Days ago, the Nobel Prize in Physiology or Medicine 2018 was awarded jointly to James P. Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation". This news has increased the attention on immunotoxicity and immune evasion mechanisms, which are once again hot research topics. Actually, increasing lines of evidence show that trichothecene mycotoxins have a strong immunosuppressive effect. These mycotoxins suppress the host immunity and make them more sensitive to the infection of pathogens, including bacteria and viruses. However, the underlying mechanism(s) in this context is still poorly understood. Interestingly, recent work showed that an immune evasion mechanism might be involved in trichothecene immunotoxicity. In this work, we discuss the potential immune evasion mechanism in trichothecene immunotoxicity. More importantly, under these circumstances, we are pleased to compile a Special Issue entitled "Biochemistry, Molecular Biology, and Toxicology of Natural and Synthetic Toxins" for the International Journal of Molecular Sciences (IJMS). Researchers are encouraged to share their latest interesting findings with the readers of IJMS.

• Klíčová slova
• T-2 toxin, immune evasion, immunotoxicity, negative immune regulations, trichothecenes,
• MeSH
• imunitní únik * MeSH
• imunosupresiva farmakologie   terapeutické užití   MeSH
• lidé MeSH
• trichotheceny farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• úvodní články MeSH
• úvodníky MeSH
• Názvy látek
• imunosupresiva MeSH
• trichotheceny MeSH

BACKGROUND: Immunotherapy by using immune checkpoint inhibitors (ICIs) heralded a new era in the treatment of patients with advanced triple-negative breast cancer (TNBC). Nevertheless, in a substantial proportion of TNBC patients, the clinical outcomes of ICIs treatment remain unpredict-able and proper bio-markers to identify tumors sensitive to immunotherapy are urgently needed. Currently, the most clinically relevant bio-markers used to predict efficacy of ICIs in patients with advanced TNBC remain the immunohistochemical analysis of programmed death-ligand 1 (PD-L1) expression, the assessment of tumor infiltrating lymphocytes (TILs) present in the tumor microenvironment (TME), and the evaluation of the tumor mutational burden (TMB). Emerging bio-markers related to activation of the transforming growth factor beta signaling pathway, the discoidin domain receptor 1, and thrombospondin-1 as well as other cellular and molecular factors present within TME, have the potential to be utilized as predictors of response to ICIs in the future. PURPOSE: In this review, we summarize the current knowledge of mechanisms regulating PD-L1 expression, of the predictive value of TILs as well as of associated cellular and molecular components present in the TME in TNBC. Furthermore, TMB and emerging bio-markers with potential value in predicting efficacy of ICIs are discussed, and new therapeutic strategies will be outlined.

• Klíčová slova
• immunotherapy, programmed death-ligand 1, triple-negative breast cancer, tumor infiltrating lymphocytes, tumor mutational burden, tumour infiltrating lymphocytes,
• MeSH
• antigeny CD274 MeSH
• biologické markery MeSH
• imunoterapie MeSH
• inhibitory kontrolních bodů MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• triple-negativní karcinom prsu * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antigeny CD274 MeSH
• biologické markery MeSH
• inhibitory kontrolních bodů MeSH

• MeSH
• hypoxie MeSH
• kontaminace léku MeSH
• kontaminace potravin analýza   MeSH
• lidé MeSH
• mykotoxiny * toxicita   analýza   MeSH
• stárnutí buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• úvodníky MeSH
• Názvy látek
• mykotoxiny * MeSH

Innate immune surveillance in the blood is executed mostly by circulating monocytes, which recognise conserved bacterial molecules such as peptidoglycan and lipopolysaccharide. Toll-like receptors (TLR) play a central role in microbe-associated molecular pattern detection. Here, we compared the differences in TLR expression and cytokine production after stimulation of peripheral blood cells with heat-killed Gram-negative and Gram-positive human pathogens Neisseria meningitidis, Escherichia coli, Staphylococcus aureus and Streptococcus pneumoniae. We found that TLR2 expression is up-regulated on monocytes after stimulation with S. aureus, S. pneumoniae, E. coli and N. meningitidis. Moreover, TLR2 up-regulation was positively associated with increasing concentrations of Gram-positive bacteria, whereas higher concentrations of Gram-negative bacteria, especially E. coli, caused a milder TLR2 expression increase compared with low doses. Cytokines were produced in similar dose-dependent profiles regardless of the stimulatory pathogen; however, Gram-negative pathogens induced higher cytokine levels than Gram-positive ones at same concentrations. These results indicate that Gram-positive and Gram-negative bacteria differ in their dose-dependent patterns of induction of TLR2 and TLR4, but not in cytokine expression.

