Activation of KGFR-Akt-mTOR-Nrf2 signaling protects human retinal pigment epithelium cells from Ultra-violet

Hu, Haitao; Hao, Lanxiang; Tang, Chun-Zhou; Zhu, Yunxi; Jiang, Qin; Yao, Jin

doi:10.1016/j.bbrc.2017.12.078

Cited by 41 publications

(31 citation statements)

References 27 publications

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“…Akt could be a upstream signaling of Nrf2 via phosphorylating Nrf2 at Ser-40 [21,23,26,29]. Here, we found that CNTF dose-dependently induced Akt activation in H9c2 cells (Fig.…”

Section: Akt Activation Mediates Cntf-induced Nrf2 Activation and Myosupporting

confidence: 51%

“…Post-transcriptional modifications of Nrf2 are essential for its activation [14]. Nrf2 Ser-40 phosphorylation can induce Nrf2-Keap1 departure [38], enabling Nrf2 protein stabilization, accumulation, and nuclear translocation [21,23,26,29]. Our results showed that CNTF activated Akt signaling, serving as a upstream signaling for Nrf2 Ser-40 phosphorylation and activation.…”

Section: Discussionmentioning

confidence: 65%

“…Fig. 2A), and CNTF dosedependently induced Nrf2 phosphorylation (at Ser-40, a key site for activation [24][25][26]) and protein accumulation in H9c2 cells (Fig. 2B).…”

Section: Cntf Protects Myocardial Cells From Ogd/re-oxygenationmentioning

confidence: 99%

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Ciliary Neurotrophic Factor (CNTF) Protects Myocardial Cells from Oxygen Glucose Deprivation (OGD)/Re-Oxygenation via Activation of Akt-Nrf2 Signaling

Zheng¹,

Zhang²,

Sheng³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Oxygen glucose deprivation (OGD)/re-oxygenation (OGDR) exposure to myocardial cells mimics ischemia-reperfusion injuries. We studied the potential activity of ciliary neurotrophic factor (CNTF) on OGDR-treated myocardial cells. Methods: CNTF and CNTFR expression were tested by RT-PCR assay and Western blotting assay. Cell viability and death were tested by MTT assay and LDH release assay, respectively. Akt-Nrf2 signalings were tested by Western blotting assay and qPCR assay. Results: CNTF and its receptor CNTFR were functionally expressed in established H9c2 myocardial cells and primary murine myocardiocytes. Pretreatment of CNTF significantly attenuated OGDR-induced viability reduction and death in myocardial cells. Further studies show that in the myocardial cells CNTF activated NF-E2-related factor 2 (Nrf2) signaling to inhibit OGDR-induced reactive oxygen species (ROS) production and programmed necrosis, preventing adenine nucleotide translocator 1 (ANT-1)-p53-cyclophilin D (Cyp-D) mitochondrial association and mitochondrial depolarization. Nrf2 silencing or knockout almost abolished CNTF-induced H9c2 cytoprotection against OGDR. CNTF activated Akt in H9c2 cells and primary murine myocardiocytes. Conversely, Akt blockage by the pharmacological inhibitors not only blocked CNTF-induced Nrf2 Ser-40 phosphorylation and activation, but also nullified anti-OGDR actions by CNTF in myocardial cells. Conclusion: CNTF activates Akt-Nrf2 signaling to protect myocardial cells from OGDR.

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“…Akt could be a upstream signaling of Nrf2 via phosphorylating Nrf2 at Ser-40 [21,23,26,29]. Here, we found that CNTF dose-dependently induced Akt activation in H9c2 cells (Fig.…”

Section: Akt Activation Mediates Cntf-induced Nrf2 Activation and Myosupporting

confidence: 51%

Section: Discussionmentioning

confidence: 65%

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Ciliary Neurotrophic Factor (CNTF) Protects Myocardial Cells from Oxygen Glucose Deprivation (OGD)/Re-Oxygenation via Activation of Akt-Nrf2 Signaling

Zheng¹,

Zhang²,

Sheng³

et al. 2018

Cell Physiol Biochem

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“…Temsirolimus suppressed NRF2 translocation into the nucleus in RCC4 cells, a human renal cell carcinoma (RCC) cell line [98]. Everolimus reduced the phosphorylation of NRF2 in ARPE-19 adult retinal pigment epithelial cells [99]. In general, KEAP1 is important for the Figure 2: NRF2-mediated pathway of glutathione synthesis.…”

