Low-concentration of perifosine surprisingly protects cardiomyocytes from oxygen glucose deprivation

Zheng, Koulong; Lu, Hongzhou; Sheng, Zhenqiang; Li, Yefei; Xu, Baojun

doi:10.1016/j.bbrc.2015.12.014

Cited by 17 publications

(21 citation statements)

References 32 publications

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“…Oxygen glucose deprivation (OGD)/re-oxygenation (OGDR) is often applied to cultured myocardial cells. In line with our previous findings [3][4][5], OGDR exposure in H9c2 cells (for 24 h) induced potent viability (MTT OD) reduction (Fig. 1C) and cell death (LDH medium release, Fig.…”

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

confidence: 93%

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

confidence: 93%

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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“…On the other hand, ROS suppression could inhibit Dex-induced osteoblastic cell damages [16]. Interestingly, recent studies have proposed potent anti-oxidant activity of AMPK [14, 16, 18, 26]. AMPK is shown to participate in maintaining NADPH content [14].…”

Section: Discussionmentioning

confidence: 99%

miR-135b expression downregulates Ppm1e to activate AMPK signaling and protect osteoblastic cells from dexamethasone

et al. 2016

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Activation of AMP-activated protein kinase (AMPK) could potently protect osteoblasts/osteoblastic cells from dexamethasone (Dex). We aim to induce AMPK activation via microRNA (“miRNA”) downregulation of its phosphatase Ppm1e. We discovered that microRNA-135b (“miR-135b”) targets the 3' untranslated regions (UTRs) of Ppm1e. In human osteoblasticOB-6 cells and hFOB1.19 cells, forced-expression of miR-135b downregulated Ppm1e and activated AMPK signaling. miR-135b also protected osteoblastic cells from Dex. shRNA-induced knockdown of Ppm1e similarly activated AMPK and inhibited Dex-induced damages. Intriguingly, in the Ppm1e-silenced osteoblastic cells, miR-135b expression failed to offer further cytoprotection against Dex. Notably, AMPK knockdown (via shRNA) or dominant negative mutation abolished miR-135b-induced AMPK activation and cytoprotection against Dex. Molecularly, miR-135b, via activating AMPK, increased nicotinamide adenine dinucleotide phosphate (NADPH) activity and inhibited Dex-induced oxidative stress. At last, we found that miR-135b level was increased in human necrotic femoral head tissues, which was correlated with Ppm1e downregulation and AMPK activation. There results suggest that miR-135b expression downregulates Ppm1e to activate AMPK signaling, which protects osteoblastic cells from Dex.

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“…Mechanisms involved in the action of perifosine include interference with the activation of Akt [1-4, 6, 8-13, 15, 16, 18, 20, 21] and stimulation of death receptor clustering [3, 22] with subsequent triggering of suicidal cell death or apoptosis [3, 8, 11-14, 16-18, 21, 23]. On the other hand, perifosine could activate AMP activated kinase AMPK and protect against cell death [24]. …”

Section: Introductionmentioning

confidence: 99%

Triggering of Eryptosis, the Suicidal Erythrocyte Death, by Perifosine

Egler

Läng²

2017

Cell Physiol Biochem

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Background/Aims: The alkylphospholipid perifosine is used for the treatment of malignancy. The substance is effective by triggering suicidal tumor cell death or apoptosis. Side effects of perifosine include anemia. At least in theory, perifosine-induced anemia could result from stimulation of suicidal erythrocyte death or eryptosis. Hallmarks of eryptosis are cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Cellular mechanisms participating in the orchestration of eryptosis include increase of cytosolic Ca²⁺ activity ([Ca²⁺]_i), oxidative stress, increase of ceramide abundance, as well as activation of staurosporine sensitive protein kinase C and/or of SB203580 sensitive p38 kinase. The present study explored, whether perifosine induces eryptosis and, if so, whether its effect involves and/or requires Ca²⁺ entry, oxidative stress, ceramide and kinase activation. Methods: Flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca²⁺]_i from Fluo3-fluorescence, reactive oxygen species (ROS) abundance from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Hemolysis was estimated from hemoglobin concentration in the supernatant. Results: A 24 hours exposure of human erythrocytes to perifosine (2.5 µg/ml) significantly increased the percentage of annexin-V-binding cells, significantly decreased average forward scatter, significantly increased the percentage of shrunken erythrocytes, and significantly decreased the percentage of swollen erythrocytes. Perifosine significantly increased the percentage of hemolytic erythrocytes. Perifosine significantly increased Fluo3-fluorescence, but decreased DCFDA fluorescence and ceramide abundance. The effect of perifosine on annexin-V-binding was significantly blunted by removal of extracellular Ca²⁺ and by addition of staurosporine (1 µM), but not by addition of SB203580 (2 µM). Conclusions: Perifosine triggers eryptosis, an effect at least in part due to Ca²⁺ entry and activation of staurosporine sensitive kinases.

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Low-concentration of perifosine surprisingly protects cardiomyocytes from oxygen glucose deprivation

Cited by 17 publications

References 32 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

miR-135b expression downregulates Ppm1e to activate AMPK signaling and protect osteoblastic cells from dexamethasone

Triggering of Eryptosis, the Suicidal Erythrocyte Death, by Perifosine

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