In esophageal squamous cell carcinoma, genetic activation of NRF2 increases resistance to chemotherapy and radiotherapy, which results in a significantly worse prognosis for patients. Therefore NRF2-activated cancers create an urgent clinical need to identify new therapeutic options. In this context, we previously identified the geldanamycin family of HSP90 inhibitors, which includes 17DMAG, to be synthetic lethal with NRF2 activity. As the first-generation of geldanamycin-derivative drugs were withdrawn from clinical trials due to hepatotoxicity, we designed second-generation compounds with C19-substituted structures in order to inhibit glutathione conjugation-mediated hepatotoxicity. In this study, using a variety of in vitro and in vivo cancer models, we found that C19-substituted 17DMAG compounds maintain their enhanced toxicity profile and synthetic lethal interaction with NRF2-NQO1-activated cancer cells. Importantly, using a xenograft mouse tumor model, we found that C19-substituted 17DMAG displayed significant anticancer efficacy against NRF2-NQO1-activated cancer cells without causing hepatotoxicity. These results clearly demonstrate the improved clinical potential for this new class of HSP90 inhibitor anticancer drugs, and suggest that patients with NRF2-NQO1-activated esophageal carcinoma may benefit from this novel therapeutic approach.
- Klíčová slova
- C19-position substituted geldanamycin derivatives, ESCC, HSP90, NQO1, NRF2-NQO1-activated cancer,
- MeSH
- benzochinony * farmakologie chemie MeSH
- faktor 2 související s NF-E2 * metabolismus genetika MeSH
- lidé MeSH
- makrocyklické laktamy * farmakologie chemie MeSH
- myši nahé MeSH
- myši MeSH
- NAD(P)H dehydrogenasa (chinon) * metabolismus genetika MeSH
- nádorové buněčné linie MeSH
- nádory jícnu * farmakoterapie metabolismus patologie MeSH
- proteiny tepelného šoku HSP90 antagonisté a inhibitory metabolismus MeSH
- protinádorové látky * farmakologie chemie MeSH
- skvamózní karcinom jícnu * farmakoterapie metabolismus MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- benzochinony * MeSH
- faktor 2 související s NF-E2 * MeSH
- geldanamycin MeSH Prohlížeč
- makrocyklické laktamy * MeSH
- NAD(P)H dehydrogenasa (chinon) * MeSH
- NFE2L2 protein, human MeSH Prohlížeč
- NQO1 protein, human MeSH Prohlížeč
- proteiny tepelného šoku HSP90 MeSH
- protinádorové látky * MeSH
INTRODUCTION: Studies have correlated living close to major roads with Alzheimer's disease (AD) risk. However, the mechanisms responsible for this link remain unclear. METHODS: We exposed olfactory mucosa (OM) cells of healthy individuals and AD patients to diesel emissions (DE). Cytotoxicity of exposure was assessed, mRNA, miRNA expression, and DNA methylation analyses were performed. The discovered altered pathways were validated using data from the human population-based Rotterdam Study. RESULTS: DE exposure resulted in an almost four-fold higher response in AD OM cells, indicating increased susceptibility to DE effects. Methylation analysis detected different DNA methylation patterns, revealing new exposure targets. Findings were validated by analyzing data from the Rotterdam Study cohort and demonstrated a key role of nuclear factor erythroid 2-related factor 2 signaling in responses to air pollutants. DISCUSSION: This study identifies air pollution exposure biomarkers and pinpoints key pathways activated by exposure. The data suggest that AD individuals may face heightened risks due to impaired cellular defenses. HIGHLIGHTS: Healthy and AD olfactory cells respond differently to DE exposure. AD cells are highly susceptible to DE exposure. The NRF2 oxidative stress response is highly activated upon air pollution exposure. DE-exposed AD cells activate the unfolded protein response pathway. Key findings are also confirmed in a population-based study.
- Klíčová slova
- Alzheimer's disease (AD), air pollution, air–liquid interface (ALI), heat shock protein (HSP), next‐generation sequencing (NGS), nuclear factor erythroid 2–related factor 2 (NRF2), traffic emissions, traffic‐related air pollution (TRAP) olfactory mucosa (OM),
- MeSH
- Alzheimerova nemoc * genetika metabolismus MeSH
- čichová sliznice metabolismus MeSH
- epigenomika MeSH
- faktor 2 související s NF-E2 genetika metabolismus MeSH
- látky znečišťující vzduch škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- metylace DNA * MeSH
- mikro RNA metabolismus genetika MeSH
- senioři MeSH
- stanovení celkové genové exprese MeSH
- transkriptom MeSH
- výfukové emise vozidel * toxicita MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- faktor 2 související s NF-E2 MeSH
- látky znečišťující vzduch MeSH
- mikro RNA MeSH
- NFE2L2 protein, human MeSH Prohlížeč
- výfukové emise vozidel * 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.
