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Oncotarget Sep 2016Hypoxia activates hypoxia-inducible factor 1, which promotes the progression of malignancy by stimulating angiogenesis and by augmenting the ability of tumors to...
Hypoxia activates hypoxia-inducible factor 1, which promotes the progression of malignancy by stimulating angiogenesis and by augmenting the ability of tumors to survive. Thus, HIF-1 is one of the most compelling targets for treating cancers. The aim of this study was to find a small molecule that inhibits HIF-1 under hypoxia in cancer cells. 7,280 compounds in a chemical library were tested in a cancer cell line expressing luciferase HIF-dependently. Through three rounds of screening, we finally picked up a compound that originates from a marine bacterium parasitizing red alga. The antibiotic potently inhibited HIF-1 expression and its transcriptional activity in cancer cells exposed to hypoxia. Through two-step fractionation, diacetoxyscirpenol was purified and identified as a HIF-inhibiting ingredient. Mechanistically, diacetoxyscirpenol inhibits the synthesis of HIF-1α protein and also interferes with the dimerization of HIF-1α and ARNT. It attenuates HIF-mediated gene expression in cancer cells exposed to hypoxia, and by doing so reduces tumorigenic and angiogenic potentials of cancer cells. More importantly, diacetoxyscirpenol retarded tumor growth in mice, and reduced HIF-1α expression and vascular formation in the tumors. Overall, diacetoxyscirpenol is considered a potential drug deregulating the HIF-1 signaling pathway, and it could be beneficially employed for treating malignant tumors with hypoxic microenvironment.
Topics: A549 Cells; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cell Adhesion; Cell Line, Tumor; Drug Discovery; Drug Screening Assays, Antitumor; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Rhodophyta; Signal Transduction; Transcription, Genetic; Trichothecenes
PubMed: 27613833
DOI: 10.18632/oncotarget.11529 -
Toxins Feb 2021In this study, we present, for the first time in Spain, the levels of 19 mycotoxins in plasma samples from healthy and sick children (digestive, autism spectrum (ASD),...
In this study, we present, for the first time in Spain, the levels of 19 mycotoxins in plasma samples from healthy and sick children (digestive, autism spectrum (ASD), and attention deficit hyperactivity (ADHD) disorders) ( = 79, aged 2-16). The samples were analyzed by liquid chromatography-mass spectrometry (triple quadrupole) (LC-MS/MS). To detect Phase II metabolites, the samples were reanalyzed after pre-treatment with β-glucuronidase/arylsulfatase. The most prevalent mycotoxin was ochratoxin A (OTA) in all groups of children, before and after enzyme treatment. In healthy children, the incidence of OTA was 92.5% in both cases and higher than in sick children before (36.7% in digestive disorders, 50% in ASD, and 14.3% in ADHD) and also after the enzymatic treatment (76.6 % in digestive disorders, 50% in ASD, and 85.7% in ADHD). OTA levels increased in over 40% of healthy children after enzymatic treatment, and this increase in incidence and levels was also observed in all sick children. This suggests the presence of OTA conjugates in plasma. In addition, differences in OTA metabolism may be assumed. OTA levels are higher in healthy children, even after enzymatic treatment (mean OTA value for healthy children 3.29 ng/mL, 1.90 ng/mL for digestive disorders, 1.90 ng/mL for ASD, and 0.82 ng/mL for ADHD). Ochratoxin B appears only in the samples of healthy children with a low incidence (11.4%), always co-occurring with OTA. Sterigmatocystin (STER) was detected after enzymatic hydrolysis with a high incidence in all groups, especially in sick children (98.7% in healthy children and 100% in patients). This supports glucuronidation as a pathway for STER metabolism in children. Although other mycotoxins were studied (aflatoxins B1, B2, G1, G2, and M1; T-2 and HT-2 toxins; deoxynivalenol, deepoxy-deoxynivalenol, 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol; zearalenone; nivalenol; fusarenon-X; neosolaniol; and diacetoxyscirpenol), they were not detected either before or after enzymatic treatment in any of the groups of children. In conclusion, OTA and STER should be highly considered in the risk assessment of mycotoxins. Studies concerning their sources of exposure, toxicokinetics, and the relationship between plasma levels and toxic effects are of utmost importance in children.
