The Experts below are selected from a list of 1662 Experts worldwide ranked by ideXlab platform
Anna-liisa Levonen - One of the best experts on this subject based on the ideXlab platform.
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MicroRNAs mediate the senescence-associated decline of NRF2 in endothelial cells.
Redox biology, 2018Co-Authors: Suvi M Kuosmanen, Emilia Kansanen, Virve Sihvola, Minna U. Kaikkonen, Anna-liisa LevonenAbstract:Abstract Oxidative Stress predisposes to several aging-associated diseases, such as cardiovascular diseases and cancer. In aging, increase in the production of reactive oxygen species is typically accompanied with a decline in adaptive Stress responses to oxidative Stress. The decline is primarily due to a decrease in antioxidant production. Nuclear factor E2-Related Factor 2 (NRF2) is a key transcription factor regulating oxidative and Electrophilic Stress responses, but it has also been shown to play a role in the regulation of cell metabolism. NRF2 expression declines in aging, but the mechanisms remain unclear. In this study, we show that microRNAs (miRNAs) that are abundant in old endothelial cells decrease NRF2 expression by direct targeting of NRF2 mRNA. The effect is reversed by miRNA inhibition. The senescence-associated downregulation of NRF2 decreases endothelial glycolytic activity and Stress tolerance both of which are restored after reinstating NRF2. Manipulation of the senescence-associated miRNA levels affects the glycolytic activity and Stress tolerance consistently with the NRF2 results. We conclude that senescence-associated miRNAs are involved in the decline of NRF2 expression, thus contributing to the repression of adaptive responses during cell senescence.
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MicroRNAs mediate the senescence-associated decline of NRF2 in endothelial cells
Elsevier, 2018Co-Authors: Suvi M Kuosmanen, Emilia Kansanen, Virve Sihvola, Minna U. Kaikkonen, Anna-liisa LevonenAbstract:Oxidative Stress predisposes to several aging-associated diseases, such as cardiovascular diseases and cancer. In aging, increase in the production of reactive oxygen species is typically accompanied with a decline in adaptive Stress responses to oxidative Stress. The decline is primarily due to a decrease in antioxidant production. Nuclear factor E2-Related Factor 2 (NRF2) is a key transcription factor regulating oxidative and Electrophilic Stress responses, but it has also been shown to play a role in the regulation of cell metabolism. NRF2 expression declines in aging, but the mechanisms remain unclear. In this study, we show that microRNAs (miRNAs) that are abundant in old endothelial cells decrease NRF2 expression by direct targeting of NRF2 mRNA. The effect is reversed by miRNA inhibition. The senescence-associated downregulation of NRF2 decreases endothelial glycolytic activity and Stress tolerance both of which are restored after reinstating NRF2. Manipulation of the senescence-associated miRNA levels affects the glycolytic activity and Stress tolerance consistently with the NRF2 results. We conclude that senescence-associated miRNAs are involved in the decline of NRF2 expression, thus contributing to the repression of adaptive responses during cell senescence. Keywords: MicroRNA, Aging, Senescence, NRF2, Endothelial cel
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Keap1 as the redox sensor of the antioxidant response.
Archives of Biochemistry and Biophysics, 2016Co-Authors: Virve Sihvola, Anna-liisa LevonenAbstract:Reactive oxygen species (ROS) and products of their reactions with cellular macromolecules such as unsaturated fatty acids have been implicated to be important regulators of signalling processes via oxidation or alkylation of redox active thiol residues in target proteins. One of key redox-sensitive signalling proteins mediating the response to oxidant Stress is Keap1 (Kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1), which is a negative regulator of transcription factor Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) and the central hub for sensing endogenous and environmental oxidative and Electrophilic Stress. In this review, we provide an overview of the mechanisms by which Keap1 orchestrates the antioxidant response and how the system can be targeted for therapy.
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the keap1 nrf2 pathway mechanisms of activation and dysregulation in cancer
Redox biology, 2013Co-Authors: Emilia Kansanen, Suvi M Kuosmanen, Hanna Leinonen, Anna-liisa LevonenAbstract:The Keap1-Nrf2 pathway is the major regulator of cytoprotective responses to oxidative and Electrophilic Stress. Although cell signaling pathways triggered by the transcription factor Nrf2 prevent cancer initiation and progression in normal and premalignant tissues, in fully malignant cells Nrf2 activity provides growth advantage by increasing cancer chemoresistance and enhancing tumor cell growth. In this graphical review, we provide an overview of the Keap1-Nrf2 pathway and its dysregulation in cancer cells. We also briefly summarize the consequences of constitutive Nrf2 activation in cancer cells and how this can be exploited in cancer gene therapy.
