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Quantitative systems pharmacology

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https://www.readbyqxmd.com/read/28633807/differential-induction-of-atf3-and-ho-1-in-myeloid-cells-and-keratinocytes-via-dimethylfumarate-or-cyclosporine-a
#1
Stefanie Müller, Nikola Smatlik, Marc Burian, Kamran Ghoreschi, Martin Röcken, Amir S Yazdi
BACKGROUND: Chronic inflammatory skin diseases are characterized by controlled proliferation of keratinocytes. Here, activating transcription factor 3 (ATF3) might play a fundamental role. In these inflammatory diseases, proliferation is controlled and only rarely leads to cancer development which can be supported by an inflammatory microenvironment. ATF3 is a dual function protein as it suppresses pro-inflammatory IL-6 and IL-8, but also acts as a pro-oncogenic factor by the suppression of p53...
June 12, 2017: Journal of Dermatological Science
https://www.readbyqxmd.com/read/28628860/in-silico-modeling-on-adme-properties-of-natural-products-classification-models-for-blood-brain-barrier-permeability-its-application-to-traditional-chinese-medicine-and-in-vitro-experimental-validation
#2
Xiuqing Zhang, Ting Liu, Xiaohui Fan, Ni Ai
In silico modeling of blood-brain barrier (BBB) permeability plays an important role in early discovery of central nervous system (CNS) drugs due to its high-throughput and cost-effectiveness. Natural products (NP) have demonstrated considerable therapeutic efficacy against several CNS diseases. However, BBB permeation property of NP is scarcely evaluated both experimentally and computationally. It is well accepted that significant difference in chemical spaces exists between NP and synthetic drugs, which calls into doubt on suitability of available synthetic chemical based BBB permeability models for the evaluation of NP...
June 7, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28628578/neuraxial-anesthesia-in-obstetric-patients-receiving-thromboprophylaxis-with-unfractionated-or-low-molecular-weight-heparin-a-systematic-review-of-spinal-epidural-hematoma
#3
Lisa R Leffert, Heloise M Dubois, Alexander J Butwick, Brendan Carvalho, Timothy T Houle, Ruth Landau
Venous thromboembolism remains a major source of morbidity and mortality in obstetrics with an incidence of 29.8/100,000 vaginal delivery hospitalizations; cesarean delivery confers a 4-fold increased risk of thromboembolism when compared with vaginal delivery. Revised national guidelines now stipulate that the majority of women delivering via cesarean and women at risk for ante- or postpartum venous thromboembolism receive mechanical or pharmacological thromboprophylaxis. This practice change has important implications for obstetric anesthesiologists concerned about the risk of spinal epidural hematoma (SEH) among anticoagulated women receiving neuraxial anesthesia...
July 2017: Anesthesia and Analgesia
https://www.readbyqxmd.com/read/28625364/semi-quantitative-models-for-identifying-potent-and-selective-transthyretin-amyloidogenesis-inhibitors
#4
Stephen Connelly, David E Mortenson, Sungwook Choi, Ian A Wilson, Evan T Powers, Jeffery W Kelly, Steven M Johnson
Rate-limiting dissociation of the tetrameric protein transthyretin (TTR), followed by monomer misfolding and misassembly, appears to cause degenerative diseases in humans known as the transthyretin amyloidoses, based on human genetic, biochemical and pharmacologic evidence. Small molecules that bind to the generally unoccupied thyroxine binding pockets in the native TTR tetramer kinetically stabilize the tetramer, slowing subunit dissociation proportional to the extent that the molecules stabilize the native state over the dissociative transition state-thereby inhibiting amyloidogenesis...
