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Tristan Pascart, Frédéric Lioté
This review article summarizes the relevant English literature on gout from 2010 through April 2017. It emphasizes that the current epidemiology of gout indicates a rising prevalence worldwide, not only in Western countries but also in Southeast Asia, in close relationship with the obesity and metabolic syndrome epidemics. New pathogenic mechanisms of chronic hyperuricaemia focus on the gut (microbiota, ABCG2 expression) after the kidney. Cardiovascular and renal comorbidities are the key points to consider in terms of management...
March 13, 2018: Rheumatology
Michael K Krapf, Jennifer Gallus, Sahel Vahdati, Michael Wiese
Multidrug resistance occurring during cancer chemotherapy is a major obstacle for effectiveness and response to therapy and is often caused by ATP-binding cassette (ABC) efflux transporters. Belonging to the family of ABC transporters, breast cancer resistance protein is getting more and more in the spotlight of research. As a strategy to overcome multidrug resistance, inhibitors of ABC transporters were synthesized, which could be applied in combination with cytostatic drugs. For this purpose, 2,4-disubstituted pyridopyrimidine derivatives were synthesized...
March 16, 2018: Journal of Medicinal Chemistry
Sandra Bien-Möller, Ellen Balz, Susann Herzog, Laura Plantera, Silke Vogelgesang, Kerstin Weitmann, Carolin Seifert, Matthias A Fink, Sascha Marx, Angela Bialke, Chitra Venugopal, Sheila K Singh, Wolfgang Hoffmann, Bernhard H Rauch, Henry W S Schroeder
Patients with glioblastoma multiforme (GBM) are at high risk to develop a relapse despite multimodal therapy. Assumedly, glioma stem cells (GSCs) are responsible for treatment resistance of GBM. Identification of specific GSC markers may help to develop targeted therapies. Here, we performed expression analyses of stem cell (ABCG2, CD44, CD95, CD133, ELF4, Nanog, and Nestin) as well as differentiation and microglia markers (GFAP, Iba1, and Sparc) in GBM compared to nonmalignant brain. Furthermore, the role of these proteins for patient survival and their expression in LN18 stem-like neurospheres was analyzed...
2018: Stem Cells International
Mohamed E M Saeed, Nuha Mahmoud, Yoshikazu Sugimoto, Thomas Efferth, Heba Abdel-Aziz
For decades, natural products represented a significant source of diverse and unique bioactive lead compounds in drug discovery field. In Clinical oncology, complete tumors remission is hampered by the development of drug-resistance. Therefore, development of cytotoxic agents that may overcome drug resistance is urgently needed. Here, the natural benzophenanthridine alkaloid sanguinarine has been studied for its cytotoxic activity against multidrug resistance (MDR) cancer cells. We investigated the role of the ATP-binding cassette (ABC) transporters BCRP/ABCG2, P-glycoprotein/ABCB1 and its close relative ABCB5 in drug resistance...
2018: Frontiers in Pharmacology
Ryoma Igarashi, Takamitsu Inoue, Nobuhiro Fujiyama, Norihiko Tsuchiya, Kazuyuki Numakura, Hideaki Kagaya, Mitsuru Saito, Shintaro Narita, Shigeru Satoh, Takenori Niioka, Masatomo Miura, Tomonori Habuchi
Axitinib is a potent second-line molecular-targeted agent for metastatic renal cell carcinoma (mRCC). Axitinib pharmacokinetics and its relation with genetic polymorphisms were evaluated to predict the adverse events (AEs) and efficacy of axitinib. We analyzed 46 patients with mRCC who were treated with axitinib. The plasma axitinib level was measured at 0, 2, 4, 8, and 12 h after administration (C0 , C2 , C4 , C8 , and C12 ; ng/mL) on day 7 of the treatment. Genetic polymorphisms related to axitinib pharmacokinetics, including SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCG2, CYP2C19, CYP3A5, and UGT1A1, were analyzed...
