Signálna dráha riadená komplexom transkripčného faktora Nrf2 a jeho represora Keap1 je súčasťou jedného z najdôležitejších defenzívnych mechanizmov bunky, ktorý ju ochraňuje pred stresom. Po uvoľnení proteínu Keap1 z komplexu Nrf2-Keap1 dochádza k translokácii Nrf2 do jadra, kde cez zvýšenie expresie cytoprotektívnych génov pomáha bunke zvládnuť oxidačný stres vyvolaný účinkom toxických či karcinogénnych látok. Nie je preto prekvapujúce, že indukcia Nrf2 chemopreventívnymi látkami môže mať potenciál pri prevencii nádorových ochorení. Podobne ako Nrf2 ochraňuje bunky zdravého tkaniva, v neoplastických bunkách môže zmierniť účinok chemoterapeutík, a podporiť tak progresiu rakoviny. Je dokázané, že zvýšená expresia a následná nadmerná akumulácia Nrf2 je u mnohých typov nádorov asociovaná so zlou prognózou liečby a prispieva aj k fenoménu liekovej rezistencie. Poznanie „dvoch tvárí“ Nrf2 ako aj aktivácie ním riadenej signálnej dráhy je preto dôležité nielen pre základný výskum, ale má aj klinické implikácie.

One of the most prominent defense mechanisms of cells undergoing stress is the Nrf2-Keap1 signaling pathway. After exposure to either carcinogens or toxic compounds inducing oxidative stress, attacked cells react by release of Keap1 from the Nrf2-Keap1 complex. Freeing Nrf2 from the complex allows its translocation into the nucleus, thus enabling start of the transcriptional program of cytoprotective genes. Therefore, induction of Nrf2 by chemopreventive compounds may show potential in cancer prevention. But while it protects normal cells, increased activity of Nrf2 signaling pathway also facilitates cancer progression and protects neoplastic cells from therapeutic agents. Increased expression and subsequent accumulation of Nrf2 contributes to acquired drug resistance and is often associated with worse prognosis. Knowing ‘both faces’ of Nrf2 signaling pathway is thus relevant not only for basic research but has also substantial clinical implications. Key words: Nrf2 – Keap1 – antioxidant – drug resistance – chemoprevention This study was supported by European Re-gional Development Fund and the State Budget of the Czech Republic (RECAMO CZ.1.05//2.1.00/03.0101), MEYS – NPS I – LO1413, MH CZ –DRO (MMCI, 00209805) and by BBMRI_CZ (LM2010004). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers. Submitted: 9. 4. 2015 Accepted: 15. 6. 2015

• Klíčová slova
• Keap1,
• MeSH
• antioxidancia MeSH
• chemoprofylaxe MeSH
• chemorezistence MeSH
• faktor 2 související s NF-E2 * MeSH
• intracelulární signální peptidy a proteiny * MeSH
• lidé MeSH
• nádory * patofyziologie   prevence a kontrola   MeSH
• signální transdukce fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

The oxidative stress plays an important role in the development of cardiovascular diseases (CVD). In CVD progression an aberrant redox regulation was observed. In this regulation levels of reactive oxygen species (ROS) play an important role in cellular signaling, where Nrf2 is the key regulator of redox homeostasis. Keap1-Nrf2-ARE system regulates a great set of detoxificant and antioxidant enzymes in cells after ROS and electrophiles exposure. In this review we focus on radical-generating systems in cardiovascular system as well as on Nrf2 as a target against oxidative stress and a key player of redox regulation in cardiovascular diseases. We also summarize the current knowledge about the role of Nrf2 in pathophysiology of several CVD (hypertension, cardiac hypertrophy, cardiomyopathies) as well as in cardioprotection against myocardial ischemia/ reperfusion injury.

• MeSH
• antioxidační responzivní elementy * MeSH
• faktor 2 související s NF-E2 metabolismus   MeSH
• kardiovaskulární nemoci metabolismus   MeSH
• lidé MeSH
• oxidační stres * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Multiple sclerosis (MS) is a neurologic autoimmune disorder featured by chronic inflammation of the central nervous system, demyelination and axonal damage. Recently, the term "oxinflammation" has been proposed to depict the vicious circle of chronic inflammation and oxidative stress (OS). OS promotes demyelination and neurodegeneration directly, by oxidation of lipids, proteins, and DNA but also indirectly, by inducing a dysregulation of the immunity and favoring the state of pro-inflammatory response. Many of the actors of this delicately tuned network are controlled by Keap1/Nrf2/ARE signaling pathway, a principal regulator of antioxidant and phase II detoxification genes. This pathway also has a pivotal role in inflammation, and therefore possesses a great potential in the treatment of MS. The aim of this review is to provide the newest insights in the preclinical and clinical evidence of Nrf2 induction in the regeneration of the antioxidant response and attenuation of inflammation in MS. Preclinical studies have indicated that activators of this pathway, such as epigallocatechin gallate (EGCG), curcumin, melatonin, resveratrol, and sulforaphane might be a promising therapeutic option in amelioration of MS symptoms, nevertheless, the efficacy and safety of these compounds have to be confirmed in future clinical trials.

