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Artigos de revistas sobre o assunto "Facteurs de transcription NRF2"
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Patra, Upayan, Urbi Mukhopadhyay, Arpita Mukherjee, Rakesh Sarkar e Mamta Chawla-Sarkar. "Progressive Rotavirus Infection Downregulates Redox-Sensitive Transcription Factor Nrf2 and Nrf2-Driven Transcription Units". Oxidative Medicine and Cellular Longevity 2020 (6 de abril de 2020): 1–48. http://dx.doi.org/10.1155/2020/7289120.
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Eukaryotic cells adopt highly tuned stress response physiology under threats of exogenous stressors including viruses to maintain cellular homeostasis. Not surprisingly, avoidance of cellular stress response pathways is an essential facet of virus-induced obligatory host reprogramming to invoke a cellular environment conducive to viral perpetuation. Adaptive cellular responses to oxidative and electrophilic stress are usually taken care of by an antioxidant defense system, core to which lies the redox-responsive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2-driven transcriptional cascade. Deregulation of host redox balance and redox stress-sensitive Nrf2 antioxidant defense have been reported for many viruses. In the current study, we aimed to study the modulation of the Nrf2-based host cellular redox defense system in response to Rotavirus (RV) infection in vitro. Interestingly, we found that Nrf2 protein levels decline sharply with progression of RV infection beyond an initial upsurge. Moreover, Nrf2 decrease as a whole was found to be accompanied by active nuclear vacuity of Nrf2, resulting in lowered expression of stress-responsive Nrf2 target genes heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1, and superoxide dismutase 1 both in the presence and absence of Nrf2-driven transcriptional inducers. Initial induction of Nrf2 concurred with RV-induced early burst of oxidative stress and therefore was sensitive to treatments with antioxidants. Reduction of Nrf2 levels beyond initial hours, however, was found to be independent of the cellular redox status. Furthermore, increasing the half-life of Nrf2 through inhibition of the Kelch-like erythroid cell-derived protein with CNC homology- (ECH-) associated protein 1/Cullin3-RING Box1-based canonical Nrf2 turnover pathway could not restore Nrf2 levels post RV-SA11 infection. Depletion of the Nrf2/HO-1 axis was subsequently found to be sensitive to proteasome inhibition with concurrent observation of increased K48-linked ubiquitination associated with Nrf2. Together, the present study describes robust downregulation of Nrf2-dependent cellular redox defense beyond initial hours of RV infection, justifying our previous observation of potent antirotaviral implications of Nrf2 agonists.
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Kondratenko, N. D., L. A. Zinovkina e R. A. Zinovkin. "Transcription Factor NRF2 in Endothelial Functions". Молекулярная биология 57, n.º 6 (1 de novembro de 2023): 1058–76. http://dx.doi.org/10.31857/s0026898423060101.
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The transcription factor NRF2 is the major regulator of cellular antioxidant defense. NRF2 is activated by various stimuli, such as oxidants and electrophiles, which induce the transcription of a number of genes whose products are involved in xenobiotic metabolism and contribute to the reduction of oxidative stress. NRF2 is one of the key transcription factors for endothelial cell function. Endothelium is a cell layer lining the inner cavity of blood vessels, which performs various homeostatic functions: it controls migration of leukocytes, regulates thrombosis and vascular tone, and drives angiogenesis. Endothelial dysfunction is often accompanied by inflammation and oxidative stress, which may lead to cellular aging as well as cell death by apoptosis, necrosis, and ferroptosis. Endothelial dysfunction contributes to the development of such common cardiovascular diseases as hypertension, diabetes, and atherosclerosis. Many pathophysiological processes in the endothelium, including senile changes, are associated with decreased NRF2 activity, leading to inflammatory activation and decreased activity of cellular antioxidant defense systems. Activation of the NRF2 signaling pathway generally contributes to the resolution of inflammation and oxidative stress. This review focuses on the importance of NRF2 in the basic functions of endothelium in normal and pathological conditions. In addition, the advantages and disadvantages of NRF2 activation as a way to prevent and treat cardiovascular diseases are discussed.
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Plafker, Kendra S., e Scott M. Plafker. "The ubiquitin-conjugating enzyme UBE2E3 and its import receptor importin-11 regulate the localization and activity of the antioxidant transcription factor NRF2". Molecular Biology of the Cell 26, n.º 2 (15 de janeiro de 2015): 327–38. http://dx.doi.org/10.1091/mbc.e14-06-1057.
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The transcription factor NF-E2 p45–related factor (Nrf2) induces the expression of cytoprotective proteins that maintain and restore redox homeostasis. Nrf2 levels and activity are tightly regulated, and three subcellular populations of the transcription factor have been identified. During homeostasis, the majority of Nrf2 is degraded in the cytoplasm by ubiquitin (Ub)-mediated degradation. A second population is transcriptionally active in the nucleus, and a third population localizes to the outer mitochondrial membrane. Still unresolved are the mechanisms and factors that govern Nrf2 distribution between its subcellular locales. We show here that the Ub-conjugating enzyme UBE2E3 and its nuclear import receptor importin 11 (Imp-11) regulate Nrf2 distribution and activity. Knockdown of UBE2E3 reduces nuclear Nrf2, decreases Nrf2 target gene expression, and relocalizes the transcription factor to a perinuclear cluster of mitochondria. In a complementary manner, Imp-11 functions to restrict KEAP1, the major suppressor of Nrf2, from prematurely extracting the transcription factor off of a subset of target gene promoters. These findings identify a novel pathway of Nrf2 modulation during homeostasis and support a model in which UBE2E3 and Imp-11 promote Nrf2 transcriptional activity by restricting the transcription factor from partitioning to the mitochondria and limiting the repressive activity of nuclear KEAP1.
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Scoazec, Jean-Yves. "Facteurs de transcription : quelles applications diagnostiques ?" Annales de Pathologie 32, n.º 5 (novembro de 2012): S32—S33. http://dx.doi.org/10.1016/j.annpat.2012.08.003.
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He, Feng, Xiaoli Ru e Tao Wen. "NRF2, a Transcription Factor for Stress Response and Beyond". International Journal of Molecular Sciences 21, n.º 13 (6 de julho de 2020): 4777. http://dx.doi.org/10.3390/ijms21134777.
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Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the cellular defense against toxic and oxidative insults through the expression of genes involved in oxidative stress response and drug detoxification. NRF2 activation renders cells resistant to chemical carcinogens and inflammatory challenges. In addition to antioxidant responses, NRF2 is involved in many other cellular processes, including metabolism and inflammation, and its functions are beyond the originally envisioned. NRF2 activity is tightly regulated through a complex transcriptional and post-translational network that enables it to orchestrate the cell’s response and adaptation to various pathological stressors for the homeostasis maintenance. Elevated or decreased NRF2 activity by pharmacological and genetic manipulations of NRF2 activation is associated with many metabolism- or inflammation-related diseases. Emerging evidence shows that NRF2 lies at the center of a complex regulatory network and establishes NRF2 as a truly pleiotropic transcription factor. Here we summarize the complex regulatory network of NRF2 activity and its roles in metabolic reprogramming, unfolded protein response, proteostasis, autophagy, mitochondrial biogenesis, inflammation, and immunity.
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Tamir, Tigist Y., Brittany M. Bowman, Megan J. Agajanian, Dennis Goldfarb, Travis P. Schrank, Trent Stohrer, Andrew E. Hale et al. "Gain-of-function genetic screen of the kinome reveals BRSK2 as an inhibitor of the NRF2 transcription factor". Journal of Cell Science 133, n.º 14 (16 de junho de 2020): jcs241356. http://dx.doi.org/10.1242/jcs.241356.
