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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 (GBM) is the most aggressive malignant primary brain tumor in adults. Several studies have shown that glioma cells up-regulate 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...
September 22, 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
The present study investigates the possible mechanism(s) underlying GSH deficiency in the mouse spinal cord during the course of MOG35-55 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. The decline in the levels of this essential antioxidant tripeptide in EAE coincides temporally and in magnitude with a reduction in the amount of γ-glutamylcysteine ligase (GCL), the rate-limiting enzyme in GSH synthesis...
August 31, 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
Arindam Bhattacharya, Johannes Weissenbock, Rephael Wenger, Artem Amirkhanov, Johann Kastner, Christoph Heinzl
This work introduces a tool for interactive exploration and visualization using MetaTracts. MetaTracts is a novel method for extraction and visualization of individual fiber bundles and weaving patterns from X-ray computed tomography (XCT) scans of endless carbon fiber reinforced polymers (CFRPs). It is designed specifically to handle XCT scans of low resolutions where the individual fibers are barely visible, which makes extraction of fiber bundles a challenging problem. The proposed workflow is used to analyze unit cells of CFRP materials integrating a recurring weaving pattern...
June 16, 2016: IEEE Transactions on Visualization and Computer Graphics
Markus T Berninger, Pouyan Mohajerani, Melanie Kimm, Stephan Masius, Xiaopeng Ma, Moritz Wildgruber, Bernhard Haller, Martina Anton, Andreas B Imhoff, Vasilis Ntziachristos, Tobias D Henning, Reinhard Meier
OBJECTIVES: To assess labelling efficiency of rabbit mesenchymal stem cells (MSCs) using the near-infrared dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) and detection of labelled MSCs for osteochondral defect repair in a rabbit model using fluorescence molecular tomography-X-ray computed tomography (FMT-XCT). METHODS: MSCs were isolated from New Zealand White rabbits and labelled with DiR (1.25-20 μg/mL). Viability and induction of apoptosis were assessed by XTT- and Caspase-3/-7-testing...
June 21, 2016: European Radiology
Huai-Qiang Ju, Yun-Xin Lu, Dong-Liang Chen, Tian Tian, Hai-Yu Mo, Xiao-Li Wei, Jian-Wei Liao, Feng Wang, Zhao-Lei Zeng, Helene Pelicano, Mitzi Aguilar, Wei-Hua Jia, Rui-Hua Xu
Colorectal cancer (CRC) is a common neoplastic disease and a frequent cause of death. Drug resistance is a major challenge to CRC treatment and stem-like side-population (SP) cells may play a key role in this resistance. Although it has been recognized that cancer stem cells may be affected by redox status, the underlying mechanisms for this effect and the roles of celllular redox adaptation and antioxidant capacity in CRC remain elusive. Our study shows that CRC SP cells are highly dependent on cellular GSH to maintain ROS levels below those of non-SP cells...
2016: Theranostics
Federico N Soria, Alazne Zabala, Olatz Pampliega, Aitor Palomino, Cristina Miguelez, Luisa Ugedo, Hideyo Sato, Carlos Matute, María Domercq
The cystine/glutamate antiporter is a membrane transport system responsible for the uptake of extracellular cystine and release of intracellular glutamate. It is the major source of cystine in most cells, and a key regulator of extrasynaptic glutamate in the CNS. Because cystine is the limiting factor in the biosynthesis of glutathione, and glutamate is the most abundant neurotransmitter, the cystine/glutamate antiporter is a central player both in antioxidant defense and glutamatergic signaling, two events critical to brain function...
August 2016: Glia
H Nurrohman, K Saeki, K Carneiro, Y C Chien, S Djomehri, S P Ho, C Qin, S J Marshall, L B Gower, G W Marshall, S Habelitz
Dentinogenesis imperfecta type II (DGI-II) lacks intrafibrillar mineral with severe compromise of dentin mechanical properties. A Dspp knockout (Dspp (-/-)) mouse, with a phenotype similar to that of human DGI-II, was used to determine if poly-L-aspartic acid [poly(ASP)] in the "polymer-induced liquid-precursor" (PILP) system can restore its mechanical properties. Dentin from six-week old Dspp (-/-) and wild-type mice was treated with CaP solution containing poly(ASP) for up to 14 days. Elastic modulus and hardness before and after treatment were correlated with mineralization from Micro x-ray computed tomography (Micro-XCT)...
February 15, 2016: Journal of Materials Research
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