The toxic mechanisms of trichothecenes, including T-2 toxin and deoxynivalenol (DON), are closely related with their effects on protein synthesis. Increasing lines of evidence show that T-2 toxin can reduce the levels of tight junction proteins, and nuclear factor erythroid 2-related factor 2 (Nrf2) by disrupting cellular barriers and the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) and Nrf2/heme oxygenase (HO)-1 pathways. Moreover, it can inhibit aggrecan synthesis, thus causing Kashin-Beck disease. Regarding type B trichothecene, DON inhibits activation marker and β-catenin synthesis by acting on immune cells and the wingless/integrated (Wnt) pathway; it also inhibits cell proliferation and immune surveillance. In addition, DON has been shown to destroy tight junctions, glucose transport, and tumor endothelial marker 8, thus disturbing intestinal function and changing cell migration. This review summarizes the inhibitory effects of the trichothecenes T-2 toxin and DON on different protein synthesis, while discussing their underlying mechanisms. Focus is given to the effects of these toxins on tight junctions, aggrecan, activation markers, and hormones including testosterone under the influence of steroidogenic enzymes. This review can extend the current understanding of the effects of trichothecenes on protein synthesis and help to further understand their toxic mechanisms.

• Klíčová slova
• Deoxynivalenol, Inhibition, Protein synthesis, T-2 toxin, Toxic mechanism,
• MeSH
• agrekany MeSH
• faktor 2 související s NF-E2 MeSH
• T-2 toxin * toxicita   MeSH
• trichotheceny * toxicita   MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• agrekany MeSH
• deoxynivalenol MeSH Prohlížeč
• faktor 2 související s NF-E2 MeSH
• T-2 toxin * MeSH
• trichotheceny * MeSH

Significance: Nuclear factor erythroid 2 (NFE2)-related factor 2 (NFE2L2, or NRF2) is a transcription factor predominantly affecting the expression of antioxidant genes. NRF2 plays a significant role in the control of redox balance, which is crucial in cancer cells. NRF2 activation regulates numerous cancer hallmarks, including metabolism, cancer stem cell characteristics, tumor aggressiveness, invasion, and metastasis formation. We review the molecular characteristics of the NRF2 pathway and discuss its interactions with the cancer hallmarks previously listed. Recent Advances: The noncanonical activation of NRF2 was recently discovered, and members of this pathway are involved in carcinogenesis. Further, cancer-related changes (e.g., metabolic flexibility) that support cancer progression were found to be redox- and NRF2 dependent. Critical Issues: NRF2 undergoes Janus-faced behavior in cancers. The pro- or antineoplastic effects of NRF2 are context dependent and essentially based on the specific molecular characteristics of the cancer in question. Therefore, systematic investigation of NRF2 signaling is necessary to clarify its role in cancer etiology. The biggest challenge in the NRF2 field is to determine which cancers can be targeted for better clinical outcomes. Further, large-scale genomic and transcriptomic studies are missing to correlate the clinical outcome with the activity of the NRF2 system. Future Directions: To exploit NRF2 in a clinical setting in the future, the druggable members of the NRF2 pathway should be identified. In addition, it will be important to study how the modulation of the NRF2 system interferes with cytostatic drugs and their combinations.

• Klíčová slova
• NRF2, breast cancer, cancer, cancer metabolism, reactive species,
• MeSH
• antioxidancia metabolismus   MeSH
• energetický metabolismus * MeSH
• epigeneze genetická MeSH
• faktor 2 související s NF-E2 genetika   metabolismus   MeSH
• hormony metabolismus   MeSH
• lidé MeSH
• metabolické sítě a dráhy * MeSH
• mikro RNA genetika   MeSH
• mutace MeSH
• nádorové biomarkery MeSH
• nádorové kmenové buňky metabolismus   MeSH
• nádory etiologie   metabolismus   patologie   MeSH
• oxidace-redukce MeSH
• oxidační stres MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• signální dráha UPR MeSH
• signální transdukce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antioxidancia MeSH
• faktor 2 související s NF-E2 MeSH
• hormony MeSH
• mikro RNA MeSH
• nádorové biomarkery MeSH
• NFE2L2 protein, human MeSH Prohlížeč

