Trichothecene mycotoxin deoxynivalenol (DON) negatively regulates immune response by damaging host immune system and harming the organism's health. We hypothesized that DON can initiate an active immunosuppressive mechanism similar to "immune evasion" to alter the cellular microenvironment and evade immune surveillance. We tested this hypothesis using the RAW264.7 macrophage model. DON rapidly increased the expression of immune checkpoints PD-1 and PD-L1, inflammatory cytokine TGF-β, and key immune evasion factors STAT3, VEGF, and TLR-4, and caused cellular hypoxia. Importantly, hypoxia-inducible factor-1α (HIF-1α) acts as a key regulator of DON-induced immunosuppression. HIF-1α accumulated in the cytoplasm and was gradually transferred to the nucleus following DON treatment. Moreover, DON activated HIF-1α through STAT3 signaling to upregulate downstream signaling, including PD-1/PD-L1. Under DON treatment, immunosuppressive miR-210-3p, lncRNA PVT1, lncRNA H19, and lncRNA HOTAIR were upregulated by the STAT3/HIF-1α axis. Moreover, DON damaged mitochondrial function, causing mitophagy, and suppressed immune defenses. Collectively, DON triggered RAW264.7 intracellular hypoxia and rapidly activated HIF-1α via STAT3 signaling, activating immune evasion signals, miRNAs, and lncRNAs, thereby initiating the key link of immune evasion. This study offers further clues for accurate prevention and treatment of immune diseases caused by mycotoxins.
This study was to evaluate the efficacy of TOXO-XL (XL), an integrated mycotoxin-mitigating agent, on aflatoxin B1 (AFB1)-induced damage in Leghorn male hepatoma (LMH), porcine jejunum epithelial cell line (IPEC-J2) and porcine alveolar macrophages (3D4/21) cells, and to explore its potential mechanisms. The results showed that 30% inhibition concentration (IC30) of AFB1 in LMH, IPEC-J2 and 3D4/21 cells was 0.5, 15.0, and 2.5 mg/L, respectively. Notably, cell viability, ROS, apoptosis and DNA lesion induced by AFB1 (IC30) could be ameliorated by the supplementation with XL at the dosage of 0.025, 0.025 and 0.005%, respectively. Additionally, the migration and phagocytosis abilities impaired by AFB1 were also restored by XL in 3D4/21. Further experiments revealed that XL supplementation markedly attenuated AFB1-induced inflammatory response by decreasing IL-1β, IL-6 and IL-10 in LMH, IL-6 in IPEC-J2 and IL-1β in 3D4/21 cells. Meanwhile, XL supplementation reversed the alterations of BAX, BCL-2 and caspase-3 induced by AFB1 in the three cells, suggesting that AFB1-induced apoptosis may be suppressed via the mitochondria-dependent pathway. Furthermore, XL may have a protective effect on the intestinal barrier through the restoration of occludin protein. Conclusively, these findings indicated that XL could alleviate AFB1-induced cytotoxicity in the three cells, potentially through the regulation of cytokines, ROS, apoptotic and DNA damage signaling.
- MeSH
- aflatoxin B1 toxicita metabolismus MeSH
- apoptóza MeSH
- epitelové buňky MeSH
- hepatocelulární karcinom * metabolismus MeSH
- interleukin-6 metabolismus MeSH
- kur domácí metabolismus MeSH
- nádory jater * metabolismus MeSH
- prasata MeSH
- reaktivní formy kyslíku metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The type B trichothecenes pollute food crops and have been associated to alimentary toxicosis resulted in emetic reaction in human and animal. This group of mycotoxins consists deoxynivalenol (DON) and four structurally related congeners: 3-acetyl-deoxynivalenol (3-ADON), 15-acetyl deoxynivalenol (15-ADON), nivalenol (NIV) and 4-acetyl-nivalenol (fusarenon X, FX). While emesis induced by intraperitoneally dosed to DON in the mink has been related to plasma up-grading of 5-hydroxytryptamine (5-HT) and neurotransmitters peptide YY (PYY), the impact of oral dosing with DON or its four congeners on secretion of these chemical substances have not been established. The aim of this work was to contraste emetic influence to type B trichothecene mycotoxins by orally dosing and involve these influence to PYY and 5-HT. All five toxins attracted marked emetic reaction that are relevant to elevated PYY and 5-HT. The reduction in vomiting induced by the five toxins and PYY was due to blocking of the neuropeptide Y2 receptor. The inhibition of the induced vomiting response by 5-HT and all five toxins is regulated by the 5-HT3 receptor inhibitor granisetron. In a word, our results indicate that PYY and 5-HT take a key role in the emetic reaction evoked by type B trichothecenes.
