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Jeffrey A. Johnson - One of the best experts on this subject based on the ideXlab platform.
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cell specific overactivation of nuclear erythroid 2 p45 Related Factor 2 mediated gene expression in myeloid cells decreases hepatic ischemia reperfusion injury
Liver Transplantation, 2016Co-Authors: Lungyi Lee, Delinda A. Johnson, Jeffrey A. Johnson, Calvin Harberg, Kristina A Matkowskyj, Shelly M Cook, Drew A Roenneburg, Sabine Werner, David P FoleyAbstract:Hepatic ischemia/reperfusion injury (IRI) is an unavoidable consequence of liver transplantation that can lead to postoperative hepatic dysfunction. Myeloid cells that include Kupffer cells, monocytes, and neutrophils contribute to the inflammatory response and cellular injury observed during hepatic IRI. We hypothesize that overactivation of the nuclear erythroid 2 p45-Related Factor 2 (Nrf2)-antioxidant response element (ARE) pathway in myeloid cells leads to decreased cellular damage after hepatic IRI. We constructed transgenic mice with constitutively active nuclear erythroid 2 p45-Related Factor 2 (caNrf2) that over activates the Nrf2-ARE pathway in myeloid cells (lysozyme M cre recombinase [LysMcre]+/caNrf2+, n = 9), and their littermate controls lacking transgene expression (LysMcre+/caNrf2-, n = 11). The mice underwent either sham or partial hepatic ischemia surgery, with 60 minutes of ischemia followed by 6 hours of reperfusion. After IRI, LysMcre+/caNrf2+ mice demonstrated significantly decreased serum alanine aminotransferase and decreased areas of necrosis. Immunohistochemistry and immunoblot of caspase 3 showed a significantly decreased cleaved to full-length caspase 3 ratio in LysMcre+/caNrf2+ animals. Lymphocyte antigen 6 complex locus G and CD68 staining demonstrated reduced inflammatory cell infiltration. LysMcre+/caNrf2+ animals also had significantly decreased gene expression of proinflammatory cytokines, including interleukin (IL) 1β, IL6, tumor necrosis Factor α, chemokine (C-C motif) ligand 2, and chemokine (C-X-C motif) ligand 10, and significantly decreased levels of 8-isoprostanes. In our model, Nrf2 overactivation in myeloid cells leads to decreased hepatocellular damage, necrosis, apoptosis, inflammation, and oxidative stress. Pharmacologic targeting of the Nrf2-ARE pathway in myeloid cells may be a novel strategy to mitigate hepatic IRI. Liver Transplantation 22 1115-1128 2016 AASLD.
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fasting induces nuclear Factor e2 Related Factor 2 and atp binding cassette transporters via protein kinase a and sirtuin 1 in mouse and human
Antioxidants & Redox Signaling, 2014Co-Authors: Supriya R Kulkarni, Delinda A. Johnson, Jeffrey A. Johnson, Ajay C Donepudi, Jialin Xu, Qiuqiong C Cheng, Maureen V Driscoll, Xiaoling Li, Angela L. SlittAbstract:Abstract Aims: The purpose of this study was to determine whether 3′-5′-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) and Sirtuin-1 (SIRT1) dependent mechanisms modulate ATP-binding Cassette (ABC) transport protein expression. ABC transport proteins (ABCC2–4) are essential for chemical elimination from hepatocytes and biliary excretion. Nuclear Factor-E2 Related-Factor 2 (NRF2) is a transcription Factor that mediates ABCC induction in response to chemical inducers and liver injury. However, a role for NRF2 in the regulation of transporter expression in nonchemical models of liver perturbation is largely undescribed. Results: Here we show that fasting increased NRF2 target gene expression through NRF2- and SIRT1–dependent mechanisms. In intact mouse liver, fasting induces NRF2 target gene expression by at least 1.5 to 5-fold. In mouse and human hepatocytes, treatment with 8-Bromoadenosine-cAMP, a cAMP analogue, increased NRF2 target gene expression and antioxidant response element activity, ...
