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https://www.readbyqxmd.com/read/29161781/in-silico-docking-studies-of-lupeol-with-mapk-pathway-proteins-raf-1-mek-erk
#1
Mital H Bhatt, Chirag K Prajapati, M N Reddy
Lupeol, A triterpenoid found in variety of plants is reported to have beneficial medicinal effects on several ailments. Lupeol is also found to show inhibitory effect on proliferation of breast cancer cells. Metastasis is considered to be a major cause for worldwide deaths related to cancer. Ras related MAPK Signaling Pathway is one of the crucial pathways leading to metastasis. Lupeols binding possibility with Ras is already reported. In present study, Interaction between with downstream proteins of Ras- MAPK pathway, Raf ,MEK ,ERK1/2 and their corresponding domains are studied using STRING Database and their structures are retrieved in PDB Format...
November 2017: Journal of Experimental Therapeutics & Oncology
https://www.readbyqxmd.com/read/29161764/mechanism-of-doxorubicin-cardiotoxicity-evaluated-by-integrating-multiple-molecular-effects-into-a-biophysical-model
#2
M Fernandez-Chas, M J Curtis, S A Niederer
BACKGROUND AND PURPOSE: Doxorubicin (DOX) is an effective cancer therapeutic agent but causes therapy-limiting cardiotoxicity. The effects of DOX and its metabolite doxorubicinol (DOXL) on individual channels have been well characterised in isolation. However, it is unknown how the action and interaction of affected channels combine to generate the phenotypic cardiotoxic outcome. We sought to develop an in silico model that links drug effects on channels to action potential duration (APD) and intracellular Ca(2+) concentration in order to address this gap in knowledge...
November 21, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29161763/quantifying-the-relationship-between-inhibition-of-vegfr-2-drug-induced-blood-pressure-elevation-and-hypertension
#3
Teresa Collins, Kelly Gray, Michal Bista, Matt Skinner, Christopher Hardy, Haiyun Wang, Jerome T Mettetal, Alexander R Harmer
BACKGROUND AND PURPOSE: Several anti-angiogenic cancer drugs that inhibit VEGF receptor (VEGFR) signalling for efficacy are associated with a 15-60% incidence of hypertension. Tyrosine kinase inhibitors (TKIs) that have off-target activity at VEGFR-2 may also cause blood pressure elevation as an undesirable side effect. Therefore, the ability to translate VEGFR-2 off-target potency into blood pressure elevation would be useful in development of novel TKIs. EXPERIMENTAL APPROACH: We sought to quantify the relationship between VEGFR-2 inhibition and blood pressure elevation for a range of kinase inhibitors...
November 21, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29161516/influence-of-grafted-block-copolymer-structure-on-thermoresponsiveness-of-superparamagnetic-core-shell-nanoparticles
#4
Steffen Kurzhals, Martina Schroffenegger, Noga Gal, Ronald Zirbs, Erik Reimhult
The morphology and topology of thermoresponsive polymers have strong impact on their responsive properties. Grafting onto spherical particles has been shown to reduce responsiveness and transition temperatures; grafting of block copolymers has shown that switchable or retained wettability of a surface or particle during desolvation of one block can take place. Here, doubly thermoresponsive block copolymers were grafted onto spherical, monodisperse and superparamagnetic iron oxide nanoparticles to investigate the effect of thermal desolvation on spherical brushes of block copolymers...
November 21, 2017: Biomacromolecules
https://www.readbyqxmd.com/read/29161509/variation-in-the-supersaturation-and-phase-behavior-of-ezetimibe-amorphous-solid-dispersions-upon-dissolution-in-different-biorelevant-media
#5
Ahmed Elkhabaz, Sreya Sarkar, Janny K Dinh, Garth J Simpson, Lynne S Taylor
The delivery of poorly water-soluble drugs using amorphous solid dispersions (ASDs) has been widely acknowledged as a promising strategy for enhancing oral bioavailability. Upon dissolution, ASDs have accelerated dissolution rates and yield supersaturated solutions leading to higher apparent solubilities. Understanding the complex phase behavior of ASDs during dissolution is crucial for developing an effective formulation. Since the absorption of a lipophilic, high permeability drug is determined primarily by the intraluminal dissolution process and the final concentration achieved, there is a need for evaluation in biorelevant dissolution media that simulate both fasting and fed gastrointestinal states...
