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https://www.readbyqxmd.com/read/29458203/precision-pharmacology-for-alzheimer-s-disease
#1
REVIEW
Harald Hampel, Andrea Vergallo, Lisi Flores Aguilar, Norbert Benda, Karl Broich, A Claudio Cuello, Jeffrey Cummings, Bruno Dubois, Howard J Federoff, Massimo Fiandaca, Remy Genthon, Marion Haberkamp, Eric Karran, Mark Mapstone, George Perry, Lon S Schneider, Lindsay A Welikovitch, Janet Woodcock, Filippo Baldacci, Simone Lista
The complex multifactorial nature of polygenic Alzheimer's disease (AD) presents significant challenges for drug development. AD pathophysiology is progressing in a non-linear dynamic fashion across multiple systems levels - from molecules to organ systems - and through adaptation, to compensation, and decompensation to systems failure. Adaptation and compensation maintain homeostasis: a dynamic equilibrium resulting from the dynamic non-linear interaction between genome, epigenome, and environment. An individual vulnerability to stressors exists on the basis of individual triggers, drivers, and thresholds accounting for the initiation and failure of adaptive and compensatory responses...
February 16, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29458193/attenuation-of-neuro-inflammation-improves-survival-and-neurodegeneration-in-a-mouse-model-of-severe-neonatal-hyperbilirubinemia
#2
Simone Vodret, Giulia Bortolussi, Alessandra Iaconcig, Elena Martinelli, Claudio Tiribelli, Andrés F Muro
All pre-term newborns and a high proportion of term newborns develop neonatal jaundice. Neonatal jaundice is usually a benign condition and self-resolves within few days after birth. However, a combination of unfavorable complications may lead to acute hyperbilirubinemia. Excessive hyperbilirubinemia may be toxic for the developing nervous system leading to severe neurological damage and death by kernicterus. Survivors show irreversible neurological deficits such as motor, sensitive and cognitive abnormalities...
February 16, 2018: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/29458162/consumption-and-exposure-assessment-to-sunscreen-products-a-key-point-for-safety-assessment
#3
Marie-Pierre Gomez-Berrada, Anne-Sophie Ficheux, Sandrine Rakotomalala, Sonia Guillou, Murièle Bellec, Dominique De Javel, Alain-Claude Roudot, Pierre-Jacques Ferret
No abstract text is available yet for this article.
February 16, 2018: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/29458156/how-to-isolate-identify-and-determine-antimicrobial-susceptibility-of-anaerobic-bacteria-in-routine-laboratories
#4
REVIEW
Elisabeth Nagy, Lyudmila Boyanova, Ulrik S Justesen
BACKGROUND: There has been an increased interest in the study of anaerobic bacteria, which cause human infection during the past decade. Many new genera and species have been described by to use 16S rRNA gene sequencing of clinical isolates obtained from different infection sites with commercially available special culture media to support the growth of anaerobes. Several systems, such as anaerobic pouches, boxes, jars and chambers provide suitable anaerobic culture conditions to isolate even strict anaerobic bacteria successfully from clinical specimens...
February 16, 2018: Clinical Microbiology and Infection
https://www.readbyqxmd.com/read/29458149/age-dependent-oxidation-of-extracellular-cysteine-cystine-redox-state-e-h-cys-cyss-in-mouse-lung-fibroblasts-is-mediated-by-a-decline-in-slc7a11-expression
#5
Yuxuan Zheng, Jeffrey D Ritzenthaler, Tom J Burke, Javier Otero, Jesse Roman, Walter H Watson
Aging is associated with progressive oxidation of the extracellular environment. The redox state of human plasma, defined by the concentrations of cysteine (Cys) and cystine (CySS), becomes more oxidized as we age. Recently, we showed that fibroblasts isolated from the lungs of young and old mice retain this differential phenotype; old cells produce and maintain a more oxidizing extracellular redox potential (Eh (Cys/CySS)) than young cells. Microarray analysis identified down-regulation of Slc7a11, the light subunit of the CySS/glutamate transporter, as a potential mediator of age-related oxidation in these cells...