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Activation of the Nuclear Factor E2-Related Factor 2 Pathway by Novel Natural Products Halomadurones A–D and a Synthetic Analogue
Marine drugs, 2013Co-Authors: Thomas P. Wyche, Doug R. Braun, Miranda Standiford, Yanpeng Hou, Delinda A. Johnson, Jeffrey A. Johnson, Tim S. BugniAbstract:Two novel chlorinated pyrones, halomadurones A and B, and two novel brominated analogues, halomadurones C and D, were isolated from a marine Actinomadura sp. cultivated from the ascidian Ecteinascidia turbinata. Additionally, a non-halogenated analogue, 2-methyl-6-((E)-3-methyl-1,3-hexadiene)-γ-pyrone, was synthesized to understand the role of the halogens for activity. Halomadurones C and D demonstrated potent nuclear Factor E2-Related Factor antioxidant response element (Nrf2-ARE) activation, which is an important therapeutic approach for treatment of neurodegenerative diseases.
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structure activity relationship of phenolic diterpenes from salvia officinalis as activators of the nuclear Factor e2 Related Factor 2 pathway
Bioorganic & Medicinal Chemistry, 2013Co-Authors: Justin T Fischedick, Miranda Standiford, Delinda A. Johnson, Jeffrey A. JohnsonAbstract:Abstract Nuclear Factor E2-Related Factor 2 (Nrf2) is a transcription Factor known to activate cytoprotective genes which may be useful in the treatment of neurodegenerative disease. In order to better understand the structure activity relationship of phenolic diterpenes from Salvia officinalis L., we isolated carnosic acid, carnosol, epirosmanol, rosmanol, 12-methoxy-carnosic acid, sageone, and carnosaldehyde using polyamide column, centrifugal partition chromatography, and semi-preparative high performance liquid chromatography. Isolated compounds were screened in vitro for their ability to active the Nrf2 and general cellular toxicity using mouse primary cortical cultures. All compounds except 12-methoxy-carnosic acid were able to activate the antioxidant response element. Furthermore both carnosol and carnoasldehyde were able to induce Nrf2-dependent gene expression as well as protect mouse primary cortical neuronal cultures from H 2 O 2 induced cell death.
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cystamine protects from 3 nitropropionic acid lesioning via induction of nf e2 Related Factor 2 mediated transcription
Experimental Neurology, 2010Co-Authors: Marcus J Calkins, Delinda A. Johnson, Jessica A Townsend, Jeffrey A. JohnsonAbstract:Systemic administration of cystamine is known to protect from both chemical and genetic models of neurotoxicity. Despite positive effects in laboratory models, cystamine has not been successfully translated to clinical application for neurodegenerative disease. Furthermore, the long held assumption that cystamine protects through tissue transglutaminase inhibition has recently been challenged. The studies described here examine other potential mechanisms of cystamine-mediated protection in an attempt to reveal molecular targets for neurodegenerative therapy. Based on previously described effects of cystamine, we examined the potential for activation of NF-E2 Related Factor 2 (Nrf2) mediated signaling through the antioxidant response element (ARE). We found that cystamine activates Nrf2/ARE both in cell culture and in brain tissue and then probed the mechanism of activation in cell culture. In live animals, we show that neuroprotection from 3-nitropropionic acid (3NP) toxicity is Nrf2-dependent. Therefore, these findings provide strong evidence that Nrf2 signaling may be an effective target for prevention of neurodegeneration.
Delinda A. Johnson - One of the best experts on this subject based on the ideXlab platform.
