NCS 613, a PDE4 inhibitor, by increasing cAMP level suppresses systemic inflammation and immune complexes deposition in kidney of MRL/lpr lupus- prone mice.

Nephritis remains the most common severe manifestation of systemic lupus erythematosus in which auto-antibodies mediate chronic inflammation and kidney damage. cAMP-phosphodiesterases regulate sodium excretion and inflammation in various tissues. How cAMP elevation can reduce systemic inflammation and suppress kidney inflammation and damage remains elusive.

NCS 613, a Potent PDE4 Inhibitor, Displays Anti-Inflammatory and Anti-Proliferative Properties on A549 Lung Epithelial Cells and Human Lung Adenocarcinoma Explants.

Chronic inflammation is a deleterious process occurring in several pulmonary diseases; it is a driving force promoting tumorigenesis. By regulating local cyclic nucleotide concentration, cyclic nucleotide phosphodiesterases (PDE) govern important biological processes, including inflammation and proliferation. The aim of this study was to investigate the anti-inflammatory and anti-proliferative effects of NCS 613, a specific PDE4 inhibitor, on TNFα-treated human lung adenocarcinoma cell line (A549) and on human lung adenocarcinoma explants.

Delphinidin Inhibits Tumor Growth by Acting on VEGF Signalling in Endothelial Cells.

The vasculoprotective properties of delphinidin are driven mainly by its action on endothelial cells. Moreover, delphinidin displays anti-angiogenic properties in both in vitro and in vivo angiogenesis models and thereby might prevent the development of tumors associated with excessive vascularization. This study was aimed to test the effect of delphinidin on melanoma-induced tumor growth with emphasis on its molecular mechanism on endothelial cells.

Tumour growth inhibition and anti-angiogenic effects using curcumin correspond to combined PDE2 and PDE4 inhibition.

Vascular endothelial growth factor (VEGF) plays a major role in angiogenesis by stimulating endothelial cells. Increase in cyclic AMP (cAMP) level inhibits VEGF-induced endothelial cell proliferation and migration. Cyclic nucleotide phosphodiesterases (PDEs), which specifically hydrolyse cyclic nucleotides, are critical in the regulation of this signal transduction.

Cyclic GMP catabolism up-regulation in MRL/lpr lupus-prone mice is associated with organ remodeling.

Production of high titer of antibodies against nuclear components is a hallmark of systemic lupus erythematosus, an autoimmune disease characterized by the progressive chronic inflammation of multiple joints and organs. Organ damage and dysfunction such as renal failure are typical clinical features in lupus. Cell hypermetabolism and hypertrophy can accelerate organ dysfunction.

Disease progression in MRL/lpr lupus-prone mice is reduced by NCS 613, a specific cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitor.

Systemic lupus erythematosus is a polymorphic and multigenic inflammatory autoimmune disease. Cyclic AMP (cAMP) modulates inflammation and the inhibition of cyclic nucleotide phosphodiesterase type 4 (PDE4), which specifically hydrolyzes cAMP, inhibits TNFα secretion. This study was aimed at investigating the evolution of PDE activity and expression levels during the course of the disease in MRL/lpr lupus-prone mice, and to evaluate in these mice the biological and clinical effects of treatments with pentoxifylline, denbufylline and NCS 613 PDE inhibitors.

Anti-proliferative effect of curcumin on melanoma cells is mediated by PDE1A inhibition that regulates the epigenetic integrator UHRF1.

Scope: Curcumin inhibits proliferation of many cancer cells. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing intracellular cyclic adenosine-3',5'-monophosphate (cAMP) and/or cyclic guanosine-3',5'-monophosphate (cGMP), play a pivotal role in signalling pathways involved in cell proliferation. Therefore, this study investigated PDE1-5 participations in the anti-proliferative properties of curcumin in B16F10 murine melanoma cells.

Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signalling network: benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments.

Cyclic nucleotide phosphodiesterases (PDEs) that specifically inactivate the intracellular messengers cAMP and cGMP in a compartmentalized manner represent an important enzyme class constituted by 11 gene-related families of isozymes (PDE1 to PDE11). Downstream receptors, PDEs play a major role in controlling the signalosome at various levels of phosphorylations and protein/protein interactions. Due to the multiplicity of isozymes, their various intracellular regulations and their different cellular and subcellular distributions, PDEs represent interesting targets in intracellular pathways.

Concerted regulation of cGMP and cAMP phosphodiesterases in early cardiac hypertrophy induced by angiotensin II.

Left ventricular hypertrophy leads to heart failure and represents a high risk leading to premature death. Cyclic nucleotides (cAMP and cGMP) play a major role in heart contractility and cyclic nucleotide phosphodiesterases (PDEs) are involved in different stages of advanced cardiac diseases. We have investigated their contributions in the very initial stages of left ventricular hypertrophy development.

Down-regulation of cyclic nucleotide phosphodiesterase PDE1A is the key event of p73 and UHRF1 deregulation in thymoquinone-induced acute lymphoblastic leukemia cell apoptosis.

