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Kevin J Sheridan, Beatrix Elisabeth Lechner, Grainne O' Keeffe, Markus A Keller, Ernst R Werner, Herbert Lindner, Gary W Jones, Hubertus Haas, Sean Doyle
Ergothioneine (EGT; 2-mercaptohistidine trimethylbetaine) is a trimethylated and sulphurised histidine derivative which exhibits antioxidant properties. Here we report that deletion of Aspergillus fumigatus egtA (AFUA_2G15650), which encodes a trimodular enzyme, abrogated EGT biosynthesis in this opportunistic pathogen. EGT biosynthetic deficiency in A. fumigatus significantly reduced resistance to elevated H2O2 and menadione, respectively, impaired gliotoxin production and resulted in attenuated conidiation...
October 17, 2016: Scientific Reports
Bastian Jöhnk, Özgür Bayram, Anja Abelmann, Thorsten Heinekamp, Derek J Mattern, Axel A Brakhage, Ilse D Jacobsen, Oliver Valerius, Gerhard H Braus
F-box proteins share the F-box domain to connect substrates of E3 SCF ubiquitin RING ligases through the adaptor Skp1/A to Cul1/A scaffolds. F-box protein Fbx15 is part of the general stress response of the human pathogenic mold Aspergillus fumigatus. Oxidative stress induces a transient peak of fbx15 expression, resulting in 3x elevated Fbx15 protein levels. During non-stress conditions Fbx15 is phosphorylated and F-box mediated interaction with SkpA preferentially happens in smaller subpopulations in the cytoplasm...
September 2016: PLoS Pathogens
Mun-Gu Jung, Sung Su Kim, Jae-Hyuk Yu, Kwang-Soo Shin
The G-protein-coupled receptor (GPCR) family represents the largest and most varied collection of membrane embedded proteins that are sensitized by ligand binding and interact with heterotrimeric G proteins. Despite their presumed critical roles in fungal biology, the functions of the GPCR family members in the opportunistic human pathogen Aspergillus fumigatus are largely unknown, as only two (GprC and GprD) of the 15 predicted GPCRs have been studied. Here, we characterize the gprK gene, which is predicted to encode a hybrid GPCR with both 7-transmembrane and regulator of G-protein signaling (RGS) domains...
2016: PloS One
Antonio Pereira-Neves, Rubem F S Menna-Barreto, Marlene Benchimol
Proteasomal proteolysis is required for a wide range of cellular processes, including protein quality control, cell cycle progression, cell death and metabolic adaptation to environment changes or stress responses. Proteasome inhibitors are useful compounds for determining the roles of proteasome in eukaryotic cells. Here, we investigated the effects of gliotoxin, a proteasome inhibitor, on the cell growth, replication, ultrastructure, DNA integrity and proteasomal proteolytic activity of the protist parasite Tritrichomonas foetus...
August 2016: Parasitology Research
Aditi Banerjee, Swagata Ghatak, Sujit Kumar Sikdar
Brain ischaemia is a highly debilitating condition where shortage of oxygen and glucose leads to profuse cell death. Lactate is a neuroprotective metabolite whose concentrations increase up to 15-30 mmol/L during ischaemia and TREK1 is a neuroprotective potassium channel which is upregulated during ischaemia. The aim of this study was to investigate the effect of l-lactate on TREK1 expression and to evaluate the role of l-lactate-TREK1 interaction in conferring neuroprotection in ischaemia-prone hippocampus...
July 2016: Journal of Neurochemistry
Daniel Schlam, Johnathan Canton, Marvin Carreño, Hannah Kopinski, Spencer A Freeman, Sergio Grinstein, Gregory D Fairn
UNLABELLED: Aspergillus fumigatus, an opportunistic fungal pathogen, spreads in the environment by releasing numerous conidia that are capable of reaching the small alveolar airways of mammalian hosts. In otherwise healthy individuals, macrophages are responsible for rapidly phagocytosing and eliminating these conidia, effectively curbing their germination and consequent invasion of pulmonary tissue. However, under some circumstances, the fungus evades phagocyte-mediated immunity and persists in the respiratory tree...
2016: MBio
Elke R Duell, Manuel Glaser, Camille Le Chapelain, Iris Antes, Michael Groll, Eva M Huber
The epipolythiodioxopiperazine (ETP) gliotoxin mediates toxicity via its reactive thiol groups and thereby contributes to virulence of the human pathogenic fungus Aspergillus fumigatus. Self-intoxication of the mold is prevented either by reversible oxidation of reduced gliotoxin or by irreversible conversion to bis(methylthio)gliotoxin. The latter is produced by the S-methyltransferase TmtA and attenuates ETP biosynthesis. Here, we report the crystal structure of TmtA in complex with S-(5'-adenosyl)-l-homocysteine...