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ABSTRACTNuclear factor erythroid 2-related factor 2 (NFE2L2, also known as NRF2) is a transcription factor and master regulator of cellular antioxidant response. Aberrantly high NRF2-dependent transcription is recurrent in human cancer, but conversely NRF2 activity diminishes with age and in neurodegenerative and metabolic disorders. Although NRF2-activating drugs are clinically beneficial, NRF2 inhibitors do not yet exist. Here, we describe use of a gain-of-function genetic screen of the kinome to identify new druggable regulators of NRF2 signaling. We found that the under-studied protein kinase brain-specific kinase 2 (BRSK2) and the related BRSK1 kinases suppress NRF2-dependent transcription and NRF2 protein levels in an activity-dependent manner. Integrated phosphoproteomics and RNAseq studies revealed that BRSK2 drives 5′-AMP-activated protein kinase α2 (AMPK) signaling and suppresses the mTOR pathway. As a result, BRSK2 kinase activation suppresses ribosome-RNA complexes, global protein synthesis and NRF2 protein levels. Collectively, our data illuminate the BRSK2 and BRSK1 kinases, in part by functionally connecting them to NRF2 signaling and mTOR. This signaling axis might prove useful for therapeutically targeting NRF2 in human disease.This article has an associated First Person interview with the first author of the paper.
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Malloy, Melanie Theodore, Deneshia J. McIntosh, Treniqka S. Walters, Andrea Flores, J. Shawn Goodwin e Ifeanyi J. Arinze. "Trafficking of the Transcription Factor Nrf2 to Promyelocytic Leukemia-Nuclear Bodies". Journal of Biological Chemistry 288, n.º 20 (29 de março de 2013): 14569–83. http://dx.doi.org/10.1074/jbc.m112.437392.
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Ubiquitylation of Nrf2 by the Keap1-Cullin3/RING box1 (Cul3-Rbx1) E3 ubiquitin ligase complex targets Nrf2 for proteasomal degradation in the cytoplasm and is an extensively studied mechanism for regulating the cellular level of Nrf2. Although mechanistic details are lacking, reports abound that Nrf2 can also be degraded in the nucleus. Here, we demonstrate that Nrf2 is a target for sumoylation by both SUMO-1 and SUMO-2. HepG2 cells treated with As2O3, which enhances attachment of SUMO-2/3 to target proteins, increased SUMO-2/3-modification (polysumoylation) of Nrf2. We show that Nrf2 traffics, in part, to promyelocytic leukemia-nuclear bodies (PML-NBs). Cell fractions harboring key components of PML-NBs did not contain biologically active Keap1 but contained modified Nrf2 as well as RING finger protein 4 (RNF4), a poly-SUMO-specific E3 ubiquitin ligase. Overexpression of wild-type RNF4, but not the catalytically inactive mutant, decreased the steady-state levels of Nrf2, measured in the PML-NB-enriched cell fraction. The proteasome inhibitor MG-132 interfered with this decrease, resulting in elevated levels of polysumoylated Nrf2 that was also ubiquitylated. Wild-type RNF4 accelerated the half-life (t½) of Nrf2, measured in PML-NB-enriched cell fractions. These results suggest that RNF4 mediates polyubiquitylation of polysumoylated Nrf2, leading to its subsequent degradation in PML-NBs. Overall, this work identifies Nrf2 as a target for sumoylation and provides a novel mechanism for its degradation in the nucleus, independent of Keap1.
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Kondratenko, N. D., L. A. Zinovkina e R. A. Zinovkin. "Transcription Factor NRF2 in Endothelial Functions". Molecular Biology 57, n.º 6 (dezembro de 2023): 1052–69. http://dx.doi.org/10.1134/s0026893323060092.
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McIntosh, Deneshia J., Treniqka S. Walters, Ifeanyi J. Arinze e Jamaine Davis. "Arkadia (RING Finger Protein 111) Mediates Sumoylation-Dependent Stabilization of Nrf2 Through K48-Linked Ubiquitination". Cellular Physiology and Biochemistry 46, n.º 1 (2018): 418–30. http://dx.doi.org/10.1159/000488475.
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Background/Aims: The transcription factor Nrf2 is a master regulator of the antioxidant defense system, protecting cells from oxidative damage. We previously reported that the SUMO-targeted E3 ubiquitin ligase (STUbL), RING finger protein 4 (RNF4) accelerated the degradation rate of Nrf2 in promyelocytic leukemia-nuclear body (PML-NB)-enriched fractions and decreased Nrf2-mediated gene transcription. The mechanisms that regulate Nrf2 nuclear levels are poorly understood. In this study, we aim to explore the role of the second mammalian STUbL, Arkadia/RNF111 on Nrf2. Methods: Arkadia mediated ubiquitination was detected using co-immunoprecipitation assays in which whole cell lysates were immunoprecipated with anti-Nrf2 antibody and Western blotted with anti-hemagglutinin (HA) antibody or anti-Lys-48 ubiquitin-specific antibody. The half-life of Nrf2 was detected in whole cell lysates and promyelocytic leukemia-nuclear body enriched fractions by cycloheximide-chase. Reporter gene assays were performed using the antioxidant response element (ARE)-containing promoter Heme oxygenase-1 (HO-1). Results: We show that Arkadia/RNF111 is able to ubiquitinate Nrf2 resulting in the stabilization of Nrf2. This stabilization was mediated through Lys-48 ubiquitin chains, contrary to traditionally degradative role of Lys-48 ubiquitination, suggesting that Lys-48 ubiquitination of Nrf2 protects Nrf2 from degradation thereby allowing Nrf2-dependent gene transcription. Conclusion: Collectively, these findings highlight a novel mechanism to positively regulate nuclear Nrf2 levels in response to oxidative stress through Arkadia-mediated K48-linked ubiquitination of Nrf2.
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Maruyama, Atsushi, Keizo Nishikawa, Yukie Kawatani, Junsei Mimura, Tomonori Hosoya, Nobuhiko Harada, Masayuki Yamamato e Ken Itoh. "The novel Nrf2-interacting factor KAP1 regulates susceptibility to oxidative stress by promoting the Nrf2-mediated cytoprotective response". Biochemical Journal 436, n.º 2 (13 de maio de 2011): 387–97. http://dx.doi.org/10.1042/bj20101748.
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The transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2) co-ordinately regulates ARE (antioxidant-response element)-mediated induction of cytoprotective genes in response to electrophiles and oxidative stress; however, the molecular mechanism controlling Nrf2-dependent gene expression is not fully understood. To identify factors that regulate Nrf2-dependent transcription, we searched for proteins that interact with the Nrf2-NT (N-terminal Nrf2 transactivation domain) by affinity purification from HeLa nuclear extracts. In the present study, we identified KAP1 [KRAB (Krüppel-associated box)-associated protein 1] as a novel Nrf2-NT-interacting protein. Pull-down analysis confirmed the interaction between KAP1 and Nrf2 in cultured cells and demonstrated that the N-terminal region of KAP1 binds to Nrf2-NT in vitro. Reporter assays showed that KAP1 facilitates Nrf2 transactivation activity in a dose-dependent manner. Furthermore, the induction of the Nrf2-dependent expression of HO-1 (haem oxygenase-1) and NQO1 [NAD(P)H quinone oxidoreductase 1] by DEM (diethyl maleate) was attenuated by KAP1 knockdown in NIH 3T3 fibroblasts. This finding established that KAP1 acts as a positive regulator of Nrf2. Although Nrf2 nuclear accumulation was unaffected by KAP1 knockdown, the ability of Nrf2 to bind to the regulatory region of HO-1 and NQO1 was reduced. Moreover, KAP1 knockdown enhanced the sensitivity of NIH 3T3 cells to tert-butylhydroquinone, H2O2 and diamide. These results support our contention that KAP1 participates in the oxidative stress response by maximizing Nrf2-dependent transcription.
Teses / dissertações sobre o assunto "Facteurs de transcription NRF2"
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Fourquet, Simon. "Régulation redox des facteurs des transcription de la famille CNC-bZip Nrf2 et Bach2". Phd thesis, Université Paris Sud - Paris XI, 2008. http://tel.archives-ouvertes.fr/tel-00553306.
