The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice

Higashi, Chika; Kawaji, Atsuko; Tsuda, Nobuyuki; Hayashi, Makiko; Saito, Ryota; Yagishita, Yoko; Suzuki, Takafumi; Uruno, Akira; Nakamura, Masaki; Nakao, Kazunari; Furusako, Shoji; Yamamoto, Masayuki

doi:10.1016/j.ejphar.2017.02.044

Cited by 36 publications

(20 citation statements)

References 53 publications

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“…This observation is in very good agreement with our previous observation that Nrf2 protein fused with beta-galactosidase in the N-terminal domain is degraded by the Keap1 pathway (42). Indeed, the latter fusion protein has been utilized as an excellent reporter to monitor Nrf2 activity (43).…”

Section: Resultssupporting

confidence: 91%

Direct and Specific Functional Evaluation of the Nrf2 and MafG Heterodimer by Introducing a Tethered Dimer into Small Maf-Deficient Cells

Katsuoka

Otsuki

Takahashi

et al. 2019

Molecular and Cellular Biology

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A group of cytoprotective genes is regulated by heterodimers composed of the cap’n’collar (CNC) family member Nrf2 and one of the small Maf (sMaf) proteins (MafF, MafG, or MafK) through the antioxidant response element (ARE, also referred to as the CNC-sMaf binding element [CsMBE]). Many lines of evidence support this model; however, a direct and specific evaluation of the Nrf2-sMaf heterodimer remains to be executed. To address this issue, we constructed a tethered Nrf2-MafG (T-N2G) heterodimer using a flexible linker peptide. We then introduced the T-N2G construct into cells lacking all three sMaf proteins to specifically evaluate the function of the tethered heterodimer without interference from other endogenous CNC-sMaf heterodimers or sMaf homodimers. In response to an Nrf2 activator, diethyl maleate, the T-N2G protein can widely activate the target genes of Nrf2 but not those of Nrf1, such as proteasome subunit genes. Genome-wide binding analysis showed that the T-N2G protein preferentially bound to the CsMBE motifs in the regulatory regions of the Nrf2 target genes. These results provide direct evidence that the Nrf2-MafG heterodimer acts as a transcriptional activator of Nrf2-dependent genes and show that this assay system will be a powerful tool to specifically examine the function of other CNC-sMaf heterodimers.

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Section: Resultssupporting

confidence: 91%

Direct and Specific Functional Evaluation of the Nrf2 and MafG Heterodimer by Introducing a Tethered Dimer into Small Maf-Deficient Cells

Katsuoka

Otsuki

Takahashi

et al. 2019

Molecular and Cellular Biology

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“…A high-throughput screening reporter strategy assessing the stability of a chimeric protein comprising the NRF2 N-terminal domain fused to LacZ (NRF2d-LacZ) 236 identified TFM735 as a lead compound (compound 12, Figure 3A). TFM735 activates NRF2 in a C151-dependent manner, inhibits the synthesis of IL-6 and IL-17 from stimulated human peripheral blood mononuclear cells, and the progression of experimental autoimmune encephalomyelitis in mice 237 . This compound is currently in preclinical development by…”

Section: Tfm735mentioning

confidence: 99%

Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

Cuadrado

Rojo

Wells

et al. 2019

Nat Rev Drug Discov

951

950

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Transcription factor NF-E2 p45-related factor 2 (NRF2, gene name NFE2L2) and its principal negative regulator, the E3 ligase adapter Kelch-like ECH-associated protein 1 (KEAP1), play a critical role in the development and progression of chronic diseases of the lung and liver, autoimmune, neurodegenerative and metabolic disorders, and also cancer. NRF2 activation provides cytoprotection against numerous pathologies characterized by chronic inflammation, metabolic alterations and redox disturbances. One NRF2 activator has received clinical approval and several electrophilic modifiers of the cysteine-based sensor KEAP1 and inhibitors of its interaction with NRF2 are now in clinical development. However, challenges regarding target specificity, pharmacodynamic properties, efficacy, and safety remain.

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“…Other pharmacological inducers of Nrf2 have shown protective effects in the experimental autoimmune encephalomyelitis model of multiple sclerosis, including the triterpenoid CDDO-trifluoroethylamide (also effective in the lysophosphatidyl choline model) [ 234 ], 3H-1,2-dithiole-3-thione [ 243 ], sulforaphane [ 230 ], the natural alkaloid matrine [ 244 ] and TFM-735, which was identified from a chemical library screen [ 245 ] ( Table 7 ). Resveratrol [ 246 , 247 , 248 , 249 , 250 , 251 , 252 ] and curcumin [ 253 , 254 ] are effective in several models of multiple sclerosis, although the role of Nrf2 was not considered in these studies.…”

Section: Multiple Sclerosismentioning

confidence: 99%

Are Astrocytes the Predominant Cell Type for Activation of Nrf2 in Aging and Neurodegeneration?

2017

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Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates hundreds of antioxidant genes, and is activated in response to oxidative stress. Given that many neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and multiple sclerosis are characterised by oxidative stress, Nrf2 is commonly activated in these diseases. Evidence demonstrates that Nrf2 activity is repressed in neurons in vitro, and only cultured astrocytes respond strongly to Nrf2 inducers, leading to the interpretation that Nrf2 signalling is largely restricted to astrocytes. However, Nrf2 activity can be observed in neurons in post-mortem brain tissue and animal models of disease. Thus this interpretation may be false, and a detailed analysis of the cell type expression of Nrf2 in neurodegenerative diseases is required. This review describes the evidence for Nrf2 activation in each cell type in prominent neurodegenerative diseases and normal aging in human brain and animal models of neurodegeneration, the response to pharmacological and genetic modulation of Nrf2, and clinical trials involving Nrf2-modifying drugs.

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The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice

Cited by 36 publications

References 53 publications

Direct and Specific Functional Evaluation of the Nrf2 and MafG Heterodimer by Introducing a Tethered Dimer into Small Maf-Deficient Cells

Direct and Specific Functional Evaluation of the Nrf2 and MafG Heterodimer by Introducing a Tethered Dimer into Small Maf-Deficient Cells

Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

Are Astrocytes the Predominant Cell Type for Activation of Nrf2 in Aging and Neurodegeneration?

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