Activation of the Nrf2-regulated antioxidant cell response inhibits HEMA-induced oxidative stress and supports cell viability

Gallorini, M.; Petzel, Christine; Bolay, Carola; Hiller, Karl‐Anton; Cataldi, Amelia; Buchalla, Wolfgang; Krifka, Stephanie; Schweikl, Helmut

doi:10.1016/j.biomaterials.2015.03.047

Cited by 94 publications

(72 citation statements)

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“…In our effort to understand how AA regulates osterix expression by transcriptional regulation, we focused on the nuclear factor-E2-related factor (NFE2, also known as Nrf) pathway since Nrf regulation of antioxidant genes via antioxidant response elements (ARE) is well known (83) . Studies in a number of laboratories have shown that to combat DNA damage by electrophiles and ROS, cells have developed elaborate defense mechanisms that involve coordinated function of genes encoding drug detoxification, GSH metabolism, and protection against oxidative damage (84–86) . Furthermore, the transcriptional activation of many of these genes involves the binding of Nrf to AREs to induce transcriptional activation (87) .…”

Section: Molecular Pathways For Vitamin C Action On Bone Cellsmentioning

confidence: 99%

“…(83) Studies in a number of laboratories have shown that to combat DNA damage by electrophiles and ROS, cells have developed elaborate defense mechanisms that involve coordinated function of genes encoding drug detoxification, GSH metabolism, and protection against oxidative damage. (84)(85)(86) Furthermore, the transcriptional activation of many of these genes involves the binding of Nrf to AREs to induce transcriptional activation. (87) Because the proximal promoter of the osterix gene contains AREs that are highly conserved among mice, rats and humans, we examined if osterix gene transcription was regulated by Nrf binding to its promoter.…”

Section: Molecular Pathways For Vitamin C Action On Bone Cellsmentioning

confidence: 99%

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The Roles and Mechanisms of Actions of Vitamin C in Bone: New Developments

Aghajanian

Hall

Wongworawat

et al. 2015

Journal of Bone and Mineral Research

187

141

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Vitamin C is an important antioxidant and cofactor which is involved in the regulation of development, function and maintenance of several cell types in the body. Deficiencies in vitamin C can lead to conditions such as scurvy, which, among other ailments, causes gingivia, bone pain and impaired wound healing. This review examines the functional importance of vitamin C as it relates to the development and maintenance of bone tissues. Analysis of several epidemiological studies and genetic mouse models regarding the effect of vitamin C shows a positive effect on bone health. Overall, vitamin C exerts a positive effect on trabecular bone formation by influencing expression of bone matrix genes in osteoblasts. Recent studies on the molecular pathway for vitamin C actions that include direct effects of vitamin C on transcriptional regulation of target genes by influencing the activity of transcription factors and by epigenetic modification of key genes involved in skeletal development and maintenance are discussed. With an understanding of mechanisms involved in the uptake and metabolism of vitamin C and knowledge of precise molecular pathways for vitamin C actions in bone cells, it is possible that novel therapeutic strategies can be developed or existing therapies can be modified for the treatment of osteoporotic fractures.

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Section: Molecular Pathways For Vitamin C Action On Bone Cellsmentioning

confidence: 99%

Section: Molecular Pathways For Vitamin C Action On Bone Cellsmentioning

confidence: 99%

The Roles and Mechanisms of Actions of Vitamin C in Bone: New Developments

Aghajanian

Hall

Wongworawat

et al. 2015

Journal of Bone and Mineral Research

187

141

View full text Add to dashboard Cite

show abstract

“…Upregulation of HMOX-1 has previously been reported at the mRNA level, in dental pulp cells exposed to TEGDMA (19,41,42). Upregulation of HMOX-1 is also reported in cells exposed to UDMA, HEMA, and Bis-GMA (34)(35)(36)(37)(38). Heme oxygenase 1 (and subsequent iron sequestration) is therefore likely to play an important role in maintaining the redox balance in cells exposed to methacrylates.…”

Section: Discussionmentioning

confidence: 80%

“…Nuclear factor (erythroid‐derived 2)‐like 2 also controls expression of other stress‐related factors, such as detoxification enzymes, proteasomes, and heat‐shock proteins . Altered levels of proteins associated with NRF2 activity have been observed in cells exposed to hydroxyethyl methacrylate (HEMA) , bisphenol A diglycidyl ether dimethacrylate (Bis‐GMA) , and urethane dimethacrylate (UDMA) , and upregulation of NRF‐2 associated factors is suggested to be a general protective mechanism in cells exposed to methacrylates .…”

