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Nrf2 AND Dimethylfumarate

J Brück, R Dringen, A Amasuno, I Pau-Charles, K Ghoreschi
Fumaric acid esters (FAEs) like dimethylfumarate (DMF) are used for the treatment of adults with moderate to severe psoriasis. The mode of action of FAEs is complex. Here we provide a comprehensive review of the literature to describe the molecular mechanisms by which DMF and its active metabolite monomethylfumarate (MMF) exert their anti-inflammatory and immune modulatory effects. MMF can bind to the hydroxy-carboxylic acid receptor 2 (HCA2) on the cell surface and both DMF and MMF react with intracellular glutathione following cell penetration...
March 30, 2018: Experimental Dermatology
Nana Akino, Osamu Wada-Hiraike, Hiromi Terao, Harunori Honjoh, Wataru Isono, Houju Fu, Mana Hirano, Yuichiro Miyamoto, Michihiro Tanikawa, Miyuki Harada, Tetsuya Hirata, Yasushi Hirota, Kaori Koga, Katsutoshi Oda, Kei Kawana, Tomoyuki Fujii, Yutaka Osuga
Nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway is one of the most important defense mechanisms against oxidative stress (OS). It is well documented that equilibration status of OS plays fundamental roles in human reproductive medicine, and the physiological role of Nrf2 in ovarian granulosa cells (GCs) has not been determined yet. Herein we aimed to study the function of Nrf2 in GCs. Human ovarian tissues were subjected to immunohistochemistry to localize Nrf2 and Keap1 and we detected the expression of Nrf2 and Keap1 in the human GCs...
October 4, 2017: Molecular and Cellular Endocrinology
Irina G Gazaryan, Bobby Thomas
This mini-review presents the authors' vision on the current status and future trends in the development of neuroprotective agents working via activation of nuclear factor erythroid 2-related factor 2 (Nrf2), and in particular, via disruption of Nrf2-Keap1 interaction. There are two opposite "chemical" mechanisms underlying such activation: the first one is a non-specific covalent modification of Keap1 thiols, resulting in side effects of varied severity, and the second one is the shift of the Nrf2-Kelch-like ECH associated protein-1 (Keap1) binding equilibrium in the presence of a competitive and chemically benign displacement agent...
November 2016: Neural Regeneration Research
Manuj Ahuja, Navneet Ammal Kaidery, Lichuan Yang, Noel Calingasan, Natalya Smirnova, Arsen Gaisin, Irina N Gaisina, Irina Gazaryan, Dmitry M Hushpulian, Ismail Kaddour-Djebbar, Wendy B Bollag, John C Morgan, Rajiv R Ratan, Anatoly A Starkov, M Flint Beal, Bobby Thomas
UNLABELLED: A promising approach to neurotherapeutics involves activating the nuclear-factor-E2-related factor 2 (Nrf2)/antioxidant response element signaling, which regulates expression of antioxidant, anti-inflammatory, and cytoprotective genes. Tecfidera, a putative Nrf2 activator, is an oral formulation of dimethylfumarate (DMF) used to treat multiple sclerosis. We compared the effects of DMF and its bioactive metabolite monomethylfumarate (MMF) on Nrf2 signaling and their ability to block 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced experimental Parkinson's disease (PD)...
June 8, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Meng-Chen Lu, Jian-Ai Ji, Zheng-Yu Jiang, Qi-Dong You
The Keap1-Nrf2-ARE ((Kelch-like ECH-Associating protein 1) nuclear factor erythroid 2 related factor 2-antioxidant response element) pathway is one of the most important defense mechanisms against oxidative and/or electrophilic stresses, and it is closely associated with inflammatory diseases, including cancer, neurodegenerative diseases, cardiovascular diseases, and aging. In recent years, progress has been made in strategies aimed at modulating the Keap1-Nrf2-ARE pathway. The Nrf2 activator DMF (Dimethylfumarates) has been approved by the FDA as a new first-line oral drug to treat patients with relapsing forms of multiple sclerosis, while a phase 3 study of another promising candidate, CDDO-Me, was terminated for safety reasons...