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Les espèces chimiques dérivées par réduction incomplète de l'oxygène, les ROS pour « Reactive Oxygen Species », et espèces réactives dérivées de l'azote, les RNS pour « Reactive Nitrogen Species », sont potentiellement toxiques pour les cellules, car leur pouvoir oxydant leur confère une grande réactivité sur la plupart des molécules biologiques. Des systèmes cellulaires existent, qui assurent leur maintien à des concentrations non toxiques. Cependant, l'oxygène est nécessaire aux cellules pour son rôle d'accepteur final d'électrons dans la chaîne respiratoire, et certains ROS ou RNS sont nécessaires à l'accomplissement de diverses fonctions biologiques. En particulier, l'H2O2 participe en tant que second messager à la signalisation cellulaire en aval de l'engagement de certains récepteurs à des facteurs de croissance. Notre objectif est de documenter le rôle possible de ces espèces réactives dans la signalisation cellulaire chez les mammifères, en mettant en évidence des protéines cibles de l'oxydation, et en étudiant l'effet fonctionnel de ces oxydations. Nous avons choisi d'étudier la formation de ponts disulfures en réponse peroxyde d'hydrogène H2O2 et au monoxyde d'azote NO dans la protéine Keap1, qui régule l'activité du facteur de transcription Nrf2, et le facteur de transcription Bach2. Nrf2 et Bach2 sont deux facteurs de transcription de la famille des protéines à CNC-bZip, et contrôlent tous deux l'expression de gènes régulés en cis par des séquences de type ARE, pour « Antioxidant Responsive Element".
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Genard, Romain. "Rôle du facteur de transcription Nrf2 dans l'immunomodulation induit par les adjuvants vaccinaux". Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS230/document.
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Les adjuvants vaccinaux permettent d’augmenter la réponse immunitaire dirigée contre un antigène donné. Certains de ces adjuvants miment des signaux de danger, tels que des agonistes des récepteurs de l’immunité, les récepteurs Toll-like (TLR) ou les récepteurs NOD-like (NLR), et permettent une activation des cellules dendritiques (DC). Les DC sont essentielles dans la mise en place d’une réponse adaptative contre un antigène : elles acquièrent un phénotype mature, contrôlé par les voies des MAPK et NF-κB, permettant la présentation de l’antigène aux lymphocyte T et l’initiation d’une réponse spécifique. La voie Nrf2/Keap1, impliquée principalement dans la détoxication des xénobiotiques et le contrôle du stress oxydant, peut être activée en réponse à des agonistes des TLR tels que le LPS (agoniste TLR 4). Nous avons mis en évidence qu’un traitement par le R848 (agoniste TLR7/8) ou le MDP (agoniste NOD2) induit la transcription des gènes cibles de Nrf2 dans les DC murines. Nrf2 participe également à la production de cytokines inflammatoires en réponse au LPS et au R848 et jouet un rôle dans la prolifération lymphocytaire induite par les DC pré-traitées avec le MDP. Par ailleurs, Nrf2 contrôle la réponse anticorps spécifiques de l’antigène chez la souris. L’injection d’anatoxine tétanique induit une production d’anticorps plus élevé chez la souris déficiente nrf2 par rapport aux souris sauvages. Cette augmentation de la production d’anticorps est corrélée avec une augmentation du nombre de lymphocyte B dans la moelle osseuse et la rateVaccine adjuvants are able to boost immune response toward antigens when there are simultaneously injected. Some of these adjuvant mimic danger signals, such as Toll like receptors (TLR) agonists or NOD-like receptors agonists, required for dendritic cell (DC) activation. DC are essentiales for adaptative immune response against antigens : they acquire mature phenotype, controlled by MAPK and NF-kB signaling pathway, leading to antigen presentation and specific immune response. The Nrf2/keap1 signaling pathway, mainly involves in xenobiotics detoxication and oxidative stress control, can be activate by TLR agonists, such as LPS (TLR 4 agonist).We showed that R848 (TLR 7/8 agonist) and MDP (NOD2 agonist) could induce Nrf2’s target genes transcription in murines dendritic cells (BMDC). Nrf2 seems also to be part of inflammatory cytokines production in response to LPS or R848 and modulated T lymphocyte proliferation induced by MDP pre-treated BMDC. Moreover, Nrf2 appears to play a role in specific antibodies response against an antigen in mice. . In fact, Tetanus toxoid (TT) injection induces higher titer of antibodies anti-TT in nrf2-/- mice compared to nrf2+/+ mice. This increase is also correlated with more specific B lymphocytes in bone marrow and spleen after TT immunisation
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Saliou, Alexa. "Study of cellular senescence in Glioblastoma : Application for the development of companion therapies". Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASL036.
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Le glioblastome (GBM) est la tumeur primitive la plus agressive du cerveau adulte. Il résiste inexorablement aux traitements et la survie moyenne des patients est fortement limitée. L’inefficacité des traitements se justifie notamment par l’hétérogénéité des cellules tumorales, l’accès restreint des molécules au cerveau et une forte immunosuppression. Cette caractéristique du microenvironnement est également responsable de l’absence de réponse des GBM aux immunothérapies. Ainsi, le développement de nouvelles thérapies est essentiel pour améliorer la survie des patients. Pour cela, nous étudions le rôle de la sénescence au cours de la gliomagénèse. Premièrement, à partir de tumeurs de patients et d’un modèle pré-clinique immunocompétent, nous avons démontré l’action protumorale de la sénescence dans le GBM. En effet, la déplétion partielle des cellules sénescentes grâce au transgène p16-3MR augmente la survie des animaux et module le système immunitaire vers un phénotype pro-inflammatoire. Nous avons identifié le facteur de transcription Nrf2 comme régulateur de la sénescence et développé une signature, conservée chez les patients, de 31 gènes associés à la sénescence. Sa forte expression corrèle avec un mauvais pronostic. Cette étude fondatrice ouvre la voie aux deux projets suivants. Deuxièmement, nous étudions la fonction régulatrice de NRF2 sur la sénescence à partir d’une analyse transcriptomique à l’échelle de la cellule unique des fractions tumorales et immunitaires de GBM murins contrôles (miR-ctl) et déplétés pour NRF2 (miR-NRF2). L’inhibition de NRF2 dans les cellules malignes induit une forte plasticité et la surexpression de gènes impliqués dans la machinerie de présentation des antigènes. Ces résultats suggèrent que NRF2 régule l’immunogénicité de la tumeur. L’analyse du transcriptome de la fraction immunitaire ainsi qu’un phénotypage par cytométrie permettront de valider ces résultats. Enfin, nous évaluons l’hypothèse qu’un sénolytique sensibiliserait le GBM aux inhibiteurs de points de contrôle immunitaire (ICB). Nous avons observé que les cellules malignes sont enrichies en gènes associés à la machinerie de présentation des antigènes dans une condition déplétée en cellules sénescentes. Ainsi, des cohortes murines ont été soumises à différents combinaisons de sénolytiques couplés à des ICBs, ce qui nous a permis de déterminer un cocktail induisant une augmentation significative de la survie. Une étude plus poussée caractérisera la fraction immunitaire, analysera les modifications induites par le traitement et identifiera le sous-type immunitaire engendrant la levée de la résistance aux immunothérapies. L’ensemble de ces travaux pourrait mener à une médecine personnalisée pour le traitement du GBM avec l’utilisation d’un sénolytique chez les patients dont la tumeur est riche en cellules sénescentes. Aussi, l’identification de nouveaux sénolytiques liés à la voie NRF2 pourrait bénéficier à de nombreuses pathologies impliquant la sénescenceDiffuse gliomas are the most common primary tumor of the adult central nervous system. Glioblastoma (GBM) accounts for the most aggressive subtype. Conventional treatments remain ineffective as the vast majority of tumors relapse and patient survival remains limited (15 months). Due to a highly immunosuppressive microenvironment, immunotherapies also fail to treat GBM. Thus, the development of novel therapies is crucial to increase patient survival. To this end, we investigate the role of cellular senescence during gliomagenesis. In the first part of my project, we demonstrated the pro-tumoral action of malignant senescent cells in GBM using patient tumor specimens and a mouse GBM model. Indeed, partial removal of malignant senescent cells modulates the immune compartment and improves survival of GBM-bearing mice. In addition, we identified the NRF2 transcription factor, as a determinant of the senescent phenotype. Based on mouse GBM transcriptomic data, we defined a 31-gene senescence signature which is conserved in human lesions. Its high expression correlates with poor outcomes in patients. These findings highlight senolytics as a potential adjuvant therapy to treat GBM. In the light of these findings, we hypothesized that (i) exploring NRF2 signaling may provide new therapeutic insights and that (ii) senolytic-driven modulation of the immune compartment may prime GBM to respond to immunotherapy. Single cell analysis of malignant and immune paired fractions from control (miR-ctl) and NRF2-KD (miR-NRF2) immunocompetent mouse GBMs showed a decrease in the malignant senescent cluster upon NRF2-KD, strengthening NRF2 as a determinant of senescence. NRF2-KD in tumoral cells enhances cellular plasticity and enables the emergence of clusters, characterized by differential upregulation of genes coding for major histocompatibility complex (MHC) molecules. This suggests that NRF2 indirectly promotes immunogenicity in GBM. Immune transcriptomic analysis and immunophenotyping by flow cytometry will help confirming these results. Furthermore, we observed that GBM-bearing mice treated with a genetic senolytic (p16-3MR+GCV) displayed an upregulation of gene signatures associated to the antigen presentation machinery. Thus, we hypothesized that senolytic and immune checkpoint blockade (ICB) might synergize and delay tumor growth. We subjected mouse cohorts to different combination of senolytic and ICBs and highlighted a specific cocktail which positively benefited mouse survival. Thus, our preliminary results suggest that senolytic might potentiates immune checkpoint blockade to hinder GBM progression. Further work is needed to immunophenotype control and treated tumors, investigate treatment-related microenvironment modifications as well as identify the immune subtype driving the response to immunotherapy. Altogether, these results open promising avenues for personalized therapies in the context of senescence enriched GBMs. Also, identification of novel senolytics associated to NRF2 could beneficiate several pathologies in which senescence role is critical
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Fourquet, Simon. "Régulation redox des facteurs des transcriptions de la famille CNC-bZip Nrf2 et Bach2". Paris 11, 2008. http://www.theses.fr/2008PA112305.