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novel insights into the regulation of antioxidant response elementmediated gene expression by electrophiles induction of the transcriptional repressor bach1 by nrf2
Biochemical Journal, 2011Co-Authors: Hennakaisa Jyrkkanen, Emilia Kansanen, Suvi M Kuosmanen, Hanna Leinonen, Merja Heinäniemi, Heidi M Laitinen, Eero Mellaaho, Seppo Ylaherttuala, Anna-liisa LevonenAbstract:A central mechanism in cellular defence against oxidative or Electrophilic Stress is mediated by transcriptional induction of genes via the ARE (antioxidant-response element), a cis -acting sequence present in the regulatory regions of genes involved in the detoxification and elimination of reactive oxidants and electrophiles. The ARE binds different bZIP (basic-region leucine zipper) transcription factors, most notably Nrf2 (nuclear factor-erythroid 2-related factor 2) that functions as a transcriptional activator via heterodimerization with small Maf proteins. Although ARE activation by Nrf2 is relatively well understood, the mechanisms by which ARE-mediated signalling is down-regulated are poorly known. Transcription factor BACH1 [BTB (broad-complex, tramtrack and bric-a-brac) and CNC (cap9n9collar protein) homology 1] binds to ARE-like sequences, functioning as a transcriptional repressor in a subset of ARE-regulated genes, thus antagonizing the activator function of Nrf2. In the present study, we have demonstrated that BACH1 itself is regulated by Nrf2 as it is induced by Nrf2 overexpression and by Nrf2-activating agents in an Nrf2-dependent manner. Furthermore, a functional ARE site was identified at +1411 from the transcription start site of transcript variant 2 of BACH1 . We conclude that BACH1 is a bona fide Nrf2 target gene and that induction of BACH1 by Nrf2 may serve as a feedback-inhibitory mechanism for ARE-mediated gene regulation.
Masayuki Yamamoto - One of the best experts on this subject based on the ideXlab platform.
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Identification of dominant transcripts in oxidative Stress response by a full-length transcriptome analysis.
Molecular and cellular biology, 2021Co-Authors: Akihito Otsuki, Yasunobu Okamura, Yuichi Aoki, Noriko Ishida, Kazuki Kumada, Naoko Minegishi, Fumiki Katsuoka, Kengo Kinoshita, Masayuki YamamotoAbstract:Our body responds to environmental Stress by changing the expression levels of a series of cytoprotective enzymes/proteins through multilayered regulatory mechanisms, including the KEAP1-NRF2 system. While NRF2 upregulates the expression of many cytoprotective genes, there are fundamental limitations in short-read RNA sequencing (RNA-Seq), resulting in confusion regarding interpreting the effectiveness of cytoprotective gene induction at transcript level. To precisely delineate isoform usage in the Stress response, we conducted independent full-length transcriptome profiling (isoform sequencing; Iso-Seq) analyses of lymphoblastoid cells from three volunteers under normal and Electrophilic Stress-induced conditions. We first determined the first exon usage in KEAP1 and NFE2L2 (encoding NRF2) and found the presence of transcript diversity. We then examined changes in isoform usage of NRF2 target genes under Stress conditions and identified a few isoforms dominantly expressed in the majority of NRF2 target genes. The expression levels of isoforms determined by Iso-Seq analyses showed striking differences from those determined by short-read RNA-Seq; the latter could be misleading in regards to the abundance of transcripts. These results support that transcript usage is tightly regulated to produce functional proteins under Electrophilic Stress. Our present study strongly argues that there are important benefits that can be achieved by long-read transcriptome sequencing.
