Enhanced Ca2+ Entry Sustains the Activation of Akt in Glucose Deprived SH-SY5Y Cells

Kourti, Maria; Liaropoulou, Danai; Paschou, Maria; Giagklisi, Ioanna; Paschalidi, Maria; Petani, Evangelia; Papazafiri, Panagiota

doi:10.3390/ijms23031386

Cited by 7 publications

(6 citation statements)

References 55 publications

(66 reference statements)

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“…LTG treatment led to a marked reduction of AKT phosphorylation and its direct downstream targets FoxO3a and GSK-3β in both ERα+ MCF-7 and ERα- MDA-MB-231 BCCs, thus LTG effect does not depend on the ERα status, but seems to occur through the induction of PTEN and FoxO3a mRNA and protein expression [ 104 ]. Considering that LTG is a VGCC blocker and that Ca ++ influx has been reported to activate the PI3K/Akt axis in different cell systems [ 105 , 106 , 107 ], our results well fit with previously published reports showing that T-type Ca++ channel inhibition is able to interfere with mTOR/AKT pathway in a human lung adenocarcinoma cell line [ 108 ] and disrupted Akt signaling, promoting apoptosis, in glioblastoma cells [ 109 ].…”

Section: Aeds In Breast Cancersupporting

confidence: 91%

From HDAC to Voltage-Gated Ion Channels: What’s Next? The Long Road of Antiepileptic Drugs Repositioning in Cancer

Pellegrino

Ricci

Ceraldi

et al. 2022

Cancers

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Cancer is a major health burden worldwide. Although the plethora of molecular targets identified in the last decades and the deriving developed treatments, which significantly improved patients’ outcome, the occurrence of resistance to therapies remains the major cause of relapse and mortality. Thus, efforts in identifying new markers to be exploited as molecular targets in cancer therapy are needed. This review will first give a glance on the diagnostic and therapeutic significance of histone deacetylase (HDAC) and voltage gated ion channels (VGICs) in cancer. Nevertheless, HDAC and VGICs have also been reported as molecular targets through which antiepileptic drugs (AEDs) seem to exert their anticancer activity. This should be claimed as a great advantage. Indeed, due to the slowness of drug approval procedures, the attempt to turn to off-label use of already approved medicines would be highly preferable. Therefore, an updated and accurate overview of both preclinical and clinical data of commonly prescribed AEDs (mainly valproic acid, lamotrigine, carbamazepine, phenytoin and gabapentin) in breast, prostate, brain and other cancers will follow. Finally, a glance at the emerging attempt to administer AEDs by means of opportunely designed drug delivery systems (DDSs), so to limit toxicity and improve bioavailability, is also given.

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Section: Aeds In Breast Cancersupporting

confidence: 91%

From HDAC to Voltage-Gated Ion Channels: What’s Next? The Long Road of Antiepileptic Drugs Repositioning in Cancer

Pellegrino

Ricci

Ceraldi

et al. 2022

Cancers

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“…During cerebral ischemia, two critical cellular insults occur, namely the deprivation of oxygen and glucose. These insults have the potential to trigger a series of events that ultimately result in neuronal death [3]. OGD is widely used as a simple and highly useful in vitro model for the elucidation of the role of the key cellular and molecular mechanisms underlying brain ischemia, which have shown similarities with the in vivo models of brain ischemia [25].…”

Section: Discussionmentioning

confidence: 99%

“…It remains a leading cause of death and lifelong disability globally, primarily due to limited treatment options for ischemic brain injury [1,2]. The loss of oxygen and loss of glucose, the two crucial cellular insults that take place during cerebral ischemia, can both activate a cascade of events that disrupts cellular homeostasis and culminates in ischemic neuronal injury [3]. Currently, therapeutic approaches for cerebral ischemic stroke primarily include thrombolysis, enhancing microcirculation, restoring blood supply to ischemic areas, anticoagulation, reducing blood viscosity, neuroprotection, minimizing ischemic cerebral edema, and addressing complications [4,5].…”

Section: Introductionmentioning

confidence: 99%

Luteolin-7-O-β-d-glucuronide Ameliorates Cerebral Ischemic Injury: Involvement of RIP3/MLKL Signaling Pathway