April 15, 2016: ACS Chemical Biology
Jens C Frisvad, Thomas O Larsen
Aspergillus fumigatus is an important opportunistic human pathogen known for its production of a large array of extrolites. Up to 63 species have been described in Aspergillus section Fumigati, some of which have also been reliably reported to be pathogenic, including A. felis, A. fischeri, A. fumigatiaffinis, A. fumisynnematus, A. hiratsukae, A. laciniosus, A. lentulus, A. novofumigatus, A. parafelis, A. pseudofelis, A. pseudoviridinutans, A. spinosus, A. thermomutatus, and A. udagawae. These species share the production of hydrophobins, melanins, and siderophores and ability to grow well at 37°C, but they only share some small molecule extrolites, that could be important factors in pathogenicity...
2015: Frontiers in Microbiology
Matxalen Vidal-García, M Pilar Domingo, Beatriz De Rueda, Lourdes Roc, M Pilar Delgado, M José Revillo, Julián Pardo, Eva M Gálvez, Antonio Rezusta
Early and accurate diagnosis of invasive aspergillosis (IA) is one of the most critical steps needed to efficiently treat the infection and reduce the high mortality rates that can occur. We have previously found that the Aspergillus spp. secondary metabolite, bis(methylthio)gliotoxin (bmGT), can be detected in the serum from patients with possible/probable IA. Thus, it could be used as a diagnosis marker of the infection. However, there is no data available concerning the sensitivity, specificity and performance of bmGT to detect the infection...
March 2016: Applied Microbiology and Biotechnology
V Alonso, C Aminahuel, L Díaz Vergara, C Pereyra, V Poloni, A Dalcero, L Cavaglieri
UNLABELLED: The aim of this manuscript was to study the influence of water activity (aW ) and pH in the ecophysiological behaviour of Aspergillus fumigatus strains at human body temperature. In addition, gliotoxin production and enzymatic ability among environmental (n = 2) and clinical (n = 5) strains were compared. Ecophysiological study of environmental strains was performed on agar silage incubated at 37°C, studying the interaction at eight aW levels (0·8, 0·85, 0·9, 0·92, 0·94, 0·96, 0·98 and 0·99) and eight pH levels (3·5, 4, 4·5, 5, 6, 7, 7·5 and 8)...
February 2016: Letters in Applied Microbiology
Lara Manzanares-Miralles, Özlem Sarikaya-Bayram, Elizabeth B Smith, Stephen K Dolan, Özgür Bayram, Gary W Jones, Sean Doyle
Gliotoxin (GT) is a redox-active metabolite, produced by Aspergillus fumigatus, which inhibits the growth of other fungi. Here we demonstrate how Aspergillus niger responds to GT exposure. Quantitative proteomics revealed that GT dysregulated the abundance of 378 proteins including those involved in methionine metabolism and induced de novo abundance of two S-adenosylmethionine (SAM)-dependent methyltransferases. Increased abundance of enzymes S-adenosylhomocysteinase (p=0.0018) required for homocysteine generation from S-adenosylhomocysteine (SAH), and spermidine synthase (p=0...
January 10, 2016: Journal of Proteomics
Mahdieh Azin, Javad Mirnajafi-Zadeh, Mohammad Javan
OBJECTIVE: Hippocampal insults have been observed in multiple sclerosis (MS) patients. Fibroblast growth factor-2 (FGF2) induces neurogenesis in the hippocampus and en- hances the proliferation, migration and differentiation of oligodendrocyte progenitor cells (OPCs). In the current study, we have investigated the effect of FGF2 on the processes of gliotoxin induced demyelination and subsequent remyelination in the hippocampus. MATERIALS AND METHODS: In this experimental study adult male Sprague-Dawley rats re- ceived either saline or lysolecithin (LPC) injections to the right hippocampi...
2015: Cell Journal
Junxiong Chen, Chenliang Wang, Wenjian Lan, Chunying Huang, Mengmeng Lin, Zhongyang Wang, Wanling Liang, Aikichi Iwamoto, Xiangling Yang, Huanliang Liu
The discovery of new bioactive compounds from marine natural sources is very important in pharmacological research. Here we developed a Wnt responsive luciferase reporter assay to screen small molecule inhibitors of cancer associated constitutive Wnt signaling pathway. We identified that gliotoxin (GTX) and some of its analogues, the secondary metabolites from marine fungus Neosartorya pseufofischeri, acted as inhibitors of the Wnt signaling pathway. In addition, we found that GTX downregulated the β-catenin levels in colorectal cancer cells with inactivating mutations of adenomatous polyposis coli (APC) or activating mutations of β-catenin...