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The Keap1-Nrf2 pathway: From mechanism to medical applications
Oxidative Stress, 2020Co-Authors: Liam Baird, Masayuki YamamotoAbstract:Abstract The Keap1-Nrf2 pathway is the body’s primary inducible response to oxidative Stress. Since the discovery in 1997 that Nrf2 is responsible for the expression of cytoprotective genes, an intricate molecular mechanism has been revealed through which the Stress sensor protein Keap1 tightly regulates Nrf2 activity. In the nonStressed state, Keap1 promotes the ubiquitin-dependent degradation of Nrf2, while in response to oxidative or Electrophilic Stress, Keap1’s ubiquitin ligase activity is inactivated, allowing Nrf2 to escape degradation and activate its antioxidant and anti-inflammatory transcription programs. Recent advances have revealed that in addition to oxidative Stress, dysfunctional autophagy, endogenous primary metabolism metabolites, and immune metabolites are also able to regulate Nrf2’s activity. This integration of Nrf2 activity into multiple cellular pathways highlights its importance for cellular survival and homeostasis and suggests that the pharmacological modulation of Nrf2 activity can provide beneficial effects in a number of diverse disease contexts.
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Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus.
Nature communications, 2017Co-Authors: Takafumi Suzuki, Shiori Seki, Keiichiro Hiramoto, Eriko Naganuma, Eri H. Kobayashi, Ayaka Yamaoka, Liam Baird, Nobuyuki Takahashi, Hiroshi Sato, Masayuki YamamotoAbstract:NF-E2-related factor-2 (Nrf2) regulates cellular responses to oxidative and Electrophilic Stress. Loss of Keap1 increases Nrf2 protein levels, and Keap1-null mice die of oesophageal hyperkeratosis because of Nrf2 hyperactivation. Here we show that deletion of oesophageal Nrf2 in Keap1-null mice allows survival until adulthood, but the animals develop polyuria with low osmolality and bilateral hydronephrosis. This phenotype is caused by defects in water reabsorption that are the result of reduced aquaporin 2 levels in the kidney. Renal tubular deletion of Keap1 promotes nephrogenic diabetes insipidus features, confirming that Nrf2 activation in developing tubular cells causes a water reabsorption defect. These findings suggest that Nrf2 activity should be tightly controlled during development in order to maintain renal homeostasis. In addition, tissue-specific ablation of Nrf2 in Keap1-null mice might create useful animal models to uncover novel physiological functions of Nrf2.
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Absolute Amounts and Status of the Nrf2-Keap1-Cul3 Complex within Cells.
Molecular and cellular biology, 2016Co-Authors: Tatsuro Iso, Liam Baird, Takafumi Suzuki, Masayuki YamamotoAbstract:The transcription factor Nrf2 (NF-E2-related-factor 2) is essential for the oxidative and Electrophilic Stress responses. Keap1 (Kelch-like-ECH-associated-protein 1), an adaptor for a cullin-3 (Cul3)-based ubiquitin ligase, regulates Nrf2 activity through proteasomal degradation, and acts as a sensor for oxidative and Electrophilic Stresses. The Keap1-Cul3 complex is a critical regulator of the cellular Nrf2 level, and yet quantitative information regarding their endogenous intracellular concentrations in homeostatic conditions and during Stress responses is unknown. We analyzed the absolute amounts of the Nrf2, Keap1, and Cul3 proteins in five murine cell lines by comparison with serial dilutions of purified recombinant protein standards in combination with quantitative immunoblot analyses. In the basal state, the amount of Nrf2 was maintained at lower levels than those of Keap1 and Cul3 proteins, whereas the Electrophilic agent diethylmaleate dramatically increased Nrf2 to a level greater than that of Keap1 and Cul3, resulting in the accumulation of Nrf2 in the nucleus. In contrast, Keap1 and Cul3 did not display any changes in their abundance, subcellular localization, or interaction in response to Electrophilic stimuli. Our results demonstrate that the regulation of the Nrf2 protein level during Stress responses is mediated by the activity but not the composition of the Nrf2-Keap1-Cul3 complex.
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the keap1 nrf2 system and diabetes mellitus
Archives of Biochemistry and Biophysics, 2015Co-Authors: Akira Uruno, Yoko Yagishita, Masayuki YamamotoAbstract:Abstract Nrf2 (NF-E2-related factor 2) plays a key role in the protection of vertebrates against environmental Stress by contributing to the inducible expression of detoxification and antioxidant enzymes. Keap1 (Kelch-like ECH-associated protein 1) is a sensor for oxidative and Electrophilic Stresses. Keap1 also acts as an E3 ubiquitin ligase substrate-recognition subunit that specifically targets Nrf2. Keap1 causes Nrf2 to be degraded through the ubiquitin–proteasome pathway and thus ensures that Nrf2 is constitutively suppressed under unStressed conditions. Upon exposure to oxidative or Electrophilic Stress, Keap1 loses its ability to ubiquitinate Nrf2. Many lines of evidence have recently clarified that the Keap1–Nrf2 system also plays critical roles in the maintenance of cellular homeostasis. One of the most salient examples is the contribution of Keap1–Nrf2 to metabolic and energy-balance regulation. In particular, how the Keap1–Nrf2 system protects the body against diabetes mellitus and how perturbations in this system provoke the disease condition are now under intense investigation. This review will summarize the recent progress made in this area.
