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Metformin Induces Cell Cycle Arrest, Reduced Proliferation, Wound Healing Impairment In Vivo and Is Associated to Clinical Outcomes in Diabetic Foot Ulcer Patients

BACKGROUND: Several epidemiological studies in diabetic patients have demonstrated a protective effect of metformin to the development of several types of cancer. The underlying mechanisms of such phenomenon is related to the effect of metformin on cell proliferation among which, mTOR, AMPK and othe...

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Autores principales: Ochoa-Gonzalez, Fatima, Cervantes-Villagrana, Alberto R., Fernandez-Ruiz, Julio C., Nava-Ramirez, Hilda S., Hernandez-Correa, Adriana C., Enciso-Moreno, Jose A., Castañeda-Delgado, Julio E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786193/
https://www.ncbi.nlm.nih.gov/pubmed/26963096
http://dx.doi.org/10.1371/journal.pone.0150900
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author Ochoa-Gonzalez, Fatima
Cervantes-Villagrana, Alberto R.
Fernandez-Ruiz, Julio C.
Nava-Ramirez, Hilda S.
Hernandez-Correa, Adriana C.
Enciso-Moreno, Jose A.
Castañeda-Delgado, Julio E.
author_facet Ochoa-Gonzalez, Fatima
Cervantes-Villagrana, Alberto R.
Fernandez-Ruiz, Julio C.
Nava-Ramirez, Hilda S.
Hernandez-Correa, Adriana C.
Enciso-Moreno, Jose A.
Castañeda-Delgado, Julio E.
author_sort Ochoa-Gonzalez, Fatima
collection PubMed
description BACKGROUND: Several epidemiological studies in diabetic patients have demonstrated a protective effect of metformin to the development of several types of cancer. The underlying mechanisms of such phenomenon is related to the effect of metformin on cell proliferation among which, mTOR, AMPK and other targets have been identified. However, little is known about the role that metformin treatment have on other cell types such as keratinocytes and whether exposure to metformin of these cells might have serious repercussions in wound healing delay and in the development of complications in diabetic patients with foot ulcers or in their exacerbation. MATERIAL AND METHODS: HaCaT Cells were exposed to various concentrations of metformin and cell viability was evaluated by a Resazurin assay; Proliferation was also evaluated with a colony formation assay and with CFSE dilution assay by flow cytometry. Cell cycle was also evaluated by flow cytometry by PI staining. An animal model of wound healing was used to evaluate the effect of metformin in wound closure. Also, an analysis of patients receiving metformin treatment was performed to determine the effect of metformin treatment on the outcome and wound area. Statistical analysis was performed on SPSS v. 18 and GraphPad software v.5. RESULTS: Metformin treatment significantly reduces cell proliferation; colony formation and alterations of the cell cycle are observed also in the metformin treated cells, particularly in the S phase. There is a significant increase in the area of the wound of the metformin treated animals at different time points (P<0.05). There is also a significant increase in the size and wound area of the patients with diabetic foot ulcers at the time of hospitalization. A protective effect of metformin was observed for amputation, probably associated with the anti inflammatory effects reported of metformin. CONCLUSIONS: Metformin treatment reduces cell proliferation and reduces wound healing in an animal model and affects clinical outcomes in diabetic foot ulcer patients. Chronic use of this drug should be further investigated to provide evidence of their security in association with DFU.
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spelling pubmed-47861932016-03-23 Metformin Induces Cell Cycle Arrest, Reduced Proliferation, Wound Healing Impairment In Vivo and Is Associated to Clinical Outcomes in Diabetic Foot Ulcer Patients Ochoa-Gonzalez, Fatima Cervantes-Villagrana, Alberto R. Fernandez-Ruiz, Julio C. Nava-Ramirez, Hilda S. Hernandez-Correa, Adriana C. Enciso-Moreno, Jose A. Castañeda-Delgado, Julio E. PLoS One Research Article BACKGROUND: Several epidemiological studies in diabetic patients have demonstrated a protective effect of metformin to the development of several types of cancer. The underlying mechanisms of such phenomenon is related to the effect of metformin on cell proliferation among which, mTOR, AMPK and other targets have been identified. However, little is known about the role that metformin treatment have on other cell types such as keratinocytes and whether exposure to metformin of these cells might have serious repercussions in wound healing delay and in the development of complications in diabetic patients with foot ulcers or in their exacerbation. MATERIAL AND METHODS: HaCaT Cells were exposed to various concentrations of metformin and cell viability was evaluated by a Resazurin assay; Proliferation was also evaluated with a colony formation assay and with CFSE dilution assay by flow cytometry. Cell cycle was also evaluated by flow cytometry by PI staining. An animal model of wound healing was used to evaluate the effect of metformin in wound closure. Also, an analysis of patients receiving metformin treatment was performed to determine the effect of metformin treatment on the outcome and wound area. Statistical analysis was performed on SPSS v. 18 and GraphPad software v.5. RESULTS: Metformin treatment significantly reduces cell proliferation; colony formation and alterations of the cell cycle are observed also in the metformin treated cells, particularly in the S phase. There is a significant increase in the area of the wound of the metformin treated animals at different time points (P<0.05). There is also a significant increase in the size and wound area of the patients with diabetic foot ulcers at the time of hospitalization. A protective effect of metformin was observed for amputation, probably associated with the anti inflammatory effects reported of metformin. CONCLUSIONS: Metformin treatment reduces cell proliferation and reduces wound healing in an animal model and affects clinical outcomes in diabetic foot ulcer patients. Chronic use of this drug should be further investigated to provide evidence of their security in association with DFU. Public Library of Science 2016-03-10 /pmc/articles/PMC4786193/ /pubmed/26963096 http://dx.doi.org/10.1371/journal.pone.0150900 Text en © 2016 Ochoa-Gonzalez et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Ochoa-Gonzalez, Fatima
Cervantes-Villagrana, Alberto R.
Fernandez-Ruiz, Julio C.
Nava-Ramirez, Hilda S.
Hernandez-Correa, Adriana C.
Enciso-Moreno, Jose A.
Castañeda-Delgado, Julio E.
Metformin Induces Cell Cycle Arrest, Reduced Proliferation, Wound Healing Impairment In Vivo and Is Associated to Clinical Outcomes in Diabetic Foot Ulcer Patients
title Metformin Induces Cell Cycle Arrest, Reduced Proliferation, Wound Healing Impairment In Vivo and Is Associated to Clinical Outcomes in Diabetic Foot Ulcer Patients
title_full Metformin Induces Cell Cycle Arrest, Reduced Proliferation, Wound Healing Impairment In Vivo and Is Associated to Clinical Outcomes in Diabetic Foot Ulcer Patients
title_fullStr Metformin Induces Cell Cycle Arrest, Reduced Proliferation, Wound Healing Impairment In Vivo and Is Associated to Clinical Outcomes in Diabetic Foot Ulcer Patients
title_full_unstemmed Metformin Induces Cell Cycle Arrest, Reduced Proliferation, Wound Healing Impairment In Vivo and Is Associated to Clinical Outcomes in Diabetic Foot Ulcer Patients
title_short Metformin Induces Cell Cycle Arrest, Reduced Proliferation, Wound Healing Impairment In Vivo and Is Associated to Clinical Outcomes in Diabetic Foot Ulcer Patients
title_sort metformin induces cell cycle arrest, reduced proliferation, wound healing impairment in vivo and is associated to clinical outcomes in diabetic foot ulcer patients
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786193/
https://www.ncbi.nlm.nih.gov/pubmed/26963096
http://dx.doi.org/10.1371/journal.pone.0150900
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