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Rita Turnaturi, Carmela Parenti, Orazio Prezzavento, Agostino Marrazzo, Paschalina Pallaki, Zafiroula Georgoussi, Emanuele Amata, Lorella Pasquinucci
The opioid pharmacological profile of cis -(-)- N -normetazocine derivatives is deeply affected by the nature of their N -substituents. Here, our efforts were focused on the synthesis and pharmacological evaluation of novel derivatives of the lead LP1, a multitarget opioid analgesic compound featuring an N -phenylpropanamido substituent. LP1 derivatives 5a - d and 6a - d were characterized by flexible groups at the N -substituent that allow them to reposition themselves relative to cis -(-)- N -normetazocine nucleus, thus producing different pharmacological profiles at the mu, delta and kappa opioid receptors (MOR, DOR and KOR) in in vitro and in vivo assays...
March 16, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Galina A Gazieva, Alexei N Izmest'ev, Lada V Anikina, Sergey A Pukhov, Marina E Meshchaneva, Dmitry V Khakimov, Natalya G Kolotyrkina, Angelina N Kravchenko
A series of tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7(1H, 6H)-diones were synthesized via the reaction of imidazotriazinethiones and bromoacetic acid followed by condensation with isatins. Amidine skeletal rearrangement of 3,3a,9,9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7 (1H, 6H)-diones into 1,3a,4,9a-tetrahydroimidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine-2,8 (3H, 7H)-diones under KOH treatment has been studied. The influence of substituents at positions 1,3,3a,6,9a of imidazothiazolotriazine on the ability to undergo rearrangement was analyzed based on experimental data and theoretical calculations...
March 14, 2018: Molecular Diversity
Valeryi K Lishko, Valentin P Yakubenko, Tatiana P Ugarova, Nataly P Podolnikova
Platelet Factor 4 (PF4) is one of the most abundant cationic proteins secreted from α-granules of activated platelets. Based on its structure, PF4 was assigned to the CXC family of chemokines and has been shown to have numerous effects on myeloid leukocytes. However, the receptor for PF4 remains unknown. Here, we demonstrate that PF4 induces leukocyte responses through the integrin Mac-1 (αM β2 , CD11b/CD18). Human neutrophils, monocytes, U937 monocytic and HEK293 cells expressing Mac-1 strongly adhered to immobilized PF4 in a concentration-dependent manner...
March 14, 2018: Journal of Biological Chemistry
Dionysios C Watson, Bryant C Yung, Cristina Bergamaschi, Bhabadeb Chowdhury, Jenifer Bear, Dimitris Stellas, Aizea Morales-Kastresana, Jennifer C Jones, Barbara K Felber, Xiaoyuan Chen, George N Pavlakis
The development of extracellular vesicles (EV) for therapeutic applications is contingent upon the establishment of reproducible, scalable, and high-throughput methods for the production and purification of clinical grade EV. Methods including ultracentrifugation (U/C), ultrafiltration, immunoprecipitation, and size-exclusion chromatography (SEC) have been employed to isolate EV, each facing limitations such as efficiency, particle purity, lengthy processing time, and/or sample volume. We developed a cGMP-compatible method for the scalable production, concentration, and isolation of EV through a strategy involving bioreactor culture, tangential flow filtration (TFF), and preparative SEC...
2018: Journal of Extracellular Vesicles
Aymeric Monteillier, Pierre-Marie Allard, Katia Gindro, Jean-Luc Wolfender, Muriel Cuendet
Lung cancer is the most lethal form of cancer in the world. Its development often involves an overactivation of the nuclear factor kappa B (NF-κB) pathway, leading to increased cell proliferation, survival, mobility, and a decrease in apoptosis. Therefore, NF-κB inhibitors are actively sought after for both cancer chemoprevention and therapy, and fungi represent an interesting unexplored reservoir for such molecules. The aim of the present work was to find naturally occurring lung cancer chemopreventive compounds by investigating the metabolites of Penicillium vulpinum , a fungus that grows naturally on dung...