March 9, 2018: Medical Oncology
Kang Wang, Lei Hu, Jian-Kang Chen
Recent preclinical and clinical evidence suggests that hyperuricemia (HU) is an independent risk factor for metabolic syndrome, hypertension, cardiovascular disease and chronic kidney disease. Receptor-interacting protein 3 (RIP3) is an important contributor in inducing programmed necrosis, representing a newly identified mechanism of cell death combining features of both apoptosis and necrosis. In our study, RIP3 was strongly expressed in mice with hyperuricemia. RIP3 deficiency attenuated hyperuricemia in mice, evidenced by reduced serum uric acid and creatinine and enhanced urinary uric acid and creatinine, as well as the improved histological alterations in renal sections...
March 5, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Guan-Nan Zhang, Yun-Kai Zhang, Yi-Jun Wang, Pranav Gupta, Charles R Ashby, Saeed Alqahtani, Tongjin Deng, Susan E Bates, Amal Kaddoumi, John N D Wurpel, Yi-Xiong Lei, Zhe-Sheng Chen
One of the major mediators of multidrug resistance (MDR) in non-small cell lung cancer (NSCLC) is the overexpression of ATP-binding cassette subfamily G member 2 (ABCG2). In this study, we conducted in vitro and in vivo experiments to determine whether PD153035, an inhibitor of EGFR, could reverse ABCG2-mediated MDR in human NSCLC and transfected cells overexpressing ABCG2. The efficacy of SN-38, topotecan, and mitoxantrone (MX) was significantly increased by PD153035, PD153035 significantly reversed ABCG2-mediated MDR by attenuating the efflux activity of this transporter...
March 5, 2018: Cancer Letters
Wenjing Xiao, Jian-Ping Guo, Chun Li, Hua Ye, Wei Wei, Yaohong Zou, Lie Dai, Zhijun Li, Miaojia Zhang, Xiangpei Li, Xiaoyan Cai, Jianhong Zhao, Youlian Wang, Yi Tao, Dongzhou Liu, Yasong Li, Min Wu, Erwei Sun, Lijun Wu, Li Luo, Rong Mu, Zhanguo Li
Iguratimod (IGU) is a novel disease-modifying anti-rheumatic drug (DMARD) in rheumatoid arthritis (RA). Like other DMARDs, IGU exhibited significant differences in effectiveness and safety. AIM: The aim of this study was to identify genetic predictorsof efficacyand toxicity of IGU in patients with RA. MATERIALS & METHODS: Seven SNPs from IGU-metabolizing genes were genotyped in 272 IGU-treated patients with RA. Results: ABCG2 rs2231142 A allele conferred a higher response to IGU, while NAT2 rs1495742 G carriersconferred a lower response to IGU...
March 8, 2018: Pharmacogenomics
Rebecca R Crawford, Praveen K Potukuchi, Erin G Schuetz, John D Schuetz
ATP-binding cassette (ABC) transporters are transmembrane efflux transporters mediating the extrusion of an array of substrates ranging from amino acids and lipids to xenobiotics, and many therapeutic compounds, including anticancer drugs. The ABC transporters are also recognized as important contributors to pharmacokinetics, especially in drug-drug interactions and adverse drug effects. Drugs and xenobiotics, as well as pathological conditions, can influence the transcription of ABC transporters, or modify their activity or intracellular localization...
March 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Sébastien Rinaldetti, Markus Pfirrmann, Kirsi Manz, Joelle Guilhot, Christian Dietz, Panayiotidis Panagiotidis, Birgit Spiess, Wolfgang Seifarth, Alice Fabarius, Martin Müller, Maria Pagoni, Maria Dimou, Jolanta Dengler, Cornelius F Waller, Tim H Brümmendorf, Regina Herbst, Andreas Burchert, Carsten Janβen, Maria Elisabeth Goebeler, Philipp J Jost, Stefan Hanzel, Philippe Schafhausen, Gabriele Prange-Krex, Thomas Illmer, Viktor Janzen, Martine Klausmann, Robert Eckert, Gerd Büschel, Alexander Kiani, Wolf-Karsten Hofmann, François-Xavier Mahon, Susanne Saussele
INTRODUCTION: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated. MATERIALS AND METHODS: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial...
