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https://www.readbyqxmd.com/read/29164831/udenafil-a-phosphodiesterase-5-inhibitor-reduces-body-weight-in-high-fat-fed-mice
#1
Seong Yul Ryu, Yoon Jung Choi, So Young Park, Jong Yeon Kim, Yong Dae Kim, Yong Woon Kim
PURPOSE: High-fat (HF) feeding induces hypothalamic leptin resistance via the activation of toll-like receptor 4 (TLR4). TLR4 deficiency confers resistance to diet-induced obesity. Udenafil, an anti-impotence drug, inhibits TLR4 in airway epithelial cells in vitro. In this study, we evaluated whether udenafil suppressed the hypothalamic expression of TLR4 and reduced body weight. MATERIALS AND METHODS: The hypothalamic expression of TLR4, phosphodiesterase 5 (PDE5), nuclear factor-κB (NF-κB), and myeloid differentiation primary response gene 88 (Myd88) was analyzed by real-time polymerase chain reaction after treating mice for 2 days with udenafil (0, 12, 120, or 600 μg/d)...
November 16, 2017: World Journal of Men's Health
https://www.readbyqxmd.com/read/29151951/potential-synergistic-effect-of-phosphodiesterase-inhibitors-with-chemotherapy-in-lung-cancer
#2
Kalliopi Domvri, Konstantinos Zarogoulidis, Nikolaos Zogas, Paul Zarogoulidis, Savvas Petanidis, Konstantinos Porpodis, Efrosini Kioseoglou, Wolfgang Hohenforst-Schmidt
Purpose: Lung cancer remains the leading cause of cancer-related deaths worldwide and novel therapeutic approaches targeting crucial pathways are urgently needed to improve its treatment. Differentiation-based therapeutics (Methylxanthines) and phosphodiesterase inhibitors (type 4 and 5), have been implicated in cancer treatment. Our objectives were to capture any potential anti-tumor effect of these drug combinations with chemotherapeutic agents in vitro. Methods: Theophylline as Methylxanthines, Roflumilast as phosphodiesterase type 4 (PDE4) inhibitor and Sildenafil as phosphodiesterase type 5 (PDE5) inhibitor are the drugs that we combined with the chemotherapeutic agents (Docetaxel, Cisplatin and Carboplatin) in vitro...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/29145710/testosterone-replacement-in-transgenic-sickle-cell-mice-controls-priapic-activity-and-upregulates-pde5-expression-and-enos-activity-in-the-penis
#3
B Musicki, S Karakus, W Akakpo, F H Silva, J Liu, H Chen, B R Zirkin, A L Burnett
Sickle cell disease (SCD)-associated priapism is characterized by decreased nitric oxide (NO) signaling and downregulated phosphodiesterase (PDE)5 protein expression and activity in the penis. Priapism is also associated with testosterone deficiency, but molecular mechanisms underlying testosterone effects in the penis in SCD are not known. Given the critical role of androgens in erection physiology and NO synthase (NOS)/PDE5 expression, we hypothesized that testosterone replacement to eugonadal testosterone levels reduces priapism by reversing impaired endothelial (e)NOS activity and molecular abnormalities involving PDE5...
November 16, 2017: Andrology
https://www.readbyqxmd.com/read/29141888/lung-cancer-associated-pulmonary-hypertension-role-of-microenvironmental-inflammation-based-on-tumor-cell-immune-cell-cross-talk
#4
Soni Savai Pullamsetti, Baktybek Kojonazarov, Samantha Storn, Henning Gall, Ylia Salazar, Janine Wolf, Andreas Weigert, Nefertiti El-Nikhely, Hossein Ardeschir Ghofrani, Gabriele A Krombach, Ludger Fink, Stefan Gattenlöhner, Ulf R Rapp, Ralph Theo Schermuly, Friedrich Grimminger, Werner Seeger, Rajkumar Savai
Dyspnea is a frequent, devastating, and poorly understood symptom of advanced lung cancer. In our cohort, among 519 patients who underwent a computed tomography scan for the diagnosis of lung cancer, 250 had a mean pulmonary artery diameter of >28 mm, indicating pulmonary hypertension (PH). In human lung cancer tissue, we consistently observed increased vascular remodeling and perivascular inflammatory cell accumulation (macrophages/lymphocytes). Vascular remodeling, PH, and perivascular inflammatory cell accumulation were mimicked in three mouse models of lung cancer (LLC1, KRas(LA2) , and cRaf-BxB)...
