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Auteur : Grafiati
Publié le 11 mars 2023

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1

Rimaniol, Anne-Cécile, Patricia Mialocq, Pascal Clayette, Dominique Dormont et Gabriel Gras. « Role of glutamate transporters in the regulation of glutathione levels in human macrophages ». American Journal of Physiology-Cell Physiology 281, no 6 (1 décembre 2001) : C1964—C1970. http://dx.doi.org/10.1152/ajpcell.2001.281.6.c1964.

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Cysteine is the limiting precursor for glutathione synthesis. Because of its low bioavailability, cysteine is generally produced from cystine, which may be taken up through two different transporters. The cystine/glutamate antiporter (x[Formula: see text] system) transports extracellular cystine in exchange for intracellular glutamate. The XAG transport system takes up extracellular cystine, glutamate, and aspartate. Both are sensitive to competition between cystine and glutamate, and excess extracellular glutamate thus inhibits glutathione synthesis, a nonexcitotoxic mechanism for glutamate toxicity. We demonstrated previously that human macrophages express the glutamate transporters excitatory amino acid transporter (EAAT)1 and EAAT2 (which do not transport cystine, X[Formula: see text] system) and overcome competition for the use of cystine transporters. We now show that macrophages take up cystine through the x[Formula: see text] and not the XAG system. We also found that glutamate, although competing with cystine uptake, dose-dependently increases glutathione synthesis. We used inhibitors to demonstrate that this increase is mediated by EAATs. EAAT expression in macrophages thus leads to glutamate-dependent enhancement of glutathione synthesis by providing intracellular glutamate for direct insertion in glutathione and also for fueling the intracellular pool of glutamate and trans-stimulating the cystine/glutamate antiporter.
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2

Knickelbein, Roy G., Tamas Seres, Gregory Lam, Richard B. Johnston et Joseph B. Warshaw. « Characterization of multiple cysteine and cystine transporters in rat alveolar type II cells ». American Journal of Physiology-Lung Cellular and Molecular Physiology 273, no 6 (1 décembre 1997) : L1147—L1155. http://dx.doi.org/10.1152/ajplung.1997.273.6.l1147.

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Cysteine availability is rate limiting for the synthesis of glutathione, an important antioxidant in the lung. We used rat alveolar epithelial type II cells to study the mechanism of cysteine and cystine uptake. Consistent with carrier-mediated transport, each uptake process was saturable with Michaelis-Menten kinetics and was inhibited at 4°C and by micromolar levels of amino acids or analogs known to be substrates for a specific transporter. A unique system XAG was found that transports cysteine and cystine (as well as glutamate and aspartate, the only substrates previously described for system XAG). We also identified a second Na+-dependent cysteine transporter system, system ASC, and two Na+-independent transporter systems, system xc for cystine and system L for cysteine. In the presence of glutathione at levels measured in rat plasma and alveolar lining fluid, cystine was reduced to cysteine and was transported on systems ASC and XAG, doubling the transport rate. Cysteinylglycine, released from glutathione at the cell surface by γ-glutamyl transpeptidase, also stimulated uptake after reduction of cystine. These findings suggest that, under physiological conditions, cysteine and cystine transport is influenced by the extracellular redox state.
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3

Zhu, Jun, Sheng Li, Zermeena M. Marshall et A. R. Whorton. « A cystine-cysteine shuttle mediated by xCT facilitates cellular responses to S-nitrosoalbumin ». American Journal of Physiology-Cell Physiology 294, no 4 (avril 2008) : C1012—C1020. http://dx.doi.org/10.1152/ajpcell.00411.2007.

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We have shown previously that extracellular cysteine is necessary for cellular responses to S-nitrosoalbumin. In this study we have investigated mechanisms involved in accumulation of extracellular cysteine outside vascular smooth muscle cells and characterized the role of cystine-cysteine release in transfer of nitric oxide (NO)-bioactivity. Incubation of cells with cystine led to cystine uptake, reduction, and cysteine release. The process was inhibitable by extracellular glutamate, suggesting a role for system xc− amino acid transporters. Smooth muscle cells express this transporter constitutively and induction of the light chain component (xCT) by either diethyl maleate or 3-morpholino-sydnonimine (SIN-1) led to glutamate-inhibitable cystine uptake and an increased rate of cysteine release from cells. Likewise, overexpression of xCT in smooth muscle cells or endothelial cells led to glutamate-inhibitable cysteine release. The resulting extracellular cysteine was found to be required for transfer of NO from extracellular S-nitrosothiols into cells via system L transporters leading to formation of cellular S-nitrosothiols. Cysteine release coupled to cystine uptake was also found to be required for cellular responses to S-nitrosoalbumin and facilitated S-nitrosoalbumin-mediated inhibition of epidermal growth factor signaling. These data show that xCT expression can constitute a cystine-cysteine shuttle whereby cystine uptake drives cysteine release. Furthermore, we show that extracellular cysteine provided by this shuttle mechanism is necessary for transfer of NO equivalents and cellular responses to S-nitrosoablumin.
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4

Zhao, Jiye, Jiayi Lv, Yang Chen, Qile Dong et Hao Dong. « Recent progress of amino acid transporters as a novel antitumor target ». Open Chemistry 20, no 1 (1 janvier 2022) : 1212–28. http://dx.doi.org/10.1515/chem-2022-0239.

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Abstract Glutamine transporters transport different amino acids for cell growth and metabolism. In tumor cells, glutamine transporters are often highly expressed and play a crucial role in their growth. By inhibiting the amino acid transport of these transporters, the growth of cancer cells can be inhibited. In recent years, more and more attention has been paid to the study of glutamine transporter. In this article, the differences between the ASC system amino acid transporter 2 (ASCT2), L-type amino acid transporter 1 (LAT1), and the cystine–glutamate exchange (xCT) transporters research progress on the mechanism of action and corresponding small molecule inhibitors are summarized. This article introduces 62 related small molecule inhibitors of different transporters of ASCT2, LAT1, and xCT. These novel chemical structures provide ideas for the research and design of targeted inhibitors of glutamine transporters, as well as important references and clues for the design of new anti-tumor drugs.
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5

Almalki, Atiah H., Hashem O. Alsaab, Walaa F. Alsanie, Ahmed Gaber, Turki Alkhalifa, Ahmad Almalki, Omar Alzahrani et al. « Potential Benefits of N-Acetylcysteine in Preventing Pregabalin-Induced Seeking-Like Behavior ». Healthcare 9, no 4 (29 mars 2021) : 376. http://dx.doi.org/10.3390/healthcare9040376.

