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https://www.readbyqxmd.com/read/28231247/favipiravir-pharmacokinetics-in-ebola-infected-patients-of-the-jiki-trial-reveals-concentrations-lower-than-targeted
#1
Thi Huyen Tram Nguyen, Jérémie Guedj, Xavier Anglaret, Cédric Laouénan, Vincent Madelain, Anne-Marie Taburet, Sylvain Baize, Daouda Sissoko, Boris Pastorino, Anne Rodallec, Géraldine Piorkowski, Sara Carazo, Mamoudou N Conde, Jean-Luc Gala, Joseph Akoi Bore, Caroline Carbonnelle, Frédéric Jacquot, Hervé Raoul, Denis Malvy, Xavier de Lamballerie, France Mentré
BACKGROUND: In 2014-2015, we assessed favipiravir tolerance and efficacy in patients with Ebola virus (EBOV) disease (EVD) in Guinea (JIKI trial). Because the drug had never been used before for this indication and that high concentrations of the drugs were needed to achieve antiviral efficacy against EBOV, a pharmacokinetic model had been used to propose relevant dosing regimen. Here we report the favipiravir plasma concentrations that were achieved in participants in the JIKI trial and put them in perspective with the model-based targeted concentrations...
February 23, 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28230989/development-of-the-first-generation-of-disulfide-based-subtype-selective-and-potent-covalent-pyruvate-dehydrogenase-kinase-1-pdk1-inhibitors
#2
Yifu Liu, Zuoquan Xie, Dan Zhao, Jin Zhu, Fei Mao, Shuai Tang, Hui Xu, Cheng Luo, Mei-Yu Geng, Min Huang, Jian Li
Pyruvate dehydrogenase kinases (PDKs) are overexpressed in most cancer cells and are responsible for aberrant glucose metabolism. We previously described Bis(4-morpholinyl thiocarbonyl)-disulfide (JX06, 16) as the first covalent inhibitor of PDK1. Here, based on the scaffold of 16, we identify two novel types of disulfide-based PDK1 inhibitors. The most potent analog, 3a, effectively inhibits PDK1 both at the molecular (kinact/Ki = 4.17×103M-1s-1) and the cellular level (down to 0.1 μM). In contrast to 16, 3a is a potent and subtype-selective inhibitor of PDK1 with >40-fold selectivity for PDK2-4...
February 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28230981/high-potency-phenylquinoxalinone-cystic-fibrosis-transmembrane-conductance-regulator-cftr-activators
#3
Jung-Ho Son, Jie S Zhu, Puay-Wah Phuan, Onur Cil, Andrew P Teuthorn, Colton K Ku, Sujin Lee, Alan S Verkman, Mark J Kurth
We previously identified phenylquinoxalinone CFTRact-J027 (4) as a cystic fibrosis transmembrane conductance regulator (CFTR) activator with an EC50 of ~200 nM, and demonstrated its therapeutic efficacy in mouse models of constipation. Here, structure-activity studies were done on 36 synthesized phenylquinoxalinone analogs to identify compounds with improved potency and altered metabolic stability. Synthesis of the phenylquinoxalinone core was generally accomplished by condensation of 1,2-phenylenediamines with substituted phenyloxoacetates...
February 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28230922/adipose-derived-aldehyde-dehydrogenase-expressing-cells-promote-dermal-regenerative-potential-with-collagen-glycosaminoglycan-scaffold
#4
Hajime Matsumine, Kazuyuki Numakura, Satoshi Tsunoda, Huan Wang, Rui Matsumine, Mihail Climov, Giorgio Giatsidis, Vikas P Sukhatme, Dennis P Orgill
Aldehyde dehydrogenase (ALDH) is an enzyme that plays an important role in retinoid metabolism and highly expressed in stem cells. This study isolated ALDH-expressing cells from subcutaneous adipose tissue and investigated their potential to enhance healing in a full-thickness skin wound in rats by co-implanting them with collagen-glycosaminoglycan (c-GAG) scaffolds. ALDH-positive cells were isolated by a fluorescence-activated cell sorting technique from Lewis rat's stromal-vascular-fraction (SVF) and transplanted with c-GAG scaffolds in a rat full-thickness skin wound model...
