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Dimethyl fumarate reduces hepatocyte senescence following paracetamol exposure.

ABSTRACT: Liver disease is a major cause of premature death. Oxidative stress in the liver represents a key disease driver. Compounds, such as dimethyl fumarate (DMF), can activate the antioxidant response and are used clinically to treat disease. In this study, we tested the protective properties of DMF before or after paracetamol exposure. Following DMF administration, Nrf2 nuclear translocation was tracked at the single-cell level and target gene transactivation confirmed. Next, the protective properties of DMF were examined following paracetamol exposure. Transcriptomic and biochemical analysis revealed that DMF rescue was underpinned by reduced Nf-kB and TGF-β signaling and cell senescence. Following on from these studies, we employed a Zebrafish model to study paracetamol exposure in vivo. We combined a genetically modified Zebrafish model, expressing green fluorescent protein exclusively in the liver, with automated microscopy. Pre-treatment with DMF, prior to paracetamol exposure, led to reduced liver damage in Zebrafish demonstrating protective properties.

SUBMITTER: Meseguer-Ripolles J

PROVIDER: S-EPMC8188562 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Dimethyl fumarate reduces hepatocyte senescence following paracetamol exposure.

Meseguer-Ripolles Jose J Lucendo-Villarin Baltasar B Tucker Carl C Ferreira-Gonzalez Sofia S Homer Natalie N Wang Yu Y Starkey Lewis Philip J PJ M Toledo Enrique E Mellado-Gomez Esther E Simpson Joanna J Flint Oliver O Jaiswal Himjyot H Beer Nicola L NL Karlsen Allan E AE Forbes Stuart J SJ Dear James W JW Hughes Jeremy J Hay David C DC

iScience 20210519 6

Liver disease is a major cause of premature death. Oxidative stress in the liver represents a key disease driver. Compounds, such as dimethyl fumarate (DMF), can activate the antioxidant response and are used clinically to treat disease. In this study, we tested the protective properties of DMF before or after paracetamol exposure. Following DMF administration, Nrf2 nuclear translocation was tracked at the single-cell level and target gene transactivation confirmed. Next, the protective properti ...[more]

PMID: 34151225

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Project description:BackgroundCerebral malaria (CM) is associated with morbidity and mortality despite the use of potent anti-malarial agents. Brain endothelial cell activation and dysfunction from oxidative and inflammatory host responses and products released by Plasmodium falciparum-infected erythrocytes (IE), are likely the major contributors to the encephalopathy, seizures, and brain swelling that are associated with CM. The development of adjunctive therapy to reduce the pathological consequences of host response pathways could improve outcomes. A potentially protective role of the nuclear factor E2-related factor 2 (NRF2) pathway, which serves as a therapeutic target in brain microvascular diseases and central nervous system (CNS) inflammatory diseases such as multiple sclerosis was tested to protect endothelial cells in an in vitro culture system subjected to tumour necrosis factor (TNF) or infected red blood cell exposure. NRF2 is a transcription factor that mediates anti-oxidant and anti-inflammatory responses.MethodsTo accurately reflect clinically relevant parasite biology a unique panel of parasite isolates derived from patients with stringently defined CM was developed. The effect of TNF and these parasite lines on primary human brain microvascular endothelial cell (HBMVEC) activation in an in vitro co-culture model was tested. HBMVEC activation was measured by cellular release of IL6 and nuclear translocation of NFκB. The transcriptional and functional effects of dimethyl fumarate (DMF), an FDA approved drug which induces the NRF2 pathway, on host and parasite induced HBMVEC activation was characterized. In addition, the effect of DMF on parasite binding to TNF stimulated HBMVEC in a semi-static binding assay was examined.ResultsTranscriptional profiling demonstrates that DMF upregulates the NRF2-Mediated Oxidative Stress Response, ErbB4 Signaling Pathway, Peroxisome Proliferator-activated Receptor (PPAR) Signaling and downregulates iNOS Signaling and the Neuroinflammation Signaling Pathway on TNF activated HBMVEC. The parasite lines derived from eight paediatric CM patients demonstrated increased binding to TNF activated HBMVEC and varied in their binding and activation of HBMVEC. Overall DMF reduced both TNF and CM derived parasite activation of HBMVEC.ConclusionsThese findings provide evidence that targeting the NRF2 pathway in TNF and parasite activated HBMVEC mediates multiple protective pathways and may represent a novel adjunctive therapy to improve infection outcomes in CM.

