Fumarates Promote Cytoprotection of Central Nervous System Cells against Oxidative Stress via the Nuclear Factor (Erythroid-Derived 2)-Like 2 Pathway

Scannevin, Robert H.; Chollate, Sowmya; Jung, M.; Shackett, Melanie N.; Patel, Hiten D.; Bista, Pradeep; Zeng, Weike; Ryan, Sarah; Yamamoto, Masayuki; Lukashev, Matvey; Rhodes, Kenneth J.

doi:10.1124/jpet.111.190132

Cited by 407 publications

(407 citation statements)

References 41 publications

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“…In randomized, double-blind, placebo-controlled DEFINE and CONFIRM studies involving patients with relapsing-remitting MS, dimethyl fumarate significantly reduced the relapse rate and improved the neuroradiological outcome compared with the placebo. 22,23 Several mechanisms of action, such as the activation of anti-oxidants, nuclear factor (erythroid-derived 2)-like 2, [11][12][13]24 or glutathione and heme oxygenase-1, have been attributed to the effects of fumarates. 14 In addition, DMF switched the immune system towards a Th2 anti-inflammatory type response through the activation of type II DCs and the suppression of type I DCs, which consequently inhibits the generation of inflammatory Th1 or Th17 cells.…”

Section: Discussionmentioning

confidence: 99%

“…11,12 Consequently, DMF protects neurons and astrocytes against oxidative stress, which induces cellular injury. 13 In addition, DMF reduces the nuclear factor NF-kB in astrocytes and C6 cells, inhibits the degradation of IkBa, and reduces the expression of nitric oxide synthase 2. 14 In the experimental autoimmune encephalomyelitis model, DMF exerts clinical effects through the reduction of macrophage-induced inflammation in the spinal cord.…”

Section: Introductionmentioning

confidence: 99%

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Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

et al. 2014

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Dimethyl fumarate (DMF) is a new drug used to treat multiple sclerosis (MS) patients. Here, we examined the effects of DMF and the DMF metabolite monomethyl fumarate (MMF) on various activities of natural killer (NK) cells. We demonstrated that MMF augments the primary CD56 1 , but not CD56 2 , NK cell lysis of K562 and RAJI tumor cells. MMF induced NKp46 expression on the surface of CD56 1 , but not CD56 2 , NK cells after incubation for 24 h. This effect was closely correlated with the upregulation of CD107a expression on the surface of CD56 1 NK cells and the induction of Granzyme B release from these cells through this metabolite. An anti-NKp46 antibody inhibited the MMF-induced upregulation of CD107a and the lysis of tumor cells through CD56 1 NK cells. Thus, these results are the first to show that MMF augments CD56 1 NK cell lysis of tumor target cells, an effect mediated through NKp46. This novel effect suggests the use of MMF for therapeutic and/or preventive protocols in cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

et al. 2014

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“…The therapeutic mechanism of action for DMF has been attributed to both immunosuppression and induction of antioxidant pathways 2, 3, 4. The induction of antioxidant response element (ARE) genes by DMF is attributed to the activation of the Nrf2 transcription factor that leads to subsequent reductions in oxidative stress and increased neuroprotection in vivo 2, 5. The induction of Nrf2 is achieved through glutathione depletion as well as direct binding of fumaric acid esters to the Nrf2 repressor KEAP1 3, 6, 7.…”

Section: Introductionmentioning

confidence: 99%

Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation

Galloway

Williams

Moore

2017

Ann Clin Transl Neurol

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ObjectiveDimethyl fumarate (DMF) is a fumaric acid ester approved for the treatment of relapsing‐remitting multiple sclerosis (RRMS). In both the brain and periphery, DMF and its metabolite monomethyl fumarate (MMF) exert anti‐inflammatory and antioxidant effects. Our aim was to compare the effects of DMF and MMF on inflammatory and antioxidant pathways within astrocytes, a critical supporting glial cell in the central nervous system (CNS). Direct effects of fumarates on neural progenitor cell (NPC) differentiation toward the oligodendrocyte lineage were also assessed.MethodsPrimary astrocyte cultures were derived from both murine and human brains. Following pretreatment with MMF, DMF, or vehicle, astrocytes were stimulated with IL‐1β for 24 h; gene and microRNA expression were measured by qPCR. Cytokine production and reactive oxygen species (ROS) generation were also measured. NPCs were differentiated into the oligodendrocyte lineage in the presence of fumarates and immunostained using early oligodendrocyte markers.ResultsIn both murine and human astrocytes, DMF, but not MMF, significantly reduced secretion of IL‐6, CXCL10, and CCL2; neither fumarate promoted a robust increase in antioxidant gene expression, although both MMF and DMF prevented intracellular ROS production. Pretreatment with fumarates reduced microRNAs ‐146a and ‐155 upon stimulation. In NPC cultures, DMF increased the number of O4+ and NG2+ cells.InterpretationThese results suggest that DMF, and to a lesser extent MMF, mediates the anti‐inflammatory effects within astrocytes. This is supported by recent observations that in the inflamed CNS, DMF may be the active compound mediating the anti‐inflammatory effects independent from altered antioxidant gene expression.

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“…Keap1 has reactive thiol groups and is considered as a sensor of oxidants or electrophilic compounds. Some of the electrophilic compounds, for example, sulforaphane, 11 curcumin, 12 zerumbone, 19,20 piperlongumine, 21 bardoxolone methyl 22 and dimethyl fumarate, 23 activate the Keap1-Nrf2 pathway. They bind directly with the thiol group of Keap1 and causes conformational changes to Keap1.…”

Section: Discussionmentioning

confidence: 99%

Allantopyrone A activates Keap1–Nrf2 pathway and protects PC12 cells from oxidative stress-induced cell death

et al. 2016

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Keap1-Nrf2 system is known as a sensor of electrophilic compounds, and protects cells from oxidative stress through induction of various antioxidant enzymes. We found by proteomic analysis that allantopyrone A, a metabolite isolated from an endophytic fungus, upregulates the expression of proteins that are regulated by the transcription factor Nrf2. Indeed, allantopyrone A increased the antioxidant enzyme heme oxygenase-1 in PC12 cells. Moreover, it induced localization of Nrf2 in the nucleus. Affinity purification of allantopyrone A-binding protein showed that this compound could bind directly to Keap1. Allantopyrone A suppressed intracellular reactive oxygen species level and cell death induced by H 2 O 2 in PC12 cells. These results indicate that allantopyrone A protects PC12 cells from oxidative stress-induced cell death through direct binding with Keap1 and activation of the Keap1-Nrf2 pathway.

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Fumarates Promote Cytoprotection of Central Nervous System Cells against Oxidative Stress via the Nuclear Factor (Erythroid-Derived 2)-Like 2 Pathway

Cited by 407 publications

References 41 publications

Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation

Allantopyrone A activates Keap1–Nrf2 pathway and protects PC12 cells from oxidative stress-induced cell death

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