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Sven Persoon, Michael Paulus, Stephan Hirt, Carsten Jungbauer, Alexander Dietl, Andreas Luchner, Christof Schmid, Lars S Maier, Christoph Birner
Implantation of left ventricular assist devices (LVADs) as bridge to transplant in end-stage heart failure allows for analyzing reverse remodeling processes of the supported heart. Whether this therapy influences the cGMP-PKG signaling pathway, which is currently under thorough investigation for developing new heart failure therapeutics, is unknown. In fourteen end-stage heart failure patients (8 with dilated cardiomyopathy, DCM; 6 with ischemic cardiomyopathy, ICM) tissue specimens of left ventricles were collected at LVAD implantation and afterwards at receiver heart explantation, respectively...
March 15, 2018: Heart and Vessels
Edgar Isaac Rojas-Bedolla, Jorge Luis Gutiérrez-Pérez, Mario Iván Arenas-López, Marco Martin González-Chávez, Juan Ramón Zapata-Morales, Claudia Leticia Mendoza-Macías, Candy Carranza-Álvarez, Juan José Maldonado-Miranda, Martha Alicia Deveze-Álvarez, Angel Josabad Alonso-Castro
ETHNOPHARMACOLOGICAL RELEVANCE: Celtis pallida Torr (Cannabaceae) is employed as a folk medicine for the treatment of inflammation, pain, skin infections, and diarrhea, among other diseases. AIM OF THE STUDY: The purpose of this work was to assess the chemical composition, the in vitro and in vivo toxicity, the antimicrobial, anti-inflammatory, antidiarrheal, antinociceptive, locomotor, and sedative effects of an ethanolic extract obtained from Celtis pallida aerial parts (CPE)...
March 12, 2018: Journal of Ethnopharmacology
Hiroyuki Takahama, Seiji Takashio, Toshio Nishikimi, Tomohiro Hayashi, Chiaki Nagai-Okatani, Yasuaki Nakagawa, Makoto Amaki, Takahiro Ohara, Takuya Hasegawa, Yasuo Sugano, Hideaki Kanzaki, Satoshi Yasuda, Kenji Kangawa, Naoto Minamino, Toshihisa Anzai
BACKGROUND: A recent study showed that both glycosylation of pro-B-type natriuretic peptide (BNP) and the proBNP/total BNP ratio are decreased in acute decompensated heart failure (ADHF). However, the following points regarding the proBNP/total BNP ratio have not been determined in patients with ADHF: 1) the relationship with the severity of ADHF, 2) the changes in the ratio during treatment, and 3) the relationship with cyclic guanosine monophosphate (cGMP)-generating activity. METHODS: Plasma proBNP and total BNP (proBNP+mature BNP) were measured in patients with ADHF (n=154)...
May 1, 2018: International Journal of Cardiology
Tatsuya Yamada, Makoto Nishiyama, Shigeyuki Oba, Henri Claver Jimbo, Kazushi Ikeda, Shin Ishii, Kyonsoo Hong, Yuichi Sakumura
Biological cells express intracellular biomolecular information to the extracellular environment as various physical responses. We show a novel computational approach to estimate intracellular biomolecular pathways from growth cone electrophysiological responses. Previously, it was shown that cGMP signaling regulates membrane potential (MP) shifts that control the growth cone turning direction during neuronal development. We present here an integrated deterministic mathematical model and Bayesian reversed-engineering framework that enables estimation of the molecular signaling pathway from electrical recordings and considers both the system uncertainty and cell-to-cell variability...
March 14, 2018: Scientific Reports
L V Tat'yanenko, N A Sanina, O V Dobrokhotova, A I Kotelnikov, N S Goryachev, I I Pihteleva, G I Kozub, T A Kondrateva
The effect of iron nitrosyl complexes, NO donors, of a general formula [Fe2 (L)2 (NO)4 ] with functional sulfur-containing ligands (L-3-nitro-phenol-2-yl, 4-nitro-phenol-2-yl, or 1-methyl-tetrazol-5-yl) on the activity of sarcoplasmic reticulum Ca2+ -ATPase and cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) was studied. The test complexes uncoupled the hydrolytic and transport functions of Ca2+ - ATPase, thus disturbing the balance of Ca2+ ions in cells, which may affect the formation of thrombi and adhesion of metastatic cells to the endothelium of capillaries...
January 2018: Doklady. Biochemistry and Biophysics
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
Nadja I Bork, Viacheslav O Nikolaev
The ubiquitous second messenger 3',5'-cyclic guanosine monophosphate (cGMP) regulates multiple physiologic processes in the cardiovascular system. Its intracellular effects are mediated by stringently controlled subcellular microdomains. In this review, we will illustrate the current techniques available for real-time cGMP measurements with a specific focus on live cell imaging methods. We will also discuss currently accepted and emerging mechanisms of cGMP compartmentation in the cardiovascular system.
