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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
Shawn J Stachel, Melissa S Egbertson, Jenny Wai, Michelle Machacek, Dawn M Toolan, John Swestock, Donnie M Eddins, Vanita Puri, Georgia McGaughey, Hua-Poo Su, Debbie Perlow, Deping Wang, Lei Ma, Gopal Parthasarathy, John C Reid, Pravien D Abeywickrema, Sean M Smith, Jason M Uslaner
An internal HTS effort identified a novel PDE2 inhibitor series that was subsequently optimized for improved PDE2 activity and off-target selectivity. The optimized lead, compound 4, improved cognitive performance in a rodent novel object recognition task as well as a non-human primate object retrieval task. In addition, co-crystallization studies of close analog of 4 in the PDE2 active site revealed unique binding interactions influencing the high PDE isoform selectivity.
April 1, 2018: Bioorganic & Medicinal Chemistry Letters
Takuji Sugiyama, Yuji Narukawa, Shunsuke Shibata, Ryo Masui, Fumiyuki Kiuchi
Agarwood (jinkoh in Japanese) is a resinous wood from Aquilaria species of the family Thymelaeaceae and has been used as incense and in traditional medicines. Characteristic chromone derivatives such as agarotetrol have been isolated from agarwood. In previous study, we isolated two new 2-(2-phenylethyl)chromones together with six known compounds from MeOH extract of agarwood. Further chemical investigation of the MeOH extract led to isolation of eighteen 2-(2-phenylethyl)chromones, including three new 5,6,7,8-tetrahydroxy-5,6,7,8-tetrahydrochromones with stereochemistry enantiomeric to agarotetrol-type, viz...
March 10, 2018: Journal of Natural Medicines
Ji-Liang Zhang, Min Liu, Chun-Nuan Zhang, Er-Chao Li, Ming-Zhen Fan, Mao-Xian Huang
The brain of fish displays sexual dimorphisms and exhibits remarkable sexual plasticity throughout their life span. Although reproductive toxicity of tributyltin (TBT) in fish is well documented in fish, it remains unknown whether TBT interrupts sexual dimorphisms of fish brains. In this work, brain transcriptomic profiles of rare minnow (Gobiocypris rarus) was characterized and sex-biased genes were identified using RNA sequencing. Functional annotation and enrichment analysis were performed to reveal differences of gene products and pathways between the brains of male and female fish...
March 7, 2018: Ecotoxicology and Environmental Safety
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
Susanne Herbst, Martin Lorkowski, Olga Sarenko, Thi Kim Loan Nguyen, Tina Jaenicke, Regine Hengge
The nucleotide second messenger c-di-GMP nearly ubiquitously promotes bacterial biofilm formation, with enzymes that synthesize and degrade c-di-GMP being controlled by diverse N-terminal sensor domains. Here, we describe a novel class of widely occurring c-di-GMP phosphodiesterases (PDE) that feature a periplasmic "CSS domain" with two highly conserved cysteines that is flanked by two transmembrane regions (TM1 and TM2) and followed by a cytoplasmic EAL domain with PDE activity. Using PdeC, one of the five CSS domain PDEs of Escherichia coli K-12 , we show that DsbA/DsbB-promoted disulfide bond formation in the CSS domain reduces PDE activity...
March 7, 2018: EMBO Journal
G Röst, Z Vizi, I Z Kiss
We present the generalized mean-field and pairwise models for non-Markovian epidemics on networks with arbitrary recovery time distributions. First we consider a hyperbolic partial differential equation (PDE) system, where the population of infective nodes and links are structured by age since infection. We show that the PDE system can be reduced to a system of integro-differential equations, which is analysed analytically and numerically. We investigate the asymptotic behaviour of the generalized model and provide an implicit analytical expression involving the final epidemic size and pairwise reproduction number...
