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Metformin rescues rapamycin-induced mitochondrial dysfunction and attenuates rheumatoid arthritis with metabolic syndrome

BACKGROUND: Rapamycin, an inhibitor of the serine/threonine protein kinase mTOR, is an immunosuppressant used to treat renal transplant recipients, but it can cause endothelial and mitochondrial dysfunction. Metformin is used for the treatment of type 2 diabetes and was reported to exert therapeutic...

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Autores principales: Kim, Eun Kyung, Min, Hong Ki, Lee, Seon-Yeong, Kim, Da-Som, Ryu, Jun-Geol, Na, Hyun Sik, Jung, Kyoung Ah, Choi, Jeong Won, Park, Sung-Hwan, Cho, Mi-La
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7149912/
https://www.ncbi.nlm.nih.gov/pubmed/32276645
http://dx.doi.org/10.1186/s13075-020-02174-3
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author Kim, Eun Kyung
Min, Hong Ki
Lee, Seon-Yeong
Kim, Da-Som
Ryu, Jun-Geol
Na, Hyun Sik
Jung, Kyoung Ah
Choi, Jeong Won
Park, Sung-Hwan
Cho, Mi-La
author_facet Kim, Eun Kyung
Min, Hong Ki
Lee, Seon-Yeong
Kim, Da-Som
Ryu, Jun-Geol
Na, Hyun Sik
Jung, Kyoung Ah
Choi, Jeong Won
Park, Sung-Hwan
Cho, Mi-La
author_sort Kim, Eun Kyung
collection PubMed
description BACKGROUND: Rapamycin, an inhibitor of the serine/threonine protein kinase mTOR, is an immunosuppressant used to treat renal transplant recipients, but it can cause endothelial and mitochondrial dysfunction. Metformin is used for the treatment of type 2 diabetes and was reported to exert therapeutic effects against rheumatoid arthritis and obesity by improving mitochondrial dysfunction via the activation of fibroblast growth factor 21. We investigated the therapeutic effects of rapamycin–metformin combination therapy in obese mice with collagen-induced arthritis (CIA). METHODS: Mouse embryonic fibroblasts were treated with rapamycin, metformin, or rapamycin–metformin, and their respiratory level and mitochondrial gene expression were assayed. Mice were fed a high-fat diet, immunized with type II collagen, and subsequently treated with rapamycin–metformin daily for 10 weeks. RESULTS: Rapamycin-treated cells exhibited dysfunction of mitochondrial respiration and decreased mitochondrial gene expression compared with rapamycin–metformin-treated cells. Moreover, rapamycin–metformin reduced the clinical arthritis score and the extent of histological inflammation and improved the metabolic profile in obese mice with CIA. Rapamycin–metformin enhanced the balance between T helper 17 and regulatory T cells in vitro and in vivo. CONCLUSIONS: These results suggest that rapamycin–metformin is a potential therapeutic option for autoimmune arthritis.
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spelling pubmed-71499122020-04-19 Metformin rescues rapamycin-induced mitochondrial dysfunction and attenuates rheumatoid arthritis with metabolic syndrome Kim, Eun Kyung Min, Hong Ki Lee, Seon-Yeong Kim, Da-Som Ryu, Jun-Geol Na, Hyun Sik Jung, Kyoung Ah Choi, Jeong Won Park, Sung-Hwan Cho, Mi-La Arthritis Res Ther Research Article BACKGROUND: Rapamycin, an inhibitor of the serine/threonine protein kinase mTOR, is an immunosuppressant used to treat renal transplant recipients, but it can cause endothelial and mitochondrial dysfunction. Metformin is used for the treatment of type 2 diabetes and was reported to exert therapeutic effects against rheumatoid arthritis and obesity by improving mitochondrial dysfunction via the activation of fibroblast growth factor 21. We investigated the therapeutic effects of rapamycin–metformin combination therapy in obese mice with collagen-induced arthritis (CIA). METHODS: Mouse embryonic fibroblasts were treated with rapamycin, metformin, or rapamycin–metformin, and their respiratory level and mitochondrial gene expression were assayed. Mice were fed a high-fat diet, immunized with type II collagen, and subsequently treated with rapamycin–metformin daily for 10 weeks. RESULTS: Rapamycin-treated cells exhibited dysfunction of mitochondrial respiration and decreased mitochondrial gene expression compared with rapamycin–metformin-treated cells. Moreover, rapamycin–metformin reduced the clinical arthritis score and the extent of histological inflammation and improved the metabolic profile in obese mice with CIA. Rapamycin–metformin enhanced the balance between T helper 17 and regulatory T cells in vitro and in vivo. CONCLUSIONS: These results suggest that rapamycin–metformin is a potential therapeutic option for autoimmune arthritis. BioMed Central 2020-04-10 2020 /pmc/articles/PMC7149912/ /pubmed/32276645 http://dx.doi.org/10.1186/s13075-020-02174-3 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Kim, Eun Kyung
Min, Hong Ki
Lee, Seon-Yeong
Kim, Da-Som
Ryu, Jun-Geol
Na, Hyun Sik
Jung, Kyoung Ah
Choi, Jeong Won
Park, Sung-Hwan
Cho, Mi-La
Metformin rescues rapamycin-induced mitochondrial dysfunction and attenuates rheumatoid arthritis with metabolic syndrome
title Metformin rescues rapamycin-induced mitochondrial dysfunction and attenuates rheumatoid arthritis with metabolic syndrome
title_full Metformin rescues rapamycin-induced mitochondrial dysfunction and attenuates rheumatoid arthritis with metabolic syndrome
title_fullStr Metformin rescues rapamycin-induced mitochondrial dysfunction and attenuates rheumatoid arthritis with metabolic syndrome
title_full_unstemmed Metformin rescues rapamycin-induced mitochondrial dysfunction and attenuates rheumatoid arthritis with metabolic syndrome
title_short Metformin rescues rapamycin-induced mitochondrial dysfunction and attenuates rheumatoid arthritis with metabolic syndrome
title_sort metformin rescues rapamycin-induced mitochondrial dysfunction and attenuates rheumatoid arthritis with metabolic syndrome
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7149912/
https://www.ncbi.nlm.nih.gov/pubmed/32276645
http://dx.doi.org/10.1186/s13075-020-02174-3
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