- MeSH
- emetika škodlivé účinky MeSH
- lidé MeSH
- mykotoxiny * škodlivé účinky MeSH
- norek MeSH
- peptid YY MeSH
- serotonin MeSH
- trichotheceny typu B * škodlivé účinky MeSH
- trichotheceny * toxicita MeSH
- zvířata MeSH
- zvracení chemicky indukované MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Synthetic food colorants are extensively used across the globe regardless of the fact that they induce deleterious side effects when used in higher amounts. In this work, a novel electrochemical sensor based on nickel nanoparticles doped lettuce-like Co3O4 anchored graphene oxide (GO) nanosheets was developed for effective detection of sulfonated azo dye sunset yellow widely used as a food colorant. Hydrothermal synthesis was adopted for the preparation of lettuce-like spinel Co3O4 nanoparticles and Ni-Co3O4 NPs/GO nanocomposite was prepared using ecofriendly and economical sonochemical method. The prepared ternary nanocomposite meticulously fabricated on a screen-printed carbon electrode exhibited remarkable electrocatalytic activity towards sunset yellow determination. This is apparent from the resultant well-defined and intense redox peak currents of Ni-Co3O4 NPs/GO nanocomposite modified electrode at very low potentials. The developed sunset yellow sensor exhibited a high sensitivity of 4.16 μA μM-1 cm-2 and a nanomolar detection limit of 0.9 nM in the linear range 0.125-108.5 μM. Furthermore, experiments were conducted to affirm excellent stability, reproducibility, repeatability, and selectivity of proposed sensor. The practicality of sunset yellow determination using the developed sensor was analyzed in different varieties of food samples including jelly, soft drink, ice cream, and candy resulting in recovery in the range of 96.16%-102.56%.
- MeSH
- azosloučeniny analýza MeSH
- elektrochemické techniky metody MeSH
- grafit MeSH
- kobalt chemie MeSH
- kovové nanočástice chemie MeSH
- limita detekce MeSH
- lineární modely MeSH
- nanokompozity chemie MeSH
- nikl chemie MeSH
- oxid hlinitý chemie MeSH
- oxid hořečnatý chemie MeSH
- oxidy chemie MeSH
- potravinářská barviva analýza MeSH
- reprodukovatelnost výsledků MeSH
- Publikační typ
- časopisecké články MeSH
Melanins belong to a group of pigments of different structure and origin. They can be produced synthetically or isolated from living organisms. A number of studies have reported testing of various melanins in neurological studies providing different outcomes. Because the structure of melanins can have an effect on obtained results in cell toxicity studies, we present here our original study which aimed to compare the biological effects of bacterial melanin (biotechnologically obtained from B. thuringiensis) with that of synthetic melanin in neuroblastoma cells. Both melanins were structurally characterized in detail. After melanin treatment (0-200 μg/mL), cell viability, glutathione levels, cell morphology and respiration were assessed in SH-SY5Y cells. The structural analysis showed that bacterial melanin is more hydrophilic according to the presence of larger number of -OH moieties. After melanin treatment, we found that synthetic melanin at similar dosage caused always larger cell impairment compared to bacterial melanin. In addition, more severe toxic effect of synthetic melanin was found in mitochondria. In general, we conclude that more hydrophilic, bacterial melanin induced lower toxicity in neuroblastoma cells in comparison to synthetic melanin. Our findings can be useable for neuroscientific studies estimating the potential use for study of neuroprotection, neuromodulation or neurotoxicity.