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Dans des cellules de mammifère, les facteurs de transcription de la famille CNC-bZip Nrf2 et Bach2 participent au contrôle des réponses à des espèces pro-oxydantes. En réponse à de nombreuses classes d'agents électrophiles, Nrf2 transactive des gènes régulés en cis par des séquences de type ARE codent notamment pour des enzymes de détoxication, permettant ainsi leur maintien homéostatique à des concentrations non toxiques. L'activation de Bach2, un répresseur de la transcription, semble importante pour une mort cellulaire en réponse à certains agents électrophiles. Nous avons cherché à examiner les mécanismes mis en jeu lors de l'activation de Bach2 et Nrf2 par des agents oxydants produits au cours de l'inflammation, tel le peroxyde d'hydrogène et le monoxyde d'azote. Nous avons pu mettre en évidence l'oxydation, sous forme de ponts disulfure, de Bach2 et de Keap1, le régulateur principal de l'activation de Nrf2, et identifier par mutagenèse dirigée, les cystéines impliquées dans les différentes formes oxydées de Keap1. De plus, nous avons montré que l'oxydation de Keap1 résulte en une levée de l'inhibition exercée sur Nrf2, et ainsi en l'activation de Nrf2. La nature et le rôle de l'oxydation de Bach2 n'ont pu être clairement définis. Enfin, nous avons décrit une régulation positive de l'oxydation de Nrf2 et Bach2 par la sur-expression de la peroxyredoxine Prx1. Cet effet est inattendu, car l'activité peroxydase de Prx1 devrait limiter la concentration efficace de peroxyde d'hydrogène disponible pour l'oxydation de Nrf2 ou Bach2. Nous proposons un modèle mécanistique inspiré du système Orp1-Yap1 de S. Cerevisiae pour rationaliser cette observationIn mammalian cells, CNC-bZip family members Nrf2 and Bach2 participate in the cellular control of prooxidant species. Many classes of electrophilic compounds allow Nrf2 to transactivate ARE cis-regulated genes coding for detoxifying enzymes, so as to achieve a homeostatic control at non toxic levels for these compounds. Activation of Bach2, which is a transcriptional repressor, participate in cell killing in response to some electrophilic species, especially in B cell. We sought to determine the mechanisms involved in Nrf2 and Bach2 activation by oxidant molecules produced by activated macrophages during inflamation, such as hydrogen peroxide and nitric oxide. We described the oxidation through disulfide bonds of Bach2 and Keap1, the main regulator of Nrf2 activation. Mutagenesis experiment identified the cysteines engaged in disulfides in the different oxidation forms of Keap1. We also showed that Keap1 oxidation leads to a derepression of Nrf2, thereby to its activation. The nature and function of Bach2 oxidation couldn't be completely understood. We described a positive regulation of peroxiredoxin Prx1 of Nrf2 and Bach2 oxidation, which as unexpected since the peroxidase activity sould have hampered other oxidation reactions. We propose a mechanistic model based on the Orp1-Yap1 peroxyde sensing system of S. Cerevisiae to rationalize this observation
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Tertil, Magdalena. "Role of thymidine phosphorylase and Nrf2 transcription factor in non-small cell lung carcinoma growth and angiogenesis". Thesis, Orléans, 2013. http://www.theses.fr/2013ORLE2043.
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Le facteur de transcription Nrf2 et les enzymes pro-angiogéniques: hème oxygénase (HO-1) et thymidine phosphorylase (TP) sont considérés comme des cibles potentielles pour les traitements combinatoires anticancéreux contre l’angiogenèse. L'objectif de la présente étude était d'examiner les interactions entre ces protéines dans la modulation du potentiel tumorigène et angiogénique de carcinome pulmonaire non à petites cellules (NSCLC). L’augmentation de l’expression de Nrf2 conduit à la réduction de la prolifération cellulaire et à leur capacité de migration, accompagnée d'une expression accrue de microARN suppresseurs de tumeurs ainsi qu’une réduction de l'oncogène miR-378. Ensuite, le rôle de TP dans les cellules NCI-H292 a été étudiée en la surexprimant in vitro (NCI-TP). Ceci a conduit à une atténuation de potentiel tumorigène comme le montre l'inhibition de la prolifération, de la migration et une amélioration concomitante de potentiel angiogénique qui est plus prononcée en hypoxie et en présence de thymidine. In vivo, les tumeurs NCI-TP ont tendance à croître plus rapidement que les témoins et ils sont également mieux oxygénés. Ces tumeurs ont une expression accrue de cytokines pro-inflammatoires IL-1β et IL-6. Nous avons montré pour la première fois que l’enzyme TP peut être régulé par Nrf2 et HO-1 dans les cellules NSCLC, ce qui peut affecter la croissance tumorale par une modulation de l'angiogenèse et de l'expression de facteurs pro-inflammatoires. La corrélation entre l’expression de TP avec celle de l'IL-1β et d'IL-6 a été également confirmée dans les échantillons cliniques de tumeurs issus de patients atteints de NSCLC. L’ensemble de nos résultats montre la potentialité de cibler l’enzyme TP pour le traitement des cancers NSCLCNrf2, heme oxygenase-1 (HO-1) and thymidine phosphorylase (TP) are considered as potential targets for combinatorial anti-cancer therapies. The aim of the study was to investigate the interplay of these proteins in regulation of growth and angiogenesis in non-small cell lung carcinoma (NSCLC) cells NCI-H292. Stable overexpression of Nrf2 (NCI-Nrf2 cell line) resulted in decreased cell proliferation and migration in vitro, upregulation of tumor suppressor microRNAs and downregulation of oncogenic miR-378 and many MMPs. Silencing of HO-1 in NCI-Nrf2 cells partially reversed the effect on MMP-1, MMP-3 and miR-378. NCI-Nrf2 cells exhibited increased expression of proangiogenic factors IL-8, angiopoietin-1 and TP, which was also upregulated in cell overexpressing HO-1. In both models, the effect was TP reversible by siRNA targeted at HO-1 and possibly mediated by modulation of oxidative status of the cell. Moreover, it was observed that overexpression of TP in vitro attenuated proliferation and migration of NSCLC cells, but increased their angiogenic potential. In vivo, NCI-TP tumors tended to grow faster, were better oxygenated and exhibited increased expression of inflammatory cytokines IL-1β and IL-6. Correlation of TP with IL-1β and IL-6 was also confirmed in clinical samples from NSCLC patients. Overall, our results enforce the notion of targeting TP for treatment of NSCLC
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Olagnier, David. "Rôle des facteurs de transcription PPARgamma et Nrf2 dans la modulation de l'expression du récepteur scavenger CD36 des macrophages : implication dans la physiopathologie du paludisme". Toulouse 3, 2011. http://thesesups.ups-tlse.fr/1308/.
