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The macrocyclic lactone oxacyclododecindione reduces fibrosis progression

Background: Renal fibrosis is one of the most important triggers of chronic kidney disease (CKD), and only a very limited number of therapeutic options are available to stop fibrosis progression. As fibrosis is characterized by inflammation, myofibroblast activation, and extracellular matrix (ECM) d...

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Autores principales: Saurin, Sabrina, Meineck, Myriam, Rohr, Markus, Roth, Wilfried, Opatz, Till, Erkel, Gerhard, Pautz, Andrea, Weinmann-Menke, Julia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10294233/
https://www.ncbi.nlm.nih.gov/pubmed/37383717
http://dx.doi.org/10.3389/fphar.2023.1200164
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author Saurin, Sabrina
Meineck, Myriam
Rohr, Markus
Roth, Wilfried
Opatz, Till
Erkel, Gerhard
Pautz, Andrea
Weinmann-Menke, Julia
author_facet Saurin, Sabrina
Meineck, Myriam
Rohr, Markus
Roth, Wilfried
Opatz, Till
Erkel, Gerhard
Pautz, Andrea
Weinmann-Menke, Julia
author_sort Saurin, Sabrina
collection PubMed
description Background: Renal fibrosis is one of the most important triggers of chronic kidney disease (CKD), and only a very limited number of therapeutic options are available to stop fibrosis progression. As fibrosis is characterized by inflammation, myofibroblast activation, and extracellular matrix (ECM) deposition, a drug that can address all these processes might be an interesting therapeutic option. Methods: We tested in vivo in an ischemia–reperfusion (I/R) model in C57BL/6 mice and in kidney tubular epithelial cells (TEC) (HK2 cell line and primary cells) whether the natural product oxacyclododecindione (Oxa) reduces fibrosis progression in kidney disease. This was evaluated by Western blot, mRNA expression, and mass spectrometry secretome analyses, as well as by immunohistochemistry. Results: Indeed, Oxa blocked the expression of epithelial–mesenchymal transition marker proteins and reduced renal damage, immune cell infiltration, and collagen expression and deposition, both in vivo and in vitro. Remarkably, the beneficial effects of Oxa were also detected when the natural product was administered at a time point of established fibrotic changes, a situation close to the clinical situation. Initial in vitro experiments demonstrated that a synthetic Oxa derivative possesses similar features. Conclusion: Although open questions such as possible side effects need to be investigated, our results indicate that the combination of anti-inflammatory and anti-fibrotic effects of Oxa make the substance a promising candidate for a new therapeutic approach in fibrosis treatment, and thus in the prevention of kidney disease progression.
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spelling pubmed-102942332023-06-28 The macrocyclic lactone oxacyclododecindione reduces fibrosis progression Saurin, Sabrina Meineck, Myriam Rohr, Markus Roth, Wilfried Opatz, Till Erkel, Gerhard Pautz, Andrea Weinmann-Menke, Julia Front Pharmacol Pharmacology Background: Renal fibrosis is one of the most important triggers of chronic kidney disease (CKD), and only a very limited number of therapeutic options are available to stop fibrosis progression. As fibrosis is characterized by inflammation, myofibroblast activation, and extracellular matrix (ECM) deposition, a drug that can address all these processes might be an interesting therapeutic option. Methods: We tested in vivo in an ischemia–reperfusion (I/R) model in C57BL/6 mice and in kidney tubular epithelial cells (TEC) (HK2 cell line and primary cells) whether the natural product oxacyclododecindione (Oxa) reduces fibrosis progression in kidney disease. This was evaluated by Western blot, mRNA expression, and mass spectrometry secretome analyses, as well as by immunohistochemistry. Results: Indeed, Oxa blocked the expression of epithelial–mesenchymal transition marker proteins and reduced renal damage, immune cell infiltration, and collagen expression and deposition, both in vivo and in vitro. Remarkably, the beneficial effects of Oxa were also detected when the natural product was administered at a time point of established fibrotic changes, a situation close to the clinical situation. Initial in vitro experiments demonstrated that a synthetic Oxa derivative possesses similar features. Conclusion: Although open questions such as possible side effects need to be investigated, our results indicate that the combination of anti-inflammatory and anti-fibrotic effects of Oxa make the substance a promising candidate for a new therapeutic approach in fibrosis treatment, and thus in the prevention of kidney disease progression. Frontiers Media S.A. 2023-06-13 /pmc/articles/PMC10294233/ /pubmed/37383717 http://dx.doi.org/10.3389/fphar.2023.1200164 Text en Copyright © 2023 Saurin, Meineck, Rohr, Roth, Opatz, Erkel, Pautz and Weinmann-Menke. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Saurin, Sabrina
Meineck, Myriam
Rohr, Markus
Roth, Wilfried
Opatz, Till
Erkel, Gerhard
Pautz, Andrea
Weinmann-Menke, Julia
The macrocyclic lactone oxacyclododecindione reduces fibrosis progression
title The macrocyclic lactone oxacyclododecindione reduces fibrosis progression
title_full The macrocyclic lactone oxacyclododecindione reduces fibrosis progression
title_fullStr The macrocyclic lactone oxacyclododecindione reduces fibrosis progression
title_full_unstemmed The macrocyclic lactone oxacyclododecindione reduces fibrosis progression
title_short The macrocyclic lactone oxacyclododecindione reduces fibrosis progression
title_sort macrocyclic lactone oxacyclododecindione reduces fibrosis progression
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10294233/
https://www.ncbi.nlm.nih.gov/pubmed/37383717
http://dx.doi.org/10.3389/fphar.2023.1200164
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