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Substance-use disorder is globally prevalent and responsible for numerous social and medical problems. Pregabalin (Lyrica), typically used to treat diabetic neuropathy, has recently emerged as a drug of abuse. Drug abuse is associated with several neuronal changes, including the downregulation of glutamate transporters such as glutamate transporter 1 and cystine/glutamate antiporter. We investigated the effects of N-acetylcysteine, a glutamate transporter 1 and xCT upregulator, on pregabalin addiction using a conditioned place preference paradigm. Pregabalin (60 mg/kg) was found to induce conditioned place preference when compared to a vehicle. A 100 mg/kg dose of N-acetylcysteine was found to block pregabalin-seeking behaviors. These results support previous findings showing that glutamate transporters play an important role in pregabalin-induced seeking behaviors. N-acetylcysteine may represent a beneficial agent in preventing the abuse potential of pregabalin.
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6

Shim, Myoung Sup, Jin Young Kim, Kwang Hee Lee, Hee Kyoung Jung, Bradley A. Carlson, Xue-Ming Xu, Dolph L. Hatfield et Byeong Jae Lee. « l(2)01810 is a novel type of glutamate transporter that is responsible for megamitochondrial formation ». Biochemical Journal 439, no 2 (28 septembre 2011) : 277–86. http://dx.doi.org/10.1042/bj20110582.

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l(2)01810 causes glutamine-dependent megamitochondrial formation when it is overexpressed in Drosophila cells. In the present study, we elucidated the function of l(2)01810 during megamitochondrial formation. The overexpression of l(2)01810 and the inhibition of glutamine synthesis showed that l(2)01810 is involved in the accumulation of glutamate. l(2)01810 was predicted to contain transmembrane domains and was found to be localized to the plasma membrane. By using 14C-labelled glutamate, l(2)01810 was confirmed to uptake glutamate into Drosophila cells with high affinity (Km=69.4 μM). Also, l(2)01810 uptakes glutamate in a Na+-independent manner. Interestingly, however, this uptake was not inhibited by cystine, which is a competitive inhibitor of Na+-independent glutamate transporters, but by aspartate. A signal peptide consisting of 34 amino acid residues targeting to endoplasmic reticulum was predicted at the N-terminus of l(2)01810 and this signal peptide is essential for the protein's localization to the plasma membrane. In addition, l(2)01810 has a conserved functional domain of a vesicular-type glutamate transporter, and Arg146 in this domain was found to play a key role in glutamate transport and megamitochondrial formation. These results indicate that l(2)01810 is a novel type of glutamate transporter and that glutamate uptake is a rate-limiting step for megamitochondrial formation.
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7

Borisova, Tatiana. « Permanent dynamic transporter-mediated turnover of glutamate across the plasma membrane of presynaptic nerve terminals : arguments in favor and against ». Reviews in the Neurosciences 27, no 1 (1 janvier 2016) : 71–81. http://dx.doi.org/10.1515/revneuro-2015-0023.

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AbstractMechanisms for maintenance of the extracellular level of glutamate in brain tissue and its regulation still remain almost unclear, and criticism of the current paradigm of glutamate transport and homeostasis has recently appeared. The main premise for this study is the existence of a definite and non-negligible concentration of ambient glutamate between the episodes of exocytotic release in our experiments with rat brain nerve terminals (synaptosomes), despite the existence of a very potent Na+-dependent glutamate uptake. Glutamate transporter reversal is considered as the main mechanisms of glutamate release under special conditions of energy deprivation, hypoxia, hypoglycemia, brain trauma, and stroke, underlying an increase in the ambient glutamate concentration and development of excitotoxicity. In the present study, a new vision on transporter-mediated release of glutamate as one of the main mechanisms involved in the maintenance of definite concentration of ambient glutamate under normal energetical status of nerve terminals is forwarded. It has been suggested that glutamate transporters act effectively in outward direction in a non-pathological manner, and this process is thermodynamically synchronized with uptake and provides effective outward glutamate current, thereby establishing and maintaining permanent and dynamic glutamatein/glutamateout gradient and turnover across the plasma membrane. In this context, non-transporter tonic glutamate release by diffusion, spontaneous exocytosis, cystine-glutamate exchanger, and leakage through anion channels can be considered as a permanently added ‘new’ exogenous substrate using two-substrate kinetic model calculations. Permanent glutamate turnover is of value for tonic activation of post/presynaptic glutamate receptors, long-term potentiation, memory formation, etc. Counterarguments against this mechanism are also considered.
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8

Han, Derick, Chandan K. Sen, Sashwati Roy, Michael S. Kobayashi, Hans J. Tritschler et Lester Packer. « Protection against glutamate-induced cytotoxicity in C6 glial cells by thiol antioxidants ». American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 273, no 5 (1 novembre 1997) : R1771—R1778. http://dx.doi.org/10.1152/ajpregu.1997.273.5.r1771.

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In many cell lines, glutamate cytotoxicity is known to be mediated by an inhibition of cystine transport. Because glutamate and cystine share the same transporter, elevated levels of extracellular glutamate competitively inhibit cystine transport leading to depletion of intracellular glutathione. A glutathione-depleted state impairs cellular antioxidant defenses resulting in oxidative stress. It was therefore of interest to investigate whether proglutathione agents, e.g., N-acetylcysteine and lipoic acid, are able to protect against glutamate cytotoxicity. Both lipoic acid (100 μM-1 mM) and N-acetylcysteine (100 μM-1 mM) completely protected C6 cells from the glutamate-induced cell death. Both agents facilitate extracellular supply of cysteine, the reduced form of cystine, that is transported into the cell by a glutamate-insensitive transport mechanism. Protection by lipoic acid and N-acetylcysteine corresponded with a sparing effect on cellular glutathione, which is usually depleted after glutamate treatment. In the presence ofl-buthionine-( S, R)-sulfoximine, a γ-glutamylcysteine synthetase inhibitor, low doses (<100 μM) of lipoic acid and N-acetylcysteine did not protect cells against glutamate-induced cytotoxicity. At higher concentrations (>500 μM), however, both lipoic acid and N-acetylcysteine provided partial protection against glutamate cytotoxicity even in glutathione synthesis-arrested cells. These results indicate that at low concentrations the primary mechanism of protection by the thiol antioxidants was mediated by their proglutathione property rather than direct scavenging of reactive oxygen. At higher concentrations (>500 μM), a GSH-independent direct antioxidant effect of lipoic acid and N-acetylcysteine was observed. Dichlorofluorescin fluorescence, a measure of intracellular peroxides, increased sixfold after glutamate treatment of C6 cells. Lipoic acid and N-acetylcysteine treatment significantly lowered glutamate-induced dichlorofluorescin fluorescence compared with that of controls. Interestingly, α-tocopherol (50 μM) also suppressed glutamate-induced dichlorofluorescin fluorescence, indicating the peroxides detected by dichlorofluorescin were likely lipid hydroperoxides. Both thiol antioxidants, particularly lipoic acid, appear to have remarkable therapeutic potential in protecting against neurological injuries involving glutamate and oxidative stress.
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9

Ewadh, M. J. A., N. Tudball et F. A. Rose. « Transport of L-cystine in human umbilical vein endothelial cells in culture ». Bioscience Reports 8, no 5 (1 octobre 1988) : 449–53. http://dx.doi.org/10.1007/bf01121643.

