Activation of Akt by SC79 decreased cerebral infarct in early cerebral ischemia-reperfusion despite increased BBB disruption

Liu, Xia; Kiss, Geza; Mellender, Scott J.; Weiss, Harvey R.; Z., Oak

doi:10.1016/j.neulet.2018.05.046

Cited by 13 publications

(8 citation statements)

References 29 publications

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“…The analysis of Cyt c phosphorylation state post-treatment resulted in complete dephosphorylation of Cyt c in the presence of wortmannin, suggesting a potential role for Akt in mediating this pathway. Interestingly, several studies have shown that Akt activator SC79 is an effective treatment for cerebral ischemia/reperfusion injury in animal models [ 54 , 55 , 56 ]. We and others have shown that activated, phosphorylated Akt translocates to the mitochondrial IMS where Cyt c resides [ 34 , 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Brain-Specific Serine-47 Modification of Cytochrome c Regulates Cytochrome c Oxidase Activity Attenuating ROS Production and Cell Death: Implications for Ischemia/Reperfusion Injury and Akt Signaling

Kalpage

Wan

Morse

et al. 2020

Cells

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We previously reported that serine-47 (S47) phosphorylation of cytochrome c (Cytc) in the brain results in lower cytochrome c oxidase (COX) activity and caspase-3 activity in vitro. We here analyze the effect of S47 modification in fibroblast cell lines stably expressing S47E phosphomimetic Cytc, unphosphorylated WT, or S47A Cytc. Our results show that S47E Cytc results in partial inhibition of mitochondrial respiration corresponding with lower mitochondrial membrane potentials (ΔΨm) and reduced reactive oxygen species (ROS) production. When exposed to an oxygen-glucose deprivation/reoxygenation (OGD/R) model simulating ischemia/reperfusion injury, the Cytc S47E phosphomimetic cell line showed minimal ROS generation compared to the unphosphorylated WT Cytc cell line that generated high levels of ROS upon reoxygenation. Consequently, the S47E Cytc cell line also resulted in significantly lower cell death upon exposure to OGD/R, confirming the cytoprotective role of S47 phosphorylation of Cytc. S47E Cytc also resulted in lower cell death upon H2O2 treatment. Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain. Akt inhibitor wortmannin abolished S47 phosphorylation of Cytc, while the Akt activator SC79 maintained S47 phosphorylation of Cytc. Overall, our results suggest that loss of S47 phosphorylation of Cytc during brain ischemia drives reperfusion injury through maximal electron transport chain flux, ΔΨm hyperpolarization, and ROS-triggered cell death.

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Section: Discussionmentioning

confidence: 99%

Brain-Specific Serine-47 Modification of Cytochrome c Regulates Cytochrome c Oxidase Activity Attenuating ROS Production and Cell Death: Implications for Ischemia/Reperfusion Injury and Akt Signaling

Kalpage

Wan

Morse

et al. 2020

Cells

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“…damage by reducing brain-derived neurotrophic factor production. 54 It is generally agreed that the increase in IOP and vascular dysregulation are two important causes of glaucoma; they can cause ischemia and hypoxia in the components of the optic nerve head and thus induce mitochondrial dysfunction and oxidative stress. 55,56 Therefore, we speculate that hypoxia in the retina of an eye with glaucoma may induce the elevation of hsa-miR-210-3p expression, which may enhance mitochon-drial dysfunction and oxidative stress in retinal ganglion cells (RGCs) and lead to RGC death and RNFL thinning.…”

Section: Discussionmentioning

confidence: 99%

Discovery and Validation of Circulating Hsa-miR-210-3p as a Potential Biomarker for Primary Open-Angle Glaucoma