November 7, 2016: Wound Repair and Regeneration
https://www.readbyqxmd.com/read/28230890/effect-of-testosterone-replacement-therapy-on-vitamin-d-and-fgf-23-levels-in-congenital-hypogonadism
#5
Cem Haymana, Alper Sonmez, Aydogan Aydogdu, Serkan Tapan, Yalcin Basaran, Coskun Meric, Kamil Baskoy, Abdullah Taslipinar, Mahmut Ilker Yilmaz, Omer Azal
INTRODUCTION: Patients with hypogonadism are at increased risk of cardiac and metabolic diseases and osteoporosis. Vitamin D and Fibroblast growth factor-23 (FGF-23) play role in the regulation of bone mineral metabolism and endothelial functions. Low vitamin D levels are reported in hypogonadism, while there is no data about the effect of testosterone replacement therapy (TRT). We investigated the effect of TRT on vitamin D and FGF-23 levels along with endothelial functions and insulin resistance in hypogonadal patients...
February 23, 2017: Endokrynologia Polska
https://www.readbyqxmd.com/read/28230703/omics-and-cachexia
#6
Brigitte Twelkmeyer, Nicolas Tardif, Olav Rooyackers
PURPOSE OF REVIEW: The purpose of this review is to recapture recent advances in cachexia-related diseases, mainly cancer cachexia, and treatment using genomic, transcriptomics, proteomic, and metabolomics-related techniques. RECENT FINDINGS: From recent studies in the cancer cachexia field it is clear that the tumor has a direct effect on distant organs via its secretome. The affected pathways on the other hand were largely known from earlier studies with changes in energy-related pathways (mainly lipid metabolism) and the protein degradation pathways...
February 21, 2017: Current Opinion in Clinical Nutrition and Metabolic Care
https://www.readbyqxmd.com/read/28230104/long-term-impact-of-temporal-sequence-from-childhood-obesity-to-hyperinsulinemia-on-adult-metabolic-syndrome-and-diabetes-the-bogalusa-heart-study
#7
Tao Zhang, Huijie Zhang, Ying Li, Shengxu Li, Camilo Fernandez, Lydia Bazzano, Jiang He, Fuzhong Xue, Wei Chen
This study aims to delineate the temporal relations between body mass index (BMI) and insulin in childhood and their impact on adult metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM).The longitudinal cohort consisted of 609 whites and 339 blacks who had BMI and fasting insulin measured twice in childhood (mean age = 10.5 years at baseline and 15.9 years at follow-up). Incident MetS and T2DM were identified in adulthood (mean age = 30.5 years). Cross-lagged panel and mediation analysis models were used...
February 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28230078/unravelling-the-metabolic-impact-of-sbs-associated-microbial-dysbiosis-insights-from-the-piglet-short-bowel-syndrome-model
#8
Prue M Pereira-Fantini, Sean G Byars, James Pitt, Susan Lapthorne, Fiona Fouhy, Paul D Cotter, Julie E Bines
Liver disease is a major source of morbidity and mortality in children with short bowel syndrome (SBS). SBS-associated microbial dysbiosis has recently been implicated in the development of SBS-associated liver disease (SBS-ALD), however the pathological implications of this association have not been explored. In this study high-throughput sequencing of colonic content from the well-validated piglet SBS-ALD model was examined to determine alterations in microbial communities, and concurrent metabolic alterations identified in urine samples via targeted mass spectrometry approaches (GC-MS, LC-MS, FIA-MS) further uncovered impacts of microbial disturbance on metabolic outcomes in SBS-ALD...
February 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28229935/mice-deficient-in-l-12-15-lipoxygenase-show-increased-vulnerability-to-3-nitropropionic-acid-neurotoxicity
#9
Yan He, Rita C Akumuo, Yuan Yang, Sandra J Hewett
Considerable evidence supports a contributory role for leukocyte-type 12/15 Lipoxygenase (L-12/15 LO) in mediating hippocampal and cortical neuronal injury in models of Alzheimer's disease and stroke. Whether L-12/15 LO contributes to neuronal injury in a model of Huntington's disease (HD) has yet to be determined. HD is characterized by marked striatal neuronal loss, which can be mimicked in humans and animals by inhibition of mitochondrial complex II using 3-Nitropropionic acid (3-NP). Herein, we compared histological and behavioral outcomes between mice that were wild-type or null for L-12/15 LO following systemic injection of 3NP...
February 13, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28229926/the-role-of-frailty-in-explaining-the-association-between-the-metabolic-syndrome-and-mortality-in-older-adults
#10
Emiel O Hoogendijk, Martijn Huisman, Adriana J van Ballegooijen
The association between the metabolic syndrome (MetS) and adverse outcomes in older adults may be explained by other health conditions. This study examined the role of frailty in explaining the association between MetS and mortality, independent of comorbidity. Data were used from 1247 men and women aged ≥65years of the Longitudinal Aging Study Amsterdam. MetS was assessed using the definition of the US National Cholesterol Education Program. Frailty was measured by the frailty phenotype. Mortality was monitored from 1995 until 2015...
