scholarly journals PTEN Is Required for The Anti-Epileptic Effects of AMPA Receptor Antagonists in Chronic Epileptic Rats

2020 ◽  
Vol 21 (16) ◽  
pp. 5643
Author(s):  
Ji-Eun Kim ◽  
Hana Park ◽  
Ji-Eun Lee ◽  
Tae-Hyun Kim ◽  
Tae-Cheon Kang
Keyword(s):  
Surface Expression ◽  
Seizure Onset ◽  
Ionotropic Receptor ◽  
Phosphatase And Tensin Homolog ◽  
Synaptic Targeting ◽  
Gyki 52466 ◽  
Tensin Homolog ◽  
Phosphorylation Level ◽  
Important Player ◽  
Phosphoinositide 3 Kinase

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is one of the ligand-gated ion channels for glutamate, which is an important player in the generation and spread of seizures. The efficacy of AMPAR functionality is regulated by the trafficking, synaptic targeting, and phosphorylation. Paradoxically, AMPAR expression and its phosphorylation level are decreased in the epileptic hippocampus. Therefore, the roles of AMPAR in seizure onset and neuronal hyperexcitability in ictogenesis remain to be elucidated. In the present study, we found that AMPAR antagonists (perampanel and GYKI 52466) decreased glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) surface expression in the epileptic rat hippocampus. They also upregulated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and restored to basal levels the upregulated phosphoinositide 3-kinase (PI3K)/AKT1 phosphorylations. Dipotassium bisperoxovanadium(pic) dihydrate (BpV(pic), a PTEN inhibitor) co-treatment abolished the anti-epileptic effects of perampanel and GYKI 52466. Therefore, our findings suggest that PTEN may be required for the anti-epileptic effects of AMPAR antagonists.

scholarly journals Src/CK2/PTEN-Mediated GluN2B and CREB Dephosphorylations Regulate the Responsiveness to AMPA Receptor Antagonists in Chronic Epilepsy Rats

2020 ◽  
Vol 21 (24) ◽  
pp. 9633
Author(s):  
Ji-Eun Kim ◽  
Duk-Shin Lee ◽  
Hana Park ◽  
Tae-Cheon Kang
Keyword(s):  
Surface Expression ◽  
Camp Response Element Binding ◽  
Ionotropic Receptor ◽  
Camp Response Element ◽  
Phosphatase And Tensin Homolog ◽  
Gyki 52466 ◽  
Tensin Homolog ◽  
Aspartate Receptor ◽  
Element Binding Protein ◽  
Refractory Seizures

Both α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) have been reported as targets for treatment of epilepsy. To investigate the roles and interactions of AMPAR and NMDAR in ictogenesis of epileptic hippocampus, we analyzed AMPAR antagonists (perampanel and GYKI 52466)-mediated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) regulation and glutamate ionotropic receptor NMDA type subunit 2B (GluN2B) tyrosine (Y) 1472 phosphorylation in epilepsy rats. Both perampanel and GYKI 52466 increased PTEN expression and its activity (reduced phosphorylation), concomitant with decreased activities (phosphorylations) of Src family-casein kinase 2 (CK2) signaling pathway. Compatible with these, they also restored the upregulated GluN2B Y1472 and Ca2+/cAMP response element-binding protein (CREB) serine (S) 133 phosphorylations and surface expression of glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) to basal level in the epileptic hippocampus. These effects of perampanel and GYKI 52466 are observed in responders (whose seizure activities are responsive to AMPAR antagonists), but not non-responders (whose seizure activities were uncontrolled by AMPAR antagonists). Therefore, our findings suggest that Src/CK2/PTEN-mediated GluN2B Y1472 and CREB S133 regulations may be one of the responsible signaling pathways for the generation of refractory seizures in non-responders to AMPAR antagonists.

scholarly journals Esthetic and Functional Improvement of Asymmetric Lower Limb Overgrowth in a Proteus Syndrome Patient: a Combined Surgical Technique

2021 ◽  
Author(s):  
Francesca Riccardi ◽  
Simone Catapano ◽  
Giuseppe Cottone ◽  
Dino Zilio ◽  
Luca Vaienti
Keyword(s):  
Adipose Tissue ◽  
Lower Limb ◽  
Vascular Malformations ◽  
Functional Improvement ◽  
Proteus Syndrome ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Genetic Mosaicism ◽  
Phosphoinositide 3 Kinase ◽  
The Right

