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Quantitative systems pharmacology

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https://www.readbyqxmd.com/read/29153034/advances-in-maldi-mass-spectrometry-within-drug-discovery
#1
Dale S Cornett, Michael D Scholle
Inhibition of NK and effector T-cell functions and activation of regulatory cell populations are the main immunosuppressive effects of indoleamine-2,3-dioxygenase1 (IDO1). By converting tryptophan (Trp) into kynurenine (Kyn), IDO1 is involved in the immune response homeostasis, and its dysregulated expression is described in immune-related pathologies, as tumors that hijack it to evade immune destruction. Thereby, IDO1 inhibitors are being developed to stimulate antitumor immune responses. Existing and standard quantitation methods of IDO1 substrate and metabolite(s) are based on the total level of Trp and its metabolites determined by liquid chromatography tandem mass spectrometry analysis in human plasma, cerebrospinal fluid, and brain...
December 2017: SLAS Discovery
https://www.readbyqxmd.com/read/29133212/quantitative-and-systems-pharmacology-2-in-silico-polypharmacology-of-g-protein-coupled-receptor-ligands-via-network-based-approaches
#2
Zengrui Wu, Weiqiang Lu, Weiwei Yu, Tianduanyi Wang, Weihua Li, Guixia Liu, Hankun Zhang, Xiufeng Pang, Jin Huang, Mingyao Liu, Feixiong Cheng, Yun Tang
G protein-coupled receptors (GPCRs) are the largest super family with more than 800 membrane receptors. Currently, over 30% of the approved drugs target human GPCRs. However, only approximately 30 human GPCRs have been resolved three-dimensional crystal structures, which limits traditional structure-based drug discovery. Recent advances in network-based systems pharmacology approaches have demonstrated powerful strategies for identifying new targets of GPCR ligands. In this study, we proposed a network-based systems pharmacology framework for comprehensive identification of new drug-target interactions on GPCRs...
November 10, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29131445/airyscan-super-resolution-microscopy-of-mitochondrial-morphology-and-dynamics-in-living-tumor-cells
#3
Vladimir L Kolossov, Mayandi Sivaguru, Joseph Huff, Katherine Luby, Kaviamuthan Kanakaraju, H Rex Gaskins
Mitochondrial morphology is regulated by continuous fusion-and-fission events that are essential for maintaining normal function. Despite the prominence of mitochondrial function in energy generation and cell signaling, understanding of processes of fusion and fission dynamics has been hampered by the lack of high-resolution optical systems that accommodate live-cell imaging. We have examined different confocal modalities in terms of resolution and signal-to-noise ratio (SNR) in a point scanning confocal microscope with Airyscan super-resolution (AS-SR)...
November 13, 2017: Microscopy Research and Technique
https://www.readbyqxmd.com/read/29128812/pharmacological-evidence-for-the-involvement-of-adenosine-triphosphate-sensitive-potassium-channels-in-chloroquine-induced-itch-in-mice
#4
Sattar Ostadhadi, Arash Foroutan, Nazgol-Sadat Haddadi, Abbas Norouzi-Javidan, Majid Momeny, Ghazaleh Zarrinrad, Seyed Hamid Ghaffari, Ahmad-Reza Dehpour
BACKGROUND: Chloroquine (CQ) evokes itch in human and scratching behavior in rodents through a histamine-independent pathway. Chloroquine directly excites peripheral sensory neurons which convey itch signals to the central nervous system. It has been revealed that ATP-sensitive potassium channels (KATP channels) are important in regulating neuronal excitability. Thus, we aimed to investigate the involvement of KATP channels in CQ-induced itch which may also reveal a linkage between metabolic state of cells and itch...
June 3, 2017: Pharmacological Reports: PR
https://www.readbyqxmd.com/read/29126144/multi-scale-mathematical-model-of-drug-induced-proximal-tubule-injury-linking-urinary-biomarkers-to-epithelial-cell-injury-and-renal-dysfunction
#5
Yeshitila Gebremichael, James Lu, Harish Shankaran, Gabriel Helmlinger, Jerome Mettetal, K Melissa Hallow
Drug-induced nephrotoxicity is a major cause of acute kidney injury (AKI), and thus detecting the potential for nephrotoxicity early in the drug development process is critical. Various urinary biomarkers exhibit different patterns following drug-induced injury that may provide greater information than traditional biomarkers like serum creatinine. In this study, we developed a multi-scale quantitative systems pharmacology model relating drug exposure to proximal tubule (PT) epithelial cell injury, and subsequently to expression of multiple urinary biomarkers and organ-level functional changes...