September 2016: Medicinal Research Reviews
Seray Demir, Sandra Heckers, Xiomara Pedreiturria, Daniela Hess, Anne-Kathrin Trampe, Andrew Chan, Ralf Gold
In this study we examined the role of fumaric acid esters (FAE) in a spontaneous and chronic animal model, the opticospinal EAE (OSE). Preventive treatment of dimethylfumarate (DMF) promotes onset of disease in animals treated with high dose DMF. This group also exhibited a significantly exacerbated disease course in a therapeutic treatment as compared to the low dose DMF approach, where less demyelination, macrophage infiltration, and increased Nrf2 expression in the spinal cord were observed. We conclude that low dose DMF treatment is effective in the therapy of the spontaneous opticospinal EAE model and mediates neuroprotective effects via the oxidative stress response pathway...
August 15, 2015: Journal of Neuroimmunology
Roberta Foresti, Claudio Bucolo, Chiara Maria Bianca Platania, Filippo Drago, Jean-Luc Dubois-Randé, Roberto Motterlini
Retinal pigment epithelial cells exert an important supporting role in the eye and develop adaptive responses to oxidative stress or high glucose levels, as observed during diabetes. Endogenous antioxidant defences are mainly regulated by Nrf2, a transcription factor that is activated by naturally-derived and electrophilic compounds. Here we investigated the effect of the Nrf2 activators dimethylfumarate (DMF) and carnosol on antioxidant pathways, oxygen consumption rate and wound healing in human retinal pigment epithelial cells (ARPE-19) cultured in medium containing normal (NG, 5mM) or high (HG, 25 mM) glucose levels...
September 2015: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Yizhi Liu, Jiaoxue Qiu, Zhong Wang, Wanchun You, Lingyun Wu, Chengyuan Ji, Gang Chen
OBJECT: Oxidative stress and the inflammatory response are thought to promote brain damage in the setting of subarachnoid hemorrhage (SAH). Previous reports have shown that dimethylfumarate (DMF) can activate the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2-antioxidant-responsive element (Keap1-Nrf2-ARE) system in vivo and in vitro, which leads to the downregulation of oxidative stress and inflammation. The aim of this study was to evaluate the potential neuroprotective effect of DMF on SAH-induced brain injury in rats...
October 2015: Journal of Neurosurgery
Chang Joo Oh, Sungmi Park, Joon-Young Kim, Han-Jong Kim, Nam Ho Jeoung, Young-Keun Choi, Younghoon Go, Keun-Gyu Park, In-Kyu Lee
Excessive proliferation of vascular smooth muscle cells (VSMCs) and incomplete re-endothelialization is a major clinical problem limiting the long-term efficacy of percutaneous coronary angioplasty. We tested if dimethylfumarate (DMF), an anti-psoriasis drug, could inhibit abnormal vascular remodeling via NF-E2-related factor 2 (Nrf2)-NAD(P)H quinone oxidoreductase 1 (NQO1) activity. DMF significantly attenuated neointimal hyperplasia induced by balloon injury in rat carotid arteries via suppression of the G1 to S phase transition resulting from induction of p21 protein in VSMCs...
2014: Redox Biology
Wanwisa Promsote, Levi Makala, Biaoru Li, Sylvia B Smith, Nagendra Singh, Vadivel Ganapathy, Betty S Pace, Pamela M Martin
PURPOSE: Sickle retinopathy (SR) is a major cause of vision loss in sickle cell disease (SCD). There are no strategies to prevent SR and treatments are extremely limited. The present study evaluated (1) the retinal pigment epithelial (RPE) cell as a hemoglobin producer and novel cellular target for fetal hemoglobin (HbF) induction, and (2) monomethylfumarate (MMF) as an HbF-inducing therapy and abrogator of oxidative stress and inflammation in SCD retina. METHODS: Human globin gene expression was evaluated by RT-quantitative (q)PCR in the human RPE cell line ARPE-19 and in primary RPE cells isolated from Townes humanized SCD mice...