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cell specific overactivation of nuclear erythroid 2 p45 Related Factor 2 mediated gene expression in myeloid cells decreases hepatic ischemia reperfusion injury
Liver Transplantation, 2016Co-Authors: Lungyi Lee, Delinda A. Johnson, Jeffrey A. Johnson, Calvin Harberg, Kristina A Matkowskyj, Shelly M Cook, Drew A Roenneburg, Sabine Werner, David P FoleyAbstract:Hepatic ischemia/reperfusion injury (IRI) is an unavoidable consequence of liver transplantation that can lead to postoperative hepatic dysfunction. Myeloid cells that include Kupffer cells, monocytes, and neutrophils contribute to the inflammatory response and cellular injury observed during hepatic IRI. We hypothesize that overactivation of the nuclear erythroid 2 p45-Related Factor 2 (Nrf2)-antioxidant response element (ARE) pathway in myeloid cells leads to decreased cellular damage after hepatic IRI. We constructed transgenic mice with constitutively active nuclear erythroid 2 p45-Related Factor 2 (caNrf2) that over activates the Nrf2-ARE pathway in myeloid cells (lysozyme M cre recombinase [LysMcre]+/caNrf2+, n = 9), and their littermate controls lacking transgene expression (LysMcre+/caNrf2-, n = 11). The mice underwent either sham or partial hepatic ischemia surgery, with 60 minutes of ischemia followed by 6 hours of reperfusion. After IRI, LysMcre+/caNrf2+ mice demonstrated significantly decreased serum alanine aminotransferase and decreased areas of necrosis. Immunohistochemistry and immunoblot of caspase 3 showed a significantly decreased cleaved to full-length caspase 3 ratio in LysMcre+/caNrf2+ animals. Lymphocyte antigen 6 complex locus G and CD68 staining demonstrated reduced inflammatory cell infiltration. LysMcre+/caNrf2+ animals also had significantly decreased gene expression of proinflammatory cytokines, including interleukin (IL) 1β, IL6, tumor necrosis Factor α, chemokine (C-C motif) ligand 2, and chemokine (C-X-C motif) ligand 10, and significantly decreased levels of 8-isoprostanes. In our model, Nrf2 overactivation in myeloid cells leads to decreased hepatocellular damage, necrosis, apoptosis, inflammation, and oxidative stress. Pharmacologic targeting of the Nrf2-ARE pathway in myeloid cells may be a novel strategy to mitigate hepatic IRI. Liver Transplantation 22 1115-1128 2016 AASLD.
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fasting induces nuclear Factor e2 Related Factor 2 and atp binding cassette transporters via protein kinase a and sirtuin 1 in mouse and human
Antioxidants & Redox Signaling, 2014Co-Authors: Supriya R Kulkarni, Delinda A. Johnson, Jeffrey A. Johnson, Ajay C Donepudi, Jialin Xu, Qiuqiong C Cheng, Maureen V Driscoll, Xiaoling Li, Angela L. SlittAbstract:Abstract Aims: The purpose of this study was to determine whether 3′-5′-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) and Sirtuin-1 (SIRT1) dependent mechanisms modulate ATP-binding Cassette (ABC) transport protein expression. ABC transport proteins (ABCC2–4) are essential for chemical elimination from hepatocytes and biliary excretion. Nuclear Factor-E2 Related-Factor 2 (NRF2) is a transcription Factor that mediates ABCC induction in response to chemical inducers and liver injury. However, a role for NRF2 in the regulation of transporter expression in nonchemical models of liver perturbation is largely undescribed. Results: Here we show that fasting increased NRF2 target gene expression through NRF2- and SIRT1–dependent mechanisms. In intact mouse liver, fasting induces NRF2 target gene expression by at least 1.5 to 5-fold. In mouse and human hepatocytes, treatment with 8-Bromoadenosine-cAMP, a cAMP analogue, increased NRF2 target gene expression and antioxidant response element activity, ...
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Activation of the Nuclear Factor E2-Related Factor 2 Pathway by Novel Natural Products Halomadurones A–D and a Synthetic Analogue
Marine drugs, 2013Co-Authors: Thomas P. Wyche, Doug R. Braun, Miranda Standiford, Yanpeng Hou, Delinda A. Johnson, Jeffrey A. Johnson, Tim S. BugniAbstract:Two novel chlorinated pyrones, halomadurones A and B, and two novel brominated analogues, halomadurones C and D, were isolated from a marine Actinomadura sp. cultivated from the ascidian Ecteinascidia turbinata. Additionally, a non-halogenated analogue, 2-methyl-6-((E)-3-methyl-1,3-hexadiene)-γ-pyrone, was synthesized to understand the role of the halogens for activity. Halomadurones C and D demonstrated potent nuclear Factor E2-Related Factor antioxidant response element (Nrf2-ARE) activation, which is an important therapeutic approach for treatment of neurodegenerative diseases.
