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Pde5 inhibition

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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
#1
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
#2
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/29071734/nitric-oxide-is-required-for-the-insulin-sensitizing-effects-of-contraction-in-mouse-skeletal-muscle
#3
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/29057299/viagra-releases-the-brakes-on-melanoma-growth
#4
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
#5
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/28986358/pulmonary-vasodilation-by-phosphodiesterase-5-inhibition-is-enhanced-and-nitric-oxide-independent-in-early-pulmonary-hypertension-after-myocardial-infarction
#6
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/28982945/exercise-training-improves-blood-flow-to-contracting-skeletal-muscle-of-older-men-via-enhanced-cgmp-signaling
#7
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/28938916/use-of-the-kladh3-promoter-for-the-quantitative-production-of-the-murine-pde5a-isoforms-in-the-yeast-kluyveromyces-lactis
#8
Silvia Cardarelli, Mauro Giorgi, Fabio Naro, Francesco Malatesta, Stefano Biagioni, Michele Saliola
BACKGROUND: Phosphodiesterases (PDE) are a superfamily of enzymes that hydrolyse cyclic nucleotides (cAMP/cGMP), signal molecules in transduction pathways regulating crucial aspects of cell life. PDEs regulate the intensity and duration of the cyclic nucleotides signal modulating the downstream biological effect. Due to this critical role associated with the extensive distribution and multiplicity of isozymes, the 11 mammalian families (PDE1 to PDE11) constitute key therapeutic targets...
September 22, 2017: Microbial Cell Factories
https://www.readbyqxmd.com/read/28798396/flavonoid-glycosides-isolated-from-epimedium-brevicornum-and-their-estrogen-biosynthesis-promoting-effects
#9
Fu Li, Bao-Wen Du, Dan-Feng Lu, Wen-Xuan Wu, Kanjana Wongkrajang, Lun Wang, Wen-Chen Pu, Chang-Lu Liu, Han-Wei Liu, Ming-Kui Wang, Fei Wang
Epimedium brevicornum Maxim has a long history of use in the treatment of estrogen deficiency-related diseases. However, the chemical constituents and mechanism of action of this medicinal plant are not fully understood. In the present study, we isolated four new isoprenylated flavonoid glycosides, as well as 16 known flavonoids (13 isoprenylated flavonoids), from this plant. The chemical structures of the new flavonoid glycosides were elucidated by extensive spectroscopic analysis. The new compounds 1-4 were potent promoters of estrogen biosynthesis in human ovarian granulosa-like KGN cells...
August 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28792962/aberrant-cgmp-signaling-persists-during-recovery-in-mice-with-oxygen-induced-pulmonary-hypertension
#10
Marta Perez, Keng Jin Lee, Herminio J Cardona, Joann M Taylor, Mary E Robbins, Gregory B Waypa, Sara K Berkelhamer, Kathryn N Farrow
Bronchopulmonary dysplasia (BPD), a common complication of preterm birth, is associated with pulmonary hypertension (PH) in 25% of infants with moderate to severe BPD. Neonatal mice exposed to hyperoxia for 14d develop lung disease similar to BPD, with evidence of associated PH. The cyclic guanosine monophosphate (cGMP) signaling pathway has not been well studied in BPD-associated PH. In addition, there is little data about the natural history of hyperoxia-induced PH in mice or the utility of phosphodiesterase-5 (PDE5) inhibition in established disease...
2017: PloS One
https://www.readbyqxmd.com/read/28729555/inhibition-of-phosphodiesterase-5-suppresses-calcineurin-nfat-mediated-trpc6-expression-in-pulmonary-artery-smooth-muscle-cells
#11
Shaojun Li, Yilin Pan, Rui Ke, Xinming Xie, Cui Zhai, Wenhua Shi, Jian Wang, Xin Yan, Limin Chai, Qingting Wang, Qianqian Zhang, Xiaofan Su, Lan Yang, Li Gao, Manxiang Li
The up-regulation of transient receptor potential channel 6 (TRPC6) has been found to contribute to the proliferation of pulmonary artery smooth muscle cells (PASMCs), and inhibition of phosphodiesterase-5 (PDE5) has been shown to suppress TRPC6 expression in PASMCs. However, the molecular mechanisms underlying the up-regulation of TRPC6 expression and PDE5 modulation of TRPC6 expression in PASMCs remain largely unclear. The aim of this study is to address these issues. Endothelin-1 (ET-1) dose and time-dependently up-regulated TRPC6 expression in primary cultured rat PASMCs, and this was accompanied with the activation of calcineurin and subsequent translocation of NFATc4 to the nucleus...