Fan,

Lin,

Chen

et al. 2024

Molecules

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Luteolin-7-O-β-d-glucuronide (LGU) is a major active flavonoid glycoside compound that is extracted from Ixeris sonchifolia (Bge.) Hance, and it is a Chinese medicinal herb mainly used for the treatment of coronary heart disease, angina pectoris, cerebral infarction, etc. In the present study, the neuroprotective effect of LGU was investigated in an oxygen glucose deprivation (OGD) model and a middle cerebral artery occlusion (MCAO) rat model. In vitro, LGU was found to effectively improve the OGD-induced decrease in neuronal viability and increase in neuronal death by a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and a lactate dehydrogenase (LDH) leakage rate assay, respectively. LGU was also found to inhibit OGD-induced intracellular Ca2+ overload, adenosine triphosphate (ATP) depletion, and mitochondrial membrane potential (MMP) decrease. By Western blotting analysis, LGU significantly inhibited the OGD-induced increase in expressions of receptor-interacting serine/threonine-protein kinase 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL). Moreover, molecular docking analysis showed that LGU might bind to RIP3 more stably and firmly than the RIP3 inhibitor GSK872. Immunofluorescence combined with confocal laser analyses disclosed that LGU inhibited the aggregation of MLKL to the nucleus. Our results suggest that LGU ameliorates OGD-induced rat primary cortical neuronal injury via the regulation of the RIP3/MLKL signaling pathway in vitro. In vivo, LGU was proven, for the first time, to protect the cerebral ischemia in a rat middle cerebral artery occlusion (MCAO) model, as shown by improved neurological deficit scores, infarction volume rate, and brain water content rate. The present study provides new insights into the therapeutic potential of LGU in cerebral ischemia.

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“…Death signal glycogen synthase kinase-3 (GSK3) is the direct target of p-Akt, which can be phosphorylated by Akt and inactivated [ 38 ]. In the OGD model of SH-SY5Y cells, the phosphorylation level of Akt could recover rapidly in response to the increase in Ca 2+ level under both hypoxia/glucose deprivation and glucose rehabilitation, and the increase in pGSK-3 was also found [ 151 ]. In this case, it can be seen that PI3K/Akt/GSK-3β pathway functions crucially in neuronal plasticity faced with ischemic challenges.…”

Section: Postsynaptic Effect Of Glutamate As the Main Mechanism Of Ne...mentioning

confidence: 99%

Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies

Fan

Xie

Xing

et al. 2022

IJMS

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Stroke is one of the leading causes of death and disability in the world, of which ischemia accounts for the majority. There is growing evidence of changes in synaptic connections and neural network functions in the brain of stroke patients. Currently, the studies on these neurobiological alterations mainly focus on the principle of glutamate excitotoxicity, and the corresponding neuroprotective strategies are limited to blocking the overactivation of ionic glutamate receptors. Nevertheless, it is disappointing that these treatments often fail because of the unspecificity and serious side effects of the tested drugs in clinical trials. Thus, in the prevention and treatment of stroke, finding and developing new targets of neuroprotective intervention is still the focus and goal of research in this field. In this review, we focus on the whole processes of glutamatergic synaptic transmission and highlight the pathological changes underlying each link to help develop potential therapeutic strategies for ischemic brain damage. These strategies include: (1) controlling the synaptic or extra-synaptic release of glutamate, (2) selectively blocking the action of the glutamate receptor NMDAR subunit, (3) increasing glutamate metabolism, and reuptake in the brain and blood, and (4) regulating the glutamate system by GABA receptors and the microbiota–gut–brain axis. Based on these latest findings, it is expected to promote a substantial understanding of the complex glutamate signal transduction mechanism, thereby providing excellent neuroprotection research direction for human ischemic stroke (IS).

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Enhanced Ca2+ Entry Sustains the Activation of Akt in Glucose Deprived SH-SY5Y Cells

Cited by 7 publications

References 55 publications

From HDAC to Voltage-Gated Ion Channels: What’s Next? The Long Road of Antiepileptic Drugs Repositioning in Cancer

From HDAC to Voltage-Gated Ion Channels: What’s Next? The Long Road of Antiepileptic Drugs Repositioning in Cancer

Luteolin-7-O-β-d-glucuronide Ameliorates Cerebral Ischemic Injury: Involvement of RIP3/MLKL Signaling Pathway

Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies

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