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structure activity relationship of phenolic diterpenes from salvia officinalis as activators of the nuclear Factor e2 Related Factor 2 pathway
Bioorganic & Medicinal Chemistry, 2013Co-Authors: Justin T Fischedick, Miranda Standiford, Delinda A. Johnson, Jeffrey A. JohnsonAbstract:Abstract Nuclear Factor E2-Related Factor 2 (Nrf2) is a transcription Factor known to activate cytoprotective genes which may be useful in the treatment of neurodegenerative disease. In order to better understand the structure activity relationship of phenolic diterpenes from Salvia officinalis L., we isolated carnosic acid, carnosol, epirosmanol, rosmanol, 12-methoxy-carnosic acid, sageone, and carnosaldehyde using polyamide column, centrifugal partition chromatography, and semi-preparative high performance liquid chromatography. Isolated compounds were screened in vitro for their ability to active the Nrf2 and general cellular toxicity using mouse primary cortical cultures. All compounds except 12-methoxy-carnosic acid were able to activate the antioxidant response element. Furthermore both carnosol and carnoasldehyde were able to induce Nrf2-dependent gene expression as well as protect mouse primary cortical neuronal cultures from H 2 O 2 induced cell death.
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cystamine protects from 3 nitropropionic acid lesioning via induction of nf e2 Related Factor 2 mediated transcription
Experimental Neurology, 2010Co-Authors: Marcus J Calkins, Delinda A. Johnson, Jessica A Townsend, Jeffrey A. JohnsonAbstract:Systemic administration of cystamine is known to protect from both chemical and genetic models of neurotoxicity. Despite positive effects in laboratory models, cystamine has not been successfully translated to clinical application for neurodegenerative disease. Furthermore, the long held assumption that cystamine protects through tissue transglutaminase inhibition has recently been challenged. The studies described here examine other potential mechanisms of cystamine-mediated protection in an attempt to reveal molecular targets for neurodegenerative therapy. Based on previously described effects of cystamine, we examined the potential for activation of NF-E2 Related Factor 2 (Nrf2) mediated signaling through the antioxidant response element (ARE). We found that cystamine activates Nrf2/ARE both in cell culture and in brain tissue and then probed the mechanism of activation in cell culture. In live animals, we show that neuroprotection from 3-nitropropionic acid (3NP) toxicity is Nrf2-dependent. Therefore, these findings provide strong evidence that Nrf2 signaling may be an effective target for prevention of neurodegeneration.
Michael R Green - One of the best experts on this subject based on the ideXlab platform.
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initiation of zebrafish haematopoiesis by the tata box binding protein Related Factor trf3
Nature, 2007Co-Authors: Daniel O Hart, Tamal Raha, Nathan D Lawson, Michael R GreenAbstract:It is shown for the first time that a vertebrate-specific member of the TATA-box-binding protein (TBP) family, called TRF3, controls haematopoiesis in zebrafish embryogenesis. TATA-box-binding protein (TBP)-Related Factor 3, TRF3 (also called TBP2), is a vertebrate-specific member of the TBP family that has a conserved carboxy-terminal region and DNA-binding domain virtually identical to that of TBP (ref. 1). TRF3 is highly expressed during embryonic development, and studies in zebrafish and Xenopus have shown that it is required for normal embryogenesis2,3. Here we show that zebrafish embryos depleted of Trf3 exhibit multiple developmental defects and, in particular, fail to undergo haematopoiesis. Expression profiling for Trf3-dependent genes identified mespa, which encodes a transcription Factor whose murine orthologue is required for mesoderm specification4, and chromatin immunoprecipitation verified that Trf3 binds to the mespa promoter. Depletion of Mespa resulted in developmental and haematopoietic defects markedly similar to those induced by Trf3 depletion. Injection of mespa messenger RNA (mRNA) restored normal development to a Trf3-depleted embryo, indicating mespa is the single Trf3 target gene required for zebrafish embryogenesis. Zebrafish embryos depleted of Trf3 or Mespa also failed to express cdx4, a caudal-Related gene required for haematopoiesis. Mespa binds to the cdx4 promoter, and epistasis analysis revealed an ordered trf3–mespa–cdx4 pathway. Thus, in zebrafish, commitment of mesoderm to the haematopoietic lineage occurs through a transcription Factor pathway initiated by a TBP-Related Factor.