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The uptake of L-cystine into cultured human umbilical vein endothelial cells has been shown to occur by a Na+-independent system which is inhibited by L-glutamate and L-homocysteine, but not by other amino acids. It is likely that the system transporting L-cystine is shared by L-glutamate. Thiol groups associated with membrane bound components appear to be essential for L-cystine uptake but it is not yet evident whether these constitute an integral part of the transporter per se.
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10

Sato, Hideyo, Ayako Shiiya, Mayumi Kimata, Kanako Maebara, Michiko Tamba, Yuki Sakakura, Nobuo Makino et al. « Redox Imbalance in Cystine/Glutamate Transporter-deficient Mice ». Journal of Biological Chemistry 280, no 45 (6 septembre 2005) : 37423–29. http://dx.doi.org/10.1074/jbc.m506439200.

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11

Nagamori, Shushi, Pattama Wiriyasermkul, Meritxell Espino Guarch, Hirohisa Okuyama, Saya Nakagomi, Kenjiro Tadagaki, Yumiko Nishinaka et al. « Novel cystine transporter in renal proximal tubule identified as a missing partner of cystinuria-related plasma membrane protein rBAT/SLC3A1 ». Proceedings of the National Academy of Sciences 113, no 3 (6 janvier 2016) : 775–80. http://dx.doi.org/10.1073/pnas.1519959113.

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Heterodimeric amino acid transporters play crucial roles in epithelial transport, as well as in cellular nutrition. Among them, the heterodimer of a membrane protein b0,+AT/SLC7A9 and its auxiliary subunit rBAT/SLC3A1 is responsible for cystine reabsorption in renal proximal tubules. The mutations in either subunit cause cystinuria, an inherited amino aciduria with impaired renal reabsorption of cystine and dibasic amino acids. However, an unsolved paradox is that rBAT is highly expressed in the S3 segment, the late proximal tubules, whereas b0,+AT expression is highest in the S1 segment, the early proximal tubules, so that the presence of an unknown partner of rBAT in the S3 segment has been proposed. In this study, by means of coimmunoprecipitation followed by mass spectrometry, we have found that a membrane protein AGT1/SLC7A13 is the second partner of rBAT. AGT1 is localized in the apical membrane of the S3 segment, where it forms a heterodimer with rBAT. Depletion of rBAT in mice eliminates the expression of AGT1 in the renal apical membrane. We have reconstituted the purified AGT1-rBAT heterodimer into proteoliposomes and showed that AGT1 transports cystine, aspartate, and glutamate. In the apical membrane of the S3 segment, AGT1 is suggested to locate itself in close proximity to sodium-dependent acidic amino acid transporter EAAC1 for efficient functional coupling. EAAC1 is proposed to take up aspartate and glutamate released into luminal fluid by AGT1 due to its countertransport so that preventing the urinary loss of aspartate and glutamate. Taken all together, AGT1 is the long-postulated second cystine transporter in the S3 segment of proximal tubules and a possible candidate to be involved in isolated cystinuria.
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Yamaguchi, Itsuki, Shige H. Yoshimura et Hironori Katoh. « High cell density increases glioblastoma cell viability under glucose deprivation via degradation of the cystine/glutamate transporter xCT (SLC7A11) ». Journal of Biological Chemistry 295, no 20 (7 avril 2020) : 6936–45. http://dx.doi.org/10.1074/jbc.ra119.012213.

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The cystine/glutamate transporter system xc− consists of the light-chain subunit xCT (SLC7A11) and the heavy-chain subunit CD98 (4F2hc or SLC3A2) and exchanges extracellular cystine for intracellular glutamate at the plasma membrane. The imported cystine is reduced to cysteine and used for synthesis of GSH, one of the most important antioxidants in cancer cells. Because cancer cells have increased levels of reactive oxygen species, xCT, responsible for cystine–glutamate exchange, is overexpressed in many cancers, including glioblastoma. However, under glucose-limited conditions, xCT overexpression induces reactive oxygen species accumulation and cell death. Here we report that cell survival under glucose deprivation depends on cell density. We found that high cell density (HD) down-regulates xCT levels and increases cell viability under glucose deprivation. We also found that growth of glioblastoma cells at HD inactivates mTOR and that treatment of cells grown at low density with the mTOR inhibitor Torin 1 down-regulates xCT and inhibits glucose deprivation-induced cell death. The lysosome inhibitor bafilomycin A1 suppressed xCT down-regulation in HD-cultured glioblastoma cells and in Torin 1–treated cells grown at low density. Additionally, bafilomycin A1 exposure or ectopic xCT expression restored glucose deprivation–induced cell death at HD. These results suggest that HD inactivates mTOR and promotes lysosomal degradation of xCT, leading to improved glioblastoma cell viability under glucose-limited conditions. Our findings provide evidence that control of xCT protein expression via lysosomal degradation is an important mechanism for metabolic adaptation in glioblastoma cells.
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Kobayashi, Sho, Mami Sato, Takayuki Kasakoshi, Takumi Tsutsui, Masahiro Sugimoto, Mitsuhiko Osaki, Futoshi Okada et al. « Cystathionine Is a Novel Substrate of Cystine/Glutamate Transporter ». Journal of Biological Chemistry 290, no 14 (20 février 2015) : 8778–88. http://dx.doi.org/10.1074/jbc.m114.625053.

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Huang, Ying, Zunyan Dai, Catalin Barbacioru et Wolfgang Sadée. « Cystine-Glutamate Transporter SLC7A11 in Cancer Chemosensitivity and Chemoresistance ». Cancer Research 65, no 16 (15 août 2005) : 7446–54. http://dx.doi.org/10.1158/0008-5472.can-04-4267.