Topics: Adolescent; Age Factors; Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Biological Monitoring; Biomarkers; Case-Control Studies; Child; Child, Preschool; Chromatography, Liquid; Digestive System Diseases; Female; Humans; Male; Metabolic Detoxication, Phase II; Mycotoxins; Ochratoxins; Risk Assessment; Spain; Spectrometry, Mass, Electrospray Ionization; Sterigmatocystin; Tandem Mass Spectrometry
PubMed: 33672088
DOI: 10.3390/toxins13020150 -
Toxins Sep 2023There is growing concern about the effects of mycotoxins on mammalian reproduction. Although the effects of single mycotoxins have been well documented, the impact of...
There is growing concern about the effects of mycotoxins on mammalian reproduction. Although the effects of single mycotoxins have been well documented, the impact of their mixtures on spermatozoon quality is less known. Here, frozen-thawed semen ( = 6 bulls) was in-vitro-cultured (2 h) without (control) or with (i) a single mycotoxin [zearalenone (ZEN), ochratoxin A (OTA), toxin 2 (T2), and diacetoxyscirpenol (DAS)] in a dose-response manner; (ii) binary mixtures (OTA + T2, OTA + ZEN, OTA + DAS, ZEN + T2, DAS + T2 and ZEN + DAS); or (iii) ternary mixtures (OTA + DAS + T2, OTA + ZEN + T2, and ZEN + DAS + T2). Then, the spermatozoa quality was characterized according to its plasma- and acrosome-membrane integrity, mitochondrial membrane potential, and oxidation status by a flow cytometer. Exposure to single mycotoxins or binary mixtures did not affect the spermatozoa characteristics. However, exposure to the ternary mixtures, OTA + DAS + T2 and OTA + ZEN + T2, reduced ( < 0.05) the mitochondrial membrane potential relative to the control. In addition, OTA + ZEN + T2 increased ( < 0.05) the proportion of spermatozoa with reactive oxygen species relative to the control. The most suggested interaction effect between the mycotoxins was found to be an additive one. A synergistic interaction, mainly regarding the oxidation status of the spermatozoa, was also found between the mycotoxins. The current study sheds light on the potential risk of exposing spermatozoa to a mycotoxin mixture.
Topics: Cattle; Animals; Male; Mycotoxins; Zearalenone; Spermatozoa; Membrane Potential, Mitochondrial; Plasma; Mammals
PubMed: 37755982
DOI: 10.3390/toxins15090556 -
Toxins Jun 2022Oat is susceptible to several Fusarium species that cause contamination with different trichothecene mycotoxins. The molecular mechanisms behind Fusarium resistance in...
Oat is susceptible to several Fusarium species that cause contamination with different trichothecene mycotoxins. The molecular mechanisms behind Fusarium resistance in oat have yet to be elucidated. In the present work, we identified and characterised two oat UDP-glucosyltransferases orthologous to barley HvUGT13248. Overexpression of the latter in wheat had been shown previously to increase resistance to deoxynivalenol (DON) and nivalenol (NIV) and to decrease disease the severity of both Fusarium head blight and Fusarium crown rot. Both oat genes are highly inducible by the application of DON and during infection with . Heterologous expression of these genes in a toxin-sensitive strain of conferred high levels of resistance to DON, NIV and HT-2 toxins, but not C4-acetylated trichothecenes (T-2, diacetoxyscirpenol). Recombinant enzymes AsUGT1 and AsUGT2 expressed in rapidly lost activity upon purification, but the treatment of whole cells with the toxin clearly demonstrated the ability to convert DON into DON-3-O-glucoside. The two UGTs could therefore play an important role in counteracting the Fusarium virulence factor DON in oat.
Topics: Avena; Fusarium; Glucosyltransferases; Mycotoxins; Plant Proteins; Trichothecenes; Uridine Diphosphate
PubMed: 35878183
DOI: 10.3390/toxins14070446 -
Toxins Jul 2021Exposure to environmental contaminants might play an important role in neurodegenerative disease pathogenesis, such as Parkinson´s disease (PD) and Alzheimer´s disease...