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trf3 a tata box binding protein Related Factor is vertebrate specific and widely expressed
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Stephan P Persengiev, Xiaochun Zhu, Bharat L Dixit, Glenn A Maston, Ellen L W Kittler, Michael R GreenAbstract:TATA-box-binding protein (TBP) is a highly conserved RNA polymerase II general transcription Factor that binds to the core promoter and initiates assembly of the preinitiation complex. Two proteins with high homology to TBP have been found: TBP-Related Factor 1 (TRF1), described only in Drosophila melanogaster, and TRF2, which is broadly distributed in metazoans. Here, we report the identification and characterization of an additional TBP-Related Factor, TRF3. TRF3 is virtually identical to TBP in the C-terminal core domain, including all residues involved in DNA binding and interaction with other general transcription Factors. Like other TBP family members, the N-terminal region of TRF3 is divergent. The TRF3 gene is present and expressed in vertebrates, from fish through humans, but absent from the genomes of the urochordate Ciona intestinalis and the lower eukaryotes D. melanogaster and Caenorhabditis elegans. TRF3 is a nuclear protein that is present in all human and mouse tissues and cell lines examined. Despite the highly homologous TBP-like C-terminal core domain, gel filtration analysis indicates that the native molecular weight of TRF3 is substantially less than that of TFIID. Interestingly, after mitosis, reimport of TRF3 into the nucleus occurs subsequent to TBP and other basal transcription Factors. In summary, TRF3 is a highly conserved vertebrate-specific TRF whose phylogenetic conservation, expression pattern, and other properties are distinct from those of TBP and all other TRFs.
Trent E. Tipple - One of the best experts on this subject based on the ideXlab platform.
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Selenium supplementation of lung epithelial cells enhances nuclear Factor E2-Related Factor 2 (Nrf2) activation following thioredoxin reductase inhibition.
Redox biology, 2018Co-Authors: Rachael Tindell, Katelyn Dunigan, Stephanie B. Wall, Rachael Wood, Trent E. TippleAbstract:The trace element selenium (Se) contributes to redox signaling, antioxidant defense, and immune responses in critically ill neonatal and adult patients. Se is required for the synthesis and function of selenoenzymes including thioredoxin (Trx) reductase-1 (TXNRD1) and glutathione peroxidases (GPx). We have previously identified TXNRD1, primarily expressed by airway epithelia, as a promising therapeutic target to prevent lung injury, likely via nuclear Factor E2-Related Factor 2 (Nrf2)-dependent mechanisms. The present studies utilized the TXNRD1 inhibitor auranofin (AFN) to test the hypothesis that Se positively influences Nrf2 activation and selenoenzyme responses in lung epithelial cells. Murine transformed Club cells (mtCCs) were supplemented with 0, 10, 25, or 100 nM Na2SeO3 to create a range of Se conditions and were cultured in the presence or absence of 0.5 μM AFN. TXNRD1 and GPX2 protein expression and enzymatic activity were significantly greater upon Se supplementation (p
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selenium supplementation of lung epithelial cells enhances nuclear Factor e2 Related Factor 2 nrf2 activation following thioredoxin reductase inhibition
