Activation of Keap1-Nrf2 signaling by 4-octyl itaconate protects human umbilical vein endothelial cells from high glucose

Tang, Chun; Tan, Shuhua; Zhang, Yiqing; Dong, Lini; Xu, Yan

doi:10.1016/j.bbrc.2018.12.032

Cited by 40 publications

(36 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1a). 4-OI was utilized at 10-25 μM, referring other studies 14,16,18 . Following disassociation with Keap1, the Nrf2 protein was stabilized and accumulated in 4-OI-treated OB-6 cells ( Fig.…”

Section: Nrf2 Cascade Activation By 4-oi In Osteoblastsmentioning

confidence: 99%

Four-octyl itaconate activates Nrf2 cascade to protect osteoblasts from hydrogen peroxide-induced oxidative injury

et al. 2020

View full text Add to dashboard Cite

Four-octyl itaconate (4-OI) is the cell-permeable derivative of itaconate that can activate Nrf2 signaling by alkylating Keap1’s cysteine residues. Here, we tested the potential effect of 4-OI on hydrogen peroxide (H2O2)-induced oxidative injury in osteoblasts. In OB-6 cells and primary murine osteoblasts, 4-OI was able to activate Nrf2 signaling cascade and cause Keap1–Nrf2 disassociation, Nrf2 protein stabilization, cytosol accumulation, and nuclear translocation. 4-OI also augmented antioxidant-response element reporter activity and promoted expression of Nrf2-dependent genes (HO1, NQO1, and GCLC). Pretreatment with 4-OI inhibited H2O2-induced reactive oxygen species production, cell death, and apoptosis in osteoblasts. Furthermore, 4-OI inhibited H2O2-induced programmed necrosis by suppressing mitochondrial depolarization, mitochondrial cyclophilin D-ANT1 (adenine nucleotide translocase 1)-p53 association, and cytosol lactate dehydrogenase release in osteoblasts. Ectopic overexpression of immunoresponsive gene 1 (IRG1) increased endogenous itaconate production and activated Nrf2 signaling cascade, thereby inhibiting H2O2-induced oxidative injury and cell death. In OB-6 cells, Nrf2 silencing or CRISPR/Cas9-induced Nrf2 knockout blocked 4-OI-induced osteoblast cytoprotection against H2O2. Conversely, forced Nrf2 activation, by CRISPR/Cas9-induced Keap1 knockout, mimicked 4-OI-induced actions in OB-6 cells. Importantly, 4-OI was ineffective against H2O2 in Keap1-knockout cells. Collectively, 4-OI efficiently activates Nrf2 signaling to inhibit H2O2-induced oxidative injury and death of osteoblasts.

show abstract

Section: Nrf2 Cascade Activation By 4-oi In Osteoblastsmentioning

confidence: 99%

Four-octyl itaconate activates Nrf2 cascade to protect osteoblasts from hydrogen peroxide-induced oxidative injury

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Reactive oxygen species (ROS) are produced by aerobic cells in the process of metabolism (Moloney & Cotter, ). Excessive accumulation of ROS can destroy the defense function of cells, leading to oxidative stress, DNA damage, and apoptosis, which is caused by the imbalance between antioxidants and oxidants (Gerardi, Cavia‐Saiz, Rivero‐Pérez, González‐Sanjosé, & Muñiz, ; Tang, Tan, Zhang, Dong, & Xu, ; Zhang & Wang, ). The occurrence of diseases such as endothelial dysfunction (Fratantonio et al, ), cancer (Poungpairoj et al, ), diabetes type II, neurodegenerative diseases (Gong et al, ), and cardiovascular diseases might be due to the overaccumulation of ROS (Alvarez‐Suarez et al, ; Wang, Wu, et al, ).…”

