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High throughput drug screening identifies resveratrol as suppressor of hepatic SELENOP expression
INTRODUCTION: Selenium (Se) is an essential trace element that exerts its effects mainly as the proteinogenic amino acid selenocysteine within a small set of selenoproteins. Among all family members, selenoprotein P (SELENOP) constitutes a particularly interesting protein as it serves as a biomarker...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9816962/ https://www.ncbi.nlm.nih.gov/pubmed/36586222 http://dx.doi.org/10.1016/j.redox.2022.102592 |
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author | Hackler, Julian Demircan, Kamil Chillon, Thilo Samson Sun, Qian Geisler, Nino Schupp, Michael Renko, Kostja Schomburg, Lutz |
author_facet | Hackler, Julian Demircan, Kamil Chillon, Thilo Samson Sun, Qian Geisler, Nino Schupp, Michael Renko, Kostja Schomburg, Lutz |
author_sort | Hackler, Julian |
collection | PubMed |
description | INTRODUCTION: Selenium (Se) is an essential trace element that exerts its effects mainly as the proteinogenic amino acid selenocysteine within a small set of selenoproteins. Among all family members, selenoprotein P (SELENOP) constitutes a particularly interesting protein as it serves as a biomarker and serum Se transporter from liver to privileged tissues. SELENOP expression is tightly regulated by dietary Se intake, inflammation, hypoxia and certain substances, but a systematic drug screening has hitherto not been performed. METHODS: A compound library of 1861 FDA approved clinically relevant drugs was systematically screened for interfering effects on SELENOP expression in HepG2 cells using a validated ELISA method. Dilution experiments were conducted to characterize dose-responses. A most potent SELENOP inhibitor was further characterized by RNA-seq analysis to assess effect-associated biochemical pathways. RESULTS: Applying a 2-fold change threshold, 236 modulators of SELENOP expression were identified. All initial hits were replicated as biological triplicates and analyzed for effects on cell viability. A set of 38 drugs suppressed SELENOP expression more than three-fold, among which were cancer drugs, immunosuppressants, anti-infectious drugs, nutritional supplements and others. Considering a 90% cell viability threshold, resveratrol, vidofludimus, and antimony potassium-tartrate were the most potent substances with suppressive effects on extracellular SELENOP concentrations. Resveratrol suppressed SELENOP levels dose-dependently in a concentration range from 0.8 μM to 50.0 μM, without affecting cell viability, along with strong effects on key genes controlling metabolic pathways and vesicle trafficking. CONCLUSION: The results highlight an unexpected direct effect of the plant stilbenoid resveratrol, known for its antioxidative and health-promoting effects, on the central Se transport protein. The suppressive effects on SELENOP may increase liver Se levels and intracellular selenoprotein expression, thereby conferring additional protection to hepatocytes at the expense of systemic Se transport. Further physiological effects from this interaction require analyses in vivo and by clinical studies. |
format | Online Article Text |
id | pubmed-9816962 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-98169622023-01-07 High throughput drug screening identifies resveratrol as suppressor of hepatic SELENOP expression Hackler, Julian Demircan, Kamil Chillon, Thilo Samson Sun, Qian Geisler, Nino Schupp, Michael Renko, Kostja Schomburg, Lutz Redox Biol Research Paper INTRODUCTION: Selenium (Se) is an essential trace element that exerts its effects mainly as the proteinogenic amino acid selenocysteine within a small set of selenoproteins. Among all family members, selenoprotein P (SELENOP) constitutes a particularly interesting protein as it serves as a biomarker and serum Se transporter from liver to privileged tissues. SELENOP expression is tightly regulated by dietary Se intake, inflammation, hypoxia and certain substances, but a systematic drug screening has hitherto not been performed. METHODS: A compound library of 1861 FDA approved clinically relevant drugs was systematically screened for interfering effects on SELENOP expression in HepG2 cells using a validated ELISA method. Dilution experiments were conducted to characterize dose-responses. A most potent SELENOP inhibitor was further characterized by RNA-seq analysis to assess effect-associated biochemical pathways. RESULTS: Applying a 2-fold change threshold, 236 modulators of SELENOP expression were identified. All initial hits were replicated as biological triplicates and analyzed for effects on cell viability. A set of 38 drugs suppressed SELENOP expression more than three-fold, among which were cancer drugs, immunosuppressants, anti-infectious drugs, nutritional supplements and others. Considering a 90% cell viability threshold, resveratrol, vidofludimus, and antimony potassium-tartrate were the most potent substances with suppressive effects on extracellular SELENOP concentrations. Resveratrol suppressed SELENOP levels dose-dependently in a concentration range from 0.8 μM to 50.0 μM, without affecting cell viability, along with strong effects on key genes controlling metabolic pathways and vesicle trafficking. CONCLUSION: The results highlight an unexpected direct effect of the plant stilbenoid resveratrol, known for its antioxidative and health-promoting effects, on the central Se transport protein. The suppressive effects on SELENOP may increase liver Se levels and intracellular selenoprotein expression, thereby conferring additional protection to hepatocytes at the expense of systemic Se transport. Further physiological effects from this interaction require analyses in vivo and by clinical studies. Elsevier 2022-12-26 /pmc/articles/PMC9816962/ /pubmed/36586222 http://dx.doi.org/10.1016/j.redox.2022.102592 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Paper Hackler, Julian Demircan, Kamil Chillon, Thilo Samson Sun, Qian Geisler, Nino Schupp, Michael Renko, Kostja Schomburg, Lutz High throughput drug screening identifies resveratrol as suppressor of hepatic SELENOP expression |
title | High throughput drug screening identifies resveratrol as suppressor of hepatic SELENOP expression |
title_full | High throughput drug screening identifies resveratrol as suppressor of hepatic SELENOP expression |
title_fullStr | High throughput drug screening identifies resveratrol as suppressor of hepatic SELENOP expression |
title_full_unstemmed | High throughput drug screening identifies resveratrol as suppressor of hepatic SELENOP expression |
title_short | High throughput drug screening identifies resveratrol as suppressor of hepatic SELENOP expression |
title_sort | high throughput drug screening identifies resveratrol as suppressor of hepatic selenop expression |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9816962/ https://www.ncbi.nlm.nih.gov/pubmed/36586222 http://dx.doi.org/10.1016/j.redox.2022.102592 |
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