Abstract
Gliotoxin is a kind of epipolythiodioxopiperazine derived from different fungi that is characterized by a disulfide bridge. Gliotoxins can be biosynthesized by a gli gene cluster and regulated by a positive GliZ regulator. Gliotoxins show cytotoxic effects via the suppression the function of macrophage immune function, inflammation, antiangiogenesis, DNA damage by ROS production, peroxide damage by the inhibition of various enzymes, and apoptosis through different signal pathways. In the other hand, gliotoxins can also be beneficial with different doses. Low doses of gliotoxin can be used as an antioxidant, in the diagnosis and treatment of HIV, and as an anti-tumor agent in the future. Gliotoxins have also been used in the control of plant pathogens, including Pythium ultimum and Sclerotinia sclerotiorum. Thus, it is important to elucidate the toxic mechanism of gliotoxins. The toxic mechanism of gliotoxins and biosynthetic strategies to reduce the toxicity of gliotoxins and their producing strains are summarized in this review.
Highlights
Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Department of Ocean Science and Hong Kong Branch of Southern Marine Science and Engineering
To investigate the role of gliotoxin in brain injury induced by Aspergillus, astrocyte and nerve cells were cultured with gradually increasing gliotoxin concentration; the results showed that gliotoxin at 300 and 1000 nM reduced the mitochondrial activity of astrocyte cells and neurons at 18 and 5 h, respectively [75]
Gliotoxin can show cytotoxic effects via antiangiogenesis, inflammation, immunosuppression mediated by the NF-κB and DNA damage, peroxide damage mediated by production of reactive oxygen species (ROS) mediated by the inhibition of nicotinamide adenine dinucleotid phosphate (NADPH) oxidase and redox cycling, and apoptosis via various signal pathways, including caspase-dependent mitochondrial membrane potential disruption, the NF-κB pathway and NOTCH2 -dependent apoptosis
Summary
Gliotoxin is a kind of epipolythiodioxopiperazine (EPT) characterized by a disulfide bond, which is produced by various kinds of fungi, including Aspergilluss fumigatus [1,2], Trichoderma virens [3], and Dichotomyces cejpiii [4,5]. Gliotoxin isolated from Trichoderma virens was reported to inhibit the growth of plant pathogens via the suppression of phagocytosis and the killing of conidia of versatile pathogenic fungi [7,8]. Gliotoxin-producing strain Trichoderma virens has been developed into other preparations, including GL-21, Glio GardTM and Soil GardTM , to control seedling diseases and root diseases of greenhouse and field crops with remarkable effects [9,10]. Gliotoxin can inhibit tumor cell proliferation and viral RNA replication and induce apoptosis of hepatic stellate cells as well as hinder the expression of nuclear factor-kappa B (NF-κB), exhibiting promising prospects in the fields of antitumor, antivirus, and anti-liver fibrosis and immunosuppression during organ transplantation [6]. A review of the toxic and detoxification mechanisms of gliotoxins would provide clues for the future broad application of gliotoxins and their derivatives as well as reduce the hazard of the gliotoxin-producing strain Aspergillus fumigatus
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