March 10, 2018: International Journal of Molecular Sciences
Shelly M Williams, Darin Sumstad, Diane Kadidlo, Julie Curtsinger, Xianghua Luo, Jeffrey S Miller, David H McKenna
BACKGROUND: Allogeneic natural killer (NK) cell adoptive immunotherapy is a growing therapeutic option for patients. Clinical-scale production of NK cells using immunomagnetic selection complies with current good manufacturing practices (cGMPs) and allows for closed-system, automated purification. We report our experience with CD3/CD19 cell-depleted (CD3/CD19dep ) NK cell production and compare to previous methods of CD3 cell depletion and CD3 cell depletion/CD56 cell enrichment. STUDY DESIGN AND METHODS: Nonmobilized mononuclear cells collected by apheresis were incubated with anti-CD3/anti-CD19 microbeads and depleted in an automated cell selection system (CliniMACS, Miltenyi)...
March 12, 2018: Transfusion
Eleonora Vighi, Dragana Trifunović, Patricia Veiga-Crespo, Andreas Rentsch, Dorit Hoffmann, Ayse Sahaboglu, Torsten Strasser, Manoj Kulkarni, Evelina Bertolotti, Angelique van den Heuvel, Tobias Peters, Arie Reijerkerk, Thomas Euler, Marius Ueffing, Frank Schwede, Hans-Gottfried Genieser, Pieter Gaillard, Valeria Marigo, Per Ekström, François Paquet-Durand
Inherited retinal degeneration (RD) is a devastating and currently untreatable neurodegenerative condition that leads to loss of photoreceptor cells and blindness. The vast genetic heterogeneity of RD, the lack of "druggable" targets, and the access-limiting blood-retinal barrier (BRB) present major hurdles toward effective therapy development. Here, we address these challenges ( i ) by targeting cGMP (cyclic guanosine- 3',5'-monophosphate) signaling, a disease driver common to different types of RD, and ( ii ) by combining inhibitory cGMP analogs with a nanosized liposomal drug delivery system designed to facilitate transport across the BRB...
March 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Babak Behnam Azad, Daniel P Holt, Hayden T Ravert, Andrew G Horti, Robert F Dannals
In this concise practitioner protocol, the radiochemical synthesis of [18 F]FNDP suitable for human PET studies is described and the results from validation productions are presented. The high specific activity radiotracer product is prepared as a sterile, apyrogenic solution that conforms to current Good Manufacturing Practice (cGMP) requirements.
March 12, 2018: Journal of Labelled Compounds & Radiopharmaceuticals
Jahidur Rashid, Kamrun Nahar, Snehal Raut, Ali Keshavarz, Fakhrul Ahsan
We investigated the feasibility of a combination therapy comprising fasudil, a Rho-kinase inhibitor, and DETA NONOate (diethylenetriamine NONOate, DN), a long acting nitric oxide donorboth loaded in liposomes modified with a homing peptide, CAR (CARSKNKDC)in the treatment of pulmonary arterial hypertension (PAH). We first prepared and characterized unmodified- and CAR-modified-liposomes of fasudil and DN. Using individual drugs alone or a mixture of fasudil and DN as controls, we studied the efficacy of the two liposomal preparations in reducing mean pulmonary arterial pressure (mPAP) in monocrotaline (MCT) and SUGEN-hypoxia induced PAH rats...
March 12, 2018: Molecular Pharmaceutics
Ipsita Mohanty, Subas Chandra Parija, Sujit Suklabaidya, Satish Rattan
Extracellular pH is an important physiological determinant of vascular tone that is normally maintained within 7.35-7.45. Any change outside this range leads to severe pathological repercussions. We investigated the unknown effects of extracellular acidosis on relaxation in the superior mesenteric artery (SMA) of goat. SMA rings were employed to maintain isometric contractions at extracellular pH (pHo ) 7.4 and 6.8. We analyzed the effect of acidosis (pHo 6.8) compared to physiological pH (pHo 7.4) on three signaling mediators of endothelium-dependent hyperpolarization: nitric oxide (NO), prostaglandin I2 (PGI2 ), and myoendothelial gap junctions (MEGJ)...
March 7, 2018: European Journal of Pharmacology
Stylianos Michalakis, Elvir Becirovic, Martin Biel
The first step in vision is the absorption of photons by the photopigments in cone and rod photoreceptors. After initial amplification within the phototransduction cascade the signal is translated into an electrical signal by the action of cyclic nucleotide-gated (CNG) channels. CNG channels are ligand-gated ion channels that are activated by the binding of cyclic guanosine monophosphate (cGMP) or cyclic adenosine monophosphate (cAMP). Retinal CNG channels transduce changes in intracellular concentrations of cGMP into changes of the membrane potential and the Ca2+ concentration...
