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Genistein‐Calcitriol Mitigates Hyperosmotic Stress‐Induced TonEBP, CFTR Dysfunction, VDR Degradation and Inflammation in Dry Eye Disease

Dry eye disease (DED) signs and symptoms are causally associated with increased ocular surface (OS) inflammation. Modulation of key regulators of aberrant OS inflammation is of interest for clinical management. We investigated the status and the potential to harness key endogenous protective factors...

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Autores principales: Panigrahi, Trailokyanath, D’Souza, Sharon, Shetty, Rohit, Padmanabhan Nair, Archana, Ghosh, Anuprita, Jacob Remington Nelson, Everette, Ghosh, Arkasubhra, Sethu, Swaminathan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877851/
https://www.ncbi.nlm.nih.gov/pubmed/32896986
http://dx.doi.org/10.1111/cts.12858
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author Panigrahi, Trailokyanath
D’Souza, Sharon
Shetty, Rohit
Padmanabhan Nair, Archana
Ghosh, Anuprita
Jacob Remington Nelson, Everette
Ghosh, Arkasubhra
Sethu, Swaminathan
author_facet Panigrahi, Trailokyanath
D’Souza, Sharon
Shetty, Rohit
Padmanabhan Nair, Archana
Ghosh, Anuprita
Jacob Remington Nelson, Everette
Ghosh, Arkasubhra
Sethu, Swaminathan
author_sort Panigrahi, Trailokyanath
collection PubMed
description Dry eye disease (DED) signs and symptoms are causally associated with increased ocular surface (OS) inflammation. Modulation of key regulators of aberrant OS inflammation is of interest for clinical management. We investigated the status and the potential to harness key endogenous protective factors, such as cystic fibrosis transmembrane conductance regulator (CFTR) and vitamin D receptor (VDR) in hyperosmotic stress‐associated inflammation in patients with DED and in vitro. Conjunctival impression cytology samples from control subjects (n = 11) and patients with DED (n = 15) were used to determine the status of hyperosmotic stress (TonEBP/NFAT5), inflammation (IL‐6, IL‐8, IL‐17A/F, TNFα, MMP9, and MCP1), VDR, and intracellular chloride ion (GLRX5) by quantitative polymerase chain reaction and/or immunofluorescence. Human corneal epithelial cells (HCECs) were used to study the effect of CFTR activator (genistein) and vitamin D (calcitriol) in hyperosmotic stress (HOs)‐induced response in vitro. Western blotting was used to determine the expression of these proteins, along with p‐p38. Significantly, higher expression of inflammatory factors, TonEBP, GLRX5, and reduced VDR were observed in patients with DED and in HOs‐induced HCECs in vitro. Expression of TonEBP positively correlated with expression of inflammatory genes in DED. Increased TonEBP and GLRX5 provides confirmation of osmotic stress and chloride ion imbalance in OS epithelium in DED. These along with reduced VDR suggests dysregulated OS homeostasis in DED. Combination of genistein and calcitriol reduced HOs‐induced TonEBP, inflammatory gene expression, and p‐p38, and abated VDR degradation in HCECs. Henceforth, this combination should be further explored for its relevance in the management of DED.
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spelling pubmed-78778512021-02-18 Genistein‐Calcitriol Mitigates Hyperosmotic Stress‐Induced TonEBP, CFTR Dysfunction, VDR Degradation and Inflammation in Dry Eye Disease Panigrahi, Trailokyanath D’Souza, Sharon Shetty, Rohit Padmanabhan Nair, Archana Ghosh, Anuprita Jacob Remington Nelson, Everette Ghosh, Arkasubhra Sethu, Swaminathan Clin Transl Sci Research Dry eye disease (DED) signs and symptoms are causally associated with increased ocular surface (OS) inflammation. Modulation of key regulators of aberrant OS inflammation is of interest for clinical management. We investigated the status and the potential to harness key endogenous protective factors, such as cystic fibrosis transmembrane conductance regulator (CFTR) and vitamin D receptor (VDR) in hyperosmotic stress‐associated inflammation in patients with DED and in vitro. Conjunctival impression cytology samples from control subjects (n = 11) and patients with DED (n = 15) were used to determine the status of hyperosmotic stress (TonEBP/NFAT5), inflammation (IL‐6, IL‐8, IL‐17A/F, TNFα, MMP9, and MCP1), VDR, and intracellular chloride ion (GLRX5) by quantitative polymerase chain reaction and/or immunofluorescence. Human corneal epithelial cells (HCECs) were used to study the effect of CFTR activator (genistein) and vitamin D (calcitriol) in hyperosmotic stress (HOs)‐induced response in vitro. Western blotting was used to determine the expression of these proteins, along with p‐p38. Significantly, higher expression of inflammatory factors, TonEBP, GLRX5, and reduced VDR were observed in patients with DED and in HOs‐induced HCECs in vitro. Expression of TonEBP positively correlated with expression of inflammatory genes in DED. Increased TonEBP and GLRX5 provides confirmation of osmotic stress and chloride ion imbalance in OS epithelium in DED. These along with reduced VDR suggests dysregulated OS homeostasis in DED. Combination of genistein and calcitriol reduced HOs‐induced TonEBP, inflammatory gene expression, and p‐p38, and abated VDR degradation in HCECs. Henceforth, this combination should be further explored for its relevance in the management of DED. John Wiley and Sons Inc. 2020-09-03 2021-01 /pmc/articles/PMC7877851/ /pubmed/32896986 http://dx.doi.org/10.1111/cts.12858 Text en © 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research
Panigrahi, Trailokyanath
D’Souza, Sharon
Shetty, Rohit
Padmanabhan Nair, Archana
Ghosh, Anuprita
Jacob Remington Nelson, Everette
Ghosh, Arkasubhra
Sethu, Swaminathan
Genistein‐Calcitriol Mitigates Hyperosmotic Stress‐Induced TonEBP, CFTR Dysfunction, VDR Degradation and Inflammation in Dry Eye Disease
title Genistein‐Calcitriol Mitigates Hyperosmotic Stress‐Induced TonEBP, CFTR Dysfunction, VDR Degradation and Inflammation in Dry Eye Disease
title_full Genistein‐Calcitriol Mitigates Hyperosmotic Stress‐Induced TonEBP, CFTR Dysfunction, VDR Degradation and Inflammation in Dry Eye Disease
title_fullStr Genistein‐Calcitriol Mitigates Hyperosmotic Stress‐Induced TonEBP, CFTR Dysfunction, VDR Degradation and Inflammation in Dry Eye Disease
title_full_unstemmed Genistein‐Calcitriol Mitigates Hyperosmotic Stress‐Induced TonEBP, CFTR Dysfunction, VDR Degradation and Inflammation in Dry Eye Disease
title_short Genistein‐Calcitriol Mitigates Hyperosmotic Stress‐Induced TonEBP, CFTR Dysfunction, VDR Degradation and Inflammation in Dry Eye Disease
title_sort genistein‐calcitriol mitigates hyperosmotic stress‐induced tonebp, cftr dysfunction, vdr degradation and inflammation in dry eye disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877851/
https://www.ncbi.nlm.nih.gov/pubmed/32896986
http://dx.doi.org/10.1111/cts.12858
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