February 16, 2018: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/29458141/long-non-coding-rnas-within-the-tumour-microenvironment-and-their-role-in-tumour-stroma-cross-talk
#6
Filippo Del Vecchio, Gui Han Lee, Joamir Hawezi, Rahul Bhome, Sian Pugh, Emre Sayan, Gareth Thomas, Graham Packham, John Primrose, Martin Pichler, Alexander Mirnezami, George Calin, Marc Bullock
Long non-coding RNAs (lncRNAs) are a diverse class of RNA transcripts which have limited protein coding potential. They perform a variety of cellular functions in health, but have also been implicated during malignant transformation. A further theme in recent years is the critical role of the tumour microenvironment and the dynamic interactions between cancer and stromal cells in promoting invasion and disease progression. Whereas the contribution of deregulated lncRNAs within cancer cells has received considerable attention, their significance within the tumour microenvironment is less well understood...
February 16, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29458125/pluripotent-stem-cells-for-uncovering-the-role-of-mitochondria-in-human-brain-function-and-dysfunction
#7
REVIEW
Annika Zink, Josef Priller, Alessandro Prigione
Mitochondrial dysfunctions are a known pathogenetic mechanism of a number of neurological and psychiatric disorders. At the same time, mutations in genes encoding for components of the mitochondrial respiratory chain cause mitochondrial diseases, which commonly exhibit neurological symptoms. Mitochondria are therefore critical for the functionality of the human nervous system. The importance of mitochondria stems from their key roles in cellular metabolism, calcium handling, redox and protein homeostasis, and overall cellular homeostasis through their dynamic network...
February 16, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29458120/major-role-for-trpv1-and-insp3r-in-par-2-elicited-inflammatory-mediator-production-in-differentiated-human-keratinocytes
#8
Olivier Gouin, Killian L'Herondelle, Paul Buscaglia, Christelle Le Gall-Ianotto, Réginald Philippe, Nelig Legoux, Olivier Mignen, Virginie Buhé, Raphael Leschiera, Mehdi Sakka, Nathalie Kerfant, Jean-Luc Carré, Raphaele Le Garrec, Luc Lefeuvre, Nicolas Lebonvallet, Laurent Misery
Proteinase-activated receptor-2 (PAR-2) activation in basal keratinocytes stimulates inflammation via the Ca2+ -dependent production of mediators such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α and thymic stromal lymphopoietin (TSLP). In this study, we investigated PAR-2 calcium signaling and the consequent production of inflammatory mediators in differentiated human primary keratinocytes (DhPKs). Stimulation with the PAR-2 activating peptide SLIGKV promoted Ca2+ store depletion in both undifferentiated human primary keratinocytes (UhPKs) and DhPKs...
February 16, 2018: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29458116/junk-food-advertising-moderates-the-indirect-effect-of-reward-sensitivity-and-food-consumption-via-the-urge-to-eat
#9
Chloe Kidd, Natalie J Loxton
The current study aimed to identify how underlying individual differences increases vulnerability to television food advertising. In particular, this study examined how reward sensitivity, a biologically-based predisposition to approach rewards (such as appetitive foods) in the environment, influenced participants' vulnerability to television food advertising and subsequent food consumption. Ninety-eight participants were randomly assigned to a cue condition (food cues versus non-food cues) and then viewed a 30 min documentary interrupted by advertising featuring a mix of food and neutral advertising (food cue condition) or only neutral advertising (non-food cue condition)...
February 16, 2018: Physiology & Behavior
https://www.readbyqxmd.com/read/29458109/modulation-of-cyp1a1-metabolism-from-adverse-health-effects-to-chemoprevention-and-therapeutic-options
#10
Melina Mescher, Thomas Haarmann-Stemmann
The human cytochrome P450 (CYP) 1A1 gene encodes a monooxygenase that metabolizes multiple exogenous and endogenous substrates. CYP1A1 has become infamous for its oxidative metabolism of benzo[a]pyrene and related polycyclic aromatic hydrocarbons, converting these chemicals into very potent human carcinogens. CYP1A1 expression is mainly controlled by the aryl hydrocarbon receptor (AHR), a transcription factor whose activation is induced by binding of persistent organic pollutants, including polycyclic aromatic hydrocarbons and dioxins...
