Breaking the cycle

Gafson, Arie; Savva, Constantinos; Thorne, Thomas; David, Mark; Gómez-Romero, María José; Lewis, Matthew R.; Nicholas, Richard; Heslegrave, Amanda; Zetterberg, Henrik; Matthews, Paul M.

doi:10.1212/nxi.0000000000000562

Cited by 13 publications

(5 citation statements)

References 52 publications

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“…The redox reaction interferes with mitochondrial electron transfer, generates a large number of oxygen free radicals, induces lipid peroxidation, and leads to mitochondrial dysfunction and impairment of the tricarboxylic acid (TCA) cycle and respiratory chain transfer [ 48 ]. We found that paraquat exposure increased citric acid levels; citric acid is an intermediate product of the TCA cycle, indicating that paraquat poisoning blocks the TCA cycle to affect energy supply [ 49 ]. Galactose is a reducing monosaccharide that can be metabolized to glucose under normal conditions, but an excess leads to formation of reactive oxygen species and advanced glycation end-products, which can result in oxidative stress, mitochondrial dysfunction, cell damage, and inflammation [ 50 – 52 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of Fluorofenidone Against Paraquat-Induced Pulmonary Fibrosis Based on Metabolomics and Network Pharmacology

Jiang

Wang

et al. 2021

Med Sci Monit

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Background Fluorofenidone (AKF-PD) is an anti-fibrotic small-molecule compound. Its mechanism of action on paraquat (PQ)-induced pulmonary fibrosis is still unclear. Material/Methods Forty-eight SD rats were divided into 4 groups: control group, PQ group, PQ+AKF-PD group, and AKF-PD group. The pathological changes of lung tissues were observed by Masson and HE staining. The UPLC-QTOF-MS analysis was performed to detect the differences in metabolites among groups, then the possible mechanisms of the anti-pulmonary fibrosis effects of fluorofenidone were further revealed by network pharmacology analysis. Biological methods were used to verify the results of the network pharmacology analysis. Results The results showed that fluorofenidone treatment significantly alleviated paraquat-induced pulmonary fibrosis. Metabolomics analysis showed that 18 metabolites were disordered in the serum of paraquat-poisoned rats, of which 13 were restored following fluorofenidone treatment. Network pharmacology analysis showed that the drug screened a total of 12 targets and mainly involved multiple signaling pathways and metabolic pathways to jointly exert anti-pulmonary fibrosis effects. Autophagy is the main pathway of fluorofenidone in treatment pulmonary fibrosis. The western blot results showed that fluorofenidone upregulated the expression of LC3-II/I and E-cadherin, and downregulated the expression of p62, α-SMA, and TGF-β1, which validated that fluorofenidone could inhibit the development of paraquat-induced pulmonary fibrosis by increasing autophagy. Conclusions In conclusion, metabolomics combined with network pharmacology research strategy revealed that fluorofenidone has a multi-target and multi-path mechanism of action in the treatment of pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

Effect of Fluorofenidone Against Paraquat-Induced Pulmonary Fibrosis Based on Metabolomics and Network Pharmacology

Jiang

Wang

et al. 2021

Med Sci Monit

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“…The endothelial toxicity of bardoxolone methyl was supposedly an Nrf-2-independent effect, since increased Nrf2 activity may modulate mitochondrial function and has a protective, rather than detrimental effect on mitochondrial integrity [ 41 , 42 ]. On the other hand, the effects of dimethyl fumarate on respiration could be linked to the metabolism of dimethyl fumarate to fumarate, feeding the citric acid cycle [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, this compound has been shown to be efficacious in the treatment of multiple sclerosis [ 14 ]. In a phase 3 clinical study in relapsing-remitting multiple sclerosis patients, dimethyl fumarate was shown to reduce the progression of disability [ 15 ], and the compound was approved by FDA in 2013 for the treatment of relapsing-remitting multiple sclerosis [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Bardoxolone Methyl Displays Detrimental Effects on Endothelial Bioenergetics, Suppresses Endothelial ET-1 Release, and Increases Endothelial Permeability in Human Microvascular Endothelium

