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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/12/20 05:30:50」(JST)
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English Journal
- Crosstalk between Phosphodiesterase 7 and Glycogen Synthase Kinase-3: Two Relevant Therapeutic Targets for Neurological Disorders.
- Morales-Garcia JA1, Palomo V, Redondo M, Alonso-Gil S, Gil C, Martinez A, Perez-Castillo A.Author information 1Instituto de Investigaciones Biomédicas (CSIC-UAM), Arturo Duperier, 4, 28029-Madrid, Spain.AbstractChronic neuroinflammation has been increasingly recognized as a primary mechanism underlying acute brain injury and neurodegenerative diseases. Enhanced expression of diverse pro-inflammatory agents in glial cells has been shown to contribute to the cell death that takes place in these disorders. Previous data from our group have shown that different inhibitors of the cyclic adenosine monophosphate (cAMP) specific phosphodiesterase 7 (PDE7) and glycogen synthase kinase-3 (GSK-3) enzymes are potent anti-inflammatory agents in different models of brain injury. In this study, we investigated cross-talk between PDE7 and GSK-3, two relevant therapeutic targets for neurological disorders, using a chemical approach. To this end, we compared specific inhibitors of GSK-3 and PDE7 with dual inhibitors of both enzymes with regard to anti-inflammatory effects in primary cultures of glial cells treated with lipopolysaccharide. Our results show that the GSK-3 inhibitors act exclusively by inhibition of this enzyme. By contrast, PDE7 inhibitors exert their effects via inhibition of PDE7 to increase intracellular cAMP levels but also through indirect inhibition of GSK-3. Activation of protein kinase A by cAMP results in phosphorylation of Ser9 of GSK-3 and subsequent inhibition. Our results indicate that the indirect inhibition of GSK-3 by PDE7 inhibitors is an important mechanism that should be considered in the future development of pharmacological treatments.
- ACS chemical neuroscience.ACS Chem Neurosci.2014 Mar 19;5(3):194-204. doi: 10.1021/cn400166d. Epub 2014 Jan 17.
- Chronic neuroinflammation has been increasingly recognized as a primary mechanism underlying acute brain injury and neurodegenerative diseases. Enhanced expression of diverse pro-inflammatory agents in glial cells has been shown to contribute to the cell death that takes place in these disorders. Pr
- PMID 24437940
- Unraveling phosphodiesterase surfaces. Identification of phosphodiesterase 7 allosteric modulation cavities.
- Redondo M1, Soteras I, Brea J, González-García A, Cadavid MI, Loza MI, Martinez A, Gil C, Campillo NE.Author information 1Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.AbstractThe last findings of our group by using chemical genetic approaches have shown that PDE7 is an interesting target in neurodegenerative diseases. The following step in this travel to unravel PDE7 is the design of more selective inhibitors. In this sense we have proposed to perform an analysis of PDE7 surface to identify possible allosteric sites following by a docking study of different PDE7 inhibitors synthesized by our group. Thanks to these studies we have proved the existence of allosteric sites in PDE7 and we have been able to explain the binding modes of the employed PDE7 inhibitors.
- European journal of medicinal chemistry.Eur J Med Chem.2013 Dec;70:781-8. doi: 10.1016/j.ejmech.2013.10.035. Epub 2013 Oct 22.
- The last findings of our group by using chemical genetic approaches have shown that PDE7 is an interesting target in neurodegenerative diseases. The following step in this travel to unravel PDE7 is the design of more selective inhibitors. In this sense we have proposed to perform an analysis of PDE7
- PMID 24239625
- Phosphodiesterase-4 inhibition augments human lung fibroblast vascular endothelial growth factor production induced by prostaglandin E2.
- Ikari J1, Michalski JM, Iwasawa S, Gunji Y, Nogel S, Park JH, Nelson AJ, Farid M, Wang X, Schulte N, Basma H, Toews ML, Feghali-Bostwick C, Tenor H, Liu X, Rennard SI.Author information 11 Department of Internal Medicine, Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, and.AbstractLung fibroblasts are believed to be a major source of vascular endothelial growth factor (VEGF), which supports the survival of lung endothelial cells and modulates the maintenance of the pulmonary microvasculature. VEGF has been related to the pathogenesis of lung diseases, including chronic obstructive pulmonary disease (COPD). Prostaglandin E2 (PGE2) stimulates VEGF production from lung fibroblasts via the E-prostanoid (EP)-2 receptor. The EP2 signaling pathway uses cyclic adenosine monophosphate (cAMP) as a second messenger, and cAMP is degraded by phosphodiesterases (PDEs). This study investigates whether phosphodiesterase inhibition modulates the human lung fibroblast VEGF production induced by PGE2. Human fetal lung fibroblasts were cultured with PGE2 and PDE inhibitors. The PDE4 inhibitors roflumilast, roflumilast N-oxide, and rolipram with PGE2 increased VEGF release, as quantified in supernatant media by ELISA. In contrast, PDE3, PDE5, and PDE7 inhibitors did not affect VEGF release. Roflumilast increased VEGF release with either an EP2 or an EP4 agonist. Roflumilast augmented the cytosolic cAMP levels induced by PGE2 and VEGF release with other agents that use the cAMP signaling pathway. Roflumilast-augmented VEGF release was completely inhibited by a protein kinase A (PKA) inhibitor. Roflumilast with PGE2 increased VEGF mRNA levels, and the blockade of mRNA synthesis inhibited the augmented VEGF release. The stimulatory effect of roflumilast on VEGF release was replicated using primary healthy and COPD lung fibroblasts. These findings demonstrate that PDE4 inhibition can modulate human lung fibroblast VEGF release by PGE2 acting through the EP2 and EP4 receptor-cAMP/PKA signaling pathway. Through this action, PDE4 inhibitors such as roflumilast could contribute to the survival of lung endothelial cells.
- American journal of respiratory cell and molecular biology.Am J Respir Cell Mol Biol.2013 Oct;49(4):571-81. doi: 10.1165/rcmb.2013-0004OC.
- Lung fibroblasts are believed to be a major source of vascular endothelial growth factor (VEGF), which supports the survival of lung endothelial cells and modulates the maintenance of the pulmonary microvasculature. VEGF has been related to the pathogenesis of lung diseases, including chronic obstru
- PMID 23656623
Japanese Journal
- Genetic variation in phosphodiesterase (PDE) 7B in chronic lymphocytic leukemia : overview of genetic variants of cyclic nucleotide PDEs in human disease
- PEIRO Ana M,TANG Chih-Min,MURRAY Fiona,ZHANG Lingzhi,BROWN Loren M,CHOU Daisy,RASSENTI Laura,KIPPS Thomas A,INSEL Paul A
- Journal of human genetics 56(9), 676-681, 2011-09-01
- NAID 10030660984
- Genetic variation in phosphodiesterase (PDE) 7B in chronic lymphocytic leukemia: overview of genetic variants of cyclic nucleotide PDEs in human disease
- Peiro Ana M.,Tang Chih-Min,Murray Fiona [他]
- Journal of human genetics 56(9), 676-681, 2011-09
- NAID 40018996985
Related Links
- である．PDE は，現在までに 21 種の遺伝子がク. ローニングされ，これらはアミノ酸 配列の相同性，. 生化学的特性及び阻害薬に対する感受性の違いか. ら 11 種類の ファミリー（PDE1~PDE11）に分類. されている. 1, 2) ．PDE7 は cAMP を特異的に分解 する ...
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