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Junfang Zheng, Lei Wang, Zhiqiang Peng, Ying Yang, Duiping Feng, Junqi He
Clear cell renal cell carcinoma (ccRCC) is the most lethal neoplasm of the urologic system. Clinical therapeutic effect varies greatly between individual ccRCC patients, so there is an urgent need to develop prognostic molecular biomarkers to help clinicians identify patients in need of early aggressive management. In this study, samples from primary ccRCC tumor and their corresponding nontumor adjacent tissues (n=18) were analyzed by quantitative proteomic assay. Proteins downregulated in tumors were studied by GO and KEGG pathways enrichment analyses...
February 2017: EBioMedicine
Toshihide Higashino, Hirotaka Matsuo, Masayuki Sakiyama, Akiyoshi Nakayama, Takahiro Nakamura, Tappei Takada, Hiraku Ogata, Yusuke Kawamura, Makoto Kawaguchi, Mariko Naito, Sayo Kawai, Yuzo Takada, Hiroshi Ooyama, Hiroshi Suzuki, Nariyoshi Shinomiya
PDZ domain containing 1 (PDZK1) is a scaffold protein that organizes a transportsome and regulates several transporters' functions including urate and drug transporters. Therefore, PDZK1 in renal proximal tubules may affect serum uric acid levels through PDZK1-binding renal urate transporters. Two previous studies in Japanese male population reported that a PDZK1 single nucleotide polymorphism (SNP), rs12129861, was not associated with gout. In the present study, we performed a further association analysis between gout and rs12129861 in a different large-scale Japanese male population and a meta-analysis with previous Japanese population studies...
December 2016: Drug Metabolism and Pharmacokinetics
Rinku Pal, Qingen Ke, German A Pihan, Ayce Yesilaltay, Marsha L Penman, Li Wang, Chandramohan Chitraju, Peter M Kang, Monty Krieger, Olivier Kocher
The HDL receptor SR-BI mediates the transfer of cholesteryl esters from HDL to cells and controls HDL abundance and structure. Depending on the genetic background, loss of SR-BI causes hypercholesterolemia, anemia, reticulocytosis, splenomegaly, thrombocytopenia, female infertility, and fatal coronary heart disease (CHD). The carboxy terminus of SR-BI ((505)QEAKL(509)) must bind to the cytoplasmic adaptor PDZK1 for normal hepatic-but not steroidogenic cell-expression of SR-BI protein. To determine whether SR-BI's carboxy terminus is also required for normal protein levels in steroidogenic cells, we introduced into SR-BI's gene a (507)Ala/STOP mutation that produces a truncated receptor (SR-BIΔCT)...
December 1, 2016: American Journal of Physiology. Heart and Circulatory Physiology
Marguerite M Vantangoli, Samantha J Madnick, Shelby Wilson, Kim Boekelheide
The development of three-dimensional (3D) cultures is increasing, as they are able to provide the utility of in vitro models and the strength of testing in physiologically relevant systems. When cultured in a scaffold-free agarose hydrogel system, MCF-7 human breast carcinoma cells organize and develop into microtissues that contain a luminal space, in stark contrast to the flat morphology of MCF-7 two-dimensional (2D) monolayer cultures. Following exposure to 1nM E2, expression of typical estrogen-responsive genes, including progesterone receptor (PGR), PDZ containing domain 1 (PDZK1) and amphiregulin (AREG) is increased in both 2D and 3D cultures...
2016: PloS One
Yi Huo, Zhiguo Zheng, Yuling Chen, Qingtao Wang, Zhenyu Zhang, Haiteng Deng
Cisplatin and other platinum-based drugs have been widely used in the treatment of ovarian cancer, but most patients acquire the drug resistance that greatly compromises the efficacy of drugs. Understanding the mechanism of drug resistance is important for finding new therapeutic approaches. In the present study, we found that the expression of vimentin was downregulated in drug-resistant ovarian cancer cell lines A2780-DR and HO-8910 as compared to their respective control cells. Overexpression of vimentin in A2780-DR cells markedly increased their sensitivity to cisplatin, whereas knockdown of vimentin in A2780, HO-8910-PM and HO-8910 cells increased the resistance to cisplatin, demonstrating that vimentin silencing enhanced cisplatin resistance in ovarian cancer cells...
