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Keigo Tsushida, Katsuyuki Tanabe, Kana Masuda, Satoshi Tanimura, Hiromasa Miyake, Yuka Arata, Hitoshi Sugiyama, Jun Wada
Acute kidney injury (AKI) has been associated with not only higher in-hospital mortality but also the subsequent development of chronic kidney disease (CKD). Recent evidence has suggested the involvement of mitochondrial dysfunction and impaired dynamics in the pathogenesis of AKI. Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that acts as a transcription factor to regulate the transcription of genes required for mitochondrial biogenesis and oxidative phosphorylation. In the present study, we examined the effects of ERRα deficiency on the progression of AKI induced by cisplatin...
March 12, 2018: Biochemical and Biophysical Research Communications
Amber W Wang, Kirk J Wangensteen, Yue J Wang, Adam M Zahm, Nicholas G Moss, Noam Erez, Klaus H Kaestner
Understanding the molecular basis of the regenerative response following hepatic injury holds promise for improved treatments of liver diseases. Here, we report an innovative method to profile gene expression specifically in the hepatocytes that regenerate the liver following toxic injury. We utilize the Fah-/- mouse, a model of hereditary tyrosinemia, which conditionally undergoes severe liver injury unless fumarylacetoacetate hydrolase (FAH) expression is reconstituted ectopically. We employ translating ribosome affinity purification followed by high-throughput RNA sequencing (TRAP-seq) to isolate mRNAs specific to repopulating hepatocytes...
March 8, 2018: Journal of Clinical Investigation
Raul Carpi-Santos, Karin C Calaza
Nrf2 (nuclear factor erythroid 2-related factor 2), a transcription factor that controls expression of several proteins that are related to cellular antioxidant capacity, such as the subunit xCT of the system xc - , is dysregulated in diabetes. Recently, it was described that system xc - is decreased in the retina after 3 weeks of diabetes. So, in the present work, the temporal relationship between xCT and Nrf2 in the retina of diabetic animals was investigated. Diabetes was induced in male Wistar rats (200 g) by a single injection of streptozotocin, and retinas were collected after 1, 2, and 6 months of diabetes induction...
February 27, 2018: Molecular Neurobiology
Raeeka Khamari, Anne Trinh, Pierre Elliott Gabert, Paola Corazao-Rozas, Samuel Riveros-Cruz, Stephane Balayssac, Myriam Malet-Martino, Salim Dekiouk, Marie Joncquel Chevalier Curt, Patrice Maboudou, Guillaume Garçon, Laura Ravasi, Pierre Guerreschi, Laurent Mortier, Bruno Quesnel, Philippe Marchetti, Jerome Kluza
Targeted therapies as BRAF and MEK inhibitor combination have been approved as first-line treatment for BRAF-mutant melanoma. However, disease progression occurs in most of the patients within few months of therapy. Metabolic adaptations have been described in the context of acquired resistance to BRAF inhibitors (BRAFi). BRAFi-resistant melanomas are characterized by an increase of mitochondrial oxidative phosphorylation and are more prone to cell death induced by mitochondrial-targeting drugs. BRAFi-resistant melanomas also exhibit an enhancement of oxidative stress due to mitochondrial oxygen consumption increase...
February 27, 2018: Cell Death & Disease
Noriko Hiyama, Takahiro Ando, Keita Maemura, Toshio Sakatani, Yosuke Amano, Kousuke Watanabe, Hidenori Kage, Yutaka Yatomi, Takahide Nagase, Jun Nakajima, Daiya Takai
Background: Cisplatin is a key drug for treating lung adenocarcinoma, and its sensitivity to cisplatin is directly related to prognosis. We aimed to reveal the roles of genes related to glutathione synthesis (glutamate-cysteine ligase catalytic subunit, GCLC) and cystine uptake (cystine/glutamate transporter, xCT and CD44v8-10) in cisplatin resistance and prognosis in lung adenocarcinoma. Methods: We established cell lines stably expressing GCLC, xCT, standard isoform of CD44, and CD44v8-10, and investigated their sensitivities to cisplatin...
