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• W2149784311 abstract "Malassezia yeasts are commensal microorganisms, which under insufficiently understood conditions can become pathogenic. We have previously shown that specific strains isolated from diseased human skin can preferentially produce agonists of the aryl hydrocarbon receptor (AhR), whose activation has been linked to certain skin diseases. Investigation of skin scale extracts from patients with Malassezia-associated diseases demonstrated 10- to 1,000-fold higher AhR-activating capacity than control skin extracts. Liquid chromatography–tandem mass spectrometry analysis of the patients’ extracts revealed the presence of indirubin, 6-formylindolo[3,2-b]carbazole (FICZ), indolo[3,2-b]carbazole (ICZ), malassezin, and pityriacitrin. The same compounds were also identified in 9 out of 12 Malassezia species culture extracts tested, connecting their presence in skin scales with this yeast. Studying the activity of the Malassezia culture extracts and pure metabolites in HaCaT cells by reverse transcriptase real-time PCR revealed significant alterations in mRNA levels of the endogenous AhR-responsive genes Cyp1A1, Cyp1B1, and AhRR. Indirubin- and FICZ-activated AhR in HaCaT and human HepG2 cells with significantly higher, yet transient, potency as compared with the prototypical AhR ligand, dioxin. In loco synthesis of these highly potent AhR inducers by Malassezia yeasts could have a significant impact on skin homeostatic mechanisms and disease development. Malassezia yeasts are commensal microorganisms, which under insufficiently understood conditions can become pathogenic. We have previously shown that specific strains isolated from diseased human skin can preferentially produce agonists of the aryl hydrocarbon receptor (AhR), whose activation has been linked to certain skin diseases. Investigation of skin scale extracts from patients with Malassezia-associated diseases demonstrated 10- to 1,000-fold higher AhR-activating capacity than control skin extracts. Liquid chromatography–tandem mass spectrometry analysis of the patients’ extracts revealed the presence of indirubin, 6-formylindolo[3,2-b]carbazole (FICZ), indolo[3,2-b]carbazole (ICZ), malassezin, and pityriacitrin. The same compounds were also identified in 9 out of 12 Malassezia species culture extracts tested, connecting their presence in skin scales with this yeast. Studying the activity of the Malassezia culture extracts and pure metabolites in HaCaT cells by reverse transcriptase real-time PCR revealed significant alterations in mRNA levels of the endogenous AhR-responsive genes Cyp1A1, Cyp1B1, and AhRR. Indirubin- and FICZ-activated AhR in HaCaT and human HepG2 cells with significantly higher, yet transient, potency as compared with the prototypical AhR ligand, dioxin. In loco synthesis of these highly potent AhR inducers by Malassezia yeasts could have a significant impact on skin homeostatic mechanisms and disease development. aryl hydrocarbon receptor AhR repressor Chemical Activated Luciferase gene expression cyclin dependent kinase formyl-indolo[3,2-b]carbazole glycogen synthase kinase glutathione S-transferase indolo[3,2-b]carbazole liquid chromatography–tandem mass spectrometry mass spectroscopy pityriasis versicolor seborrheic dermatitis 2,3,7,8-tetrachlorodibenzo-p-dioxin Healthy human skin harbors a significant amount of commensal yeasts belonging to the genus Malassezia that can become pathogenic under currently inadequately understood conditions (Ashbee, 2007Ashbee H.R. Update on the genus Malassezia.Med Mycol. 