N-acetyl cysteine attenuates oxidative stress and glutathione-dependent redox imbalance caused by high glucose/high palmitic acid treatment in pancreatic Rin-5F cells

Hyperglycemia and hyperlipidemia are the hallmarks of diabetes and obesity. Experimental and epidemiological studies have suggested that dietary management and caloric restriction are beneficial in reducing the complications of diabesity. Studies have suggested that increased availability of energy metabolites like glucose and saturated fatty acids induces metabolic, oxidative, and mitochondrial stress, accompanied by inflammation that may lead to chronic complications in diabetes. In the present study, we used human hepatoma HepG2 cells to investigate the effects of high glucose (25 mM) and high palmitic acid (up to 0.3 mM) on metabolic-, inflammatory-, and redox-stress-associated alterations in these cells. Our results showed increased lipid, protein, and DNA damage, leading to caspase-dependent apoptosis and mitochondrial dysfunction. Glucolipotoxicity increased ROS production and redox stress appeared to alter mitochondrial membrane potential and bioenergetics. Our results also demonstrate the enhanced ability of cytochrome P450s-dependent drug metabolism and antioxidant adaptation in HepG2 cells treated with palmitic acid, which was further augmented with high glucose. Altered NF-kB/AMPK/mTOR-dependent cell signaling and inflammatory (IL6/TNF-α) responses were also observed. Our results suggest that the presence of high-energy metabolites enhances apoptosis while suppressing autophagy by inducing inflammatory and oxidative stress responses that may be responsible for alterations in cell signaling and metabolism.

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Hyperglycemia and Hyperlipidemia Induced Inflammation and Oxidative Stress in Human T Lymphocytes and Salutary Effects of ω- 3 Fatty Acid.

10.46940/sjdcc.01.1002 ◽

2020 ◽

pp. 1-9

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Fatty Acids ◽

T Cells ◽

Fatty Acid ◽

T Lymphocytes ◽

Palmitic Acid ◽

Linolenic Acid ◽

High Glucose ◽

Human T Lymphocytes

Abstract Type 2 Diabetes conditions are associated with hyperglycemia and hyperlipidemia; however, the role of Saturated Fatty Acids (SFA) vs. Unsaturated Fatty Acids (UFA) and high glucose on human T lymphocytes (T cells) is not known. We investigated the salutary effect of the UFA ω-3 fatty acid, α- linolenic acid, on glucose and SFA, palmitic acid, induced activation on T cells as a cause of the inflammatory process with high glucose and SFA foods. These cells in the presence of palmitic acid and/or high glucose but not linolenic acid exhibited a concentration and time-dependent emergence of insulin receptors (INSR), expression, generation of ROS, lipid peroxidation, cytokines and NF-kB p65 translocation to the nucleus. Whereas, activation of the cells by elevated levels of glucose and palmitic acid were additive, addition of linolenic acid in a dose-related manner inhibited activation of cells by glucose and palmitic acid and reduced markers of oxidative stress, lipid peroxidation and cytokines. We propose that UFAs such as α-linolenic acid may serve as a protective mechanism against the deleterious effects of hyperglycemia and hyperlipidemia of high sugar and SFA foods as in diabetes.

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Prokineticin 2 (PK2) Rescues Cardiomyocytes from High Glucose/High Palmitic Acid-Induced Damage by Regulating the AKT/GSK3β Pathway In Vitro

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/3163629 ◽

2020 ◽

Vol 2020 ◽

pp. 1-17 ◽

Cited By ~ 1

Author(s):

Zhen Yang ◽

Yin Wu ◽

Linge Wang ◽

Peng Qiu ◽

Wenliang Zha ◽

...

Keyword(s):