• MeSH
• faktor 2 související s NF-E2 účinky léků   MeSH
• KEAP-1 účinky léků   MeSH
• lidé MeSH
• roztroušená skleróza farmakoterapie   MeSH
• signální transdukce účinky léků   MeSH
• vezikulární transportní proteiny účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The natural flavonoid quercetin is known to activate the transcription factor Nrf2, which regulates the expression of cytoprotective enzymes such as heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). In this study, a novel semisynthetic flavonoid 7-O-galloylquercetin (or quercetin-7-gallate, 3) was prepared by direct galloylation of quercetin, and its effect on the Nrf2 pathway was examined. A luciferase reporter assay showed that 7-O-galloylquercetin, like quercetin, significantly activated transcription via the antioxidant response element in a stably transfected human AREc32 reporter cell line. In addition, 7-O-galloylquercetin caused the accumulation of Nrf2 and induced the expression of HO-1 at both the mRNA and protein levels in murine macrophage RAW264.7 cells. The induction of HO-1 by 7-O-galloylquercetin was significantly suppressed by N-acetyl-l-cysteine and SB203580, indicating the involvement of reactive oxygen species and p38 mitogen-activated protein kinase activity, respectively. HPLC/MS analyses also showed that 7-O-galloylquercetin was not degalloylated to quercetin, but it was conjugated with glucuronic acid and/or methylated in RAW264.7 cells. Furthermore, 7-O-galloylquercetin was found to increase the protein levels of Nrf2 and HO-1, and also the activity of NQO1 in murine hepatoma Hepa1c1c7 cells. Taken together, we conclude that 7-O-galloylquercetin increases Nrf2 activity and induces Nrf2-dependent gene expression in RAW264.7 and Hepa1c1c7 cells.

• MeSH
• biotransformace účinky léků   MeSH
• enzymová indukce účinky léků   MeSH
• faktor 2 související s NF-E2 metabolismus   MeSH
• hemoxygenasa-1 biosyntéza   MeSH
• hmotnostní spektrometrie MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• metabolom účinky léků   MeSH
• mitogenem aktivované proteinkinasy p38 metabolismus   MeSH
• myši MeSH
• NAD(P)H dehydrogenasa (chinon) metabolismus   MeSH
• nádorové buněčné linie MeSH
• quercetin chemická syntéza   chemie   farmakologie   MeSH
• RAW 264.7 buňky MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• regulace genové exprese účinky léků   MeSH
• reportérové geny MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články 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.

• MeSH
• faktor 2 související s NF-E2 metabolismus   MeSH
• keratinocyty MeSH
• kůže metabolismus   MeSH
• lidé MeSH
• reaktivní formy kyslíku MeSH
• signální transdukce * MeSH
• transkripční faktor GABP MeSH
• ultrafialové záření * škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem 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

Reactive oxygen species are an important element of redox regulation in cells and tissues. During physiological processes, molecules undergo chemical changes caused by reduction and oxidation reactions. Free radicals are involved in interactions with other molecules, leading to oxidative stress. Oxidative stress works two ways depending on the levels of oxidizing agents and products. Excessive action of oxidizing agents damages biomolecules, while a moderate physiological level of oxidative stress (oxidative eustress) is necessary to control life processes through redox signaling required for normal cellular operation. High levels of reactive oxygen species (ROS) mediate pathological changes. Oxidative stress helps to regulate cellular phenotypes in physiological and pathological conditions. Nrf2 (nuclear factor erythroid 2-related factor 2, NFE2L2) transcription factor functions as a target nuclear receptor against oxidative stress and is a key factor in redox regulation in hypertension and cardiovascular disease. Nrf2 mediates transcriptional regulation of a variety of target genes. The Keap1-Nrf2-ARE system regulates many detoxification and antioxidant enzymes in cells after the exposure to reactive oxygen species and electrophiles. Activation of Nrf2/ARE signaling is differentially regulated during acute and chronic stress. Keap1 normally maintains Nrf2 in the cytosol and stimulates its degradation through ubiquitination. During acute oxidative stress, oxidized molecules modify the interaction of Nrf2 and Keap1, when Nrf2 is released from the cytoplasm into the nucleus where it binds to the antioxidant response element (ARE). This triggers the expression of antioxidant and detoxification genes. The consequence of long-term chronic oxidative stress is activation of glycogen synthase kinase 3beta (GSK-3beta) inhibiting Nrf2 activity and function. PPARgamma (peroxisome proliferator-activated receptor gamma) is a nuclear receptor playing an important role in the management of cardiovascular diseases, hypertension and metabolic syndrome. PPARgamma targeting of genes with peroxisome proliferator response element (PPRE) has led to the identification of several genes involved in lipid metabolism or oxidative stress. PPARgamma stimulation is triggered by endogenous and exogenous ligands - agonists and it is involved in the activation of several cellular signaling pathways involved in oxidative stress response, such as the PI3K/Akt/NOS pathway. Nrf2 and PPARgamma are linked together with their several activators and Nrf2/ARE and PPARgamma/PPRE pathways can control several types of diseases.