Yunbo Li - One of the best experts on this subject based on the ideXlab platform.
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Potent Induction of Total Cellular and Mitochondrial Antioxidants and Phase 2 Enzymes by Cruciferous Sulforaphane in Rat Aortic Smooth Muscle Cells: Cytoprotection Against Oxidative and Electrophilic Stress
Cardiovascular Toxicology, 2008Co-Authors: Jeannine S. Strobl, Hara P. Misra, Marion Ehrich, Yunbo LiAbstract:Sulforaphane, a cruciferous isothiocyanate compound, upregulates cytoprotective genes in liver, but its effects on antioxidants and phase 2 defenses in vascular cells are unknown. Here we report that incubation of rat aortic smooth muscle A10 cells with sulforaphane (0.25–5 μM) resulted in concentration-dependent induction of a spectrum of important cellular antioxidants and phase 2 enzymes, including superoxide dismutase (SOD), catalase, the reduced form of glutathione (GSH), glutathione peroxidase, glutathione reductase (GR), glutathione S-transferase (GST), and NAD(P)H:quinone oxidoreductase 1 (NQO1). Sulforaphane also increased levels/activities of SOD, catalase, GSH and GST in isolated mitochondria of aortic smooth muscle cells. Time-dependent sulforaphane-induced increases in the mRNA levels for MnSOD, catalase, the catalytic subunit of γ-glutamylcysteine ligase, GR, GST-A1, GST-P1, and NQO1 were observed. Pretreatment with sulforaphane (0.5, 1, and 5 μM) protected aortic smooth muscle cells from oxidative and Electrophilic cytotoxicity induced by xanthine oxidase (XO)/xanthine, H_2O_2, SIN-1-derived peroxynitrite, 4-hydroxy-2-nonenal, and acrolein. Furthermore, sulforaphane pretreatment prevented intracellular accumulation of reactive oxygen species (ROS) after exposure of the cells to XO/xanthine, H_2O_2, or SIN-1. Taken together, this study demonstrates that in the aortic smooth muscle cells sulforaphane at physiologically relevant concentrations potently induces a series of total cellular as well as mitochondrial antioxidants and phase 2 enzymes, which is accompanied by dramatically increased resistance of these vascular cells to oxidative and Electrophilic Stress.
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Nuclear Factor E2-Related Factor 2-Dependent Myocardiac Cytoprotection Against Oxidative and Electrophilic Stress
Cardiovascular Toxicology, 2008Co-Authors: Bhaba R. Misra, Masayuki Yamamoto, Li Zhang, Michael A. Trush, Hara P. Misra, Yunbo LiAbstract:Nuclear factor E2-related factor 2 (Nrf2) is a critical regulator of cytoprotective gene expression. However, the role of this transcription factor in myocardiac cytoprotection against oxidative and Electrophilic Stress remains unknown. This study was undertaken to investigate if Nrf2 signaling could control the constitutive and inducible expression of antioxidants and phase 2 enzymes in primary cardiomyocytes as well as the susceptibility of these cells to oxidative and Electrophilic injury. The basal expression of a series of antioxidants and phase 2 enzymes was significantly lower in cardiomyocytes from Nrf2^−/− mice than those from wild-type littermates. Incubation of wild-type cardiomyocytes with 3 H -1,2-dithiole-3-thione (D3T) led to significant induction of various antioxidants and phase 2 enzymes, including catalase, glutathione, glutathione peroxidase (GPx), glutathione reductase, glutathione S-transferase, NAD(P)H:quinone oxidoreductase 1, and heme oxygenase-1. The inducibility of the above cellular defenses except GPx by D3T was abolished in Nrf2^−/− cardiomyocytes. As compared to wild-type cells, Nrf2^−/− cardiomyocytes were much more susceptible to cell injury induced by H_2O_2, peroxynitrite, and 4-hydroxy-2-nonenal. Treatment of wild-type cardiomyocytes with D3T, which upregulated the cellular defenses, resulted in increased resistance to the above oxidant- and electrophile-induced cell injury, whereas D3T treatment of Nrf2^−/− cardiomyocytes provided no cytoprotection. This study demonstrates that Nrf2 is an important factor in controlling both constitutive and inducible expression of a wide spectrum of antioxidants and phase 2 enzymes in cardiomyocytes and is responsible for protecting these cells against oxidative and Electrophilic Stress. These findings also implicate Nrf2 as an important signaling molecule for myocardiac cytoprotection.