Section: Introductionmentioning

confidence: 99%

Protective effect of apple phlorizin on hydrogen peroxide‐induced cell damage in HepG2 cells

et al. 2019

View full text Add to dashboard Cite

Apple phlorizin has many biological activities, such as antioxidant and liver protection. The present study aimed to evaluate the roles of apple phlorizin against hydrogen peroxide (H2O2)‐induced oxidative damage in HepG2 cells. In this study, treatment with apple phlorizin (100 and 150 μg/ml) decreased the production of reactive oxygen species and alleviated apoptosis as well as DNA damage in H2O2‐induced HepG2 cells. These effects were associated with the increased activity of antioxidant enzymes, enhanced the ARE‐driven phase II antioxidant gene expression and its upstream Nrf2 protein expression, and decreased apoptosis‐related gene expression. However, the phase II antioxidant gene expression and Nrf2 protein expression upregulated by phlorizin were reversed by Nrf2 shRNA transfection. These results showed that phlorizin relieves oxidative stress, DNA damage, and apoptosis in H2O2‐induced HepG2 cells, at least partially, by regulating the expression of Nrf2 protein and apoptosis‐related genes. Practical applications Apple phlorizin is a polyphenol compound extracted from apple or apple juice. This report highlighted a protective effect of phlorizin on antioxidant stress, DNA damage, and apoptosis in H2O2‐induced HepG2 cells. These results suggested that phlorizin may be developed for functional foods.

show abstract

“…1g). Furthermore, mRNA and protein expression of two key Nrf2-dependent genes, including HO1 and NQO1 [33,[53][54][55], were significantly increased in miR-941-overexpressing cells (Fig. 1e and h), with the NQO1 activity significantly boosted (Fig.…”

Section: Mir-941 Targets Keap1 and Activates Nrf2 Signaling In Human mentioning

confidence: 93%

Keap1-targeting microRNA-941 protects endometrial cells from oxygen and glucose deprivation-re-oxygenation via activation of Nrf2 signaling

Cheng

et al. 2020

Cell Commun Signal

View full text Add to dashboard Cite

Background: Mimicking ischemia-reperfusion injury, oxygen and glucose deprivation (OGD)-re-oxygenation (OGDR) applied to endometrial cells produces significant oxidative stress and programmed necrosis, which can be inhibited by nuclear-factor-E2-related factor 2 (Nrf2) signaling. MicroRNA (miRNA)-induced repression of Keap1, a Nrf2 suppressor protein that facilitates Nrf2 degradation, is novel strategy to activate Nrf2 cascade. Methods: MicroRNA-941 (miR-941) was exogenously expressed in HESC and primary human endometrial cells, and the Nrf2 pathway examined by Western blotting and real-time quantitative PCR analysis. The endometrial cells were treated with OGDR, cell programmed necrosis and apoptosis were tested. Results: MiR-941 is a novel Keap1-targeting miRNA that regulates Nrf2 activity. In T-HESC cells and primary human endometrial cells, ectopic overexpression of miR-941 suppressed Keap1 3′-UTR (untranslated region) expression and downregulated its mRNA/protein expression, leading to activation of the Nrf2 cascade. Conversely, inhibition of miR-941 elevated Keap1 expression and activity in endometrial cells, resulting in suppression of Nrf2 activation. MiR-941 overexpression in endometrial cells attenuated OGDR-induced oxidative stress and programmed necrosis, whereas miR-941 inhibition enhanced oxidative stress and programmed necrosis. MiR-941 overexpression and inhibition were completely ineffective in Keap1−/Nrf2-KO T-HESC cells (using CRISPR/Cas9 strategy). Restoring Keap1 expression, using an UTR-depleted Keap1 construct, abolished miR-941-induced anti-OGDR activity in T-HESC cells. Thus Keap1-Nrf2 cascade activation is required for miR-941-induced endometrial cell protection. Conclusions: Targeting Keap1 by miR-941 activates Nrf2 cascade to protect human endometrial cells from OGDRinduced oxidative stress and programmed necrosis.

show abstract

Activation of Keap1-Nrf2 signaling by 4-octyl itaconate protects human umbilical vein endothelial cells from high glucose

Cited by 40 publications

References 26 publications

Four-octyl itaconate activates Nrf2 cascade to protect osteoblasts from hydrogen peroxide-induced oxidative injury

Four-octyl itaconate activates Nrf2 cascade to protect osteoblasts from hydrogen peroxide-induced oxidative injury

Protective effect of apple phlorizin on hydrogen peroxide‐induced cell damage in HepG2 cells

Keap1-targeting microRNA-941 protects endometrial cells from oxygen and glucose deprivation-re-oxygenation via activation of Nrf2 signaling

Contact Info

Product

Resources

About