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Ning Wei, Michelle L Gumz, Anita T Layton
Major renal functions such as renal blood flow, glomerular filtration rate, and urinary excretion are known to exhibit circadian oscillations. However, the underlying mechanisms that govern these variations have yet to be fully elucidated. To better understand the impact of the circadian clock on renal solute and water transport, we have developed a computational model of the renal circadian clock, and coupled that model to an epithelial transport model of the proximal convoluted cell of the rat kidney. The activity of the Na$^+$-H$^+$ exchanger 3 (NHE3) is assumed to be regulated by changes in transcription of the NHE3 mRNA due to regulation by circadian clock proteins...
March 14, 2018: American Journal of Physiology. Renal Physiology
Vinod K Bhutani, M Jeffrey Maisels, David L Schutzman, Martin E Castillo Cuadrado, Janelle L Aby, Debra L Bogen, Robert D Christensen, Jon F Watchko, Ronald J Wong, David K Stevenson
AIM: To identify neonates at risk for haemolytic hyperbilirubinaemia through near-concurrrent measurements of total serum/plasma bilirubin (TB) or transcutaneous bilirubin (TcB) and end-tidal breath carbon monoxide (CO), corrected for ambient CO (ETCOc), an index of bilirubin production and haemolysis. METHODS: Paired TB/TcB (mg/dL) and ETCOc (ppm) measurements were obtained in newborns (n=283) at 20 to <60h of age in five nurseries. TB/TcB values were assigned TB/TcB percentile risk using the Bhutani hour-specific nomogram...
March 13, 2018: Acta Paediatrica
Ji-Liang Zhang, Min Liu, Chun-Nuan Zhang, Er-Chao Li, Ming-Zhen Fan, Mao-Xian Huang
The brain of fish displays sexual dimorphisms and exhibits remarkable sexual plasticity throughout their life span. Although reproductive toxicity of tributyltin (TBT) in fish is well documented in fish, it remains unknown whether TBT interrupts sexual dimorphisms of fish brains. In this work, brain transcriptomic profiles of rare minnow (Gobiocypris rarus) was characterized and sex-biased genes were identified using RNA sequencing. Functional annotation and enrichment analysis were performed to reveal differences of gene products and pathways between the brains of male and female fish...
March 7, 2018: Ecotoxicology and Environmental Safety
Jian-Xiang Wei, Jing Wang, Yun-Xia Zhu, Jun Sun, Hou-Ming Xu, Ming Li
BACKGROUND: Traditional Chinese Medicine (TCM) is a style of traditional medicine informed by modern medicine but built on a foundation of more than 2500 years of Chinese medical practice. According to statistics, TCM accounts for approximately 14% of total adverse drug reaction (ADR) spontaneous reporting data in China. Because of the complexity of the components in TCM formula, which makes it essentially different from Western medicine, it is critical to determine whether ADR reports of TCM should be analyzed independently...
March 9, 2018: BMC Medical Informatics and Decision Making
Qin Zhu, Peifen Zheng, Xinyu Chen, Feng Zhou, Qiaona He, Yuefeng Yang
Ulcerative colitis (UC) is a chronic and nonspecific intestinal inflammatory disease, which may increase the risk of colon cancer. Andrographolide is a main active component of Andrographis paniculata . The anti-inflammatory ability of andrographolide suggested its potential therapeutic effect against UC. In the present study, elevated serum concentrations of proinflammatory factors, including (TNF)-α, interleukin (IL)-1β, IL-6 and IL-23, as well as increased percentages of Th17 cells (IL-17+CD4+ cells) in CD4+ cells were detected in UC patients compared to that in healthy donors...
2018: American Journal of Translational Research
Mitsunori Kono, Atsuko Ochida, Tsuneo Oda, Takashi Imada, Yoshihiro Banno, Naohiro Taya, Shinichi Masada, Tetsuji Kawamoto, Kazuko Yonemori, Yoshi Nara, Yoshiyuki Fukase, Tomoya Yukawa, Hidekazu Tokuhara, Robert Skene, Bi-Ching Sang, Isaac D Hoffman, Gyorgy P Snell, Keiko Uga, Akira Shibata, Keiko Igaki, Yoshiki Nakamura, Hideyuki Nakagawa, Noboru Tsuchimori, Masashi Yamasaki, Junya Shirai, Satoshi Yamamoto
A series of tetrahydronaphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydroisoquinoline compound 1 by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound 7 with a lower logD value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [cis-3-({(5R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl}carbonyl)cyclobutyl]acetic acid, TAK-828F (10), which showed potent RORγt inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile...