• MeSH
• aktivace transkripce MeSH
• cytokiny biosyntéza   MeSH
• gramnegativní bakterie genetika   imunologie   MeSH
• grampozitivní bakterie genetika   imunologie   MeSH
• lidé MeSH
• monocyty imunologie   MeSH
• přirozená imunita MeSH
• regulace genové exprese MeSH
• signální transdukce imunologie   MeSH
• toll-like receptor 2 biosyntéza   genetika   imunologie   MeSH
• toll-like receptor 4 biosyntéza   genetika   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• toll-like receptor 2 MeSH
• toll-like receptor 4 MeSH

BACKGROUND/AIM: Triple-negative breast cancer (TNBC) constitutes 15-20% of all breast carcinomas, affecting younger women more often and has a worse prognosis than other types of breast cancer, due to the combination of more aggressive clinical behavior and lack of molecular targets for therapy. This study assessed the effects of non-genotoxic concentrations of tributyltin isothiocyanate (TBT-ITC) and triphenyltin isothiocyanate (TPT-ITC) on MDA-MB-231 cells. MATERIALS AND METHODS: MTT assay, comet assay, kinetic imaging and flow cytometry were used for analysis of MDA-MB-231 cells. RESULTS: The results showed that 100 nM concentration of TBT-ITC and TPT-ITC, that did not affect viability or DNA integrity, slowed-down migration by CD44 down-regulation. Moreover, both compounds demonstrated immunomodulatory properties, attenuating PD-L1 expression in MDA-MB-231 cells. CONCLUSION: TPT-ITC was more effective in down-regulating CD44 expression and reducing migration than TBT-ITC, while TBT-ITC was more potent in lowering PD-L1 expression in comparison with TPT-ITC.

• Klíčová slova
• DNA damage, Triorganotin isothiocyanate derivatives, breast cancer, immunomodulation, migration, nuclear retinoid X receptor, surface adhesive molecules,
• MeSH
• antitumorózní látky chemie   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• imunofenotypizace MeSH
• isothiokyanatany chemie   farmakologie   MeSH
• lidé MeSH
• nádorové biomarkery * MeSH
• nádorové buněčné linie MeSH
• organocínové sloučeniny chemie   MeSH
• pohyb buněk účinky léků   MeSH
• poškození DNA účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• triple-negativní karcinom prsu metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky MeSH
• isothiokyanatany MeSH
• nádorové biomarkery * MeSH
• organocínové sloučeniny MeSH
• triphenyltin MeSH Prohlížeč

• MeSH
• imunita rostlin * MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• signální transdukce MeSH
• zpětná vazba fyziologická * MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• reaktivní formy kyslíku MeSH

The tube-within-tube body plan of earthworms is appropriate for studying the interactions of microorganisms with the immune system of body cavities such as the digestive tract and coelom. This study aims to describe the immune response on the molecular and cellular level in the coelomic cavity and the gut of the earthworm Eisenia andrei after experimental microbial challenge by administering two bacterial strains (Escherichia coli and Bacillus subtilis) or yeast Saccharomyces cerevisiae to the environment. The changes in mRNA levels of defense molecules (pattern recognition receptor CCF, lysozyme, fetidin/lysenins) in the coelomocytes and gut tissue were determined by quantitative PCR. The immune response at a cellular level was captured in histological sections, and the expression of CCF was localized using in situ hybridization. Coelomocytes respond to the presence of bacteria in the coelomic cavity by increasing the mRNA levels of defense molecules, especially CCF. The immune response in gut tissue is less affected by microbial stimulation because the epithelial cells of gut exhibit basically strong mRNA synthesis of ccf as a defense against the continuous microbial load in the gut lumen. The cellular immune response is mediated by coelomocytes released from the mesenchymal lining of the coelomic cavity. These combined immune mechanisms are necessary for the survival of earthworms in the microbially rich environment of soil.