November 21, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29161398/role-of-gabaa-receptor-subtypes-in-the-behavioural-effects-of-intravenous-general-anaesthetics
#6
C J Weir, S J Mitchell, J J Lambert
Since the introduction of general anaesthetics into clinical practice, researchers have been mystified as to how these chemically disparate drugs act to produce their dramatic effects on central nervous system function and behaviour. Scientific advances, particularly during the last 25 years, have now begun to reveal the molecular mechanisms underpinning their behavioural effects. For certain i.v. general anaesthetics, such as etomidate and propofol, a persuasive case can now be made that the GABAA receptor, a major inhibitory receptor in the mammalian central nervous system, is an important target...
December 1, 2017: British Journal of Anaesthesia
https://www.readbyqxmd.com/read/29161395/postoperative-cognitive-dysfunction-and-dementia-what-we-need-to-know-and-do
#7
M J Needham, C E Webb, D C Bryden
Approximately 12% of apparently previously cognitively well patients undergoing anaesthesia and noncardiac surgery will develop symptoms of cognitive dysfunction after their procedure. Recent articles in this Journal have highlighted the difficulties of confirming any clear links between anaesthesia and cognitive dysfunction, in part because of the lack of consistency regarding definition and diagnosis. Postoperative cognitive dysfunction (POCD) is usually self-limiting and rarely persists in the longer term, although plausible biological mechanisms for an impact on brain protein deposition do exist...
December 1, 2017: British Journal of Anaesthesia
https://www.readbyqxmd.com/read/29161390/thiopental-to-desflurane-an-anaesthetic-journey-where-are-we-going-next
#8
J R Sneyd
Development targets in anaesthetic pharmacology have evolved from minimizing harm caused by unwanted effects through an era in which rapid onset and offset of drug effect were prioritised. Today's anaesthetists have access to a library of effective drugs whose characteristics offer controllable hypnosis, analgesia and paralysis with manageable off-target effects. The availability of these agents at generic prices inhibits commercial interest and this is reflected in the limited number of current anaesthetic drug development projects...
December 1, 2017: British Journal of Anaesthesia
https://www.readbyqxmd.com/read/29161298/controlled-placement-of-multiple-cns-cell-populations-to-create-complex-neuronal-cultures
#9
D Soscia, A Belle, N Fischer, H Enright, A Sales, J Osburn, W Benett, E Mukerjee, K Kulp, S Pannu, E Wheeler
In vitro brain-on-a-chip platforms hold promise in many areas including: drug discovery, evaluating effects of toxicants and pathogens, and disease modelling. A more accurate recapitulation of the intricate organization of the brain in vivo may require a complex in vitro system including organization of multiple neuronal cell types in an anatomically-relevant manner. Most approaches for compartmentalizing or segregating multiple cell types on microfabricated substrates use either permanent physical surface features or chemical surface functionalization...
2017: PloS One
https://www.readbyqxmd.com/read/29161243/the-combined-activation-of-kca3-1-and-inhibition-of-kv11-1-herg1-currents-contribute-to-overcome-cisplatin-resistance-in-colorectal-cancer-cells
#10
Serena Pillozzi, Massimo D'Amico, Gianluca Bartoli, Luca Gasparoli, Giulia Petroni, Olivia Crociani, Tiziano Marzo, Angela Guerriero, Luigi Messori, Mirko Severi, Roberto Udisti, Heike Wulff, K George Chandy, Andrea Becchetti, Annarosa Arcangeli
BACKGROUND: Platinum-based drugs such as Cisplatin are commonly employed for cancer treatment. Despite an initial therapeutic response, Cisplatin treatment often results in the development of chemoresistance. To identify novel approaches to overcome Cisplatin resistance, we tested Cisplatin in combination with K(+) channel modulators on colorectal cancer (CRC) cells. METHODS: The functional expression of Ca(2+)-activated (KCa3.1, also known as KCNN4) and voltage-dependent (Kv11...
