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Pleun Hombrink, Christina Helbig, Ronald A Backer, Berber Piet, Anna E Oja, Regina Stark, Giso Brasser, Aldo Jongejan, René E Jonkers, Benjamin Nota, Onur Basak, Hans C Clevers, Perry D Moerland, Derk Amsen, René A W van Lier
Tissue-resident memory T cells (TRM cells) in the airways mediate protection against respiratory infection. We characterized TRM cells expressing integrin αE (CD103) that reside within the epithelial barrier of human lungs. These cells had specialized profiles of chemokine receptors and adhesion molecules, consistent with their unique localization. Lung TRM cells were poised for rapid responsiveness by constitutive expression of deployment-ready mRNA encoding effector molecules, but they also expressed many inhibitory regulators, suggestive of programmed restraint...
October 24, 2016: Nature Immunology
Peter M Fischer
Kinase inhibitor research is a comparatively recent branch of medicinal chemistry and pharmacology and the first small-molecule kinase inhibitor, imatinib, was approved for clinical use only 15 years ago. Since then, 33 more kinase inhibitor drugs have received regulatory approval for the treatment of a variety of cancers and the volume of reports on the discovery and development of kinase inhibitors has increased to an extent where it is now difficult-even for those working in the field-easily to keep an overview of the compounds that are being developed, as currently there are 231 such compounds, targeting 38 different protein and lipid kinases (not counting isoforms), in clinical use or under clinical investigation...
October 24, 2016: Medicinal Research Reviews
Michael J Waring, Huawei Chen, Alfred A Rabow, Graeme Walker, Romel Bobby, Scott Boiko, Rob H Bradbury, Rowena Callis, Edwin Clark, Ian Dale, Danette L Daniels, Austin Dulak, Liz Flavell, Geoff Holdgate, Thomas A Jowitt, Alexey Kikhney, Mark McAlister, Jacqui Méndez, Derek Ogg, Joe Patel, Philip Petteruti, Graeme R Robb, Matthew B Robers, Sakina Saif, Natalie Stratton, Dmitri I Svergun, Wenxian Wang, David Whittaker, David M Wilson, Yi Yao
Proteins of the bromodomain and extraterminal (BET) family, in particular bromodomain-containing protein 4 (BRD4), are of great interest as biological targets. BET proteins contain two separate bromodomains, and existing inhibitors bind to them monovalently. Here we describe the discovery and characterization of probe compound biBET, capable of engaging both bromodomains simultaneously in a bivalent, in cis binding mode. The evidence provided here was obtained in a variety of biophysical and cellular experiments...
October 24, 2016: Nature Chemical Biology
Miao Long, Yi Liu, Yu Cao, Nan Wang, Meng Dang, Jianbin He
Lead is harmful for human health and animals. Proanthocyanidins (PCs), a natural antioxidant, possess a broad spectrum of pharmacological and medicinal properties. However, its protective effects against lead-induced liver damage have not been clarified. This study was aimed to evaluate the protective effect of PCs on the hepatotoxicity of male Kunming mice induced by chronic lead exposure. A total of 70 healthy male Kunming mice were averagely divided into four groups: control group, i.e., the group exposed to lead, the group treated with PCs, and the group co-treated with lead and PCs...
October 21, 2016: Nutrients
Mariangela Marrelli, Filomena Conforti, Fabrizio Araniti, Giancarlo A Statti
Obesity is one of the greatest public health problems. This complex condition has reached epidemic proportions in many parts of the world, and it constitutes a risk factor for several chronic disorders, such as hypertension, cardiovascular diseases and type 2 diabetes. In the last few decades, several studies dealt with the potential effects of natural products as new safe and effective tools for body weight control. Saponins are naturally-occurring surface-active glycosides, mainly produced by plants, whose structure consists of a sugar moiety linked to a hydrophobic aglycone (a steroid or a triterpene)...
October 20, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Hayriye Genç, Ramazan Kalin, Zeynep Köksal, Nastaran Sadeghian, Umit M Kocyigit, Mustafa Zengin, İlhami Gülçin, Hasan Özdemir
β-Lactams are pharmacologically important compounds because of their various biological uses, including antibiotic and so on. β-Lactams were synthesized from benzylidene-inden derivatives and acetoxyacetyl chloride. The inhibitory effect of these compounds was examined for human carbonic anhydrase I and II (hCA I, and II) and acetylcholinesterase (AChE). The results reveal that β-lactams are inhibitors of hCA I, II and AChE. The Ki values of β-lactams (2a-k) were 0.44-6.29 nM against hCA I, 0.93-8.34 nM against hCA II, and 0...