Anthracycline anticancer drugs (e.g., doxorubicin or daunorubicin) can induce chronic cardiotoxicity and heart failure (HF), both of which are believed to be based on oxidative injury and mitochondrial damage. In this study, molecular and functional changes induced by chronic anthracycline treatment with progression into HF in post-treatment follow-up were analyzed with special emphasis on nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) pathways. Chronic cardiotoxicity was induced in rabbits with daunorubicin (3 mg/kg, weekly for 10 weeks), and the animals were followed for another 10 weeks. Echocardiography revealed a significant drop in left ventricular (LV) systolic function during the treatment with marked progression to LV dilation and congestive HF in the follow-up. Although daunorubicin-induced LV lipoperoxidation was found, it was only loosely associated with cardiac performance. Furthermore, although LV oxidized glutathione content was increased, the oxidized-to-reduced glutathione ratio itself remained unchanged. Neither Nrf2, the master regulator of antioxidant response, nor the majority of its target genes showed up-regulation in the study. However, down-regulation of manganese superoxide dismutase and NAD(P)H dehydrogenase [quinone] 1 were observed together with heme oxygenase 1 up-regulation. Although marked perturbations in mitochondrial functions were found, no induction of PGC1α-controlled mitochondrial biogenesis pathway was revealed. Instead, especially in the post-treatment period, an impaired regulation of this pathway was observed along with down-regulation of the expression of mitochondrial genes. These results imply that global oxidative stress need not be a factor responsible for the development of anthracycline-induced HF, whereas suppression of mitochondrial biogenesis might be involved.

• MeSH
• antracykliny toxicita   MeSH
• buněčné jádro účinky léků   metabolismus   MeSH
• daunomycin farmakologie   MeSH
• echokardiografie MeSH
• faktor 2 související s NF-E2 biosyntéza   MeSH
• funkční vyšetření srdce MeSH
• glutathion metabolismus   MeSH
• králíci MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• myokard patologie   MeSH
• nemoci srdce chemicky indukované   metabolismus   MeSH
• oxidační stres účinky léků   MeSH
• peroxidace lipidů účinky léků   MeSH
• přežití MeSH
• protinádorová antibiotika toxicita   MeSH
• srdeční komory účinky léků   metabolismus   MeSH
• srdeční mitochondrie účinky léků   metabolismus   MeSH
• transkripční faktory metabolismus   MeSH
• troponin T metabolismus   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antracykliny MeSH
• daunomycin MeSH
• faktor 2 související s NF-E2 MeSH
• glutathion MeSH
• peroxisome-proliferator-activated receptor-gamma coactivator-1 MeSH Prohlížeč
• protinádorová antibiotika MeSH
• transkripční faktory MeSH
• troponin T MeSH

NF-E2-related factor 2 (NRF2) is a basic leucine zipper transcription factor, a master regulator of redox homeostasis regulating a variety of genes for antioxidant and detoxification enzymes. NRF2 was, therefore, initially thought to protect the liver from oxidative stress. Recent studies, however, have revealed that mutations in NRF2 cause aberrant accumulation of NRF2 in the nucleus and exert the upregulation of NRF2 target genes. Moreover, among all molecular changes in hepatocellular carcinoma (HCC), NRF2 activation has been revealed as a more prominent pathway contributing to the progression of precancerous lesions to malignancy. Nevertheless, how its activation leads to poor prognosis in HCC patients remains unclear. In this review, we provide an overview of how aberrant activation of NRF2 triggers HCC development. We also summarize the emerging roles of other NRF family members in liver cancer development.

• Klíčová slova
• NF-E2-related factor 2, hepatocellular carcinoma, oxidative stress, redox homeostasis, transcription factor,
• MeSH
• aktivace transkripce * MeSH
• analýza přežití MeSH
• faktor 2 související s NF-E2 genetika   metabolismus   MeSH
• genové regulační sítě MeSH
• hepatocelulární karcinom diagnóza   genetika   mortalita   patologie   MeSH
• karcinogeneze genetika   metabolismus   patologie   MeSH
• KEAP-1 genetika   metabolismus   MeSH
• lidé MeSH
• mutace MeSH
• nádorové buněčné linie MeSH
• nádory jater diagnóza   genetika   mortalita   patologie   MeSH
• oxidace-redukce MeSH
• oxidační stres MeSH
• prognóza MeSH
• regulace genové exprese u nádorů * MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• faktor 2 související s NF-E2 MeSH
• KEAP-1 MeSH
• KEAP1 protein, human MeSH Prohlížeč
• NFE2L2 protein, human MeSH Prohlížeč