February 2018: Proceedings. Mathematical, Physical, and Engineering Sciences
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
Andreas Krause, Jochen Zisowsky, Jasper Dingemanse
BACKGROUND: Macitentan is the first endothelin receptor antagonist with demonstrated efficacy on morbidity and mortality in pulmonary arterial hypertension (PAH) in the pivotal study SERAPHIN. METHODS: The pharmacokinetics (PK) of macitentan and its active metabolite, ACT-132577, were characterized in a population model. Efficacy and hemodynamics (pharmacodynamics, PD) were related to PK based on PK/PD modeling. RESULTS: Sex, age, and body weight influenced the PK to a statistically significant extent...
February 28, 2018: Pulmonary Pharmacology & Therapeutics
Yoichi Kadoh, Haruko Miyoshi, Takehiko Matsumura, Yoshihito Tanaka, Mitsuya Hongu, Mayumi Kimura, Kei Takedomi, Kenji Omori, Jun Kotera, Takashi Sasaki, Tamaki Kobayashi, Hiroyuki Taniguchi, Yumi Watanabe, Koki Kojima, Toshiaki Sakamoto, Toshiyuki Himiyama, Eiji Kawanishi
Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5...
2018: Chemical & Pharmaceutical Bulletin
Yang Fu, Zhaoqing Yu, Shu Liu, Bo Chen, Li Zhu, Zhou Li, Shan-Ho Chou, Jin He
C-di-GMP has been well investigated to play significant roles in the physiology of many Gram-negative bacteria. However, its effect on Gram-positive bacteria is less known. In order to more understand the c-di-GMP functions in Gram-positive bacteria, we have carried out a detailed study on the c-di-GMP-metabolizing enzymes and their physiological functions in Bacillus thuringiensis , a Gram-positive entomopathogenic bacterium that has been applied as an insecticide successfully. We performed a systematic study on the ten putative c-di-GMP-synthesizing enzyme diguanylate cyclases (DGCs) and c-di-GMP-degrading enzyme phosphodiesterases (PDEs) in B...
2018: Frontiers in Microbiology
Ateş Kadıoğlu, Emre Salabaş, Abdulkadir Özmez, Abdullah Feyyaz Ural, Ömer Barış Yücel, Mazhar Ortaç, Yaşar Pazır, Bahadır Ermeç
Objective: To assess the outcomes of the surgical techniques used in Peyronie's disease (PD) surgery. Material and methods: Two hundred and sixty-eight patients received surgical treatment for PD. Fifty four and 144 patients underwent simple corporoplasties (shortening procedure, SP, group 1) or plaque incision and grafting surgery (lengthening surgery, LP, group 2), respectively, whereas 70 patients with erectile dysfunction underwent penile prosthesis implantation...
January 2018: Turkish Journal of Urology
Yuehui Tian, Shiqiang Gao, Shang Yang, Georg Nagel
It is since many years textbook knowledge that the concentration of the second messenger cGMP is regulated in animal rod and cone cells by type-II rhodopsins via a G protein signaling cascade. Microbial rhodopsins with enzymatic activity for regulation of cGMP concentration were only recently discovered: in 2014 light-activated guanylyl cyclase opsins in fungi and in 2017 a novel rhodopsin phosphodiesterase in the protist Salpingoeca rosetta ( Sr RhoPDE). The light-regulation of Sr RhoPDE however, seemed very weak or absent...
February 26, 2018: Biochemical Journal
Bahia A Moussa, Asmaa A El-Zaher, Mohamed K El-Ashrey, Marwa A Fouad
In the present work, we designed and synthesized new roflumilast analogues with preferential-selective PDE-4B inhibition activity and improved pharmacokinetic properties. The unsubstituted benzo[d]thiazol-2-yl and -6-yl benzamide derivatives (4a and 6a) showed both good potency and preferential selectivity for PDE-4B. More remarkably, 6c revealed 6 times preferential PDE-4B/4D selectivity with a significant increase of in vitro cAMP and good % inhibition of TNF-α concentration. In addition, the in vitro pharmacokinetics of 6c showed good metabolic stability with in vitro CLint (5...