August 2014: Investigative Ophthalmology & Visual Science
Ian M Copple, Luke M Shelton, Joanne Walsh, Denise V Kratschmar, Adam Lister, Alex Odermatt, Christopher E Goldring, Albena T Dinkova-Kostova, Tadashi Honda, B Kevin Park
The transcription factor Nrf2 protects against a number of experimental pathologies, and is a promising therapeutic target. The clinical investigation of a potent Nrf2-inducing agent, the triterpenoid (TP) bardoxolone methyl (BARD), was recently halted due to adverse cardiovascular events in chronic kidney disease patients, although the underlying mechanisms are yet to be resolved. The majority of small molecule Nrf2 inducers are electrophilic and trigger Nrf2 accumulation via the chemical modification of its redox-sensitive repressor Keap1...
August 1, 2014: Toxicological Sciences: An Official Journal of the Society of Toxicology
Karelle Bénardais, Refik Pul, Vikramjeet Singh, Thomas Skripuletz, De-Hyung Lee, Ralf A Linker, Viktoria Gudi, Martin Stangel
The blood-brain barrier (BBB) is composed of a network of tight junctions (TJ) which interconnect cerebral endothelial cells (EC). Alterations in the TJ proteins are common in inflammatory diseases of the central nervous system (CNS) like multiple sclerosis (MS). Modulation of the BBB could thus represent a therapeutic mechanism. One pathway to modulate BBB integrity could be the induction of nuclear-factor (erythroid derived 2) related factor-2 (Nrf2) mediated oxidative stress responses which are targeted by fumaric acid esters (FAE)...
October 25, 2013: Neuroscience Letters
Hyeon-Ji Kang, Hyun-Ae Seo, Younghoon Go, Chang Joo Oh, Nam Ho Jeoung, Keun-Gyu Park, In-Kyu Lee
The excessive accumulation of adipocytes contributes to the development of obesity and obesity-related diseases. The interactions of several transcription factors, such as C/EBPβ, PPARγ, C/EBPα, Nrf2, and STAT3, are required for adipogenic differentiation. Dimethylfumarate (DMF), an immune modulator and antioxidant, may function as an inhibitor of STAT3 and an activator of Nrf2. This study examined whether DMF inhibits adipogenic differentiation of 3T3-L1 preadipocytes by inhibiting STAT3 or activating Nrf2...
2013: PloS One
Daniela Maydt, Silke De Spirt, Christian Muschelknautz, Wilhelm Stahl, Thomas J J Müller
Abstract 1. Chalcones are structural analogues of benzalacetophenone (BAP). Several derivatives have been identified in plants and anticarcinogenic and anti-inflammatory properties were attributed to the compounds, probably related to their direct antioxidant activity or stimulatory effects on the expression of endogenous defence enzymes like hemeoxygenase-1 (HO-1). HO-1 expression is triggered by the Nrf2-Keap1 signalling pathway, initiated by the addition of chalcones to thiol groups of Keap1 via Michael-type reaction...
August 2013: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
De-Hyung Lee, Ralf Gold, Ralf A Linker
Oxidative stress plays a crucial role in many neurodegenerative conditions such as Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's as well as Huntington's disease. Inflammation and oxidative stress are also thought to promote tissue damage in multiple sclerosis (MS). Recent data point at an important role of anti-oxidative pathways for tissue protection in chronic-progressive MS, particularly involving the transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for MS treatment...
2012: International Journal of Molecular Sciences
Chang Joo Oh, Joon-Young Kim, Young-Keun Choi, Han-Jong Kim, Ji-Yun Jeong, Kwi-Hyun Bae, Keun-Gyu Park, In-Kyu Lee
TGF-β plays a key role in the development of renal fibrosis. Suppressing the TGF-β signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-β signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-β signaling. Results showed that DMF increased nuclear levels of Nrf2, and both DMF and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (α-SMA), fibronectin and type 1 collagen expression in TGF-β-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F)...
