4μ8C Inhibits Insulin Secretion Independent of IRE1α RNase Activity

Sato, Hitomi; Shiba, Yoko; Tsuchiya, Yosuke; Saito, Michiko; Kohno, Kenji

doi:10.1247/csf.17002

Cited by 17 publications

(11 citation statements)

References 23 publications

(38 reference statements)

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“…RNAse domain demonstrating that 4u8C is able to block insulin secretion independent of the IRE1α/XBP1 pathway [21]. Given the results presented in this report, it is possible that the inhibitory effects of 4u8C on insulin secretion are through the scavenging of ROS.…”

Section: Discussionmentioning

confidence: 53%

“…This inhibitor has provided valuable insights into defining the mechanism of action of IRE1α in both cellular physiology and pathophysiology (e.g. [13][14][15][16][17][18][19]) . 4µ8C has also been used in animal studies [20] although its effectiveness in vivo is uncertain.…”

Section: Introductionmentioning

confidence: 99%

“…4µ8C has also been used in animal studies [20] although its effectiveness in vivo is uncertain. A recent study investigating the effect of 4µ8C on insulin secretion has highlighted the potential of this inhibitor to have off-target effects [21].…”

Section: Introductionmentioning

confidence: 99%

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The inositol-requiring enzyme 1 (IRE1α) RNAse inhibitor, 4µ8C, is also a potent cellular antioxidant

Chan

Lowe

Bernard

et al. 2018

Biochemical Journal

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Inositol-requiring enzyme 1 alpha (IRE1α) is an endoplasmic reticulum (ER)-transmembrane endonuclease that is activated in response to ER stress as part of the unfolded protein response (UPR). Chronic activation of the UPR has been implicated in the pathogenesis of many common diseases including diabetes, cancer, and neurological pathologies such as Huntington's and Alzheimer's disease. 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde (4µ8C) is widely used as a specific inhibitor of IRE1α ribonuclease activity (IC of 6.89 µM in cultured cells). However, in this paper, we demonstrate that 4µ8C acts as a potent reactive oxygen species (ROS) scavenger, both in a cell-free assay and in cultured cells, at concentrations lower than that widely used to inhibit IRE1α activity. we show that, 4µ8C effectively decreases xanthine/xanthine oxidase catalysed superoxide production with an IC of 0.2 µM whereas in cultured endothelial and clonal pancreatic β-cells, 4µ8C inhibits angiotensin II-induced ROS production with IC values of 1.92 and 0.29 µM, respectively. In light of this discovery, conclusions reached using 4µ8C as an inhibitor of IRE1α should be carefully evaluated. However, this unexpected off-target effect of 4µ8C may prove therapeutically advantageous for the treatment of pathologies that are thought to be caused by, or exacerbated by, both oxidative and ER stress such as endothelial dysfunction and/or diabetes.

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Section: Discussionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

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The inositol-requiring enzyme 1 (IRE1α) RNAse inhibitor, 4µ8C, is also a potent cellular antioxidant

Chan

Lowe

Bernard

et al. 2018

Biochemical Journal

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“…Four MIN6 ( Ire1α fl/fl ) cell lines were established from insulinomas that developed in independent mice. One MIN6 ( Ire1α fl/fl ) cell line (original name; MINS#12) with high insulin secretion in high-glucose and high-insulin content was then selected ( Sato et al, 2017 ). In the adenovirus infection experiments, two experimental controls were used.…”

Section: Methodsmentioning

confidence: 99%

IRE1–XBP1 pathway regulates oxidative proinsulin folding in pancreatic β cells

Tsuchiya

Saito

Kadokura

et al. 2018

Journal of Cell Biology

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100

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“…To decipher the contribution of each branch to FB1-inducd apoptosis in liver cells, we evaluated the influence of the specific inactivation of PERK or IRE1α on apoptosis induction by FB1 in AML12 cells. 4µ8C [16] and GSK2606414 [17] were used to specifically inhibit IRE1α and PERK respectively, and apoptosis was measured by Annexin-V/PI staining. As shown in Figure 1E, FB1-induced apoptosis was significantly suppressed in the presence of 4µ8C but not of GSK2606414 in AML12 cells.…”

Section: Activation Of Ire1α But Not the Perk Axis Of Er Stress Respomentioning

confidence: 99%

Activation of the IRE1α Arm, but not the PERK Arm, of the Unfolded Protein Response Contributes to Fumonisin B1-Induced Hepatotoxicity

Liu

Zhang

Yin

et al. 2020

Toxins

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Previous studies by us or others have shown that endoplasmic reticulum (ER) stress was activated by fumonisin 1 (FB1) exposure, which is considered to be a critical event in the FB1-induced toxic effect. However, the detailed mechanisms underlying FB1-induced ER stress-mediated liver toxicity remain elusive. The objectives of the present study were designed to address the following issues: (1) the contribution of each arm of the unfolded protein response (UPR); (2) the downstream targets of ER stress that mediated FB1-induced liver toxicity; and (3) the relationship between ER stress and oxidative stress triggered by FB1. We also investigated whether the inhibition of ER stress by its inhibitor could offer protection against FB1-induced hepatotoxicity in vivo, which has not been critically addressed previously. The results showed that the activation of the IRE1α axis, but not of the PERK axis, of UPR contributed to FB1-induced ER stress-mediated hepatocyte toxicity; the activation of the Bax/Bak-mediated mitochondrial pathway lay downstream of IRE1α to trigger mitochondrial-dependent apoptosis in response to FB1; FB1-induced oxidative stress and ER stress augmented each other through a positive feedback mechanism; tauroursodeoxycholic acid (TUDCA)-mediated ER stress inactivation is an effective approach to counteract FB1-induced hepatotoxicity in vivo. The data of the present study allow us to better understand the mechanisms of FB1-induced hepatotoxicity.

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4μ8C Inhibits Insulin Secretion Independent of IRE1α RNase Activity

Cited by 17 publications

References 23 publications

The inositol-requiring enzyme 1 (IRE1α) RNAse inhibitor, 4µ8C, is also a potent cellular antioxidant

The inositol-requiring enzyme 1 (IRE1α) RNAse inhibitor, 4µ8C, is also a potent cellular antioxidant

IRE1–XBP1 pathway regulates oxidative proinsulin folding in pancreatic β cells

Activation of the IRE1α Arm, but not the PERK Arm, of the Unfolded Protein Response Contributes to Fumonisin B1-Induced Hepatotoxicity

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