2007; 45: 287-303Crossref PubMed Scopus (154) Google Scholar; Gaitanis et al., 2012Gaitanis G. Magiatis P. Hantschke M. et al.The Malassezia genus in skin and systemic diseases.Clin Microbiol Rev. 2012; 25: 106-141Crossref PubMed Scopus (405) Google Scholar). These yeasts are implicated in the pathogenesis of skin diseases with diverse clinical presentation. Malassezia yeasts can cause pityriasis versicolor (PV), a minimally inflammatory condition despite a concomitant heavy fungal load, which, however, modifies the function of melanocytes, as evidenced by the formation of hyper- or hypopigmented plaques (Thoma et al., 2005Thoma W. Kramer H.J. Mayser P. Pityriasis versicolor alba.J Eur Acad Dermatol Venereol. 2005; 19: 147-152Crossref PubMed Scopus (47) Google Scholar). On the other hand, Malassezia yeasts are also implicated in exacerbations of certain inflammatory dermatoses, such as atopic dermatitis and seborrheic dermatitis (SD; Gupta et al., 2004Gupta A.K. Batra R. Bluhm R. et al.Skin diseases associated with Malassezia species.J Am Acad Dermatol. 2004; 51: 785-798Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar). All the aforementioned skin conditions are common and may have a significant impact on the quality of life of afflicted individuals (Sugita et al., 2010Sugita T. Boekhout T. Velegraki A. et al.Epidemiology of Malassezia-related skin diseases.in: Boekhout T. Gueho E. Mayser P. Velegraki A. Malassezia and the skin. Science and clinical practice. Springer, Berlin2010: 65-120Crossref Scopus (54) Google Scholar). Currently, the genus Malassezia comprises 14 species (Gaitanis et al., 2012Gaitanis G. Magiatis P. Hantschke M. et al.The Malassezia genus in skin and systemic diseases.Clin Microbiol Rev. 2012; 25: 106-141Crossref PubMed Scopus (405) Google Scholar). The most prevalent species in humans are M. globosa, M. restricta, M. sympodialis, and M. furfur, with the first two species present on the skin of almost all individuals (Tajima et al., 2008Tajima M. Sugita T. Nishikawa A. et al.Molecular analysis of Malassezia microflora in seborrheic dermatitis patients: comparison with other diseases and healthy subjects.J Invest Dermatol. 2008; 128: 345-351Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar). A major challenge in our effort to comprehend the role of Malassezia yeasts in skin diseases is to delineate pathogenic species or strains and to attribute virulence factors. During the last decade, an array of indolic substances synthesized in vitro by M. furfur has been identified. These substances have been associated with the pathogenic potential of this species (Mayser and Gaitanis, 2010Mayser P. Gaitanis G. Physiology and biochemistry in Malassezia and the kin.in: Boekhout T. Gueho E. Mayser P. Velegraki A. Science and Clinical Practice. Springer, Berlin2010Google Scholar). We have previously observed that M. furfur strains isolated from SD lesions (and from PV; unpublished observation) synthesize substances as are malassezin, indolo[3,2-b]carbazole (ICZ), and pityriacitrin in significantly higher quantities in vitro compared with healthy skin isolates (Gaitanis et al., 2008Gaitanis G. Magiatis P. Stathopoulou K. et al.AhR ligands, malassezin, and indolo[3,2-b]carbazole are selectively produced by Malassezia furfur strains isolated from seborrheic dermatitis.J Invest Dermatol. 