Szczęsny-Małysiak

Stojak

Campagna

et al. 2020

Oxidative Medicine and Cellular Longevity

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Nrf2 is a master regulator of antioxidant cellular defence, and agents activating the Nrf2 pathway have been tested in various diseases. However, unexpected side effects of cardiovascular nature reported for bardoxolone methyl in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (the BEACON trial) still have not been fully explained. Here, we aimed to characterize the effects of bardoxolone methyl compared with other Nrf2 activators—dimethyl fumarate and L-sulforaphane—on human microvascular endothelium. Endothelial toxicity, bioenergetics, mitochondrial membrane potential, endothelin-1 (ET-1) release, endothelial permeability, Nrf2 expression, and ROS production were assessed in human microvascular endothelial cells (HMEC-1) incubated for 3 and 24 hours with 100 nM–5 μM of either bardoxolone methyl, dimethyl fumarate, or L-sulforaphane. Three-hour incubation with bardoxolone methyl (100 nM–5 μM), although not toxic to endothelial cells, significantly affected endothelial bioenergetics by decreasing mitochondrial membrane potential ( concentrations ≥ 3 μ M ), decreasing spare respiratory capacity ( concentrations ≥ 1 μ M ), and increasing proton leak ( concentrations ≥ 500 nM ), while dimethyl fumarate and L-sulforaphane did not exert such actions. Bardoxolone methyl at concentrations ≥ 3 μ M also decreased cellular viability and induced necrosis and apoptosis in the endothelium upon 24-hour incubation. In turn, endothelin-1 decreased permeability in endothelial cells in picomolar range, while bardoxolone methyl decreased ET-1 release and increased endothelial permeability even after short-term (3 hours) incubation. In conclusion, despite that all three Nrf2 activators exerted some beneficial effects on the endothelium, as evidenced by a decrease in ROS production, bardoxolone methyl, the most potent Nrf2 activator among the tested compounds, displayed a distinct endothelial profile of activity comprising detrimental effects on mitochondria and cellular viability and suppression of endothelial ET-1 release possibly interfering with ET-1–dependent local regulation of endothelial permeability.

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“…DMF (Tecfidera) is FDAapproved for treating multiple sclerosis due to its neuroprotective and antioxidant effects [39,40]. It has been shown to mitigate damage in rodent models of neurological disorders, including traumatic brain injury [41][42][43][44][45][46][47]. As MEA implantation may be considered a form of focal traumatic brain injury, we hypothesized that DMF could alleviate and improve the biological response after device implantation.…”

Section: Introductionmentioning

confidence: 99%

Antioxidant Dimethyl Fumarate Temporarily but Not Chronically Improves Intracortical Microelectrode Performance

Hoeferlin,

Bajwa,

Olivares

et al. 2023

Micromachines

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Intracortical microelectrode arrays (MEAs) can be used in a range of applications, from basic neuroscience research to providing an intimate interface with the brain as part of a brain-computer interface (BCI) system aimed at restoring function for people living with neurological disorders or injuries. Unfortunately, MEAs tend to fail prematurely, leading to a loss in functionality for many applications. An important contributing factor in MEA failure is oxidative stress resulting from chronically inflammatory-activated microglia and macrophages releasing reactive oxygen species (ROS) around the implant site. Antioxidants offer a means for mitigating oxidative stress and improving tissue health and MEA performance. Here, we investigate using the clinically available antioxidant dimethyl fumarate (DMF) to reduce the neuroinflammatory response and improve MEA performance in a rat MEA model. Daily treatment of DMF for 16 weeks resulted in a significant improvement in the recording capabilities of MEA devices during the sub-chronic (Weeks 5–11) phase (42% active electrode yield vs. 35% for control). However, these sub-chronic improvements were lost in the chronic implantation phase, as a more exacerbated neuroinflammatory response occurs in DMF-treated animals by 16 weeks post-implantation. Yet, neuroinflammation was indiscriminate between treatment and control groups during the sub-chronic phase. Although worse for chronic use, a temporary improvement (<12 weeks) in MEA performance is meaningful. Providing short-term improvement to MEA devices using DMF can allow for improved use for limited-duration studies. Further efforts should be taken to explore the mechanism behind a worsened neuroinflammatory response at the 16-week time point for DMF-treated animals and assess its usefulness for specific applications.

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Breaking the cycle

Cited by 13 publications

References 52 publications

Effect of Fluorofenidone Against Paraquat-Induced Pulmonary Fibrosis Based on Metabolomics and Network Pharmacology

Effect of Fluorofenidone Against Paraquat-Induced Pulmonary Fibrosis Based on Metabolomics and Network Pharmacology

Bardoxolone Methyl Displays Detrimental Effects on Endothelial Bioenergetics, Suppresses Endothelial ET-1 Release, and Increases Endothelial Permeability in Human Microvascular Endothelium

Antioxidant Dimethyl Fumarate Temporarily but Not Chronically Improves Intracortical Microelectrode Performance

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