March 7, 2018: International Journal of Molecular Sciences
Teemu T Turunen, Ari Koskelainen
Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze the second messengers cAMP and cGMP. PDEs control numerous cellular processes making them promising targets for the development of therapeutic agents. Unfortunately, many PDE inhibitor molecules are non-selective among PDE classes and efficient methods for quantitative studies on the isoform-specificity of PDE inhibitors in the natural environments of PDEs are unavailable. The PDE in photoreceptors, PDE6, mediates the conversion of photon information into electrical signals making the retina an exceptional model system for examinations of the pharmacological effects of PDE inhibitors on PDE6...
March 5, 2018: Toxicology and Applied Pharmacology
Oksana O Gerlits, James C Campbell, Matthew P Blakeley, Choel Kim, Andrey Y Kovalevsky
As one of main receptors of a second messenger, cGMP, cGMP-dependent protein kinase (PKG) isoforms I and II regu-late distinct physiological processes. Design of isoform specific activators is thus of great biomedical importance and requires detailed structural information on PKG isoforms bound with activators, including accurate positions of hydrogen atoms and description of hydrogen bonding and water architecture. Here, we determined a 2.2 Å room-temperature joint X-ray/neutron (XN) structure of the human PKG II carboxyl cyclic nucleotide binding (CNB-B) domain bound with a potent PKG II activator, 8-pCPT-cGMP...
March 8, 2018: Biochemistry
Mariachiara Zuccarini, Patricia Giuliani, Monica Frinchi, Giuseppa Mudò, Rosa Maria Serio, Natale Belluardo, Silvana Buccella, Marzia Carluccio, Daniele F Condorelli, Francesco Caciagli, Renata Ciccarelli, Patrizia Di Iorio
Mounting evidence suggests that the guanine-based purines stand out as key player in cell metabolism and in several models of neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases. Guanosine (GUO) and guanine (GUA) are extracellular signaling molecules derived from the breakdown of the correspondent nucleotide, GTP, and their intracellular and extracellular levels are regulated by the fine-tuned activity of two major enzymes, purine nucleoside phosphorylase (PNP) and guanine deaminase (GDA)...
2018: Frontiers in Pharmacology
Kirsten K Ahring, Allan M Lund, Erik Jensen, Thomas G Jensen, Karen Brøndum-Nielsen, Michael Pedersen, Allan Bardow, Jens Juul Holst, Jens F Rehfeld, Lisbeth B Møller
Introduction: Management of phenylketonuria (PKU) is achieved through low-phenylalanine (Phe) diet, supplemented with low-protein food and mixture of free-synthetic (FS) amino acid (AA). Casein glycomacropeptide (CGMP) is a natural peptide released in whey during cheese-making and does not contain Phe. Lacprodan® CGMP-20 used in this study contained a small amount of Phe due to minor presence of other proteins/peptides. Objective: The purpose of this study was to compare absorption of CGMP-20 to FSAA with the aim of evaluating short-term effects on plasma AAs as well as biomarkers related to food intake...
2018: Journal of Nutrition and Metabolism
Neema S Patel, Jennifer Klett, Katy Pilarzyk, Dong Ik Lee, David Kass, Frank S Menniti, Michy P Kelly
3',5'-Cyclic nucleotide phosphodiesterases (PDEs) degrade 3',5' cyclic adenonosine monophosphate (cAMP) and 3',5' cyclic guanosine monophosphate (cGMP), with PDE9A having the highest affinity for cGMP. We show PDE9A6 and 3 novel PDE9 isoforms (PDE9X-100, PDE9X-120, and PDE9X-175) are reliably detected in the brain and lung of mice, whereas PDE9A2 and other isoforms are found elsewhere. PDE9A localizes to the membrane in all organs except the bladder, where it is cytosolic. Brain additionally shows PDE9 in the nuclear fraction...
February 5, 2018: Neurobiology of Aging
Sirada Srihirun, Barbora Piknova, Nathawut Sibmooh, Alan N Schechter
Nitrite is recognized as a bioactive nitric oxide (NO) metabolite. We have shown that nitrite inhibits platelet activation and increases platelet cGMP levels in the presence of partially deoxygenated erythrocytes. In this study, we investigated the effect of nitrite on phosphorylation of vasodilator-stimulated phosphoprotein on residue serine 239 (P-VASPSer239), a marker of protein kinase G (PKG) activation, in human platelets. In platelet-rich plasma (PRP), nitrite itself had no effect on levels of P-VASPSer239 while DEANONOate increased P-VASPSer239...
2018: PloS One
Wenshan Lv, George W Booz, Fan Fan, Yangang Wang, Richard J Roman
Chronic kidney disease (CKD) is a significant worldwide healthcare problem. Regardless of the initial injury, renal fibrosis is the common final pathway leading to end stage renal disease. Although the underlying mechanisms are not fully defined, evidence indicates that besides inflammation, oxidative stress plays a crucial role in the etiology of renal fibrosis. Oxidative stress results from an imbalance between the production of free radicals that are often increased by inflammation and mitochondrial dysfunction, and reduced anti-oxidant defenses...
2018: Frontiers in Physiology
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