2008; 128: 1620-1625Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). Malassezin has been shown to induce apoptosis in human melanocytes through aryl hydrocarbon receptor (AhR) activation, whereas ICZ is a known potent ligand of this receptor. Furthermore, the existence of malassezin on human skin could be a chemical marker for the presence of M. furfur, as the former has been described to be produced only by this species. To date, the production of these bioactive indoles had been shown only in vitro and only for M. furfur species, thus causing reservation with respect to their clinical relevance. AhR is an orphan, ligand-dependent nuclear receptor with multifaceted biological functions. It has been shown to participate in the maintenance of skin homeostasis (Bock and Kohle, 2009Bock K.W. Kohle C. The mammalian aryl hydrocarbon (Ah) receptor: from mediator of dioxin toxicity toward physiological functions in skin and liver.Biol Chem. 2009; 390: 1225-1235Crossref PubMed Scopus (80) Google Scholar), the enhancement of wound healing (Barouti et al., 2009Barouti N. Fontao L. Pardo B. et al.AhR pathway as a novel pharmacological target for wound healing.J Invest Dermatol. 2009; 129 (Abstr): S80Google Scholar), and the partial mediation of UVR damage through the photochemical intracellular production of the potent AhR ligand, 6-formylindolo[3,2-b]carbazole (FICZ; Fritsche et al., 2007Fritsche E. Schäfer C. Calles C. et al.Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmic target fro ultravioliet B radiation.Proc Natl Acad Sci USA. 2007; 104: 8851-8856Crossref PubMed Scopus (338) Google Scholar). Regarding skin pathophysiology, it is well known that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes its detrimental effects through persistent activation of this receptor and the downstream signaling pathway. The appearance of chloracne, a characteristic acne-like eruption, is one of the heralding signs of TCDD intoxication in humans (Panteleyev and Bickers, 2006Panteleyev A.A. Bickers D.R. Dioxin-induced chloracne-reconstructing the cellular and molecular mechanisms of a classic environmental disease.Exp Dermatol. 2006; 15: 705-730Crossref PubMed Scopus (111) Google Scholar; Sorg et al., 2009Sorg O. Zennegg M. Schmid P. et al.2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: identification and measurement of TCDD metabolites.Lancet. 2009; 374: 1179-1185Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar). Furthermore, activation of the AhR has an important role in mediating the biological/toxicological effects of a variety of environmental xenobiotics, including the Malassezia produced indirubin and ICZ, on the immune system (Esser et al., 2009Esser C. Rannug A. Stockinger B. The aryl hydrocarbon receptor in immunity.Trends Immunol. 2009; 30: 447-454Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar; Vlachos et al., 2012Vlachos C. Schulte B.M. Magiatis P. et al.Malassezia-derived indoles activate the aryl hydrocarbon receptor and inhibit Toll-like receptor-induced maturation in monocyte-derived dendritic cells.Br J Dermatol. 2012; 167: 496-505Crossref PubMed Scopus (62) Google Scholar). After documenting the preferential production of the AhR ligands ICZ and malassezin in M. furfur SD isolates, we decided to validate their in vivo existence in Malassezia-associated skin diseases (SD and PV) as compared with appropriate control samples. This was carried out by employing the very sensitive chemical activated luceferase gene expression (CALUX) bioassay (Denison et al., 2004Denison M.S. Zhao B. Baston D.S. et al.Recombinant cell bioassay systems for the detection and relative quantitation of halogenated dioxins and related chemicals.Talanta. 