November 21, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29161210/index-use-of-smoflipid-in-a-tertiary-intestinal-rehabilitation-and-transplantation-program
#11
Kwai Lam, Thomas Schiano, Maria Isabel Fiel, Kishore Iyer
Long-term parenteral nutrition (PN) may be complicated by PN-associated liver disease (PNALD), and some studies suggest an association between the use of soy-based fat emulsions and PNALD development. Patients' liver function typically improves and PNALD resolves after reducing or stopping a soy-based fat emulsion, and thus lipid minimization has been the primary strategy for managing PNALD in many intestinal rehabilitation programs. However, fat emulsions often cannot be stopped entirely, leading some patients to develop PNALD even after lipid reduction strategies have been implemented...
November 1, 2017: JPEN. Journal of Parenteral and Enteral Nutrition
https://www.readbyqxmd.com/read/29161196/emergence-of-mixed-oil-fat-emulsions-for-use-in-parenteral-nutrition
#12
Manpreet S Mundi, Robert Martindale, Ryan T Hurt
Since early work by Wretlind and Schuberth led to the development of a stable and safe intravenous fat emulsion (IFE) using soybean oil (SO) and egg phospholipid emulsifier, IFEs have become a crucial source of essential fatty acids and nonprotein energy in parenteral nutrition. However, largely due to their high ω-6 polyunsaturated fatty acid (PUFA) and phytosterol content, SO IFEs have been associated with complications, including a proinflammatory profile and hypertriglyceridemia, as well as intestinal failure-associated liver disease...
November 1, 2017: JPEN. Journal of Parenteral and Enteral Nutrition
https://www.readbyqxmd.com/read/29161167/depression-and-marijuana-use-among-a-sample-of-urban-females-is-stage-of-development-important
#13
Leah Floyd Campbell
BACKGROUND: Increasing rates of marijuana use and high rates of depression among females are major public health concerns and ambiguous study results suggest a complex association between the two. Inconsistent findings may be due to differences in sample characteristics (e.g., females vs. males) and result from differences in the relationship over time (i.e., across developmental stages). OBJECTIVES: Presently, the extent to which the relationship between depression and marijuana use differed for females in emerging adulthood, compared to young adult females, was examined...
November 21, 2017: Substance Use & Misuse
https://www.readbyqxmd.com/read/29161016/selective-voltage-gated-sodium-channel-peptide-toxins-from-animal-venom-pharmacological-probes-and-analgesic-drug-development
#14
Ying Wu, Hui Ma, Fan Zhang, Chun-Lei Zhang, Xiaohan Zou, Zhengyu Cao
Voltage-gated sodium channels (Navs) play critical roles in action potential generation and propagation. Nav channelopathy as well as pathological sensitization contribute to allodynia and hyperalgesia. Recent evidence has demonstrated the significant roles of Nav subtypes (Nav1.3, 1.7, 1.8 and 1.9) in nociceptive transduction and therefore these Navs may represent attractive targets for analgesic drug discovery. Animal toxins are structurally diverse peptides that are highly potent yet selective on ion channel subtypes and therefore representing valuable probes to elucidate the structures, gating properties and cellular functions of ion channels...
November 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29161011/the-design-of-plasmodium-vivax-hypoxanthine-guanine-phosphoribosyltransferase-inhibitors-as-potential-antimalarial-therapeutics
#15
Dianne T Keough, Dominik Rejman, Radek Pohl, Eva Zborníková, Dana Hockova, Tristan Croll, Michael D Edstein, Geoff W Birrell, Marina Chavchich, Lieve M J Naesens, Gregory K Pierens, Ian M Brereton, Luke W Guddat
Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) are the foremost causative agents of malaria. Due to the development of resistance to current antimalarial medications, new drugs for this parasitic disease need to be discovered. The activity of hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase, HG[X]PRT, is reported to be essential for the growth of both of these parasites, making it an excellent target for antimalarial drug discovery. Here, we have used rational structure-based methods to design an inhibitor, [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine, of PvHGPRT and PfHGXPRT which has Ki values of 8 nM and 7 nM, respectively for these two enzymes...