February 21, 2018: Japanese Journal of Clinical Oncology
Aileen Hoehne, Michelle L James, Israt S Alam, John A Ronald, Bernadette Schneider, Aloma D'Souza, Timothy H Witney, Lauren E Andrews, Haley C Cropper, Deepak Behera, Gayatri Gowrishankar, Zhaoqing Ding, Tony Wyss-Coray, Frederick T Chin, Sandip Biswal, Sanjiv S Gambhir
BACKGROUND: The cystine/glutamate antiporter (xc-) has been implicated in several neurological disorders and, specifically, in multiple sclerosis (MS) as a mediator of glutamate excitotoxicity and proinflammatory immune responses. We aimed to evaluate an xc-specific positron emission tomography (PET) radiotracer, (4S)-4-(3-[18 F]fluoropropyl)-L-glutamate ([18 F]FSPG), for its ability to allow non-invasive monitoring of xc- activity in a mouse model of MS. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by subcutaneous injection of myelin oligodendrocyte glycoprotein (MOG35-55 ) peptide in complete Freund's adjuvant (CFA) followed by pertussis toxin...
February 22, 2018: Journal of Neuroinflammation
Meizi Qian, Yingying Lou, Yixiu Wang, Minyuan Zhang, Qun Jiang, Yunchang Mo, Kunyuan Han, Shenhui Jin, Qinxue Dai, Yulong Yu, Zhen Wang, Junlu Wang
The role of oxidative stress has been well documented in the development of sepsis-induced acute lung injury (ALI). Protein interaction with C-kinase 1 (PICK1) participates in oxidative stress-related neuronal diseases. However, its function in lung infections and inflammatory diseases is not known. We therefore sought to investigate whether PICK1 is involved in sepsis-induced ALI. Cecal ligation and puncture (CLP) was performed in anesthetized wild type (WT) and PICK1 knock out (KO, PICK1-/- ) mice with C57BL/6 background...
February 19, 2018: Free Radical Biology & Medicine
Nana Kobayashi, Shogo Okazaki, Oltea Sampetrean, Junichiro Irie, Hiroshi Itoh, Hideyuki Saya
CD44 variant (CD44v) contributes to cancer stemness by stabilizing the xCT subunit of system xc(-) and thereby promoting its glutamate-cystine antiporter activity. CD44 has also been implicated in autoimmune insulitis and inflammation in diabetic islets, but whether CD44v regulates insulin secretion has remained unclear. Here we show that CD44v inhibits insulin secretion by attenuating amino acid transport mediated by the L-type amino acid transporter LAT1. CD44v expression level was inversely related to insulin content in islets of normal and diabetic model mice...
February 12, 2018: Scientific Reports
Benjamin A Sherer, Ling Chen, Misun Kang, Alex R Shimotake, Scott V Wiener, Tom Chi, Marshall L Stoller, Sunita P Ho
The development of new modalities for kidney stone prevention rests upon understanding the progression of mineralization within the renal pyramid. The progression from small foci of mineralization within the renal pyramid to larger interstitial plaques that ultimately lead to the formation of clinically detectable calcium-based stones on calcium phosphate stems will be presented through correlative microscopy approach. High resolution X-ray computed tomography (micro-XCT), electron microscopy, and energy dispersive X-ray (EDX) compositional analyses of interstitial plaques, stems, and attached stones were performed...
February 8, 2018: Acta Biomaterialia
Weixiong Zhong, Heidi L Weiss, Rani D Jayswal, Patrick J Hensley, Laura M Downes, Daret K St Clair, Luksana Chaiswing
AIM: Extracellular superoxide dismutase (ECSOD) and the cysteine/glutamate transporter (Cys)/(xCT) are tumor microenvironment (TME) redox state homeostasis regulators. Altered expression of ECSOD and xCT can lead to imbalance of the TME redox state and likely have a profound effect on cancer invasion. In the present study, we investigated whether ECSOD and xCT could be therapeutic targets for prostate cancer (PCa) invasion. RESULTS: Immunohistochemistry of tumor microarray PCa tissues (N = 165) with high Gleason scores indicated that xCT protein expression is significantly increased while ECSOD protein expression is significantly decreased...