February 16, 2018: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29458087/ngf-fak-signal-pathway-is-implicated-in-angiogenesis-after-acute-cerebral-ischemia-in-rats
#11
Hai-Ting Zhao, Yu-Hu Zhang, Ying-Hui Zhang, Yue Shen, Yi-Dan Zhang, Fang-Fang Bi, Bo Xiao, Hao Zhang, Wen Ye, Hong-Hai Zhang, Yi-Wei Liao
Neurogenesis in the cerebral infarction after an ischemic event is important to the rehabilitation of patients. However, the mechanism of angiogenesis around cerebral ischemia is not clear. Our study designed to test whether the nerve growth factor (NGF)-P-focal adhesion kinase (FAK) signaling pathway for associations with angiogenesis plays a key role in post-acute cerebral ischemia of rats. Firstly, we implanted the Matrigel, a carrier of basement membrane matrix, into the abdominal skin of rats to identify the relevant components of the NGF-P-FAK signaling pathway related to angiogenesis...
February 16, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29458076/bone-marrow-mesenchymal-stem-cells-bmscs-improved-functional-recovery-of-spinal-cord-injury-partly-by-promoting-axonal-regeneration
#12
REVIEW
Liya Lin, Hefeng Lin, Shi Bai, Lianshun Zheng, Xiaoming Zhang
Spinal cord injury (SCI) disrupts the spinal cord and results in the loss of sensory and motor function below the lesion site. The treatment of SCI became a challenge because the injured neurons fail to axon regenerate and repair after injury. Promoting axonal regeneration plays a key role in the treatment strategies for SCI. It would meet the goal of reconstruction the injured spinal cord and improving the functional recovery. Bone marrow mesenchymal stem cells (BMSCs) are attractive therapeutic potential cell sources for SCI, and it could rebuild the injured spinal cord through neuroprotection, neural regeneration and remyelinating...
February 16, 2018: Neurochemistry International
https://www.readbyqxmd.com/read/29458066/volitional-voiding-of-the-bladder-following-spinal-cord-injury-validation-of-bilateral-lower-extremity-motor-function-as-a-key-predictor
#13
Christopher S Elliott, Kai B Dallas, Dimitar Zlatev, Craig V Comiter, James Crew, Kazuko Shem
INTRODUCTION: For many with spinal cord injury (SCI), a return of volitional bladder voiding is considered more important than regaining motor function. Recently a predictive model using only composite bilateral lower extremity motor (LEM) scores for levels L2-S1 (range 0-50) was put forth by the European Multicenter Spinal Cord Injury (EMSCI) study group that showed exceptional predictive power with an area under the curve (AUC) of 0.912. We sought to further validate the EMSCI model using a national SCI cohort...
February 16, 2018: Journal of Urology
https://www.readbyqxmd.com/read/29458062/an-unexpected-degradation-pathway-of-a-1-2-4-triazolo-4-3-a-pyridine-derivative-the-formation-of-two-cationic-pseudodimers-of-an-11%C3%AE-hydroxysteroid-dehydrogenase-type-1-inhibitor-drug-candidate-in-a-stressed-capsule-formulation
#14
Yande Huang, Qinggang Wang, Yongmei Wu
Degradation of an active pharmaceutical ingredient (API), a 2-(3-(1-(4-chlorophenyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)propan-2-ol hydrochloride salt, was observed in a capsule formulation stressed at 50°C or 40°C/75% relative humidity conditions for one month. Two unknown degradants were identified as cationic pseudodimers of the API via accurate mass liquid chromatography-mass spectrometry and one- and two-dimensional NMR analyses. A plausible degradation pathway of the API was postulated which led to the identification of two key N-oxide degradants in the stressed capsule formulation at trace levels...
February 16, 2018: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29458059/modest-enhancement-of-sensory-axon-regeneration-in-the-sciatic-nerve-with-conditional-co-deletion-of-pten-and-socs3-in-the-dorsal-root-ganglia-of-adult-mice
#15
Zachary R Gallaher, Oswald Steward
Axons within the peripheral nervous system are capable of regeneration, but full functional recovery is rare. Recent work has shown that conditional deletion of two key signaling inhibitors of the PI3K and Jak/Stat pathways-phosphatase and tensin homolog (PTEN) and suppressor of cytokine signaling-3 (SOCS3), respectively-promotes regeneration of normally non-regenerative central nervous system axons. Moreover, in studies of optic nerve regeneration, co-deletion of both PTEN and SOCS3 has an even greater effect...
