Inhibition of thioredoxin 2 by intracellular methylglyoxal accumulation leads to mitochondrial dysfunction and apoptosis in INS-1 cells

Liu, Chongxiao; Cao, Baige; Zhang, Qianren; Zhang, Yifan; Chen, Xueru; Xiang, Kuanhui; Dong, Yan

doi:10.1007/s12020-020-02191-x

Cited by 11 publications

(10 citation statements)

References 29 publications

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“…The activity of Trx2 can be inhibited by thioredoxin-interacting protein (Txnip), a natural inhibitor of Trx [ 14 ], and increased expression of Txnip has recently been found to contribute to high-glucose-induced beta-cell injury [ 15 ]. Our previous study confirmed that Trx2 inhibition was involved in high-glucose-induced oxidative injury in INS-1 cells, in which it damaged normal mitochondrial function [ 16 ]. However, we have no clue about the role played by Trx2 in lipotoxicity-induced oxidative stress in beta-cells.…”

Section: Introductionsupporting

confidence: 53%

“…Our previous study revealed that the mitochondrial antioxidant enzyme Trx2 might be critical for HG-induced oxidative stress and cell dysfunction [ 16 ], indicating that Trx2 plays antioxidant and antiapoptotic roles in beta-cell injury. In this study, we explored an increase in mitochondrial ROS in PA-treated INS-1 cells compared to a BSA group, but PA and Irisin cotreatment significantly decreased mitochondrial ROS levels compared to the levels in the PA group, implying that Trx2 might be related to Irisin-induced inhibition of oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

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Irisin Ameliorates Oxidative Stress-Induced Injury in Pancreatic Beta-Cells by Inhibiting Txnip and Inducing Stat3-Trx2 Pathway Activation

Liu

Zhou

et al. 2022

Oxidative Medicine and Cellular Longevity

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Lipotoxicity can lead to beta-cell dysfunction and apoptosis because it induces oxidative stress. Recent studies have found that Irisin prevents pancreatic beta-cell dysfunction induced by palmitic acid (PA). However, an association between the protection against oxidative stress conferred by Irisin and beta-cell dysfunction has not been fully elucidated. In this study, we observed that Irisin treatment prevented INS-1 cell apoptosis induced by PA treatment and preserved the insulin-secreting function of INS-1 cells in vitro. These effects probably resulted from the Irisin-induced decrease in intracellular ROS levels triggered by PA treatment. In addition, PA treatment induced oxidative stress partially by inhibiting the activation of thioredoxin 2 (Trx2) through its increase of thioredoxin-interacting protein (Txnip) expression. However, Irisin administration blocked the increase in Txnip expression, which reversed the PA-induced inactivation of Trx2. Irisin also increased the nuclear translocation of Stat3, and the inhibition of Stat3 by siRNAs blocked Irisin-induced Trx2 expression, indicating that both Txnip and Stat3 are involved in Irisin-induced activation of Trx2. Furthermore, blockade of Stat3 by siRNAs led to the decreased gene expression of MafA and Ins and to cessation of glucose-induced insulin secretion that had been enhanced by Irisin. In vivo, HFD treatment led to reduced glucose tolerance and an increase in the level of the oxidative marker malondialdehyde (MDA) compared to that in the control group. However, these effects were ameliorated by Irisin injection due to the inhibition of beta-cell apoptosis and the activation of Trx2, probably through Txnip inhibition and Stat3 activation. In conclusion, our results reveal a possible mechanism for Irisin-induced beta-cell protection, which is mediated through Txnip inhibition and activation of the Stat3-Trx2 pathway.

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Section: Introductionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Irisin Ameliorates Oxidative Stress-Induced Injury in Pancreatic Beta-Cells by Inhibiting Txnip and Inducing Stat3-Trx2 Pathway Activation

Liu

Zhou

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Interestingly, recent studies have shown that mitochondrial ROS contribute to the MG toxicity in other tissue damage associated with diabetes. A recent report by Liu et al [46] demonstrated that MG-induced mitochondrial ROS in rat pancreatic beta cells. Mitochondrial ROS production is increased when mitochondrial ETC systems are defective, leading to the upregulation of pathological mechanisms contributing to MG-induced tissue damage [22].…”

Section: Discussionmentioning

confidence: 97%

Methylglyoxal-Induced Dysfunction in Brain Endothelial Cells via the Suppression of Akt/HIF-1α Pathway and Activation of Mitophagy Associated with Increased Reactive Oxygen Species