Redox biology, 2018Co-Authors: Rachael Tindell, Katelyn Dunigan, Stephanie B. Wall, Rachael Wood, Trent E. TippleAbstract:The trace element selenium (Se) contributes to redox signaling, antioxidant defense, and immune responses in critically ill neonatal and adult patients. Se is required for the synthesis and function of selenoenzymes including thioredoxin (Trx) reductase-1 (TXNRD1) and glutathione peroxidases (GPx). We have previously identified TXNRD1, primarily expressed by airway epithelia, as a promising therapeutic target to prevent lung injury, likely via nuclear Factor E2-Related Factor 2 (Nrf2)-dependent mechanisms. The present studies utilized the TXNRD1 inhibitor auranofin (AFN) to test the hypothesis that Se positively influences Nrf2 activation and selenoenzyme responses in lung epithelial cells. Murine transformed Club cells (mtCCs) were supplemented with 0, 10, 25, or 100 nM Na2SeO3 to create a range of Se conditions and were cultured in the presence or absence of 0.5 μM AFN. TXNRD1 and GPX2 protein expression and enzymatic activity were significantly greater upon Se supplementation (p < 0.05). AFN treatment (0.5 μM AFN for 1 h) significantly inhibited TXNRD1 but not GPx activity (p < 0.001). Recovery of TXNRD1 activity following AFN treatment was significantly enhanced by Se supplementation (p < 0.041). Finally, AFN-induced Nrf2 transcriptional activation was significantly greater in mtCCs supplemented in 25 or 100 nM Na2SeO3 when compared to non-supplemented controls (p < 0.05). Our novel studies indicate that Se levels positively influence Nrf2 activation and selenoenzyme responses following TXNRD1 inhibition. These data suggest that Se status significantly influences physiologic responses to TXNRD1 inhibitors. In conclusion, correction of clinical Se deficiency, if present, will be necessary for optimal therapeutic effectiveness of TXNRD1 inhibitors in the prevention of lung disease.
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thioredoxin reductase inhibition attenuates neonatal hyperoxic lung injury and enhances nuclear Factor e2 Related Factor 2 activation
American Journal of Respiratory Cell and Molecular Biology, 2016Co-Authors: Stephanie B. Wall, Lynette K. Rogers, Morgan L. Locy, Markus Velten, Changchun Ren, Cynthia L Hill, Trent E. TippleAbstract:Oxygen toxicity and antioxidant deficiencies contribute to the development of bronchopulmonary dysplasia. Aurothioglucose (ATG) and auranofin potently inhibit thioredoxin reductase-1 (TrxR1), and TrxR1 disruption activates nuclear Factor E2-Related Factor 2 (Nrf2), a regulator of endogenous antioxidant responses. We have shown previously that ATG safely and effectively prevents lung injury in adult murine models, likely via Nrf2-dependent mechanisms. The current studies tested the hypothesis that ATG would attenuate hyperoxia-induced lung developmental deficits in newborn mice. Newborn C3H/HeN mice were treated with a single dose of ATG or saline within 12 hours of birth and were exposed to either room air or hyperoxia (85% O2). In hyperoxia, ATG potently inhibited TrxR1 activity in newborn murine lungs, attenuated decreases in body weight, increased the transcription of Nrf2-regulated genes nicotinamide adenine dinucleotide phosphate reduced quinone oxidoreductase-1 (NQO1) and heme oxygenase 1, and attenuated alterations in alveolar development. To determine the impact of TrxR1 inhibition on Nrf2 activation in vitro, murine alveolar epithelial-12 cells were treated with auranofin, which inhibited TrxR1 activity, enhanced Nrf2 nuclear levels, and increased NQO1 and heme oxygenase 1 transcription. Our novel data indicate that a single injection of the TrxR1 inhibitor ATG attenuates hyperoxia-induced alterations in alveolar development in newborn mice. Furthermore, our data support a model in which the effects of ATG treatment likely involve Nrf2 activation, which is consistent with our findings in other lung injury models. We conclude that TrxR1 represents a novel therapeutic target to prevent oxygen-mediated neonatal lung injury.
Youngjoon Surh - One of the best experts on this subject based on the ideXlab platform.
