 acetylation, significant changes in GSK-3b phosphorylation could only be obtained in response to prolonged incubation at high drug concentration. There was an association between changes in H3 acetylation and GSK-3b-Tyr216 phosphorylation, whereas none of these end-points were associated with changes in Erk1 ⁄ 2 phosphorylation. These results suggest that the teratogenic potencies of VPA and VPA derivatives are related to effects on both Erk1 ⁄ 2 and histone deacetylase activities, whereas changes in GSK-3b activity are possibly a secondary effect.Valproic acid (VPA) is a widely used antiepileptic drug [1] that is also used for the treatment of migraine, mood disorders and cancer [2,3]. Adverse effects associated with VPA treatment include weight gain, hair loss and hepatotoxicity. Additionally, the drug is a teratogen that induces various malformations, including neural tube defects, in human foetuses exposed to the compound during early pregnancy [2].In addition to effects related to its antiepileptic function, VPA affects many cellular and biochemical processes, including cell proliferation, morphology, differentiation, survival, apoptosis and the activity of Erk1 ⁄ 2, glycogen synthase kinase-3b (GSK-3b) and histone deacetylases (HDACs) [4,5]. The teratogenic potencies of VPA and VPA derivatives have been correlated with drug-induced changes in the proliferation [6-9], area and motility of L929 cells [10,11] and the aggregation of primary neurons in culture [12]. Moreover, the HDAC inhibitory activity of VPA and VPA derivatives has been related to the teratogenic potencies of the compounds [13][14][15]. The HDAC inhibitory activity of VPA has also been proposed to account for the anticancer effects and other potentially beneficial effects of the drug [3,16].In the present study, VPA and seven VPA derivatives with different in vivo teratogenic potencies were tested in vitro in L929 cells for their effects on proliferation, growth, cell cycle distribution, area, speed, GSK-3b and Erk1 ⁄ 2 phosphorylation, and HDAC activity (reflected by histone H3 acetylation).Several of the estimated drug-induced changes in the cellular and biochemical end-points correlated with the teratogenic potencies of the respective VPA derivatives. However, relative to changes in Erk1 ⁄ 2 phosphorylation and H3 acetylation, significant changes in GSK-3b phosphorylation required longer ...