May 26, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28611062/selective-imaging-of-internalized-proteopathic-%C3%AE-synuclein-seeds-in-primary-neurons-reveals-mechanistic-insight-into-transmission-of-synucleinopathies
#5
Richard J Karpowicz, Conor M Haney, Tiberiu S Mihaila, Raizel M Sandler, E James Petersson, Virginia M-Y Lee
Direct cell-to-cell transmission of proteopathic alpha-synuclein (α-syn) aggregates is thought to underlie the progression of neurodegenerative synucleinopathies. However, the specific intracellular processes governing this transmission remain unclear because currently-available model systems are limited. For example, in cell culture models of α-syn-seeded aggregation, it is difficult to discern intracellular from extracellular exogenously applied α-syn seed species. Herein, we employed fluorescently labeled α-syn preformed fibrils (pffs) in conjunction with the membrane-impermeable fluorescence quencher trypan blue to selectively image internalized α-syn seeds in cultured primary neurons and to quantitatively characterize the concentration dependence, time course, and inhibition of pff uptake...
June 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28585415/methodologies-for-quantitative-systems-pharmacology-models-qsp-design-and-estimation
#6
EDITORIAL
B Ribba, H P Grimm, B Agoram, M R Davies, K Gadkar, S Niederer, N van Riel, J Timmis, P H van der Graaf
No abstract text is available yet for this article.
June 6, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28583429/towards-the-virtual-human-patient-quantitative-systems-pharmacology-in-alzheimer-s-disease
#7
Hugo Geerts, Athan Spiros, Patrick Roberts, Robert Carr
Development of successful therapeutic interventions in Central Nervous Systems (CNS) disorders is a daunting challenge with a low success rate. Probable reasons include the lack of translation from preclinical animal models, the individual variability of many pathological processes converging upon the same clinical phenotype, the pharmacodynamical interaction of various comedications and last but not least the complexity of the human brain. This paper argues for a re-engineering of the pharmaceutical CNS Research & Development strategy using ideas focused on advanced computer modeling and simulation from adjacent engineering-based industries...
June 2, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28575545/can-patient-navigators-improve-adherence-to-disease-modifying-antirheumatic-drugs-quantitative-findings-from-the-med-assist-pilot-study
#8
Candace H Feldman, Alyssa Wohlfahrt, Anarosa Campos, Joshua J Gagne, Maura D Iversen, Elena Massarotti, Daniel H Solomon, Ichiro Kawachi
OBJECTIVE: Non-adherence to DMARDs is common, worsens during the treatment course, and results in adverse outcomes. We studied whether patient navigators - laypersons trained in care coordination, motivational interviewing, basic pharmacology and disease management- improved oral DMARD adherence. METHODS: We enrolled 107 patients aged ≥18 years with systemic rheumatic diseases who initiated an oral DMARD within 6 months. Navigators interacted with patients up to 2-4 times per week for 6 months...
June 2, 2017: Arthritis Care & Research
https://www.readbyqxmd.com/read/28574986/an-ethnobotanical-survey-of-indigenous-medicinal-plants-in-hafizabad-district-punjab-pakistan
#9
Muhammad Umair, Muhammad Altaf, Arshad Mehmood Abbasi
Present paper offers considerable information on traditional uses of medicinal plants by the inhabitants of Hafizabad district, Punjab-Pakistan. This is the first quantitative ethnobotanical study from the area comprising popularity level of medicinal plant species intendedby using relative popularity level (RPL) and rank order priority (ROP) indices.Ethnobotanical data were collected by interviewing 166 local informants and 35 traditional health practioners (THPs) from different localities of Hafizabad district...
2017: PloS One
https://www.readbyqxmd.com/read/28570535/visualization-and-quantitative-analysis-of-embryonic-angiogenesis-in-xenopus-tropicalis
#10
Jiyeon Ohk, Hosung Jung
Blood vessels supply oxygen and nutrients throughout the body, and the formation of the vascular network is under tight developmental control. The efficient in vivo visualization of blood vessels and the reliable quantification of their complexity are key to understanding the biology and disease of the vascular network. Here, we provide a detailed method to visualize blood vessels with a commercially available fluorescent dye, human plasma acetylated low density lipoprotein DiI complex (DiI-AcLDL), and to quantify their complexity in Xenopus tropicalis...