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Le paludisme demeure la maladie parasitaire la plus meurtrière à travers le monde. La mise en place de nouvelles approches thérapeutiques dans la lutte contre ce pathogène semble indispensable. Les macrophages via le récepteur CD36 jouent un rôle crucial dans la reconnaissance et l'élimination des hématies infectées par P. Falciparum. Ainsi, le maintien d'un niveau élevé d'expression du récepteur CD36 à la surface des macrophages est un élément capital dans la lutte contre le parasite. L'établissement de l'infection est toujours associé à une production excessive de médiateurs pro-inflammatoires. Dans ce travail, nous montrons in vitro que les processus inflammatoires régulent négativement l'expression du récepteur CD36 à la surface des macrophages humains et murins et diminuent la clairance des hématies infectées. Dans ces conditions inflammatoires, nous démontrons que les ligands du récepteur nucléaire PPARgamma sont inefficaces pour promouvoir l'expression du récepteur CD36, phénomène directement associé à un défaut d'expression et d'activation de PPARgamma. Cependant, nous mettons en évidence pour la première fois que l'activation du facteur de transcription Nrf2 permet de restaurer indépendamment de PPARgamma l'expression et les fonctions antiplasmodiales du récepteur CD36. L'ensemble de ces résultats ont été reproduits in vivo dans un modèle de paludisme murin où seulement les activateurs de Nrf2 et non les ligands de PPARgamma contribuent à améliorer l'évolution de l'infection. Ces données soulignent le rôle important du facteur de transcription Nrf2 dans le traitement du paludisme via la modulation d'expression du récepteur CD36 des macrophagesMalaria remains the deadliest parasitic disease in the world. The introduction of new pharmacological approaches in the fight against this pathogen is essential. Macrophages through the expression of CD36 receptor play a crucial role in the recognition and the elimination of P. Falciparum infected erythrocytes. Therefore, maintaining an elevated level of CD36 receptor on the surface of macrophages is a crucial element in the struggle against the parasite. The establishment of malaria infection is always associated with an excessive production of pro-inflammatory mediators. In this work, we show in vitro that inflammatory processes negatively regulate the expression of CD36 receptor on the surface of human and mouse macrophages and hence decrease the clearance of parasitized erythrocytes. In these inflammatory conditions, we demonstrate that PPARgamma activators are ineffective to promote CD36 expression on macrophages, a phenomenon directly associated with a defect of both PPARgamma expression and activation. However, we highlight here for the first time that the activation of the Nrf2 transcription factor controls independently of PPARgamma the expression of CD36 receptor and its antiplasmodial function. All these results have been reproduced in vivo in a murine malaria model where only Nrf2 activators and not PPARgamma ligands contribute to improve the outcome of infection. Collectively, these data highlight the important role of the Nrf2 transcription factor in the control of malaria through the modulation of CD36 expression on macrophages
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El, ali Zeina. "Rôle du facteur de transcription Nrf2 dans le contrôle de l'allergie cutanée en réponse aux molécules allergisantes". Thesis, Paris 11, 2013. http://www.theses.fr/2013PA114847/document.
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Les réactions allergiques telles que les réactions d’hypersensibilité de contact (HSC) sont un problème de santé publique. Il s’agit d’une réaction inflammatoire aiguë qui survient suite à des expositions répétées d’une molécule allergisante avec la peau et dans laquelle les cellules dendritiques (DC) jouent un rôle essentiel. Les composés chimiques tels que le dinitrochlorobenzène (DNCB) ou le cinnamaldéhyde (CinA), responsables d'HSC, sont capables d’induire un stress chimique et de produire des espèces réactives de l’oxygène (ERO). Parmi les voies de détoxication en réponse aux xénobiotiques, la voie Nrf2/Keap1 est une voie centrale connue pour la détection de composés électrophiles. A l’état basal et en absence de stress, Nrf2 est couplé à son répresseur cytosolique Keap1 qui assure sa dégradation via le protéasome. En présence d’un stress chimique, Nrf2 transloque dans le noyau et induit l’expression des gènes antioxydants [hème-oxygénase 1 (ho-1), NADPH quinone oxydoréductase (nqo1), glutathione-s-transférase (gst)]. En absence de Nrf2, nous avons montré que le DNCB et le CinA induisent la mort cellulaire des DC via l'activation des caspases impliquées dans la voie mitochondriale ou intrinsèque de l'apoptose. Cette mort cellulaire induite par le DNCB est ERO dépendante tandis que celle induite par le CinA est moins sensible à la production des ERO. En présence de Nrf2, la survie des DC est régulée par l'expression de bcl-2, un gène antiapoptotique, et des gènes antioxydants. Nrf2 semblerait activer ou réprimer la transcription des gènes et ce en fonction de la molécule testée, du temps de traitement. Par ailleurs, nous avons également montré que Nrf2 joue un rôle clef dans les phases de sensibilisation et d'élicitation de la réaction d'HSC mais également au cours de l'irritation. Des transferts adoptifs de DC ont permis de montrer le rôle clef de Nrf2 dans la DC au cours de l'HSC. Enfin, notre étude montre que Nrf2 régule les Treg au niveau du tissu cutané et participe à la tolérance cutanéeAllergic reactions such as contact hypersensitivity (CHS) are a problem of public health occurring after repeated exposures to contact sensitizers. CHS is a common skin disease involving dendritic cells (DC) playing a key role in this pathology. Contact sensitizers, like dinitrochlorobenzene (DNCB) or cinnamaldehyde (CinA) are known to induce reactive oxygen species (ROS) production. The Nrf2/Keap1 pathway is central for detoxification. In the absence of a chemical stress, Keap1 associates with Nrf2 and leading to its degradation. In the presence of an electrophilic compound like contact sensitizers, Keap1’s conformation is modified leading to Nrf2 translocation to the nucleus and transcription of its target genes [heme-oxygénase 1 (ho-1), NADPH quinone oxydoreductase (nqo1), glutathione-s-transferase (gst)]. We showed, for the first time, that Nrf2 controls the loss of mitochondrial membrane potential and caspase-3/7 activity in DC activated by contact sensitizers. In the absence of Nrf2, DNCB and CinA induced DC apoptosis via caspase activation involved in intrinsic pathway of apoptosis also called ‘mitochondrial pathway’. This apoptosis was mainly mediated by the production of ROS in response to DNCB. However, ROS faintly control CinA-induced cell death. We also showed that Nrf2 controls the transcription of the anti-apoptotic gene bcl-2 in response to DNCB or CinA and also the transcription of immune related and antioxidant genes that could be implicated in DC apoptosis.Otherwise, we also showed that Nrf2 plays a key role in sensitization and elicitation phases of CHS and even in the irritation phase. Adoptive transfer experiments showed that Nrf2 plays a crucial role in DC during CHS.Finally, we showed that Nrf2 regulates skin Treg and participates to skin tolerance
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Helou, Doumet. "Rôle du facteur de transcription Nrf2 dans la régulation des fonctions du neutrophile in vitro et dans l’allergie cutanée". Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS305/document.
