Cargando…
ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition
Hypoglycemia, a complication of insulin or sulfonylurea therapy in diabetic patients, leads to brain damage. Furthermore, glucose replenishment following hypoglycemic coma induces neuronal cell death. In this study, we investigated the molecular mechanism underlying glucose deficiency-induced cytoto...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372684/ https://www.ncbi.nlm.nih.gov/pubmed/28335557 http://dx.doi.org/10.3390/ijms18030674 |
_version_ | 1782518671617294336 |
---|---|
author | Lamichhane, Santosh Bastola, Tonking Pariyar, Ramesh Lee, Eun-Sol Lee, Ho-Sub Lee, Dae Ho Seo, Jungwon |
author_facet | Lamichhane, Santosh Bastola, Tonking Pariyar, Ramesh Lee, Eun-Sol Lee, Ho-Sub Lee, Dae Ho Seo, Jungwon |
author_sort | Lamichhane, Santosh |
collection | PubMed |
description | Hypoglycemia, a complication of insulin or sulfonylurea therapy in diabetic patients, leads to brain damage. Furthermore, glucose replenishment following hypoglycemic coma induces neuronal cell death. In this study, we investigated the molecular mechanism underlying glucose deficiency-induced cytotoxicity and the protective effect of d-β-hydroxybutyrate (D-BHB) using SH-SY5Y cells. The cytotoxic mechanism of metformin under glucose deficiency was also examined. Cell viability under 1 mM glucose (glucose deficiency) was significantly decreased which was accompanied by increased production of reactive oxygen species (ROS) and decreased phosphorylation of extracellular signal-regulated kinase (ERK) and glycogen synthase 3 (GSK3β). ROS inhibitor reversed the glucose deficiency-induced cytotoxicity and restored the reduced phosphorylation of ERK and GSK3β. While metformin did not alter cell viability in normal glucose media, it further increased cell death and ROS production under glucose deficiency. However, D-BHB reversed cytotoxicity, ROS production, and the decrease in phosphorylation of ERK and GSK3β induced by the glucose deficiency. ERK inhibitor reversed the D-BHB-induced increase in cell viability under glucose deficiency, whereas GSK3β inhibitor did not restore glucose deficiency-induced cytotoxicity. Finally, the protective effect of D-BHB against glucose deficiency was confirmed in primary neuronal cells. We demonstrate that glucose deficiency-induced cytotoxicity is mediated by ERK inhibition through ROS production, which is attenuated by D-BHB and intensified by metformin. |
format | Online Article Text |
id | pubmed-5372684 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-53726842017-04-10 ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition Lamichhane, Santosh Bastola, Tonking Pariyar, Ramesh Lee, Eun-Sol Lee, Ho-Sub Lee, Dae Ho Seo, Jungwon Int J Mol Sci Article Hypoglycemia, a complication of insulin or sulfonylurea therapy in diabetic patients, leads to brain damage. Furthermore, glucose replenishment following hypoglycemic coma induces neuronal cell death. In this study, we investigated the molecular mechanism underlying glucose deficiency-induced cytotoxicity and the protective effect of d-β-hydroxybutyrate (D-BHB) using SH-SY5Y cells. The cytotoxic mechanism of metformin under glucose deficiency was also examined. Cell viability under 1 mM glucose (glucose deficiency) was significantly decreased which was accompanied by increased production of reactive oxygen species (ROS) and decreased phosphorylation of extracellular signal-regulated kinase (ERK) and glycogen synthase 3 (GSK3β). ROS inhibitor reversed the glucose deficiency-induced cytotoxicity and restored the reduced phosphorylation of ERK and GSK3β. While metformin did not alter cell viability in normal glucose media, it further increased cell death and ROS production under glucose deficiency. However, D-BHB reversed cytotoxicity, ROS production, and the decrease in phosphorylation of ERK and GSK3β induced by the glucose deficiency. ERK inhibitor reversed the D-BHB-induced increase in cell viability under glucose deficiency, whereas GSK3β inhibitor did not restore glucose deficiency-induced cytotoxicity. Finally, the protective effect of D-BHB against glucose deficiency was confirmed in primary neuronal cells. We demonstrate that glucose deficiency-induced cytotoxicity is mediated by ERK inhibition through ROS production, which is attenuated by D-BHB and intensified by metformin. MDPI 2017-03-21 /pmc/articles/PMC5372684/ /pubmed/28335557 http://dx.doi.org/10.3390/ijms18030674 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lamichhane, Santosh Bastola, Tonking Pariyar, Ramesh Lee, Eun-Sol Lee, Ho-Sub Lee, Dae Ho Seo, Jungwon ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition |
title | ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition |
title_full | ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition |
title_fullStr | ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition |
title_full_unstemmed | ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition |
title_short | ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition |
title_sort | ros production and erk activity are involved in the effects of d-β-hydroxybutyrate and metformin in a glucose deficient condition |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372684/ https://www.ncbi.nlm.nih.gov/pubmed/28335557 http://dx.doi.org/10.3390/ijms18030674 |
work_keys_str_mv | AT lamichhanesantosh rosproductionanderkactivityareinvolvedintheeffectsofdbhydroxybutyrateandmetformininaglucosedeficientcondition AT bastolatonking rosproductionanderkactivityareinvolvedintheeffectsofdbhydroxybutyrateandmetformininaglucosedeficientcondition AT pariyarramesh rosproductionanderkactivityareinvolvedintheeffectsofdbhydroxybutyrateandmetformininaglucosedeficientcondition AT leeeunsol rosproductionanderkactivityareinvolvedintheeffectsofdbhydroxybutyrateandmetformininaglucosedeficientcondition AT leehosub rosproductionanderkactivityareinvolvedintheeffectsofdbhydroxybutyrateandmetformininaglucosedeficientcondition AT leedaeho rosproductionanderkactivityareinvolvedintheeffectsofdbhydroxybutyrateandmetformininaglucosedeficientcondition AT seojungwon rosproductionanderkactivityareinvolvedintheeffectsofdbhydroxybutyrateandmetformininaglucosedeficientcondition |