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potent induction of total cellular gsh and nqo1 as well as mitochondrial gsh by 3h 1 2 dithiole 3 thione in sh sy5y neuroblastoma cells and primary human neurons protection against neurocytotoxicity elicited by dopamine 6 hydroxydopamine 4 hydroxy 2
Brain Research, 2008Co-Authors: Hara P. Misra, Yunbo LiAbstract:Abstract Evidence suggests oxidative and Electrophilic Stress as a major factor contributing to the neuronal cell death in neurodegenerative disorders, especially Parkinson's disease. Consistent with this concept, administration of exogenous antioxidants has been shown to be protective against oxidative/Electrophilic neurodegeneration. However, whether induction of endogenous antioxidants and phase 2 enzymes by the unique chemoprotectant, 3H-1,2-dithiole-3-thione (D3T) in neuronal cells also affords protection against oxidative and Electrophilic neurocytotoxicity has not been carefully investigated. In this study, we showed that incubation of SH-SY5Y neuroblastoma cells or primary human neurons with micromolar concentrations (10–100 μM) of D3T for 24 h resulted in significant increases in the levels of reduced glutathione (GSH) and NAD(P)H:quinone oxidoreductase 1 (NQO1), two crucial cellular defenses against oxidative and Electrophilic Stress. D3T treatment also caused increases in mRNA expression of γ-glutamylcysteine ligase catalytic subunit and NQO1 in SH-SY5Y cells. In addition, D3T treatment of the neuronal cells also resulted in a marked elevation of GSH content in the mitochondrial compartment. To determine the protective effects of the D3T-induced cellular defenses on neurotoxicant-elicited cell injury, SH-SY5Y cells were pretreated with D3T for 24 h and then exposed to dopamine, 6-hydroxydopamine (6-OHDA), 4-hydroxy-2-nonenal (HNE), or H2O2, agents that are known to be involved in neuron degeneration. We observed that D3T-pretreatment of SH-SY5Y cells led to significant protection against the cytotoxicity elicited by the above neurotoxicants. Similar neurocytoprotective effects of D3T-pretreatment were also observed in primary human neurons exposed to 6-OHDA or HNE. Taken together, this study demonstrates that D3T potently induces neuronal cellular GSH and NQO1 as well as mitochondrial GSH, and that such upregulated endogenous defenses are accompanied by increased resistance to oxidative and Electrophilic neurocytotoxicity.
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upregulation of endogenous antioxidants and phase 2 enzymes by the red wine polyphenol resveratrol in cultured aortic smooth muscle cells leads to cytoprotection against oxidative and Electrophilic Stress
Pharmacological Research, 2006Co-Authors: Yunbo LiAbstract:Abstract Resveratrol (3,4′,5-trihydroxystilbene), a polyphenolic compound found in mulberries, grapes and red wine has been demonstrated to be capable of protecting against oxidative cardiovascular pathophysiology. However, the underlying cellular and biochemical mechanisms remain to be elucidated. This study was undertaken to determine if resveratrol could upregulate endogenous antioxidants and phase 2 enzymes in cultured aortic smooth muscle cells (ASMCs), and if such increased cellular defenses could provide protection against oxidative and Electrophilic vascular cell injury. Incubation of rat ASMCs with resveratrol at low micromolar concentrations resulted in a significant induction of a scope of cellular antioxidants and phase 2 enzymes in a concentration- and/or time-dependent fashion. These cytoprotective factors include superoxide dismutase, catalase, glutathione, glutathione reductase, glutathione peroxidase, glutathione S-transferase (GST), and NAD(P)H:quinone oxidoreductase-1 (NOQ1). Notably, induction of catalase, GST, and NOQ1 was most remarkable among the above resveratrol-inducible antioxidants and phase 2 enzymes. Moreover, resveratrol treatment also significantly increased the mRNA expression of catalase, GSTA1, and NQO1 in a time-dependent manner. Pretreatment of ASMCs with resveratrol afforded a remarkable protection against xanthine oxidase (XO)/xanthine- or 4-hydroxy-2-nonenal-induced cytotoxicity, as assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Resveratrol pretreatment also led to a marked reduction in intracellular accumulation of reactive oxygen species in ASMCs after incubation with XO/xanthine. Taken together, this study demonstrates that a scope of key endogenous antioxidants and phase 2 enzymes in cultured ASMCs can be upregulated by resveratrol at low micromolar concentrations, and that such chemically-elevated cellular defenses rendered cells increased resistance to oxidative and Electrophilic Stress. The results of this study thus suggested a new mechanism, which might contribute to the cardiovascular protective effects of resveratrol.