February 8, 2018: Clinical Lymphoma, Myeloma & Leukemia
Jessica Cusato, Amedeo De Nicolò, Lucio Boglione, Fabio Favata, Alessandra Ariaudo, Simone Mornese Pinna, Chiara Carcieri, Federica Guido, Valeria Avataneo, Giuseppe Cariti, Giovanni Di Perri, Antonio D'Avolio
Background: Sofosbuvir is a potent nucleotide HCV NS5B polymerase inhibitor that is also a P-glycoprotein (encoded by the ABCB1 gene) and breast cancer resistance protein (encoded by the ABCG2 gene) substrate. Concerning previous anti-HCV therapies, pharmacogenetics had a significant impact, particularly considering the association of interleukin28B polymorphisms with dual-therapy (ribavirin + pegylated IFN) outcomes. Objectives: In this work, we investigated the association between sofosbuvir and its prevalent metabolite (GS-331007) plasma concentrations at 1 month of therapy and genetic variants (SNPs) in genes encoding transporters and nuclear factors (ABCB1, ABCG2 and HNF4α) related to sofosbuvir transport...
March 2, 2018: Journal of Antimicrobial Chemotherapy
Karolina Tecza, Jolanta Pamula-Pilat, Joanna Lanuszewska, Dorota Butkiewicz, Ewa Grzybowska
The differences in patients' response to the same medication, toxicity included, are one of the major problems in breast cancer treatment. Chemotherapy toxicity makes a significant clinical problem due to decreased quality of life, prolongation of treatment and reinforcement of negative emotions associated with therapy. In this study we evaluated the genetic and clinical risk factors of FAC chemotherapy-related toxicities in the group of 324 breast cancer patients. Selected genes and their polymorphisms were involved in FAC drugs transport ( ABCB1, ABCC2, ABCG2,SLC22A16 ), metabolism ( ALDH3A1, CBR1, CYP1B1, CYP2C19, DPYD, GSTM1, GSTP1, GSTT1, MTHFR,TYMS ), DNA damage recognition, repair and cell cycle control ( ATM, ERCC1, ERCC2, TP53, XRCC1 )...
February 6, 2018: Oncotarget
Denise Damasceno Guerreiro, Laritza Ferreira de Lima, Gildas Tetaping Mbemya, Carolina Mielgo Maside, André Marrocos Miranda, Kaio César Simiano Tavares, Benner Geraldo Alves, Luciana Rocha Faustino, Johan Smitz, José Ricardo de Figueiredo, Ana Paula Ribeiro Rodrigues
The multidrug resistance proteins ABCB1, ABCC2 and ABCG2 are an energy-dependent efflux pump that functions in systemic detoxification processes. Physiologically expressed in a variety of tissues, most abundantly in the liver and intestinal epithelia, placenta, blood-brain barrier and various stem cells, until now, these pumps were not identified in goat ovarian tissue. Therefore, the aim of this study is to analyze ABCB1, ABCC2, and ABCG2 mRNA and protein expression in goat preantral follicles. Fragments (3 × 3 × 1 mm) from five pairs of ovary (n = 10) obtained from five goat were collected and immediately submitted to qPCR, Western blot, and immunofluorescence assay for mRNA detection and identification and localization of the ABC transporters, respectively...
February 27, 2018: Cell and Tissue Research
Pranav Gupta, Yun-Kai Zhang, Xiao-Yu Zhang, Yi-Jun Wang, Kimberly W Lu, Timothy Hall, Richard Peng, Dong-Hua Yang, Ni Xie, Zhe-Sheng Chen
BACKGROUND/AIMS: The overexpression of ATP-Binding Cassette (ABC) transporters has known to be one of the major obstacles impeding the success of chemotherapy in drug resistant cancers. In this study, we evaluated voruciclib, a CDK 4/6 inhibitor, for its chemo-sensitizing activity in ABCB1- and ABCG2- overexpressing cells. METHODS: Cytotoxicity and reversal effect of voruciclib was determined by MTT assay. The intracellular accumulation and efflux of ABCB1 and ABCG2 substrates were measured by scintillation counter...
