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https://www.readbyqxmd.com/read/28603047/tadalafil-induces-antiproliferation-apoptosis-and-phosphodiesterase-type-5-downregulation-in-idiopathic-pulmonary-arterial-hypertension-in-vitro
#1
Aya Yamamura, Eri Fujitomi, Naoki Ohara, Kikuo Tsukamoto, Motohiko Sato, Hisao Yamamura
Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease of the pulmonary artery resulting from a currently unidentified etiology. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. Vascular remodeling is mediated by enhanced proliferation and reduced apoptosis in pulmonary arterial smooth muscle cells (PASMCs). Based on its pathological mechanism, specific phosphodiesterase type 5 (PDE5) inhibitors have been used in the treatment of IPAH...
June 8, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28596298/sex-differences-in-pulmonary-vascular-control-focus-on-the-nitric-oxide-pathway
#2
Daphne P M de Wijs-Meijler, A H Jan Danser, Irwin K M Reiss, Dirk J Duncker, Daphne Merkus
Although the incidence of pulmonary hypertension is higher in females, the severity and prognosis of pulmonary vascular disease in both neonates and adults have been shown to be worse in male subjects. Studies of sex differences in pulmonary hypertension have mainly focused on the role of sex hormones. However, the contribution of sex differences in terms of vascular signaling pathways regulating pulmonary vascular function remains incompletely understood. Consequently, we investigated pulmonary vascular function of male and female swine in vivo, both at rest and during exercise, and in isolated small pulmonary arteries in vitro, with a particular focus on the NO-cGMP-PDE5 pathway...
June 2017: Physiological Reports
https://www.readbyqxmd.com/read/28506928/distinct-phosphodiesterase-5a-containing-compartments-allow-selective-regulation-of-cgmp-dependent-signalling-in-human-arterial-smooth-muscle-cells
#3
Lindsay S Wilson, Manhong Guo, M Bibiana Umana, Donald H Maurice
Cyclic GMP (cGMP) translates and integrates much of the information encoded by nitric oxide (NO(·)) and several natriuretic peptides, including the atrial natriuretic peptide (ANP). Previously, we reported that integration of a cGMP-specific cyclic nucleotide phosphodiesterase, namely phosphodiesterase 5A (PDE5A), into a protein kinase G (PKG)- and inositol-1,4,5-trisphosphate receptor (IP3R)-containing endoplasmic reticulum (ER) signalosome allows localized control of PDE5A activity and of PKG-dependent inhibition of IP3-mediated release of ER Ca(2+) in human platelets...
May 12, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28469435/inhibition-of-phosphodiesterase-5-and-increasing-the-level-of-cyclic-guanosine-3-5-monophosphate-by-hydroalcoholic-achillea-wilhelmsii-c-koch-extract-in-human-breast-cancer-cell-lines-mcf-7-and-mda-mb-468
#4
Ramin Saravani, Hamid Reza Galavi, Ali Shahraki
This study aimed to investigate the effect of hydroalcoholic Achillea wilhelmsii C. Koch extract (HAWE) on phosphodiesterase 5 (PDE5) gene expression and cyclic guanosine 3',5' monophosphate (cGMP) signaling in the MCF-7 and MDA-Mb-468 cell lines. The effective dose (ED50) of HAWE was examined in both cell lines using a 3-(4,5-dimethylhiazol-2-yl)-2,5-diphenyltetrazolium bromide viability test, and the type of cell death was detected by flow cytometry. The expression of PDE5 and the concentration of cGMP were measured in a time-dependent manner in the ED50 by real-time polymerase chain reaction and a colorimetric assay, respectively...
2017: Breast Cancer: Basic and Clinical Research
https://www.readbyqxmd.com/read/28414103/apoptosis-induction-of-poly-s-nitrosated-human-serum-albumin-in-resistant-solid-tumor-under-hypoxia-can-be-restored-by-phosphodiesterase-5-inhibition
#5
Mayumi Ikeda, Yu Ishima, Victor T G Chuang, Tsuyoshi Ikeda, Ryo Kinoshita, Hiroshi Watanabe, Tatsuhiro Ishida, Masaki Otagiri, Toru Maruyama
Poly-S-nitrosated human serum albumin (Poly-SNO-HSA) delivered and accumulated nitric oxide (NO) in tumors and induces apoptosis. Tumor hypoxia is strongly associated with malignant progression and tumor resistance to therapy. In this study, we examined the cytotoxic effect of Poly-SNO-HSA under hypoxia on the murine colon 26 adenocarcinoma (C26) cells in vitro and in vivo. Under hypoxia, at about 4 times LD50 dose of Poly-SNO-HSA in vitro, the reactive oxygen species production was hindered but apoptotic cells were induced via cGMP pathway as the effect was suppressed by a soluble guanylate cyclase inhibitor, NS2028...
April 13, 2017: Nitric Oxide: Biology and Chemistry
https://www.readbyqxmd.com/read/28398017/differential-effects-of-phosphodiesterase-5-inhibition-in-chronic-cardiac-decompensation-depending-on-the-type-whether-hfref-or-hfpef-of-heart-failure-a-meta-analysis
#6
Renato DE Vecchis, Arturo Cesaro, Carmelina Ariano
INTRODUCTION: According to 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension(PH), no specific drug is currently indicated for PH related to left heart disease( PH-LDH), i.e., the one secondary to left chronic heart failure (CHF), which coincides with the group 2 of the PH classification endorsed by the above-mentioned guidelines. In fact, adoption of therapies that specifically apply for so-called pulmonary arterial hypertension (group 1 of the PH classification) has been regarded as substantially contraindicated in patients with PH- LHD, according to current ESC/ERS guidelines...
April 10, 2017: Minerva Cardioangiologica
https://www.readbyqxmd.com/read/28337142/icariside-ii-effectively-reduces-spatial-learning-and-memory-impairments-in-alzheimer-s-disease-model-mice-targeting-beta-amyloid-production
#7
Lingli Yan, Yuanyuan Deng, Jianmei Gao, Yuangui Liu, Fei Li, Jingshan Shi, Qihai Gong
Icariside II (ICS II) is a broad-spectrum anti-cancer natural compound extracted from Herba Epimedii Maxim. Recently, the role of ICS II has been investigated in central nervous system, especially have a neuroprotective effect in Alzheimer's disease (AD). In this study, we attempted to investigate the effects of ICS II, on cognitive deficits and beta-amyloid (Aβ) production in APPswe/PS1dE9 (APP/PS1) double transgenic mice. It was found that chronic ICS II administrated not only effectively ameliorated cognitive function deficits, but also inhibited neuronal degeneration and reduced the formation of plaque burden...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28316997/sildenafil-can-affect-innate-and-adaptive-immune-system-in-both-experimental-animals-and-patients
#8
REVIEW
Monika Kniotek, Agnieszka Boguska
Sildenafil, a type 5 phosphodiesterase inhibitor (PDE5-I), is primarily used for treating erectile dysfunction. Sildenafil inhibits the degradation of cyclic guanosine monophosphate (cGMP) by competing with cGMP for binding site of PDE5. cGMP is a secondary messenger activating protein kinases and a common regulator of ion channel conductance, glycogenolysis, and cellular apoptosis. PDE5 inhibitors (PDE-Is) found application in cardiology, nephrology, urology, dermatology, oncology, and gynecology. Positive result of sildenafil treatment is closely connected with its immunomodulatory effects...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28294194/phosphodiesterase-5-inhibition-preserves-renal-hemodynamics-and-function-in-mice-with-diabetic-kidney-disease-by-modulating-mir-22-and-bmp7
#9
Riccardo Pofi, Daniela Fiore, Rita De Gaetano, Giuseppe Panio, Daniele Gianfrilli, Carlotta Pozza, Federica Barbagallo, Yang Kevin Xiang, Konstantinos Giannakakis, Susanna Morano, Andrea Lenzi, Fabio Naro, Andrea M Isidori, Mary Anna Venneri
Diabetic Nephropathy (DN) is the leading cause of end-stage renal disease. Preclinical and experimental studies show that PDE5 inhibitors (PDE5is) exert protective effects in DN improving perivascular inflammation. Using a mouse model of diabetic kidney injury we investigated the protective proprieties of PDE5is on renal hemodynamics and the molecular mechanisms involved. PDE5i treatment prevented the development of DN-related hypertension (P < 0.001), the increase of urine albumin creatinine ratio (P < 0...
March 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28213937/targeting-phosphodiesterase-5-as-a-therapeutic-option-against-myocardial-ischemia-reperfusion-injury-and-in-treating-heart-failure
#10
REVIEW
Sevil Korkmaz-Icöz, Tamás Radovits, Gábor Szabó
Phosphodiesterase type 5 (PDE5) selectively hydrolyses the second messenger cyclic 3´-5´guanosine monophosphate (cGMP) into 5'-GMP, thereby regulating its intracellular concentrations. Dysregulation of the cGMP-dependent pathway plays a significant role in various cardiovascular diseases. Therefore, its modulation by drugs, such as PDE5 inhibitors, may represent an effective therapeutic approach. There are currently four PDE5 inhibitors available for the treatment of erectile dysfunction: sildenafil, vardenafil, tadalafil, and avanafil...
February 18, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28155571/the-augmentation-of-bk-channel-activity-by-nitric-oxide-signaling-in-rat-cerebral-arteries-involves-co-localized-regulatory-elements
#11
Barry D Kyle, Ramesh C Mishra, Andrew P Braun
Large conductance, Ca(2+)-activated K(+) (BK) channels control cerebrovascular tone; however, the regulatory processes influencing these channels remain poorly understood. Here, we investigate the cellular mechanisms underlying the enhancement of BK current in rat cerebral arteries by nitric oxide (NO) signaling. In isolated cerebral myocytes, BK current magnitude was reversibly increased by sodium nitroprusside (SNP, 100 μM) and sensitive to the BK channel inhibitor, penitrem-A (100 nM). Fostriecin (30 nM), a protein phosphatase type 2A (PP2A) inhibitor, significantly prolonged the SNP-induced augmentation of BK current and a similar effect was produced by sildenafil (30 nM), a phosphodiesterase 5 (PDE5) inhibitor...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/28124739/the-regulation-of-transient-receptor-potential-canonical-4-trpc4-channel-by-phosphodiesterase-5-inhibitor-via-the-cyclic-guanosine-3-5-monophosphate
#12
Jinhong Wie, SeungJoo Jeong, Misun Kwak, Jongyun Myeong, MeeRee Chae, Jong Kwan Park, Sung Won Lee, Insuk So
The transient receptor potential (TRP) protein superfamily consists of a diverse group of cation channels that bear structural similarities to the fruit fly Drosophila TRP. The TRP superfamily is distinct from other groups of ion channels in displaying a large diversity in ion selectivity, modes of activation, and physiological functions. Classical TRP (transient receptor potential canonical (TRPC)) channels are activated by stimulation of Gq-PLC-coupled receptors and modulated by phosphorylation. The cyclic guanosine monophosphate (cGMP)-PKG pathway is involved in the regulation of TRPC3 and TRPC6 channels...
January 26, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28099939/type-5-phosphodiesterase-regulates-glioblastoma-multiforme-aggressiveness-and-clinical-outcome
#13
Valeriana Cesarini, Maurizio Martini, Lucia Ricci Vitiani, Giovanni Luca Gravina, Silvia Di Agostino, Grazia Graziani, Quintino Giorgio D'Alessandris, Roberto Pallini, Luigi M Larocca, Pellegrino Rossi, Emmanuele A Jannini, Susanna Dolci
Expression of type 5 phosphodiesterase (PDE5), a cGMP-specific hydrolytic enzyme, is frequently altered in human cancer, but its specific role in tumorigenesis remains controversial. Herein, by analyzing a cohort of 69 patients affected by glioblastoma multiforme (GBM) who underwent chemo- and radiotherapy after surgical resection of the tumor, we found that PDE5 was strongly expressed in cancer cells in about 50% of the patients. Retrospective analysis indicated that high PDE5 expression in GBM cells significantly correlated with longer overall survival of patients...
February 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28088782/pde5-inhibitors-enhance-the-lethality-of-pemetrexed-sorafenib
#14
Laurence Booth, Jane L Roberts, Andrew Poklepovic, Paul Dent
The combination of pemetrexed and sorafenib has significant clinical activity against a wide variety of tumor types in patients and the present studies were performed to determine whether sildenafil enhances the killing potential of [pemetrexed + sorafenib]. In multiple genetically diverse lung cancer cell lines, sildenafil enhanced the lethality of [pemetrexed + sorafenib]. The three-drug combination reduced the activities of AKT, mTOR and STAT transcription factors; increased the activities of eIF2α and ULK-1; lowered the expression of MCL-1, BCL-XL, thioredoxin and SOD2; and increased the expression of Beclin1...
February 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28052870/phosphodiesterase-5-inhibition-ameliorates-angiotensin-ii-dependent-hypertension-and-renal-vascular-dysfunction
#15
Manuel Thieme, Sema Hayriye Sivritas, Evanthia Mergia, Sebastian Alexander Potthoff, Guang Yang, Lydia Hering, Katharina Grave, Henning Hoch, Lars Christian Rump, Johannes Stegbauer
Changes in renal hemodynamics have a major impact on blood pressure (BP). Angiotensin (Ang) II has been shown to induce vascular dysfunction by interacting with phosphodiesterases (PDE)1 and PDE5. The predominant PDE isoform responsible for renal vascular dysfunction in hypertension is unknown. Here, we measured effects of PDE5-(sildenafil) or PDE1-(vinpocetine) inhibition on renal blood flow (RBF), BP and renal vascular function in normotensive and hypertensive mice. During acute short-term Ang II infusion, sildenafil decreased BP and increased RBF in C57BL/6 (WT) mice...
January 4, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28017777/the-cardioprotective-effect-of-sildenafil-is-mediated-by-the-activation-of-malate-dehydrogenase-and-an-increase-in-the-malate-aspartate-shuttle-in-cardiomyocytes
#16
Federica Gevi, Federica Campolo, Fabio Naro, Lello Zolla
Recent evidence has shown the cardioprotective effect of PDE5 inhibition in myocardial ischemia/reperfusion injury, heart failure and cardiac hypertrophy. To investigate the biochemical changes that occur during PDE5 inhibition in cardiac cells, this study assessed the metabolic profile of the HL1 cell line, a murine atrial cell line with adult cardiomyocyte properties. After one hour of treatment with sildenafil, glycolysis was moderately but selectively stimulated, unlike the pentose phosphate pathway and the Krebs cycle...
March 1, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28009175/carbon-11-and-fluorine-18-radiolabeled-pyridopyrazinone-derivatives-for-positron-emission-tomography-pet-imaging-of-phosphodiesterase-5-pde5
#17
Rufael Chekol, Olivier Gheysens, Muneer Ahamed, Jan Cleynhens, Peter Pokreisz, Greet Vanhoof, Stefan Janssens, Alfons Verbruggen, Guy Bormans
The cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) plays an important role in various pathologies including pulmonary arterial hypertension and cardiomyopathy. PDE5 represents an important therapeutic and/or prognostic target, but noninvasive assessment of PDE5 expression is lacking. The purpose of this study was to develop and evaluate pyridopyrazinone derivatives labeled with carbon-11 or fluorine-18 as PDE5-specific PET tracers. In biodistribution studies, highest PDE5-specific retention was observed for [(11)C]-12 and [(18)F]-17 in the lungs of wild-type mice and in the myocardium of transgenic mice with cardiomyocyte-specific PDE5 overexpression at 30 min postinjection...
December 23, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27957675/the-importance-of-l-arginine-no-cgmp-pathway-in-tolerance-to-flunitrazepam-in-mice
#18
Sylwia Talarek, Joanna Listos, Jolanta Orzelska-Gorka, Malgorzata Jakobczuk, Jolanta Kotlinska, Grazyna Biala
The goal of the study was to investigate the effects of drugs modifying L-arginine:NO:cGMP pathway on the development of tolerance to flunitrazepam (FNZ)-induced motor impairment in mice. FNZ-induced motor incoordination was assessed on the 1st and 8th days of experiment, using the rotarod and chimney tests. It was found that (a) both a non-selective nitric oxide synthase (NOS) inhibitor: N (G)-nitro-L-arginine methyl ester (L-NAME) and an unselective neuronal NOS inhibitor: 7-nitroindazole (7-NI) inhibited the development of tolerance to the motor-impairing effects of FNZ in the rotarod and the chimney tests and (b) both a NO precursor: L-arginine and a selective inhibitor of phosphodiesterase 5 (PDE5): sildenafil did not affect the development of tolerance to FNZ-induced motor impairment in mice...
February 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/27936591/impact-of-scaffold-exploration-on-novel-dual-acting-histone-deacetylases-and-phosphodiesterase-5-inhibitors-for-the-treatment-of-alzheimer-s-disease
#19
Juan A Sánchez-Arias, Obdulia Rabal, Mar Cuadrado-Tejedor, Irene de Miguel, Marta Pérez-González, Ana Ugarte, Elena Sáez, Maria Espelosin, Susana Ursua, Tan Haizhong, Wu Wei, Xu Musheng, Ana Garcia-Osta, Julen Oyarzabal
A novel systems therapeutics approach, involving simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylase (HDAC), has been validated as a potentially novel therapeutic strategy for the treatment of Alzheimer's disease (AD). First-in-class dual inhibitors bearing a sildenafil core have been very recently reported, and the lead molecule 7 has proven this strategy in AD animal models. Because scaffolds may play a critical role in primary activities and ADME-Tox profiling as well as on intellectual property, we have explored alternative scaffolds (vardenafil- and tadalafil-based cores) and evaluated their impact on critical parameters such as primary activities, permeability, toxicity, and in vivo (pharmacokinetics and functional response in hippocampus) to identify a potential alternative lead molecule bearing a different chemotype for in vivo testing...
December 27, 2016: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/27903966/pde5-inhibitors-enhance-the-lethality-of-pemetrexed-through-inhibition-of-multiple-chaperone-proteins-and-via-the-actions-of-cyclic-gmp-and-nitric-oxide
#20
Laurence Booth, Jane L Roberts, Andrew Poklepovic, Sarah Gordon, Paul Dent
Phosphodiesterase 5 (PDE5) inhibitors prevent the breakdown of cGMP that results in prolonged protein kinase G activation and the generation of nitric oxide. PDE5 inhibitors enhanced the anti-NSCLC cell effects of the NSCLC therapeutic pemetrexed. [Pemetrexed + sildenafil] activated an eIF2α - ATF4 - CHOP - Beclin1 pathway causing formation of toxic autophagosomes; activated a protective IRE1 - XBP-1 - chaperone induction pathway; and activated a toxic eIF2α - CHOP - DR4 / DR5 / CD95 induction pathway. [Pemetrexed + sildenafil] reduced the expression of c-FLIP-s, MCL-1 and BCL-XL that was blocked in a cell-type -dependent fashion by either over-expression of HSP90 / GRP78 / HSP70 / HSP27 or by blockade of eIF2α-CHOP signaling...
January 3, 2017: Oncotarget
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