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Sakakura, Yuki, Hideyo Sato, Ayako Shiiya, Michiko Tamba, Jun-ichi Sagara, Manabu Matsuda, Naomichi Okamura, Nobuo Makino et Shiro Bannai. « Expression and function of cystine/glutamate transporter in neutrophils ». Journal of Leukocyte Biology 81, no 4 (2 janvier 2007) : 974–82. http://dx.doi.org/10.1189/jlb.0606385.

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Takizawa, Kohei, Koji Muramatsu, Kouji Maruyama, Kenichi Urakami, Takashi Sugino, Masatoshi Kusuhara, Ken Yamaguchi, Hiroyuki Ono et Yuko Kitagawa. « Metabolic Profiling of Human Gastric Cancer Cells Treated With Salazosulfapyridine ». Technology in Cancer Research & ; Treatment 19 (1 janvier 2020) : 153303382092862. http://dx.doi.org/10.1177/1533033820928621.

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Purpose: The adhesion molecule cluster of differentiation 44v9 interacts with and stabilizes the cystine/glutamate exchanger protein, which functions as a transporter of cystine. Stabilized cystine/glutamate exchanger increases extracellular cystine uptake and enhances glutathione production. Augmented levels of reduced glutathione mitigate reactive oxygen species and protect cancer cells from apoptosis. Salazosulfapyridine blocks cystine/glutamate exchanger activity and mitigates the supply of cystine to increase intracellular ROS production, thereby increasing cell susceptibility to apoptosis. This enhances the effect of anticancer drugs such as cisplatin. Currently, salazosulfapyridine is being developed as a promising anticancer agent. In the present study, we elucidated the molecular mechanism associated with salazosulfapyridine by investigating the salazosulfapyridine-induced changes in glutathione metabolism in cultured gastric cancer cell lines. Methods: The effect of salazosulfapyridine treatment on glutathione metabolism was investigated in 4 gastric cancer (AGS, MKN1, MKN45, and MKN74) and 2 colorectal cancer (HCT15 and HCT116) cell lines using metabolomic analyses. In addition, the effect of inhibition of the reduced form of nicotinamide adenine dinucleotide phosphate by 2-deoxyglucose on glutathione metabolism was evaluated. Results: Under hypoxia, enhanced glycolysis resulted in lactate accumulation with an associated reduction in nicotinamide adenine dinucleotide phosphate. Salazosulfapyridine treatment decreased the cysteine content and inhibited the formation of glutathione. Combined treatment with salazosulfapyridine and 2-deoxyglucose significantly inhibited cell proliferation. 2-Deoxyglucose, an inhibitor of glycolysis, depleted nicotinamide adenine dinucleotide phosphate required for the formation of glutathione. Conclusions: Our results indicate that in cancer cells having a predominant glycolytic pathway, metabolomic analyses under hypoxic conditions enable the profiling of global metabolism. In addition, inhibiting the supply of nicotinamide adenine dinucleotide phosphate by blocking glycolysis is a potential treatment strategy for cancer, in addition to cystine blockade by salazosulfapyridine.
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Beury, Daniel, Phillip Fitzgerald et Suzanne Ostrand-Rosenberg. « Blockade of cystine transport inhibits glutathione synthesis and survival of inflammation-induced myeloid-derived suppressor cells (66.6) ». Journal of Immunology 186, no 1_Supplement (1 avril 2011) : 66.6. http://dx.doi.org/10.4049/jimmunol.186.supp.66.6.

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Abstract Tumor-induced myeloid derived suppressor cells (MDSC) are responsible for immune suppression in tumor bearing individuals and are a major obstacle to effective immunotherapy. MDSC suppress T cell activation through several mechanisms including their production of reactive oxygen species (ROS). MDSC accumulation, suppressive activity, and ROS production are enhanced by inflammation. However, MDSC production of ROS does not negatively impact MDSC themselves. Since MDSC sequester cystine/cysteine from their local environment, and cysteine is the rate limiting reagent for glutathione (GSH), which is the predominant antioxidant, we hypothesized that inflammation-induced MDSC utilize high GSH production to attenuate ROS-mediated damage. This hypothesis is supported by our data showing that inflammation-induced MDSC upregulate the subunits of the xc- (cystine/glutamate) transporter, resulting in greater uptake of cystine and higher GSH synthesis. Since MDSC only generate cysteine via the uptake of cystine, the xc- inhibitor sulfasalazine (SASP) may decrease MDSC survival and suppressive activity. This concept is supported by our findings that MDSC treated with SASP are depleted of GSH and are less viable and that inflammation further enhances these effects. Because of their ability to reduce MDSC survival and block MDSC-mediated suppression, xc- inhibitors are potential supplements to cancer immunotherapies.
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Du, Jie, Xiao-Hui Li, Wang Zhang, Yong-Mei Yang, Yue-Han Wu, Wen-Qun Li, Jun Peng et Yuan-Jian Li. « Involvement of glutamate–cystine/glutamate transporter system in aspirin-induced acute gastric mucosa injury ». Biochemical and Biophysical Research Communications 450, no 1 (juillet 2014) : 135–41. http://dx.doi.org/10.1016/j.bbrc.2014.05.069.

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Phelps, D. T., S. M. Deneke, D. F. Baxter et B. L. Fanburg. « Erythrocytes fail to induce glutathione in response to diethyl maleate or hyperoxia ». American Journal of Physiology-Lung Cellular and Molecular Physiology 257, no 4 (1 octobre 1989) : L272—L276. http://dx.doi.org/10.1152/ajplung.1989.257.4.l272.

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We have previously found that exposure of pulmonary artery endothelial cells to hyperoxia or low concentrations of diethyl maleate (DEM) results in elevation of both cellular glutathione (GSH) and uptakes of glutamate and cystine. The present study confirms that this elevation occurs for a variety of lung cells (bovine pulmonary artery endothelial and smooth muscle cells and rat lung fibroblast and epithelial-like cells) but not for human, rat, and chicken erythrocytes. In fact, human and rat erythrocyte GSH levels were reduced substantially at DEM concentrations from 0.05 to 0.5 mM, whereas the GSH level of chicken erythrocytes was almost totally eliminated by 0.05 mM DEM. Also, all erythrocytes failed to accumulate measurable amounts of radioactive glutamate or cystine. The findings suggest the presence of different mechanisms for the regulation of cellular GSH in lung cells from those of erythrocytes. They are consistent with a requirement for a cystine-glutamate transporter and transcriptional and translational events for the elevation of cellular GSH in response to hyperoxia or low levels of DEM in the lung cells.
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Sato, Hideyo, Shinobu Nomura, Kanako Maebara, Kanako Sato, Michiko Tamba et Shiro Bannai. « Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation ». Biochemical and Biophysical Research Communications 325, no 1 (décembre 2004) : 109–16. http://dx.doi.org/10.1016/j.bbrc.2004.10.009.