- MeSH
- Bacteria MeSH
- glutathion MeSH
- lidé MeSH
- melaniny * MeSH
- mitochondrie MeSH
- neuroblastom * farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
Oxime reactivators are causal antidotes for organophosphate intoxication. Herein, the toxicity, pharmacokinetics, and reactivation effectiveness of o-chlorinated bispyridinium oxime K870 are reported. Oxime K870 was found to have a safe profile at a dose of 30 mg/kg in rats. It exhibited rapid absorption and renal clearance similar to those of other charged oximes after intramuscular administration. Its isoxazole-pyridinium degradation product was identified in vivo. Although it showed some improvement in brain targeting, it was nevertheless rapidly effluxed from the central nervous system. Its reactivation effectiveness was evaluated in rats and mice intoxicated with sarin, tabun, VX, and paraoxon and compared with pralidoxime and asoxime. K870 was found to be less effective in reversing tabun poisoning compared to its parent unchlorinated oxime K203. However, K870 efficiently reactivated blood acetylcholinesterase for all tested organophosphates in rats. In addition, K870 significantly protected against intoxication by all tested organophosphates in mice. For these reasons, oxime K870 seems to have a broader reactivation spectrum against multiple organophosphates. It seems important to properly modulate the oximate forming properties (pKa) to obtain more versatile oxime reactivators.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- antidota MeSH
- cholinesterasové inhibitory metabolismus toxicita MeSH
- krysa rodu rattus MeSH
- myši MeSH
- organofosfáty MeSH
- oximy * MeSH
- pyridinové sloučeniny toxicita MeSH
- reaktivátory cholinesterázy * terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The nerve agents of the A-series are relatively recent chemical weapons with no antidote available yet. Once inside the human body, those chemicals act similarly to the classic nerve agents, by binding to the catalytic residue Serine 203 (Ser203) of human acetylcholinesterase (HssAChE) and thus preventing the proper function of this enzyme. However, there is no experimental evidence yet if the current antidotes for intoxication by nerve agents are also capable of restoring AChE inhibited by the nerve agents of the A-series. In order to launch some light on this issue, we used computational techniques (molecular docking, molecular dynamics and MM-PBSA interaction energy calculations) to assess the performances of the four currently available commercial oximes (2-PAM, HI-6, obidoxime and trimedoxime) when in contact with HssAChE inhibited by the agent A-242. Based on the near-attack conformation (NAC) criterion, our results suggest that the commercial oximes would have limited efficacy to reactivate the enzyme since they are not able to properly approach the adduct Ser203-A-242. Among those oximes, trimedoxime seems to be the most promising, since it showed lower values of energy in the MM-PBSA calculations, a higher stability inside the catalytic anionic center (CAS) of HssAChE, and was able to adopt a position closer to the NAC that could enable the reactivation mechanism.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- antidota farmakologie MeSH
- cholinesterasové inhibitory chemie toxicita MeSH
- lidé MeSH
- nervová bojová látka * toxicita MeSH
- organofosfáty MeSH
- oximy chemie farmakologie MeSH
- pyridinové sloučeniny farmakologie MeSH
- reaktivátory cholinesterázy * farmakologie MeSH
- simulace molekulového dockingu MeSH
- trimedoxim farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The mycotoxin zearalenone (ZEA) in food and feed seriously harms human and animal health. How to reduce its toxicity is an important direction of current research on food safety. This study aim to assess the effects of procyanidins (PC) on cell apoptosis caused by ZEA and to clarify the role of Nrf2 in the process. Swine testicle (ST) cells were treated with ZEA (57.5 μmol/L) and/or PC (10 mg/L) for 24 h. Cell viability was detected by CCK-8 assay. Cell apoptosis and the level of ROS were detected by flow cytometry. The expression levels of mRNA and protein was detected by qRT-PCR and western blotting. Our results showed that ZEA reduced the antioxidant capacity of the ST cells, induced the cell apoptosis and inhibited the gene and protein expression of Nrf2 and its downstream genes (ho-1,nqo1), while PC improved the cell antioxidant capacity, reduced the degree of ZEA-induced cell apoptosis and promoted the gene and protein expression of Nrf2 and its downstream genes. However, when the Nrf2 small molecule inhibitor ML385 was added, the ability of PC to inhibit ZEA-induced cell apoptosis and promote the expression of Nrf2 and its downstream genes were decreased. Our results demonstrated that ZEA induced oxidative stress and apoptosis of ST cells, which were alleviated by PC intervention via activating Nrf2 signaling pathway. This finding of this study provided a molecular basis for the clinical application of PC to prevent ZEN-caused reproductive toxicity.