March 12, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Élie Besserer-Offroy, Patrick Bérubé, Jérôme Côté, Alexandre Murza, Jean-Michel Longpré, Robert Dumaine, Olivier Lesur, Mannix Auger-Messier, Richard Leduc, Éric Marsault, Philippe Sarret
The apelinergic system is an important player in the regulation of both vascular tone and cardiovascular function, making this physiological system an attractive target for drug development for hypertension, heart failure and ischemic heart disease. Indeed, apelin exerts a positive inotropic effect in humans whilst reducing peripheral vascular resistance. In this study, we investigated the signaling pathways through which apelin exerts its hypotensive action. We synthesized a series of apelin-13 analogs whereby the C-terminal Phe13 residue was replaced by natural or unnatural amino acids...
March 9, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Anja Schiffmann, Gerald Gimpl
The oxytocin receptor, a class A G protein coupled receptor (GPCR), is essentially involved in the physiology of reproduction. Two parameters are crucially important to support high-affinity agonist binding of the receptor: Mg2+ and cholesterol, both acting as positive modulators. Using displacement assays with a high-affinity fluorescent antagonist (OTAN-A647), we now show that sodium functions as a negative allosteric modulator of the oxytocin receptor. In membranes from HEK293 cells stably expressing the oxytocin receptor, oxytocin binding occurred with about 15-fold lower affinity when sodium chloride was increased from 0 to 300 mM, whereas antagonist binding remained largely unchanged...
March 7, 2018: Biochimica et Biophysica Acta
Daniel R Crooks, Nunziata Maio, Andrew N Lane, Michal Jarnik, Richard M Higashi, Ronald G Haller, Ye Yang, T W M Fan, Marston Linehan, Tracey A Rouault
Iron-sulfur (Fe-S) clusters are ancient cofactors in cells and participate in diverse biochemical functions, including electron transfer and enzymatic catalysis. Although cell lines derived from individuals carrying mutations in the Fe-S cluster biogenesis pathway or siRNA-mediated knockdown of the Fe-S assembly components provide excellent models for investigating Fe-S cluster formation in mammalian cells, these experimental strategies focus on the consequences of prolonged impairment of Fe-S assembly. Here, we constructed and expressed dominant-negative variants of the primary Fe-S biogenesis scaffold protein iron-sulfur cluster assembly enzyme 2 (ISCU2) in human HEK293 cells...
March 9, 2018: Journal of Biological Chemistry
Amelie Perron, Yoshihiro Nishikawa, Jun Iwata, Hiromi Shimojo, Junichiro Takaya, Kumiko Kobayashi, Itaru Imayoshi, Naasson Mbambi Mbenza, Mihoko Takenoya, Ryoichiro Kageyama, Yuzo Kodama, Motonari Uesugi
The transcription factor Hes family bHLH transcription factor 1 (Hes1) is a downstream effector of Notch signaling and plays a crucial role in orchestrating developmental processes during the embryonic stage. However, its aberrant signaling in adulthood is linked to the pathogenesis of cancer. In the present study, we report the discovery of small organic molecules (JI051 and JI130) that impair the ability of Hes1 to repress transcription. Hes1 interacts with the transcriptional corepressor transducing-like enhancer of split 1 (TLE1) via an interaction domain comprising two tryptophan residues, prompting us to search a chemical library of 1,800 small molecules enriched for indole-like π-electron-rich pharmacophores for a compound that blocks Hes1-mediated transcriptional repression...
March 9, 2018: Journal of Biological Chemistry
Jeremy Streuli, Alan G Harris, Cecilia Cottiny, Florent Allagnat, Adrian F Daly, Eric Grouzmann, Karim Abid
BACKGROUND: Somatostatin analogs (SSAs) are first-line medical therapy for the treatment of acromegaly and neuroendocrine tumors that express somatostatin receptors (SSTR). Somatostatin suppresses secretion of a large number of hormones through the stimulation of the five SSTR. However, unbalanced inhibition of secretion as observed with the highly potent SSAs pasireotide causes hyperglycaemia mainly by inhibiting insulin secretion. In contrast, AP102 a new SSAs has neutral effect on blood glucose while suppressing GH secretion...