July 19, 2016: Oncotarget
Denise A Monahan, Jun Wang, Oukseub Lee, Elizabeth Revesz, Nancy Taft, David Ivancic, Nora M Hansen, Kevin P Bethke, C Zalles, Seema A Khan
PURPOSE: The contralateral unaffected breast (CUB) of women with unilateral breast cancer provides a model for the study of breast tissue-based risk factors. Using random fine needle aspiration (rFNA), we have investigated hormonal and gene expression patterns related to atypia in the CUBs of newly diagnosed breast cancer patients. METHODS: 83 women underwent rFNA of the CUB. Cytologic analysis was performed using the Masood Score (MS), atypia was defined as MS > 14...
December 2016: Surgical Oncology
Bernardo L Trigatti, Mark Fuller
Atherosclerosis is a leading underlying factor in cardiovascular disease and stroke, important causes of morbidity and mortality across the globe. Abundant epidemiological studies demonstrate that high levels of high density lipoprotein (HDL) are associated with reduced risk of atherosclerosis and preclinical, animal model studies demonstrate that this association is causative. Understanding the molecular mechanisms underlying the protective effects of HDL will allow more strategic approaches to development of HDL based therapeutics...
August 20, 2015: Journal of Biomedical Research
Chaitanya P Puranik, Kathleen A Ryan, Zhaoyu Yin, E Angeles Martinez-Mier, John S Preisser, Eric T Everett
The study objective was to investigate the effects of fluoride on intact parathyroid hormone (iPTH) secretion. Thyro-parathyroid complexes (TPC) from C3H (n = 18) and B6 (n = 18) mice were cultured in Ca²⁺-optimized medium. TPC were treated with 0, 250, or 500 µM NaF for 24 h and secreted iPTH assayed by ELISA. C3H (n = 78) and B6 (n = 78) mice were gavaged once with distilled or fluoride (0.001 mg [F⁻]/g of body weight) water. At serial time points (0.5-96 h) serum iPTH, fluoride, total calcium, phosphorus, and magnesium levels were determined...
2015: Cells, Tissues, Organs
Kyle Jansson, Jessica Venugopal, Gladis Sánchez, Brenda S Magenheimer, Gail A Reif, Darren P Wallace, James P Calvet, Gustavo Blanco
Cyst enlargement in autosomal dominant polycystic kidney disease (ADPKD) requires the transepithelial secretion of fluid into the cyst lumen. We previously showed that physiological amounts of ouabain enhance cAMP-dependent fluid secretion and cyst growth of human ADPKD cyst epithelial cells in culture and formation of cyst-like dilations in metanephric kidneys from Pkd1 mutant mice. Here, we investigated the mechanisms by which ouabain promotes cAMP-dependent fluid secretion and cystogenesis. Ouabain (3 nM) enhanced cAMP-induced cyst-like dilations in embryonic kidneys from Pkd1 (m1Bei) mice, but had no effect on metanephroi from Pkd1 (m1Bei) mice that lack expression of the cystic fibrosis transmembrane conductance regulator (CFTR)...
December 2015: Journal of Membrane Biology
Hua Yang, Lihui Gao, Yanfen Niu, Yuanfang Zhou, Hua Lin, Jing Jiang, Xiangfu Kong, Xu Liu, Ling Li
Mangiferin, a natural glucosyl xanthone from the leaves of Mangifera indica L., was previously shown to exert potent hypouricemic effects associated with inhibition of the activity of xanthine dehydrogenase/oxidase. The present study aimed to evaluate its uricosuric effect and possible molecular mechanisms underlying the renal urate transporters responsible for urate reabsorption in vivo. Mangiferin (1.5-24.0 mg/kg) was administered intragastrically to hyperuricemic mice and rats induced by the intraperitoneal injection of uric acid and potassium oxonate, respectively...