- MeSH
- antioxidancia metabolismus farmakologie MeSH
- apoptóza MeSH
- faktor 2 související s NF-E2 genetika metabolismus MeSH
- oxidační stres MeSH
- prasata MeSH
- proantokyanidiny * farmakologie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- signální transdukce MeSH
- testis metabolismus MeSH
- zearalenon * metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The frequencies of adverse outcomes associated with male reproductive health, including infertility and testicular cancer, are increasing. These adverse trends are partially attributed to increased exposure to environmental agents such as endocrine-disrupting chemicals (EDCs). This study addresses effects on EDCs on adjacent prepubertal Sertoli TM4 cells, specifically on 1) testicular gap junctional intercellular communication (GJIC), one of the hallmarks of non-genotoxic carcinogenicity, 2) GJIC building blocks connexins (Cx), and 3) mitogen-activated protein kinases MAPKs. We selected eight representatives of EDCs: organochlorine chemicals such as pesticides dichlorodiphenyltrichloroethane, lindane, methoxychlor, and vinclozolin, industrial chemicals bisphenol A and 2,2',4,4',5,5'-hexachlorobiphenyl, and components of personal care products, triclocarban and triclosan. EDCs rapidly dysregulated GJIC in Sertoli TM4 cells mainly via MAPK p38 and/or Erk1/2 pathways by the intermediate hyper- or de-phosphorylation of Cx43 (Ser368, Ser282) and translocation of Cx43 from the plasma membrane, suggesting disturbed intracellular trafficking of Cx43 protein. Surprisingly, EDCs did not rapidly activate MAPK Erk1/2 or p38; on the contrary, TCC and TCS decreased their activity (phosphorylation). Our results indicate that EDCs might disrupt testicular homeostasis and development via testicular GJIC, junctional and non-junctional functions of Cx43 and MAPK-signaling pathways in Sertoli cells.
Ochratoxin A (OTA) exposure can result in chronic renal diseases and cancer. The incidence of kidney, renal pelvis, and ureter malignant neoplasms in the Czech Republic is approximately 29.5 renal tumours per 100,000 inhabitants. The question arises whether mycotoxins are also involved in kidney disease and cancer. A sensitive validated analytical methodology, based on an immunoaffinity clean-up followed by HPLC with fluorescence detection, was developed to explore whether OTA accumulates in clear renal cell carcinoma-adenocarcinoma in Czech patients. Simultaneously, DNA-adducts and OTA metabolites were qualitatively analysed in tissues and urine. OTA was analysed in 33 kidney and tumour samples from 26 men and 7 women collected during nephrectomy from patients of the East Bohemian region from 2015 to 2017. OTA was found in 76% of the analysed samples. Its concentrations ranged from not detectable to 390 ng/kg with a median of 167 ng/kg in kidney samples and from not detectable to 430 ng/kg with a median of 122 ng/kg in tumour samples. Urinary OTA metabolites and DNA adducts were qualitatively analysed for the corresponding 20 patients. The presence of some OTA metabolites such as ochratoxin A hydroquinone and/or decarboxylated ochratoxin A hydroquinone correlate with the presence of OTA-DNA adducts.
- MeSH
- adukty DNA MeSH
- karcinom z renálních buněk * metabolismus patologie MeSH
- ledviny metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery analýza MeSH
- nádory ledvin * metabolismus patologie MeSH
- ochratoxiny analýza MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