Exposure to environmental contaminants might play an important role in neurodegenerative disease pathogenesis, such as Parkinson´s disease (PD) and Alzheimer´s disease (AD). For the first time in Spain, the plasmatic levels of 19 mycotoxins from patients diagnosed with a neurodegenerative disease (44 PD and 24 AD) and from their healthy companions (25) from La Rioja region were analyzed. The studied mycotoxins were aflatoxins B1, B2, G1, G2 and M1, T-2 and HT-2, ochratoxins A (OTA) and B (OTB), zearalenone, sterigmatocystin (STER), nivalenol, deoxynivalenol, 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol, deepoxy-deoxynivalenol, neosolaniol, diacetoxyscirpenol and fusarenon-X. Samples were analyzed by LC-MS/MS before and after treatment with β-glucuronidase/arylsulfatase in order to detect potential metabolites. Only OTA, OTB and STER were detected in the samples. OTA was present before (77% of the samples) and after (89%) the enzymatic treatment, while OTB was only detectable before (13%). Statistically significant differences in OTA between healthy companions and patients were observed but the observed differences might seem more related to gender (OTA levels higher in men, -value = 0.0014) than the disease itself. STER appeared only after enzymatic treatment (88%). Statistical analysis on STER, showed distributions always different between healthy controls and patients (patients' group > controls, -value < 0.0001). Surprisingly, STER levels weakly correlated positively with age in women (rho = 0.3384), while OTA correlation showed a decrease of levels with age especially in the men with PD (rho = -0.4643).
Topics: Alzheimer Disease; Biological Monitoring; Chromatography, Liquid; Humans; Mycotoxins; Neurodegenerative Diseases; Ochratoxins; Parkinson Disease; Sterigmatocystin; Tandem Mass Spectrometry; Trichothecenes; Zearalenone
PubMed: 34357949
DOI: 10.3390/toxins13070477 -
Plant Disease Mar 2023Rice (Oryza sativa L.) panicle blight, caused by various fungal and bacterial pathogens, is an emerging threat to rice production, due to the impact on rice yield and...
Rice (Oryza sativa L.) panicle blight, caused by various fungal and bacterial pathogens, is an emerging threat to rice production, due to the impact on rice yield and quality. In the autumn of 2020, a survey was conducted to understand the etiology of the disease in Liaoning province, an important rice growing area in northeastern China. Rice seeds with typical reddish or brown spots on the glumes were collected from various rice fields. Symptomatic seeds were sterilized with 5% sodium hypochlorite and 75% ethanol, rinsed in sterile distilled water, and placed on potato dextrose agar (PDA) plates. After 3 to 5 days of incubation at 25°C, suspected Fusarium strains showing cream to salmon colonies on PDA were purified by the single-spore isolation method. The identification of these strains were performed based on morphological and molecular characteristics. Fusarium incarnatum-equiseti species complex was the most frequently, followed by the members of Fusarium graminearum species complex and Fusarium fujikuroi species complex. However, one strain was identified as F. sporotrichioides Sherb. based on the following results: (I) Colonies on PDA produced dense mycelia and typical red pigment on the undersurface. Macroconidia were usually 3- to 5-septate, moderately curved to straight, and 27.46 ± 7.16 × 3.78 ± 0.8 μm (n = 50). Microconidia were ellipsoid to fusoid and 9.77 ± 2.29 × 2.99 ± 0.65 μm (n = 50). (II) Genomic DNA was extracted by AxyPrep Multisource Genomic DNA Miniprep Kit according to the manufacturer's instructions; the sequence analysis of partial translation elongation factor-1α (TEF-1α) and RNA polymerase II second largest subunit (RPB2) were accomplished with the primers EF1/2 and RPB5F/7CR, respectively. BLAST searches of the obtained sequences had 99-100% homology with several F. sporotrichioides strains from GenBank. DNA sequences of partial TEF-1α and RPB2 were deposited in GenBank as OQ068267 and OQ068269, respectively. (III) This strain can synthesis T-2, HT-2, diacetoxyscirpenol (DAS), and Neosolaniol (NEO) toxin at the concentration of about 5000, 600, 700 and 8000 μg/kg in rice culture, respectively, according to the previous culture and analysis methods (1,2). (IV) Pathogenicity tests were conducted with the rice variety Nanjing 9108 by spraying spore suspension (106 conidia/ml) on rice spikes (5 mL per spike) at the flowering stage. Control spikes were inoculated with sterile distilled water. Three weeks after inoculation, the inoculated rice glumes showed similar symptoms with the original samples in the field. No symptoms were observed on controls. Besides, F. sporotrichioides was successfully recovered from the inoculated rice spikes but not from controls. To our knowledge, this is the first report of F. sporotrichioides causing rice panicle blight in China and this disease appears to be a serious risk to food safety and human health. Funding: This work was supported by Jiangsu Agriculture Science and Technology (CX(21)1005). References: (1) J. J. Mateo et al. Int. J. Food Microbiol. 72:115, 2002. (2) J. Qiu et al. Plant Dis. 104:2193, 2020.