February 14, 2017: Experimental Gerontology
https://www.readbyqxmd.com/read/28229521/microbial-potential-for-carbon-and-nutrient-cycling-in-a-geogenic-supercritical-carbon-dioxide-reservoir
#11
Adam J E Freedman, BoonFei Tan, Janelle R Thompson
Microorganisms catalyze carbon cycling and biogeochemical reactions in the deep subsurface and thus may be expected to influence the fate of injected supercritical (sc) CO2 following geological carbon sequestration (GCS). We hypothesized that natural subsurface scCO2 reservoirs, which serve as analogs for the long-term fate of sequestered scCO2 , harbor a "deep carbonated biosphere" with carbon cycling potential. We sampled subsurface fluids from scCO2 -water separators at a natural scCO2 reservoir at McElmo Dome, Colorado for analysis of 16S rRNA gene diversity and metagenome content...
February 22, 2017: Environmental Microbiology
https://www.readbyqxmd.com/read/28229374/effect-of-short-term-fasting-on-systemic-cytochrome-p450-mediated-drug-metabolism-in-healthy-subjects-a-randomized-controlled-crossover-study-using-a-cocktail-approach
#12
Laureen A Lammers, Roos Achterbergh, Ron H N van Schaik, Johannes A Romijn, Ron A A Mathôt
BACKGROUND AND OBJECTIVE: Short-term fasting can alter drug exposure but it is unknown whether this is an effect of altered oral bioavailability and/or systemic clearance. Therefore, the aim of our study was to assess the effect of short-term fasting on oral bioavailability and systemic clearance of different drugs. METHODS: In a randomized, controlled, crossover trial, 12 healthy subjects received a single administration of a cytochrome P450 (CYP) probe cocktail, consisting of caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), omeprazole (CYP2C19) and warfarin (CYP2C9), on four occasions: an oral (1) and intravenous (2) administration after an overnight fast (control) and an oral (3) and intravenous (4) administration after 36 h of fasting...
February 22, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28229360/thyroid-hormone-acting-via-tr%C3%AE-induces-expression-of-browning-genes-in-mouse-bone-marrow-adipose-tissue
#13
Richard C Lindsey, Subburaman Mohan
PURPOSE: Mutant hypothyroid mouse models have recently shown that thyroid hormone is critical for skeletal development during an important prepubertal growth period. Additionally, thyroid hormone negatively regulates total body fat, consistent with the well-established effects of thyroid hormone on energy and fat metabolism. Since bone marrow mesenchymal stromal cells differentiate into both adipocytes and osteoblasts and a relationship between bone marrow adipogenesis and osteogenesis has been predicted, we hypothesized thyroid hormone deficiency during the postnatal growth period increases marrow adiposity in mice...
February 22, 2017: Endocrine
https://www.readbyqxmd.com/read/28229243/correlation-of-insulin-resistance-and-motor-function-in-spinal-and-bulbar-muscular-atrophy
#14
Hideaki Nakatsuji, Amane Araki, Atsushi Hashizume, Yasuhiro Hijikata, Shinichiro Yamada, Tomonori Inagaki, Keisuke Suzuki, Haruhiko Banno, Noriaki Suga, Yohei Okada, Manabu Ohyama, Tohru Nakagawa, Ken Kishida, Tohru Funahashi, Iichiro Shimomura, Hideyuki Okano, Masahisa Katsuno, Gen Sobue
This study aimed to evaluate various metabolic parameters in patients with spinal and bulbar muscular atrophy (SBMA), to investigate the association between those indices and disease severity, and to explore the underlying molecular pathogenesis. We compared the degree of obesity, metabolic parameters, and blood pressure in 55 genetically confirmed SBMA patients against those in 483 age- and sex-matched healthy control. In SBMA patients, we investigated the correlation between these factors and motor functional indices...