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Kim, Hee-Hoon, Sung Eun Choi et Won-Il Jeong. « Oxidative stress and glutamate excretion in alcoholic steatosis : Metabolic synapse between hepatocyte and stellate cell ». Clinical and Molecular Hepatology 26, no 4 (1 octobre 2020) : 697–704. http://dx.doi.org/10.3350/cmh.2020.0152.

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Chronic alcohol consumption induces the development of alcoholic steatosis in the liver, which is one of the most widespread liver diseases worldwide. During general alcohol metabolism, hepatocytes generate mitochondria- and cytochrome P450 2E1 (CYP2E1)-mediated reactive oxygen species (ROS) whose accumulation elicits activation of the hepatic anti-oxidant system, including glutathione (GSH). However, chronic alcohol consumption decreases GSH generation through cysteine deficiency by suppressing the methionine cycle and trans-sulfuration system, whereas it turns on an alternative defense pathway, such as the xCT transporter, to compensate for GSH shortage. The xCT transporter mediates the uptake of cystine coupled to the efflux of glutamate, leading to an increase in blood glutamate. In response to the elevated glutamate in the liver, the expression of metabotropic glutamate receptor 5 (mGluR5) is up-regulated in hepatic stellate cells (HSCs) along with enhanced production of 2-arachidonoylglycerol, which in turn stimulates cannabinoid receptor 1 (CB1R) on neighboring hepatocytes to increase de novo lipogenesis. On the other hand, blockade of mGluR5 and CB1R attenuates alcoholic steatosis. Interestingly, although the increased expression of CYP2E1-mediated xCT and ROS generation are mainly observed at the perivenous area (zone 3), fat accumulation is mostly detected at hepatic zone 2. To resolve this discrepancy, this review summarizes recent advances on glutamate/mGluR5-derived alcoholic steatosis and zone-dependently different responses to alcohol intake. In addition, the bidirectional loop pathway and its unique metabolic synapse between hepatocytes and HSCs are discussed.
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Asanuma, Masato, et Ikuko Miyazaki. « Glutathione and Related Molecules in Parkinsonism ». International Journal of Molecular Sciences 22, no 16 (13 août 2021) : 8689. http://dx.doi.org/10.3390/ijms22168689.

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Glutathione (GSH) is the most abundant intrinsic antioxidant in the central nervous system, and its substrate cysteine readily becomes the oxidized dimeric cystine. Since neurons lack a cystine transport system, neuronal GSH synthesis depends on cystine uptake via the cystine/glutamate exchange transporter (xCT), GSH synthesis, and release in/from surrounding astrocytes. Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), a detoxifying master transcription factor, is expressed mainly in astrocytes and activates the gene expression of various phase II drug-metabolizing enzymes or antioxidants including GSH-related molecules and metallothionein by binding to the antioxidant response element (ARE) of these genes. Accumulating evidence has shown the involvement of dysfunction of antioxidative molecules including GSH and its related molecules in the pathogenesis of Parkinson’s disease (PD) or parkinsonian models. Furthermore, we found several agents targeting GSH synthesis in the astrocytes that protect nigrostriatal dopaminergic neuronal loss in PD models. In this article, the neuroprotective effects of supplementation and enhancement of GSH and its related molecules in PD pathology are reviewed, along with introducing new experimental findings, especially targeting of the xCT-GSH synthetic system and Nrf2–ARE pathway in astrocytes.
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Hammad, Alaa M., et Youssef Sari. « Effects of Cocaine Exposure on Astrocytic Glutamate Transporters and Relapse-Like Ethanol-Drinking Behavior in Male Alcohol-Preferring Rats ». Alcohol and Alcoholism 55, no 3 (24 février 2020) : 254–63. http://dx.doi.org/10.1093/alcalc/agaa010.

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Abstract Aim Glutamate has been considered as neurotransmitter that is critical in triggering relapse to drugs of abuse, including ethanol and cocaine. Extracellular glutamate concentrations are tightly regulated by several mechanisms, including reuptake through glutamate transporters. Glutamate transporter type 1 (GLT-1) is responsible for clearing the majority of extracellular glutamate. The astrocytic cystine/glutamate antiporter (xCT) regulates also glutamate homeostasis. In this study, we investigated the effects of cocaine exposure and ampicillin/sulbactam (AMP/SUL), a β-lactam antibiotic known to upregulate GLT-1 and xCT, on relapse-like ethanol intake and the expression of astrocytic glutamate transporters in mesocorticolimbic brain regions. Methods Male alcohol-preferring (P) rats had free access to ethanol for 5 weeks. On Week 6, rats were exposed to either cocaine (20 mg/kg, i.p.) or saline for 12 consecutive days. Ethanol bottles were then removed for 7 days; during the last 5 days, either AMP/SUL (100 or 200 mg/kg, i.p.) or saline was administered to the P rats. Ethanol bottles were reintroduced, and ethanol intake was measured for 4 days. Results Cocaine exposure induced an alcohol deprivation effect (ADE), which was associated in part by a decrease in the expression of GLT-1 and xCT in the nucleus accumbens (NAc) core. AMP/SUL (100 mg/kg, i.p.) attenuated the ADE, while AMP/SUL (200 mg/kg, i.p.) reduced ethanol intake during 4 days of ethanol re-exposure and upregulated GLT-1 and xCT expression in the NAc core, NAc shell and dorsomedial prefrontal cortex (dmPFC). Conclusion This study suggests that these astrocytic glutamate transporters might be considered as potential targets for the treatment of polysubstance abuse.
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Taguchi, Kumiko, Michiko Tamba, Shiro Bannai et Hideyo Sato. « Induction of cystine/glutamate transporter in bacterial lipopolysaccharide induced endotoxemia in mice ». Journal of Inflammation 4, no 1 (2007) : 20. http://dx.doi.org/10.1186/1476-9255-4-20.

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Kobayashi⁎, S., Y. Sambe, T. Tsutsui, S. Bannai et H. Sato. « Role of cystine/glutamate transporter, system xc-, on NO release from macrophages ». Free Radical Biology and Medicine 53 (septembre 2012) : S184—S185. http://dx.doi.org/10.1016/j.freeradbiomed.2012.08.388.

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Sato, Hideyo, Michiko Tamba, Suzuka Okuno, Kanako Sato, Kazuko Keino-Masu, Masayuki Masu et Shiro Bannai. « Distribution of Cystine/Glutamate Exchange Transporter, System xc−, in the Mouse Brain ». Journal of Neuroscience 22, no 18 (15 septembre 2002) : 8028–33. http://dx.doi.org/10.1523/jneurosci.22-18-08028.2002.

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Joly, James H., Alireza Delfarah, Philip S. Phung, Sydney Parrish et Nicholas A. Graham. « A synthetic lethal drug combination mimics glucose deprivation–induced cancer cell death in the presence of glucose ». Journal of Biological Chemistry 295, no 5 (30 décembre 2019) : 1350–65. http://dx.doi.org/10.1074/jbc.ra119.011471.

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Metabolic reprogramming in cancer cells can increase their dependence on metabolic substrates such as glucose. As such, the vulnerability of cancer cells to glucose deprivation creates an attractive opportunity for therapeutic intervention. Because it is not possible to starve tumors of glucose in vivo, here we sought to identify the mechanisms in glucose deprivation–induced cancer cell death and then designed inhibitor combinations to mimic glucose deprivation–induced cell death. Using metabolomic profiling, we found that cells undergoing glucose deprivation–induced cell death exhibited dramatic accumulation of intracellular l-cysteine and its oxidized dimer, l-cystine, and depletion of the antioxidant GSH. Building on this observation, we show that glucose deprivation–induced cell death is driven not by the lack of glucose, but rather by l-cystine import. Following glucose deprivation, the import of l-cystine and its subsequent reduction to l-cysteine depleted both NADPH and GSH pools, thereby allowing toxic accumulation of reactive oxygen species. Consistent with this model, we found that the glutamate/cystine antiporter (xCT) is required for increased sensitivity to glucose deprivation. We searched for glycolytic enzymes whose expression is essential for the survival of cancer cells with high xCT expression and identified glucose transporter type 1 (GLUT1). Testing a drug combination that co-targeted GLUT1 and GSH synthesis, we found that this combination induces synthetic lethal cell death in high xCT-expressing cell lines susceptible to glucose deprivation. These results indicate that co-targeting GLUT1 and GSH synthesis may offer a potential therapeutic approach for targeting tumors dependent on glucose for survival.
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Sasaki, Hiromi, Hideyo Sato, Kazumi Kuriyama-Matsumura, Kanako Sato, Kanako Maebara, Hongyu Wang, Michiko Tamba, Ken Itoh, Masayuki Yamamoto et Shiro Bannai. « Electrophile Response Element-mediated Induction of the Cystine/Glutamate Exchange Transporter Gene Expression ». Journal of Biological Chemistry 277, no 47 (13 septembre 2002) : 44765–71. http://dx.doi.org/10.1074/jbc.m208704200.

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Lu, Lin, Bruce T. Hope et Yavin Shaham. « The cystine–glutamate transporter in the accumbens : a novel role in cocaine relapse ». Trends in Neurosciences 27, no 2 (février 2004) : 74–76. http://dx.doi.org/10.1016/j.tins.2003.11.007.

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Lim, J., G. Leprivier et P. Sorensen. « Oncogenic KRAS signalling supports tumorigenicity through induction of the cystine/glutamate transporter, xCT ». European Journal of Cancer 69 (décembre 2016) : S141. http://dx.doi.org/10.1016/s0959-8049(16)33020-9.

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Tsujita, T., V. Peirce, L. Baird, Y. Matsuyama, M. Takaku, S. V. Walsh, J. L. Griffin, A. Uruno, M. Yamamoto et J. D. Hayes. « Transcription Factor Nrf1 Negatively Regulates the Cystine/Glutamate Transporter and Lipid-Metabolizing Enzymes ». Molecular and Cellular Biology 34, no 20 (4 août 2014) : 3800–3816. http://dx.doi.org/10.1128/mcb.00110-14.

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Watson, Walter H., Tom J. Burke, Igor N. Zelko, Edilson Torres-González, Jeffrey D. Ritzenthaler et Jesse Roman. « Differential Regulation of the Extracellular Cysteine/Cystine Redox State (EhCySS) by Lung Fibroblasts from Young and Old Mice ». Oxidative Medicine and Cellular Longevity 2016 (2016) : 1–11. http://dx.doi.org/10.1155/2016/1561305.

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Aging is associated with progressive oxidation of plasma cysteine (Cys)/cystine (CySS) redox state, expressed asEhCySS. Cultured cells condition their media to reproduce physiologicalEhCySS, but it is unknown whether aged cells produce a more oxidized extracellular environment reflective of that seen in vivo. In the current study, we isolated primary lung fibroblasts from young and old female mice and measured the mediaEhCySSbefore and after challenge with Cys or CySS. We also measured expression of genes related to redox regulation and fibroblast function. These studies revealed that old fibroblasts produced a more oxidizing extracellularEhCySSthan young fibroblasts and that old fibroblasts had a decreased capacity to recover from an oxidative challenge due to a slower rate of reduction of CySS to Cys. These defects were associated with 10-fold lower expression of the Slc7a11 subunit of the xCT cystine-glutamate transporter. Extracellular superoxide dismutase (Sod3) was the only antioxidant or thiol-disulfide regulating enzyme among 36 examined that was downregulated in old fibroblasts by more than 2-fold, but there were numerous changes in extracellular matrix components. Thus, aging fibroblasts not only contribute to remodeling of the extracellular matrix but also have a profound effect on the extracellular redox environment.
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Kim, Ju Young, Yoshikatsu Kanai, Arthit Chairoungdua, Seok Ho Cha, Hirotaka Matsuo, Do Kyung Kim, Jun Inatomi, Hiroki Sawa, Yoshiteru Ida et Hitoshi Endou. « Human cystine/glutamate transporter : cDNA cloning and upregulation by oxidative stress in glioma cells ». Biochimica et Biophysica Acta (BBA) - Biomembranes 1512, no 2 (juin 2001) : 335–44. http://dx.doi.org/10.1016/s0005-2736(01)00338-8.

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D’Elia, Michele, Julie Patenaude, Charles Dupras et Jacques Bernier. « Burn injury induces the expression of cystine/glutamate transporter (xc−) in mouse T cells ». Immunology Letters 125, no 2 (août 2009) : 137–44. http://dx.doi.org/10.1016/j.imlet.2009.06.011.

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Huang, T. J., D. Li, Y. Li, S. P. Kar, S. Krishnan, J. L. Abbruzzese, R. A. Wolff et M. M. Javle. « Study of genotypic variations and protein expression of the xCT subunit of cystine/glutamate transporter in pancreatic cancer. » Journal of Clinical Oncology 29, no 4_suppl (1 février 2011) : 210. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.210.

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210 Background: The plasma membrane xCT cystine-specific subunit of the cystine/glutamate transporter contributes to chemotherapy resistance in pancreatic cancer by regulating intracellular glutathione levels and protecting cancer cells against oxidative stress. We previously noted that the rs7674870 single nucleotide polymorphism (SNP) of xCT correlated with overall survival in pancreatic cancer and may be predictive of platinum resistance. There are no data regarding xCT protein expression in pancreatic cancer or the functional significance of this SNP. Methods: Paraffin-embedded core and surgical biopsy tumor specimens from 49 patients with metastatic pancreatic adenocarcinoma were analyzed by immunohistochemistry (IHC) using an xCT specific antibody (Novus Biologicals). xCT protein IHC expression scores (product of intensity and percentage of staining cells) were analyzed in relation to overall survival and genotype of the patients using the one factor ANOVA test, Kaplan-Meier plot, log-rank test, and Cox regression analysis. Overall survival was measured from the date of diagnosis to the date of death or last follow-up. Results: Positive xCT expression was detected in 38 (78%) of the 49 samples, and 9 (18%) patients had high levels of expression. High xCT expression was associated with lower overall survival as compared with low expression (5.1 months versus 8.8 months; p = 0.119). In a multivariate Cox regression model with adjustment for prognostic parameters of age, sex, performance status and CA19-9 level, high xCT expression was associated with a 2.1-fold increased risk of death (p = 0.096). Performance status also correlated with overall survival (p = 0.027). Preliminary analysis on the genotype-phenotype association (n = 12) indicated that xCT expression was higher with the TT genotype than the TC/CC genotype (p = 0.115), which is consistent with the previous observation that the TT genotype was associated with reduced survival. Conclusions: These data provide supporting evidence for a possible role of cystine/glutamate transporter xCT subunit in pancreatic cancer progression and survival. Further pharmacogenomic and clinicopathologic studies are ongoing. No significant financial relationships to disclose.
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Hu, Rebecca G., Julie Lim, Paul J. Donaldson et Michael Kalloniatis. « Characterization of the cystine/glutamate transporter in the outer plexiform layer of the vertebrate retina ». European Journal of Neuroscience 28, no 8 (octobre 2008) : 1491–502. http://dx.doi.org/10.1111/j.1460-9568.2008.06435.x.

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Wang, Hongyu, Michiko Tamba, Mayumi Kimata, Kazuichi Sakamoto, Shiro Bannai et Hideyo Sato. « Expression of the activity of cystine/glutamate exchange transporter, system xc−, by xCT and rBAT ». Biochemical and Biophysical Research Communications 305, no 3 (juin 2003) : 611–18. http://dx.doi.org/10.1016/s0006-291x(03)00808-8.

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Liu, Ruqing, Paul E. Blower, Anh-Nhan Pham, Jialong Fang, Zunyan Dai, Carolyn Wise, Bridgette Green et al. « Cystine-Glutamate Transporter SLC7A11 Mediates Resistance to Geldanamycin but Not to 17-(Allylamino)-17-demethoxygeldanamycin ». Molecular Pharmacology 72, no 6 (17 septembre 2007) : 1637–46. http://dx.doi.org/10.1124/mol.107.039644.

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Lu, Haiquan, Debangshu Samanta, Lisha Xiang, Huimin Zhang, Hongxia Hu, Ivan Chen, John W. Bullen et Gregg L. Semenza. « Chemotherapy triggers HIF-1–dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype ». Proceedings of the National Academy of Sciences 112, no 33 (30 juillet 2015) : E4600—E4609. http://dx.doi.org/10.1073/pnas.1513433112.

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Triple negative breast cancer (TNBC) accounts for 10–15% of all breast cancer but is responsible for a disproportionate share of morbidity and mortality because of its aggressive characteristics and lack of targeted therapies. Chemotherapy induces enrichment of breast cancer stem cells (BCSCs), which are responsible for tumor recurrence and metastasis. Here, we demonstrate that chemotherapy induces the expression of the cystine transporter xCT and the regulatory subunit of glutamate-cysteine ligase (GCLM) in a hypoxia-inducible factor (HIF)-1–dependent manner, leading to increased intracellular glutathione levels, which inhibit mitogen-activated protein kinase kinase (MEK) activity through copper chelation. Loss of MEK-ERK signaling causes FoxO3 nuclear translocation and transcriptional activation of the gene encoding the pluripotency factor Nanog, which is required for enrichment of BCSCs. Inhibition of xCT, GCLM, FoxO3, or Nanog blocks chemotherapy-induced enrichment of BCSCs and impairs tumor initiation. These results suggest that, in combination with chemotherapy, targeting BCSCs by inhibiting HIF-1–regulated glutathione synthesis may improve outcome in TNBC.
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Hakami, Alqassem Y., Fahad S. Alshehri, Yusuf S. Althobaiti et Youssef Sari. « Effects of orally administered Augmentin on glutamate transporter 1, cystine-glutamate exchanger expression and ethanol intake in alcohol-preferring rats ». Behavioural Brain Research 320 (mars 2017) : 316–22. http://dx.doi.org/10.1016/j.bbr.2016.12.016.

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Lee, Duk-Shin, et Ji-Eun Kim. « P2X7 Receptor Augments LPS-Induced Nitrosative Stress by Regulating Nrf2 and GSH Levels in the Mouse Hippocampus ». Antioxidants 11, no 4 (13 avril 2022) : 778. http://dx.doi.org/10.3390/antiox11040778.