Project description:BackgroundAvailable treatments for neuropathic pain have modest efficacy and significant adverse effects, including abuse potential. Because oxidative stress is a key mechanistic node for neuropathic pain, the authors focused on the master regulator of the antioxidant response-nuclear factor erythroid 2-related factor 2 (NFE2L2; Nrf2)-as an alternative target for neuropathic pain. The authors tested whether dimethyl fumarate (U.S. Food and Drug Administration-approved treatment for multiple sclerosis) would activate NFE2L2 and promote antioxidant activity to reverse neuropathic pain behaviors and oxidative stress-dependent mechanisms.MethodsMale Sprague Dawley rats, and male and female wild type and Nfe2l2 mice were treated with oral dimethyl fumarate/vehicle for 5 days (300 mg/kg; daily) after spared nerve injury/sham surgery (n = 5 to 8 per group). Allodynia was measured in von Frey reflex tests and hyperalgesia in operant conflict-avoidance tests. Ipsilateral L4/5 dorsal root ganglia were assayed for antioxidant and cytokine/chemokine levels, and mitochondrial bioenergetic capacity.ResultsDimethyl fumarate treatment reversed mechanical allodynia (injury-vehicle, 0.45 ± 0.06 g [mean ± SD]; injury-dimethyl fumarate, 8.2 ± 0.16 g; P < 0.001) and hyperalgesia induced by nerve injury (injury-vehicle, 2 of 6 crossed noxious probes; injury-dimethyl fumarate, 6 of 6 crossed; P = 0.013). The antiallodynic effect of dimethyl fumarate was lost in nerve-injured Nfe2l2 mice, but retained in nerve-injured male and female wild type mice (wild type, 0.94 ± 0.25 g; Nfe2l2, 0.02 ± 0.01 g; P < 0.001). Superoxide dismutase activity was increased by dimethyl fumarate after nerve injury (injury-vehicle, 3.96 ± 1.28 mU/mg; injury-dimethyl fumarate, 7.97 ± 0.47 mU/mg; P < 0.001). Treatment reduced the injury-dependent increases in cytokines and chemokines, including interleukin-1β (injury-vehicle, 13.30 ± 2.95 pg/mg; injury-dimethyl fumarate, 6.33 ± 1.97 pg/mg; P = 0.022). Injury-impaired mitochondrial bioenergetics, including basal respiratory capacity, were restored by dimethyl fumarate treatment (P = 0.025).ConclusionsDimethyl fumarate, a nonopioid and orally-bioavailable drug, alleviated nociceptive hypersensitivity induced by peripheral nerve injury via activation of NFE2L2 antioxidant signaling. Dimethyl fumarate also resolved neuroinflammation and mitochondrial dysfunction-oxidative stress-dependent mechanisms that drive nociceptive hypersensitivity after nerve injury.

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Project description:Background: The pharmacological activity of dimethyl fumarate (DMF) in treating psoriasis and multiple sclerosis (MS) is not fully understood. DMF is hydrolysed to monomethyl fumarate (MMF) in vivo, which is believed to account for the therapeutic effects of DMF. However, previous studies have provided evidence that DMF also enters the circulation. Given that DMF is short-lived in the blood, whether DMF has a therapeutic impact is still unclear. Methods: Lipopolysaccharide (LPS)-mediated RAW264.7 cell activation was used as a model of inflammation to explore the anti-inflammatory effects of short-term DMF exposure in vitro. Whole blood LPS stimulation assay was applied to compare the anti-inflammatory effects of DMF and MMF in vivo. Griess assay was performed to examined nitrite release. The expression of pro-inflammatory cytokines and transcription factors were measured by quantitative PCR (qPCR), ELISA and Western blot. Depletion of intracellular glutathione (GSH) was evaluated by Ellman’s assay. Luciferase reporter assays were performed to evaluate DMF effects on Nrf2-ARE pathway activation, promoter activity of Nfkbiz and mRNA stability of Nfkbiz. Binding of STAT3 to the IκBζ promoter were examined using Chromatin immunoprecipitation (ChIP) assay. Results: Short-term exposure to DMF significantly inhibited the inflammatory response of RAW264.7 cells and suppressed LPS-induced IκBζ expression. Importantly, oral DMF but not oral MMF administration significantly inhibited IκBζ transcription in murine peripheral blood cells. We demonstrated that the expression of IκBζ is affected by the availability of intracellular GSH and regulated by the transcription factor Nrf2 and STAT3. DMF with strong electrophilicity can rapidly deplete intracellular GSH, activate the Nrf2-ARE pathway, and inhibit the binding of STAT3 to the IκBζ promoter, thereby suppressing IκBζ expression in macrophages. Conclusion: These results demonstrate the rapid anti-inflammatory effects of DMF in macrophages, providing evidence to support the direct anti-inflammatory activity of DMF.

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Dimethyl fumarate reduces hepatocyte senescence following paracetamol exposure.

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Dimethyl fumarate reduces hepatocyte senescence following paracetamol exposure.

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