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https://www.readbyqxmd.com/read/29778746/betulinic-acid-a-natural-pde-inhibitor-restores-hippocampal-camp-cgmp-and-bdnf-improve-cerebral-blood-flow-and-recover-memory-deficits-in-permanent-bccao-induced-vascular-dementia-in-rats
#1
Madhu Kaundal, Saima Zameer, Abul Kalam Najmi, Suhel Parvez, Mohd Akhtar
Vascular dementia (VaD) is the second most common form of senile dementia, embraces memory deficits, neuroinflammation, executive function damage, mood and behavioral changes and abnormal cerebral blood flow. The purpose of the study was to explore the therapeutic potential of betulinic acid in bilateral common carotid artery occlusion (BCCAO) induced VaDin experimental rats.VaD was induced by BCCAO in rats and betulinic acid (10 and 15mg/kg/day po) was administered 1 week after surgery. The cerebral blood pressure of the animal was recorded before and after the treatment using Laser Doppler flow meter...
May 17, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29733479/levosimendan-differentially-modulates-electrophysiological-activities-of-sinoatrial-nodes-pulmonary-veins-and-the-left-and-right-atria
#2
Yung-Kuo Lin, Yao-Chang Chen, Yi-Ann Chen, Jen-Hung Huang, Shih-Ann Chen, Yi-Jen Chen
INTRODUCTION: Calcium overload increases the risk of atrial fibrillation (AF). Levosimedan, a calcium sensitizer, increases myofilament contractility. Clinical reports suggested that levosimendan might increase AF occurrence, but the electrophysiological effects of levosimendan on AF substrates and triggers (pulmonary veins, PVs) are not clear. METHODS AND RESULTS: Conventional microelectrodes were used to record action potentials (APs) in isolated rabbit PVs, sinoatrial nodes (SANs), the left atrium (LA), and right atrium (RA) before and after application of different concentrations of levosimendan with or without milrinone (a phosphodiesterase (PDE) III inhibitor) and glibenclamide (an ATP-sensitive potassium channel (KATP ) inhibitor)...
May 7, 2018: Journal of Cardiovascular Electrophysiology
https://www.readbyqxmd.com/read/29729992/proteomics-functional-characterization-and-antivenom-neutralization-of-the-venom-of-pakistani-russell-s-viper-daboia-russelii-from-the-wild
#3
Tasnim Faisal, Kae Yi Tan, Si Mui Sim, Naeem Quraishi, Nget Hong Tan, Choo Hock Tan
The venom proteome of wild Pakistani Russell's viper (Daboia russelii) was investigated through nano-ESI-LCMS/MS of the reverse-phase HPLC fractions. A total of 54 venom proteins were identified and clustered into 11 protein families. Phospholipase A2 (PLA2 , 63.8%) and Kunitz-type serine protease inhibitor (KSPI, 16.0%) were most abundant, followed by snake venom serine protease (SVSP, 5.5%, mainly Factor V activating enzyme), vascular endothelial growth factor (VEGF, 4.3%), snake venom metalloprotease (SVMP, 2...
May 3, 2018: Journal of Proteomics
https://www.readbyqxmd.com/read/29721383/myeloid-derived-macrophages-and-secreted-hsp90%C3%AE-induce-pancreatic-ductal-adenocarcinoma-development
#4
Chia-Chi Chen, Li-Li Chen, Chung-Pin Li, Yu-Ting Hsu, Shih-Sheng Jiang, Chi-Shuan Fan, Kee Voon Chua, Sheng-Xiang Huang, Yi-Ming Shyr, Li-Tzong Chen, Tze-Sing Huang
We detected a significant elevation of serum HSP90α levels in pancreatitis patients and even more in pancreatic ductal adenocarcinoma (PDAC) patients. However, there was no significant difference in the serum HSP90α levels between patients with early-stage and late-stage PDAC. To study whether elevation of serum HSP90α levels occurred early during PDAC development, we used LSL-KrasG12D/Pdx1-Cre transgenic mice as a studying model. Elevated serum HSP90α levels were detected before PDAC formation and an extracellular HSP90α (eHSP90α) inhibitor effectively prevented PDAC development...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29718668/discovery-of-potent-and-selective-periphery-restricted-quinazoline-inhibitors-of-the-cyclic-nucleotide-phosphodiesterase-pde1
#5
John M Humphrey, Matthew Movsesian, Christopher W Am Ende, Stacey L Becker, Thomas A Chappie, Stephen Jenkinson, Jennifer L Liras, Spiros Liras, Christine C Orozco, Jayvardhan Pandit, Felix F Vajdos, Fabrice Vandeput, Eddie Yang, Frank S Menniti
We disclose the discovery and X-ray co-crystal data of potent, selective quinazoline inhibitors of PDE1. Inhibitor (S)-3 readily attains free plasma concentrations above PDE1 IC50 values and has restricted brain access. The racemic compound 3 inhibits >75% of PDE hydrolytic activity in soluble samples of human myocardium, consistent with heightened PDE1 activity in this tissue. These compounds represent promising new tools to probe the value of PDE1 inhibition in the treatment of cardiovascular disease.
