gliotoxin

Postoperative ileus (POI) is the cessation or reduction of gastrointestinal (GI) motility after surgery. Reactive enteric glial cells (EGCs) are critical for maintaining bowel function. However, the triggering mechanisms and downstream effects of reactive EGCs in POI were poorly understood. The goal of this current study was to investigate whether the inducible nitric oxide synthase (iNOS)-driven reactive EGCs participated in GI motility disorders and mechanisms underlying altered GI motility in POI. Intestinal manipulation (IM)-induced POI mice and iNOS-/- mice were used in the study...

Aspergillus fumigatus is a saprophytic fungus that can cause a variety of human diseases known as aspergillosis. Mycotoxin gliotoxin (GT) production is important for its virulence and must be tightly regulated to avoid excess production and toxicity to the fungus. GT self-protection by GliT oxidoreductase and GtmA methyltransferase activities is related to the subcellular localization of these enzymes and how GT can be sequestered from the cytoplasm to avoid increased cell damage. Here, we show that GliT:GFP and GtmA:GFP are localized in the cytoplasm and in vacuoles during GT production...

The most studied epipolythiodioxopiperazine (ETP) alkaloids, such as chetomin, gliotoxin and chaetocin, were reported to exert their antitumor effects through targeting HIF-1α. Chaetocochin J (CJ) is another ETP alkaloid, of which the effect and mechanism on cancer are not fully elucidated. Considering the high incidence and mortality of hepatocellular carcinoma (HCC) in China, in the present study, using HCC cell lines and tumor-bearing mice as models, we explored the anti-HCC effect and mechanism of CJ...

The study aimed to investigate the effects of gliotoxin (GTX), a secondary fungal metabolite belonging to the epipolythiodioxopiperazines class, on Gram-positive and Gram-negative bacteria. While the cytotoxic mechanism of GTX on eukaryotes is well understood, its interaction with bacteria is not yet fully comprehended. The study discovered that S. epidermidis displayed a higher uptake rate of GTX than E.coli. However, Gram-negative bacteria required higher doses of GTX than Gram-positive bacteria to experience the bactericidal effect, which occurred within 4 hours for both types of bacteria...

Astrocytes participate in information processing by releasing neuroactive substances termed gliotransmitters, including ATP. Individual astrocytes come into contact with thousands of synapses with their ramified structure, but the spatiotemporal dynamics of ATP gliotransmission remains unclear, especially in physiological brain tissue. Using a genetically encoded fluorescent sensor, GRABATP1.0 , we discovered that extracellular ATP increased locally and transiently in absence of stimuli in neuron-glia co-cultures, cortical slices, and the anesthetized mouse brain...

BACKGROUND AND PURPOSE: ET-1 signalling modulates intestinal motility and inflammation, but the role of ET-1/ETB receptor signalling is poorly understood. Enteric glia modulate normal motility and inflammation. We investigated whether glial ETB signalling regulates neural-motor pathways of intestinal motility and inflammation. EXPERIMENTAL APPROACH: We studied ETB signalling using: ETB drugs (ET-1, SaTX, BQ788), activity-dependent stimulation of neurons (high K+ -depolarization, EFS), gliotoxins, Tg (Ednrb-EGFP)EP59Gsat/Mmucd mice, cell-specific mRNA in Sox10CreERT2 ;Rpl22-HAflx or ChATCre ;Rpl22-HAflx mice, Sox10CreERT2 ::GCaMP5g-tdT, Wnt1Cre2 ::GCaMP5g-tdT mice, muscle tension recordings, fluid-induced peristalsis, ET-1 expression, qPCR, western blots, 3-D LSM-immunofluorescence co-labelling studies in LMMP-CM and a postoperative ileus (POI) model of intestinal inflammation...

Aspergillus fumigatus is the most commonly isolated fungus in chronic lung diseases, with a prevalence of up to 60% in cystic fibrosis patients. Despite this, the impact of A. fumigatus colonisation on lung epithelia has not been thoroughly explored. We investigated the influence of A. fumigatus supernatants and the secondary metabolite, gliotoxin, on human bronchial epithelial cells (HBE) and CF bronchial epithelial (CFBE) cells. CFBE (F508del CFBE41o- ) and HBE (16HBE14o- ) trans-epithelial electrical resistance (TEER) was measured following exposure to A...

Recent years have seen a lot of interest in transition metal carbides/carbonitrides (MXenes), Which is one of newly proliferating two-dimensional (2D) materials.The advantages and applications of synthesizing MXenes-based biosensing systems are interesting. There is an urgent requirement for synthesis of MXenes. Through foliation, physical adsorption, and interface modification,it has been proposed that many biological disorders are related to genetic mutation. Majority of mutations were discovered to be nucleotide mismatches...

Using the structure of gliotoxin as a starting point, we have prepared two different chemotypes with selective affinity to the kappa opioid receptor (KOR). Using medicinal chemistry approaches and structure-activity relationship (SAR) studies, structural features required for the observed affinity were identified, and advanced molecules with favorable Multiparameter Optimization (MPO) and Ligand Lipophilicity (LLE) profiles were prepared. Using the Thermal Place Preference Test (TPPT), we have shown that compound2 blocks the antinociceptive effect of U50488, a known KOR agonist...

Gliotoxin (GT) biosynthesis in fungi is encoded by the gli biosynthetic gene cluster. While GT addition autoinduces biosynthesis, Zn2+ has been shown to attenuate cluster activity, and it was speculated that identification of Zn2Cys6 binuclear transcription factor GliZ binding partners might provide insight into this observation. Using the Tet-ON induction system, doxycycline (DOX) presence induced GliZ fusion protein expression in, and recovery of GT biosynthesis by, A. fumigatus ΔgliZ::HA-gliZ and ΔgliZ::TAP-gliZ strains, respectively...