- Klíčová slova
- full-thickness skin model, obacunone, photodamage, photoprotection,
- 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
- Názvy látek
- faktor 2 související s NF-E2 MeSH
- obacunone MeSH Prohlížeč
- radioprotektivní látky * MeSH
NRF2 is a master regulator of the cellular protection against oxidative damage in mammals and of multiple pathways relevant in the mammalian aging process. In the epidermis of the skin NRF2 contributes additionally to the formation of an antioxidant barrier to protect from environmental insults and is involved in the differentiation process of keratinocytes. In chronological aging of skin, the capacity for antioxidant responses and the ability to restore homeostasis after damage are impaired. Surprisingly, in absence of extrinsic stressors, NRF2 deficient mice do not show any obvious skin phenotype, not even at old age. We investigated the differences in chronological epidermal aging of wild type and NRF2-deficient mice to identify the changes in aged epidermis that may compensate for absence of this important transcriptional regulator. While both genotypes showed elevated epidermal senescence markers (increased Lysophospholipids, decreased LaminB1 expression), the aged NRF2 deficient mice displayed disturbed epidermal differentiation manifested in irregular keratin 10 and loricrin expression. The tail skin displayed less age-related epidermal thinning and a less pronounced decline in proliferating basal epidermal cells compared to the wildtype controls. The stratum corneum lipid composition also differed, as we observed elevated production of barrier protective linoleic acid (C18:2) and reduced abundance of longer chain saturated lignoceric acid (C24:0) among the stratum corneum fatty acids in the aged NRF2-deficient mice. Thus, despite epidermal differentiation being disturbed in aged NRF2-deficient animals in homeostasis, adaptations in keratinocyte proliferation and barrier lipid synthesis could explain the lack of a more severe phenotype.
- Klíčová slova
- NRF2, aging, epidermis, lipid, skin,
- MeSH
- antioxidancia * metabolismus MeSH
- buněčná diferenciace genetika MeSH
- epidermální buňky MeSH
- epidermis metabolismus MeSH
- faktor 2 související s NF-E2 * genetika metabolismus MeSH
- keratinocyty MeSH
- myši MeSH
- ocas MeSH
- savci MeSH
- stárnutí genetika MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antioxidancia * MeSH
- faktor 2 související s NF-E2 * 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.
- Klíčová slova
- Apoptosis, Nrf2, Oxidative stress, Procyanidins, Zearalenone,
- 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
- Názvy látek
- antioxidancia MeSH
- faktor 2 související s NF-E2 MeSH
- proantokyanidiny * MeSH
- reaktivní formy kyslíku MeSH
- zearalenon * MeSH
The aim of this study was to evaluate therapeutic potential of edaravone in the murine model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) and to expand the knowledge of its mechanism of action. Edaravone (6 mg/kg/day) was administered intraperitoneally from the onset of clinical symptoms until the end of the experiment (28 days). Disease progression was assessed daily using severity scores. At the peak of the disease, histological analyses, markers of oxidative stress (OS) and parameters of mitochondrial function in the brains and spinal cords (SC) of mice were determined. Gene expression of inducible nitric oxide synthase (iNOS), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha was determined at the end of the experiment. Edaravone treatment ameliorated EAE severity and attenuated inflammation in the SC of the EAE mice, as verified by histological analysis. Moreover, edaravone treatment decreased OS, increased the gene expression of the Nrf2 and HO-1, increased the activity of the mitochondrial complex II/III, reduced the activity of the mitochondrial complex IV and preserved ATP production in the SC of the EAE mice. In conclusion, findings in this study provide additional evidence of edaravone potential for the treatment of multiple sclerosis and expand our knowledge of the mechanism of action of edaravone in the EAE model.