February 2, 2018: Free Radical Biology & Medicine
Mai Froberg Sørensen, Sólborg Berglind Heimisdóttir, Mia Dahl Sørensen, Casper Schau Mellegaard, Helle Wohlleben, Bjarne Winther Kristensen, Christoph Patrick Beier
Epileptic seizures are an important cause of morbidity in glioma patients. Substantial lines of evidence support the concept of the excitatory neurotransmitter glutamate being a crucial mediator of glioma-associated seizures. In gliomas, non-vesicular secretion of glutamate via the cystine-glutamate exchanger (SLC7A11, xCT) constitutes the main mechanism contributing to high extracellular glutamate concentrations. However, a convincing "proof-of-relevance" of this mechanism in patient material is lacking. A cohort of 229 consecutive patients with newly diagnosed glioma was analyzed with respect to presence, time course, and severity of epileptic seizures...
February 5, 2018: Journal of Neuro-oncology
Elisabetta Bolli, John P O'Rourke, Laura Conti, Stefania Lanzardo, Valeria Rolih, Jayne M Christen, Giuseppina Barutello, Marco Forni, Federica Pericle, Federica Cavallo
Aggressive forms of breast cancer, such as Her2+ and triple negative breast cancer (TNBC), are enriched in breast cancer stem cells (BCSC) and have limited therapeutic options. BCSC represent a key cellular reservoir for relapse, metastatic progression and therapeutic resistance. Their ability to resist common cytotoxic therapies relies on different mechanisms, including improved detoxification. The cystine-glutamate antiporter protein xCT (SLC7A11) regulates cystine intake, conversion to cysteine and subsequent glutathione synthesis, protecting cells against oxidative and chemical insults...
2018: Oncoimmunology
Masayuki Hagiwara, Eiji Kikuchi, Nobuyuki Tanaka, Takeo Kosaka, Shuji Mikami, Hideyuki Saya, Mototsugu Oya
BACKGROUND: Cisplatin is the most commonly used chemotherapeutic agent in the treatment of patients with metastatic and/or recurrent urothelial cancer. However, the effectiveness of these treatments is severely limited due to the development of cisplatin resistance. Cancer stem cells have been documented as one of the key hypotheses involved in chemoresistance. CD44v8-10 has been identified as one of the new cancer stem cells markers and was recently shown to enhance the antioxidant system by interaction with xCT, a subunit of the cystine transporter modulating intracellular glutathione synthesis...
January 31, 2018: BMC Cancer
Yusuke Hattori, Tomomi Takaku, Makoto Otsuka
The relationships between the physicochemical properties of milled starch and drug release from tablets were investigated quantitatively using a drug release kinetic method and X-ray computed tomography (XCT). The samples were prepared from raw β-starch by milling in a planetary ball mill. The tablets, containing 5% theophylline (TH), 94% milled starch, and 1% magnesium stearate, were compressed at 6 kN. The drug-release and gel-forming processes were measured simultaneously using an original dissolution tester with an XCT instrument...
January 20, 2018: International Journal of Pharmaceutics
Sigrid Ottestad-Hansen, Qiu Xiang Hu, Virgine Veronique Follin-Arbelet, Eduard Bentea, Hideyo Sato, Ann Massie, Yun Zhou, Niels Christian Danbolt
The cystine-glutamate exchanger (xCT) promotes glutathione synthesis by catalyzing cystine uptake and glutamate release. The released glutamate may modulate normal neural signaling and contribute to excitotoxicity in pathological situations. Uncertainty, however, remains as neither the expression levels nor the distribution of xCT have been unambiguously determined. In fact, xCT has been reported in astrocytes, neurons, oligodendrocytes and microglia, but most of the information derives from cell cultures. Here, we show by immunohistochemistry and by Western blotting that xCT is widely expressed in the central nervous system of both sexes...