Yoshito Kumagai - One of the best experts on this subject based on the ideXlab platform.
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Redox Signaling and Reactive Sulfur Species to Regulate Electrophilic Stress
Yakugaku Zasshi-journal of The Pharmaceutical Society of Japan, 2020Co-Authors: Hironori Kanda, Yoshito KumagaiAbstract:Humans are exposed to various xenobiotic electrophiles on a daily basis. Electrophiles form covalent adducts with nucleophilic residues of proteins. Redox signaling, which consists of effector molecules (e.g., kinases and transcription factors) and redox sensor proteins with low pKa cysteine residues, is involved in cell survival, cell proliferation, quality control of cellular proteins and oxidative Stress response. Herein, we showed that at a low dose, xenobiotic electrophiles selectively modified redox sensor proteins through covalent modification of their reactive thiols, resulting in activation of a variety of redox signaling pathways. However, increasing the dose of xenobiotic electrophiles caused non-selective and extensive modification of cellular proteins involved in toxicity. Of interest, reactive sulfur species (RSS), such as hydrogen sulfide (H2S), cysteine persulfide (CysSSH), glutathione persulfide (GSSH) and even synthetic polysulfide (e.g., Na2S4), readily captured xenobiotic electrophiles, forming their sulfur adducts, which was associated with inactivation of the electrophiles. Our findings suggest that an adaptive response through redox signaling activation and RSS-mediated electrophile capturing is involved in the regulation of Electrophilic Stress.
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Nrf2 Activation and Its Coordination with the Protective Defense Systems in Response to Electrophilic Stress.
International journal of molecular sciences, 2020Co-Authors: Takamitsu Unoki, Masahiro Akiyama, Yoshito KumagaiAbstract:Molecular responses mediated by sensor proteins are important for biological defense against Electrophilic Stresses, such as xenobiotic electrophile exposure. NF-E2-related factor 2 (Nrf2) has an essential function as a master regulator of such cytoprotective molecular responses along with sensor protein Kelch-like ECH-associated protein 1. This review focuses on Nrf2 activation and its involvement with the protective defense systems under Electrophilic Stresses integrated with our recent findings that reactive sulfur species (RSS) mediate detoxification of electrophiles. The Nrf2 pathway does not function redundantly with the RSS-generating cystathionine γ-lyase pathway, and vice versa.
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Adaptive Responses to Electrophilic Stress and Reactive Sulfur Species as their Regulator Molecules
Toxicological Research, 2019Co-Authors: Yoshito Kumagai, Masahiro Akiyama, Takamitsu UnokiAbstract:We are exposed to numerous xenobiotic electrophiles on a daily basis through the environment, lifestyle, and dietary habits. Although such reactive species have been associated with detrimental effects, recent accumulated evidence indicates that xenobiotic electrophiles appear to act as signaling molecules. In this review, we introduce our findings on 1) activation of various redox signaling pathways involved in cell proliferation, detoxification/ excretion of electrophiles, quality control of cellular proteins, and cell survival during exposure to xenobiotic electrophiles at low concentrations through covalent modification of thiol groups in sensor proteins, and 2) negative regulation of reactive sulfur species (RSS) in the modulation of redox signaling and toxicity caused by xenobiotic electrophiles.
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Sulfane Sulfur in Toxicology: A Novel Defense System Against Electrophilic Stress.