February 22, 2017: Journal of Neurology
https://www.readbyqxmd.com/read/28229048/anaplasma-phagocytophilum-infection-subverts-carbohydrate-metabolic-pathways-in-the-tick-vector-ixodes-scapularis
#15
Alejandro Cabezas-Cruz, Pilar Alberdi, James J Valdés, Margarita Villar, José de la Fuente
The obligate intracellular pathogen, Anaplasma phagocytophilum, is the causative agent of human, equine, and canine granulocytic anaplasmosis and tick-borne fever (TBF) in ruminants. A. phagocytophilum has become an emerging tick-borne pathogen in the United States, Europe, Africa, and Asia, with increasing numbers of infected people and animals every year. It has been recognized that intracellular pathogens manipulate host cell metabolic pathways to increase infection and transmission in both vertebrate and invertebrate hosts...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28228925/what-can-mathematical-modelling-say-about-cho-metabolism-and-protein-glycosylation
#16
REVIEW
Sarah N Galleguillos, David Ruckerbauer, Matthias P Gerstl, Nicole Borth, Michael Hanscho, Jürgen Zanghellini
Chinese hamster ovary cells have been in the spotlight for process optimization in recent years, due to being the major, long established cell factory for the production of recombinant proteins. A deep, quantitative understanding of CHO metabolism and mechanisms involved in protein glycosylation has proven to be attainable through the development of high throughput technologies. Here we review the most notable accomplishments in the field of modelling CHO metabolism and protein glycosylation.
2017: Computational and Structural Biotechnology Journal
https://www.readbyqxmd.com/read/28228748/chromogranin-a-regulation-of-obesity-and-peripheral-insulin-sensitivity
#17
REVIEW
Gautam K Bandyopadhyay, Sushil K Mahata
Chromogranin A (CgA) is a prohormone and granulogenic factor in endocrine and neuroendocrine tissues, as well as in neurons, and has a regulated secretory pathway. The intracellular functions of CgA include the initiation and regulation of dense-core granule biogenesis and sequestration of hormones in neuroendocrine cells. This protein is co-stored and co-released with secreted hormones. The extracellular functions of CgA include the generation of bioactive peptides, such as pancreastatin (PST), vasostatin, WE14, catestatin (CST), and serpinin...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28228713/metabolic-and-cardiovascular-benefits-and-risks-of-emd386088-a-5-ht6-receptor-partial-agonist-and-dopamine-transporter-inhibitor
#18
Magdalena Kotańska, Joanna Śniecikowska, Magdalena Jastrzębska-Więsek, Marcin Kołaczkowski, Karolina Pytka
Since 5-HT6 receptors play role in controlling feeding and satiety and dopamine is essential for normal feeding behavior, we evaluated the ability of EMD 386088-5-HT6 receptor partial agonist and dopamine transporter inhibitor-to reduce body weight in obese rats, as well as its anorectic properties (calorie intake reduction) in rat model of excessive eating and the influence on metabolism (plasma glucose and glycerol levels). We also determined the effect of the studied compound on pica behavior in rats and its influence on blood pressure after single administration...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28228514/differentiating-causality-and-correlation-in-allometric-scaling-ant-colony-size-drives-metabolic-hypometry
#19
James S Waters, Alison Ochs, Jennifer H Fewell, Jon F Harrison
Metabolic rates of individual animals and social insect colonies generally scale hypometrically, with mass-specific metabolic rates decreasing with increasing size. Although this allometry has wide ranging effects on social behaviour, ecology and evolution, its causes remain controversial. Because it is difficult to experimentally manipulate body size of organisms, most studies of metabolic scaling depend on correlative data, limiting their ability to determine causation. To overcome this limitation, we experimentally reduced the size of harvester ant colonies (Pogonomyrmex californicus) and quantified the consequent increase in mass-specific metabolic rates...
February 22, 2017: Proceedings. Biological Sciences
https://www.readbyqxmd.com/read/28228413/determination-of-human-hepatic-cyp2c8-and-cyp1a2-age-dependent-expression-to-support-human-health-risk-assessment-for-early-ages
#20
Gina Song, Xueying Sun, Ronald N Hines, D Gail McCarver, Brian G Lake, Thomas G Osimitz, Moire R Creek, Harvey J Clewell, Miyoung Yoon
Predicting age-specific metabolism is important for evaluating age-related drug and chemical sensitivity. Multiple cytochrome P450s (CYP) and carboxylesterase (CES) enzymes are responsible for human pyrethroid metabolism. Complete ontogeny data for each enzyme is needed to support in vitro to in vivo extrapolation (IVIVE). This study was designed to determine age-dependent human hepatic CYP2C8 expression, for which only limited ontogeny data are available, and to further define CYP1A2 ontogeny. CYP2C8 and 1A2 protein levels were measured by quantitative Western blotting using liver microsomal samples prepared from 222 subjects with ages ranging from 8 weeks gestation to 18 years after birth...
February 22, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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