Novel multifunctional tacrines for Alzheimer's disease were obtained by Ugi-reaction between ferulic (or lipoic acid), a melatonin-like isocyanide, formaldehyde, and tacrine derivatives, according to the antioxidant additive approach in order to modulate the oxidative stress as therapeutic strategy. Compound 5c has been identified as a promising permeable agent showing excellent antioxidant properties, strong cholinesterase inhibitory activity, less hepatotoxicity than tacrine, and the best neuroprotective capacity, being able to significantly activate the Nrf2 transcriptional pathway.

• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• antioxidancia chemická syntéza   chemie   farmakologie   MeSH
• buněčná smrt účinky léků   MeSH
• buňky Hep G2 MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• cholinesterasy metabolismus   MeSH
• faktor 2 související s NF-E2 agonisté   metabolismus   MeSH
• kyseliny kumarové chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• melatonin chemická syntéza   chemie   farmakologie   MeSH
• molekulární struktura MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antioxidancia MeSH
• cholinesterasové inhibitory MeSH
• cholinesterasy MeSH
• faktor 2 související s NF-E2 MeSH
• ferulic acid MeSH Prohlížeč
• kyseliny kumarové MeSH
• melatonin MeSH

Nrf2 and NF-κB transcription factors act in wound healing via their anti-inflammatory and anti-oxidant effects or through the immune response. Studying this process is a matter of some importance given the high cost of wound treatment. A major contribution in this regard is being made by models that enable investigation of the involvement of multiple factors in wound healing and testing new curative substances. This literature review was carried out via searches in the PubMed and Web of Science databases up to 2016. It covers skin wound healing, available models for its study (part I), the role of Nrf2 and NF-κB, substances that influence them and whether they can be used as markers (part II). Was found that in vitro assays are used for their availability but a holistic view must be established in vivo. In silico approaches are facilitating assessment of a vast amount of research data. Nfr2 and NF-κB play a crucial and reciprocal role in wound healing. Nrf2 controls repair-associated inflammation and protects against excessive accumulation of ROS while Nf-κB activates the innate immune reaction, proliferation and migration of cells, modulates expression of matrix metalloproteinases, secretion and stability of cytokines and growth factors for wound healing.

• Klíčová slova
• NF-κB, Nrf2, in vitro and in vivo models, skin wound healing,
• MeSH
• biologické modely MeSH
• biotest metody   MeSH
• faktor 2 související s NF-E2 antagonisté a inhibitory   fyziologie   MeSH
• hojení ran imunologie   fyziologie   MeSH
• kůže * MeSH
• lidé MeSH
• NF-kappa B antagonisté a inhibitory   fyziologie   MeSH
• oxidační stres fyziologie   MeSH
• pohyb buněk imunologie   fyziologie   MeSH
• přirozená imunita fyziologie   MeSH
• proliferace buněk fyziologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• faktor 2 související s NF-E2 MeSH
• NF-kappa B MeSH
• NFE2L2 protein, human MeSH Prohlížeč
• reaktivní formy kyslíku MeSH

Lilial (also called lysmeral) is a fragrance ingredient presented in many everyday cosmetics and household products. The concentrations of lilial in the final products is rather low. Its maximum concentration in cosmetics was limited and recently, its use in cosmetics products was prohibited in the EU due to the classification as reproductive toxicant. Additionally, according to the European Chemicals Agency, it was under assessment as one of the potential endocrine disruptors, i.e. a substance that may alter the function of the endocrine system and, as a result, cause health problems. Its ability to act as an androgen receptor agonist and the estrogenic and androgenic activity of its metabolites, to the best of our knowledge, have not yet been tested. The aim of this work was to determine the intestinal absorption, cytotoxicity, nephrotoxicity, mutagenicity, activation of cellular stress-related signal pathways and, most importantly, to test the ability to disrupt the endocrine system of lilial and its Phase I metabolites. This was tested using set of in vitro assays including resazurin assay, the CHO/HPRT mutation assay, γH2AX biomarker-based genotoxicity assay, qPCR and in vitro reporter assays based on luminescence of luciferase for estrogen, androgen, NF-κB and NRF2 signalling pathway. It was determined that neither lilial nor its metabolites have a negative effect on cell viability in the concentration range from 1 nM to 100 µM. Using human cell lines HeLa9903 and MDA-kb2, it was verified that this substance did not have agonistic activity towards estrogen or androgen receptor, respectively. Lilial metabolites, generated by incubation with the rat liver S9 fraction, did not show the ability to bind to estrogen or androgen receptors. Neither lilial nor its metabolites showed a nephrotoxic effect on human renal tubular cells (RPTEC/TERT1 line) and at the same time they were unable to activate the NF-κB and NRF2 signalling pathway at a concentration of 50 µM (HEK 293/pGL4.32 or pGL4.37). Neither lilial nor its metabolites showed mutagenic activity in the HPRT gene mutation test in CHO-K1 cells, nor were they able to cause double-strand breaks in DNA (γH2AX biomarker) in CHO-K1 and HeLa cells. In our study, no negative effects of lilial or its in vitro metabolites were observed up to 100 µM using different in vitro tests.