PubMed: 36916843
DOI: 10.1094/PDIS-01-23-0018-PDN -
Toxins Aug 2022Studies on microorganism response spaceflight date back to 1960. However, nothing conclusive is known concerning the effects of spaceflight on virulence and...
Studies on microorganism response spaceflight date back to 1960. However, nothing conclusive is known concerning the effects of spaceflight on virulence and environmental tolerance of entomopathogenic fungi; thus, this area of research remains open to further exploration. In this study, the entomopathogenic fungus (strain SB010) was exposed to spaceflight (ChangZheng 5 space shuttle during 5 May 2020 to 8 May 2020) as a part of the Key Research and Development Program of Guangdong Province, China, in collaboration with the China Space Program. The study revealed significant differences between the secondary metabolite profiles of the wild isolate (SB010) and the spaceflight-exposed isolate (BHT021, BH030, BHT098) of . Some of the secondary metabolites/toxins, including enniatin A2, brevianamide F, macrosporin, aphidicolin, and diacetoxyscirpenol, were only produced by the spaceflight-exposed isolate (BHT021, BHT030). The study revealed increased insecticidal activities for of crude protein extracts of spaceflight mutants (BHT021 and BH030, respectively) against 5 days post application when compared crude protein extracts of the wild isolate (SB010). The data obtained support the idea of using space mutation as a tool for development/screening of fungal strains producing higher quantities of secondary metabolites, ultimately leading to increased toxicity/virulence against the target insect host.
Topics: Animals; Beauveria; China; Insecta; Space Flight; Virulence
PubMed: 36006216
DOI: 10.3390/toxins14080555 -
Journal of Dairy Science Jan 2018We surveyed the presence of 22 mycotoxins in 191 Spanish cow milk samples. Mycotoxins could be carried over from diet into animal milk and have toxic effects on human...
We surveyed the presence of 22 mycotoxins in 191 Spanish cow milk samples. Mycotoxins could be carried over from diet into animal milk and have toxic effects on human and animal health. The interaction of different mycotoxins may be additive or synergetic. Therefore, surveillance of mycotoxin co-occurrence in milk is recommended. Aflatoxins M, B, B, G, and G, ochratoxins A and B, nivalenol, deoxynivalenol, deepoxy-deoxynivalenol, 3- and 15-acetyldeoxynivalenol, diacetoxyscirpenol, neosolaniol, fusarenon X, T-2 and HT-2 toxins, fumonisins B, B, and B, sterigmatocystin, and zearalenone were analyzed. Samples were treated by liquid-liquid extraction with acidified acetonitrile, followed by an acetonitrile-water phase separation using sodium acetate. The analysis was carried out by HPLC coupled to a triple quadrupole mass spectrometer. None of the analyzed mycotoxins had a concentration level higher than their detection limit (0.05-10.1 µg/L). The aflatoxin M in the samples never exceeded the level established by the European Union.
Topics: Aflatoxin B1; Animals; Cattle; Chromatography, High Pressure Liquid; Female; Food Contamination; Fumonisins; Limit of Detection; Milk; Mycotoxins; Ochratoxins; Spain; T-2 Toxin; Tandem Mass Spectrometry; Trichothecenes; Zearalenone
PubMed: 29055539
DOI: 10.3168/jds.2017-13290 -
Toxicology and Applied Pharmacology Oct 1996Acute toxicity, absorption, excretion, and tissue distribution of topically administered diacetoxyscirpenol (DAS, anguidine) were studied in Fischer rats and CD-1 mice....