Section: Mtor-dependent Antioxidant Mechanism In Solidmentioning

confidence: 99%

mTOR-Mediated Antioxidant Activation in Solid Tumor Radioresistance

Woo

Lee

Jung

et al. 2019

Journal of Oncology

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Radiotherapy is widely used for the treatment of cancer patients, but tumor radioresistance presents serious therapy challenges. Tumor radioresistance is closely related to high levels of mTOR signaling in tumor tissues. Therefore, targeting the mTOR pathway might be a strategy to promote solid tumor sensitivity to ionizing radiation. Radioresistance is associated with enhanced antioxidant mechanisms in cancer cells. Therefore, examination of the relationship between mTOR signaling and antioxidant mechanism-linked radioresistance is required for effective radiotherapy. In particular, the effect of mTOR signaling on antioxidant glutathione induction by the Keap1-NRF2-xCT pathway is described in this review. This review is expected to assist in the identification of therapeutic adjuvants to increase the efficacy of radiotherapy.

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“…Nrf2 short hairpin RNA Lentiviral human Nrf2 short hairpin RNA (shRNA) was purchased from Santa Cruz Biotechnology (sc-37030-V) [29]. Nrf2 shRNA lentivirus (20 μL virus/mL medium) was added directly to THP-1 cells for 36 h. Thereafter, puromycin (5.0 μg/mL) was added to select stable cells for 12 days.…”

Section: Co-immunoprecipitation Assaymentioning

confidence: 99%

4-Octyl Itaconate Activates Nrf2 Signaling to Inhibit Pro-Inflammatory Cytokine Production in Peripheral Blood Mononuclear Cells of Systemic Lupus Erythematosus Patients

Tang¹,

Wang²,

Xie³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Increased production of multiple pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, plays an essential pathogenic role in the progression of systemic lupus erythematosus (SLE). Recent studies have characterized itaconate as a novel and potent nuclear-factor-E2-related factor 2 (Nrf2) activator that activates Nrf2 signaling by alkylating cysteine residues on Keap1 (Kelch-like ECH-associated protein 1). Methods: THP-1 human macrophages and peripheral blood mononuclear cells (PBMCs) of SLE patients were treated with 4-octyl itaconate (OI). Nrf2 signaling activation was tested by qPCR assay and western blotting. mRNA expression and the production of multiple pro-inflammatory cytokines were tested by qPCR and enzyme-linked immunosorbent assays, respectively. Nuclear factor (NF)-κB activation was tested by the p65 DNA-binding assay. Results: We demonstrated that OI, the cell-permeable derivative of itaconate, induced Keap1-Nrf2 dissociation, Nrf2 protein accumulation, and nuclear translocation, which enabled the transcription and expression of multiple Nrf2-dependentantioxidant enzymes (heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, and glutamate-cysteine ligase modifier subunit) in THP-1 human macrophages. OI also induced significant Nrf2 activation in SLE patient-derived PBMCs. OI pretreatment inhibited mRNA expression and the production of multiple pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in SLE patient-derived PBMCs and lipopolysaccharide (LPS)-activated THP-1 cells. OI potently inhibited NF-κB activation in SLE patient-derived PBMCs and LPS-activated THP-1 cells. Importantly, Nrf2 silencing (by targeted short hairpin RNA) or knockout (by CRISPR/Cas9 gene-editing method) almost abolished OI-induced anti-oxidant and anti-inflammatory actions in SLE patient-derived PBMCs and LPS-activated THP-1 cells. Conclusion: OI activates Nrf2 signaling to inhibit the production of pro-inflammatory cytokines in human macrophages and SLE patient-derived PBMCs. OI and itaconate could have important therapeutic value for the treatment of SLE.

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Activation of KGFR-Akt-mTOR-Nrf2 signaling protects human retinal pigment epithelium cells from Ultra-violet

Cited by 41 publications

References 27 publications

Ciliary Neurotrophic Factor (CNTF) Protects Myocardial Cells from Oxygen Glucose Deprivation (OGD)/Re-Oxygenation via Activation of Akt-Nrf2 Signaling

Ciliary Neurotrophic Factor (CNTF) Protects Myocardial Cells from Oxygen Glucose Deprivation (OGD)/Re-Oxygenation via Activation of Akt-Nrf2 Signaling

mTOR-Mediated Antioxidant Activation in Solid Tumor Radioresistance

4-Octyl Itaconate Activates Nrf2 Signaling to Inhibit Pro-Inflammatory Cytokine Production in Peripheral Blood Mononuclear Cells of Systemic Lupus Erythematosus Patients

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