November 6, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29106979/development-of-a-population-pharmacokinetic-model-to-predict-brain-distribution-and-dopamine-d2-receptor-occupancy-of-raclopride-in-non-anesthetized-rat
#6
Yin Cheong Wong, Trayana Ilkova, Rob C van Wijk, Robin Hartman, Elizabeth C M de Lange
BACKGROUND: Raclopride is a selective antagonist of the dopamine D2 receptor. It is one of the most frequently used in vivo D2 tracers (at low doses) for assessing drug-induced receptor occupancy (RO) in animals and humans. It is also commonly used as a pharmacological blocker (at high doses) to occupy the available D2 receptors and antagonize the action of dopamine or drugs on D2 in preclinical studies. The aims of this study were to comprehensively evaluate its pharmacokinetic (PK) profiles in different brain compartments and to establish a PK-RO model that could predict the brain distribution and RO of raclopride in the freely moving rat using a LC-MS based approach...
November 4, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29093681/quantitative-and-systems-pharmacology-3-network-based-identification-of-new-targets-for-natural-products-enables-potential-uses-in-aging-associated-disorders
#7
Jiansong Fang, Li Gao, Huili Ma, Qihui Wu, Tian Wu, Jun Wu, Qi Wang, Feixiong Cheng
Aging that refers the accumulation of genetic and physiology changes in cells and tissues over a lifetime has been shown a high risk of developing various complex diseases, such as neurodegenerative disease, cardiovascular disease and cancer. Over the past several decades, natural products have been demonstrated as anti-aging interveners via extending lifespan and preventing aging-associated disorders. In this study, we developed an integrated systems pharmacology infrastructure to uncover new indications for aging-associated disorders by natural products...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29075176/retinal-and-cortical-blood-flow-dynamics-following-systemic-blood-neural-barrier-disruption
#8
Flora Hui, Christine T O Nguyen, Zheng He, Algis J Vingrys, Rachel Gurrell, Rebecca L Fish, Bang V Bui
To consider whether imaging retinal vasculature may be used as a marker for cortical vessels, we compared fluorescein angiography flow dynamics before and after pharmacological disruption of blood-neural barriers. Sodium fluorescein (1%, 200 μl/kg) was intravenously delivered in anesthetized adult Long Evans rats (n = 44, brain = 18, retina = 26). In the brain cohort, a cranial window was created to allow direct visualization of surface cortical vessels. Video fluorescein angiography was captured using a rodent retinal camera at 30 frames/second and fluorescence intensity profiles were evaluated for the time to reach 50% brightness (half-rise), 50% decay (half-fall), and the plateau level of remnant fluorescence (offset, %)...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29071465/toward-whole-brain-dopamine-movies-a-critical-review-of-pet-imaging-of-dopamine-transmission-in-the-striatum-and-cortex
#9
Heather Liu, Yasmin Zakiniaeiz, Kelly P Cosgrove, Evan D Morris
The mesocorticolimbic dopamine (DA) circuit, comprising the mesolimbic and mesocortical DA pathways, plays a crucial role in reward, cognitive control, and motivation. The positron emission tomography (PET) radiotracer, [C-11]raclopride, has been used widely to image DA receptors and DA changes in the mesolimbic pathway before and after pharmacological and behavioral challenges. In certain circumstances, properties of traditional kinetic models-used to analyze dynamic PET data-are not well-suited to describing the effects of stimulus-induced DA release...
October 25, 2017: Brain Imaging and Behavior
https://www.readbyqxmd.com/read/29039968/characteristics-biological-properties-and-analytical-methods-of-ursolic-acid-a-review
#10
Andressa Maria Pironi, Patricia Rocha de Araújo, Mariza Aires Fernandes, Hérida Regina Nunes Salgado, Marlus Chorilli
Ursolic acid (UA) is a naturally occurring triterpenoid which is a promising candidate for the development of new therapeutic approaches and for the prevention and treatment of several diseases owing to its pharmacological importance. However, its low solubility in aqueous medium affects its therapeutic application. Several strategies have been used to overcome this obstacle. In this study, the incorporation of UA in to different drug delivery systems was found to be highly efficient. In addition, important investigations were performed about methods for qualitative and quantitative analyses of UA in various raw materials, including plants, biological fluids, and drug delivery systems, were investigated...
