|Title:||Metformin activation of AMPK suppresses AGE-induced inflammatory response in hNSCs||Authors:||Chung M.-M.
|Issue Date:||2017||Journal Volume:||352||Journal Issue:||1||Start page/Pages:||75-83||Source:||Experimental Cell Research||Abstract:||
A growing body of evidence suggests type 2 diabetes mellitus (T2DM) is linked to neurodegenerative diseases such as Alzheimer's disease (AD). Although the precise mechanisms remain unclear, T2DM may exacerbate neurodegenerative processes. AMP-activated protein kinase (AMPK) signaling is an evolutionary preserved pathway that is important during homeostatic energy biogenesis responses at both the cellular and whole-body levels. Metformin, a ubiquitously prescribed anti-diabetic drug, exerts its effects by AMPK activation. However, while the roles of AMPK as a metabolic mediator are generally well understood, its performance in neuroprotection and neurodegeneration are not yet well defined. Given hyperglycemia is accompanied by an accelerated rate of advanced glycosylation end product (AGE) formation, which is associated with the pathogenesis of diabetic neuronal impairment and, inflammatory response, clarification of the role of AMPK signaling in these processes is needed. Therefore, we tested the hypothesis that metformin, an AMPK activator, protects against diabetic AGE induced neuronal impairment in human neural stem cells (hNSCs). In the present study, hNSCs exposed to AGE had significantly reduced cell viability, which correlated with elevated inflammatory cytokine expression, such as IL-1α, IL-1β, IL-2, IL-6, IL-12 and TNF-α. Co-treatment with metformin significantly abrogated the AGE-mediated effects in hNSCs. In addition, metformin rescued the transcript and protein expression levels of acetyl-CoA carboxylase (ACC) and inhibitory kappa B kinase (IKK) in AGE-treated hNSCs. NF-κB is a transcription factor with a key role in the expression of a variety of genes involved in inflammatory responses, and metformin did prevent the AGE-mediated increase in NF-κB mRNA and protein levels in the hNSCs exposed to AGE. Indeed, co-treatment with metformin significantly restored inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) levels in AGE-treated hNSCs. These findings extend our understanding of the central role of AMPK in AGE induced inflammatory responses, which increase the risk of neurodegeneration in diabetic patients. ? 2017 Elsevier Inc.
|URI:||https://scholars.lib.ntu.edu.tw/handle/123456789/453186||ISSN:||00144827||DOI:||10.1016/j.yexcr.2017.01.017||SDG/Keyword:||acetyl coenzyme A carboxylase; advanced glycation end product; cyclooxygenase 2; hydroxymethylglutaryl coenzyme A reductase kinase; I kappa B kinase; immunoglobulin enhancer binding protein; inducible nitric oxide synthase; interleukin 12; interleukin 1alpha; interleukin 1beta; interleukin 2; interleukin 6; messenger RNA; metformin; tumor necrosis factor; advanced glycation end product; antidiabetic agent; hydroxymethylglutaryl coenzyme A reductase kinase; messenger RNA; metformin; Article; cell growth; cell viability; concentration response; cytokine release; diabetes mellitus; enzyme activation; gene expression; genetic transcription; human; human cell; nervous system inflammation; neural stem cell; neuroprotection; priority journal; protein expression; protein function; apoptosis; cell culture; cell proliferation; drug effects; genetics; inflammation; metabolism; neural stem cell; pathology; phosphorylation; real time polymerase chain reaction; reverse transcription polymerase chain reaction; signal transduction; Western blotting; AMP-Activated Protein Kinases; Apoptosis; Blotting, Western; Cell Proliferation; Cells, Cultured; Glycosylation End Products, Advanced; Humans; Hypoglycemic Agents; Inflammation; Metformin; Neural Stem Cells; Phosphorylation; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction
|Appears in Collections:||昆蟲學系|
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