February 17, 2018: European Journal of Medicinal Chemistry
Nathani Minaz, Rema Razdan, Lokesh Pathak
BACKGROUND: Well known risk factors for diabetic erectile dysfunction include impaired nitric oxide synthesis and endothelial dysfunction. We proposed to evaluate the efficacy of nitric oxide donor, molsidomine in rat model of diabetic erectile dysfunction. METHODS: Streptozotocin (52 mg/kg, ip) induced diabetic male rats were treated with molsidomine (5 and 10 mg/kg, po) for 8 weeks. The sexual behaviour of male rat in presence of the female rat in oestrous phase was observed at the end of study...
September 4, 2017: Pharmacological Reports: PR
Prabhjot Singh, Shilpa Vijayakumar, Andreas Kalogeroupoulos, Javed Butler
PURPOSE OF REVIEW: This review discusses the integral role of the nitric oxide (NO) pathway in the pathophysiology of heart failure (HF). We emphasize potential therapeutic targets in the NO pathway and review contemporary clinical trials evaluating these novel therapeutic options. RECENT FINDINGS: Nitrates, neprilysin inhibitors, and phosphodiesterase (PDE) inhibitors have all proven to be efficacious in HF patients with systolic dysfunction, with the former two classes of medications producing a net mortality benefit...
February 24, 2018: Current Heart Failure Reports
Maria Ercu, Enno Klussmann
A-kinase anchoring proteins (AKAPs) and cyclic nucleotide phosphodiesterases (PDEs) are essential enzymes in the cyclic adenosine 3'-5' monophosphate (cAMP) signaling cascade. They establish local cAMP pools by controlling the intensity, duration and compartmentalization of cyclic nucleotide-dependent signaling. Various members of the AKAP and PDE families are expressed in the cardiovascular system and direct important processes maintaining homeostatic functioning of the heart and vasculature, e.g., the endothelial barrier function and excitation-contraction coupling...
February 20, 2018: Journal of Cardiovascular Development and Disease
Fernando Bartolome, Macarena de la Cueva, Consuelo Pascual, Desiree Antequera, Tamara Fernandez, Carmen Gil, Ana Martinez, Eva Carro
BACKGROUND: The phosphodiesterase (PDE) 7 inhibitor S14 is a cell-permeable small heterocyclic molecule that is able to cross the blood-brain barrier. We previously found that intraperitoneal treatment with S14 exerted neuroprotection in an Alzheimer's disease (AD) model (in APP/PS1 mice). The objective of this study was to investigate the neurogenic and cellular effects of oral administration of S14 on amyloid β (Aβ) overload. METHODS: We orally administered the PDE7 inhibitor S14 (15 mg/kg/day) or vehicle in 6-month-old APP/PS1 mice...
February 20, 2018: Alzheimer's Research & Therapy
P R A Heckman, A Blokland, E P P Bollen, J Prickaerts
The corticostriatal and hippocampal circuits contribute to the neurobiological underpinnings of several neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease and schizophrenia. Based on biological function, these circuits can be clustered into motor circuits, associative/cognitive circuits and limbic circuits. Together, dysfunctions in these circuits produce the wide range of symptoms observed in related neuropsychiatric disorders. Intracellular signaling in these circuits is largely mediated through the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway with an additional role for the cyclic guanosine monophosphate (cGMP)/ protein kinase G (PKG) pathway, both of which can be regulated by phosphodiesterase inhibitors (PDE inhibitors)...
February 15, 2018: Neuroscience and Biobehavioral Reviews
Jake P Taylor-King, Etienne Baratchart, Andrew Dhawan, Elizabeth A Coker, Inga Hansine Rye, Hege Russnes, S Jon Chapman, David Basanta, Andriy Marusyk
Intra-tumour phenotypic heterogeneity limits accuracy of clinical diagnostics and hampers the efficiency of anti-cancer therapies. Dealing with this cellular heterogeneity requires adequate understanding of its sources, which is extremely difficult, as phenotypes of tumour cells integrate hardwired (epi)mutational differences with the dynamic responses to microenvironmental cues. The later comes in form of both direct physical interactions, as well as inputs from gradients of secreted signalling molecules. Furthermore, tumour cells can not only receive microenvironmental cues, but also produce them...
February 14, 2018: Mathematical Medicine and Biology: a Journal of the IMA
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