FGF-2 induces neuronal death through upregulation of system xc-

Liu, Xiaoqian; Albano, Rebecca; Lobner, Doug

doi:10.1016/j.brainres.2013.12.018

Cited by 16 publications

(15 citation statements)

References 72 publications

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“…EAAT3 is another subtype of the XAG system, which has little effect on the uptake of Glu in synaptic cleft, but has a high affinity for extracellular Cys. Studies have shown that there was an obvious decrease of GSH level of neurons in EAAT3‐deficient mice, with a higher sensitivity to oxidants . Results of the present study showed that MeHg upregulated EAAT3 transcription level but downregulated the protein expression.…”

Section: Discussionsupporting

confidence: 57%

Oxidative stress accelerates synaptic glutamate dyshomeostasis and NMDARs disorder during methylmercury‐induced neuronal apoptosis in rat cerebral cortex

Yang

Liu

et al. 2020

Environmental Toxicology

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Methylmercury (MeHg) is a potent neurotoxin,which leads to a wide range of intracellular effects. The molecular mechanismsassociated to MeHg-induced neurotoxicity have not been fully understood.Oxidative stress, as well as synaptic glutamate (Glu) dyshomeostasis have beenidentified as two critical mechanisms during MeHg-mediated cytotoxicity. Here,we developed a rat model of MeHg poisoning to evaluate its neurotoxic effectsby focusing on cellular oxidative stress and synaptic Glu disruption.Inaddition, we investigated the neuroprotective role of alpha-lipoic acid (α-LA), a natural antioxidant, todeeply explore the underlying interaction between them. Fifty-six rats wererandomly divided into four groups: saline control, MeHg treatment (4 or 12μmol/kg MeHg), and α-LApre-treatment (35 μmol/kg α-LA+12μmol/kg MeHg). Rats exposed to 12 μmol/kg MeHg induced neuronal oxidativestress, with ROS accumulation and cellular antioxidant system impairment. Nrf2 andxCT pathways were activated with MeHg treatment. The enzymatic or non-enzymaticof cellular GSH synthesis were also disrupted by MeHg. On the other hand, the abnormalactivities of GS and PAG disturbed the "Glu-Gln cycle", leading to NMDARsover-activation, Ca2+ overload, and the calpain activation, which acceleratedNMDARs degradation. Meanwhile, the high expressions of phospho-p44/42 MAPK,phospho-p38 MAPK, phospho-CREB, and the high levels of caspase 3 and Bax/Bcl-2 finallyindicated the neuronal apoptosis after MeHg exposure. Pre-treatment with α-LA significantly preventedMeHg-induced neurotoxicity. In conclusion, the oxidative stress and syn-apticGlu dyshomeostasis contributed to MeHg-induced neuronal apoptosis. Alpha-LAattenuated these toxic effects through mechanisms of anti-oxidation andindirect Glu dyshomeostasis prevention K E Y W O R D S apoptosis, glutamate, methylmercury, NMDARs, oxidative stress

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Section: Discussionsupporting

confidence: 57%

Oxidative stress accelerates synaptic glutamate dyshomeostasis and NMDARs disorder during methylmercury‐induced neuronal apoptosis in rat cerebral cortex

Yang

Liu

et al. 2020

Environmental Toxicology

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“…In astrocytes, fibroblast growth factor 2 up‐regulates system x c − by a transcriptional mechanism, whereas IGF‐1 is ineffective (Liu et al . , ). Thus, some of the responses to growth factors might be cell type‐specific.…”

Section: New Insights Into the Regulation Of Xct Expression And Systementioning

confidence: 99%

Main path and byways: non‐vesicular glutamate release by system x_c⁻ as an important modifier of glutamatergic neurotransmission

Massie

Boillée

Hewett

et al. 2015

Journal of Neurochemistry

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System xc− is a cystine/glutamate antiporter that exchanges extracellular cystine for intracellular glutamate. Cystine is intracellularly reduced to cysteine, a building block of GSH. As such, system xc− can regulate the antioxidant capacity of cells. Moreover, in several brain regions, system xc− is the major source of extracellular glutamate. As such this antiporter is able to fulfill key physiological functions in the CNS, while evidence indicates it also plays a role in certain brain pathologies. Since the transcription of xCT, the specific subunit of system xc−, is enhanced by the presence of reactive oxygen species and inflammatory cytokines, system xc− could be involved in toxic extracellular glutamate release in neurological disorders that are associated with increased oxidative stress and neuroinflammation. System xc− has also been reported to contribute to the invasiveness of brain tumors and, as a source of extracellular glutamate, could participate in the induction of peritumoral seizures. Two independent reviews (Lewerenz et al. 2013, Bridges et al. 2012), approached from a different perspective, have recently been published on the functions of system xc− in the central nervous system. In this review, we highlight novel achievements and insights covering the regulation of system xc− as well as its involvement in emotional behavior, cognition, addiction, neurological disorders and glioblastomas, acquired in the past few years.