March 6, 2018: Journal of Medicinal Chemistry
Yuki Ohba, Hajime Tei
Circadian rhythms are generated by the cyclic expression of several clock genes in mammals. The rhythmic expression of these genes is maintained by multiple transcriptional-translational feedback loops in addition to the posttranslational regulation of the clock proteins. Transcription of one of the key clock genes, Bmal1, which exhibits a nocturnal transcriptional rhythm in the suprachiasmatic nucleus of the mouse brain, is induced and repressed by RORs and REV-ERBs, respectively. Thus, the dynamics of the RORs and REV-ERBs expression, modification, subcellular localization and degradation of these transcriptional factors are critical for the transcriptional regulation of Bmal1...
March 6, 2018: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Yan Liu, Xiao-Xiao Rui, Hui Shi, Yi-Hua Qiu, Yu-Ping Peng
BACKGROUND Norepinephrine (NE), a neurotransmitter released from the sympathetic nerves, has been shown to be involved in rheumatoid arthritis (RA). However, its role in the sympathetic nervous system in RA is divergent. Herein, we demonstrate that the sympathetic neurotransmitter NE exerts an anti-inflammatory effect in collagen-induced arthritis (CIA), a mouse model of RA, by inhibiting Th17 cell differentiation and function via β2-adrenergic receptor (β2-AR) signaling. MATERIAL AND METHODS CIA was prepared by intradermal injection of collagen type II in the tail base of DBA1/J mice...
February 27, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Alexandra Fane De Salis, Reza Saatchi, Paul Dimitri
Vertebral fractures are common in children with osteogenesis imperfecta (OI). Current imaging methods for fracture detection (X-ray and DXA) use ionising radiation. This pilot study explored whether the alteration in blood flow in vertebral fractures results in skin temperature changes that may be detected using high resolution thermal imaging (HRTI) and thus assist diagnosis and monitoring of fractures in OI patients. Eleven participants aged 5-18 years with OI and known vertebral fractures were enrolled...
February 26, 2018: Medical & Biological Engineering & Computing
Matteo Dal Prà, Davide Carta, Gyorgy Szabadkai, Matteo Suman, Yahima Frión-Herrera, Nicola Paccagnella, Giulia Castellani, Sara De Martin, Maria Grazia Ferlin
Designing novel inverse agonists of NR RORγt still represents a challenge for the pharmaceutical community to develop therapeutics for treating immune diseases. By exploring the structure of NRs natural ligands, the representative arotenoid ligands and RORs specific ligands share some chemical homologies which can be exploited to design a novel molecular structure characterized by a polycyclic core bearing a polar head and a hydrophobic tail. Compound MG 2778 (8), a cyclopenta[a]phenantrene derivative, was identified as lead compound which was chemically modified at position 2 in order to obtain a small library for preliminary SARs...
February 15, 2018: Bioorganic & Medicinal Chemistry
Megan A Evans, Hyun Ah Kim, Yeong Hann Ling, Sandy Uong, Antony Vinh, T Michael De Silva, Thiruma V Arumugam, Andrew N Clarkson, Graeme R Zosky, Grant R Drummond, Brad R S Broughton, Christopher G Sobey
Acute inflammation can exacerbate brain injury after ischemic stroke. Beyond its well-characterized role in calcium metabolism, it is becoming increasingly appreciated that the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25-VitD3 ), has potent immunomodulatory properties. Here, we aimed to determine whether 1,25-VitD3 supplementation could reduce subsequent brain injury and associated inflammation after ischemic stroke. Male C57Bl6 mice were randomly assigned to be administered either 1,25-VitD3 (100 ng/kg/day) or vehicle i...
February 23, 2018: Neuromolecular Medicine
Jiaming Wang, Mei Ding
Growing axons are exposed to various guidance cues en route to their targets, but the mechanisms that govern the response of growth cones to combinations of signals remain largely elusive. Here, we found that the sole Robo receptor, SAX-3, in Caenorhabditis elegans functions as a coreceptor for Wnt/CWN-2 molecules. SAX-3 binds to Wnt/CWN-2 and facilitates the membrane recruitment of CWN-2. SAX-3 forms a complex with the Ror/CAM-1 receptor and its downstream effector Dsh/DSH-1, promoting signal transduction from Wnt to Dsh...
February 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
Daniel Caldeira, Raquel Rodrigues, Daisy Abreu, Ana Marta Anes, Mário M Rosa, Joaquim J Ferreira
OBJECTIVE: In this pharmacovigilance study, we aimed to determine the incidence of spontaneously reported suspected adverse drug reactions (ADRs) related to oral anticoagulants: non-vitamin K antagonist oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban, rivaroxaban) and vitamin K antagonists (VKA) Research design and methods: In this retrospective observational study, we extracted all the individual case safety reports related to oral anticoagulants recorded in the Portuguese Pharmacovigilance Database (January 2010 to April 2015)...