Acute toxicity, absorption, excretion, and tissue distribution of topically administered diacetoxyscirpenol (DAS, anguidine) were studied in Fischer rats and CD-1 mice. Mortality (75%) was observed in rats treated with a single dose of 2.625 mg of DAS to 1.44 cm2 of skin, whereas the proportionate (0.75 mg to 0.42 cm2 of skin) and even higher doses were not lethal to mice. Histopathological lesions induced in the rat were similar to those observed by administration through other routes, mainly involving lymphohematopoietic tissues and the gastrointestinal tract. Although lesions in internal organs were less severe, the skin of the mouse was more severely damaged at the application site than that of the rat. During the 90-min period after topical application of a single dose of [3H]DAS, the rat absorbed and retained more [3H]DAS and excreted less radioactivity through urine and feces than the mouse. By 24 hr after treatment, the rat had absorbed, excreted, and retained about twice as much [3H]DAS as had the mouse (p < 0.05 or < 0.005). At 7 days posttreatment, the rat had absorbed more than four times the amount of [3H]DAS than had the mouse (13.1 vs 57.5%; p < 0.005). However, tissues of the mouse retained a higher proportion of administered radioactivity (4.1%) than those of the rat (1.0%; p < 0.05). Total excretion of radiolabel by the rat was approximately sixfold higher than that of the mouse (56 to 9%; p < 0.005). The ratio of excretion in urine to that in feces in the rat was about 2 to 1 (37 to 18%) and in the mouse was about 3.5 to 1 (7 to 2%). Significant differences in the time course of tissue distribution of [3H]DAS in the rat and mouse were found when data were expressed as the percentage of absorbed dose present in tissues or as specific radioactivity (dpm) per gram tissue. These results demonstrated a significant interspecies difference in acute percutaneous toxicity of DAS and different patterns of absorption, excretion, and tissue distribution of topically administered [3H]DAS in rats and mice.
Topics: Absorption; Administration, Topical; Animals; Femur; Male; Mice; Mice, Inbred Strains; Mycotoxins; Organ Specificity; Rats; Rats, Inbred F344; Thymus Gland; Trichothecenes; Viscera
PubMed: 8887442
DOI: 10.1006/taap.1996.0221 -
Toxins May 2019Poland is one of Europe's leading producers and exporters of beer. The study, herein, describes the measurement of ochratoxin A, deoxynivalenol, nivalenol, T-2 toxin,...
Poland is one of Europe's leading producers and exporters of beer. The study, herein, describes the measurement of ochratoxin A, deoxynivalenol, nivalenol, T-2 toxin, HT-2 toxin, diacetoxyscirpenol, and zearalenone levels in 69 Polish beers. Analytical methodologies based on high performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) and fluorescence detection were developed, validated, and used to perform the above determinations. The most prevalent mycotoxins were deoxynivalenol (96%), ochratoxin A (93%), and HT-2 toxin (74%), respectively. Three quarters of the samples contained at least three analytes. The mean ochratoxin A concentration was 0.057 (SD 0.065) ng/mL, and in four beer samples its level exceeded 0.2 ng/mL, a value postulated in the literature to be the maximum limit. Deoxynivalenol was found at a maximum level of 56.2 ng/mL, and its mean concentration was 17.1 (SD 9.0) ng/mL. An evaluation of the estimated daily intake (EDI) of mycotoxins from beer in different European populations was made using food-consumption data prepared by WHO. Based on the mean ochratoxin A concentration in beers, the EDI represented 0.8-1.1% of the tolerable daily intake (TDI), while in a worst-case scenario (maximum concentration) it reached 5.0-7.5% of TDI. For deoxynivalenol, the EDI was in the range of 4.1-6.0% of TDI, whereas, based on maximum values, it reached the level of 14-21% of TDI. There were no significant differences between "scenarios" in the HT-2 case (mean-5.0-7.5% of TDI; maximum-6.5-9.7% of TDI) due to the fact that its concentration was near the limit of quantification (LOQ) value taken for calculation. The significance of these results are discussed, herein.
Topics: Adult; Beer; Dietary Exposure; Environmental Monitoring; Food Contamination; Humans; Mycotoxins; Poland; Risk Assessment
PubMed: 31067689
DOI: 10.3390/toxins11050254