October 17, 2017: Critical Reviews in Analytical Chemistry
https://www.readbyqxmd.com/read/29018993/dopaminergic-and-non-dopaminergic-gait-components-assessed-by-instrumented-timed-up-and-go-test-in-parkinson-s-disease
#11
Valeria Dibilio, Alessandra Nicoletti, Giovanni Mostile, Simona Toscano, Antonina Luca, Loredana Raciti, Giorgia Sciacca, Rosario Vasta, Calogero Edoardo Cicero, Donatella Contrafatto, Mario Zappia
The timed up and go test (TUG) is a widely used clinical test for the evaluation of balance and mobility. An instrumented version of TUG (iTUG) has been proposed to provide quantitative information on TUG performances. Here, we hypothesized that L-dopa may differently influence gait parameters recorded by a portable inertial sensor. To test this idea, we evaluated iTUG test in patients with Parkinson's disease (PD), both in L-dopa OFF and ON state. Twenty-eight PD patients performed the iTUG. Subjects were instructed to perform the task both in practical "OFF" and "ON" state...
October 10, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/28986871/selective-cell-surface-expression-of-triheteromeric-nmda-receptors
#12
Feng Yi, Stephen F Traynelis, Kasper B Hansen
The NMDA-type ionotropic glutamate receptors play pivotal roles in many brain functions, but are also involved in numerous brain disorders. Seven NMDA receptor subunits exist (GluN1, GluN2A-D, and GluN3A-B) that assemble into a diverse array of tetrameric receptor subtypes with distinct functional properties and physiological roles. Most NMDA receptors are composed of two GluN1 and two GluN2 subunits, which can assemble into four diheteromeric receptor subtypes composed of GluN1 and one type of GluN2 subunit (e...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28966249/bacterial-expression-of-a-single-chain-variable-fragment-scfv-antibody-against-ganoderic-acid-a-a-cost-effective-approach-for-quantitative-analysis-using-the-scfv-based-enzyme-linked-immunosorbent-assay
#13
Gorawit Yusakul, Poomraphie Nuntawong, Seiichi Sakamoto, Pahweenvaj Ratnatilaka Na Bhuket, Toshitaka Kohno, Nao Kikkawa, Pornchai Rojsitthisak, Kuniyoshi Shimizu, Hiroyuki Tanaka, Satoshi Morimoto
Due to the highly specific binding between an antibody and its target, superior analytical performances was obtained by immunoassays for phytochemical analysis over conventional chromatographic techniques. Here, we describe a simple method for producing a functional single-chain variable fragment (scFv) antibody against ganoderic acid A (GAA), a pharmacologically active metabolite from Ganoderma lingzhi. The Escherichia coli BL21(DE3) strain produced a large amount of anti-GAA scFv. However, in vitro refolding steps, which partially recovered the reactivity of the scFv, were required...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28962172/psoralen-stimulates-osteoblast-proliferation-through-the-activation-of-nuclear-factor-%C3%AE%C2%BAb-mitogen-activated-protein-kinase-signaling
#14
Feimeng Li, Qihuo Li, Xiaoqing Huang, Yunting Wang, Chana Ge, Yong Qi, Wei Guo, Hongtao Sun
Osteoporosis is a systemic skeletal disease that leads to increased bone fragility and susceptibility to fracture. Approximately 50% of postmenopausal women develop osteoporosis as a result of postmenopausal estrogen deficiency. To reduce fractures related to osteoporosis in women, previous studies have focused on therapeutic strategies that aim to increase bone formation or decrease bone resorption. However, pharmacological agents that aim to improve bone fracture susceptibility exhibit side effects. Current studies are investigating natural alternatives that possess the benefits of selective estrogen receptor modulators (SERMs) without the adverse effects...
September 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28956927/quantitative-and-systems-pharmacology-1-in-silico-prediction-of-drug-target-interactions-of-natural-products-enables-new-targeted-cancer-therapy
#15
Jiansong Fang, Zengrui Wu, Chuipu Cai, Qi Wang, Yun Tang, Feixiong Cheng
Natural products with diverse chemical scaffolds have been recognized as an invaluable source of compounds in drug discovery and development. However, systematic identification of drug targets for natural products at the human proteome level via various experimental assays is highly expensive and time-consuming. In this study, we proposed a systems pharmacology infrastructure to predict new drug targets and anticancer indications of natural products. Specifically, we reconstructed a global drug-target network with 7,314 interactions connecting 751 targets and 2,388 natural products and built predictive network models via a balanced substructure-drug-target network-based inference approach...