• MeSH
• androgeny MeSH
• biologické markery MeSH
• estrogeny toxicita   metabolismus   MeSH
• faktor 2 související s NF-E2 MeSH
• HEK293 buňky MeSH
• HeLa buňky MeSH
• hypoxanthinfosforibosyltransferasa * MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• NF-kappa B * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• androgeny MeSH
• biologické markery MeSH
• estrogeny MeSH
• faktor 2 související s NF-E2 MeSH
• hypoxanthinfosforibosyltransferasa * MeSH
• lilial MeSH Prohlížeč
• NF-kappa B * MeSH

The harmful effects of low energy UVA photons (315-400 nm) are associated with the massive production of reactive oxygen species resulting in oxidative stress. In response to oxidative damage, NF-E2-related factor 2 (Nrf2) is translocated to the nucleus and drives the expression of detoxication and antioxidant enzymes. UVA's effect on Nrf2 has been quite well characterised in dermal fibroblasts. However, there is a dearth of such information for keratinocytes. This study aimed to evaluate and compare the effect of UVA radiation on the Nrf2 pathway and oxidative stress related proteins in primary human dermal fibroblasts (NHDF), epidermal keratinocytes (NHEK) and human keratinocyte cell line HaCaT. NHDF were exposed to doses of 2.5-7.5 J/cm2, NHEK and HaCaT to 10-20 J/cm2 using a solar simulator. Effects on Nrf2 translocation were evaluated after 1, 3 and 6 h and Nrf2-controlled proteins (heme oxygenase 1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione reductase (GSR), glutathione-S-transferase (GST), interleukine-6 (IL-6), and matrix metalloproteinases (MMP-1, MMP-2)) after 3, 6 and 24 h. The results showed the fastest Nrf2 translocation was in UVA-irradiated HaCaT (1 h), persisting until the subsequent time interval (3 h), while in primary keratinocytes the effect of radiation was minimal. In NHDF, UVA-stimulated Nrf2 translocation was conspicuous 3 h after UVA treatment. In NHDF, most of the studied proteins (NQO1, HO-1, GSR, GSTM1 and MMP-1) showed the highest level 24 h after UVA exposure, except for MMP-2 and IL-6 which had their highest level at a shorter time incubation interval (3 h). In NHEK, NQO1, HO-1 and GST were increased 6 h after UVA exposure, GSR and MMP-2 level was slightly below or above the control level, and MMP-1 and IL-6 increased at shorter time intervals. When comparing NHEK and HaCaT, these cells displayed contrary responses in most of the Nrf2-controlled proteins. Thus, primary keratinocytes cannot be replaced with HaCaT when studying cell signalling such as the Nrf2 driven pathway and Nrf2-controlled proteins.