2004; 63: 1123-1133Crossref PubMed Scopus (94) Google Scholar) that measures the ability and relative potency of a chemical or extract to activate the AhR and AhR-dependent gene expression. The extracts from diseased skin scales revealed significantly higher AhR activation potential in the CALUX bioassay as compared with controls. In parallel and in order to expand the biological significance of AhR ligands synthesis by Malassezia yeasts, we: (1) analyzed Malassezia culture and skin scale extracts for the existence of additional indolic AhR activators; (2) screened Malassezia species for the production of AhR ligands in order to establish the wider significance of this biochemical trait in this genus; (3) assessed the effect of Malassezia culture extracts and indolic ingredients on HaCaT keratinocytes. Organic solvent skin scale extracts were prepared from 10 patients with SD (N=6) or PV (N=4) and 6 healthy volunteers and evaluated for their ability to activate AhR-dependent gene expression in recombinant human hepatoma (HG2L7.5c1) cells containing a stably transfected AhR-responsive luciferase reporter gene. The extracts originating from the patients’ lesional skin scales were between 10 and 1,000 times more potent in stimulating AhR-dependent luciferase activity than those from control healthy facial skin samples (N=3) or skin samples from anatomic areas that are not expected under physiological conditions to be colonized by Malassezia yeasts (N=3; Table 1).Table 1Quantitation (mol per mg of extract) of malassezin, indirubin, ICZ, FICZ, and pityriacitrin by HPLC/MS/MS in the extracts of skin originating from patients with SD or PV, and healthy subjects (healthy1–3: elbows, palms, and soles, healthy4–6: facial skin)Malassezin, mol per mg skin extractICZ, mol per mg skin extractFICZ, mol per mg skin extractIndirubin, mol per mg skin extractPityriacitrin, mol per mg skin extractEC50 μgml−1SD1ND1Limits of detection (molmg−1): malassezin: 4 × 10−14; ICZ: 8 × 10−12; FICZ: 2.9 × 10−13; indirubin: 6 × 10−13; pityriacitrin: 3 × 10−13.NDND8.1 × 10−11ND0.1SD2NDNDND1.5 × 10−10ND0.08SD32 × 10−13ND1.1 × 10−11ND7.5 × 10−110.88SD4NDND5 × 10−134.2 × 10−12ND0.67SD5NDNDNDNDND>100SD62 × 10−131.0 × 10−11NDND4.1 × 10−127.9PV1ND2.1 × 10−11NDND1.5 × 10−114.9PV22.5 × 10−12NDND2.6 × 10−10ND0.07PV31.1 × 10−12NDND1.3 × 10−11ND0.09PV4NDNDNDNDND>100Healthy1NDNDNDNDND53Healthy2NDNDNDNDND>100Healthy3NDNDNDNDND100Healthy4NDNDNDNDND83Healthy5NDNDNDNDND>100Healthy6NDNDNDNDND>100Abbreviations: FICZ, 6-formylindolo[3,2-b]carbazole; ICZ, indolo[3,2-b]carbazole; MS/MS, tandem mass spectrometry; ND, not detected; PV, pityriasis versicolor; SD, seborrheic dermatitis.Values are means of two independent measurements. The EC50 for stimulating aryl hydrocarbon receptor–dependent luciferase activity of each skin extract has been measured by the chemical activated luceferase gene expression cell bioassay.1 Limits of detection (molmg−1): malassezin: 4 × 10−14; ICZ: 8 × 10−12; FICZ: 2.9 × 10−13; indirubin: 6 × 10−13; pityriacitrin: 3 × 10−13. Open table in a new tab Abbreviations: FICZ, 6-formylindolo[3,2-b]carbazole; ICZ, indolo[3,2-b]carbazole; MS/MS, tandem mass spectrometry; ND, not detected; PV, pityriasis versicolor; SD, seborrheic dermatitis. Values are means of two independent measurements. The EC50 for stimulating aryl hydrocarbon receptor–dependent luciferase activity of each skin extract has been measured by the chemical activated luceferase gene expression cell bioassay. Using our previously described methodology (Gaitanis et al., 2008Gaitanis G. Magiatis P. Stathopoulou K. et al.AhR ligands, malassezin, and indolo[3,2-b]carbazole are selectively produced by Malassezia furfur strains isolated from seborrheic dermatitis.J Invest Dermatol. 