Liu

Wang

Chen

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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Citation: Liu Y, Wang Y, Chen Y, et al. Discovery and validation of circulating hsa-miR-210-3p as a potential biomarker for primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2019;60:2925-2934. https://doi.org/ 10.1167/iovs.19-26663PURPOSE. Blood-based examination tools for glaucoma diagnosis in clinical practice, which can be useful for screening patients when traditional ophthalmic examinations cannot be utilized, are not available thus far. This study aimed to identify circulating microRNAs (miRNAs) associated with primary open-angle glaucoma (POAG) and explore their utility as diagnostic markers. METHODS.A total of 136 POAG patients and controls were enrolled. Next-generation RNA sequencing was used to explore the expression profile of circulating miRNAs in the sequencing set, and potential miRNAs from independent samples in both the screening and validation sets were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) analysis was used to evaluate the ability of certain miRNAs to distinguish POAG patients from control subjects. RESULTS.Using sequencing and qRT-PCR, hsa-miR-210-3p was found to be elevated in POAG patients in all sets. ROC analysis of the screening and validation sets revealed that hsa-miR-210-3p differentiated between POAG patients and matched controls with an area under the curve (AUC) of 0.846 (sensitivity: 84.6%; specificity: 80.8%) and 0.813 (sensitivity: 84.8%; specificity: 69.7%), respectively. In case of all nonsequencing participants, analysis revealed that hsa-miR-210-3p differentiated between severe POAG patients and controls with an AUC of 0.880 (sensitivity: 85.4%; specificity: 85.7%). In addition, the expression of hsa-miR-210-3p was associated with visual field defects of jmean deviationj (b ¼ 0.237; P ¼ 0.022) and average retinal nerve fiber layer thickness (b ¼ À5.792; P ¼ 0.014). CONCLUSIONS.Circulating hsa-miR-210-3p may serve as a potential diagnostic marker for POAG (especially for severe POAG patients).

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“…SC79 is a unique specific AKT activator that may be used to enhance AKT activity in various physiological and pathological conditions 24 . In the early stage of cerebral ischemia-reperfusion, SC79-induced AKT activation produced a decrease in the percentage of cortical infarct out of total cortical area 42 . In our studies, activation of AKT by SC79 also played a protective role in DBP-induced germ cells toxicity.…”

Section: Discussionmentioning

confidence: 95%

Di-n-butyl phthalate epigenetically induces reproductive toxicity via the PTEN/AKT pathway

Xing

et al. 2019

Cell Death Dis

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Di-n-butyl phthalate (DBP) is a kind of ubiquitous chemical linked to hormonal disruptions that affects male reproductive system. However, the mechanism of DBP-induced germ cells toxicity remains unclear. Here, we demonstrate that DBP induces reduction of proliferation, increase of apoptosis and DNA damage dependent on the PTEN/AKT pathway. Mechanistically, DBP decreases PTEN promoter methylation and increases its transcriptional activity, leading to increased PTEN expression. Notably, DNMT3b is confirmed as a target of miR-29b and miR-29b-mediated status of PTEN methylation is involved in the effects of DBP treatment. Meanwhile, DBP decreases AKT pathway expression via increasing PTEN expression. In addition, the fact that DBP decreases the sperm number and the percentage of motile and progressive sperm is associated with downregulated AKT pathway and sperm flagellum-related genes. Collectively, these findings indicate that DBP induces aberrant PTEN demethylation, leading to inhibition of the AKT pathway, which contributes to the reproductive toxicity.

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Activation of Akt by SC79 decreased cerebral infarct in early cerebral ischemia-reperfusion despite increased BBB disruption

Cited by 13 publications

References 29 publications

Brain-Specific Serine-47 Modification of Cytochrome c Regulates Cytochrome c Oxidase Activity Attenuating ROS Production and Cell Death: Implications for Ischemia/Reperfusion Injury and Akt Signaling

Brain-Specific Serine-47 Modification of Cytochrome c Regulates Cytochrome c Oxidase Activity Attenuating ROS Production and Cell Death: Implications for Ischemia/Reperfusion Injury and Akt Signaling

Discovery and Validation of Circulating Hsa-miR-210-3p as a Potential Biomarker for Primary Open-Angle Glaucoma

Di-n-butyl phthalate epigenetically induces reproductive toxicity via the PTEN/AKT pathway

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