March 2, 2018: Neuropeptides
Stephanie Häfner, Finn Burg, Martina Kannler, Nicole Urban, Peter Mayer, Alexander Dietrich, Dirk Trauner, Johannes Broichhagen, Michael Schaefer
Natural products have many health benefits and their application can improve the quality of life. Recently, the diterpene (+) larixol and its acetylated congeners demonstrated a selective inhibition of the second messenger-gated cation channel transient receptor potential canonical 6 (TRPC6) over its close isoforms TRPC3 and TRPC7. Building on this knowledge, we expand these findings by chemical diversification of (+)-larixol mostly at position C6. Implementing High-Throughput Ca2+ FLIPR screening assays and electrophysiological patch-clamp recordings, we showcase larixyl N-methylcarbamate, dubbed SH045, as a compound with nanomolar affinity and a 13-fold subtype selectivity over TRPC3 in stably expressing HEK293 cells...
March 9, 2018: ChemMedChem
Vita Dauksaite, Michael Gotthardt
RNA-binding motif protein 20 (RBM20) is a cardiac splice regulator that adapts cardiac filling via its diverse substrates-including the sarcomeric protein titin. The molecular basis and regulation of RBM20-dependent exon exclusion are largely unknown. In tissue culture experiments, we show that the combination of RNA recognition motif (RRM) and C-terminus is necessary and sufficient for RBM20 activity, indicating an important function of the ZnF2 domain in splicing repression. Using splice reporter and in vitro binding assays targeting titin exons 241-243, we identified a minimal genomic segment that is necessary for RBM20-mediated splicing repression of the alternative exon...
March 6, 2018: Nucleic Acids Research
Sabrina Ribeiro de Almeida Queiroz, José Valter Joaquim Silva Júnior, Andréa Nazaré Monteiro Rangel da Silva, Amanda Gomes de Oliveira Carvalho, Jefferson José da Silva Santos, Laura Helena Vega Gonzales Gil
INTRODUCTION: Pseudo-infectious yellow fever viral particles (YFV-PIVs) have been used to study vaccines and viral packaging. Here, we report the development of a packaging cell line, which expresses the YFV prM/E proteins. METHODS: HEK293 cells were transfected with YFV prM/E and C (84 nt) genes to generate HEK293-YFV-PrM/E-opt. The cells were evaluated for their ability to express the heterologous proteins and to package the replicon repYFV-17D-LucIRES, generating YFV-PIVs...
January 2018: Revista da Sociedade Brasileira de Medicina Tropical
Diego Milani, Megan C Bakeberg, Jane L Cross, Vince W Clark, Ryan S Anderton, David J Blacker, Neville W Knuckey, Bruno P Meloni
We have previously demonstrated that arginine-rich and poly-arginine peptides possess potent neuroprotective properties, with poly-arginine peptide R18 identified as being highly effective at reducing infarct volume following middle cerebral artery occlusion (MCAO) in the Sprague Dawley rat. Since peptides synthesised using D-isoform amino acids have greater stability than L-isoform peptides due to increased resistance to proteolytic degradation, they represent potentially more effective peptide therapeutics...
2018: PloS One
Jie Qian, Shobha Mummalaneni, James Larsen, John R Grider, Andrew I Spielman, Mehmet Hakan Özdener, Vijay Lyall
In rodents, CHRNs are involved in bitter taste transduction of nicotine and ethanol. Currently, it is not clear if CHRNs are expressed in human taste cells and if they play a role in transducing the bitter taste of nicotine and ethanol or in the synthesis and release of neurohumoral peptides. Accordingly, we investigated the expression and functional role of CHRNs in HBO cells. Using molecular techniques, we demonstrate that a subset of HBO cells express CHRNs that also co-express TRPM5, T1R3 or T2R38. Exposing HBO cells to nicotine or ethanol acutely or to nicotine chronically induced a differential increase in the expression of CHRN mRNA and protein in a dose- and time-dependent manner...