2008; 128: 1620-1625Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar), we re-evaluated the M. furfur culture extracts that had been included in the previous study. By chromatographic separations, we isolated and identified by nuclear magnetic resonance and mass spectroscopy three additional indolic compounds known to be potent AhR activators, namely indirubin, FICZ, and tryptanthrin. The quantitation of the more prevalent indolic AhR ligands in culture extracts of M. furfur strains was performed by HPLC/UV or liquid chromatography–tandem mass spectrometry (LC/MS/MS) using as analytical standards pure synthetic substances (Supplementary Figure S1 online). In order to rule out the likelihood of the photochemical production of these indoles, all cultures were performed in the dark. As a negative control, extracts from agar slants without Malassezia inoculum were included. Comparison of M. furfur strains isolated from healthy skin with SD isolates showed that the latter had elevated levels of FICZ (P=0.001), indirubin (P=0.001), tryptanthrin (P=0.005), and pityriacitrin (P=0.001; Table 2), in addition to the previously documented elevated levels of ICZ (P<0.001) and malassezin (P=0.001; Gaitanis et al., 2008Gaitanis G. Magiatis P. Stathopoulou K. et al.AhR ligands, malassezin, and indolo[3,2-b]carbazole are selectively produced by Malassezia furfur strains isolated from seborrheic dermatitis.J Invest Dermatol. 2008; 128: 1620-1625Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). Download .pdf (.51 MB) Help with pdf files Supplementary InformationTable 2Quantitation (μg per mg of extract) of malassezin, indirubin, ICZ, tryptanthrin, and FICZ by HPLC/UV in the extracts of clinical Malassezia furfur strains originating from SD, PV, folliculitis, and HSsStrainSkin origin of the sampleMalassezin (μgmg−1)Indirubin (μgmg−1)ICZ (μgmg−1)Tryptanthrin (μgmg−1)FICZ (μgmg−1)Pityriacitrin (μgmg−1)M. furfur Bul19SD4.08±0.350.084±0.0100.26±0.010.59±0.031.33±0.154.82±0.33M. furfur Bul22SD3.33±0.383.90±0.332.50±0.111.52±0.091.14±0.103.62±0.30M. furfur Bul23SD3.52±0.290.25±0.020.36±0.020.38±0.030.45±0.043.63±0.28M. furfur Bul412SD2.02±0.183.36±0.340.95±0.070.53±0.030.72±0.052.76±0.27M. furfur CBS9585SD2.02±0.201.40±0.130.40±0.020.24±0.020.73±0.064.93±0.35M. furfur CBS9596SD4.12±0.252.66±0.211.60±0.120.58±0.030.68±0.062.31±0.23M. furfur GS19ASD2.16±0.150.022±0.010.38±0.020.05±0.01ND2.49±0.25M. furfur WCH114SD4.21±0.401.37±0.151.47±0.110.66±0.050.58±0.030.75±0.35M. furfur WCH100PV3.17±0.371.58±0.140.82±0.051.65±0.110.67±0.043.07±0.28M. furfur WCH106Folliculitis5.99±0.511.48±0.143.27±0.294.50±0.380.57±0.058.27±0.45M. furfur GS1BHS0.38±0.030.006±0.001ND0.029±0.005ND0.41±0.04M. furfur GS2AHS0.40±0.030.006±0.001ND0.031±0.005ND0.57±0.03M. furfur GS2BHS0.39±0.040.009±0.002ND0.094±0.007ND0.55±0.03M. furfur GS4AHS0.39±0.040.009±0.002ND0.16±0.01ND1.18±0.09M. furfur GS46AHS0.45±0.020.010±0.001ND0.19±0.01ND0.77±0.06M. furfur GS9AHS0.56±0.040.026±0.002ND0.37±0.02ND0.35±0.05M. furfur GA9BHS0.43±0.040.008±0.002ND0.088±0.07ND0.68±0.05Abbreviations: FICZ, 6-formylindolo[3,2-b]carbazole; HS, healthy subject; ICZ, indolo[3,2-b]carbazole; ND, not detected; PV, pityriasis versicolor; SD, seborrheic dermatitis.Values are means±standard deviations of three independent measurements. Open table in a new tab Abbreviations: FICZ, 6-formylindolo[3,2-b]carbazole; HS, healthy subject; ICZ, indolo[3,2-b]carbazole; ND, not detected; PV, pityriasis versicolor; SD, seborrheic dermatitis. Values are means±standard deviations of three independent measurements. To expand the significance of indole synthesis by Malassezia species, we screened type strains of species that are mainly isolated from human skin. At least one of these AhR ligands was detected in 9 out of 12 Malassezia species strains studied (Table 3). Overall, the M. furfur pathogenic strains were the most efficient producers of these indoles (Tables 2 and 3). However, with the