2012: PloS One
Kai Takaya, Takafumi Suzuki, Hozumi Motohashi, Ko Onodera, Susumu Satomi, Thomas W Kensler, Masayuki Yamamoto
The Keap1-Nrf2 system plays a critical role in cellular defense against electrophiles and reactive oxygen species. Keap1 possesses a number of cysteine residues, some of which are highly reactive and serves as sensors for these insults. Indeed, point mutation of Cys151 abrogates the response to certain electrophiles. However, this mutation does not affect the other set of electrophiles, suggesting that multiple sensor systems reside within the cysteine residues of Keap1. The precise contribution of each reactive cysteine to the sensor function of Keap1 remains to be clarified...
August 15, 2012: Free Radical Biology & Medicine
Houman Ashrafian, Gabor Czibik, Mohamed Bellahcene, Dunja Aksentijević, Anthony C Smith, Sarah J Mitchell, Michael S Dodd, Jennifer Kirwan, Jonathan J Byrne, Christian Ludwig, Henrik Isackson, Arash Yavari, Nicolaj B Støttrup, Hussain Contractor, Thomas J Cahill, Natasha Sahgal, Daniel R Ball, Rune I D Birkler, Iain Hargreaves, Daniel A Tennant, John Land, Craig A Lygate, Mogens Johannsen, Rajesh K Kharbanda, Stefan Neubauer, Charles Redwood, Rafael de Cabo, Ismayil Ahmet, Mark Talan, Ulrich L Günther, Alan J Robinson, Mark R Viant, Patrick J Pollard, Damian J Tyler, Hugh Watkins
The citric acid cycle (CAC) metabolite fumarate has been proposed to be cardioprotective; however, its mechanisms of action remain to be determined. To augment cardiac fumarate levels and to assess fumarate's cardioprotective properties, we generated fumarate hydratase (Fh1) cardiac knockout (KO) mice. These fumarate-replete hearts were robustly protected from ischemia-reperfusion injury (I/R). To compensate for the loss of Fh1 activity, KO hearts maintain ATP levels in part by channeling amino acids into the CAC...
March 7, 2012: Cell Metabolism
Ralf A Linker, De-Hyung Lee, Sarah Ryan, Anne M van Dam, Rebecca Conrad, Pradeep Bista, Weike Zeng, Xiaoping Hronowsky, Alex Buko, Sowmya Chollate, Gisa Ellrichmann, Wolfgang Brück, Kate Dawson, Susan Goelz, Stefan Wiese, Robert H Scannevin, Matvey Lukashev, Ralf Gold
Inflammation and oxidative stress are thought to promote tissue damage in multiple sclerosis. Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for multiple sclerosis treatment. BG00012 is an oral formulation of dimethylfumarate. In a phase II multiple sclerosis trial, BG00012 demonstrated beneficial effects on relapse rate and magnetic resonance imaging markers indicative of inflammation as well as axonal destruction. First we have studied effects of dimethylfumarate on the disease course, central nervous system, tissue integrity and the molecular mechanism of action in an animal model of chronic multiple sclerosis: myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis in C57BL/6 mice...
March 2011: Brain: a Journal of Neurology
Gisa Ellrichmann, Elisabeth Petrasch-Parwez, De-Hyung Lee, Christiane Reick, Larissa Arning, Carsten Saft, Ralf Gold, Ralf A Linker
Huntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disease. The exact sequel of events finally resulting in neurodegeneration is only partially understood and there is no established protective treatment so far. Some lines of evidence speak for the contribution of oxidative stress to neuronal tissue damage. The fumaric acid ester dimethylfumarate (DMF) is a new disease modifying therapy currently in phase III studies for relapsing-remitting multiple sclerosis. DMF potentially exerts neuroprotective effects via induction of the transcription factor "nuclear factor E2-related factor 2" (Nrf2) and detoxification pathways...
2011: PloS One
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