October 2015: Marine Drugs
Daniel H Scharf, Axel A Brakhage, Prasun K Mukherjee
Gliotoxin (GT) is the most important epidithiodioxopiperazine (ETP)-type fungal toxin. GT was originally isolated from Trichoderma species as an antibiotic substance involved in biological control of plant pathogenic fungi. A few isolates of GT-producing Trichoderma virens are commercially marketed for biological control and widely used in agriculture. Furthermore, GT is long known as an immunosuppressive agent and also reported to have anti-tumour properties. However, recent publications suggest that GT is a virulence determinant of the human pathogen Aspergillus fumigatus...
April 2016: Environmental Microbiology
María J Nichea, Sofia A Palacios, Stella M Chiacchiera, Michael Sulyok, Rudolf Krska, Sofia N Chulze, Adriana M Torres, María L Ramirez
The aim of this study was to evaluate the occurrence of several fungal metabolites, including mycotoxins in natural grasses (Poaceae) intended for grazing cattle. A total number of 72 and 77 different metabolites were detected on 106 and 69 grass samples collected during 2011 and 2014, respectively. A total of 60 metabolites were found across both years. Among the few mycotoxins considered toxic for ruminants, no samples of natural grasses were contaminated with aflatoxins, ochratoxin A, ergot alkaloids, and gliotoxin, among others...
August 2015: Toxins
Antonio Gallo, Gianluca Giuberti, Jens C Frisvad, Terenzio Bertuzzi, Kristian F Nielsen
Ruminant diets include cereals, protein feeds, their by-products as well as hay and grass, grass/legume, whole-crop maize, small grain or sorghum silages. Furthermore, ruminants are annually or seasonally fed with grazed forage in many parts of the World. All these forages could be contaminated by several exometabolites of mycotoxigenic fungi that increase and diversify the risk of mycotoxin exposure in ruminants compared to swine and poultry that have less varied diets. Evidence suggests the greatest exposure for ruminants to some regulated mycotoxins (aflatoxins, trichothecenes, ochratoxin A, fumonisins and zearalenone) and to many other secondary metabolites produced by different species of Alternaria spp...
August 2015: Toxins
Henrik Harms, Barbora Orlikova, Seungwon Ji, Damun Nesaei-Mosaferan, Gabriele M König, Marc Diederich
The Ascomycota Dichotomomyces cejpii was isolated from the marine sponge Callyspongia cf. C. flammea. A new gliotoxin derivative, 6-acetylmonodethiogliotoxin (1) was obtained from fungal extracts. Compounds 2 and 3, methylthio-gliotoxin derivatives were formerly only known as semi-synthetic compounds and are here described as natural products. Additionally the polyketide heveadride (4) was isolated. Compounds 1, 2 and 4 dose-dependently down-regulated TNFα-induced NF-κB activity in human chronic myeloid leukemia cells with IC50s of 38...
August 2015: Marine Drugs
David Acton, Gareth B Miles
Despite considerable evidence that glia can release modulators to influence the excitability of neighbouring neurons, the importance of gliotransmission for the operation of neural networks and in shaping behaviour remains controversial. Here we characterise the contribution of glia to the modulation of the mammalian spinal central pattern generator for locomotion, the output of which is directly relatable to a defined behaviour. Glia were stimulated by specific activation of protease-activated receptor-1 (PAR1), an endogenous G-protein coupled receptor preferentially expressed by spinal glia during ongoing activity of the spinal central pattern generator for locomotion...
2015: PloS One
Rebecca A Owens, Grainne O'Keeffe, Elizabeth B Smith, Stephen K Dolan, Stephen Hammel, Kevin J Sheridan, David A Fitzpatrick, Thomas M Keane, Gary W Jones, Sean Doyle
Mechanistic studies on gliotoxin biosynthesis and self-protection in Aspergillus fumigatus, both of which require the gliotoxin oxidoreductase GliT, have revealed a rich landscape of highly novel biochemistries, yet key aspects of this complex molecular architecture remain obscure. Here we show that an A. fumigatus ΔgliA strain is completely deficient in gliotoxin secretion but still retains the ability to efflux bisdethiobis(methylthio)gliotoxin (BmGT). This correlates with a significant increase in sensitivity to exogenous gliotoxin because gliotoxin trapped inside the cell leads to (i) activation of the gli cluster, as disabling gli cluster activation, via gliZ deletion, attenuates the sensitivity of an A...
September 2015: Eukaryotic Cell
Kwang-Soo Shin, Young Hwan Kim, Jae-Hyuk Yu
The opportunistic human pathogenic fungus Aspergillus fumigatus primarily reproduces by forming a large number of asexual spores (conidia). Sequential activation of the central regulators BrlA, AbaA and WetA is necessary for the fungus to undergo asexual development. In this study, to address the presumed roles of these key developmental regulators during proliferation of the fungus, we analyzed and compared the proteomes of vegetative cells of wild type (WT) and individual mutant strains. Approximately 1300 protein spots were detectable from 2-D electrophoresis gels...
July 31, 2015: Biochemical and Biophysical Research Communications
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