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a protective role of nuclear Factor erythroid 2 Related Factor 2 nrf2 in inflammatory disorders
Mutation Research, 2010Co-Authors: Jiyoung Kim, Youngnam Cha, Youngjoon SurhAbstract:Nuclear Factor-erythroid 2-Related Factor-2 (Nrf2) is a key transcription Factor that plays a central role in cellular defense against oxidative and electrophilic insults by timely induction of antioxidative and phase-2 detoxifying enzymes and Related stress-response proteins. The 5'-flanking regions of genes encoding these cytoprotective proteins contain a specific consensus sequence termed antioxidant response element (ARE) to which Nrf2 binds. Recent studies have demonstrated that Nrf2-ARE signaling is also involved in attenuating inflammation-associated pathogenesis, such as autoimmune diseases, rheumatoid arthritis, asthma, emphysema, gastritis, colitis and atherosclerosis. Thus, disruption or loss of Nrf2 signaling causes enhanced susceptibility not only to oxidative and electrophilic stresses but also to inflammatory tissue injuries. During the early-phase of inflammation-mediated tissue damage, activation of Nrf2-ARE might inhibit the production or expression of pro-inflammatory mediators including cytokines, chemokines, cell adhesion molecules, matrix metalloproteinases, cyclooxygenase-2 and inducible nitric oxide synthase. It is likely that the cytoprotective function of genes targeted by Nrf2 may cooperatively regulate the innate immune response and also repress the induction of pro-inflammatory genes. This review highlights the protective role of Nrf2 in inflammation-mediated disorders with special focus on the inflammatory signaling modulated by this redox-regulated transcription Factor.
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triphlorethol a induces heme oxygenase 1 via activation of erk and nf e2 Related Factor 2 transcription Factor
FEBS Letters, 2007Co-Authors: Kyoung Ah Kang, Kyoung Hwa Lee, Jae Woo Park, Nam Ho Lee, Youngjoon Surh, Ho Jin You, Myung Hee Chung, Jin Won HyunAbstract:Triphlorethol-A, phlorotannin found in Ecklonia cava, induced heme oxygenase-1 (HO-1) expression at mRNA and protein levels, leading to increased HO-1 activity. Transcription Factor NF-E2 Related Factor 2 (Nrf2) regulates antioxidant response element (ARE) of phase 2 detoxifying and antioxidant enzymes. Triphlorethol-A increased nuclear translocation, ARE binding, and transcriptional activity of Nrf2. Triphlorethol-A exhibited activation of ERK and U0126, inhibitor of ERK kinase, suppressed triphlorethol-A induced activation of Nrf2, finally decreased HO-1 protein level. Taken together, these data suggest that triphlorethol-A augments cellular antioxidant defense capacity through induction of HO-1 via ERK-Nrf2-ARE signaling pathway, thereby protecting cells from oxidative stress.
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resveratrol upregulates heme oxygenase 1 expression via activation of nf e2 Related Factor 2 in pc12 cells
Biochemical and Biophysical Research Communications, 2005Co-Authors: Chuyue Chen, Junghee Jang, Youngjoon SurhAbstract:Abstract Resveratrol (3,4′,5-trihydroxy stilbene), a phytoalexin found in the skin and seeds of grapes, has been reported to possess anti-inflammatory, anticarcinogenic, and antioxidant activities. In this work, we assessed the ability of resveratrol to upregulate heme oxygenase-1 (HO-1) gene expression via activation of NF-E2-Related Factor 2 (Nrf2) in cultured PC12 cells. Nrf2 is a transcription Factor involved in the cellular protection against oxidative stress through antioxidant response element (ARE)-directed induction of several phase 2 detoxifying and antioxidant enzymes, such as HO-1. Here, we report that resveratrol induces HO-1 expression via the ARE-mediated transcriptional activation of Nrf2. Moreover, PC12 cells treated with resveratrol exhibited transient activation of Akt/protein kinase B and extracellular signal-regulated protein kinase 1/2 (ERK1/2). LY294002 and U0126, pharmacological inhibitors of phosphatidylinositol 3-kinase and MEK1/2 which are upstream of Akt and ERK1/2, respectively, attenuated resveratrol-induced HO-1 expression and exhibited antioxidant effects. Taken together, the above findings suggest that resveratrol augments cellular antioxidant defense capacity through induction of HO-1 via Nrf2-ARE signaling, thereby protecting PC12 cells from oxidative stress.