July 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28705807/augmentation-of-cgmp-pkg-pathway-and-colonic-motility-by-hydrogen-sulfide
#12
Ancy D Nalli, Sayak Bhattacharya, Hongxia Wang, Derek M Kendig, John R Grider, Karnam S Murthy
Hydrogen sulfide (H2S), like nitric oxide (NO), causes smooth muscle relaxation, but unlike NO, does not stimulate soluble guanylyl cyclase (sGC) activity and generate cyclic guanosine 5'-monophosphate (cGMP). The aim of this study was to investigate the interplay between NO and H2S in colonic smooth muscle. In colonic smooth muscle from rabbit, mouse, and human, l-cysteine, substrate of cystathionine-γ-lyase (CSE), or NaHS, an H2S donor, inhibited phosphodiesterase 5 (PDE5) activity and augmented the increase in cGMP levels, IP3 receptor phosphorylation at Ser(1756) (measured as a proxy for PKG activation), and muscle relaxation in response to NO donor S-nitrosoglutathione (GSNO), suggesting augmentation of cGMP/PKG pathway by H2S...
October 1, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/28686445/discovery-and-optimization-of-chromeno-2-3-c-pyrrol-9-2h-ones-as-novel-selective-and-orally-bioavailable-phosphodiesterase-5-inhibitors-for-the-treatment-of-pulmonary-arterial-hypertension
#13
Deyan Wu, Tianhua Zhang, Yiping Chen, Yadan Huang, Haiju Geng, Yanfa Yu, Chen Zhang, Zengwei Lai, Yinuo Wu, Xiaolei Guo, Jianwen Chen, Hai-Bin Luo
Phosphodiesterase 5 (PDE5) inhibitors have been used as clinical agents to treat erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, we detail the discovery of a novel series of chromeno[2,3-c]pyrrol-9(2H)-one derivatives as selective and orally bioavailable inhibitors against phosphodiesterase 5. Medicinal chemistry optimization resulted in 2, which exhibits a desirable inhibitory potency of 5.6 nM with remarkable selectivity as well as excellent pharmacokinetic properties and an oral bioavailability of 63...
August 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28677661/a-novel-therapeutic-approach-in-the-treatment-of-pulmonary-arterial-hypertension-allium-ursinum-liophylisate-alleviates-symptoms-comparably-to-sildenafil
#14
Mariann Bombicz, Daniel Priksz, Balazs Varga, Andrea Kurucz, Attila Kertész, Akos Takacs, Aniko Posa, Rita Kiss, Zoltan Szilvassy, Bela Juhasz
Right-sided heart failure-often caused by elevated pulmonary arterial pressure-is a chronic and progressive condition with particularly high mortality rates. Recent studies and our current findings suggest that components of Wild garlic (Allium ursinum, AU) may play a role in reducing blood pressure, inhibiting angiotensin-converting enzyme (ACE), as well as improving right ventricle function in rabbit models with heart failure. We hypothesize that AU may mitigate cardiovascular damage caused by pulmonary arterial hypertension (PAH) and has value in the supplementary treatment of the complications of the disease...
July 4, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28648945/phosphodiesterase-5-inhibition-as-a-therapeutic-target-for-ischemic-stroke-a-systematic-review-of-preclinical-studies
#15
Joakim N E Ölmestig, Ida R Marlet, Atticus H Hainsworth, Christina Kruuse
Phosphodiesterase 5 inhibitors (PDE5i), such as sildenafil (Viagra®) are widely used for erectile dysfunction and pulmonary hypertension. Preclinical studies suggest that PDE5i may improve functional outcome following ischemic stroke. In this systematic review we aimed to evaluate the effects of selective PDE5i in animal models of brain ischaemia. A systematic search in Medline, Embase, and The Cochrane Library was performed including studies in English assessing the effects of selective PDE5i. 32 publications were included describing outcome in 3646 animals...
June 22, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28603047/tadalafil-induces-antiproliferation-apoptosis-and-phosphodiesterase-type-5-downregulation-in-idiopathic-pulmonary-arterial-hypertension-in-vitro
#16
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...
September 5, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28596298/sex-differences-in-pulmonary-vascular-control-focus-on-the-nitric-oxide-pathway
#17
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
#18
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
#19
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
#20
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
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