Section: Discussionmentioning

confidence: 99%

Dose‐ and time‐dependent effects of triethylene glycol dimethacrylate on the proteome of human THP‐1 monocytes

Nilsen

Simón-Santamaría

Örtengren

et al. 2018

European J Oral Sciences

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Triethylene glycol dimethacrylate (TEGDMA) is commonly used in polymer resin-based dental materials. This study investigated the molecular mechanisms of TEGDMA toxicity by identifying its time- and dose-dependent effects on the proteome of human THP-1 monocytes. The effects of different concentrations (0.07-5 mM) and exposure times (0-72 h) of TEGDMA on cell viability, proliferation, and morphology were determined using a real-time viability assay, automated cell counting, and electron microscopy, and laid the fundament for choice of exposure scenarios in the proteomic experiments. Solvents were not used, as TEGDMA is soluble in cell culture medium (determined by photon correlation spectroscopy). Cells were metabolically labeled [using the stable isotope labeled amino acids in cell culture (SILAC) strategy], and exposed to 0, 0.3 or 2.5 mM TEGDMA for 6 or 16 h before liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses. Regulated proteins were analyzed in the STRING database. Cells exposed to 0.3 mM TEGDMA showed increased viability and time-dependent upregulation of proteins associated with stress/oxidative stress, autophagy, and cytoprotective functions. Cells exposed to 2.5 mM TEGDMA showed diminished viability and a protein expression profile associated with oxidative stress, DNA damage, mitochondrial dysfunction, and cell cycle inhibition. Altered expression of immune genes was observed in both groups. The study provides novel knowledge about TEGDMA toxicity at the proteomic level. Of note, even low doses of TEGDMA induced a substantial cellular response.

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“…Although oxidative stress in HEMA‐exposed cells may cause Keap1 activation, a direct binding to the cysteines is also likely based on the reported spontaneous adduct formation with GSH through the cysteine residue . Although both mechanisms of activation by HEMA are possible, and previously suggested, there are currently no published studies that clearly describe the underlying mechanism. The knowledge of HEMA as a sensitizer, however, supports the ability to form adducts with proteins and possibly direct interaction with Keap1.…”

Section: Discussionmentioning

confidence: 97%

The dental monomer HEMA causes proteome changes in human THP‐1 monocytes

Samuelsen

Michelsen

Bruun

et al. 2019

J Biomedical Materials Res

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Resin‐based biomaterials are widely used in medical and dental treatment, and both clinicians and patients are exposed to the materials. The knowledge of toxicity is mainly based on in vitro studies at exposure concentrations that induce cell death. However, severe cell damage and cell death signaling may overshadow essential cellular events caused by a possible toxicant. For dental resins, the knowledge of interaction with living cells at more clinical relevant exposure doses is sparse. 2‐Hydroxyethylmethacrylate (HEMA) is a commonly used monomer in dental resins. Measuring cellular adaptation to HEMA at concentrations that did not reduce cell viability was the main focus of this study. Stable isotope labeling with amino acids in cell culture was used to measure proteome changes in cultured THP‐1 cells exposed to HEMA. Western blotting verified the results. Cells exposed to HEMA increased their level of several cytoprotective proteins. The observed adaptation is compatible with increased oxidative burden caused by GSH depletion and the electrophilic characteristic of HEMA. The present approach to analyzing the toxic potential of HEMA yielded information on interactions with living cells is not previously reported. This detailed information is of great value to make better predictions of possible side effects in the clinic. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 851–859, 2019.

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Activation of the Nrf2-regulated antioxidant cell response inhibits HEMA-induced oxidative stress and supports cell viability

Cited by 94 publications

References 50 publications

The Roles and Mechanisms of Actions of Vitamin C in Bone: New Developments

The Roles and Mechanisms of Actions of Vitamin C in Bone: New Developments

Dose‐ and time‐dependent effects of triethylene glycol dimethacrylate on the proteome of human THP‐1 monocytes

The dental monomer HEMA causes proteome changes in human THP‐1 monocytes

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