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Les neutrophiles constituent une première ligne de défense contre les agents infectieux. En revanche, leur activation incontrôlée peut exacerber certaines pathologies inflammatoires telles que les allergies cutanées. Notre équipe a montré précédemment que le facteur de transcription Nrf2 connu pour son rôle anti-oxydant, régulait l’inflammation cutanée dans l’hypersensibilité de contact (HSC). Ainsi ce travail a été mené pour évaluer in vitro l’implication de la voie Nrf2 dans les fonctions des neutrophiles et pour identifier son rôle dans le recrutement et l’activation des neutrophiles dans l’HSC.In vitro, nous montrons que la protéine Nrf2 est fortement exprimée dans les neutrophiles de la moelle osseuse. Nrf2 est fonctionnelle dans les neutrophiles stimulés : il active la transcription de gènes cibles cytoprotecteurs et diminue celle des gènes de l’inflammation. Ainsi, le prétraitement des neutrophiles avec un activateur de Nrf2 tel que le sulforaphane, réduit la production des formes réactives de l’oxygène (FRO)en réponse à une stimulation. En parallèle, l’absence de Nrf2 ne semble pas affecter la phagocytose et la nétose, deux fonctions clés du neutrophile. Enfin, Nrf2 est indispensable pour une migration optimale des neutrophiles en réponse aux chimiokines.Au cours de l’HSC induite par le dinitrochlorobenzène (DNCB), Nrf2 régule indirectement le recrutement des neutrophiles, en contrôlant le stress oxydant cutané et les voies inflammatoires impliquées dans la production de chimiokines, notamment CCL2, CCL4 et CCL11. En outre, Nrf2 induit l’augmentation d’expression du scavenger CD36 dans les macrophages et augmente ainsi leur capacité à éliminer les neutrophiles apoptotiques pour initier la résolution de l’inflammation.En conclusion, l’activation de Nrf2 dans les neutrophiles participe au contrôle de la production des FRO et la migration. En outre, Nrf2 émerge comme un effecteur clé dans le contrôle du recrutement et de la clairance des neutrophiles au cours de la réponse inflammatoire cutanée aux molécules allergisantes. La mise en évidence de ces mécanismes protecteurs de Nrf2 nous permet de proposer cette protéine comme nouvelle cible thérapeutique dans le contrôle d’inflammations cutanées chroniquesNeutrophils form the first line of defense against infectious agents. However, their uncontrolled activation may exacerbate certain inflammatory conditions such as cutaneous allergies. Our team has previously shown that Nrf2 transcription factor known for its antioxidant role, regulates skin inflammation in contact hypersensitivity (CHS). Thus, our work was carried out to evaluate in vitro the involvement of Nrf2 pathway in neutrophil functions and to identify Nrf2 role in neutrophil recruitment and activation in CHS.In vitro, we showed that the protein Nrf2 was highly expressed in bone marrow neutrophils. Nrf2 is functional in stimulated neutrophils: it activates the transcription of cytoprotective genes and downregulates that of inflammatory genes. Thus, pretreatment of neutrophils with an Nrf2 activator such as sulforaphane reduces the production of reactive oxygen species (ROS) in response to stimulation. In parallel, Nrf2 does not affect two key functions of neutrophil, phagocytosis and netosis.Finally, Nrf2 is essential for optimal migration of neutrophils toward chemokines. In CHS induced by the dinitrochlorobenzene (DNCB), Nrf2 indirectly regulates the recruitment of neutrophils, through regulation of skin oxidant stress and inflammatory pathways that are involved in chemokines production, including CCL2, CCL4 and CCL11. In addition, Nrf2 induces the up-regulation of scavenger CD36 in macrophages and thus increases their ability to eliminate apoptotic neutrophils leading to the resolution of inflammation.In conclusion, Nrf2 activation in neutrophils participates in the control of ROS production and migration. In addition, Nrf2 emerges as an important effector in the control of neutrophil recruitment and clearance during the skin inflammatory response to allergenic molecules. The demonstration of Nrf2 protective mechanisms leads us to suggest this protein as a new therapeutic target in the control of chronic skin inflammations
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Raffalli, Chloé. "Les allergies cutanées aux fragrances : mécanisme d'action et rôle du facteur de transcription Nrf2. Du modèle 2D au modèle 3D". Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS045/document.
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La dermatite allergique de contact (DAC) est une réaction inflammatoire aiguë, médiée par les cellules dendritiques (DCs) survenant suite à l’exposition répétée de la peau avec une molécule allergisante. La prévalence estimée des cas de DAC aux substances parfumantes est de 1,7 % à 4,1 % dans la population générale. Les molécules allergisantes sont des molécules appelées haptènes, qui vont se conjuguer avec des protéines de l’épiderme ou du derme. C’est le cas du cinnamaldéhyde (CinA), une molécule retrouvée dans la cannelle. Le linalol et le limonène sont des terpènes présents dans la lavande et l’orange, qui vont s’autoxyder au contact de l’air pour former des allergènes puissants, tels que les hydroperoxydes allyliques. Le premier objectif de cette thèse a été d’étudier le mécanisme d’action de ces terpènes et leurs hydroperoxydes allyliques respectifs sur la lignée cellulaire THP-1, qui sert de substitut aux cellules dendritiques. Le rôle du facteur de transcription Nrf2, majeur dans la lutte contre le stress oxydant, a également été investigué.Les consommateurs de produits cosmétiques sont exposés à de faibles concentrations de molécules allergisantes, mais plusieurs fois par jour ou par semaine. Nous avons souhaité étudier l’exposition répétée à de faibles doses d’haptène sur la peau.Les kératinocytes jouent également un rôle dans la DAC : ce sont les premières cellules qui vont rencontrer la molécule allergisante dans la peau. La deuxième partie de ce travail a été d’étudier l’impact d’une exposition répétée de CinA à de faible concentration sur ces KCs et plus particulièrement sur la différenciation de l’épiderme, en utilisant un modèle organotypique de peau en 3DAllergic contact dermatitis (ACD) represents a severe health problem. It is a dendritic cells (DCs) mediated skin disease caused by repeated exposure to an allergenic compound. ACD cases of fragrances in general population is estimated from 1.7 % to 4.1%. Contact sensitizers are compounds termed haptens and they will form a conjugate with epidermis and dermis proteins. Example is cinnamaldehyde (CinA), a molecule found in cinnamon. Linalool and limonene are terpenes found in lavender and oranges. In contact with the air, they will autoxidize to form highly allergenic compounds: allylic hydroperoxides. The first aim of this thesis was to study the mechanism of action of those terpenes and their respective allylic hydroperoxides on THP-1 cell-line, described as a surrogate of DCs. The transcription factor Nrf2 is playing a major role in oxidative stress and was also investigated.Consumers of cosmetic products are exposed to low quantities of allergenic compounds, but several times a day or a week. We wanted to study repeated exposure of low concentration of haptens on the skin.KCs also play a key role in ACD: they are the first cells that will encounter the allergenic compound in the skin. The second aim of this thesis was to study the impact of repeated exposure of low concentrations of CinA on those KCs and more particularly on the epidermis differenciation, using a 3D organotypic culture of skin
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Salamito, Mélanie. "Le facteur de transcription antioxydant NRF2 comme nouveau régulateur de la matrice extracellulaire des fibroblastes de peau humaine". Thesis, Lyon, 2020. http://www.theses.fr/2020LYSEN058.