February 20, 2018: Expert Opinion on Drug Safety
Ichiro Takada, Megumi Tsuchiya, Kaori Yanaka, Shinya Hidano, Sayuri Takahashi, Takashi Kobayashi, Hidesato Ogawa, Sinichi Nakagawa, Makoto Makishima
Transcription and pre-mRNA splicing are complex, coupled processes that involve transcriptional co-regulators. Ess2 (also termed Dgcr14) is a nuclear protein that enhances the transcriptional activity of retinoic acid receptor-related orphan receptor gamma/gamma-t (Rorγ/γt). Ess2 is also a component of the spliceosomal C complex (containing U2, U5 and U6 snRNAs). However, the domains in Ess2 that function in splicing and transcription have not been identified. To elucidate the roles of Ess2 in splicing and transcription, we performed RNA immunoprecipitation (RIP) assays to detect Ess2-interacting snRNAs...
February 15, 2018: Biochemical and Biophysical Research Communications
M H Kuizenga, P J Colin, K M E M Reyntjens, D J Touw, H Nalbat, F H Knotnerus, H E M Vereecke, M M R F Struys
BACKGROUND: Neural inertia is defined as the tendency of the central nervous system to resist transitions between arousal states. This phenomenon has been observed in mice and Drosophila anaesthetized with volatile anaesthetics: the effect-site concentration required to induce anaesthesia in 50% of the population (C50 ) was significantly higher than the effect-site concentration for 50% of the population to recover from anaesthesia. We evaluated this phenomenon in humans using propofol or sevoflurane (both with or without remifentanil) as anaesthetic agents...
March 2018: British Journal of Anaesthesia
Ivana Sestak, Richard Buus, Jack Cuzick, Peter Dubsky, Ralf Kronenwett, Carsten Denkert, Sean Ferree, Dennis Sgroi, Catherine Schnabel, Frederick L Baehner, Elizabeth Mallon, Mitch Dowsett
Importance: Multiple molecular signatures are available for managing estrogen receptor (ER)-positive breast cancer but with little direct comparative information to guide the patient's choice. Objective: To conduct a within-patient comparison of the prognostic value of 6 multigene signatures in women with early ER-positive breast cancer who received endocrine therapy for 5 years. Design, Setting, and Participants: This retrospective biomarker analysis included 774 postmenopausal women with ER-positive ERBB2 (formerly HER2)-negative breast cancer...
February 15, 2018: JAMA Oncology
Hiroyuki Tanaka, Yuka Yoshiba, Tomoko Watanabe, Mitsutoshi Satoh, Toshihiro Ishii
PURPOSE: In order to clarify the occurrence of hypomagnesemia in Japan, we conducted a database search and analysis using the Japanese Adverse Drug Event Report database (JADER). METHODS: Among the cases recorded in JADER between April 2004 and December 2015, we targeted "hypomagnesemia" and analyzed the patients' backgrounds, drug involvement, other adverse events reported with hypomagnesemia, the time of hypomagnesemia onset, outcomes, and year when reported...
2018: Journal of Pharmacy & Pharmaceutical Sciences: a Publication of the Canadian Society for Pharmaceutical Sciences
Bernadette M Levesque, Anh Tran, Emily Levesque, Hira Shrestha, Ramona Silva, Marsha Adams, Marilyn Valles, Judith Burke, Alison Corning-Clarke, Carole Ferguson
OBJECTIVE: Language exposure is important for neurodevelopment, but is sparse in the neonatal intensive care unit (NICU). STUDY DESIGN: We introduced Reach Out and Read (ROR) in the NICU as a quality improvement initiative to increase language exposure. Measures included availability of books, accessibility of parents, and enrollment of infants, percent infants read to by their parents, and data from parental surveys. RESULT: 98 infants were included (40 before, 58 after)...
February 12, 2018: Journal of Perinatology: Official Journal of the California Perinatal Association
Muhe Shang, Xianghu Wang, Ying Zhang, Zhikui Gao, Tian Wang, Ran Liu
Background and objective: In an attempt to discover a new biomarker for early diagnosis and prognosis of esophageal squamous cell carcinoma (ESCC), the regulation mechanism of large intergenic non-coding RNA-regulator of reprogramming (lincRNA-ROR) as a microRNA (miRNA) sponge was studied. Patients and methods: ROR expression in 91 pairs of ESCC tissue samples and matched adjacent tissues was quantified with real-time fluorescent quantitative polymerase chain reaction (qRT-PCR)...
2018: OncoTargets and Therapy
Beatrice A Golomb, Abril Verden, Alexis K Messner, Hayley J Koslik, Keith B Hoffman
INTRODUCTION: Apparent elevations in reporting of amyotrophic lateral sclerosis (ALS)-like conditions associated with statin use have been previously described from data obtained via US and European databases. OBJECTIVE: The aim of this study was to examine US FDA Adverse Event Reporting System (FAERS) data to compare reporting odds ratios (RORs) of ALS and ALS-like conditions between statins and other drugs, for each statin agent. METHODS: We assessed for disproportional rates of reported ALS and ALS-related conditions for each statin agent separately by using the ROR formula...
February 9, 2018: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
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