Oxidative Stress ◽

Palmitic Acid ◽

High Glucose ◽

Kinase Inhibitor ◽

Signalling Pathway ◽

Akt Inhibitor ◽

Prokineticin 2 ◽

Physiological Processes ◽

High Concentrations

Prokineticin 2 (PK2) is a small 8 kDa protein that participates in many physiological processes, such as angiogenesis, inflammation, and neurogenesis. This experiment investigated the effect of PK2 on high glucose/high palmitic acid-induced oxidative stress, apoptosis, and autophagy in cardiomyocytes and the AKT/GSK3β signalling pathway. H9c2 cells were exposed to normal and high concentrations (33 mM) of glucose and palmitic acid (150 μM) with or without PK2 (10 nM) for 48 h. Reactive oxygen species were detected using the fluorescent probes DCFH-DA and DHE. Changes in apoptosis were assessed using flow cytometry, and autophagosomes were detected using Ad-GFP-LC3. Apoptotic proteins, such as Cleaved Caspase3, Bax, and Bcl-2; autophagy proteins, including Beclin-1 and LC3B; and PK2/PKR/AKT/GSK3β signals were evaluated using western blotting. Cardiomyocytes exposed to high glucose/high palmitic acid exhibited increases in intracellular ROS, apoptosis, and autophagosomes, and these increases were robustly prevented by PK2. In addition, high glucose/high palmitic acid remarkably suppressed PK2, PKR1, and PKR2 expression and p-AKT/AKT and p-GSK3β/GSK3β ratios, and these effects were significantly prevented by PK2. Moreover, an AKT1/2 kinase inhibitor (AKT inhibitor, 10 μM) blocked the effects of PK2 on the changes in cardiomyocyte exposure to high glucose/high palmitic acid. These results suggest that PK2 attenuates high glucose/high palmitic acid-induced cardiomyocyte apoptosis by inhibiting oxidative stress and autophagosome accumulation and that this protective effect is most likely mediated by the AKT-related signalling pathway.

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Inhibitory Effect of Paeonol on Apoptosis, Oxidative Stress, and Inflammatory Response in Human Umbilical Vein Endothelial Cells Induced by High Glucose and Palmitic Acid Induced Through Regulating SIRT1/FOXO3a/NF-κB Pathway

Journal of Interferon & Cytokine Research ◽

10.1089/jir.2019.0236 ◽

2021 ◽

Vol 41 (3) ◽

pp. 111-124

Author(s):

Hanqing Tang ◽

Keming Li ◽

Shitian Zhang ◽

Huangqi Lan ◽

Lingling Liang ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Inflammatory Response ◽

Palmitic Acid ◽

High Glucose ◽

Umbilical Vein ◽

Inhibitory Effect ◽

Human Umbilical Vein ◽

Umbilical Vein Endothelial Cells

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Mitigation of Glucolipotoxicity-Induced Apoptosis, Mitochondrial Dysfunction, and Metabolic Stress by N-Acetyl Cysteine in Pancreatic β-Cells

Biomolecules ◽

10.3390/biom10020239 ◽

2020 ◽

Vol 10 (2) ◽

pp. 239 ◽

Cited By ~ 1

Author(s):

Arwa Alnahdi ◽

Annie John ◽

Haider Raza

Keyword(s):

Energy Metabolism ◽

Palmitic Acid ◽

Mitochondrial Dysfunction ◽

High Glucose ◽

High Energy ◽

Metabolic Adaptation ◽

Β Cells ◽

Pancreatic Β Cells ◽

Mitochondrial Energy Metabolism ◽

Acetyl Cysteine

Glucolipotoxicity caused by hyperglycemia and hyperlipidemia are the common features of diabetes-induced complications. Metabolic adaptation, particularly in energy metabolism; mitochondrial dysfunction; and increased inflammatory and oxidative stress responses are considered to be the main characteristics of diabetes and metabolic syndrome. However, due to various fluctuating endogenous and exogenous stimuli, the precise role of these factors under in vivo conditions is not clearly understood. In the present study, we used pancreatic β-cells, Rin-5F, to elucidate the molecular and metabolic changes in glucolipotoxicity. Cells treated with high glucose (25 mM) and high palmitic acid (up to 0.3 mM) for 24 h exhibited increased caspase/poly-ADP ribose polymerase (PARP)-dependent apoptosis followed by DNA fragmentation, alterations in mitochondrial membrane permeability, and bioenergetics, accompanied by alterations in glycolytic and mitochondrial energy metabolism. Our results also demonstrated alterations in the expression of mammalian target of rapamycin (mTOR)/5′ adenosine monophosphate-activated protein kinase (AMPK)-dependent apoptotic and autophagy markers. Furthermore, pre-treatment of cells with 10 mM N-acetyl cysteine attenuated the deleterious effects of high glucose and high palmitic acid with improved cellular functions and survival. These results suggest that the presence of high energy metabolites enhance mitochondrial dysfunction and apoptosis by suppressing autophagy and adapting energy metabolism, mediated, at least in part, via enhanced oxidative DNA damage and mTOR/AMPK-dependent cell signaling.

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