Kim

et al. 2020

Antioxidants

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Methylglyoxal (MG) is a dicarbonyl compound, the level of which is increased in the blood of diabetes patients. MG is reported to be involved in the development of cerebrovascular complications in diabetes, but the exact mechanisms need to be elucidated. Here, we investigated the possible roles of oxidative stress and mitophagy in MG-induced functional damage in brain endothelial cells (ECs). Treatment of MG significantly altered metabolic stress as observed by the oxygen-consumption rate and barrier-integrity as found in impaired trans-endothelial electrical resistance in brain ECs. The accumulation of MG adducts and the disturbance of the glyoxalase system, which are major detoxification enzymes of MG, occurred concurrently. Reactive oxygen species (ROS)-triggered oxidative damage was observed with increased mitochondrial ROS production and the suppressed Akt/hypoxia-inducible factor 1 alpha (HIF-1α) pathway. Along with the disturbance of mitochondrial bioenergetic function, parkin-1-mediated mitophagy was increased by MG. Treatment of N-acetyl cysteine significantly reversed mitochondrial damage and mitophagy. Notably, MG induced dysregulation of tight junction proteins including occludin, claudin-5, and zonula occluden-1 in brain ECs. Here, we propose that diabetic metabolite MG-associated oxidative stress may contribute to mitochondrial damage and autophagy in brain ECs, resulting in the dysregulation of tight junction proteins and the impairment of permeability.

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“…Then, activated PKC can promote the production of NADPH oxidase-dependent ROS [65,66]. O 2 − in mitochondria can increase the production of intracellular advanced glycation end products (AGEs) in cells [67,68]. AGEs can add oxygen radical, and the activation of AGEs receptor can cause intracellular oxidative stress, which in turn causes inflammation in endothelial cells [69][70][71].…”

Section: Atherosclerosismentioning

confidence: 99%

Effects of REDOX in Regulating and Treatment of Metabolic and Inflammatory Cardiovascular Diseases

Wang

Dong

Liu

et al. 2020

Oxidative Medicine and Cellular Longevity

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Reduction oxidation (REDOX) reaction is crucial in life activities, and its dynamic balance is regulated by ROS. Reactive oxygen species (ROS) is associated with a variety of metabolic diseases involving in multiple cellular signalling in pathologic and physiological signal transduction. ROS are the by-products of numerous enzymatic reactions in various cell compartments, including the cytoplasm, cell membrane, endoplasmic reticulum (ER), mitochondria, and peroxisome. ROS signalling is not only involved in normal physiological processes but also causes metabolic dysfunction and maladaptive responses to inflammatory signals, which depends on the cell type or tissue environment. Excess oxidants are able to alter the normal structure and function of DNA, lipids, and proteins, leading to mutations or oxidative damage. Therefore, excessive oxidative stress is usually regarded as the cause of various pathological conditions, such as cancer, neurodegeneration, cardiovascular diseases (CVDs), diabetes, and kidney diseases. Currently, it has been possible to detect diabetes and other cardiac diseases by detecting derivatives accompanied by oxidative stress in vivo as biomarkers, but there is no effective method to treat these diseases. In consequence, it is essential for us to seek new therapy targeting these diseases through understanding the role of ROS signalling in regulating metabolic activity, inflammatory activation, and cardiac diseases related to metabolic dysfunction. In this review, we summarize the current literature on REDOX and its role in the regulation of cardiac metabolism and inflammation, focusing on ROS, local REDOX signalling pathways, and other mechanisms.

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Inhibition of thioredoxin 2 by intracellular methylglyoxal accumulation leads to mitochondrial dysfunction and apoptosis in INS-1 cells

Cited by 11 publications

References 29 publications

Irisin Ameliorates Oxidative Stress-Induced Injury in Pancreatic Beta-Cells by Inhibiting Txnip and Inducing Stat3-Trx2 Pathway Activation

Irisin Ameliorates Oxidative Stress-Induced Injury in Pancreatic Beta-Cells by Inhibiting Txnip and Inducing Stat3-Trx2 Pathway Activation

Methylglyoxal-Induced Dysfunction in Brain Endothelial Cells via the Suppression of Akt/HIF-1α Pathway and Activation of Mitophagy Associated with Increased Reactive Oxygen Species

Effects of REDOX in Regulating and Treatment of Metabolic and Inflammatory Cardiovascular Diseases

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