November 15, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29132113/fluorometric-detection-of-protein-ligand-engagement-the-case-of-phosphodiesterase5
#5
Giulia Di Rocco, Ilaria Martinelli, Salvatore Pacifico, Remo Guerrini, Elena Cichero, Paola Fossa, Silvia Franchini, Silvia Cardarelli, Mauro Giorgi, Marco Sola, Glauco Ponterini
Phosphodiesterases (PDEs) regulate the intracellular levels of cAMP and cGMP. The great clinical success of the PDE5 inhibitors, Sildenafil (Viagra), Vardenafil (Levitra) and Tadalafil (Cialis) has led to an increasing interest for this class of enzymes. Recent studies have shown a correlation between tumor growth and PDE5 overexpression, making PDE5-selective inhibitors promising candidates for cancer treatment. The search for such inhibitors rests today on radioactive assays. In this work, we exploit the conserved catalytic domain of the enzyme and propose a faster and safer method for detecting the binding of ligands and evaluate their affinities...
November 10, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29118812/pde5-overexpression-in-well-differentiated-thyroid-carcinomas-is-associated-with-lymph-node-metastasis
#6
Ning Zhang, Zeng Fang, Qiufang Li, Kebing Wang, Songqi Li, Wen Li, Shenming Wang
Overexpression of PDE5 is observed in certain human cancers, but PDE5 expression in well-differentiated thyroid carcinoma (WDTC) is unknown. We therefore examined PDE5 expression and its relationship with the clinicopathological features of WDTC. Real-time qPCR and Western blotting were performed to analyze the expression of PDE5 mRNA and protein in paired WDTC tumor and adjacent nontumor tissues. Immunohistochemistry was used to analyze the expression of PDE5 in paraffin-embedded tissues obtained from 103 cases of WDTC...
2017: International Journal of Endocrinology
https://www.readbyqxmd.com/read/29101001/icariside-ii-a-pde5-inhibitor-from-epimedium-brevicornum-promotes-neuron-like-pheochromocytoma-pc12-cell-proliferation-via-activating-no-cgmp-pkg-pathway
#7
Jianmei Gao, Yingshu Xu, Ming Lei, Jingshan Shi, Qihai Gong
Icariside II (ICS II), a phosphodiesterase 5 inhibitor (PDE 5-I), is a major ingredient of Epimedium brevicornum, with wide spectrum of neuroprotective properties. However, little is known about the potential beneficial effect of ICS II on neuronal cell proliferation, and its possible underlying mechanism remains still unclear. We hypothesized that the beneficial effect of ICS II on neuron-like highly differentiated rat pheochromocytoma (PC12) cell proliferation is correlated with the nitric oxide (NO) signaling pathway and its upstream of PI3K/AKT pathway...
October 31, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/29094165/phosphodiesterase-inhibitors-sildenafil-and-vardenafil-reduce-zebrafish-rod-photoreceptor-outer-segment-shedding
#8
Leah J Campbell, Abbie M Jensen
Purpose: The vertebrate rod photoreceptor undergoes daily growth and shedding to renew the rod outer segment (ROS), a modified cilium that contains the phototransduction machinery. It has been demonstrated that ROS shedding is regulated by the light-dark cycle; however, we do not yet have a satisfactory understanding of the molecular mechanisms that underlie this regulation. Given that phototransduction relies on the hydrolysis of cGMP via phosphodiesterase 6 (PDE6), we examined ROS growth and shedding in zebrafish treated with cGMP-specific PDE inhibitors...
November 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29089445/novel-imaging-of-the-prostate-reveals-spontaneous-gland-contraction-and-excretory-duct-quiescence-together-with-different-drug-effects
#9
Robert Kügler, Andrea Mietens, Mathias Seidensticker, Sabine Tasch, Florian M Wagenlehner, Andre Kaschtanow, Yudy Tjahjono, Claudia U Tomczyk, Daniela Beyer, Gail P Risbridger, Betty Exintaris, Stuart J Ellem, Ralf Middendorff
Prostate carcinoma and benign prostate hyperplasia (BPH) with associated lower urinary tract symptoms (LUTS) are among the most prevalent and clinically relevant diseases in men. BPH is characterized by an enlargement of prostate tissue associated with increased tone of smooth muscle cells (SMCs) which surround the single glands composing the prostate. Secretions of the glands leave the prostate through local excretory ducts during the emission phase of ejaculation. Pharmacological treatment of BPH suggests different local drug targets based on reduction of prostate smooth muscle tone as the main effect and disturbed ejaculation as a common side effect...
October 31, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29071734/nitric-oxide-is-required-for-the-insulin-sensitizing-effects-of-contraction-in-mouse-skeletal-muscle
#10
Xinmei Zhang, Danielle Hiam, Yet-Hoi Hong, Anthony Zulli, Alan Hayes, Stephen Rattigan, Glenn K McConell
The factors regulating the increase in skeletal muscle insulin sensitivity after exercise are unclear. We examined whether nitric oxide (NO) is required for the increase in insulin sensitivity after ex vivo contractions. Isolated C57BL/6J mouse EDL muscles were contracted for 10 min or remained at rest (basal) with or without the NO synthase (NOS) inhibition (L-NMMA; 100 μm). 3.5 h post contraction/basal, muscles were exposed to saline or insulin (120 μU ml(-1) ) with or without L-NMMA during the last 30 min...
October 25, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/29068218/design-synthesis-and-biological-evaluation-of-orally-available-first-generation-dual-target-selective-inhibitors-of-acetylcholinesterase-ache-and-phosphodiesterase-5-pde5-for-the-treatment-of-alzheimer-s-disease
#11
Fei Mao, Huan Wang, Wei Ni, Xinyu Zheng, Manjiong Wang, Keting Bao, Dazheng Ling, Xiaokang Li, Yixiang Xu, Haiyan Zhang, Jian Li
Through drug discovery strategies of repurposing and redeveloping existing drugs, a series of novel tadalafil derivatives were rationally designed, synthesized and evaluated to seek dual-target AChE/PDE5 inhibitors as good candidate drugs for AD. Among these derivatives, 1p and 1w exhibited excellent selective dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier (BBB) penetrability. Importantly, 1w·Cit (citrate of 1w) could reverse the cognitive dysfunction of scopolamine-induced AD mice and exhibited an excellent effect on enhancing cAMP response element-binding protein (CREB) phosphorylation in vivo, a crucial factor in memory formation and synaptic plasticity...
October 25, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29057723/treatment-effects-of-phosphodiesterase-5-inhibitors-may-improve-with-time-following-nerve-sparing-radical-prostatectomy
#12
Mikkel Fode, Peter Busch Østergren, Christian Fuglesang S Jensen, Henrik Jakobsen, Jens Sønksen
OBJECTIVE: Erectile dysfunction (ED) is common following radical prostatectomies, and phosphodiesterase type 5 inhibitors (PDE5 inhibitors) are generally considered the first choice of treatment. The purpose of this study was to analyze the long-term efficacy of PDE5 inhibitors in a group of men who did not achieve sufficient erectile function from the medication in the short term following surgery. MATERIALS AND METHODS: Prospectively collected data from patients with postprostatectomy ED, initial failure of PDE5-inhibitor treatment at 3 and/or 6 months and at least 12 months' follow-up were included...
October 23, 2017: Scandinavian Journal of Urology
https://www.readbyqxmd.com/read/29057299/viagra-releases-the-brakes-on-melanoma-growth
#13
Robert Feil
Use of the phosphodiesterase 5 (PDE5) blocker sildenafil (Viagra) has been linked to an increased risk of melanoma. In a recent study we discovered a growth-promoting cGMP pathway in melanoma cells. cGMP degradation via PDE5 acts as a brake on this pathway. Inhibition of PDE5 releases this brake, providing a mechanism for the promelanoma effects of sildenafil.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/29051185/cgmp-elevating-compounds-and-ischemic-conditioning-provide-cardioprotection-against-ischemia-and-reperfusion-injury-via-cardiomyocyte-specific-bk-channels
#14
Sandra Frankenreiter, Piotr Bednarczyk, Angelina Kniess, Nadja Bork, Julia Straubinger, Piotr Koprowski, Antoni Wrzosek, Eva Mohr, Angela Logan, Michael P Murphy, Meinrad Gawaz, Thomas Krieg, Adam Szewczyk, Viacheslav O Nikolaev, Peter Ruth, Robert Lukowski
Background -The nitric oxide-sensitive guanylyl cyclase (NO-GC)/cyclic guanosine-3',5'-monophosphate (cGMP)/cGMP-dependent protein kinase type I (cGKI)-signaling pathway can afford protection against the ischemia and reperfusion (I/R) injury that occurs during myocardial infarction (MI). Reportedly, voltage and Ca(2+)-activated K(+) channels of the BK-type are stimulated by cGMP/cGKI and recent ex-vivo studies implicated that increased BK activity favors the survival of the myocardium at I/R. It remains unclear, however, whether the molecular events downstream of cGMP involve BK channels present in cardiomyocytes (CMs) or in other cardiac cell types...
October 19, 2017: Circulation
https://www.readbyqxmd.com/read/29024896/identification-of-a-soluble-guanylate-cyclase-in-rbcs-preserved-activity-in-patients-with-coronary-artery-disease
#15
Miriam M Cortese-Krott, Evanthia Mergia, Christian M Kramer, Wiebke Lückstädt, Jiangning Yang, Georg Wolff, Christina Panknin, Thilo Bracht, Barbara Sitek, John Pernow, Johannes-Peter Stasch, Martin Feelisch, Doris Koesling, Malte Kelm
Endothelial dysfunction is associated with decreased NO bioavailability and impaired activation of the NO receptor soluble guanylate cyclase (sGC) in the vasculature and in platelets. Red blood cells (RBCs) are known to produce NO under hypoxic and normoxic conditions; however evidence of expression and/or activity of sGC and downstream signaling pathway including phopshodiesterase (PDE)-5 and protein kinase G (PKG) in RBCs is still controversial. In the present study, we aimed to investigate whether RBCs carry a functional sGC signaling pathway and to address whether this pathway is compromised in coronary artery disease (CAD)...
September 8, 2017: Redox Biology
https://www.readbyqxmd.com/read/28986358/pulmonary-vasodilation-by-phosphodiesterase-5-inhibition-is-enhanced-and-nitric-oxide-independent-in-early-pulmonary-hypertension-after-myocardial-infarction
#16
Richard W B van Duin, Birgit Houweling, Andre Uitterdijk, Dirk J Duncker, Daphne Merkus
Myocardial infarction (MI) may result in pulmonary hypertension (PH). Inhibition of phosphodiesterase 5 (PDE5), the enzyme responsible for the breakdown of cGMP in vascular smooth muscle, has become part of the contemporary therapeutic armamentarium for pulmonary arterial hypertension and may also be of benefit in PH secondary to MI. Nitric oxide (NO) is an important source of cGMP and can be enhanced in early PH and decreased in severe PH. In the present study we investigated if PDE5-inhibition ameliorates pulmonary hemodynamics in swine with PH secondary to MI and whether NO is essential...
October 6, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28985058/identification-of-a-novel-1-2-3-4-tetrahydrobenzo-b-1-6-naphthyridine-analogue-as-a-potent-phosphodiesterase-5-inhibitor-with-improved-aqueous-solubility-for-the-treatment-of-alzheimer-s-disease
#17
Jole Fiorito, Jeremie Vendome, Faisal Saeed, Agnieszka Staniszewski, Hong Zhang, Shijun Yan, Shi-Xian Deng, Ottavio Arancio, Donald W Landry
Phosphodiesterase 5 (PDE5) hydrolyzes cyclic guanosine monophosphate (cGMP) leading to increased levels of the cAMP response element binding protein (CREB), a transcriptional factor involved with learning and memory processes. We previously reported potent quinoline-based PDE5 inhibitors (PDE5Is) for the treatment of Alzheimer's disease (AD). However, the low aqueous solubility rendered them undesirable drug candidates. Here we report a series of novel PDE5Is with two new scaffolds, 1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridine and 2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one...
October 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28982945/exercise-training-improves-blood-flow-to-contracting-skeletal-muscle-of-older-men-via-enhanced-cgmp-signaling
#18
Peter Piil, Tue Smith Jørgensen, Jon Egelund, Rasmus Damsgaard, Lasse Gliemann, Ylva Hellsten, Michael Nyberg
Physical activity has the potential to offset age-related impairments in the regulation of blood flow and O2 delivery to the exercising muscles; however, the mechanisms underlying this effect of physical activity remain poorly understood. The present study examined the role of cGMP in training-induced adaptations in the regulation of skeletal muscle blood flow and oxidative metabolism during exercise in aging humans. We measured leg hemodynamics and oxidative metabolism during exercise engaging the knee-extensor muscles in young (n=15, 25 ± 1 years) and older (n=15, 72 ± 1 years) subjects before and after a period of aerobic high-intensity exercise training...
October 5, 2017: Journal of Applied Physiology
https://www.readbyqxmd.com/read/28977106/daily-use-of-phosphodiesterase-type-5-inhibitors-as-prevention-for-recurrent-priapism
#19
Archimedes Nardozza, Marcelo Rodrigues Cabrini
OBJECTIVE: The pathogenesis of recurrent priapism is currently being investigated based on the regulation of the phosphodiesterase 5 (PDE5) enzyme. We explored the daily use of PDE5 inhibitors to treat and prevent priapism recurrences. METHOD: We administered PDE5 inhibitors using a long-term therapeutic regimen in seven men with recurrent priapism, with a mean age of 29.2 years (range 21 to 35 years). Six men (85.7%) had idiopathic priapism recurrences and one man (24...
August 2017: Revista da Associação Médica Brasileira
https://www.readbyqxmd.com/read/28964803/cyclic-guanosine-monophosphate-modulates-accumulation-of-phosphodiesterase-5-inhibitors-in-human-platelets
#20
Gzona Bajraktari, Jürgen Burhenne, Peter Bugert, Walter Emil Haefeli, Johanna Weiss
Sildenafil and tadalafil are widely-used phosphodiesterase 5 (PDE5) inhibitors for which no clear dose-response relationship could be established. Using isolated and/or recombinant PDE5, it has been demonstrated that cGMP can increase the affinity of this enzyme for sildenafil and tadalafil. We thus hypothesized that in cells expressing the nitric oxide - soluble guanylyl cyclase - cyclic guanosine monophosphate - PDE5 (NO-sGC-cGMP-PDE5) pathway such as platelets, the presence of NO increases the intracellular cGMP content and thus promotes the intracellular accumulation of sildenafil or tadalafil...
September 28, 2017: Biochemical Pharmacology
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