ArticleThe Journal of biological chemistry2010
Withaferin A targets intermediate filaments glial fibrillary acidic protein and vimentin in a model of retinal gliosis.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 95 citations in OpenAlex.
- Brillouin microscopic assessment of retinal stiffness during reactive Müller gliosis.Experimental eye research · 2026Article
- Neuroimaging evidence of mitochondrial dysfunction and inflammation in psychiatric disorders: a review.Psychoradiology · 2026Review
- Rho-kinase inhibition reduces subretinal fibrosis.Cell death discovery · 2025Article
- Targeting glial fibrillary acidic protein in glaucoma: a monoclonal antibody approach to modulate glial reactivity and neuroinflammation for neuroprotection.Journal of neuroinflammation · 2025Article
- VCP's nuclear journey: Initiated by interacting with KPNB1 to repair DNA damage.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Intermediate filaments and their associated molecules.Journal of biomedical research · 2025Article
- Vimentin modulates regulatory T cell receptor-ligand interactions at distal pole complex, leading to dysregulated host response to viral pneumonia.Cell reports · 2024Article
- Prediction of clinical progression in nervous system diseases: plasma glial fibrillary acidic protein (GFAP).European journal of medical research · 2024Review
- Vitreous Biomarkers for Proliferative Vitreoretinopathy Prognostication in Patients Undergoing Primary Retinal Detachment Repair.Translational vision science & technology · 2024Article
- A corneo-retinal hypercitrullination axis underlies ocular injury to nitrogen mustard.Experimental eye research · 2023Article
- Peptidyl arginine deiminase 4 deficiency protects against subretinal fibrosis by inhibiting Müller glial hypercitrullination.Journal of neuroscience research · 2023Article
- Vimentin and cytokeratin: Good alone, bad together.Seminars in cancer biology · 2022Review
- The Natural Products Withaferin A and Withanone from the Medicinal HerbJournal of natural products · 2022Article
- Genetics behind Cerebral Disease with Ocular Comorbidity: Finding Parallels between the Brain and Eye Molecular Pathology.International journal of molecular sciences · 2022Review
- Metabolomic Profiling and Neuroprotective Effects of Purslane Seeds Extract Against Acrylamide Toxicity in Rat's Brain.Neurochemical research · 2021Article
- Tackling Chronic Inflammation with Withanolide Phytochemicals-A Withaferin a Perspective.Antioxidants (Basel, Switzerland) · 2020Review
- A Comprehensive Review and Perspective on Anticancer Mechanisms of Withaferin A in Breast Cancer.Cancer prevention research (Philadelphia, Pa.) · 2020Review
- Broad-spectrum antitumor properties of Withaferin A: a proteomic perspective.RSC medicinal chemistry · 2020Review
- Impeding the single-strand annealing pathway of DNA double-strand break repair by withaferin A-mediated FANCA degradation.DNA repair · 2019Article
- Latent Sensitization in a Mouse Model of Ocular Neuropathic Pain.Translational vision science & technology · 2019Article
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Authors and funding
14 authors at 2 institutions in 2 countries.
Funding
Abstract
Gliosis is a biological process that occurs during injury repair in the central nervous system and is characterized by the overexpression of the intermediate filaments (IFs) glial fibrillary acidic protein (GFAP) and vimentin. A common thread in many retinal diseases is reactive Müller cell gliosis, an untreatable condition that leads to tissue scarring and even blindness. Here, we demonstrate that the vimentin-targeting small molecule withaferin A (WFA) is a novel chemical probe of GFAP. Using molecular modeling studies that build on the x-ray crystal structure of tetrameric vimentin rod 2B domain we reveal that the WFA binding site is conserved in the corresponding domain of tetrameric GFAP. Consequently, we demonstrate that WFA covalently binds soluble recombinant tetrameric human GFAP at cysteine 294. In cultured primary astrocytes, WFA binds to and down-regulates soluble vimentin and GFAP expression to cause cell cycle G(0)/G(1) arrest. Exploiting a chemical injury model that overexpresses vimentin and GFAP in retinal Müller glia, we demonstrate that systemic delivery of WFA down-regulates soluble vimentin and GFAP expression in mouse retinas. This pharmacological knockdown of soluble IFs results in the impairment of GFAP filament assembly and inhibition of cell proliferative response in Müller glia. We further show that a more severe GFAP filament assembly deficit manifests in vimentin-deficient mice, which is partly rescued by WFA. These findings illustrate WFA as a chemical probe of type III IFs and illuminate this class of withanolide as a potential treatment for diverse gliosis-dependent central nervous system traumatic injury conditions and diseases, and for orphan IF-dependent pathologies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.