ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner

Trace metals such as zinc (Zn), copper (Cu), and nickel (Ni) play important roles in various physiological functions such as immunity, cell division, and protein synthesis in a wide variety of species. However, excessive amounts of these trace metals cause disorders in various tissues of the central nervous system, respiratory system, and other vital organs. Our previous analysis focusing on neurotoxicity resulting from interactions between Zn and Cu revealed that Cu2+ markedly enhances Zn2+-induced neuronal cell death by activating oxidative stress and the endoplasmic reticulum (ER) stress response. However, neurotoxicity arising from interactions between zinc and metals other than copper has not been examined. Thus, in the current study, we examined the effect of Ni2+ on Zn2+-induced neurotoxicity. Initially, we found that nontoxic concentrations (0–60 μM) of Ni2+ enhance Zn2+-induced neurotoxicity in an immortalized hypothalamic neuronal cell line (GT1-7) in a dose-dependent manner. Next, we analyzed the mechanism enhancing neuronal cell death, focusing on the ER stress response. Our results revealed that Ni2+ treatment significantly primed the Zn2+-induced ER stress response, especially expression of the CCAAT-enhancer-binding protein homologous protein (CHOP). Finally, we examined the effect of carnosine (an endogenous peptide) on Ni2+/Zn2+-induced neurotoxicity and found that carnosine attenuated Ni2+/Zn2+-induced neuronal cell death and ER stress occurring before cell death. Based on our results, Ni2+ treatment significantly enhances Zn2+-induced neuronal cell death by priming the ER stress response. Thus, compounds that decrease the ER stress response, such as carnosine, may be beneficial for neurological diseases.

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The The Effects of Centella asiatica Extract (CAE) on Methamphetamine-Induced Neurotoxicity via Human Neuroblastoma Cell Line

ASM Science Journal ◽

10.32802/asmscj.2021.907 ◽

2021 ◽

Vol 16 ◽

pp. 1-9

Author(s):

Mazatulikhma Mat Zain Mat Zain ◽

Nursyamila Shamsuddin ◽

Mohd Shihabuddin Ahmad Noorden

Keyword(s):

Cell Death ◽

Neuroblastoma Cell ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Centella Asiatica ◽

Human Neuroblastoma Cell ◽

Asiatic Acid ◽

Dependent Manner ◽

Human Neuroblastoma

Methamphetamine (METH) was reported to caused neurotoxicity and cell death, in vitro. Centella asiatica or ‘pegaga’ is a native tropical herb with antioxidant and neuroprotective activities. Although the effects of Centella asiatica against oxidative stress and neuronal cell death have been reported in previous studies, however, the potential effects of Centella asiatica against psychostimulant methamphetamine (METH) are limited. Therefore, this study was aimed to evaluate the effects of Centella asiatica extract (CAE) against METH on all-trans retinoic acid, RA-differentiated human neuroblastoma, SH-SY5Y cells. The RA-differentiated SH-SY5Y cells were used to resemble dopaminergic neuronal-like cells. Cell viability was quantitatively assessed by 3-(4,5-dimethylthiazol-2-yl)-2 tetrazolium bromide, MTS assay. CAE at varying concentrations from 1pg/mL to 1mg/mL significantly decreased the viability of the undifferentiated SH-SY5Y cells in a concentration-dependent manner. At 1mg/mL of CAE, significantly increased the viability of differentiated SH-SY5Y cells. Meanwhile, CAE at 100µg/mL and 1mg/mL significantly reversed the METH-induced neuronal cell death. The results revealed that promising treatment of CAE on METH-induced neurotoxicity is mediated by its high content of asiaticoside, asiatic acid, madecassoside and madecassic acid. Taken together, this study may suggest CAE as a potential therapeutic treatment for METH-induced neurotoxicity, in vitro.