Toxicological sciences : an official journal of the Society of Toxicology, 2019Co-Authors: Yasuhiro Shinkai, Yoshito KumagaiAbstract:Electrophiles can undergo covalent modification of cellular proteins associated with its dysfunction, thereby exerting toxicity. Small nucleophilic molecules such as glutathione protect cells from Electrophilic insult by binding covalently to electrophiles to form adducts that are excreted into the extracellular space. Recent studies indicate that sulfane sulfur, which is defined as a sulfur atom with 6 valence electrons and no charge, plays an essential role in protection against electrophile toxicity because sulfane sulfur can be highly nucleophilic compared to the corresponding thiol group. Advances in the development of assays to detect sulfane sulfur have revealed that sulfane sulfur-containing molecules such as persulfide/polysulfide species are ubiquitous in cells and tissues. Also, there is growing evidence that the binding of sulfane sulfur to electrophiles forms sulfur adducts as detoxified metabolites. Although the biosynthesis pathways of sulfane sulfur are known, its regulatory function in toxicology is still unclear. This review outlines the current knowledge of the synthesis, chemical properties, detection methods, interactions with electrophiles, and toxicological significance of sulfane sulfur, as well as suggesting directions for future research.
Emilia Kansanen - One of the best experts on this subject based on the ideXlab platform.
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MicroRNAs mediate the senescence-associated decline of NRF2 in endothelial cells.
Redox biology, 2018Co-Authors: Suvi M Kuosmanen, Emilia Kansanen, Virve Sihvola, Minna U. Kaikkonen, Anna-liisa LevonenAbstract:Abstract Oxidative Stress predisposes to several aging-associated diseases, such as cardiovascular diseases and cancer. In aging, increase in the production of reactive oxygen species is typically accompanied with a decline in adaptive Stress responses to oxidative Stress. The decline is primarily due to a decrease in antioxidant production. Nuclear factor E2-Related Factor 2 (NRF2) is a key transcription factor regulating oxidative and Electrophilic Stress responses, but it has also been shown to play a role in the regulation of cell metabolism. NRF2 expression declines in aging, but the mechanisms remain unclear. In this study, we show that microRNAs (miRNAs) that are abundant in old endothelial cells decrease NRF2 expression by direct targeting of NRF2 mRNA. The effect is reversed by miRNA inhibition. The senescence-associated downregulation of NRF2 decreases endothelial glycolytic activity and Stress tolerance both of which are restored after reinstating NRF2. Manipulation of the senescence-associated miRNA levels affects the glycolytic activity and Stress tolerance consistently with the NRF2 results. We conclude that senescence-associated miRNAs are involved in the decline of NRF2 expression, thus contributing to the repression of adaptive responses during cell senescence.
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MicroRNAs mediate the senescence-associated decline of NRF2 in endothelial cells
Elsevier, 2018Co-Authors: Suvi M Kuosmanen, Emilia Kansanen, Virve Sihvola, Minna U. Kaikkonen, Anna-liisa LevonenAbstract:Oxidative Stress predisposes to several aging-associated diseases, such as cardiovascular diseases and cancer. In aging, increase in the production of reactive oxygen species is typically accompanied with a decline in adaptive Stress responses to oxidative Stress. The decline is primarily due to a decrease in antioxidant production. Nuclear factor E2-Related Factor 2 (NRF2) is a key transcription factor regulating oxidative and Electrophilic Stress responses, but it has also been shown to play a role in the regulation of cell metabolism. NRF2 expression declines in aging, but the mechanisms remain unclear. In this study, we show that microRNAs (miRNAs) that are abundant in old endothelial cells decrease NRF2 expression by direct targeting of NRF2 mRNA. The effect is reversed by miRNA inhibition. The senescence-associated downregulation of NRF2 decreases endothelial glycolytic activity and Stress tolerance both of which are restored after reinstating NRF2. Manipulation of the senescence-associated miRNA levels affects the glycolytic activity and Stress tolerance consistently with the NRF2 results. We conclude that senescence-associated miRNAs are involved in the decline of NRF2 expression, thus contributing to the repression of adaptive responses during cell senescence. Keywords: MicroRNA, Aging, Senescence, NRF2, Endothelial cel
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the keap1 nrf2 pathway mechanisms of activation and dysregulation in cancer
Redox biology, 2013Co-Authors: Emilia Kansanen, Suvi M Kuosmanen, Hanna Leinonen, Anna-liisa LevonenAbstract:The Keap1-Nrf2 pathway is the major regulator of cytoprotective responses to oxidative and Electrophilic Stress. Although cell signaling pathways triggered by the transcription factor Nrf2 prevent cancer initiation and progression in normal and premalignant tissues, in fully malignant cells Nrf2 activity provides growth advantage by increasing cancer chemoresistance and enhancing tumor cell growth. In this graphical review, we provide an overview of the Keap1-Nrf2 pathway and its dysregulation in cancer cells. We also briefly summarize the consequences of constitutive Nrf2 activation in cancer cells and how this can be exploited in cancer gene therapy.