February 16, 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29457923/flipping-social-determinants-on-its-head-medical-student-perspectives-on-the-flipped-classroom-and-simulated-patients-to-teach-social-determinants-of-health
#16
N Gostelow, J Barber, F Gishen, A Berlin
BACKGROUND: Inequalities in healthcare are increasing. Engaging medical students to tackle this urgent challenge alongside clinical sciences can be demanding. This study examines medical student perceptions of a flipped approach to health inequalities co-designed by faculty and sixth-year students. INNOVATION: A flipped learning session was piloted for year 4 medical students combining an online lesson followed by a tutorial with a simulated patient. METHODS: A mixed-methods approach collected questionnaire data using 4-point Likert scales and free text answers...
February 19, 2018: Medical Teacher
https://www.readbyqxmd.com/read/29457901/c-sp3-h-bond-functionalization-of-benzo-c-oxepines-via-c-o-bond-cleavage-formal-3-3-synthesis-of-multi-substituted-chromans
#17
Miao Wang, Bo-Cheng Tang, Jia-Chen Xiang, Yan Cheng, Zi-Xuan Wang, Jin-Tian Ma, Yan-Dong Wu, An-Xin Wu
An efficient base-promoted C(sp3)-H bond functionalization strategy for the synthesis of multi-substituted chromans from the formal [3+3] cycloaddition of benzo[c]oxepines and electron-rich phenols has been developed. The corresponding 4H-chromenes can be easily obtained in excellent yields by simple filtration from chromans. Preliminary mechanistic studies indicate that the C-O bond cleavage is the key step for the C(sp3)-H bond functionalization and this reaction could have occurred through a tandem C-O bond cleavage/ Michael addition/ annulation reactions...
February 19, 2018: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/29457894/small-molecule-allosteric-modulators-of-g-protein-coupled-receptors-drug-target-interactions
#18
Shaoyong Lu, Jian Zhang
G-protein-coupled receptors (GPCRs) are the largest class of signaling receptors that are most frequently targeted by therapeutic drugs. Allosteric modulators bound to GPCRs at allosteric sites provide the potential for differential selectivity and improved safety compared with traditional orthosteric ligands. The recent breakthroughs in GPCR structural biology have made structures of GPCRs from classes A, B, C, and F complexed with small-molecule allosteric modulators available. Knowledge on the detailed receptor-modulator interactions at the allosteric sites is useful for structure-based GPCR drug design of novel therapeutics...
February 19, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29457782/hypothalamic-er-associated-degradation-regulates-pomc-maturation-feeding-and-age-associated-obesity
#19
Geun Hyang Kim, Guojun Shi, Diane Rm Somlo, Leena Haataja, Soobin Song, Qiaoming Long, Eduardo A Nillni, Malcolm J Low, Peter Arvan, Martin G Myers, Ling Qi
Pro-opiomelanocortin (POMC) neurons function as key regulators of metabolism and physiology by releasing prohormone-derived neuropeptides with distinct biological activities. However, our understanding of early events in prohormone maturation in the ER remains incomplete. Highlighting the significance of this gap in knowledge, a single POMC cysteine-to-phenylalanine mutation at position 28 (POMC-C28F) is defective for ER processing and causes early onset obesity in a dominant-negative manner in humans through an unclear mechanism...
February 19, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29457732/total-synthesis-of-plusbacin-a3-and-its-dideoxy-derivative-using-a-solvent-dependent-diastereodivergent-joulli%C3%A3-ugi-three-component-reaction
#20
Akira Katsuyama, Fumika Yakushiji, Satoshi Ichikawa
Full details of our synthetic studies toward plusbacin A3 (1), which is a depsipeptide with antibacterial activity, and its dideoxy derivative are described. To establish an efficient synthetic route of 1, a solvent-dependent diastereodivergent Joullié-Ugi three-component reaction (JU-3CR) was used to construct trans-Pro(3-OH) in a small number of steps. Two strategies were investigated toward the total synthesis. In the first synthetic strategy, the key steps were the trans-selective JU-3CR and a macrolactonization at the final stage of the synthesis...
February 19, 2018: Journal of Organic Chemistry
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