November 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29161006/top-dnj-a-selective-inhibitor-of-endoplasmic-reticulum-%C3%AE-glucosidase-ii-exhibiting-anti-flaviviral-activity
#16
J L Kiappes, Michelle L Hill, Dominic S Alonzi, Joanna L Miller, Ren Iwaki, Andrew C Sayce, Alessandro T Caputo, Atsushi Kato, Nicole Zitzmann
Iminosugars have therapeutic potential against a range of diseases, due to their efficacy as glycosidase inhibitors. A major challenge in the development of iminosugar drugs lies in making a compound that is selective for the glycosidase associated with a given disease. We report the synthesis of ToP-DNJ, an antiviral iminosugar-tocopherol conjugate. Tocopherol was incorporated into the design of the iminosugar in order to direct the drug to the liver and immune cells, specific tissues of interest for antiviral therapy...
November 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29160846/a-triphenylphosphonium-functionalized-mitochondriotropic-nanocarrier-for-efficient-co-delivery-of-doxorubicin-and-chloroquine-and-enhanced-antineoplastic-activity
#17
Katerina N Panagiotaki, Zili Sideratou, Spiros A Vlahopoulos, Maria Paravatou-Petsotas, Michael Zachariadis, Nikolas Khoury, Vassilis Zoumpourlis, Dimitris Tsiourvas
Drug delivery systems that target subcellular organelles and, in particular, mitochondria are considered to have great potential in treating disorders that are associated with mitochondrial dysfunction, including cancer or neurodegenerative diseases. To this end, a novel hyperbranched mitochondriotropic nanocarrier was developed for the efficient co-delivery of two different (both in chemical and pharmacological terms) bioactive compounds. The carrier is based on hyperbranched poly(ethyleneimine) functionalized with triphenylphosphonium groups that forms ~100 nm diameter nanoparticles in aqueous media and can encapsulate doxorubicin (DOX), a well-known anti-cancer drug, and chloroquine (CQ), a known chemosensitizer with arising potential in anticancer medication...
November 21, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/29160839/inkjet-printing-of-drug-loaded-mesoporous-silica-nanoparticles-a-platform-for-drug-development
#18
Henrika Wickström, Ellen Hilgert, Johan O Nyman, Diti Desai, Didem Şen Karaman, Thomas de Beer, Niklas Sandler, Jessica M Rosenholm
Mesoporous silica nanoparticles (MSNs) have shown great potential in improving drug delivery of poorly water soluble (BCS class II, IV) and poorly permeable (BCS class III, IV) drugs, as well as facilitating successful delivery of unstable compounds. The nanoparticle technology would allow improved treatment by reducing adverse reactions of currently approved drugs and possibly reintroducing previously discarded compounds from the drug development pipeline. This study aims to highlight important aspects in mesoporous silica nanoparticle (MSN) ink formulation development for digital inkjet printing technology and to advice on choosing a method (2D/3D) for nanoparticle print deposit characterization...
November 21, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29160791/antimalarial-activity-of-acetylenic-thiophenes-from-echinops-hoehnelii-schweinf
#19
Helen Bitew, Wendimagegn Mammo, Ariaya Hymete, Mariamawit Yonathan Yeshak
Malaria is one of the world's most severe endemic diseases and due to the emergence of resistance to the currently available medicines, the need for new targets and relevant antimalarial drugs remains acute. The crude extract, four solvent fractions and two isolated compounds from the roots of Echinops hoehnelii were tested for their antimalarial activity using the standard four-day suppressive method in Plasmodium berghei-infected mice. The 80% methanol extract exhibited suppression of 4.6%, 27.8%, 68.5% and 78...
November 21, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29160732/optimization-and-characterization-of-sertaconazole-nitrate-flexisomes-embedded-in-hydrogel-for-improved-antifungal-activity
#20
Satish K Mandlik, Shridhar S Siras, Kiran R Birajdar
The aim of the present research work was to develop, characterize and optimize sertaconazole nitrate (STZN) embedded flexisomes (STZN-FS) to improve the cutaneous anti-fungal activity of STZN. Flexisomes are self-aggregating, flexible, deformable lipidic vesicles possessing an aqueous core. A 3(2) factorial design was implemented to optimize the effects of the critical material attributes of concentration of phospholipid (X1) and edge activator (X2) on the critical quality attributes of particle size (Y1), entrapment efficiency (Y2) and deformability index (Y3)...
November 21, 2017: Journal of Liposome Research
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