| 1. |
- Hosseinzadeh, Ava, et al.
(författare)
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Stable Redox-Cycling Nitroxide Tempol has Antifungal and Immune-modulatory Properties
- 2019
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Ingår i: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Invasive mycoses remain underdiagnosed and difficult to treat. Hospitalized individuals with compromised immunity increase in number and constitute the main risk group for severe fungal infections. Current antifungal therapy is hampered by slow and insensitive diagnostics and frequent toxic side effects of standard antifungal drugs. Identification of new antifungal compounds with high efficacy and low toxicity is therefore urgently required. We investigated the antifungal activity of tempol, a cell-permeable nitroxide. To narrow down possible mode of action we used RNA-seq technology and metabolomics to probe for pathways specifically disrupted in the human fungal pathogen Candida albicans due to tempol administration. We found genes upregulated which are involved in iron homeostasis, mitochondrial stress, steroid synthesis, and amino acid metabolism. In an ex vivo whole blood infection, tempol treatment reduced C. albicans colony forming units and at the same time increased the release of pro-inflammatory cytokines, such as interleukin 8 (IL-8, monocyte chemoattractant protein-1, and macrophage migration inhibitory factor). In a systemic mouse model, tempol was partially protective with a significant reduction of fungal burden in the kidneys of infected animals during infection onset. The results obtained propose tempol as a promising new antifungal compound and open new opportunities for the future development of novel therapies.
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| 2. |
- Lopes, José Pedro, 1986-, et al.
(författare)
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Cryptococcus neoformans Induces MCP-1 Release and Delays the Death of Human Mast Cells
- 2019
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Ingår i: Frontiers in Cellular and Infection Microbiology. - : Frontiers Media S.A.. - 2235-2988. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Cryptococcosis, caused by the basidiomycete Cryptococcus neoformans, is a life-threatening disease affecting approximately one million people per year worldwide. Infection can occur when C. neoformans cells are inhaled by immunocompromised people. In order to establish infection, the yeast must bypass recognition and clearance by immune cells guarding the tissue. Using in vitro infections, we characterized the role of mast cells (MCs) in cryptococcosis. We found that MCs recognize C. neoformans and release inflammatory mediators such as tryptase and cytokines. From the latter group MCs released mainly CCL-2/MCP-1, a strong chemoattractant for monocytic cells. We demonstrated that supernatants of infected MCs recruit monocytes but not neutrophils. During infection with C. neoformans, MCs have a limited ability to kill the yeast depending on the serotype. C. neoformans, in turn, modulates the lifespan of MCs both, by presence of its polysaccharide capsule and by secreting soluble modulators. Taken together, MCs might have important contributions to fungal clearance during early stages of cryptocococis where these cells regulate recruitment of monocytes to mucosal tissues.
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| 3. |
- Stylianou, Marios, 1981-, et al.
(författare)
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Distinct transcriptional response of Caenorhabditis elegans to different exposure routes of perfluorooctane sulfonic acid
- 2019
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Ingår i: Environmental Research. - : Academic Press. - 0013-9351 .- 1096-0953. ; 168, s. 406-413
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Tidskriftsartikel (refereegranskat)abstract
- Although people are exposed daily to per- and polyfluorinated alkyl substances (PFASs), the biological consequences are poorly explored. The health risks associated with PFAS exposure are currently based on chemical analysis with a weak correlation to potential harmful effects in man and animals. In this study, we show that perfluorooctane sulfonic acid (PFOS), often the most enriched PFAS in the environment, can be transferred via bacteria to higher organisms such as Caenorhabditis elegans. C. elegans nematodes were exposed to PFOS directly in buffer or by feeding on bacteria pretreated with PFOS, and this led to distinct gene expression profiles. Specifically, heavy metal and heat shock associated genes were significantly, although inversely, expressed following the different PFOS exposures. The innate immunity receptor for microbial pathogens, clec-60, was shown for the first time to be down-regulated by PFOS. This is in line with a previous study indicating that PFOS is associated with children's susceptibility to certain infectious diseases. Furthermore, bar-1, a gene associated with various cancers was highly up-regulated only when C. elegans were exposed to PFOS pretreated live bacteria. Furthermore, dead bacterial biomass had higher binding capacity for linear and isomeric PFOS than live bacteria, which correlated to the higher levels of PFOS detected in C. elegans when fed the treated E. toll, respectively. These results reveal new aspects concerning trophic chain transport of PFOS.
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