AbstractProteus syndrome is a rare, sporadic, congenital syndrome that causes asymmetric and disproportionate overgrowth of limbs, connective tissue nevi, epidermal nevi, alteration of adipose tissue, and vascular malformations. Genetic mosaicism, such as activating mutations involving protein kinase AKT1, phosphoinositide 3 kinase (PI3-K), and phosphatase and tensin homolog (PTEN), may be important causes of Proteus syndrome. However, many patients have no evidence of mutations in these genes. Currently, the diagnosis is clinical and based on phenotypic features. This article reports a case of Proteus syndrome in a 14-year-old female patient who presented with linear epidermal nevi, viscera anomalies, and adipose tissue dysregulation. She showed an asymmetric progressive overgrowth of the right lower limb after birth bringing relevant functional and esthetic consequences. Therefore, she asked a plastic surgery consultation and a surgical treatment with a combined technique was planned. With our approach, we were able to reduce leg diameter and improve joint mobility reliably and safely with satisfying esthetic results.

scholarly journals PTEN Alterations and Their Role in Cancer Management: Are We Making Headway on Precision Medicine?

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 719
Author(s):  
Nicola Fusco ◽  
Elham Sajjadi ◽  
Konstantinos Venetis ◽  
Gabriella Gaudioso ◽  
Gianluca Lopez ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Mammalian Target Of Rapamycin ◽  
Genetic Alterations ◽  
Phosphatase And Tensin Homolog ◽  
Cancer Management ◽  
Tensin Homolog ◽  
Current State ◽  
Tumor Immune Microenvironment ◽  
Damage Response ◽  
Phosphoinositide 3 Kinase

Alterations in the tumor suppressor phosphatase and tensin homolog (PTEN) occur in a substantial proportion of solid tumors. These events drive tumorigenesis and tumor progression. Given its central role as a downregulator of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, PTEN is deeply involved in cell growth, proliferation, and survival. This gene is also implicated in the modulation of the DNA damage response and in tumor immune microenvironment modeling. Despite the actionability of PTEN alterations, their role as biomarkers remains controversial in clinical practice. To date, there is still a substantial lack of validated guidelines and/or recommendations for PTEN testing. Here, we provide an update on the current state of knowledge on biologic and genetic alterations of PTEN across the most frequent solid tumors, as well as on their actual and/or possible clinical applications. We focus on possible tailored schemes for cancer patients’ clinical management, including risk assessment, diagnosis, prognostication, and treatment.

scholarly journals The Changing Therapeutic Landscape in Metastatic Prostate Cancer

2017 ◽  
Vol 13 (02) ◽  
pp. 112
Author(s):  
Alan J Koletsky ◽  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Disease ◽  
Metastatic Prostate Cancer ◽  
Focal Point ◽  
Castration Resistant Prostate Cancer ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Truncating Mutation ◽  
Radium 223 ◽  
Phosphoinositide 3 Kinase

Over the past several years a number of novel and diverse agents have provided a significant clinical benefit for patients with metastatic castration-resistant prostate cancer including abiraterone, enzalutamide, sipuleucel-T, cabazitaxel, and radium-223. The early use of docetaxel or abiraterone at initiation of standard androgen deprivation therapy in patients with metastatic hormone-sensitive prostate cancer has also led to substantial improvements in overall survival. The identification of a truncating mutation in the androgen receptor (ARV7), a biomarker of resistance, may help clarify a more optimal sequencing of hormonal and chemotherapy-based therapies for patients with metastatic disease. The genomic landscape of both primary and metastatic prostate cancer has been an important focal point of translational research. The most widely studied pathways that affect tumorigenesis are the phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/protein kinase B (AKT) and poly ADP ribose polymerase (PARP) and DNA repair pathways. This review will highlight recent clinical trials which have had a major impact on the management of patients with metastatic disease with an emphasis on treatments driven by common genomic aberrations present in advanced prostate cancer.

scholarly journals Modeling PTEN overexpression-induced microcephaly in human brain organoids

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Navroop Dhaliwal ◽  
Wendy W.Y. Choi ◽  
Julien Muffat ◽  
Yun Li
Keyword(s):  
Human Brain ◽  
Human Genetics ◽  
Negative Regulator ◽  
Akt Inhibitor ◽  
Chromosome 10 ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pi3k Signaling Pathway ◽  
Brain Organoid ◽  
Phosphoinositide 3 Kinase

AbstractThe phosphatase and tensin homolog (PTEN) protein, encoded by the PTEN gene on chromosome 10, is a negative regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway. Loss of PTEN has been linked to an array of human diseases, including neurodevelopmental disorders such as macrocephaly and autism. However, it remains unknown whether increased dosage of PTEN can lead to human disease. A recent human genetics study identifies chromosome 10 microduplication encompassing PTEN in patients with microcephaly. Here we generated a human brain organoid model of increased PTEN dosage. We showed that mild PTEN overexpression led to reduced neural precursor proliferation, premature neuronal differentiation, and the formation of significantly smaller brain organoids. PTEN overexpression resulted in decreased AKT activation, and treatment of wild-type organoids with an AKT inhibitor recapitulated the reduced brain organoid growth phenotypes. Together, our findings provide functional evidence that PTEN is a dosage-sensitive gene that regulates human neurodevelopment, and that increased PTEN dosage in brain organoids results in microcephaly-like phenotypes.