October 20, 2016: International Journal of Molecular Sciences
Igor V Ukrainets, Lidiya A Petrushova, Svitlana V Shishkina, Lina A Grinevich, Galina Sim
In order to obtain and then test pharmocologically any possible conformers of the new feasible analgesic N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxamide, its 4-O-sodium salt was synthesized using two methods. X-ray diffraction study made possible to determine that, depending on the chosen synthesis conditions, the above-mentioned compound forms either monosolvate with methanol or monohydrate, where organic anion exists in the form of three different conformers. Pharmacological testing of the two known pseudo-enantiomeric forms of the original N-benzylamide and of the two solvates of its sodium salt was performed simultaneously under the same conditions and in equimolar doses...
October 19, 2016: Scientia Pharmaceutica
Søren B van Witteloostuijn, Søren L Pedersen, Knud J Jensen
Peptides and proteins constitute a vast pool of excellent drug candidates. Evolution has equipped these molecules with superior drug-like properties such as high specificity and potency. However, native peptides and proteins suffer from an inadequate pharmacokinetic profile, and their outstanding pharmacological potential can only be realized if this issue is addressed during drug development. To overcome this challenge, a variety of half-life extension techniques relying on covalent chemical modification have been developed...
October 24, 2016: ChemMedChem
Miao Liu, Xing Xing Liu, Xiao Lin He, Li Juan Liu, Hao Wu, Cai Xian Tang, Yong Song Zhang, Chong Wei Jin
Nitric oxide (NO) and ethylene respond to biotic and abiotic stresses through either similar or independent processes. This study examines the mechanism underlying the effects of NO and ethylene on promoting root hair development in Arabidopsis under magnesium (Mg) deficiency. The interaction between NO and ethylene in the regulation of Mg deficiency-induced root hair development was investigated using NO- and ethylene-related mutants and pharmacological methods. Mg deficiency triggered a burst of NO and ethylene, accompanied by a stimulated development of root hairs...
October 24, 2016: New Phytologist
Matthew Osmond, Sarah M Bernier, Mina B Pantcheva, Melissa D Krebs
Glaucoma is a disease in which damage to the optic nerve leads to progressive, irreversible vision loss. The intraocular pressure (IOP) is the only modifiable risk factor for glaucoma and its lowering is considered a useful strategy for preventing or slowing down the progression of glaucomatous neuropathy. Elevated intraocular pressure associated with glaucoma is due to increased aqueous humor outflow resistance, primarily through the trabecular meshwork (TM) of the eye. Current in vitro models of the trabecular meshwork are oversimplified and do not capture the organized and complex three-dimensional nature of this tissue that consists primarily of collagen and glycoasaminoglycans...
October 24, 2016: Biotechnology and Bioengineering
Zhi-Dan Fan, Ya-Yuan Zhang, Yi-Hong Guo, Na Huang, Hui-Hui Ma, Hui Huang, Hai-Guo Yu
Interleukin (IL)-17 producing T helper (Th17) cells are major effector cells in the pathogenesis of rheumatoid arthritis (RA). The P2X7 receptor (P2X7R) has emerged as a potential site in the regulation of inflammation in RA but little is known of its functional role on the differentiation of Th17 cells. This study investigates the in vitro and in vivo effects of P2X7R on Th17 cell differentiation during type II collagen (CII) induced experimental arthritis model. In CII-treated dendritic cells (DCs) and DC/CD4(+) T coculture system, pretreatment with pharmacological antagonists of P2X7R (Suramin and A-438079) caused strong inhibition of production of Th17-promoting cytokines (IL-1β, TGF-β1, IL-23p19 and IL-6)...
October 24, 2016: Scientific Reports
Viviana Guadagni, Chiara Cerri, Ilaria Piano, Elena Novelli, Claudia Gargini, Carla Fiorentini, Matteo Caleo, Enrica Strettoi
Retinitis pigmentosa (RP) comprises a group of inherited pathologies characterized by progressive photoreceptor degeneration. In rodent models of RP, expression of defective genes and retinal degeneration usually manifest during the first weeks of postnatal life, making it difficult to distinguish consequences of primary genetic defects from abnormalities in retinal development. Moreover, mouse eyes are small and not always adequate to test pharmacological and surgical treatments. An inducible paradigm of retinal degeneration potentially extensible to large animals is therefore desirable...
October 24, 2016: Scientific Reports
Behjat Javadi, Amirhossein Sahebkar, Seyed Ahmad Emami
OBJECTIVE: To search major Traditional Persian Medicine (TPM) textbooks for medicinal plants used to treat asthma. The conformity of the TPM findings on the anti-asthmatic efficacy of plants with the findings of pharmacological studies was also explored. METHODS: Major TPM textbooks were hand searched to find medicinal plants used for the treatment of asthma. Scientific names of TPM-suggested plants were determined using botanical databases and were used for a multi-database electronic search in PubMed, Scopus, ScienceDirect and Google Scholar databases...