2015: Biological & Pharmaceutical Bulletin
Ben J Wu, Sudichhya Shrestha, Kwok L Ong, Douglas Johns, Louise L Dunn, Liming Hou, Philip J Barter, Kerry-Anne Rye
BACKGROUND: High density lipoprotein (HDL) infusions increase new blood vessel formation (angiogenesis) in rodents with ischemic injury. This study asks if increasing HDL levels by inhibiting cholesteryl ester transfer protein (CETP) activity increases angiogenesis in New Zealand White (NZW) rabbits with hindlimb ischemia. METHODS AND RESULTS: NZW rabbits were maintained for 6weeks on chow or chow supplemented with 0.07% or 0.14% (wt/wt) of the CETP inhibitor, des-fluoro-anacetrapib...
November 15, 2015: International Journal of Cardiology
Hogyoung Kim, Abdelmetalab Tarhuni, Zakaria Y Abd Elmageed, A Hamid Boulares
BACKGROUND: We and others have extensively investigated the role of PARP-1 in cell growth and demise in response to pathophysiological cues. Most of the clinical trials on PARP inhibitors are targeting primarily estrogen receptor (ER) negative cancers with BRCA-deficiency. It is surprising that the role of the enzyme has yet to be investigated in ER-mediated cell growth. It is noteworthy that ER is expressed in the majority of breast cancers. We recently showed that the scaffolding protein PDZK1 is critical for 17β-estradiol (E2)-induced growth of breast cancer cells...
2015: Journal of Translational Medicine
Helen M Reid, B Therese Kinsella
The prostanoid Prostacyclin plays diverse physiologic roles within the vasculature and other systems, and is widely implicated in several cardiovascular, pulmonary and renal diseases. Despite this, knowledge of the factors regulating expression of the I prostanoid receptor (the IP) remained largely unknown. This review details recent advances in understanding the key transcriptional regulators determining expression of the PTGIR gene in the human vasculature and the identification of novel interacting partners of the IP that impact on its function therein...
September 2015: Prostaglandins & Other Lipid Mediators
Tony R Merriman
Genome-wide association studies that scan the genome for common genetic variants associated with phenotype have greatly advanced medical knowledge. Hyperuricemia is no exception, with 28 loci identified. However, genetic control of pathways determining gout in the presence of hyperuricemia is still poorly understood. Two important pathways determining hyperuricemia have been confirmed (renal and gut excretion of uric acid with glycolysis now firmly implicated). Major urate loci are SLC2A9 and ABCG2. Recent studies show that SLC2A9 is involved in renal and gut excretion of uric acid and is implicated in antioxidant defense...
April 10, 2015: Arthritis Research & Therapy
Wan Ru Lee, Anastasia Sacharidou, Erica Behling-Kelly, Sarah C Oltmann, Weifei Zhu, Mohamed Ahmed, Robert D Gerard, David Y Hui, Jun-ichi Abe, Philip W Shaul, Chieko Mineo
Scavenger receptor class B, type I (SR-BI) and its adaptor protein PDZK1 mediate responses to HDL cholesterol in endothelium. Whether the receptor-adaptor protein tandem serves functions in other vascular cell types is unknown. The current work determined the roles of SR-BI and PDZK1 in vascular smooth muscle (VSM). To evaluate possible VSM functions of SR-BI and PDZK1 in vivo, neointima formation was assessed 21 days post-ligation in the carotid arteries of wild-type, SR-BI-/- or PDZK1-/- mice. Whereas neointima development was negligible in wild-type and SR-BI-/-, there was marked neointima formation in PDZK1-/- mice...