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“…Notably, FGF-2 activates the stress related transcription factor ATF4 in vascular smooth muscle cells [64] and osteoblasts [65]. FGF-2 upregulated GSH synthesis in glial [66] and Sertoli cells [67] and cystine/glutamate transport (system

x_{c^{-}}

) in astrocytes [68]. These results suggest that cystine transport activity may be upregulated in the presence of FGF-2 in stem cells or differentiating cells via FGF-2/ATF4 signaling, leading to improved survival and growth, however, to our knowledge this hypothesis remains to be investigated.…”

Section: Importance Of Redox Balance In Stem Cell Culturementioning

confidence: 99%

Redox status in mammalian cells and stem cells during culture in vitro: Critical roles of Nrf2 and cystine transporter activity in the maintenance of redox balance

2014

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Culturing cells and tissues in vitro has provided valuable insights into the molecular mechanisms regulating redox signaling in cells with implications for medicine. However, standard culture techniques maintain mammalian cells in vitro under an artificial physicochemical environment such as ambient air and 5% CO2. Oxidative stress is caused by the rapid oxidation of cysteine to cystine in culture media catalyzed by transition metals, leading to diminished intracellular cysteine and glutathione (GSH) pools. Some cells, such as fibroblasts and macrophages, express cystine transport activity, designated as system xc-, which enables cells to maintain these pools to counteract oxidative stress. Additionally, many cells have the ability to activate the redox sensitive transcription factor Nrf2, a master regulator of cellular defenses against oxidative stress, and to upregulate xCT, the subunit of the xc- transport system leading to increases in cellular GSH. In contrast, some cells, including lymphoid cells, embryonic stem cells and iPS cells, express relatively low levels of xCT and cannot maintain cellular cysteine and GSH pools. Thus, fibroblasts have been used as feeder cells for the latter cell types based on their ability to supply cysteine. Other key Nrf2 regulated gene products include heme oxygenase 1, peroxiredoxin 1 and sequestosome1. In macrophages, oxidized LDL activates Nrf2 and upregulates the scavenger receptor CD36 forming a positive feedback loop to facilitate removal of the oxidant from the vascular microenvironment. This review describes cell type specific responses to oxygen derived stress, and the key roles that activation of Nrf2 and membrane transport of cystine and cysteine play in the maintenance and proliferation of mammalian cells in culture.

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FGF-2 induces neuronal death through upregulation of system xc-

Cited by 16 publications

References 72 publications

Oxidative stress accelerates synaptic glutamate dyshomeostasis and NMDARs disorder during methylmercury‐induced neuronal apoptosis in rat cerebral cortex

Oxidative stress accelerates synaptic glutamate dyshomeostasis and NMDARs disorder during methylmercury‐induced neuronal apoptosis in rat cerebral cortex

Main path and byways: non‐vesicular glutamate release by system x_c⁻ as an important modifier of glutamatergic neurotransmission

Redox status in mammalian cells and stem cells during culture in vitro: Critical roles of Nrf2 and cystine transporter activity in the maintenance of redox balance

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FGF-2 induces neuronal death through upregulation of system xc-

Cited by 16 publications

References 72 publications

Oxidative stress accelerates synaptic glutamate dyshomeostasis and NMDARs disorder during methylmercury‐induced neuronal apoptosis in rat cerebral cortex

Oxidative stress accelerates synaptic glutamate dyshomeostasis and NMDARs disorder during methylmercury‐induced neuronal apoptosis in rat cerebral cortex

Main path and byways: non‐vesicular glutamate release by system xc− as an important modifier of glutamatergic neurotransmission

Redox status in mammalian cells and stem cells during culture in vitro: Critical roles of Nrf2 and cystine transporter activity in the maintenance of redox balance

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Main path and byways: non‐vesicular glutamate release by system x_c⁻ as an important modifier of glutamatergic neurotransmission