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novel insights into the regulation of antioxidant response elementmediated gene expression by electrophiles induction of the transcriptional repressor bach1 by nrf2
Biochemical Journal, 2011Co-Authors: Hennakaisa Jyrkkanen, Emilia Kansanen, Suvi M Kuosmanen, Hanna Leinonen, Merja Heinäniemi, Heidi M Laitinen, Eero Mellaaho, Seppo Ylaherttuala, Anna-liisa LevonenAbstract:A central mechanism in cellular defence against oxidative or Electrophilic Stress is mediated by transcriptional induction of genes via the ARE (antioxidant-response element), a cis -acting sequence present in the regulatory regions of genes involved in the detoxification and elimination of reactive oxidants and electrophiles. The ARE binds different bZIP (basic-region leucine zipper) transcription factors, most notably Nrf2 (nuclear factor-erythroid 2-related factor 2) that functions as a transcriptional activator via heterodimerization with small Maf proteins. Although ARE activation by Nrf2 is relatively well understood, the mechanisms by which ARE-mediated signalling is down-regulated are poorly known. Transcription factor BACH1 [BTB (broad-complex, tramtrack and bric-a-brac) and CNC (cap9n9collar protein) homology 1] binds to ARE-like sequences, functioning as a transcriptional repressor in a subset of ARE-regulated genes, thus antagonizing the activator function of Nrf2. In the present study, we have demonstrated that BACH1 itself is regulated by Nrf2 as it is induced by Nrf2 overexpression and by Nrf2-activating agents in an Nrf2-dependent manner. Furthermore, a functional ARE site was identified at +1411 from the transcription start site of transcript variant 2 of BACH1 . We conclude that BACH1 is a bona fide Nrf2 target gene and that induction of BACH1 by Nrf2 may serve as a feedback-inhibitory mechanism for ARE-mediated gene regulation.
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Novel insights into the regulation of the antioxidant response element mediated gene expression by electrophiles: induction of the transcriptional repressor BACH1 by NRF2
Biochemical Journal, 2011Co-Authors: Hennakaisa Jyrkkanen, Emilia Kansanen, Suvi M Kuosmanen, Hanna Leinonen, Merja Heinäniemi, Heidi Laitinen, Eero Mella-aho, Seppo Ylä-herttuala, Anna-liisa LevonenAbstract:A central mechanism in cellular defence against oxidative or Electrophilic Stress is mediated by transcriptional induction of genes via the Antioxidant Response Element (ARE), a cis-acting sequence present in the regulatory regions of genes involved in the detoxification and elimination of reactive oxidants and electrophiles. The ARE binds different basic-region leucine zipper (bZIP) transcription factors, most notably NF-E2 related factor-2 (Nrf2) that functions as a transcriptional activator via heterodimerization with small Maf proteins. While the ARE activation by Nrf2 is relatively well understood, the mechanisms by which ARE mediated signalling is downregulated is poorly known. Transcription factor BACH1 (BTB and CNC homology 1) binds to ARE-like sequences, functioning as a transcriptional repressor in a subset of ARE-regulated genes thus antagonizing the activator function of Nrf2. Herein, we demonstrate that BACH1 itself is regulated by Nrf2 as it is induced by Nrf2 overexpression and by Nrf2 activating agents in an Nrf2-dependent manner. Furthermore, a functional ARE site was identified at +1411 from the transcription start site of transcript variant 2 of BACH1. We conclude that BACH1 is a bona fide Nrf2 target gene, and that induction of BACH1 by Nrf2 may serve as a feedback inhibitory mechanism for ARE-mediated gene regulation.