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

• Klíčová slova
• bardoxolon metyl,
• MeSH
• chronické selhání ledvin MeSH
• faktor 2 související s NF-E2 MeSH
• klinické zkoušky jako téma MeSH
• kongresy jako téma MeSH
• NF-kappa B 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.

• 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

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.

• 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

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.

• 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

• MeSH
• experimenty na zvířatech MeSH
• exprese genu MeSH
• faktor 2 související s NF-E2 genetika   MeSH
• financování organizované MeSH
• hypertenze genetika   komplikace   MeSH
• krevní glukóza genetika   metabolismus   MeSH
• krysa rodu rattus MeSH
• metabolický syndrom genetika   MeSH
• metabolismus lipidů genetika   MeSH
• oxidační stres genetika   MeSH
• statistika jako téma MeSH
• technika přenosu genů MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH

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.

• 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

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

Lipid nitroalkenes - nitro-fatty acids (NO2-FAs) are formed in vivo via the interaction of reactive nitrogen species with unsaturated fatty acids. The resulting electrophilic NO2-FAs play an important role in redox homeostasis and cellular stress response. This study investigated the physicochemical properties and reactivity of two NO2-FAs: 9/10-nitrooleic acid (1) and its newly prepared 1-monoacyl ester, (E)-2,3-hydroxypropyl 9/10-nitrooctadec-9-enoate (2), both synthesized by a direct radical nitration approach. Compounds 1 and 2 were investigated in an aqueous medium and after incorporation into lipid nanoparticles prepared from 1-monoolein, cubosomes 1@CUB and 2@CUB. Using an electrochemical analysis and LC-MS, free 1 and 2 were found to be unstable under acidic conditions, and their degradation occurred in an aqueous environment within a few minutes or hours. This degradation was associated with the production of the NO radical, as confirmed by fluorescence assay. In contrast, preparations 1@CUB and 2@CUB exhibited a significant increase in the stability of the loaded 1 and 2 up to several days to weeks. In addition to experimental data, density functional theory-based calculation results on the electronic structure and structural variability (open and closed configuration) of 1 and 2 were obtained. Finally, experiments with a human HaCaT keratinocyte cell line demonstrated the ability of 1@CUB and 2@CUB to penetrate through the cytoplasmic membrane and modulate cellular pathways, which was exemplified by the Keap1 protein level monitoring. Free 1 and 2 and the cubosomes prepared from them showed cytotoxic effect on HaCaT cells with IC50 values ranging from 1 to 8 μM after 24 h. The further development of cubosomal preparations with embedded electrophilic NO2-FAs may not only contribute to the field of fundamental research, but also to their application using an optimized lipid delivery vehicle.

• MeSH
• dusíkaté sloučeniny MeSH
• faktor 2 související s NF-E2 MeSH
• KEAP-1 MeSH
• lidé MeSH
• mastné kyseliny * MeSH
• oxid dusnatý * metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Solar radiation can cause damage to the skin, leading to various adverse effects such as sunburn, reactive oxygen species production, inflammation, DNA damage, and photoaging. To study the potential of photoprotective agents, full-thickness skin models are increasingly being used as in vitro tools. One promising approach to photoprotection involves targeting the redox-sensitive transcription factor Nrf2, which is responsible for regulating various cellular defense mechanisms, including the antioxidant response, inflammatory signaling, and DNA repair. Obacunone, a natural triterpenoid, has been identified as a potent Nrf2 agonist. The present study aims to evaluate the relevance of full-thickness (FT) skin models in photoprotection studies and to explore the potential photoprotective effects of obacunone on those models and in human keratinocytes. Phenion® full-thickness skin models and keratinocytes were incubated with increasing concentrations of obacunone and irradiated with solar-simulated radiation (SSR). Various photodamage markers were evaluated, including histological integrity, oxidative stress, apoptosis, inflammation, photoaging-related dermal markers, and photocarcinogenesis markers. Increasing doses of SSR were found to modulate various biomarkers related to sun damage in the FT skin models. However, obacunone attenuated cytotoxicity, inflammation, oxidative stress, sunburn reaction, photoaging, and photocarcinogenesis in both keratinocytes and full thickness skin models exposed to SSR. These results suggest that obacunone may have potential as a photoprotective agent for preventing the harmful effects of solar radiation on the skin.

• MeSH
• faktor 2 související s NF-E2 genetika   MeSH
• keratinocyty MeSH
• kůže patologie   MeSH
• lidé MeSH
• radioprotektivní látky * farmakologie   MeSH
• sluneční spáleniny * MeSH
• ultrafialové záření škodlivé účinky   MeSH
• zánět prevence a kontrola   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH