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Fahad S Alshehri, Yusuf S Althobaiti, Youssef Sari
Exposure to ethanol (EtOH) or methamphetamine (MA) can lead to increase in extracellular glutamate concentration in the brain. Although studies from ours showed the effects of EtOH exposure on key glial glutamate transporters, little is known about the effects of sequential exposure to EtOH and MA or MA alone on certain glial glutamate transporters. In this study, we investigated the effects of sequential exposure to EtOH and MA on the expression of the major glutamate transporters, glutamate transporter 1 (GLT-1), as well as cystine/glutamate antiporter (xCT) and glutamate aspartate transporter (GLAST) in striatum and hippocampus...
November 25, 2016: Journal of Molecular Neuroscience: MN
Shira L Cramer, Achinto Saha, Jinyun Liu, Surendar Tadi, Stefano Tiziani, Wupeng Yan, Kendra Triplett, Candice Lamb, Susan E Alters, Scott Rowlinson, Yan Jessie Zhang, Michael J Keating, Peng Huang, John DiGiovanni, George Georgiou, Everett Stone
Cancer cells experience higher oxidative stress from reactive oxygen species (ROS) than do non-malignant cells because of genetic alterations and abnormal growth; as a result, maintenance of the antioxidant glutathione (GSH) is essential for their survival and proliferation. Under conditions of elevated ROS, endogenous L-cysteine (L-Cys) production is insufficient for GSH synthesis. This necessitates uptake of L-Cys that is predominantly in its disulfide form, L-cystine (CSSC), via the xCT(-) transporter. We show that administration of an engineered and pharmacologically optimized human cyst(e)inase enzyme mediates sustained depletion of the extracellular L-Cys and CSSC pool in mice and non-human primates...
November 21, 2016: Nature Medicine
Xing-Wang Zhou, Xiang Wang, Yuan Yang, Jie-Wen Luo, Hui Dong, Yan-Hui Liu, Qing Mao
Increasing evidence indicates that genetic biomarkers play important roles in the development of glioma-associated seizures. Thus, we performed a systematic review to summarise biomarkers that are associated with seizures in glioma patients. An electronic literature search of public databases (PubMed, Embase and Medline) was performed using the keywords glioma, seizure and epilepsy. A totall of 26 eligible studies with 2224 cases were included in this systematic review of publications to 20 June, 2016. Genetic biomarkers such as isocitrate dehydrogenase 1 (IDH1) mutations, low expression of excitatory amino acid transporter 2 (EAAT2), high xCT expression, overexpression of adenosine kinase (ADK) and low expression of very large G-protein-coupled receptor-1 (VLGR1) are primarily involved in synaptic transmission, whereas BRAF mutations, epidermal growth factor receptor (EGFR) amplification, miR-196b expression and low ki-67 expression are associated with regulation of cell proliferation...
December 2016: Clinical Neurology and Neurosurgery
Chia-Hung Hsieh, Yu-Jung Lin, Wei-Ling Chen, Yen-Chih Huang, Chi-Wei Chang, Fu-Chou Cheng, Ren-Shyan Liu, Woei-Cherng Shyu
Hypoxia-inducible factor 1α (HIF-1α) controls many genes involved in physiological and pathological processes. However, its roles in glutamatergic transmission and excitotoxicity are unclear. Here, we proposed that HIF-1α might contribute to glutamate-mediated excitotoxicity during cerebral ischaemia-reperfusion (CIR) and investigated its molecular mechanism. We showed that an HIF-1α conditional knockout mouse displayed an inhibition in CIR-induced elevation of extracellular glutamate and N-methyl-D-aspartate receptor (NMDAR) activation...
November 1, 2016: Journal of Pathology
Hua Yang, Silvia Jenni, Milena Colovic, Helen Merkens, Carlee Poleschuk, Isabel Rodrigo, Qing Miao, Bruce F Johnson, Michael J Rishel, Vesna Sossi, Jack M Webster, François Bénard, Paul Schaffer
: The cystine transporter (system xC-) is an antiporter of cystine and glutamate. It has relatively low basal expression in most tissues and becomes upregulated in cells under oxidative stress (OS) as one of the genes expressed in response to the antioxidant response element (ARE) promoter. We have developed (18)F-5-fluoro-aminosuberic acid (FASu), a Positron Emission Tomography (PET) tracer that targets system xC-. The goal of this study was to evaluate the suitability of (18)F-FASu as a specific gauge for system xC- activity in vivo and its potential usefulness for breast cancer imaging...
October 27, 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Yusuf S Althobaiti, Fahad S Alshehri, Atiah H Almalki, Youssef Sari
Methamphetamine (METH) is one of the psychostimulants that is co-abused with ethanol. Repeated exposure to high dose of METH has been shown to cause increases in extracellular glutamate concentration. We have recently reported that ethanol exposure can also increase the extracellular glutamate concentration and downregulate the expression of glutamate transporter subtype 1 (GLT-1). GLT-1 is a glial transporter that regulates the majority of extracellular glutamate. A Wistar rat model of METH and ethanol co-abuse was used to examine the expression of GLT-1 as well as other glutamate transporters such as cystine/glutamate exchanger (xCT) and glutamate aspartate transporter (GLAST)...
2016: Frontiers in Neuroscience
Sheng-Fan Wang, Meng-Shian Chen, Yueh-Ching Chou, Yune-Fang Ueng, Pen-Hui Yin, Tien-Shun Yeh, Hsin-Chen Lee
Mitochondrial DNA mutations and defects in mitochondrial enzymes have been identified in gastric cancers, and they might contribute to cancer progression. In previous studies, mitochondrial dysfunction was induced by oligomycin-enhanced chemoresistance to cisplatin. Herein, we dissected the regulatory mechanism for mitochondrial dysfunction-enhanced cisplatin resistance in human gastric cancer cells. Repeated cisplatin treatment-induced cisplatin-resistant cells exhibited high SLC7A11 (xCT) expression, and xCT inhibitors (sulfasalazine or erastin), xCT siRNA, or a GSH synthesis inhibitor (buthionine sulphoximine, BSO) could sensitize these cells to cisplatin...
September 30, 2016: Oncotarget
Monika D Polewski, Rosyli F Reveron-Thornton, Gregory A Cherryholmes, Georgi K Marinov, Kaniel Cassady, Karen S Aboody
: Glioblastoma multiforme is the most aggressive malignant primary brain tumor in adults. Several studies have shown that glioma cells upregulate the expression of xCT (SLC7A11), the catalytic subunit of system xc(-), a transporter involved in cystine import, that modulates glutathione production and glioma growth. However, the role of system xc(-) in regulating the sensitivity of glioma cells to chemotherapy is currently debated. Inhibiting system xc(-) with sulfasalazine decreased glioma growth and survival via redox modulation, and use of the chemotherapeutic agent temozolomide together with sulfasalazine had a synergistic effect on cell killing...
December 2016: Molecular Cancer Research: MCR
Walter H Watson, Tom J Burke, Igor N Zelko, Edilson Torres-González, Jeffrey D Ritzenthaler, Jesse Roman
Aging is associated with progressive oxidation of plasma cysteine (Cys)/cystine (CySS) redox state, expressed as EhCySS. Cultured cells condition their media to reproduce physiological EhCySS, 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 media EhCySS before and after challenge with Cys or CySS. We also measured expression of genes related to redox regulation and fibroblast function...
2016: Oxidative Medicine and Cellular Longevity
Tina Sehm, Manfred Rauh, Kurt Wiendieck, Michael Buchfelder, IIker Y Eyüpoglu, Nicolai E Savaskan
The glutamate exchanger xCT (SLC7a11) is causally linked with the malignancy grade of brain tumors and represents a key player in glutamate, cystine and glutathione metabolism. Although blocking xCT is not cytotoxic for brain tumors, xCT inhibition disrupts the neurodegenerative and microenvironment-toxifying activity of gliomas. Here, we report on the use of various xCT inhibitors as single modal drugs and in combination with the autophagy-inducing standard chemotherapeutic agent temozolomide (Temodal/Temcad®, TMZ)...
September 6, 2016: Oncotarget
Peter J Siska, Bumki Kim, Xiangming Ji, Megan D Hoeksema, Pierre P Massion, Kathryn E Beckermann, Jianli Wu, Jen-Tsan Chi, Jiyong Hong, Jeffrey C Rathmell
T and B lymphocytes undergo metabolic re-programming upon activation that is essential to allow bioenergetics, cell survival, and intermediates for cell proliferation and function. To support changes in the activity of signaling pathways and to provide sufficient and necessary intracellular metabolites, uptake of extracellular nutrients increases sharply with metabolic re-programming. One result of increased metabolic activity can be reactive oxygen species (ROS), which can be toxic when accumulated in excess...
November 2016: Journal of Immunological Methods
Itzy E Morales Pantoja, Che-Lin Hu, Nora I Perrone-Bizzozero, Jianzheng Zheng, Oscar A Bizzozero
This study investigates the possible mechanism(s) underlying glutathione (GSH) deficiency in the mouse spinal cord during the course of myelin oligodendrocyte glycoprotein35-55 peptide-induced experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of multiple sclerosis. Using the classical enzymatic recycling method and a newly developed immunodot assay, we first demonstrated that total GSH levels (i.e. free GSH plus all its adducts) are reduced in EAE, suggesting an impaired synthesis...
November 2016: Journal of Neurochemistry
Robert A Jones, Tyler J Robinson, Jeff C Liu, Mariusz Shrestha, Veronique Voisin, YoungJun Ju, Philip E D Chung, Giovanna Pellecchia, Victoria L Fell, SooIn Bae, Lakshmi Muthuswamy, Alessandro Datti, Sean E Egan, Zhe Jiang, Gustavo Leone, Gary D Bader, Aaron Schimmer, Eldad Zacksenhaus
Triple-negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which no specific treatment is currently available. Although the retinoblastoma tumor-suppressor gene (RB1) is frequently lost together with TP53 in TNBC, it is not directly targetable. There is thus great interest in identifying vulnerabilities downstream of RB1 that can be therapeutically exploited. Here, we determined that combined inactivation of murine Rb and p53 in diverse mammary epithelial cells induced claudin-low-like TNBC with Met, Birc2/3-Mmp13-Yap1, and Pvt1-Myc amplifications...
October 3, 2016: Journal of Clinical Investigation
Min Yang, Wen Zhang, Xiaojun Wu, Dongtao Wei, Yixin Zhao, Gang Zhao, Xu Han, Shunli Zhang
For the analysis of interior geometry and property changes of a large-sized analog model during a loading or other medium (water or oil) injection process with a non-destructive way, a consecutive X-ray computed tomography (XCT) short-scan method is developed to realize an in-situ tomography imaging. With this method, the X-ray tube and detector rotate 270° around the center of the guide rail synchronously by switching positive and negative directions alternately on the way of translation until all the needed cross-sectional slices are obtained...
2016: PloS One
Yantao Chen, Kunshui Zhang, Yang Li, Qing He
Osteosarcoma patients often exhibit pulmonary metastasis, which results in high patient mortality. Understanding the mechanisms of advanced metastasis in osteosarcoma cell is important for the targeted treatment and drug development. Our present study revealed that transforming growth factor-β (TGF-β) treatment can significantly promote the in vitro migration and invasion of human osteosarcoma MG-63 and HOS cells. The loss of epithelial characteristics E-cadherin (E-Cad) and up regulation of mesenchymal markers Vimentin (Vim) suggested TGF-β induced epithelial-mesenchymal transition (EMT) of osteosarcoma cells...
August 17, 2016: Cell Adhesion & Migration
Katja Linher-Melville, Mina G Nashed, Robert G Ungard, Sina Haftchenary, David A Rosa, Patrick T Gunning, Gurmit Singh
Pharmacologically targeting activated STAT3 and/or STAT5 has been an active area of cancer research. The cystine/glutamate antiporter, system xc-, contributes to redox balance and export of intracellularly produced glutamate in response to up-regulated glutaminolysis in cancer cells. We have previously shown that blocking STAT3/5 using the small molecule inhibitor, SH-4-54, which targets the SH2 domains of both proteins, increases xCT expression, thereby increasing system xc- activity in human breast cancer cells...
2016: PloS One
Vikas Singh, Ruchi Gera, Rajesh Kushwaha, Anuj Kumar Sharma, Satyakam Patnaik, Debabrata Ghosh
Arsenic-induced altered microglial activity leads to neuronal death, but the causative mechanism remains unclear. The present study showed, arsenic-exposed (10 μM) microglial (N9) culture supernatant induced bystander death of neuro-2a (N2a), which was further validated with primary microglia and immature neuronal cultures. Results indicated that arsenic-induced GSH synthesis by N9 unfavorably modified the extracellular milieu for N2a by lowering cystine and increasing glutamate concentration. Similar result was observed in N9-N2a co-culture...
2016: Scientific Reports
K K Starheim, T Holien, K Misund, I Johansson, K A Baranowska, A-M Sponaas, H Hella, G Buene, A Waage, A Sundan, G Bjørkøy
Multiple myeloma (myeloma in short) is an incurable cancer of antibody-producing plasma cells that comprise 13% of all hematological malignancies. The proteasome inhibitor bortezomib has improved treatment significantly, but inherent and acquired resistance to the drug remains a problem. We here show that bortezomib-induced cytotoxicity was completely dampened when cells were supplemented with cysteine or its derivative, glutathione (GSH) in ANBL-6 and INA-6 myeloma cell lines. GSH is a major component of the antioxidative defense in eukaryotic cells...
2016: Blood Cancer Journal
Kimberly J Briggs, Peppi Koivunen, Shugeng Cao, Keriann M Backus, Benjamin A Olenchock, Hetalben Patel, Qing Zhang, Sabina Signoretti, Gary J Gerfen, Andrea L Richardson, Agnieszka K Witkiewicz, Benjamin F Cravatt, Jon Clardy, William G Kaelin
The HIF transcription factor promotes adaptation to hypoxia and stimulates the growth of certain cancers, including triple-negative breast cancer (TNBC). The HIFα subunit is usually prolyl-hydroxylated by EglN family members under normoxic conditions, causing its rapid degradation. We confirmed that TNBC cells secrete glutamate, which we found is both necessary and sufficient for the paracrine induction of HIF1α in such cells under normoxic conditions. Glutamate inhibits the xCT glutamate-cystine antiporter, leading to intracellular cysteine depletion...
June 30, 2016: Cell
Peng Zhang, Wei Wang, Zhenhui Wei, L I Xu, Xuanning Yang, Yuanhong DU
Tongue squamous cell carcinoma (TSCC), which is a subtype of head and neck cancer, is the most common type of oral cancer. Due to its high recurrence rate and chemoresistance, the average survival rate for patients with TSCC remains unsatisfactory. At present, cisplatin (CDDP) is utilized as the first-line treatment for numerous solid neoplasms, including TSCC. CDDP resistance develops in the majority of patients; however, the mechanism of such resistance remains unknown. Therefore, the present study aimed to clarify the mechanism of CDDP resistance and attempted to reduce chemoresistance...
July 2016: Oncology Letters
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