scholarly journals Effect of 6-Shogaol on the Glucose Uptake and Survival of HT1080 Fibrosarcoma Cells

2019 ◽  
Vol 12 (3) ◽  
pp. 131 ◽  
Author(s):  
Angie C. Romero-Arias ◽  
Luis G. Sequeda-Castañeda ◽  
Andres F. Aristizábal-Pachón ◽  
Ludis Morales
Keyword(s):  
Cell Viability ◽  
Glucose Uptake ◽  
Tumor Cells ◽  
Southern China ◽  
Mammalian Target Of Rapamycin ◽  
Ros Production ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
P Proteins ◽  
Phosphoinositide 3 Kinase

Ginger is a plant that is native to southern China. In the last decade and research on the components of ginger has significantly increased; of these components, 6-shogaol exhibits the greatest potential antitumor capacity. However, the molecular mechanism through which 6-shogaol exerts its effects has not yet been elucidated. In this study, the effect of 6-shogaol on tumor cells that were derived from human fibrosarcoma (HT1080) was evaluated. Cell viability was determined by a (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) MTT assay testing different concentrations of 6-shogaol (2.5–150 μM). Subsequently, the effect of 6-shogaol on reactive oxygen species (ROS) production, glucose uptake, and protein expression of the signaling pathway phosphatase and tensin homolog/ protein kinase B /mammalian target of rapamycin (PTEN/Akt/mTOR) was measured. 6-Shogaol reduced the viability of the tumor cells and caused an increase in ROS production, which was attenuated with the addition of N-acetylcysteine, and the recovery of cell viability was observed. The increase in ROS production in response to 6-shogaol was associated with cell death. Similarly, glucose uptake decreased with incremental concentrations of 6-shogaol, and an increase in the expression of mTOR-p and Akt-p proteins was observed; PTEN was active in all the treatments with 6-shogaol. Thus, the results suggest that cells activate uncontrolled signaling pathways, such as phosphoinositide 3-kinase (PI3K)/Akt/mTOR, among other alternative mechanisms of metabolic modulation and of survival in order to counteract the pro-oxidant effect of 6-shogaol and the decrease in glucose uptake. Interestingly, a differential response was observed when non-cancerous cells were treated with 6-shogaol.

scholarly journals The Major Target of the Endogenously Generated Reactive Oxygen Species in Response to Insulin Stimulation Is Phosphatase and Tensin Homolog and Not Phosphoinositide-3 Kinase (PI-3 Kinase) in the PI-3 Kinase/Akt Pathway

2005 ◽  
Vol 16 (1) ◽  
pp. 348-357 ◽  
Author(s):  
Ji Hae Seo ◽  
Younghee Ahn ◽  
Seung-Rock Lee ◽  
Chang Yeol Yeo ◽  
Kyu Chung Hur
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Lines ◽  
Membrane Fraction ◽  
Akt Pathway ◽  
Oxygen Species ◽  
Insulin Stimulation ◽  
Phosphatase And Tensin Homolog ◽  
Downstream Signaling ◽  
Tensin Homolog ◽  
Phosphoinositide 3 Kinase

Phosphoinositide-3 kinase (PI-3 kinase) and its downstream signaling molecules PDK-1 and Akt were analyzed in SK-N-SH and SK-N-BE(2) human neuroblastoma cell lines. When cells were stimulated with insulin, PI-3 kinase was activated in both cell lines, whereas the translocation of PDK-1 to the membrane fraction and phosphorylated Akt were observed only in SK-N-SH cells. Analyses of the insulin-mediated reactive oxygen species (ROS) generation and Phosphatase and Tensin homolog (PTEN) oxidation indicate that PTEN oxidation occurred in SK-N-SH cells, which can produce ROS, but not in SK-N-BE(2) cells, which cannot increase ROS in response to insulin stimulation. When SK-N-SH cells were pretreated with the NADPH oxidase inhibitor diphenyleneiodonium chloride before insulin stimulation, insulin-mediated translocation of PDK-1 to the membrane fraction and phosphorylation of Akt were remarkably reduced, whereas PI-3 kinase activity was not changed significantly. These results indicate that not only PI-3 kinase activation but also inhibition of PTEN by ROS is needed to increase cellular level of phosphatidylinositol 3,4,5-trisphosphate for recruiting downstream signaling molecules such as PDK-1 and Akt in insulin-mediated signaling. Moreover, the ROS generated by insulin stimulation mainly contributes to the inactivation of PTEN and not to the activation of PI-3 kinase in the PI-3 kinase/Akt pathway.

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