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Le facteur de transcription nuclear factor erythroid-2-related factor (NRF2) est connu dans différentes espèces pour son rôle dans la défense cellulaire contre les stress oxydatifs et xénobiotiques. SKN-1, l'homologue de NRF2 chez C.elegans, est un important régulateur de la longévité du nématode qui, dans certaines conditions métaboliques spécifiques, agit de manière surprenante par l'activation de l'expression des collagènes en plus des gènes de détoxification. Les fibroblastes sont les principaux producteurs et organisateurs de tissus riches en collagène et, à ce titre, jouent un rôle clé dans l'homéostasie du derme. Nous avons étudié le nouveau rôle potentiel de NRF2 dans la régulation de l'expression de la matrice extracellulaire (MEC) dans les fibroblastes cutanés humains. La dérégulation de NRF2 a été réalisée en utilisant siRNA et shRNA. Une analyse transcriptomique globale des fibroblastes cutanés humains siNrf2, effectuée par RNA-seq, a révélé qu’en plus des cibles NRF2 connues, les gènes du matrisome et du tissu-squelette étaient les catégories de gènes les plus affectées, comprenant certains gènes clés de la MEC. L'analyse de la production et de l'organisation de la MEC a ensuite été réalisée en utilisant une combinaison de microscopies (SHG, confocal, TEM et AFM) dans des fibroblastes shNrf2 en culture. La sous-expression à long terme de NRF2 dans les fibroblastes (shNRF2) affecte les niveaux d’expression du collagène I, ainsi que la formation des fibrilles de collagènes, probablement dû au ratio collagène I/collagène V perturbé. L’analyse transcriptomique a également permis d’identifier en tant que nouvelle cible de NRF2, un second facteur de transcription, décrit comme régulateur de l'expression des collagènes et impliqué dans une maladie du tissu conjonctif. Le marquage de ce facteur par immunofluorescence a révélé que sa localisation subcellulaire, et en particulier sa translocation, est affectée par la sous-expression de NRF2 (siRNA et shRNA). Nos résultats montrent ainsi que la sous-expression de NRF2 dans les fibroblastes cutanés humains impacte les gènes de la MEC et en particulier l’expression des collagènes. Le second facteur de transcription identifié pourrait être un intermédiaire ou un co-facteur spécifique de NRF2 impliqué dans la régulation de l’expression des gènes de la MEC. NRF2 peut ainsi être considéré comme nouveau régulateur des gènes de la MEC dans les fibroblastes cutanés humains et représente une nouvelle cible pour maintenir l'homéostasie du dermeThe nuclear factor-erythroid 2-related factor 2 (NRF2) is a transcription factor involved in cell defense against oxidative and xenobiotic stresses. SKN-1, the nematode homologue of NRF2 is a master regulator of longevity that, under specific metabolic conditions, surprisingly acts through the activation of collagens expression. Fibroblasts are the major producers and organizers of collagen-rich tissues and, as such, play a key role in dermis homeostasis. Therefore, we investigated the potential new role of NRF2 in regulating extracellular matrix (ECM) expression in human skin fibroblasts. Dysregulation of NRF2 was realized using siRNA and shRNA. A global transcriptomic analysis of siNrf2 human skin fibroblasts performed by RNA-seq revealed that, in addition to known NRF2 targets, matrisome and tissue skeleton genes were the most represented gene sets, including some key ECM genes. Analysis of ECM production and organization was further conducted in cultured shNrf2 fibroblasts using a combination of microscopies (SHG, confocal, TEM and AFM). Long-term effect of silencing NRF2 in fibroblasts (shNrf2) resulted in defects in collagen expression and fibril formation, likely due to a disturbed collagen I to collagen V ratio. Interestingly, a transcription factor involved in connective tissue disease and described as a regulator of collagen expression was identified as a novel target of NRF2. Immunofluorescence staining of silenced NRF2 fibroblasts (siRNA and shRNA) strikingly revealed that NRF2 downregulation impacts its translocation rate into the nucleus. Our results demonstrate that silencing NRF2 impacts ECM and especially collagens in human skin fibroblasts. A transcription factor known to regulate collagen expression, could act as a specific cofactor of NRF2 in the regulation of ECM gene expression. NRF2 can thus be considered as a novel regulator of ECM genes in human skin fibroblasts and represents a new target to maintain dermis homeostasis
Livros sobre o assunto "Facteurs de transcription NRF2"
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Stephen, Goodbourn, ed. Eukaryotic gene transcription. Oxford: IRL Press at Oxford University Press, 1996.
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Latchman, David S. Eukaryotic transcription factors. 5a ed. Great Britain: Academic Press, 2008.
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Latchman, David S. Eukaryotic transcription factors. 5a ed. Amsterdam: Elsevier/Academic Press, 2008.
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E, Angel Peter, e Herrlich Peter 1940-, eds. The fos and jun families of transcription factors. Boca Raton: CRC Press, 1994.
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T, Smale Stephen, e NetLibrary Inc, eds. Transcriptional regulation in eukaryotes: Concepts, strategies, and techniques. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2000.
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B, La Thangue Nicholas, e Bandara Lasantha R, eds. Targets for cancer chemotherapy: Transcription factors and other nuclear proteins. Totowa, N.J: Humana Press, 2002.
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B, La Thangue Nicholas, e Bandara Lasantha R, eds. Targets for cancer chemotherapy: Transcription factors and other nuclear proteins. Totowa, N.J: Humana Press, 2002.
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NATO Advanced Study Institute on Molecular Mechanisms of Signal Transduction (1999 Spetsai Island, Greece). Molecular mechanisms of signal transduction. Amsterdam: IOS Press, 2000.
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Morales-Gonzalez, Jose Antonio, Angel Morales-Gonzalez e Eduardo Osiris Madrigal-Santillan, eds. A Master Regulator of Oxidative Stress - The Transcription Factor Nrf2. InTech, 2016. http://dx.doi.org/10.5772/62743.
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Eukaryotic transcription factors. 4a ed. Oxford: Academic, 2004.
Encontre o texto completo da fonteCapítulos de livros sobre o assunto "Facteurs de transcription NRF2"
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Reddy, Narsa M., Wajiha Qureshi, Haranath Potteti, Dhananjaya V. Kalvakolanu e Sekhar P. Reddy. "Regulation of Mitochondrial Functions by Transcription Factor NRF2". In Mitochondrial Function in Lung Health and Disease, 27–50. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4939-0829-5_2.
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Pfefferlé, Marc, e Florence Vallelian. "Transcription Factor NRF2 in Shaping Myeloid Cell Differentiation and Function". In Transcription factors in blood cell development, 159–95. Cham: Springer Nature Switzerland, 2024. http://dx.doi.org/10.1007/978-3-031-62731-6_8.
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Dinkova-Kostova, Albena T., Ying Zhang, Sharadha Dayalan Naidu, Rumen V. Kostov, Ashley Pheely e Vittorio Calabrese. "Sulfhydryl-Reactive Phytochemicals as Dual Activators of Transcription Factors NRF2 and HSF1". In 50 Years of Phytochemistry Research, 95–119. Cham: Springer International Publishing, 2013. http://dx.doi.org/10.1007/978-3-319-00581-2_6.
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Lambros, Mandy L., e Scott M. Plafker. "Oxidative Stress and the Nrf2 Anti-Oxidant Transcription Factor in Age-Related Macular Degeneration". In Retinal Degenerative Diseases, 67–72. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-17121-0_10.
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Florczyk, Urszula, Alicja Józkowicz e Józef Dulak. "Nrf2 Transcription Factor and Heme Oxygenase-1 as Modulators of Vascular Injury and Angiogenesis". In Angiogenesis and Vascularisation, 213–39. Vienna: Springer Vienna, 2013. http://dx.doi.org/10.1007/978-3-7091-1428-5_10.
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Mendonca, Patricia, e Karam F. A. Soliman. "Nutraceutical Activation of the Transcription Factor Nrf2 as a Potential Approach for Modulation of Aging". In Nutraceuticals for Aging and Anti-Aging, 113–31. Boca Raton: CRC Press, 2021. http://dx.doi.org/10.1201/9781003110866-6.
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Verma, Neeraj. "NRF2 in Neurological Disorders: A Molecular Beacon for Therapeutics". In The Role of NRF2 Transcription Factor [Working Title]. IntechOpen, 2024. http://dx.doi.org/10.5772/intechopen.1004774.
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Neurological disorders represent a complex spectrum of conditions, ranging from neurodegenerative diseases to acute injuries, each posing unique challenges to treatment. This chapter delves into the emerging role of the NRF2 transcription factor as a molecular beacon with therapeutic implications in the realm of neurological disorders. NRF2, a master regulator of cellular defense mechanisms, orchestrates antioxidant responses and mitigates oxidative stress—processes intricately linked to neuroprotection. The chapter explores the intricate interplay between NRF2 and neurological pathologies, emphasizing its influence on the progression of conditions such as Alzheimer’s, Parkinson’s, and ischemic stroke. By dissecting the molecular pathways through which NRF2 modulates inflammation, oxidative damage, and apoptosis in the nervous system, we gain insights into potential therapeutic strategies. Exciting research on NRF2 activators, both natural and synthetic, offers promising avenues for drug development. Furthermore, the chapter navigates through preclinical and clinical studies, highlighting the potential of NRF2-targeted interventions in preserving neuronal function and promoting recovery. As we unravel the molecular intricacies of NRF2 in neurological contexts, this chapter serves as a guide to understanding its therapeutic potential, paving the way for innovative strategies aimed at mitigating the burden of neurological disorders.
