K6PC-5 Activates SphK1-Nrf2 Signaling to Protect Neuronal Cells from Oxygen Glucose Deprivation/Re-Oxygenation

Liu, Hua; Zhang, Zhiqing; Xu, Min; Xu, Rong; Wang, Zhichun; Di, Guangfu

doi:10.1159/000495716

Cited by 26 publications

(26 citation statements)

References 37 publications

(78 reference statements)

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“…Besides apoptosis, DEX-provoked ROS production concurrently induces mitochondrial programmed necrosis pathway in human osteoblasts, as reported by other studies 8,24,30,34,35 . Here we show that DEX (1 μM) treatment in control OB-6 cells induced significant mitochondrial depolarization (JC-1 green fluorescence accumulation 26,36 , Fig. 3c, d), mitochondrial CyPD-ANT-1 association (an initial step of programmed necrosis progression 8,24,35 , Fig.…”

Section: Resultsmentioning

confidence: 59%

PGK1 depletion activates Nrf2 signaling to protect human osteoblasts from dexamethasone

et al. 2019

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Activation of nuclear-factor-E2-related factor 2 (Nrf2) cascade can alleviate dexamethasone (DEX)-induced oxidative injury and death of human osteoblasts. A recent study has shown that phosphoglycerate kinase 1 (PGK1) inhibition/depletion will lead to Kelch-like ECH-associated protein 1 (Keap1) methylglyoxal modification, thereby activating Nrf2 signaling cascade. Here, in OB-6 osteoblastic cells and primary human osteoblasts, PGK1 silencing, by targeted shRNA, induced Nrf2 signaling cascade activation, causing Nrf2 protein stabilization and nuclear translocation, as well as increased expression of ARE-dependent genes (HO1, NQO1, and GCLC). Functional studies demonstrated that PGK1 shRNA largely attenuated DEX-induced oxidative injury and following death of OB-6 cells and primary osteoblasts. Furthermore, PGK1 knockout, by the CRISPR/Cas9 method, similarly induced Nrf2 signaling activation and protected osteoblasts from DEX. Importantly, PGK1 depletion-induced osteoblast cytoprotection against DEX was almost abolished by Nrf2 shRNA. In addition, Keap1 shRNA mimicked and nullified PGK1 shRNA-induced anti-DEX osteoblast cytoprotection. At last we show that PGK1 expression is downregulated in human necrotic femoral head tissues of DEX-taking patients, correlating with HO1 depletion. Collectively, these results show that PGK1 depletion protects human osteoblasts from DEX via activation of Keap1-Nrf2 signaling cascade.

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Section: Resultsmentioning

confidence: 59%

PGK1 depletion activates Nrf2 signaling to protect human osteoblasts from dexamethasone

et al. 2019

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“…OB-6 cells were seeded into six-well tissue-culture plates. The detailed protocols of isolating mitochondrial fraction lysates and mito-IP were described before 24 .…”

Section: Mitochondrial Immunoprecipitation (Mito-ip)mentioning

confidence: 99%

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

et al. 2020

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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.

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“…To test whether OGD/R can affect miR-422a expression, differentiated SH-SY5Y cells were exposed to oxygen glucose deprivation (OGD) for 4 h, as previously-described 24 , 25 , 32 . After OGD exposure, cells were maintained in regular medium (“re-oxygenation”, OGD/R) for various time periods.…”

Section: Resultsmentioning

confidence: 99%

“…Authentication by STR profiling, population doubling time, and morphology were routinely confirmed as well to verify the genotype. The primary murine neurons were provided by Dr. Di [23][24][25] , and cultured by the previously-described protocols 23 . At day-10 (DIV), over 95% of cells were cortical neurons.…”

Section: Cell Culturementioning

confidence: 99%

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Oxygen glucose deprivation/re-oxygenation-induced neuronal cell death is associated with Lnc-D63785 m6A methylation and miR-422a accumulation

Chen

et al. 2020

Cell Death Dis

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Oxygen glucose deprivation/re-oxygenation (OGD/R) induces neuronal injury via mechanisms that are believed to mimic the pathways associated with brain ischemia. In SH-SY5Y cells and primary murine neurons, we report that OGD/R induces the accumulation of the microRNA miR-422a, leading to downregulation of miR-422a targets myocyte enhancer factor-2D (MEF2D) and mitogen-activated protein kinase kinase 6 (MAPKK6). Ectopic miR-422a inhibition attenuated OGD/R-induced cell death and apoptosis, whereas overexpression of miR-422a induced significant neuronal cell apoptosis. In addition, OGD/R decreased the expression of the long non-coding RNA D63785 (Lnc-D63785) to regulate miR-422a accumulation. Lnc-D63785 directly associated with miR-422a and overexpression of Lnc-D63785 reversed OGD/R-induced miR-422a accumulation and neuronal cell death. OGD/R downregulated Lnc-D63785 expression through increased methyltransferase-like protein 3 (METTL3)-dependent Lnc-D63785 m6A methylation. Conversely METTL3 shRNA reversed OGD/R-induced Lnc-D63785 m6A methylation to decrease miR-422a accumulation. Together, Lnc-D63785 m6A methylation by OGD/R causes miR-422a accumulation and neuronal cell apoptosis.

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K6PC-5 Activates SphK1-Nrf2 Signaling to Protect Neuronal Cells from Oxygen Glucose Deprivation/Re-Oxygenation

Cited by 26 publications

References 37 publications

PGK1 depletion activates Nrf2 signaling to protect human osteoblasts from dexamethasone

PGK1 depletion activates Nrf2 signaling to protect human osteoblasts from dexamethasone

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

Oxygen glucose deprivation/re-oxygenation-induced neuronal cell death is associated with Lnc-D63785 m6A methylation and miR-422a accumulation

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