- MeSH
- edaravon farmakologie MeSH
- encefalomyelitida autoimunitní experimentální * patologie MeSH
- encefalomyelitida * MeSH
- exprese genu MeSH
- faktor 2 související s NF-E2 genetika metabolismus MeSH
- hemoxygenasa-1 genetika metabolismus MeSH
- myši MeSH
- stupeň závažnosti nemoci MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- edaravon MeSH
- faktor 2 související s NF-E2 MeSH
- hemoxygenasa-1 MeSH
Background: Oxidative stress is a key factor in the pathophysiology of many diseases. This study aimed to verify the antioxidant activity of selected plant phenolics in cell-based assays and determine their direct or indirect effects. Methods: The cellular antioxidant assay (CAA) assay was employed for direct scavenging assays. In the indirect approach, the influence of each test substance on the gene and protein expression and activity of selected antioxidant enzymes was observed. One assay also dealt with activation of the Nrf2-ARE pathway. The overall effect of each compound was measured using a glucose oxidative stress protection assay. Results: Among the test compounds, acteoside showed the highest direct scavenging activity and no effect on the expression of antioxidant enzymes. It increased only the activity of catalase. Diplacone was less active in direct antioxidant assays but positively affected enzyme expression and catalase activity. Morusin showed no antioxidant activity in the CAA assay. Similarly, pomiferin had only mild antioxidant activity and proved rather cytotoxic. Conclusions: Of the four selected phenolics, only acteoside and diplacone demonstrated antioxidant effects in cell-based assays.
- Klíčová slova
- CAA, Nrf2-ARE, antioxidants, catalase, glucose toxicity, plant phenolics, superoxide dismutase,
- MeSH
- antioxidační responzivní elementy MeSH
- antioxidancia chemie farmakologie MeSH
- biologické markery MeSH
- exprese genu MeSH
- faktor 2 související s NF-E2 genetika metabolismus MeSH
- fenoly chemie farmakologie MeSH
- glukosa MeSH
- lidé MeSH
- molekulární struktura MeSH
- oxidační stres MeSH
- protinádorové látky chemie farmakologie MeSH
- rostlinné extrakty chemie farmakologie MeSH
- superoxiddismutasa 1 genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antioxidancia MeSH
- biologické markery MeSH
- faktor 2 související s NF-E2 MeSH
- fenoly MeSH
- glukosa MeSH
- NFE2L2 protein, human MeSH Prohlížeč
- protinádorové látky MeSH
- rostlinné extrakty MeSH
- SOD1 protein, human MeSH Prohlížeč
- superoxiddismutasa 1 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
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
The stilbenoids, a group of naturally occurring phenolic compounds, are found in a variety of plants, including some berries that are used as food or for medicinal purposes. They are known to be beneficial for human health as anti-inflammatory, chemopreventive, and antioxidative agents. We have investigated a group of 19 stilbenoid substances in vitro using a cellular model of THP-1 macrophage-like cells and pyocyanin-induced oxidative stress to evaluate their antioxidant or pro-oxidant properties. Then we have determined any effects that they might have on the expression of the enzymes catalase, glutathione peroxidase, and heme oxygenase-1, and their effects on the activation of Nrf2. The experimental results showed that these stilbenoids could affect the formation of reactive oxygen species in a cellular model, producing either an antioxidative or pro-oxidative effect, depending on the structure pinostilbene (2) worked as a pro-oxidant and also decreased expression of catalase in the cell culture. Piceatannol (4) had shown reactive oxygen species (ROS) scavenging activity, whereas isorhapontigenin (18) had a mild direct antioxidant effect and activated Nrf2-antioxidant response element (ARE) system and elevated expression of Nrf2 and catalase. Their effects shown on cells in vitro warrant their further study in vivo.
- Klíčová slova
- Nrf2, antioxidant, macrophages, pro-oxidant, pyocyanin, stilbenoid,
- MeSH
- antioxidační responzivní elementy účinky léků MeSH
- antioxidancia chemie farmakologie MeSH
- buňky Hep G2 MeSH
- faktor 2 související s NF-E2 genetika MeSH
- lidé MeSH
- peroxidace lipidů účinky léků MeSH
- pyokyanin chemie MeSH
- stilbeny chemie farmakologie MeSH
- thiobarbituráty chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antioxidancia MeSH
- faktor 2 související s NF-E2 MeSH
- NFE2L2 protein, human MeSH Prohlížeč
- pyokyanin MeSH
- stilbeny MeSH
- thiobarbituráty MeSH
- thiobarbituric acid MeSH Prohlížeč