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Bruneska Gondim Martins, Danyelly, Ananda Cristina de Aguiar, Francielle Maria de Araújo Barbosa e Glauber Moreira Leitão. "The Dual Role of NRF2 Transcription Factor in Female Cancer". In The Role of NRF2 Transcription Factor [Working Title]. IntechOpen, 2024. http://dx.doi.org/10.5772/intechopen.1005041.
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Nuclear factor erythroid 2-related factor 2 (NRF2) is an essential transcription factor that is involved in cellular defense against oxidative stress and is assumed to be an important molecule in the transcription and regulation of cytoprotective genes. NRF2 is not only responsible for protecting healthy cells but plays a role in neoplastic cells once high expression of NRF2 has been observed in cancer cells. However, the increase in NRF2 levels may be correlated with resistance to therapy, making it interesting to understand the duality of the protective action of this molecule in the scenario of the cancer hallmarks, NRF2-regulated target genes involved in redox homeostasis, drug metabolism and excretion, amino acid metabolism, iron metabolism, energetic metabolism, survival, autophagy, proliferation, DNA repair, proteasomal degradation, and mitochondrial physiology. Therefore, NRF2 has emerged as a promising target in cancer treatment, and many efforts have been made to identify therapeutic strategies that inhibit its oncogenic role.
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A. Samak, Mai. "Nrf2: The Guardian of Cellular Harmony – Unveiling Its Role in Cell Biology and Senescence". In The Role of NRF2 Transcription Factor [Working Title]. IntechOpen, 2024. http://dx.doi.org/10.5772/intechopen.1005182.
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Nrf2, a key cellular regulator, plays a complex and multifaceted role in both protecting healthy cells and potentially promoting disease progression. This chapter delves into the intricate mechanisms by which Nrf2 exerts its protective effects, including combating carcinogens, maintaining cellular integrity, and inducing controlled cell death under severe stress. However, the chapter also explores the “dark side” of Nrf2, where its activity in cancer cells can contribute to chemoresistance, adaptation, and growth, hindering effective treatment. The chapter further investigates current research avenues for harnessing Nrf2’s potential for therapeutic benefit. Strategies for both activation and inhibition are explored, highlighting the importance of context-dependent effects, balancing protection and potential harm, and minimizing off-target effects. Promising new directions, such as developing tissue-specific modulators, identifying predictive biomarkers, and combining Nrf2 modulators with other therapeutic approaches, are also discussed. By understanding Nrf2’s complex and context-dependent roles, we can pave the way for the development of safer and more effective therapeutic strategies that leverage its beneficial effects while mitigating its potential drawbacks in various diseases.
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Bruneska Gondim Martins, Danyelly, Thaysa Walleria Aragão Santos, Maria Helena Menezes Estevam Alves e Rosângela Ferreira Frade de Araújo. "The Role of NRF2 Transcription Factor in Metabolic Syndrome". In The Role of NRF2 Transcription Factor [Working Title]. IntechOpen, 2024. http://dx.doi.org/10.5772/intechopen.1005035.
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Metabolic syndrome includes several diseases that are associated with metabolic abnormalities such as obesity, dyslipidemia, hypertension, type 2 diabetes, obesity, cardiac diseases, and insulin resistance. In order to maintain cellular homeostasis, it is necessary to regulate the signaling pathways involved in controlling oxidative stress. Nuclear factor erythroid-2 factor 2 (NRF2) is a transcription factor largely expressed in several tissues and cells and participates in the oxidative stress regulation signaling pathways. NRF2 also mediates transcriptional regulation of a variety of target genes to signalize and regulate acute and chronic stress pathways in metabolic syndrome. Deregulation of NRF2 could contribute to a worst prognosis/profile of individuals with metabolic syndrome. Therefore, NRF2 and its activators might play a role in its treatment, highlighted as targets for modulation by pharmacological agents.
Trabalhos de conferências sobre o assunto "Facteurs de transcription NRF2"
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Tian, Yijun, Qian Liu, Shengnan Yu, Qian Chu, Yuan Chen, Kongming Wu e Liang Wang. "Abstract 3587: NRF2-driven KEAP1 transcription in human lung cancers". In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-3587.
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Kweider, N., J. Lambertz, T. Pufe e W. Rath. "Activation of the Transcription factor Nrf2 involved in human trophoblast syncytialization (in vitro study)". In 28. Deutscher Kongress für Perinatale Medizin. Georg Thieme Verlag KG, 2017. http://dx.doi.org/10.1055/s-0037-1607808.
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Abalenikhina, Y. V., A. A. Seidkuliyeva, E. D. Rokunov, D. S. Nemtinov, A. V. Shchulkin e E. N. Yakusheva. "PARTICIPATION OF NUCLEAR FACTOR OF ERYTHROID ORIGIN-2 IN REGU-LATION P-GLYCOPROTEIN IN MODELING ENDOGENOUS OXIDATIVE STRESS". In NOVEL TECHNOLOGIES IN MEDICINE, BIOLOGY, PHARMACOLOGY AND ECOLOGY. Institute of information technology, 2022. http://dx.doi.org/10.47501/978-5-6044060-2-1.251-257.
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The article discusses the mechanisms of regulation of the P-glycoprotein transporter protein (Pgp) in cells of the Caco2 line under conditions of modeling endogenous oxidative stress caused by exposure to DL-butyonine sulfoximine (BSO, a glutathione synthesis inhibitor). Ex-periments have shown that exposure to BSO at concentrations of 10-100 μM leads to a de-crease in the concentration of glutathione, an increase in the amount of Pgp and nuclear factor of erythroid origin 2 (Nrf2). Inhibition of Nrf2 contributed to the normalization of Pgp levels, which proves the participation of the transcription factor in the regulation of the transporter protein under the conditions of modeling endogenous oxidative stress.
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Kweider, N., J. Hock, B. Altunay, U. Pecks, C. Wruck, T. Pufe e W. Rath. "The transcription factor Nrf2 and the placental inflammatory response; potential implication in the pathogenesis of IUGR". In 28. Deutscher Kongress für Perinatale Medizin. Georg Thieme Verlag KG, 2017. http://dx.doi.org/10.1055/s-0037-1607684.
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Barker, Emily, John J. Letterio e Gregory P. Tochtrop. "Abstract 2258: Celastrol shows chemopreventive properties in an inflammatory driven model for colon cancer via induction of Nrf2 transcription." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-2258.
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Korfei, M., T. Luboeinski, C. Ruppert, R. Schmidt, M. Wygrecka, W. Seeger, A. Guenther e P. Markart. "Alveolar Oxidative Stress in Patients with Sporadic Idiopathic Pulmonary Fibrosis Is Associated with Oxidant-Antioxidant Imbalance Despite Induction of the Antioxidant Transcription Factor Nrf2." In American Thoracic Society 2009 International Conference, May 15-20, 2009 • San Diego, California. American Thoracic Society, 2009. http://dx.doi.org/10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a2733.
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Dey, Souvik, Carly M. Sayers, Stacey L. Lehman, Yi Cheng, George J. Cerniglia, Stephen W. Tuttle, Michael D. Feldman et al. "Abstract 1262: The transcription factor ATF4 regulates resistance to anoikis and promotes metastasis in fibrosarcoma via cooperative upregulation of Heme Oxygenase-1 with Nrf2". In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-1262.
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Novik, Victoria, Irene Bobilev, Andrzej Kutner, Itai Levi, Ofer Shpilberg, Yoav Sharoni, George P. Studzinski e Michael Danilenko. "Abstract 282A: The Nrf2 transcription factor is a positive regulator of differentiation of acute myeloid leukemia cells induced by vitamin D derivatives and plant polyphenols". In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-282a.
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