2018: PloS One
Suman Joshi D S Doddapaneni, Chander Amgoth, Arunasree M Kalle, Surya Narayana Suryadevara, Krishna Satya Alapati
The synthesis and characterization of an aggregate of AgNPs coated with plant extract (PE) from Alphonsea sclerocarpa and its significant antimicrobial activity and inhibition on K562 (blood cancer) cells have been appended in the article. Synthesis of aggregate [(AgNPs)-(PE)] has been followed by a facile eco-friendly approach without using any harmful chemicals. The morphology of an aggregate [(AgNPs)-(PE)] was confirmed by TEM and SEM microscopic characterizations. Properties like solid state, the presence of functional groups, and elemental composition have been characterized through the XRD, FTIR, and EDAX...
March 2018: 3 Biotech
Dawn Sow Zong Leong, Brian Kah Hui Teo, Janice Gek Ling Tan, Hayati Kamari, Yuan Sheng Yang, Peiqing Zhang, Say Kong Ng
Oligosaccharides are generally considered to be un-utilized for growth of mammalian cells because their permeability across the cell membrane is low. However, in our previous study, we discovered that CHO and HEK293 cells consume maltose in culture media without serum and glucose. This is interesting because the transporter for maltose in mammalian cells has not been discovered to-date, and the only animal disaccharide transporter that is recently discovered is a sucrose transporter. The application of oligosaccharides in mammalian cell-based biopharmaceutical manufacturing can be beneficial, because it can theoretically increase carbohydrate content of the culture medium and decrease lactate production...
March 6, 2018: Scientific Reports
D K Jones, A Johnson, E C Roti Roti, F Liu, R Uelmen, R A Ayers, I Baczko, D J Tester, M J Ackerman, M C Trudeau, G A Robertson
Reduced levels of hERG protein and the corresponding repolarizing current IKr can cause arrhythmia and sudden cardiac death, but the underlying cellular mechanisms controlling hERG surface expression are not well understood. We identified TRIOBP-1, an F-actin binding protein previously associated with actin polymerization, as a putative hERG-interacting protein in a yeast-two hybrid screen of a cardiac library. We corroborated this interaction using Förster resonance energy transfer (FRET) in HEK293 cells and co-immunoprecipitation in HEK293 cells and native cardiac tissue...
March 5, 2018: Journal of Cell Science
Concepción Alonso, María Fuertes, Endika Martín-Encinas, Asier Selas, Gloria Rubiales, Cinzia Tesauro, Birgitta K Knudssen, Francisco Palacios
This work describes the synthesis of 1,2,3,4-tetrahydroquinolinylphosphine oxides, phosphanes and phosphine sulfides as well as that of quinolinylphosphine oxides and phosphine sulfides, which were synthesized in good to high overall yield. The synthetic route involves a multicomponent reaction of (2-phosphine-oxide)-, 2-phosphine- or (2-phosphine-sulfide)-aniline, aldehydes and olefins and allows the selective generation of two stereogenic centres in a short, efficient and reliable synthesis. The selective dehydrogenation of 1,2,3,4-tetrahydroquinolinylphosphine oxides and phosphine sulfides leads to the formation of corresponding phosphorus substituted quinolines...
February 22, 2018: European Journal of Medicinal Chemistry
Petr Pecina, Hana Nůsková, Vendula Karbanová, Vilma Kaplanová, Tomáš Mráček, Josef Houštěk
The central stalk of mitochondrial ATP synthase consists of subunits γ, δ, and ε, and along with the membraneous subunit c oligomer constitutes the rotor domain of the enzyme. Our previous studies showed that mutation or deficiency of ε subunit markedly decreased the content of ATP synthase, which was otherwise functionaly and structuraly normal. Interestingly, it led to accumulation of subunit c aggregates, suggesting the role of the ε subunit in assembly of individual enzyme domains. In the present study we focused on the role of subunits γ and δ...
February 27, 2018: Biochimica et Biophysica Acta
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