Aspergillus fumigatus causes aspergillosis with high morbidity and mortality in the duck industry. As a vital virulence factor produced by A. fumigatus, gliotoxin (GT) is widely present in food and feed, threatening duck industry and human health. Quercetin is a polyphenol flavonoid compound from natural plants with anti-inflammatory and antioxidant functions. However, the effects of quercetin on ducklings with GT poisoning are unknown. The model of ducklings with GT poisoning was established, and the protective effects and molecular mechanisms of quercetin on ducklings with GT poisoning were investigated...

Pathogenic helminths have evolved mechanisms to preserve reproductive function while surviving long-term in the host via robust protective responses. A protective role of antioxidant enzymes in preventing DNA degradation has long been proposed, but little evidence has been provided. Here, we show that omega-class glutathione transferases (GSTOs) are critical for maintaining viability by protecting the reproductive cell DNA of the carcinogenic liver fluke, Clonorchis sinensis . Clonorchis sinensis GSTO (CsGSTO) activities modified by changes in the GSH/GSSG and NADPH/NADP+ molar ratios suppressed the overproduction of reactive oxygen species...

Gliotoxin can be developed as potent biopesticide. In this study, the positive transcriptional factor gliZ and glutathione-S transferase encoding gene gliG were firstly deleted by CRISPR/Cas9 system, which abolished the production of gliotoxin-like compounds in Dichotomomyces cejpii. CRISPR/dCas9 system targeting promoter of gliG was used to activate the biosynthetic genes in gli cluster. The overexpression of gliZ, gliN and gliG can significantly improve the yield of gliotoxin-like compunds. The gliotoxin yields was improved by 16...

Antimicrobial resistance (AMR) is a major global problem and threat to humanity. The search for new antibiotics is directed towards targeting of novel microbial systems and enzymes, as well as augmenting the activity of pre-existing antimicrobials. Sulphur-containing metabolites (e.g., auranofin and bacterial dithiolopyrrolones [e.g., holomycin]) and Zn2+-chelating ionophores (PBT2) have emerged as important antimicrobial classes. The sulphur-containing, non-ribosomal peptide gliotoxin, biosynthesised by Aspergillus fumigatus and other fungi exhibits potent antimicrobial activity, especially in the dithiol form (dithiol gliotoxin; DTG)...

Aspergillus fumigatus is an opportunistic fungal pathogen capable of inducing chronic and acute infection in susceptible patients. A. fumigatus interacts with numerous bacteria that compose the microbiota of the lung, including Pseudomonas aeruginosa and Klebsiella pneumoniae , both of which are common isolates from cystic fibrosis sputum. Exposure of A. fumigatus to K. pneumoniae culture filtrate reduced fungal growth and increased gliotoxin production. Qualitative proteomic analysis of the K. pneumoniae culture filtrate identified proteins associated with metal sequestering, enzymatic degradation and redox activity, which may impact fungal growth and development...

Invasive pulmonary aspergillosis (IPA) may be a rare cause of granulomatous pneumonia in horses. The mortality of IPA is almost 100%; direct diagnostic tools in horses are needed. Bronchoalveolar lavage fluid (BALF) and serum samples were collected from 18 horses, including individuals suffering from IPA (n = 1), equine asthma (EA, n = 12), and 5 healthy controls. Serum samples were collected from another 6 healthy controls. Samples of BALF (n = 18) were analyzed for Aspergillus spp. DNA, fungal galactomannan (GM), ferricrocin (Fc), triacetylfusarinin C (TafC), and gliotoxin (Gtx)...

As one of the mycotoxins produced by Aspergillus fumigatus, gliotoxin has a variety of pharmacological effects, such as anti-tumor, antibacterial, immunosuppressive. Antitumor drugs induce tumor cell death in several forms, including apoptosis, autophagy, necrosis and ferroptosis. Ferroptosis is a recently identified unique form of programmed cell death characterized by iron-dependent accumulation of lethal lipid peroxides, which induces cell death. A large amount of preclinical evidence suggests that ferroptosis inducers may enhance the sensitivity of chemotherapy and the induction of ferroptosis may be an effective therapeutic strategy to prevent acquired drug resistance...

Recently, we reported that zinc regulates gliotoxin biosynthesis via ZafA, which is a zinc-responsive transcriptional activator. From an HPLC analysis of culture media of Aspergillus fumigatus, we found a trend of decreasing gliotoxin production but increasing pseurotin A and fumagillin production in proportion to the zinc concentration. The expression of the genes involved in pseurotin A biosynthesis was upregulated under high zinc concentrations. Furthermore, upregulated expression of pseurotin A biosynthetic genes and higher production of pseurotin A were observed in the zafA deletion strain...

Trichoderma virens is a beneficial fungus that helps plants fight pathogens and abiotic stresses and thereby enhances crop yields. Unlike other Trichoderma spp., there are two well-defined strains (P and Q) of T. virens, classified by secondary metabolites profiling, primarily the biosynthesis of the nonribosomal, strong antimicrobial agents gliotoxin (Q) and gliovirin (P). We have studied the phenotypic and biocontrol properties of two well-studied representative isolates ( T. virens Gv29-8 and T. virens GvW/IMI304061) that represent a Q strain and a P strain of T...

Fungi biosynthesize a diversity of secondary metabolites, small organic bioactive molecules that play diverse roles in fungal ecology. Fungal secondary metabolites are often encoded by physically clustered sets of genes known as biosynthetic gene clusters (BGCs). Fungi in the genus Penicillium produce diverse secondary metabolites that have been both useful (e.g., the antibiotic penicillin and the cholesterol-lowering drug mevastatin) and harmful (e.g., the mycotoxin patulin and the immunosuppressant gliotoxin) to human affairs...