May 2, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29713919/phosphodiesterase-4-and-7-inhibitors-produce-protective-effects-against-high-glucose-induced-neurotoxicity-in-pc12-cells-via-modulation-of-the-oxidative-stress-apoptosis-and-inflammation-pathways
#6
Nazanin Namazi Sarvestani, Saeedeh Saberi Firouzi, Reza Falak, Mohammad Yahya Karimi, Mohammad Davoodzadeh Gholami, Akram Rangbar, Asieh Hosseini
Diabetic neuropathy (DN) is the most common diabetic complication. It is estimated diabetic population will increase to 592 million by the year 2035. This is while at least 50-60% of all diabetic patients will suffer from neuropathy in their lifetime. Oxidative stress, mitochondrial dysfunction, apoptosis, and inflammation are crucial pathways in development and progression of DN. Since there is also no selective and effective therapeutic agent to prevent or treat high glucose (HG)-induced neuronal cell injury, it is crucial to explore tools by which one can reduce factors related to these pathways...
April 30, 2018: Metabolic Brain Disease
https://www.readbyqxmd.com/read/29704309/the-neuroprotective-and-antidepressant-like-effects-of-hcyb1-a-novel-selective-pde2-inhibitor
#7
Li Liu, Jing Zheng, Xian-Feng Huang, Xia Zhu, Shu-Ming Ding, Heng-Ming Ke, James M O'Donnell, Han-Ting Zhang, Guo-Qiang Song, Ying Xu
AIMS: Depression is currently the most common mood disorder. Regulation of intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) signaling by phosphodiesterase (PDE) inhibition has been paid much attention for treatment of depression. This study aimed to investigate the neuroprotective effects of Hcyb1, a novel PDE2 inhibitor, in HT-22 cells and antidepressant-like effects in mouse models of depression. METHODS: Hcyb1 was synthesized and its selectivity upon PDE2 was tested...
April 27, 2018: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/29693432/phosphodiesterase-pde-4b-knock-out-prevents-skeletal-muscle-atrophy-in-rats-with-burn-injury
#8
Ambikaipakan Balasubramaniam, Sulaiman Sheriff, Lou Ann Friend, J Howard James
PDE4-cAMP pathway plays a predominant role in mediating skeletal muscle proteolysis in burn injury. The present investigations to determine the PDE4 isoform(s) involved in this action revealed that burn injury increased the expression of rat skeletal muscle PDE4B mRNA by 6-fold, but had little or no effect on expression of other PDE4 isoforms. These observations led us to study the effects of burn in PDE4B KO-rats. As reported by us previously, burn injury significantly increased EDL muscle total and myofibrillar proteolysis in WT-rats, but there were no significant effects on either total or myofibrillar protein breakdown in EDL muscle of PDE4B KO-rat with burn injury...
April 25, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/29684551/measurement-of-cgmp-generating-and-degrading-activities-and-cgmp-levels-in-cells-and-tissues-focus-on-fret-based-cgmp-indicators
#9
REVIEW
Michael Russwurm, Doris Koesling
The intracellular messenger molecule cGMP has an established function in the regulation of numerous physiological events. Yet for the identification of further biological cGMP-mediated functions, precise information whether a cGMP response exists in a certain cell type or tissue is mandatory. In this review, the techniques to measure cGMP i.e. cGMP-formation, -degradation or -levels are outlined and discussed. As a superior method to measure cGMP, the article focusses on FRET-based cGMP indicators, describes the different cGMP-indicators and discusses their advantages and drawbacks...
April 20, 2018: Nitric Oxide: Biology and Chemistry
https://www.readbyqxmd.com/read/29672041/targeting-a-subpocket-in-trypanosoma-brucei-phosphodiesterase-b1-tbrpdeb1-enables-the-structure-based-discovery-of-selective-inhibitors-with-trypanocidal-activity
#10
Antoni R Blaazer, Abhimanyu Kumar Singh, Erik de Heuvel, Ewald Edink, Kristina M Orrling, Johan J N Veerman, Toine van den Bergh, Chimed Jansen, Erin Balasubramaniam, Wouter J Mooij, Hans Custers, Maarten Sijm, Daniel N A Tagoe, Titilola D Kalejaiye, Jane C Munday, Hermann Tenor, An Matheeussen, Maikel Wijtmans, Marco Siderius, Chris de Graaf, Louis Maes, Harry P de Koning, David S Bailey, Geert Jan Sterk, Iwan J P De Esch, David G Brown, Rob Leurs
Several trypanosomatid cyclic nucleotide phosphodiesterases (PDEs) possess a unique, parasite-specific cavity near the ligand-binding region that is referred to as the P-pocket. One of these enzymes, Trypanosoma brucei PDE B1 (TbrPDEB1), is considered a drug target for the treatment of African sleeping sickness. Here, we elucidate the molecular determinants of inhibitor binding and reveal that the P-pocket is amenable to directed design. By iterative cycles of design, synthesis, pharmacological evaluation, and by elucidating the structures of inhibitor-bound TbrPDEB1, hPDE4B and hPDE4D complexes, we have developed 4a,5,8,8a-tetrahydrophthalazinones as the first selective TbrPDEB1 inhibitor series...
April 19, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29593534/east-indian-sandalwood-oil-is-a-phosphodiesterase-inhibitor-a-new-therapeutic-option-in-the-treatment-of-inflammatory-skin-disease
#11
Manju Sharma, Corey Levenson, John C Browning, Emily M Becker, Ian Clements, Paul Castella, Michael E Cox
Cyclic adenosine monophosphate phosphodiesterases (PDEs) regulate pro-inflammatory cytokine production. One isoform, PDE4, is overactive in chronic relapsing inflammatory skin diseases: psoriasis and eczema/atopic dermatitis, and in several cancers. East Indian sandalwood oil (EISO) has significant anti-inflammatory properties. Here, we report that 75% of pediatric eczema/atopic dermatitis patients treated with topical EISO formulations achieved a >50% reduction in their Eczema Area and Severity Index score...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29574946/cyclic-amp-and-glycogen-synthase-kinase-3-form-a-regulatory-loop-in-spermatozoa
#12
Souvik Dey, Suranjana Goswami, Alaa Eisa, Rahul Bhattacharjee, Cameron Brothag, Douglas Kline, Srinivasan Vijayaraghavan
The multifaceted glycogen synthase kinase (GSK3) has an essential role in sperm and male fertility. Since cyclic AMP (cAMP) plays an important role in sperm function, we investigated whether GSK3 and cAMP pathways may be interrelated. We used GSK3 and soluble adenylyl cyclase (sAC) knockout mice and pharmacological modulators to examine this relationship. Intracellular cAMP levels were found to be significantly lower in sperm lacking GSK3α or GSK3β. A similar outcome was observed when sperm cells were treated with SB216763, a GSK3 inhibitor...
March 25, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29574203/inhibitors-of-phosphodiesterase-as-cancer-therapeutics
#13
REVIEW
Ting Peng, Jun Gong, Yongzhe Jin, Yanping Zhou, Rongsheng Tong, Xin Wei, Lan Bai, Jianyou Shi
Phosphodiesterases (PDEs) are a class of enzymes that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which is involved in many physiological processes including visual transduction, cell proliferation and differentiation, cell-cycle regulation, gene expression, inflammation, apoptosis, and metabolic function. PDEs are composed of 11 different families and each family contains different subtypes. The distribution, expression, regulation mode and sensitivity to inhibitors of each subtype are different, and they are involved in cancer, inflammation, asthma, depression, erectile dysfunction and other pathological processes of development...
March 16, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29568269/camp-catalyzing-phosphodiesterases-control-cholinergic-muscular-activity-but-their-inhibition-does-not-enhance-5-ht-4-receptor-mediated-facilitation-of-cholinergic-contractions-in-the-murine-gastrointestinal-tract
#14
Vicky Pauwelyn, Romain A Lefebvre
Background: As the signal transduction of 5-HT4 receptors on cholinergic neurons innervating smooth muscle is controlled by phosphodiesterase (PDE) 4 in porcine stomach and colon, and human large intestine, the in vivo gastroprokinetic effects of a 5-HT4 receptor agonist might be enhanced by combination with a selective PDE4 inhibitor. The presence of 5-HT4 receptors on cholinergic neurons towards murine gastrointestinal circular muscle was recently shown. If the control of this receptor pathway by PDE4 is also present in mice, this might be a good model for in vivo testing of the combination therapy...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29557941/effects-of-the-phosphodiesterase-5-pde-5-inhibitors-avanafil-and-zaprinast-on-bone-remodeling-and-oxidative-damage-in-a-rat-model-of-glucocorticoid-induced-osteoporosis
#15
Zübeyir Huyut, Nuri Bakan, Serkan Yıldırım, Hamit Hakan Alp
No abstract text is available yet for this article.
March 13, 2018: Medical Science Monitor Basic Research
https://www.readbyqxmd.com/read/29550808/phosphodiesterase-4-inhibitor-roflumilast-protects-rat-hippocampal-neurons-from-sevoflurane-induced-injury-via-modulation-of-mek-erk-signaling-pathway
#16
Sheng Peng, Hong-Zhu Yan, Pei-Rong Liu, Xiao-Wei Shi, Chun-Liang Liu, Qi Liu, Yu Zhang
BACKGROUND/AIMS: Sevoflurane, a commonly used volatile anesthetic, recently has been found has neurotoxicity in the central nervous system of neonatal rodents. This study aimed to reveal whether phosphodiesterase 4 (PDE-4) inhibitor roflumilast has protective functions in sevoflurane-induced nerve damage. METHODS: Hippocampal neurons were isolated from juvenile rats, and were exposed to sevoflurane with or without roflumilast treatment. Cell viability and apoptosis were respectively assessed by CCK-8 and flow cytometry...
March 13, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29549244/effects-of-sildenafil-treatment-on-thermogenesis-and-glucose-homeostasis-in-diet-induced-obese-mice
#17
Kornelia Johann, Marlen Colleen Reis, Lisbeth Harder, Beate Herrmann, Sogol Gachkar, Jens Mittag, Rebecca Oelkrug
Stimulation of thermogenic pathways appears to be a promising approach to find new ways of tackling metabolic diseases like obesity and diabetes mellitus type 2. Thermogenic, weight reducing and insulin sensitizing effects of phosphodiesterase 5 (PDE 5) inhibitors have recently been postulated, suggesting that modulators of endogenous cGMP signaling have the therapeutic potential to treat metabolic disorders. However, most studies have been performed in vitro or in animals that were not glucose intolerant. We, thus, aimed to test the metabolic effects of the PDE 5 inhibitor sildenafil by treating diet-induced obese (DIO) mice orally for 8 days...
March 13, 2018: Nutrition & Diabetes
https://www.readbyqxmd.com/read/29534798/indole-acids-as-a-novel-pde2-inhibitor-chemotype-that-demonstrate-pro-cognitive-activity-in-multiple-species
#18
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
https://www.readbyqxmd.com/read/29518412/electrophysiological-determination-of-phosphodiesterase-6-inhibitor-inhibition-constants-in-intact-mouse-retina
#19
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...
April 15, 2018: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29501590/modeling-of-pharmacokinetics-efficacy-and-hemodynamic-effects-of-macitentan-in-patients-with-pulmonary-arterial-hypertension
#20
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...
April 2018: Pulmonary Pharmacology & Therapeutics
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