January 19, 2018: Glia
Maša Ždralević, Milica Vučetić, Boutaina Daher, Ibtissam Marchiq, Scott K Parks, Jacques Pouysségur
The evolution of life from extreme hypoxic environments to an oxygen-rich atmosphere has progressively selected for successful metabolic, enzymatic and bioenergetic networks through which a myriad of organisms survive the most extreme environmental conditions. From the two lethal environments anoxia/high O2, cells have developed survival strategies through expression of the transcriptional factors ATF4, HIF1 and NRF2. Cancer cells largely exploit these factors to thrive and resist therapies. In this review, we report and discuss the potential therapeutic benefit of disrupting the major Myc/Hypoxia-induced metabolic pathway, also known as fermentative glycolysis or "Warburg effect", in aggressive cancer cell lines...
December 28, 2017: Advances in Biological Regulation
Vito G Ruggieri, Karl Bounader, Jean Philippe Verhoye, Francesco Onorati, Antonino S Rubino, Giuseppe Gatti, Tuomas Tauriainen, Marisa De Feo, Daniel Reichart, Magnus Dalén, Peter Svenarud, Giuseppe Faggian, Giuseppe Santarpino, Daniele Maselli, Riccardo Gherli, Giovanni Mariscalco, Antonio Salsano, Francesco Nicolini, Tiziano Gherli, Matteo Saccocci, Juhani K E Airaksinen, Sidney Chocron, Andrea Perrotti, Fausto Biancari
BACKGROUND: The prognostic impact of cross-clamp time (XCT) in patients undergoing isolated coronary artery bypass grafting (CABG) has not been thoroughly investigated. MATERIAL AND METHODS: 2957 patients who underwent on-pump isolated CABG from the prospective multicentre E-CABG study were the subjects of this analysis. RESULTS: The mean XCT in this series was 58±25minutes Cross-clamp time was >60 minutes in 1134 patients (38.3%), >75minutes in 619 patients (20...
October 6, 2017: Heart, Lung & Circulation
Evan C Lien, Laura Ghisolfi, Renee C Geck, John M Asara, Alex Toker
The precursor homocysteine is metabolized either through the methionine cycle to produce methionine or through the transsulfuration pathway to synthesize cysteine. Alternatively, cysteine can be obtained through uptake of its oxidized form, cystine. Many cancer cells exhibit methionine dependency such that their proliferation is impaired in growth media in which methionine is replaced by homocysteine. We showed that oncogenic PIK3CA and decreased expression of SLC7A11, a gene that encodes a cystine transporter also known as xCT, correlated with increased methionine dependency in breast cancer cells...
December 19, 2017: Science Signaling
Yong-Ju Xu, Yang Lei, Ran Li, Ling-Li Zhang, Zhi-Xue Zhao, Jing-Hao Zhao, Jing Fan, Yan Li, Hui Yang, Jing Shang, Shunyuan Xiao, Wen-Ming Wang
Ectopic expression of the Arabidopsis RESISTANCE TO POWDERY MILDEW8.1 (RPW8.1) boosts pattern-triggered immunity leading to enhanced resistance to different pathogens in Arabidopsis and rice. However, the underlying regulatory mechanism remains largely elusive. Here, we report that XAP5 CIRCADIAN TIMEKEEPER (XCT, At2g21150) positively regulates RPW8.1-mediated cell death and disease resistance. Forward genetic screen identified the b3-17 mutant that exhibited less cell death and susceptibility to powdery mildew and bacterial pathogens...
2017: Frontiers in Plant Science
Hans Bolinsson, Yi Lu, Stephen Hall, Lars Nilsson, Andreas Håkansson
This study suggests a novel method for determination of the channel height in asymmetrical flow field-flow fractionation (AF4), which can be used for calibration of the channel for hydrodynamic radius determinations. The novel method uses an oil-in-water nanoemulsion together with multi angle light scattering (MALS) and elution theory to determine channel height from an AF4 experiment. The method is validated using two orthogonal methods; first, by using standard particle elution experiments and, secondly, by imaging an assembled and carrier liquid filled channel by x-ray computed tomography (XCT)...
December 12, 2017: Journal of Chromatography. A
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