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Lipocalin-type prostaglandin D synthase protects against oxidative stress-induced neuronal cell death

Biochemical Journal ◽

10.1042/bj20111889 ◽

2012 ◽

Vol 443 (1) ◽

pp. 75-84 ◽

Cited By ~ 29

Author(s):

Ayano Fukuhara ◽

Mao Yamada ◽

Ko Fujimori ◽

Yuya Miyamoto ◽

Toshihide Kusumoto ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Neuroblastoma Cell ◽

Neuronal Cells ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Dependent Manner ◽

Functional Protein ◽

Prostaglandin D Synthase ◽

Induced Apoptosis

L-PGDS [lipocalin-type PGD (prostaglandin D) synthase] is a dual-functional protein, acting as a PGD2-producing enzyme and a lipid transporter. L-PGDS is a member of the lipocalin superfamily and can bind a wide variety of lipophilic molecules. In the present study we demonstrate the protective effect of L-PGDS on H2O2-induced apoptosis in neuroblastoma cell line SH-SY5Y. L-PGDS expression was increased in H2O2-treated neuronal cells, and the L-PGDS level was highly associated with H2O2-induced apoptosis, indicating that L-PGDS protected the neuronal cells against H2O2-mediated cell death. A cell viability assay revealed that L-PGDS protected against H2O2-induced cell death in a concentration-dependent manner. Furthermore, the titration of free thiols in H2O2-treated L-PGDS revealed that H2O2 reacted with the thiol of Cys65 of L-PGDS. The MALDI–TOF (matrix-assisted laser-desorption ionization–time-of-flight)-MS spectrum of H2O2-treated L-PGDS showed a 32 Da increase in the mass relative to that of the untreated protein, showing that the thiol was oxidized to sulfinic acid. The binding affinities of oxidized L-PGDS for lipophilic molecules were comparable with those of untreated L-PGDS. Taken together, these results demonstrate that L-PGDS protected against neuronal cell death by scavenging reactive oxygen species without losing its ligand-binding function. The novel function of L-PGDS could be useful for the suppression of oxidative stress-mediated neurodegenerative diseases.

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Hypothermia Reduces Toll-Like Receptor 3-Activated Microglial Interferon-βand Nitric Oxide Production

Mediators of Inflammation ◽

10.1155/2013/436263 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 10

Author(s):

Tomohiro Matsui ◽

Yukari Motoki ◽

Yusuke Yoshida

Keyword(s):

Nitric Oxide ◽

Cell Death ◽

Therapeutic Hypothermia ◽

Neuroprotective Effect ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Dependent Manner ◽

Cns Injury ◽

Concentration Dependent Manner ◽

Polycytidylic Acid

Therapeutic hypothermia protects neurons after injury to the central nervous system (CNS). Microglia express toll-like receptors (TLRs) that play significant roles in the pathogenesis of sterile CNS injury. To elucidate the possible mechanisms involved in the neuroprotective effect of therapeutic hypothermia, we examined the effects of hypothermic culture on TLR3-activated microglial release of interferon (IFN)-βand nitric oxide (NO), which are known to be associated with neuronal cell death. When rat or mouse microglia were cultured under conditions of hypothermia (33°C) and normothermia (37°C) with a TLR3 agonist, polyinosinic-polycytidylic acid, the production of IFN-βand NO in TLR3-activated microglia at 48 h was decreased by hypothermia compared with that by normothermia. In addition, exposure to recombinant IFN-βand sodium nitroprusside, an NO donor, caused death of rat neuronal pheochromocytoma PC12 cells in a concentration-dependent manner after 24 h. Taken together, these results suggest that the attenuation of microglial production of IFN-βand NO by therapeutic hypothermia leads to the inhibition of neuronal cell death.

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Caffeine Potentiates Ethanol-Induced Neurotoxicity Through mTOR/p70S6K/4E-BP1 Inhibition in SH-SY5Y Cells

International Journal of Toxicology ◽

10.1177/1091581819900150 ◽

2020 ◽

Vol 39 (2) ◽

pp. 131-140

Author(s):