Thymoquinone (TQ), the active principle of Nigella sativa black seeds, has anti-proliferative properties on numerous cancer cell types. Others and we have previously reported that TQ acts as agent that triggers cell cycle arrest and apoptosis through either a p53- or p73-dependent pathway. However, the immediate targets recruited upon TQ-induced cytotoxicity have not yet been clearly identified.

Cyclic nucleotide phosphodiesterases (PDE) and peptide motifs.

Cyclic nucleotide phosphodiesterase (PDE), that is a multigenic enzyme superfamily ubiquitously distributed in mammalians, mainly contributes to intracellular signaling regulation. Its various isozymes specifically control in a spatio-temporal manner intracellular levels of cAMP and cGMP downstream receptor activation and nearby functional proteins. The PDE superfamily is constituted by 11 gene families (PDE1-PDE11), comprising 21 genes represented by more than 100 mRNA products due to alternative splicing.

PDEs1-5 activity and expression in tissues of cirrhotic rats reveal a role for aortic PDE3 in NO desensitization.

Liver cirrhosis is associated with increased nitric oxide (NO) production in the vasculature. We have previously demonstrated that aorta from rats with liver cirrhosis have a reduced relaxant response to NO donors that is corrected by DMPPO, a PDE5-specific inhibitor. Vasodilator responses to DMPPO itself were also reduced in rings from cirrhotic rats.

The flavonoid dioclein is a selective inhibitor of cyclic nucleotide phosphodiesterase type 1 (PDE1) and a cGMP-dependent protein kinase (PKG) vasorelaxant in human vascular tissue.

The inhibitory effect of the flavonoid dioclein was assessed on purified vascular cyclic nucleotide phosphodiesterase isoforms (EC 3.1.4.

Assessment of phosphodiesterase isozyme contribution in cell and tissue extracts.

Cyclic nucleotide phosphodiesterases (PDEs), which are ubiquitously distributed in mammalian tissues, play a major role in cell signaling by hydrolyzing cyclic adenosine 3',5'-monophosphate and cyclic guanosine 3',5'-monophosphate. Owing to their diversity, which allows specific distribution at the cellular and subcellular level, PDEs can selectively regulate various cellular functions. We present here a convenient and sensitive radioenzymatic assay for characterizing and determining the contribution of the various PDE families in cell and tissue extracts.

Modulation of VEGF-induced endothelial cell cycle protein expression through cyclic AMP hydrolysis by PDE2 and PDE4.

Endothelial cell proliferation in response to VEGF plays an important role in physiological and pathological angiogenesis. The role of PDE2 and PDE4 in VEGF-induced proliferation in HUVEC was investigated: 1) VEGF increased cAMP-hydrolytic activity by up-regulating the expression of PDE2 and PDE4 isozymes; 2) VEGF increased progression in cell cycle with an increase in p42/p44 MAP kinase, cyclin A and cyclin D1 expressions and with a decrease in p21 waf1/cip1 and p27 kip1 expressions; 3) EHNA (20 micro M), a selective PDE2 inhibitor, RP73401 (10 micro M), a selective PDE4 inhibitor blocked the VEGF-induced increase in p42/p44 MAP kinase expression; 4) RP73401, but not EHNA, blocked the VEGF-induced increase in cyclin A and decrease in p27 kip1 expressions; 5) EHNA, contrary to RP73401, enhanced the VEGF-induced increase of cyclin A and decrease of p27 kip1. 6) EHNA and RP73401 together blocked the VEGF-induced increase in cyclin D1 and decrease in p21 waf1/cip1 expressions; 7) Inhibition of VEGF-upregulated PDE2 and PDE4 reversed the VEGF-induced alterations in cell cycle protein expression, bringing back endothelial cells to a non-proliferating status.

Involvement of cyclin-dependent pathway in the inhibitory effect of delphinidin on angiogenesis.

Objective: Epidemiologic studies have shown that a diet rich in fruits and vegetables has a beneficial preventive effect for cancer and cardiovascular diseases. The mechanisms of these beneficial effects are not known although there is evidence that polyphenolic compounds in food may be of some benefit. The purpose of this study was to define the effect of delphinidin, a vasoactive polyphenol belonging to the class of anthocyanin, on endothelial cell proliferation and migration as well as on in vivo angiogenesis.

VEGF-induced HUVEC migration and proliferation are decreased by PDE2 and PDE4 inhibitors.

Migration and proliferation of endothelial cells in response to VEGF play an important role in angiogenesis associated to pathologies such as atherosclerosis, diabetes and tumor development. Elevation of cAMP in endothelial cells has been shown to inhibit growth factor-induced proliferation. Our hypothesis was that inactivation of cAMP-specific phosphodiesterases (PDEs) would inhibit angiogenesis.

Red wine polyphenolic compounds inhibit vascular endothelial growth factor expression in vascular smooth muscle cells by preventing the activation of the p38 mitogen-activated protein kinase pathway.

Objective: Moderate consumption of red wine has a beneficial effect on the cardiovascular system. This study examines whether red wine polyphenolic compounds (RWPCs) affect vascular endothelial growth factor (VEGF) expression, a major angiogenic and proatherosclerotic factor in vascular smooth muscle cells (VSMCs).

Methods And Results: VEGF mRNA expression was assessed by Northern blot analysis and the release of VEGF by immunoassay in cultured VSMCs.