2015: PloS One
Aguirre A de Cubas, Esther Korpershoek, Lucia Inglada-Pérez, Eric Letouzé, Maria Currás-Freixes, Agustin F Fernández, Iñaki Comino-Méndez, Francesca Schiavi, Veronika Mancikova, Graeme Eisenhofer, Massimo Mannelli, Guiseppe Opocher, Henri Timmers, Felix Beuschlein, Ronald de Krijger, Alberto Cascon, Cristina Rodríguez-Antona, Mario F Fraga, Judith Favier, Anne-Paule Gimenez-Roqueplo, Mercedes Robledo
PURPOSE: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors, associated with highly variable postoperative evolution. The scarcity of reliable PPGL prognostic markers continues to complicate patient management. In this study, we explored genome-wide DNA methylation patterns in the context of PPGL malignancy to identify novel prognostic markers. EXPERIMENTAL DESIGN: We retrospectively investigated DNA methylation patterns in PPGL with and without metastases using high-throughput DNA methylation profiling data (Illumina 27K) from two large, well-characterized discovery (n = 123; 24 metastatic) and primary validation (n = 154; 24 metastatic) series...
July 1, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Henry A Dunn, Stephen S G Ferguson
G protein-coupled receptors (GPCRs) contribute to the regulation of every aspect of human physiology and are therapeutic targets for the treatment of numerous diseases. As a consequence, understanding the myriad of mechanisms controlling GPCR signaling and trafficking is essential for the development of new pharmacological strategies for the treatment of human pathologies. Of the many GPCR-interacting proteins, postsynaptic density protein of 95 kilodaltons, disc large, zona occludens-1 (PDZ) domain-containing proteins appear most abundant and have similarly been implicated in disease mechanisms...
October 2015: Molecular Pharmacology
Changsuk Moon, Weiqiang Zhang, Aixia Ren, Kavisha Arora, Chandrima Sinha, Sunitha Yarlagadda, Koryse Woodrooffe, John D Schuetz, Koteswara Rao Valasani, Hugo R de Jonge, Shiva Kumar Shanmukhappa, Mohamed Tarek M Shata, Randal K Buddington, Kaushik Parthasarathi, Anjaparavanda P Naren
Diarrhea is one of the most common adverse side effects observed in ∼7% of individuals consuming Food and Drug Administration (FDA)-approved drugs. The mechanism of how these drugs alter fluid secretion in the gut and induce diarrhea is not clearly understood. Several drugs are either substrates or inhibitors of multidrug resistance protein 4 (MRP4), such as the anti-colon cancer drug irinotecan and an anti-retroviral used to treat HIV infection, 3'-azido-3'-deoxythymidine (AZT). These drugs activate cystic fibrosis transmembrane conductance regulator (CFTR)-mediated fluid secretion by inhibiting MRP4-mediated cAMP efflux...
May 1, 2015: Journal of Biological Chemistry
Kyriaki Michailidou, Jonathan Beesley, Sara Lindstrom, Sander Canisius, Joe Dennis, Michael J Lush, Mel J Maranian, Manjeet K Bolla, Qin Wang, Mitul Shah, Barbara J Perkins, Kamila Czene, Mikael Eriksson, Hatef Darabi, Judith S Brand, Stig E Bojesen, Børge G Nordestgaard, Henrik Flyger, Sune F Nielsen, Nazneen Rahman, Clare Turnbull, Olivia Fletcher, Julian Peto, Lorna Gibson, Isabel dos-Santos-Silva, Jenny Chang-Claude, Dieter Flesch-Janys, Anja Rudolph, Ursula Eilber, Sabine Behrens, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Sofia Khan, Kirsimari Aaltonen, Habibul Ahsan, Muhammad G Kibriya, Alice S Whittemore, Esther M John, Kathleen E Malone, Marilie D Gammon, Regina M Santella, Giske Ursin, Enes Makalic, Daniel F Schmidt, Graham Casey, David J Hunter, Susan M Gapstur, Mia M Gaudet, W Ryan Diver, Christopher A Haiman, Fredrick Schumacher, Brian E Henderson, Loic Le Marchand, Christine D Berg, Stephen J Chanock, Jonine Figueroa, Robert N Hoover, Diether Lambrechts, Patrick Neven, Hans Wildiers, Erik van Limbergen, Marjanka