ArticleExperimental eye research2014
Valproic acid suppresses Nrf2/Keap1 dependent antioxidant protection through induction of endoplasmic reticulum stress and Keap1 promoter DNA demethylation in human lens epithelial cells.
Article in Experimental eye research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 79 citations in OpenAlex.
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- Aging of the human eye lens: Epigenetic landscape and therapeutic targets in age‑related cataracts (Review).International journal of molecular medicine · 2025Review
- Chitosan Nanoformulations of Mycosporine-like Amino Acid (MAA)-Rich Extracts fromInternational journal of molecular sciences · 2025Article
- Sulforaphane protects developing neural networks from VPA-induced synaptic alterations.Molecular psychiatry · 2025Article
- MicroRNAs as Epigenetic Biomarkers of Pathogenetic Mechanisms of the Metabolic Syndrome Induced by Antiseizure Medications: Systematic Review.Journal of clinical medicine · 2025Review
- The effects of hesperidin on valproic acid-induced reduction in hippocampal neurogenesis through the antioxidant and apoptotic pathways in adult rats.Scientific reports · 2024Article
- Minimizing Oxidative Stress in the Lens: Alternative Measures for Elevating Glutathione in the Lens to Protect against Cataract.Antioxidants (Basel, Switzerland) · 2024Review
- Article
- Valproic Acid Causes Redox-Regulated Post-Translational Protein Modifications That Are Dependent upon P19 Cellular Differentiation States.Antioxidants (Basel, Switzerland) · 2024Article
- Three Decades of Valproate: A Current Model for Studying Autism Spectrum Disorder.Current neuropharmacology · 2024Review
- Antioxidant System and Endoplasmic Reticulum Stress in Cataracts.Cellular and molecular neurobiology · 2023Review
- Endoplasmic reticulum stress: molecular mechanism and therapeutic targets.Signal transduction and targeted therapy · 2023Review
- Duality of Valproic Acid Effects on Inflammation, Oxidative Stress and Autophagy in Human Eosinophilic Cells.International journal of molecular sciences · 2023Article
- Redox Regulation in Age-Related Cataracts: Roles for Glutathione, Vitamin C, and the NRF2 Signaling Pathway.Nutrients · 2023Review
- The Aqueous Stem Bark Extract ofScientifica · 2023Article
- Potential Properties of Natural Nutraceuticals and Antioxidants in Age-Related Eye Disorders.Life (Basel, Switzerland) · 2022Review
- Senescence marker protein30 protects lens epithelial cells against oxidative damage by restoring mitochondrial function.Bioengineered · 2022Article
- Detailed Molecular Mechanisms Involved in Drug-Induced Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: An Update.Biomedicines · 2022Review
- Aged Nrf2-Null Mice Develop All Major Types of Age-Related Cataracts.Investigative ophthalmology & visual science · 2021Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Recent epidemiological studies confirm the prevalence of cataract in epileptic patients. Similarly, the drugs used to treat epilepsy also show the connection with increased cataract formation. In this present study, we investigated the suppression of Nrf2/Keap1 dependent antioxidant protection through induction of endoplasmic (ER) stress and Keap1 promoter DNA demethylation in human lens epithelial cells (HLECs) treated with valproic acid (VPA), an antiepileptic drug. 20 mM VPA induces ER stress and activates the unfolded protein response (UPR) within 4 h by activating the ER stress sensor proteins, such as PERK, IRE1α, and ATF6 in HLECs. Consequently, the integrated ER stress signals, such as eIF2α, ATF4, BiP, and CHOP are altered accordingly to induce ER-Ca2+ release, reactive oxygen species (ROS) overproduction, and cell death in HLECs treated with VPA. VPA also suppresses the Nrf2, catalase, and glutathione reductase expressions with significant increases in Keap1 protein. Bisulphite genomic DNA sequencing reveals the promoter DNA demethylation in the Keap1 promoter, which results in the overexpression of Keap1 mRNA and protein in HLECs treated with 20 mM VPA. VPA also alters the expression profiles of passive DNA demethylation pathway enzymes such Dnmt1, Dnmt3a, Dnmt3b, and active DNA demethylation pathway enzyme, TET1 leading to DNA demethylation in the Keap1 promoter of HLECs. Overexpressed Keap1 decreases the Nrf2 level, thereby abolishing the Nrf2 dependent antioxidant protection. This might be responsible for lenticular proteins oxidation and cataract formation.
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