May 25, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28558193/influence-of-size-and-shape-on-the-anatomical-distribution-of-endotoxin-free-gold-nanoparticles
#11
Laura Talamini, Martina B Violatto, Qi Cai, Marco P Monopoli, Karsten Kantner, Željka Krpetić, André Perez-Potti, Jennifer Cookman, David Garry, Camila P Silveira, Luca Boselli, Beatriz Pelaz, Tommaso Serchi, Sébastien Cambier, Arno C Gutleb, Neus Feliu, Yan Yan, Mario Salmona, Wolfgang J Parak, Kenneth A Dawson, Paolo Bigini
The transport and the delivery of drugs through nanocarriers is a great challenge of pharmacology. Since the production of liposomes to reduce the toxicity of doxorubicin in patients, a plethora of nanomaterials have been produced and characterized. Although it is widely known that elementary properties of nanomaterials influence their in vivo kinetics, such interaction is often poorly investigated in many preclinical studies. The present study aims to evaluate the actual effect of size and shape on the biodistribution of a set of gold nanoparticles (GNPs) after intravenous administration in mice...
June 6, 2017: ACS Nano
https://www.readbyqxmd.com/read/28557618/microenvironment-tumor-metabolic-interactions-highlighted-by-qmsi-application-to-the-tryptophan-kynurenine-pathway-in-immuno-oncology
#12
Rima Ait-Belkacem, Vanesa Bol, Gregory Hamm, Florence Schramme, Benoit Van Den Eynde, Lauranne Poncelet, Fabien Pamelard, Jonathan Stauber, Bruno Gomes
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...
May 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28556624/a-quantitative-systems-physiology-model-of-renal-function-and-blood-pressure-regulation-application-in-salt-sensitive-hypertension
#13
K M Hallow, Y Gebremichael
Salt-sensitivity (SS) refers to changes in blood pressure in response to changes in sodium intake. SS individuals are at greater risk for developing kidney disease, and also respond differently to antihypertensive therapies compared to salt-resistant (SR) individuals. In this study we used a systems pharmacology model of renal function (presented in a companion article) to evaluate the ability of proposed mechanisms to produce salt-sensitivity. The model reproduced previously published data on renal functional changes in response to salt-intake, and also predicted that glomerular pressure, a variable that is not easily evaluated clinically but is a key factor in renal injury, increases with salt intake in SS hypertension...
May 27, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28549678/use-of-mathematics-to-guide-target-selection-in-systems-pharmacology-application-to-receptor-tyrosine-kinase-rtk-pathways
#14
Neil Benson, Piet H van der Graaf, Lambertus A Peletier
A key element of the drug discovery process is target selection. Although the topic is subject to much discussion and experimental effort, there are no defined quantitative rules around optimal selection. Often 'rules of thumb', that have not been subject to rigorous exploration, are used. In this paper we explore the 'rule of thumb' notion that the molecule that initiates a pathway signal is the optimal target. Given the multi-factorial and complex nature of this question, we have simplified an example pathway to its logical minimum of two steps and used a mathematical model of this to explore the different options in the context of typical small and large molecule drugs...
May 23, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28548387/a-quantitative-systems-physiology-model-of-renal-function-and-blood-pressure-regulation-model-description
#15
K M Hallow, Y Gebremichael
Renal function plays a central role in cardiovascular, kidney, and multiple other diseases, and many existing and novel therapies act through renal mechanisms. Even with decades of accumulated knowledge of renal physiology, pathophysiology, and pharmacology, the dynamics of renal function remain difficult to understand and predict, often resulting in unexpected or counterintuitive therapy responses. Quantitative systems pharmacology modeling of renal function integrates this accumulated knowledge into a quantitative framework, allowing evaluation of competing hypotheses, identification of knowledge gaps, and generation of new experimentally testable hypotheses...