• Klíčová slova
• Fibroblasts, HaCaT, Keratinocytes, Nrf2 pathway, Primary skin cells, UVA radiation,
• MeSH
• faktor 2 související s NF-E2 metabolismus   MeSH
• keratinocyty metabolismus   účinky záření   MeSH
• kultivované buňky MeSH
• kůže cytologie   metabolismus   účinky záření   MeSH
• lidé MeSH
• signální transdukce účinky záření   MeSH
• transport proteinů MeSH
• ultrafialové záření * MeSH
• viabilita buněk účinky záření   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• faktor 2 související s NF-E2 MeSH
• NFE2L2 protein, human MeSH Prohlížeč

Metabolic reprogramming of cancer cells is a common hallmark of malignant transformation. The preference for aerobic glycolysis over oxidative phosphorylation in tumors is a well-studied phenomenon known as the Warburg effect. Importantly, metabolic transformation of cancer cells also involves alterations in signaling cascades contributing to lipid metabolism, amino acid flux and synthesis, and utilization of ketone bodies. Also, redox regulation interacts with metabolic reprogramming during malignant transformation. Flavonoids, widely distributed phytochemicals in plants, exert various beneficial effects on human health through modulating molecular cascades altered in the pathological cancer phenotype. Recent evidence has identified numerous flavonoids as modulators of critical components of cancer metabolism and associated pathways interacting with metabolic cascades such as redox balance. Flavonoids affect lipid metabolism by regulating fatty acid synthase, redox balance by modulating nuclear factor-erythroid factor 2-related factor 2 (Nrf2) activity, or amino acid flux and synthesis by phosphoglycerate mutase 1. Here, we discuss recent preclinical evidence evaluating the impact of flavonoids on cancer metabolism, focusing on lipid and amino acid metabolic cascades, redox balance, and ketone bodies.

• Klíčová slova
• Cancer cells, Carcinogenesis, Flavonoids, Metabolic reprogramming, Metabolism,
• MeSH
• aminokyseliny * MeSH
• faktor 2 související s NF-E2 metabolismus   MeSH
• flavonoidy farmakologie   MeSH
• ketolátky metabolismus   MeSH
• lidé MeSH
• metabolismus lipidů MeSH
• nádorová transformace buněk metabolismus   MeSH
• nádory * farmakoterapie   metabolismus   MeSH
• oxidace-redukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• aminokyseliny * MeSH
• faktor 2 související s NF-E2 MeSH
• flavonoidy MeSH
• ketolátky MeSH

PURPOSE: Excessive exposure of skin to solar radiation is associated with greatly increased production of reactive oxygen and nitrogen species (ROS, RNS) resulting in oxidative stress (OS), inflammation, immunosuppression, the production of matrix metalloproteinase, DNA damage and mutations. These events lead to increased incidence of various skin disorders including photoaing and both non-melanoma and melanoma skin cancers. The ultraviolet (UV) part of sunlight, in particular, is responsible for structural and cellular changes across the different layers of the skin. Among other effects, UV photons stimulate oxidative damage to biomolecules via the generation of unstable and highly reactive compounds. In response to oxidative damage, cytoprotective pathways are triggered. One of these is the pathway driven by the nuclear factor erythroid-2 related factor 2 (Nrf2). This transcription factor translocates to the nucleus and drives the expression of numerous genes, among them various detoxifying and antioxidant enzymes. Several studies concerning the effects of UV radiation on Nrf2 activation have been published, but different UV wavelengths, skin cells or tissues and incubation periods were used in the experiments that complicate the evaluation of UV radiation effects. CONCLUSIONS: This review summarizes the effects of UVB (280-315 nm) and UVA (315-400 nm) radiation on the Nrf2 signaling pathway in dermal fibroblasts and epidermal keratinocytes and melanocytes. The effects of natural compounds (pure compounds or mixtures) on Nrf2 activation and level as well as on Nrf2-driven genes in UV irradiated human skin fibroblasts, keratinocytes and melanocytes are briefly mentioned as well.HighlightsUVB radiation is a rather poor activator of the Nrf2-driven pathway in fibroblastsUVA radiation stimulates Nrf2 activation in dermal fibroblastsEffects of UVA on the Nrf2 pathway in keratinocytes and melanocytes remain unclearLong-term Nrf2 activation in keratinocytes disturbs their normal differentiationPharmacological activation of Nrf2 in the skin needs to be performed carefully.

• Klíčová slova
• Nrf2, UV radiation, oxidative stress, photoprotection, phytochemicals, skin,
• MeSH
• faktor 2 související s NF-E2 * metabolismus   MeSH
• keratinocyty MeSH
• kůže metabolismus   MeSH
• lidé MeSH
• reaktivní formy kyslíku MeSH
• signální transdukce * MeSH
• ultrafialové záření * škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• faktor 2 související s NF-E2 * MeSH
• reaktivní formy kyslíku MeSH