exception of M. sympodialis and M. restricta, all other isolates from humans (M. furfur, M. obtusa, M. globosa, M. slooffiae, M. japonica, and M. yamatoensis) in addition to the animal isolates, M. pachydermatis and M.nana, synthesize at least some AhR ligands.Table 3Quantitation (μgper mg of extract) of malassezin, indirubin, ICZ, tryptanthrin, and FICZ by HPLC/UV in the extracts of 13 type and reference Malassezia species strainsMalassezia speciesMalassezin (μgmg−1)Indirubin (μgmg−1)ICZ (μgmg−1)Tryptanthrin (μgmg−1)FICZ (μgmg−1)Pityriacitrin (μgmg−1)M. furfur CBS18782.02±0.180.062±0.0050.42±0.030.49±0.040.84±0.020.75±0.05M. furfur CBS60013.52±0.25NDNDNDNDNDM. pachydermatis CBS65340.28±0.020.002NDTracesNDNDM. sympodialis CBS7222NDNDNDNDNDNDM. obtusa CBS7876Traces1Trace: detectable but not quantifiable.0.006±0.001NDTracesNDNDM. globosa CBS7966Traces0.006±0.001ND0.074±0.04NDNDM. slooffiae CBS7971TracesNDNDNDNDNDM. restricta CBS7991NDNDNDNDNDNDM. dermatis CBS9170TracesNDNDNDNDNDM. japonica CBS94320.30±0.020.005±0.001ND0.017±0.02ND0.33±0.05M. nana CBS95570.34±0.03NDNDNDNDNDM. yamatoensis CBS97260.29±0.020.002±0.001TracesTracesND0.24±0.04M. caprae CBS10434NDNDNDNDNDNDAbbreviations: FICZ, 6-formylindolo[3,2-b]carbazole; ICZ, indolo[3,2-b]carbazole; ND, not detected.Values are means±standard deviations of three independent measurements.1 Trace: detectable but not quantifiable. Open table in a new tab Abbreviations: FICZ, 6-formylindolo[3,2-b]carbazole; ICZ, indolo[3,2-b]carbazole; ND, not detected. Values are means±standard deviations of three independent measurements. The identification of indirubin and FICZ, along with the previously known Malassezia metabolites malassezin, pityriacitrin, and ICZ, in EtOAc extracts of human skin scales was performed by LC/MS/MS. FICZ and ICZ were identified in 2 out of 7 patients’ samples, pityriacitrin in 3 out of 10, malassezin in 4 out of 10, whereas indirubin was found in 5 out of 10 samples. The concentration of the identified metabolites ranged between 0.2 and 260pmolmg−1 of lesional skin scale extract (Table 1). None of these compounds was found in the control skin samples. Using the human hepatoma CALUX cell bioassay, the Malassezia metabolites were evaluated for their ability to stimulate AhR-dependent reporter gene expression at 6hours of incubation. All tested compounds were potent AhR activators, with ICZ and FICZ equipotent to the prototypical AhR agonist TCDD; malassezin and tryptanthrin were 20- and 200-fold less potent than TCDD, respectively. Interestingly, indirubin was 20-fold more potent than TCDD as an activator of the AhR in the human cell line (compare EC50s of 26pM to 523pM, respectively; EC50s: FICZ at 348pM, ICZ at 600pM, malassezin at 11nM, and tryptanthrin at 107nM; Figure 1). The significant variability of Malassezia culture extracts in their overall composition in indolic compounds with AhR activity complicates comparison of their relative potency. For this reason, in order to compare culture extracts of different M. furfur strains, we normalized extract dilutions for testing to 100nM ICZ. This was selected because besides being identified in all tested strains, it is one of the most active AhR-inducers. However, as ICZ was only found in M. furfur strains, comparisons are restricted to M. furfur lesional skin isolates. Alterations in the expression of AhR-related genes (Cyp1a1, Cyp1b1, AhRR, Aldh3a1) as well as AhR-responsive Phase II genes (Gstp1, Gstt1; Yu et al., 2009Yu S.T. Chen T.M. Chern J.W. et al.Downregulation of GSTpi expression by tryptanthrin contributing to sensitization of doxorubicin-resistant MCF-7 cells through c-jun NH2-terminal kinase-mediated apoptosis.Anticancer Drugs. 