May 26, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28542505/alzhcpi-a-knowledge-base-for-predicting-chemical-protein-interactions-towards-alzheimer-s-disease
#16
Jiansong Fang, Ling Wang, Yecheng Li, Wenwen Lian, Xiaocong Pang, Hong Wang, Dongsheng Yuan, Qi Wang, Ai-Lin Liu, Guan-Hua Du
Alzheimer's disease (AD) is a complicated progressive neurodegeneration disorder. To confront AD, scientists are searching for multi-target-directed ligands (MTDLs) to delay disease progression. The in silico prediction of chemical-protein interactions (CPI) can accelerate target identification and drug discovery. Previously, we developed 100 binary classifiers to predict the CPI for 25 key targets against AD using the multi-target quantitative structure-activity relationship (mt-QSAR) method. In this investigation, we aimed to apply the mt-QSAR method to enlarge the model library to predict CPI towards AD...
2017: PloS One
https://www.readbyqxmd.com/read/28540623/qsp-toolbox-computational-implementation-of-integrated-workflow-components-for-deploying-multi-scale-mechanistic-models
#17
Yougan Cheng, Craig J Thalhauser, Shepard Smithline, Jyotsna Pagidala, Marko Miladinov, Heather E Vezina, Manish Gupta, Tarek A Leil, Brian J Schmidt
Quantitative systems pharmacology (QSP) modeling has become increasingly important in pharmaceutical research and development, and is a powerful tool to gain mechanistic insights into the complex dynamics of biological systems in response to drug treatment. However, even once a suitable mathematical framework to describe the pathophysiology and mechanisms of interest is established, final model calibration and the exploration of variability can be challenging and time consuming. QSP models are often formulated as multi-scale, multi-compartment nonlinear systems of ordinary differential equations...
May 24, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28539709/multipathway-integrated-adjustment-mechanism-of-glycyrrhiza-triterpenes-curing-gastric-ulcer-in-rats
#18
Ying Wang, Shuai Wang, Yongrui Bao, Tianjiao Li, Xin Chang, Guanlin Yang, Xiansheng Meng
BACKGROUND: Gastric ulcer is a common chronic disease in human digestive system, which is difficult to cure, easy to relapse, and endangers human health seriously. Compared with western medicine, traditional Chinese medicine has a unique advantage in improving the general situation, stablizing medical condition, and with little side effects. Glycyrrhiza known as "king of all the medicine", has a range of pharmacological activities and is commonly used in a variety of proprietary Chinese medicines and formulations...
April 2017: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/28528284/biomarkers-in-epilepsy-a-modelling-perspective
#19
REVIEW
Sven C van Dijkman, Rob A Voskuyl, Elizabeth C de Lange
Biomarkers can be categorised from type 0 (genotype or phenotype), through 6 (clinical scales), each level representing a part of the processes involved in the biological system and drug treatment. This classification facilitates the identification and connection of information required to fully (mathematically) model a disease and its treatment using integrated information from biomarkers. Two recent reviews thoroughly discussed the current status and development of biomarkers for epilepsy, but a path towards the integration of such biomarkers for the personalisation of anti-epileptic drug treatment is lacking...
May 17, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28514967/at1-receptor-response-to-non-saturating-ang-ii-concentrations-is-amplified-by-calcium-channel-blockers
#20
Kristoffer Bernhem, Kalaiselvan Krishnan, Alexander Bondar, Hjalmar Brismar, Anita Aperia, Lena Scott
BACKGROUND: Blockers of angiotensin II type 1 receptor (AT1R) and the voltage gated calcium channel 1.2 (CaV1.2) are commonly used for treatment of hypertension. Yet there is little information about the effect of physiological concentrations of angiotensin II (AngII) on AT1R signaling and whether there is a reciprocal regulation of AT1R signaling by CaV1.2. METHODS: To elucidate these questions, we have studied the Ca(2+) signaling response to physiological and pharmacological AngII doses in HEK293a cells, vascular smooth muscle cells and cardiomyocytes using a Ca(2+) sensitive dye as the principal sensor...
May 17, 2017: BMC Cardiovascular Disorders
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