K Schmidt, Annegien Broeks, Senno Verhoef, Sten Cornelissen, Fergus J Couch, Janet E Olson, Emily Hallberg, Celine Vachon, Quinten Waisfisz, Hanne Meijers-Heijboer, Muriel A Adank, Rob B van der Luijt, Jingmei Li, Jianjun Liu, Keith Humphreys, Daehee Kang, Ji-Yeob Choi, Sue K Park, Keun-Young Yoo, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Kazuo Tajima, Pascal Guénel, Thérèse Truong, Claire Mulot, Marie Sanchez, Barbara Burwinkel, Frederik Marme, Harald Surowy, Christof Sohn, Anna H Wu, Chiu-chen Tseng, David Van Den Berg, Daniel O Stram, Anna González-Neira, Javier Benitez, M Pilar Zamora, Jose Ignacio Arias Perez, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Hui Cai, Angela Cox, Simon S Cross, Malcolm W R Reed, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Elinor J Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Annika Lindblom, Sara Margolin, Soo Hwang Teo, Cheng Har Yip, Nur Aishah Mohd Taib, Gie-Hooi Tan, Maartje J Hooning, Antoinette Hollestelle, John W M Martens, J Margriet Collée, William Blot, Lisa B Signorello, Qiuyin Cai, John L Hopper, Melissa C Southey, Helen Tsimiklis, Carmel Apicella, Chen-Yang Shen, Chia-Ni Hsiung, Pei-Ei Wu, Ming-Feng Hou, Vessela N Kristensen, Silje Nord, Grethe I Grenaker Alnaes, Graham G Giles, Roger L Milne, Catriona McLean, Federico Canzian, Dimitrios Trichopoulos, Petra Peeters, Eiliv Lund, Malin Sund, Kay-Tee Khaw, Marc J Gunter, Domenico Palli, Lotte Maxild Mortensen, Laure Dossus, Jose-Maria Huerta, Alfons Meindl, Rita K Schmutzler, Christian Sutter, Rongxi Yang, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Mikael Hartman, Hui Miao, Kee Seng Chia, Ching Wan Chan, Peter A Fasching, Alexander Hein, Matthias W Beckmann, Lothar Haeberle, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Alan Ashworth, Nick Orr, Minouk J Schoemaker, Anthony J Swerdlow, Louise Brinton, Montserrat Garcia-Closas, Wei Zheng, Sandra L Halverson, Martha Shrubsole, Jirong Long, Mark S Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Hiltrud Brauch, Ute Hamann, Thomas Brüning, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Loris Bernard, Natalia V Bogdanova, Thilo Dörk, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Peter Devilee, Robert A E M Tollenaar, Caroline Seynaeve, Christi J Van Asperen, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska, Tomasz Huzarski, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Susan Slager, Amanda E Toland, Christine B Ambrosone, Drakoulis Yannoukakos, Maria Kabisch, Diana Torres, Susan L Neuhausen, Hoda Anton-Culver, Craig Luccarini, Caroline Baynes, Shahana Ahmed, Catherine S Healey, Daniel C Tessier, Daniel Vincent, Francois Bacot, Guillermo Pita, M Rosario Alonso, Nuria Álvarez, Daniel Herrero, Jacques Simard, Paul P D P Pharoah, Peter Kraft, Alison M Dunning, Georgia Chenevix-Trench, Per Hall, Douglas F Easton
Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8)...
April 2015: Nature Genetics
Tobias Hebel, Kristina Eisinger, Markus Neumeier, Lisa Rein-Fischboeck, Rebekka Pohl, Elisabeth M Meier, Alfred Boettcher, Stanley C Froehner, Marvin E Adams, Gerhard Liebisch, Sabrina Krautbauer, Christa Buechler
The syntrophins alpha (SNTA) and beta 2 (SNTB2) are molecular adaptor proteins shown to stabilize ABCA1, an essential regulator of HDL cholesterol. Furthermore, SNTB2 is involved in glucose stimulated insulin release. Hyperglycemia and dyslipidemia are characteristic features of the metabolic syndrome, a serious public health problem with rising prevalence. Therefore, it is important to understand the role of the syntrophins herein. Mice deficient for both syntrophins (SNTA/B2-/-) have normal insulin and glucose tolerance, hepatic ABCA1 protein and cholesterol...
May 2015: Biochimica et Biophysica Acta
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