2009; 20: 382-388Crossref PubMed Google Scholar) by these indoles were assessed by reverse transcriptase real-time PCR. The extracts tested did not produce any obvious signs of toxicity in HaCaT cells when used at the equivalent of 100nM ICZ (Supplementary Figure S2 online). Extracts at this ICZ equivalent concentration significantly induced expression of two prototypical markers of the AhR signaling pathway, namely Cyp1a1 and Cyp1b1, with the level of CYP1A1 mRNA approximately sevenfold greater than that of CYP1B1 (Figure 2a and b). With the exception of WCH106, these extracts significantly downregulated the level of AhR repressor (AhRR) mRNA (Figure 2c) and both GSTP1 and GSTT1 mRNAs (P<0.05 compared with control; Supplementary Figure S3 online). A concentration–response protocol was applied to expose HaCaT cells to different concentrations of ICZ, malassezin, indirubin, FICZ, and tryptanthrin. A clear concentration-dependent increase in mRNA levels of the AhR-related genes Cyp1A1 and Cyp1b1 was observed in addition to Aldh3a1 (Figure 3 and Supplementary Figure S4 online). FICZ, ICZ, and indirubin proved to be more potent AhR agonists than malassezin and tryptanthrin (Figure 3 and Supplementary Figure S4 online). This was also applicable for ALDH3A1 mRNA. Interestingly, Cyp1a1 induction by FICZ, ICZ, and indirubin was higher at 24hours as compared with 3 and 6hours, a situation that is typically reversed for these compounds given that they are readily metabolized in intact cells (Supplementary Figure S5 online). The data presented herein demonstrate the identification of an array of indolic metabolites possessing potent AhR activity in skin scales of patients with SD and PV and attribute their origin to the skin commensal and pathogen Malassezia. In addition to the previously found ICZ and malassezin, three more compounds, indirubin, FICZ, and tryptanthrin, were identified as Malassezia metabolites. Up to now, only tryptanthrin has been shown to be produced by the yeast species Yarrowia (Candida) lipolytica (Schrenk et al., 1997Schrenk D. Riebniger D. Till M. et al.Typtanthrins: a novel class of agonists of the aryl hydrocarbon receptor.Biochem Pharmacol. 1997; 54: 165-171Crossref PubMed Scopus (35) Google Scholar) and Candida glabrata (Mayser et al., 2007Mayser P. Wenzel M. Krämer H.J. et al.Production of indole pigments by Candida glabrata.Med Mycol. 2007; 45: 519-524Crossref PubMed Scopus (20) Google Scholar). Both FICZ (Wincent et al., 2009Wincent E. Amini N. Luecke S. et al.The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans.J Biol Chem. 2009; 284: 2690-2696Crossref PubMed Scopus (221) Google Scholar, Wincent et al., 2012Wincent E. Bengtsson J. Mohammadi Bardbori A. et al.Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor.Proc Natl Acad Sci USA. 2012; 109: 4479-4484Crossref PubMed Scopus (156) Google Scholar) and indirubin (Prochazkova et al., 2011Prochazkova J. Kozubik A. Machala M. et al.Differential effects of indirubin and 2,3,7,8-tetrachlorodibenzo-p-dioxin on the aryl hydrocarbon receptor (AhR) signalling in liver progenitor cells.Toxicology. 2011; 279: 146-154Crossref PubMed Scopus (22) Google Scholar) are proposed as endogenous AhR ligands and have multiple biological functions. Indirubin inhibits CDKs as well as the GSK-3 (Hoessel et al., 1999Hoessel R. Leclerc S. Endicott J.A. et al.Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases.Nat Cell Biol. 1999; 1: 60-67Crossref PubMed Scopus (733) Google Scholar) and can modulate key cellular signaling pathways like Wnt and NF-kB (Tian et al., 1999Tian Y. Ke S. Denison M. et al.Ah receptor and NF-kappaB interactions, a potential mechanism for dioxin toxicity.J Biol Chem. 1999; 274: 510-515Crossref PubMed Scopus (325) Google Scholar). Also, bacteria can cause purple urine syndrome through the synthesis of indirubin (Kang et al., 2011Kang K.H. Jeong K.H. Baik S.K. et al.Purple urine bag syndrome: case report and literature review.Clin Nephrol. 2011; 75: 557-559Crossref PubMed Scopus (9) Google Scholar). FICZ has drawn attention as it has been implicated in the mediation of UV damage through AhR activation (Fritsche et al., 2007Fritsche E. Schäfer C. Calles C. et al.Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmic target fro ultravioliet B radiation.Proc Natl Acad Sci USA. 2007; 104: 8851-8856Crossref PubMed Scopus (338) Google Scholar). However, both could also cause indirect skin damage by the local leak of free radicals after AhR-induced hyperactivation of CYP enzymes (Park et al., 1996Park J.Y.K. Shigenaga M.K. Ames B.N. Induction of cytochrome P4501A1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin or indolo(3,2-b)carbazole is associated with oxidative DNA damage.Proc Natl Acad Sci USA. 1996; 93: 2322-2327Crossref PubMed Scopus (242) Google Scholar). Presently, the identification of malassezin and pityriacitrin exclusively in lesional skin scale extracts points to Malassezia as the source of origin. Malassezin is uniquely produced by Malassezia species, and can be considered as a chemical marker of this genus. In humans, pityriacitrin has been shown to be produced also by Candida glabrata (Mayser et al., 2007Mayser P. Wenzel M. Krämer H.J. et al.Production of indole pigments by Candida glabrata.Med Mycol. 2007; 45: 519-524Crossref PubMed Scopus (20) Google Scholar), the colon yeast equivalent of Malassezia. Cross-contamination only of the SD and PV samples with pityriacitrin originating from Candida strains residing in the colon is highly improbable and thus isolation of this indole from skin scales further corroborates toward its Malassezia origin. Regarding the clinical significance of AhR ligand production by Malassezia yeasts, we have two important complementary findings: (1) these ligands are produced in vitro by the majority of Malassezia species and in particular by the ubiquitous M. globosa (Tajima et al., 2008Tajima M. Sugita T. Nishikawa A. et al.Molecular analysis of Malassezia microflora in seborrheic dermatitis patients: comparison with other diseases and healthy subjects.J Invest Dermatol. 2008; 128: 345-351Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar) and (2) their presence was confirmed on the skin scales of PV and SD by both analytical and biological assays. The quantitative differences in the identified indoles from the skin scales could represent variations in the activity of the yet unknown biosynthetic pathway or in loco modification by environmental factors as is the skin pH and/or solar radiation (Fritsche et al., 2007Fritsche E. Schäfer C. Calles C. et al.Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmic target fro ultravioliet B radiation.Proc Natl Acad Sci USA. 2007; 104: 8851-8856Crossref PubMed Scopus (338) Google Scholar). Thus, ICZ has been proposed to be easily produced through transformation of malassezin (Wille et al., 2001Wille G. Mayser P. Thoma W. et al.Malassezin-A novel agonist of the arylhydrocarbon receptor from the yeast Malassezia furfur.Bioorg Med Chem. 2001; 9: 955-960Crossref Pu" @default.
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• W2149784311 title "Malassezia Yeasts Produce a Collection of Exceptionally Potent Activators of the Ah (Dioxin) Receptor Detected in Diseased Human Skin" @default.
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