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Rg1 protects H9C2 cells from high glucose-/palmitate-induced injury via activation of AKT/GSK-3?/Nrf2 pathway.

ABSTRACT: Our previous studies have assessed ginsenoside Rg1 (Rg1)-mediated protection in a type 1 diabetes rat model. To uncover the mechanism through which Rg1 protects against cardiac injury induced by diabetes, we mimicked diabetic conditions by culturing H9C2 cells in high glucose/palmitate. Rg1 had no toxic effect, and it alleviated the high glucose/palmitate damage in a dose-dependent manner, as indicated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and lactate dehydrogenase release to the culture medium. Rg1 prevented high glucose/palmitate-induced cell apoptosis, assessed using cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labelling staining. Rg1 also reduced high glucose-/palmitate-induced reactive oxygen species formation and increased intracellular antioxidant enzyme activity. We found that Rg1 activates protein kinase B (AKT)/glycogen synthase kinase-3 (GSK-3?) pathway and antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, indicated by increased phosphorylation of AKT and GSK-3?, and nuclear translocation of Nrf2. We used phosphatidylinositol-3-kinase inhibitor Ly294002 to block the activation of the AKT/GSK-3? pathway and found that it partially reversed the protection by Rg1 and decreased Nrf2 pathway activation. The results suggest that Rg1 exerts a protective effect against high glucose and palmitate damage that is partially AKT/GSK-3?/Nrf2-mediated. Further studies are required to validate these findings using primary cardiomyocytes and animal models of diabetes.

SUBMITTER: Yu H

PROVIDER: S-EPMC7348154 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Rg1 protects H9C2 cells from high glucose-/palmitate-induced injury via activation of AKT/GSK-3β/Nrf2 pathway.

Yu Haitao H Zhen Juan J Yang Yang Y Du Jian J Leng Jiyan J Tong Qian Q

Journal of cellular and molecular medicine 20200616 14

Our previous studies have assessed ginsenoside Rg1 (Rg1)-mediated protection in a type 1 diabetes rat model. To uncover the mechanism through which Rg1 protects against cardiac injury induced by diabetes, we mimicked diabetic conditions by culturing H9C2 cells in high glucose/palmitate. Rg1 had no toxic effect, and it alleviated the high glucose/palmitate damage in a dose-dependent manner, as indicated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and lactate dehydrogena ...[more]

PMID: 32548942

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Project description:BackgroundMounting evidence points to a crucial role of amyloid-? (A?) in the pathophysiology of Alzheimer's disease (AD), a disorder in which brain glucose hypometabolism, downregulation of central elements of phosphorylation pathways, reduced ATP levels, and enhanced oxidative damage coexist, and sometimes precede, synaptic alterations and clinical manifestations. Since the brain has limited energy storage capacity, mitochondria play essential roles in maintaining the high levels of energy demand, but, as major consumers of oxygen, these organelles are also the most important generators of reactive oxygen species (ROS). Thus, it is not surprising that mitochondrial dysfunction is tightly linked to synaptic loss and AD pathophysiology. In spite of their relevance, the mechanistic links among ROS homeostasis, metabolic alterations, and cell bioenergetics, particularly in relation to A?, still remain elusive.MethodsWe have used classic biochemical and immunocytochemical approaches together with the evaluation of real-time changes in global energy metabolism in a Seahorse Metabolic Analyzer to provide insights into the detrimental role of oligA? in SH-SY5Y and primary neurons testing their pharmacologic protection by small molecules.ResultsOur findings indicate that oligomeric A? induces a dramatic increase in ROS production and severely affects neuronal metabolism and bioenergetics. Assessment of global energy metabolism in real time demonstrated A?-mediated reduction in oxygen consumption affecting basal and maximal respiration and causing decreased ATP production. Pharmacologic targeting of A?-challenged neurons with a set of small molecules of known antioxidant and cytoprotective activity prevented the metabolic/bioenergetic changes induced by the peptide, fully restoring mitochondrial function while inducing an antioxidant response that counterbalanced the ROS production. Search for a mechanistic link among the protective small molecules tested identified the transcription factor Nrf2-compromised by age and downregulated in AD and transgenic models-as their main target and the PI3K/GSK-3 axis as the central pathway through which the compounds elicit their A? protective action.ConclusionsOur study provides insights into the complex molecular mechanisms triggered by oligA? which profoundly affect mitochondrial performance and argues for the inclusion of small molecules targeting the PI3K/GSK-3 axis and Nrf2-mediated pathways as part of the current or future combinatorial therapies.

Dataset Information

Rg1 protects H9C2 cells from high glucose-/palmitate-induced injury via activation of AKT/GSK-3?/Nrf2 pathway.

Publications

Rg1 protects H9C2 cells from high glucose-/palmitate-induced injury via activation of AKT/GSK-3β/Nrf2 pathway.

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