February 19, 2018: Cellular Physiology and Biochemistry
Rommel G Tirona, Zahra Kassam, Ruth Strapp, Mala Ramu, Catherine Zhu, Melissa Liu, Ute I Schwarz, Richard B Kim, Bandar Al-Judaibi, Melanie D Beaton
There is little known about the impact of nonalcoholic fatty liver disease (NAFLD) on drug metabolism and transport. We examined the pharmacokinetics of oral apixaban (2.5 mg) and rosuvastatin (5 mg) when administered simultaneously in subjects with magnetic resonance imaging-confirmed NAFLD (N=22) and healthy controls (N=12). The areas under the plasma concentration-time curve (AUC0-12 ) for apixaban were not different between control and NAFLD subjects (671 and 545 ng/mL×hr, respectively; P=0.15). In multivariable linear regression analyses, only participant weight but not NAFLD, age or SLCO1B1/ABCG2/CYP3A5 genotypes, was associated with apixaban and rosuvastatin AUC0-12 (P<0...
February 22, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Rachel J Eclov, Mee J Kim, Robin P Smith, Nadav Ahituv, Deanna L Kroetz
ABCG2 encodes the breast cancer resistance protein (BCRP), an efflux membrane transporter important in detoxification of xenobiotics. In the present study, the basal activity of the ABCG2 promoter in liver, kidney, intestine and breast cell lines was examined using luciferase reporter assays. The promoter activity of reference and variant ABCG2 sequences were compared in HepG2, HEK293T, HCT116 and MCF-7 cell lines. The ABCG2 promoter activity was strongest in the kidney and intestine cell lines. Four variants in the basal ABCG2 promoter (rs76656413, rs66664036, rs139256004 and rs59370292) decreased the promoter activity by 25-50% in at least three of the four cell lines...
February 21, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Jaqueline Pazinato, Otávio M Cruz, Karine P Naidek, Amanda R A Pires, Eduard Westphal, Hugo Gallardo, Hélène Baubichon-Cortay, Maria E M Rocha, Glaucia R Martinez, Sheila M B Winnischofer, Attilio Di Pietro, Herbert Winnischofer
A new series of amphiphilic η6 -areneruthenium(II) compounds containing phenylazo ligands (group I: compounds 1a, 1b, 2a and 2b) and phenyloxadiazole ligands (group II: compounds 3a, 3b, 4a and 4b) were synthesized and characterized for their anti-glioblastoma activity. The effects of the amphiphilic η6 -areneruthenium(II) complexes on the viability of three human glioblastoma cell lines, U251, U87MG and T98G, were evaluated. The azo-derivative ruthenium complexes (group I) showed high cytotoxicity to all cell lines, whilst most oxadiazole-derivative complexes (group II) were less cytotoxic, except for compound 4a...
February 12, 2018: European Journal of Medicinal Chemistry
Xiaoran Guo, Kenneth K W To, Zhen Chen, Xiaokun Wang, Jianye Zhang, Min Luo, Fang Wang, Shirong Yan, Liwu Fu
BACKGROUND: ATP-binding cassette subfamily G member 2 (ABCG2), a member of the ABC transporter superfamily proteins, mediates multidrug resistance (MDR) by transporting substrate anticancer drugs out of cancer cells and decreasing their intracellular accumulation. MDR is a major hurdle to successful chemotherapy. A logical approach to overcome MDR is to inhibit the transporter. However, no safe and effective MDR inhibitor has been approved in the clinic. METHODS: The MTT assay was used to evaluate cell cytotoxicity and MDR reversal effect...
February 20, 2018: Journal of Experimental & Clinical Cancer Research: CR
Won-Yong Jeong, Hye-Young Yoo, Chan-Wha Kim
Corneal epithelial cells (CECs) play an important role in the function of the cornea, and are maintained by corneal epithelial stem cells (CESCs). Recent studies have shown that neuronal growth factors affect the proliferation and migration of CESCs. Neuregulin-1 (NR-1) is a neuronal growth factor that is expressed in the early stages of brain development. The aim of this study was to determine whether NR-1 activates corneal wound healing. We observed that NR-1 activated both proliferation and migration of CECs...
February 20, 2018: Growth Factors
Kenta Yagi, Akira Shimada, Toshiaki Sendo
Imatinib (IMA) is the standard treatment for CML; however, stopping IMA sometimes results in disease relapse, which suggests that leukemic stem cells (LSCs) remain in such patients, even after complete molecular remission has been achieved. Therefore, new strategies will be required to eradicate LSCs. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is part of the BCR-ABL signaling network, and it is activated in CML, especially in LSCs. JAK2 is known to be associated with CML survival, but the role of JAK3 in CML remains unknown...
February 16, 2018: European Journal of Pharmacology
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