• Klíčová slova
• CCF, Coelomocyte, Earthworm, Microorganism, Mucosal immunity,
• MeSH
• Bacillus subtilis imunologie   MeSH
• buněčná imunita MeSH
• Escherichia coli imunologie   MeSH
• gramnegativní bakteriální infekce imunologie   MeSH
• grampozitivní bakteriální infekce imunologie   MeSH
• lektiny genetika   metabolismus   MeSH
• mezoderm imunologie   patologie   MeSH
• mykózy imunologie   MeSH
• Oligochaeta imunologie   MeSH
• receptory rozpoznávající vzory genetika   metabolismus   MeSH
• Saccharomyces imunologie   MeSH
• slizniční imunita MeSH
• střevní sliznice imunologie   mikrobiologie   virologie   MeSH
• upregulace MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• coelomic cytolytic factor 1, Eisenia fetida MeSH Prohlížeč
• lektiny MeSH
• receptory rozpoznávající vzory MeSH

Trichothecene mycotoxins have a strong immunosuppressive effect, which may even escape host immune surveillance and damage the immune repair to show an "immune evasion" effect. Increasing lines of evidence have shown that hypoxia and hypoxia-inducible factors (HIFs) are key mediators of trichothecenes, and these toxins appear to be closely related to the "immune evasion" mechanisms. Therefore, we used RAW264.7 cell model to explore the association of T-2 toxins with "immune evasion" process and hypoxia, as well as their cross-linking effects induced by T-2 toxin. Our results showed that HIF-1α is an important toxicity target of T-2 toxin, which could induce intracellular hypoxia. T-2 toxin induced an "immune evasion" process by activating the PD-1/PD-L1 signaling pathway. Interestingly, when HIF-1α activation was blocked, the "immune evasion" process regulated by PD-1/PD-L1 signaling was activated, resulting in the cells damage, suggesting that hypoxia induced by T-2 toxin plays a protective role for RAW264.7 cell damage. Thus, our work shows that HIF-1α inhibits T-2 toxin-mediated "immune evasion" process by negatively regulating PD-1/PD-L1signaling. This study contributes to a better understanding of the immunotoxicity mechanism of trichothecenes.

• Klíčová slova
• HIF-1α, Hypoxia, Immune evasion, PD-1/PD-L1, T-2 toxin,
• MeSH
• antigeny CD274 metabolismus   MeSH
• antigeny CD279 metabolismus   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa farmakologie   MeSH
• hypoxie MeSH
• lidé MeSH
• T-2 toxin * toxicita   MeSH
• trichotheceny * toxicita   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD274 MeSH
• antigeny CD279 MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• T-2 toxin * MeSH
• trichotheceny * MeSH

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.

• Klíčová slova
• Deoxynivalenol, HIF-1, Immune evasion, STAT3, lncRNA,
• MeSH
• antigeny CD274 * metabolismus   MeSH
• antigeny CD279 MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus   MeSH
• imunita MeSH
• nádorové buněčné linie MeSH
• RNA dlouhá nekódující * MeSH
• transkripční faktor STAT3 metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD274 * MeSH
• antigeny CD279 MeSH
• deoxynivalenol MeSH Prohlížeč
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• RNA dlouhá nekódující * MeSH
• transkripční faktor STAT3 MeSH

Innate immune surveillance in the blood is executed mostly by circulating monocytes, which recognize conserved bacterial molecules such as peptidoglycan and lipopolysaccharide. Toll-like receptors (TLR) play a central role in microbe-associated molecular pattern detection. The aim of this study was to compare the differences in TLR expression and cytokine production after stimulation of peripheral blood cells with heat-killed gram-negative and gram-positive human pathogens: Neisseria meningitidis, Escherichia coli, Staphylococcus aureus, and Streptococcus pneumoniae. We found that TLR2 expression is up-regulated on monocytes after stimulation with S. aureus, S. pneumoniae, E. coli, and N. meningitidis. Moreover, TLR2 up-regulation was positively associated with increasing concentrations of gram-positive bacteria, whereas higher concentrations of gram-negative bacteria, especially E. coli, caused a milder TLR2 expression increase when compared to low doses. Cytokines were produced in similar dose-dependent profiles regardless of the stimulatory pathogen; however, gram-negative pathogens induced higher cytokine levels when compared to gram-positive bacteria at the same density. These results indicate that gram-positive and gram-negative bacteria differ in their dose-dependent patterns of induction of TLR2 and TLR4, but not cytokine expression.

• MeSH
• cytokiny metabolismus   MeSH
• gramnegativní bakterie imunologie   MeSH
• grampozitivní bakterie imunologie   MeSH
• kultivované buňky MeSH
• leukocyty mononukleární imunologie   MeSH
• lidé MeSH
• toll-like receptor 2 biosyntéza   MeSH
• toll-like receptor 4 biosyntéza   MeSH
• vysoká teplota * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• TLR2 protein, human MeSH Prohlížeč
• TLR4 protein, human MeSH Prohlížeč
• toll-like receptor 2 MeSH
• toll-like receptor 4 MeSH