Pongsak Sangaunchom ◽

Permphan Dharmasaroja

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Neuronal Cells ◽

Neuronal Cell Death ◽

Neuroblastoma Cells ◽

Neuronal Cell ◽

Apoptotic Cell Death ◽

Dependent Manner ◽

Ethanol Pretreatment ◽

Marked Cell

Caffeine is a popular psychostimulant, which is frequently consumed with ethanol. However, the effects of caffeine on neuronal cells constantly exposed to ethanol have not been investigated. Apoptosis and oxidative stress occurring in ethanol-induced neurotoxicity were previously associated with decreased phosphorylation of the mTOR/p70S6K/4E-BP1 signaling proteins. Evidence also suggested that caffeine inhibits the mTOR pathway. In this study, human SH-SY5Y neuroblastoma cells were exposed to caffeine after pretreatment for 24 hours with ethanol. Results indicated that both ethanol and caffeine caused neuronal cell death in a dose- and time-dependent manner. Exposure to 20-mM caffeine for 24 hours magnified reduced cell viability and enhanced apoptotic cell death induced by 200 mM of ethanol pretreatment. The phosphorylation of mTOR, p70S6K, and 4E-BP1 markedly decreased in cells exposed to caffeine after ethanol pretreatment, associated with a decrease of the mitochondrial membrane potential (ΔΨm). These findings suggested that caffeine treatment after neuronal cells were exposed to ethanol resulted in marked cell damages, mediated through enhanced inhibition of mTOR/p70S6K/4E-BP1 signaling leading to impaired ΔΨm and, eventually, apoptotic cell death.

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In vitro Model of Hypoxia: Basic Fibroblast Growth Factor Can Rescue Cultured CNS Neurons from Oxygen-Deprived Cell Death

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1993.130 ◽

1993 ◽

Vol 13 (6) ◽

pp. 1029-1032 ◽

Cited By ~ 27

Author(s):

Yukio Akaneya ◽

Yasushi Enokido ◽

Mitsuo Takahashi ◽

Hiroshi Hatanaka

Keyword(s):

Cell Death ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Basic Fibroblast Growth Factor ◽

Hippocampal Neurons ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Dependent Manner ◽

Fibroblast Growth

We established an in vitro hypoxia model and investigated the protective effect of basic fibroblast growth factor (bFGF) against neuronal cell death caused by hypoxia. Hippocampal neurons obtained from rats on embryonic day (E) 17 and 20 and on postnatal day (P) 4 were cultured for 6–24 h in an oxygen-deprived state. This in vitro hypoxia study showed that the cultured neurons were sensitive to the oxygen deprivation. The cultured P4 rat hippocampal neurons seemed to be weaker in the hypoxia condition than those of E17 and E20 rats, suggesting that the cultured postnatal cells might be sensitive to hypoxia. bFGF, but not nerve growth factor, prevented the neuronal cell death caused by hypoxia in a dose-dependent manner.

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Attenuation of potassium cyanide-mediated neuronal cell death by adenosine

Journal of Neurosurgery ◽

10.3171/jns.1993.79.1.0111 ◽

1993 ◽

Vol 79 (1) ◽

pp. 111-115 ◽

Cited By ~ 15

Author(s):

Christopher D. Sturm ◽

William A. Frisella ◽

Kong-Woo Yoon

Keyword(s):

Cell Death ◽

Neuroprotective Effect ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Potassium Cyanide ◽

Dependent Manner ◽

Specific Receptor ◽

Content Type ◽

Dose Dependent ◽

Fine Print

✓ Glutamate has been shown to play an important role in delayed neuronal cell death occurring due to ischemia. Attenuation of synaptically released glutamate can be accomplished by modulators such as adenosine and baclofen. This study focused on the ability of adenosine to attenuate the excitotoxicity secondary to glutamate receptor activation in vitro after exposure to potassium cyanide (KCN) in hippocampal neuronal cell cultures. For this study, hippocampal cell cultures were obtained from 1-day-old rats and trypan blue staining was used for assessment of cell viability. It was found that the N-methyl-D-aspartate-specific antagonist MK801 (10 µM) attenuated neuronal cell death resulting from exposure to 1 mM KCN for 60 minutes. Adenosine (10 to 1000 µM) decreased neuronal cell death secondary to the same concentration of KCN in a dose-dependent manner. This same neuroprotective effect is mimicked by the adenosine A1-specific receptor agonist N6-cyclopentyladenosine (10 µM). The A1-specific receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (10 to 1000 nM) blocked the neuroprotective effect of adenosine in a dose-dependent manner. Therefore, neuronal cell death produced by KCN in the experimental model described was mediated at least in part by glutamate. This neuronal cell death was attenuated by adenosine via the A1-specific mechanism.

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