October 21, 2016: Current Pharmaceutical Design
Sarvenaz Sabouri-Rad, Sara Sabouri-Rad, Amirhossein Sahebkar, Zahra Tayarani-Najaran
Ginseng has gained fame as one of the most popular herbs originating from Eastern countries. Among different species which are known as ginseng, Panax ginseng C. A. Mey. (Korean or Asian ginseng) is the most frequently used one. Ginsenosides have been proposed to account for most of the biological activities of ginseng. The widely appreciated health-promoting effect of ginseng pertains to the beneficial effects of this plant against immune, cardiovascular and sexual diseases and cancer. In addition, there are some new aspects of the pharmacological activity of this plant which justify its use in dermatologic diseases...
October 21, 2016: Current Pharmaceutical Design
Subha Rastogi, Madan Mohan Pandey, Aks Rawat
BACKGROUND: Dietary factors play a key role in the development as well as prevention of certain human diseases, including cardiovascular diseases. Currently there has been an increase in global interest to identify medicinal plants that are pharmacologically effective and have low or no side effects for use in preventive medicine. Culinary herbs and spices are an important part of human nutrition in all the cultures of the world. There is a growing amount of literature concerning the potential benefits of these herbs and spices from a health perspective especially in conferring protection against cardiovascular diseases...
October 21, 2016: Current Pharmaceutical Design
Ekaterina S Dolinina, Elena V Parfenyuk
BACKGROUND: Warfarin, commonly used anticoagulant in clinic, has serious shortcomings due to its unsatisfactory pharmacodynamics. One of efficient ways of improvement of pharmacological and consumer properties of drugs is development of optimal drug delivery systems. OBJECTIVE: The aim of this work is synthesis of novel warfarin - silica composites and study in vitro the drug release kinetics to obtain the composites with controlled release. METHODS: The composites of warfarin with unmodified (UMS) and mercaptopropy modified silica (MPMS) were synthesized by sol-gel method...
October 21, 2016: Current Drug Delivery
Prithviraj Bose, Srdan Verstovsek
INTRODUCTION: Primary myelofibrosis (PMF) is the least common but the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms. Survival is much shorter in PMF than in polycythemia vera (PV) or essential thrombocythemia (ET). Post-PV/ET myelofibrosis (MF) is clinically indistinguishable from PMF and approached similarly. AREAS COVERED: Current pharmacologic therapy of MF revolves around the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib, which dramatically improves constitutional symptoms and splenomegaly in the majority of patients, and improves overall survival (OS)...
October 22, 2016: Expert Opinion on Pharmacotherapy
Yoonbae Oh, Cheonho Park, Do Hyoung Kim, Hojin Shin, Yu Min Kang, Mark DeWaele, Jeyeon Lee, Hoon-Ki Min, Charles D Blaha, Kevin Bennet, In Young Kim, Kendall H Lee, Dong Pyo Jang
Dopamine (DA) modulates central neuronal activity through both phasic (second to second) and tonic (minutes to hours) terminal release. Conventional fast-scan cyclic voltammetry (FSCV), in combination with carbon fiber microelectrodes, has been used to measure phasic DA release in vivo by adopting a background subtraction procedure to remove background capacitive currents. However, to-date, measuring tonic changes in DA concentrations using conventional FSCV has been difficult because background capacitive currents are inherently unstable over long recording periods...
October 24, 2016: Analytical Chemistry
Patricia Yuste-Checa, Sandra Brasil, Alejandra Gámez, Jarl Underhaug, Lourdes R Desviat, Magdalena Ugarte, Celia Pérez-Cerdá, Aurora Martinez, Belén Pérez
The congenital disorder of glycosylation (CDG) due to phosphomannomutase 2 deficiency (PMM2-CDG), the most common N-glycosylation disorder, is a multisystem disease for which no effective treatment is available. The recent functional characterization of disease-causing mutations described in patients with PMM2-CDG led to the idea of a therapeutic strategy involving pharmacological chaperones (PC) to rescue PMM2 loss-of-function mutations. The present work describes the high-throughput screening, by differential scanning fluorimetry, of 10,000 low molecular weight compounds from a commercial library, to search for possible PCs for the enzyme PMM2...
October 24, 2016: Human Mutation
Pedro Casado, Maruan Hijazi, David Britton, Pedro R Cutillas
Signalling pathways driven by protein and lipid kinases are altered in most human diseases. Therefore, pharmacological inhibitors of cell signalling are one of the most intensively pursued therapeutic approaches for the treatment of diseases such as cancer, neurodegeneration and metabolic syndromes. Phosphoproteomics is a technique that measures the products of kinase activities and, with the appropriate bioinformatics techniques, the methodology can also provide measures of kinase pathway activation and network circuitry...
October 24, 2016: Proteomics
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