• MeSH
• antioxidační responzivní elementy MeSH
• faktor 2 související s NF-E2 metabolismus   MeSH
• hypertenze metabolismus   patofyziologie   MeSH
• kardiovaskulární nemoci metabolismus   patofyziologie   MeSH
• KEAP-1 metabolismus   MeSH
• krevní tlak * MeSH
• lidé MeSH
• oxidační stres * MeSH
• PPAR gama metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Silybum marianum (milk thistle) is a medicinal plant used for the treatment of various liver disorders. This study examined whether the main flavonolignans from S. marianum (i.e. silybin, silychristin, silydianin) and their 2,3-dehydro derivatives (i.e. 2,3-dehydrosilybin, 2,3-dehydrosilychristin, 2,3-dehydrosilydianin) activate the Nrf2 pathway, which regulates the expression of genes encoding many cytoprotective enzymes, including NAD(P)H:quinone oxidoreductase 1 (NQO1). After 48h of exposure, 2,3-dehydrosilydianin at concentrations of 25μM and higher significantly elevated the activity of NQO1 in murine hepatoma Hepa1c1c7 cells. In contrast, other tested compounds at non-cytotoxic concentrations had a mild or negligible effect on the NQO1 activity. Using a luciferase reporter assay, 2,3-dehydrosilydianin was found to significantly activate transcription via the antioxidant response element in stably transfected human AREc32 reporter cells. Moreover, 2,3-dehydrosilydianin caused the accumulation of Nrf2 and significantly induced the expression of the Nqo1 gene at both the mRNA and protein levels in Hepa1c1c7 cells. We found that 2,3-dehydrosilydianin also increased to some extent the expression of other Nrf2 target genes, namely of the heme oxygenase-1 gene (Hmox1) and the glutamate-cysteine ligase modifier subunit gene (Gclm). We conclude that 2,3-dehydrosilydianin activates Nrf2 and induces Nrf2-mediated gene expression in Hepa1c1c7 cells.

• MeSH
• exprese genu účinky léků   MeSH
• faktor 2 související s NF-E2 metabolismus   MeSH
• glutamátcysteinligasa genetika   metabolismus   MeSH
• hemoxygenasa-1 genetika   metabolismus   MeSH
• lidé MeSH
• membránové proteiny genetika   metabolismus   MeSH
• molekulární struktura MeSH
• myši MeSH
• NAD(P)H dehydrogenasa (chinon) genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• ostropestřec mariánský chemie   MeSH
• silymarin farmakologie   MeSH
• upregulace MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata 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

Linoleic acid (LA) not only functions as an essential nutrient, but also profoundly modulates oxidative stress and inflammatory response. However, the potential mechanisms have not been adequately researched. Hence, this study examined the potential pharmacological roles of LA and the underlying mechanisms in mice with lipopolysaccharide (LPS)-associated acute liver injury (ALI). The results indicated that treatment with LA alleviated the histopathological abnormalities in the hepatic and plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and glutathione-S-transferase (GST) in mice with LPS exposure. In addition, LA inhibited the LPS-associated generation of proinflammatory factors, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and downregulated the hepatic myeloperoxidase (MPO) level. In addition, the administration of LA resulted in a reduction in hepatic malondialdehyde (MDA) levels and an elevation in liver superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT), and glutathione peroxidase (GSH-PX) levels. Further investigations revealed that LA promoted the expression of nuclear factor E2-related factor (Nrf2) and NAD(P)H: quinone oxidoreductase 1 (NQO1). In addition, the beneficial outcomes of LA on LPS-induced acute liver failure were revered when Nrf2 was pharmacologically suppressed by ML385. These experimental results demonstrated that LA supplementation attenuated LPS-associated acute hepatic impairment in mice via the activation of Nrf2.

• MeSH
• faktor 2 související s NF-E2 * metabolismus   MeSH
• játra účinky léků   metabolismus   patologie   MeSH
• kyselina linolová * farmakologie   MeSH
• lékové postižení jater * metabolismus   farmakoterapie   patologie   prevence a kontrola   MeSH
• lipopolysacharidy * toxicita   MeSH
• myši MeSH
• oxidační stres účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH