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Pde5 inhibition

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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
#1
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...
November 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27872007/the-role-of-pde5-inhibitors-and-the-no-cgmp-pathway-in-cancer
#2
REVIEW
Taylor C Peak, Ashley Richman, Serap Gur, Faysal A Yafi, Wayne J G Hellstrom
INTRODUCTION: Phosphodiesterase 5 (PDE5) inhibitors (PDE5i) have been used clinically for the treatment of erectile dysfunction, acting on the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling pathway. Simultaneously, researchers have elucidated the roles that this pathway plays in the regulation of cell proliferation, tumor development, and progression. As a result, our knowledge of PDE5i and cancer biology has expanded and provides an integration that holds great promise for some, but concern for others...
January 2016: Sexual Medicine Reviews
https://www.readbyqxmd.com/read/27855624/the-women-s-heart-insights-into-new-potential-targeted-therapy
#3
Daniele Gianfrilli, Ricardo Pofi, Tiziana Feola, Andrea Lenzi, Elisa Giannetta
Cardiovascular disease represents an increasing cause of death in women. The analysis of cardiovascular risk factors in women has not reached a consensus with respect to a specific and personalized treatment designed in pre-menopausal and post-menopausal phases. Clinically significant cardioprotective and antiremodeling effects were detected in animal and human study exploring chronic inhibition of Phosphodiesterase type 5 (PDE5). The relationship between heart, estrogens and PDE5 inhibitors (PDE5i) remains unclear...
November 18, 2016: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/27784679/hydrogen-sulfide-an-enhancer-of-vascular-nitric-oxide-signalling-mechanisms-and-implications
#4
Csaba Szabo
Nitric oxide (NO) vascular signalling has long been considered an independent, self-sufficient pathway. However, recent data indicate that the novel gaseous mediator, hydrogen sulfide (H2S), serves as an essential enhancer/stimulator of vascular NO signalling. The current article overviews the multiple levels at which this enhancement/stimulation takes place. The first level of interaction relates to the formation of biologically active hybrid S/N species and the stimulation of NO release from its various stable "pools" (e...
October 26, 2016: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/27763717/additive-effects-of-the-rho-kinase-inhibitor-y-27632-and-vardenafil-on-relaxation-of-the-corpus-cavernosum-tissue-of-patients-with-erectile-dysfunction-and-clinical-phosphodiesterase-type-5-inhibitor-failure
#5
Pieter Uvin, Maarten Albersen, Ine Bollen, Maarten Falter, Emmanuel Weyne, Loes Linsen, Hanna Tinel, Peter Sandner, Trinity J Bivalacqua, Dirk J M K De Ridder, Frank Van der Aa, Bert Brône, Koenraad Van Renterghem
OBJECTIVES: To evaluate the expression of the Rho/Rho-associated protein kinase (ROCK) pathway in the corpus cavernosum of patients with severe erectile dysfunction (ED) compared with healthy human corpus cavernosum, and to test the functional effects of two Rho kinase inhibitors (RKIs) on erectile tissue of patients with severe ED, which did not respond to phosphodiesterase type 5 inhibitors (PDE5Is). PATIENTS AND METHODS: Human corpus cavernosum samples were obtained after consent from men undergoing penile prosthesis implantation (n = 7 for organ bath experiments, n = 17 for quantitative PCR [qPCR])...
October 20, 2016: BJU International
https://www.readbyqxmd.com/read/27747306/chemotherapeutic-efficacy-of-phosphodiesterase-inhibitors-in-chagasic-cardiomyopathy
#6
Jian-Jun Wen, Xianxiu Wan, John Thacker, Nisha Jain Garg
BACKGROUND: Chagasic cardiomyopathy (CCM) caused by Trypanosoma cruzi (Tc) infection is prevalent in Latin America and recognized as an emerging infectious heart disease in the US. The NO-cGMP-PKG1α pathway maintains cardiac homeostasis and inotropy and may be disturbed due to phosphodiesterase (PDE5) mediated cGMP catabolism in CCM. METHODS AND RESULTS: C57BL/6 mice were infected with Tc, and at the end of acute parasitemia (i.e. 45 days post-infection), treated with sildenafil (SIL, 1 mg/kg) twice per week for 3 weeks...
June 2016: JACC. Basic to Translational Science
https://www.readbyqxmd.com/read/27685753/inhibition-of-phosphodiesterase-3-4-and-5-induces-endolymphatic-hydrops-in-mouse-inner-ear-as-evaluated-with-repeated-9-4t-mri
#7
Eva Degerman, Rene In 't Zandt, Annki Pålbrink, Lena Eliasson, Per Cayé-Thomasen, Måns Magnusson
CONCLUSION: The data indicate important roles for phosphodiesterase (PDE) 3, 4, 5, and related cAMP and cGMP pools in the regulation of inner ear fluid homeostasis. Thus, dysfunction of these enzymes might contribute to pathologies of the inner ear. OBJECTIVE: The mechanisms underlying endolymphatic hydrops, a hallmark of inner ear dysfunction, are not known in detail; however, altered balance in cAMP and cGMP signaling systems appears to be involved. Key components of these systems are PDEs, enzymes that modulate the amplitude, duration, termination, and specificity of cAMP and cGMP signaling...
August 15, 2016: Acta Oto-laryngologica
https://www.readbyqxmd.com/read/27606546/design-synthesis-and-biological-evaluation-of-first-in-class-dual-acting-histone-deacetylases-hdacs-and-phosphodiesterase-5-pde5-inhibitors-for-the-treatment-of-alzheimer-s-disease
#8
Obdulia Rabal, Juan A Sánchez-Arias, Mar Cuadrado-Tejedor, Irene de Miguel, Marta Pérez-González, Carolina García-Barroso, Ana Ugarte, Ander Estella-Hermoso de Mendoza, Elena Sáez, Maria Espelosin, Susana Ursua, Tan Haizhong, Wu Wei, Xu Musheng, Ana Garcia-Osta, Julen Oyarzabal
Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). To further extend this concept, we designed and synthesized the first chemical series of dual acting PDE5 and HDAC inhibitors, and we validated this systems therapeutics approach. Following the implementation of structure- and knowledge-based approaches, initial hits were designed and were shown to validate our hypothesis of dual in vitro inhibition...
October 13, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27568988/sgc-cgmp-pkg-pathway-stimulation-protects-the-healthy-but-not-the-failing-right-ventricle-of-rats-against-ischemia-and-reperfusion-injury
#9
Asger Andersen, Jonas Agerlund Povlsen, Jacob Johnsen, Nichlas Riise Jespersen, Hans Erik Bøtker, Jens Erik Nielsen-Kudsk
BACKGROUND: To investigate whether modulation of the sGC-cGMP-PKG pathway protects against ischemia and reperfusion injury in the healthy and the failing right ventricle (RV). METHODS: Hearts from male Wistar rats with a healthy RV (n=39) or a hypertrophic and failing RV induced by pulmonary trunk banding (n=57) were isolated and perfused in a pressure-controlled modified Langendorff setup. The isolated hearts were randomized to control, ischemic preconditioning (IPC, 2×5min of global ischemia), a phosphodiesterase-5 (PDE5) inhibitor vardenafil (66nM) alone and in combination with a cGMP-dependent protein kinase (PKG) blocker KT 5823 (1μM)...
November 15, 2016: International Journal of Cardiology
https://www.readbyqxmd.com/read/27550730/a-first-in-class-small-molecule-that-acts-as-a-dual-inhibitor-of-hdac-and-pde5-and-that-rescues-hippocampal-synaptic-impairment-in-alzheimer-s-disease-mice
#10
Mar Cuadrado-Tejedor, Carolina Garcia-Barroso, Juan A Sánchez-Arias, Obdulia Rabal, Marta Pérez-González, Sara Mederos, Ana Ugarte, Rafael Franco, Victor Segura, Gertrudis Perea, Julen Oyarzabal, Ana Garcia-Osta
The targeting of two independent but synergistic enzymatic activities, histone deacetylases (HDACs, class I and HDAC6) and phosphodiesterase 5 (PDE5), has recently been validated as a potentially novel therapeutic approach for Alzheimerś disease (AD). Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMP responsive element binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation...
August 23, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27511125/neuroprotective-effects-of-sodium-hydrosulfide-against-%C3%AE-amyloid-induced-neurotoxicity
#11
Xiao-Hui Li, Yuan-Yuan Deng, Fei Li, Jing-Shan Shi, Qi-Hai Gong
Alzheimer's disease (AD) is known to be caused by the accumulation of amyloid-β peptide (Aβ). The accumulation of Aβ has been shown to cause learning and memory impairment in rats, and it has been shown that hydrogen sulfide donors, such as sodium hydrosulfide (NaHS) can attenuate these effects. However, the underlying mechanisms have not yet been fully eludicated. This study was designed to investigate whether NaHS attenuates the inflammation and apoptosis induced by Aβ. We demonstrated that NaHS attenuated Aβ25‑35-induced neuronal reduction and apoptosis, and inhibited the activation of pro-caspase-3...
October 2016: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/27451093/the-endothelium-dependent-nitric-oxide-cgmp-pathway
#12
F Z Mónica, K Bian, F Murad
Nitric oxide (NO)-cyclic 3'-5' guanosine monophosphate (cGMP) signaling plays a critical role on smooth muscle tone, platelet activity, cardiac contractility, renal function and fluid balance, and cell growth. Studies of the 1990s established endothelium dysfunction as one of the major causes of cardiovascular diseases. Therapeutic strategies that benefit NO bioavailability have been applied in clinical medicine extensively. Basic and clinical studies of cGMP regulation through activation of soluble guanylyl cyclase (sGC) or inhibition of cyclic nucleotide phosphodiesterase type 5 (PDE5) have resulted in effective therapies for pulmonary hypertension, erectile dysfunction, and more recently benign prostatic hyperplasia...
2016: Advances in Pharmacology
https://www.readbyqxmd.com/read/27438594/tadalafil-promotes-the-recovery-of-peripheral-neuropathy-in-type-ii-diabetic-mice
#13
Lei Wang, Michael Chopp, Alexandra Szalad, XueRong Lu, LongFei Jia, Mei Lu, Rui Lan Zhang, Zheng Gang Zhang
We previously demonstrated that treatment of diabetic peripheral neuropathy with the short (4 hours) half-life phosphodiesterase 5 (PDE5) inhibitor, sildenafil, improved functional outcome in diabetic db/db mice. To further examine the effect of PDE5 inhibition on diabetic peripheral neuropathy, we investigated the effect of another potent PDE5 inhibitor, tadalafil, on diabetic peripheral neuropathy. Tadalafil is pharmacokinetically distinct from sildenafil and has a longer half-life (17+hours) than sildenafil...
2016: PloS One
https://www.readbyqxmd.com/read/27421045/functional-and-structural-evaluation-of-sildenafil-in-a-rat-model-of-acute-retinal-ischemia-reperfusion-injury
#14
Raaya Ezra-Elia, Germana Alegro da Silva, Diogo Sousa Zanoni, Renée Laufer-Amorim, Andréia Vitor Couto do Amaral, José Luiz Laus, Ron Ofri
PURPOSE: Retinal ischemia is a common cause of visual impairment and blindness. Sildenafil, a PDE5 inhibitor which inhibits cGMP degradation and in turn prolongs the effect of nitric oxide, has been shown to be protective in a number of ischemia/reperfusion (I/R) injuries, as well as in neuronal damage. We hypothesized that treatment with sildenafil might be neuroprotective in a model of acute retinal I/R injury. METHODS: Anterior chamber cannulation was performed to induce unilateral I/R injury in 38 Lewis rats...
July 15, 2016: Current Eye Research
https://www.readbyqxmd.com/read/27366192/icariin-inhibits-pulmonary-hypertension-induced-by-monocrotaline-through-enhancement-of-no-cgmp-signaling-pathway-in-rats
#15
Li-Sheng Li, Yun-Mei Luo, Juan Liu, Yu Zhang, Xiao-Xia Fu, Dan-Li Yang
It has been reported that icariin (ICA) increased contents of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) by improving expression of endothelial nitric oxide synthase (eNOS) and inhibition of phosphodiesterase type 5 (PDE5). In addition, dysfunction of the NO/cGMP pathway may play a crucial role in the pathogenesis of pulmonary hypertension (PH). In this study, the potential protective effects of ICA on PH induced by monocrotaline (MCT, 50 mg/kg) singly subcutaneous injection were investigated and the possible mechanisms involved in NO/cGMP pathway were explored in male Sprague Dawley rats...
2016: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/27342776/phosphodiesterase-5-inhibition-limits-doxorubicin-induced-heart-failure-by-attenuating-protein-kinase-g-i%C3%AE-oxidation
#16
Oleksandra Prysyazhna, Joseph Robert Burgoyne, Jenna Scotcher, Steven Grover, David Kass, Philip Eaton
Phosphodiesterase 5 (PDE5) inhibitors limit myocardial injury caused by stresses, including doxorubicin chemotherapy. cGMP binding to PKG Iα attenuates oxidant-induced disulfide formation. Because PDE5 inhibition elevates cGMP and protects from doxorubicin-induced injury, we reasoned that this may be because it limits PKG Iα disulfide formation. To investigate the role of PKG Iα disulfide dimerization in the development of apoptosis, doxorubicin-induced cardiomyopathy was compared in male wild type (WT) or disulfide-resistant C42S PKG Iα knock-in (KI) mice...
August 12, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27326921/l-cys-cse-h2s-pathway-modulates-mouse-uterus-motility-and-sildenafil-effect
#17
Emma Mitidieri, Teresa Tramontano, Erminia Donnarumma, Vincenzo Brancaleone, Giuseppe Cirino, Roberta d'Emmanuele di Villa Bianca, Raffaella Sorrentino
Sildenafil, a selective phosphodiesterase type 5 (PDE5) inhibitor, commonly used in the oral treatment for erectile dysfunction, relaxes smooth muscle of human bladder through the activation of hydrogen sulfide (H2S) signaling. H2S is an endogenous gaseous transmitter with myorelaxant properties predominantly formed from l-cysteine (l-Cys) by cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE). Sildenafil also relaxes rat and human myometrium during preterm labor but the underlying mechanism is still unclear...
September 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27299522/phosphodiesterase-type-5-inhibitors-and-risk-of-malignant-melanoma-matched-cohort-study-using-primary-care-data-from-the-uk-clinical-practice-research-datalink
#18
Anthony Matthews, Sinéad M Langan, Ian J Douglas, Liam Smeeth, Krishnan Bhaskaran
BACKGROUND: Laboratory evidence suggests that reduced phosphodiesterase type 5 (PDE5) expression increases the invasiveness of melanoma cells; hence, pharmacological inhibition of PDE5 could affect melanoma risk. Two major epidemiological studies have investigated this and come to differing conclusions. We therefore aimed to investigate whether PDE5 inhibitor use is associated with an increased risk of malignant melanoma, and whether any increase in risk is likely to represent a causal relationship...
June 2016: PLoS Medicine
https://www.readbyqxmd.com/read/27179930/phosphodiesterase-5-protein-kinase-g-signal-governs-stemness-of-prostate-cancer-stem-cells-through-hippo-pathway
#19
Naihua Liu, Liu Mei, Xueying Fan, Chao Tang, Xing Ji, Xinhua Hu, Wei Shi, Yu Qian, Musaddique Hussain, Junsong Wu, Chaojun Wang, Shaoqiang Lin, Ximei Wu
Cancer stem cells (CSC) are critical for initiation, metastasis, and relapse of cancers, however, the underlying mechanism governing stemness of CSC remains unknown. Herein, we have investigated the roles of phosphodiesterase 5 (PDE5) in stemness of prostate cancer cells. Both PDE5 and WW domain-containing transcription regulator protein-1 (TAZ), a core effector of Hippo pathway, are highly expressed in the PC3-derived cancer stem cells (PCSC). Either TAZ knockdown or inhibition of PDE5 activity attenuated colony formation, altered expression patterns of stem cell markers, and enhanced cisplatin cytotoxicity, resulting in attenuation of stemness in PCSC...
August 1, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27164419/calcilytics-enhance-sildenafil-induced-antiproliferation-in-idiopathic-pulmonary-arterial-hypertension
#20
Aya Yamamura, Satomi Yagi, Naoki Ohara, Kikuo Tsukamoto
Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and fatal disease of the pulmonary artery resulting from currently unidentified etiology. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. Phosphodiesterase type 5 (PDE5) inhibitors have been clinically used in the treatment of IPAH. Recently, we have shown that Ca(2+)-sensing receptor (CaSR) antagonists, or calcilytics, inhibit excessive cell proliferation of pulmonary arterial smooth muscle cells (PASMCs) from IPAH patients...
August 5, 2016: European Journal of Pharmacology
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