October 13, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28955237/understanding-the-effect-of-statins-and-patient-adherence-in-atherosclerosis-via-a-quantitative-systems-pharmacology-model-using-a-novel-hybrid-and-multi-scale-approach
#16
Cesar Pichardo-Almarza, Vanessa Diaz-Zuccarini
Background and Objective: Statins are one of the most prescribed drugs to treat atherosclerosis. They inhibit the hepatic HMG-CoA reductase, causing a reduction of circulating cholesterol and LDL levels. Statins have had undeniable success; however, the benefits of statin therapy crystallize only if patients adhere to the prescribed treatment, which is far away from reality since adherence decreases with time with around half of patients discontinue statin therapy within the first year. The objective of this work is to; firstly, demonstrate a formal in-silico methodology based on a hybrid, multiscale mathematical model used to study the effect of statin treatment on atherosclerosis under different patient scenarios, including cases where the influence of medication adherence is examined and secondly, to propose a flexible simulation framework that allows extensions or simplifications, allowing the possibility to design other complex simulation strategies, both interesting features for software development...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28951721/mechanistic-systems-modeling-to-improve-understanding-and-prediction-of-cardiotoxicity-caused-by-targeted-cancer-therapeutics
#17
Jaehee V Shim, Bryan Chun, Johan G C van Hasselt, Marc R Birtwistle, Jeffrey J Saucerman, Eric A Sobie
Tyrosine kinase inhibitors (TKIs) are highly potent cancer therapeutics that have been linked with serious cardiotoxicity, including left ventricular dysfunction, heart failure, and QT prolongation. TKI-induced cardiotoxicity is thought to result from interference with tyrosine kinase activity in cardiomyocytes, where these signaling pathways help to control critical processes such as survival signaling, energy homeostasis, and excitation-contraction coupling. However, mechanistic understanding is limited at present due to the complexities of tyrosine kinase signaling, and the wide range of targets inhibited by TKIs...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28930822/five-years-experience-on-3-4-diaminopyridine-phosphate-in-lambert-eaton-syndrome-case-reports
#18
Simona Portaro, Teresa Brizzi, Stefano Sinicropi, Alberto Cacciola, Maria Cristina De Cola, Alessia Bramanti, Demetrio Milardi, Antonino Lupica, Placido Bramanti, Antonio Toscano, Carmelo Rodolico
RATIONALE: To report our experience on 7 patients (4 males and 3 females), affected by nonparaneoplastic Lambert-Eaton myasthenic syndrome, treated with 3,4-diaminopyridine phosphate (3,4-DAPP) either alone or in combination with other immunosuppressants or steroids. PATIENT CONCERNS: Patients have been evaluated at specific timepoints (ie, baseline and last 5 year follow-up), with neurological examination, autoantibodies against presynaptic voltage-gated Cav2.1 (P/Q type) calcium ion channel (VGCC) dosage, neurophysiological evaluation focusing on the increased amplitude of the compound muscle action potential (cMAP) after maximum voluntary effort, quantitative myasthenia gravis (QMG) and activities of daily living scales, and autonomic nervous system involvement evaluation...
September 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28930267/%C3%AE-selinene-rich-essential-oils-from-the-parts-of-callicarpa-macrophylla-and-their-antioxidant-and-pharmacological-activities
#19
Mahesh Chandra, Om Prakash, Ravendra Kumar, Rakesh Kumar Bachheti, Brij Bhushan, Mahesh Kumar, Anil Kumar Pant
Background:Callicarpa macrophylla (Varbenaceae) is a medicinal shrub and is traditionally used in India, China, and South Asia. Methods: The plant material was collected from lower Himalayan region of Uttarakhand in India. The essential oils from three different aerial parts were analyzed by GC-MS. Antioxidant activity, phenolic assay, and various pharmacological activities were determined by using existing methods which are generally practiced widely. Results: Over 51, 53, and 40 compounds were identified in C...
July 10, 2017: Medicines (Basel, Switzerland)
https://www.readbyqxmd.com/read/28924075/edoxaban-enhances-thromboprophylaxis-by-physiotherapy-after-total-knee-arthroplasty%C3%A3-the-randomized-controlled-escort-tka-trial
#20
Daisuke Sueta, Koichi Kaikita, Nobukazu Okamoto, Soichiro Yamabe, Masanobu Ishii, Yuichiro Arima, Miwa Ito, Yu Oimatsu, Tatsuro Mitsuse, Satomi Iwashita, Eiichi Nakamura, Seiji Hokimoto, Hiroshi Mizuta, Hisao Ogawa, Kenichi Tsujita
BACKGROUND: The pharmacological advantage of combining physiotherapy with anticoagulants for the prevention of venous thromboembolism (VTE) after total knee arthroplasty (TKA) is not fully known. Herein we investigated the potential benefit of this combination therapy in patients undergoing TKA.Methods and Results:The 38 patients were randomly assigned to a physiotherapy group (n=19) or a physiotherapy plus 30 mg/day edoxaban group (n=19). The occurrence of VTE was evaluated, as were serial changes in parameters measured by the Total Thrombus-formation Analysis System, a novel system for quantitatively analyzing thrombus formation using microchips with thrombogenic surfaces (collagen plus tissue factor, atheroma [AR]-chip)...
September 16, 2017: Circulation Journal: Official Journal of the Japanese Circulation Society
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