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P2X7 receptor (P2X7R) regulates inducible nitric oxide synthase (iNOS) expression/activity in response to various harmful insults. Since P2X7R deletion paradoxically decreases the basal glutathione (GSH) level in the mouse hippocampus, it is likely that P2X7R may increase the demand for GSH for the maintenance of the intracellular redox state or affect other antioxidant defense systems. Therefore, the present study was designed to elucidate whether P2X7R affects nuclear factor-erythroid 2-related factor 2 (Nrf2) activity/expression and GSH synthesis under nitrosative stress in response to lipopolysaccharide (LPS)-induced neuroinflammation. In the present study, P2X7R deletion attenuated iNOS upregulation and Nrf2 degradation induced by LPS. Compatible with iNOS induction, P2X7R deletion decreased S-nitrosylated (SNO)-cysteine production under physiological and post-LPS treated conditions. P2X7R deletion also ameliorated the decreases in GSH, glutathione synthetase, GS and ASCT2 levels concomitant with the reduced S-nitrosylations of GS and ASCT2 following LPS treatment. Furthermore, LPS upregulated cystine:glutamate transporter (xCT) and glutaminase in P2X7R+/+ mice, which were abrogated by P2X7R deletion. LPS did not affect GCLC level in both P2X7R+/+ and P2X7R−/− mice. Therefore, our findings indicate that P2X7R may augment LPS-induced neuroinflammation by leading to Nrf2 degradation, aberrant glutamate-glutamine cycle and impaired cystine/cysteine uptake, which would inhibit GSH biosynthesis. Therefore, we suggest that the targeting of P2X7R, which would exert nitrosative stress with iNOS in a positive feedback manner, may be one of the important therapeutic strategies of nitrosative stress under pathophysiological conditions.
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Ceder, Anna Sophia, Sofi E. Eriksson, Emarndeena Haji Cheteh, Vladimir J. N. Bykov, Lars Abrahmsen et Klas G. Wiman. « Impact of combined MRP1 inhibition and mutant p53-targeting compound APR-246. » Journal of Clinical Oncology 37, no 15_suppl (20 mai 2019) : e14712-e14712. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14712.

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e14712 Background: The tumor suppressor gene TP53 is the most frequently mutated gene in cancer. Mutant p53 protein is often expressed at high levels and accompanied with gain-of-function activities that promote tumor development and resistance towards conventional treatment. APR-246 is a mutant p53-reactivating small molecule undergoing a Phase III clinical study in myelodysplastic syndrome (MDS), and several phase II studies. APR-246 is non-enzymatically converted to its active product methylene quinuclidinone (MQ) which binds to cysteine residues in p53. This stimulates proper folding of p53's DNA-binding core domain, leading to cell death. APR-246 also exhibits pro-oxidant activity as the electrophile MQ binds and inactivates important antioxidants such as glutathione and thioredoxin reductase, which both are essential for cellular defense against oxidative and electrophilic stress. Methods: All results are in vitro experiments by LC-MS as well as experiments in cultured cells, including 14C-APR-246/MQ detection, cell viability measurements, LC-MS analysis, enzyme recycling measurements and Western blotting. Results: We have utilized 14C-labelled APR-246 to investigate the effect of APR-246 and its active moiety MQ in tumor cell cultures upon inhibition of efflux transporter multidrug resistance protein 1 (MRP1) or cystine-glutamate transporter (xCT). Transient downregulation or small molecule inhibitors (MK-571, reversan, sulfasalazin) targeting MRP1 or xCT increased drug content and shifted intra- and extracellular thiol status. Missense mutant TP53-carrying cells exhibited higher sensitivity to APR-246 and combination therapies. MRP1 inhibition showed strong synergy with APR-246 and increased intracellular levels of MQ conjugated to glutathione (GS-MQ). We found that GS-MQ conjugate formation is reversible, and suggest that the intrinsic reversibility of MQ adduct formation is an important aspect of the mechanism of action of APR-246. This reversibility may also in part account for the benign safety profile reported from clinical studies with APR-246. Conclusions: Sensitivity to APR-246 is affected by MRP1 efflux activity and the redox status, reflected in ratios of cysteine/cystine and reduced/oxidized glutathione (GSH/GSSG).
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Alasmari, Fawaz, Sawsan Abuhamdah et Youssef Sari. « Effects of ampicillin on cystine/glutamate antiporter and glutamate transporter 1 isoforms as well as ethanol drinking in male P rats ». Neuroscience Letters 600 (juillet 2015) : 148–52. http://dx.doi.org/10.1016/j.neulet.2015.06.015.

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Watanabe, Ren, Tomoe Takano, Sho Sasaki, Mizuho Obara, Ken Umeno, Hideyo Sato et Naoko Kimura. « Retention of higher fertility depending on ovarian follicle reserve in cystine-glutamate transporter gene-deficient mice ». Histochemistry and Cell Biology 157, no 3 (mars 2022) : 347–57. http://dx.doi.org/10.1007/s00418-022-02077-1.

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Dai, Lu, Yueyu Cao, Yihan Chen, Chris Parsons et Zhiqiang Qin. « Targeting xCT, a cystine-glutamate transporter induces apoptosis and tumor regression for KSHV/HIV-associated lymphoma ». Journal of Hematology & ; Oncology 7, no 1 (2014) : 30. http://dx.doi.org/10.1186/1756-8722-7-30.

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Kobayashi, Sho, Shinji Hamashima, Takujiro Homma, Mami Sato, Ryosuke Kusumi, Shiro Bannai, Junichi Fujii et Hideyo Sato. « Cystine/glutamate transporter, system x c − , is involved in nitric oxide production in mouse peritoneal macrophages ». Nitric Oxide 78 (août 2018) : 32–40. http://dx.doi.org/10.1016/j.niox.2018.05.005.

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Sato, Hideyo, Michiko Tamba, Tetsuro Ishii et Shiro Bannai. « Cloning and Expression of a Plasma Membrane Cystine/Glutamate Exchange Transporter Composed of Two Distinct Proteins ». Journal of Biological Chemistry 274, no 17 (23 avril 1999) : 11455–58. http://dx.doi.org/10.1074/jbc.274.17.11455.

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Polewski, Monika Dagmara, Rosyli Francis Reveron, Gregory Allan Cherryholmes et Karen Saida Aboody. « The Cystine-Glutamate Transporter System Xc-Mediates Chemoresistance and the Cancer Stem CellPhenotype in Glioblastoma Multiforme ». Free Radical Biology and Medicine 76 (novembre 2014) : S129—S130. http://dx.doi.org/10.1016/j.freeradbiomed.2014.10.205.

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Ringheim, Garth E., et Yu Jin. « O3-04-03 Aβ induces microglial cystine-glutamate transporter (XCT) gene expression and glutamate release that is suppressed by anti-inflammatory cytokines ». Neurobiology of Aging 25 (juillet 2004) : S59—S60. http://dx.doi.org/10.1016/s0197-4580(04)80200-8.

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Prokudin, M. Yu, B. V. Martynov, A. I. Yakovenko, I. V. Litvinenko, V. Yu Lobzin, D. V. Svistov, V. S. Chirskiy, K. A. Chemodakova et O. А. Klitsenko. « The role of glutamine synthetase expression and cystine/glutamate transporter (SLC7A11, xCT) in epilepsy pathogenesis of patients with supratentorial brain gliomas ». Epilepsy and paroxysmal conditions 14, no 2 (27 juillet 2022) : 204–13. http://dx.doi.org/10.17749/2077-8333/epi.par.con.2022.118.

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