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1
ERDOGAN, Suat, and Miles D. HOUSLAY. "Challenge of human Jurkat T-cells with the adenylate cyclase activator forskolin elicits major changes in cAMP phosphodiesterase (PDE) expression by up-regulating PDE3 and inducing PDE4D1 and PDE4D2 splice variants as well as down-regulating a novel PDE4A splice variant." Biochemical Journal 321, no. 1 (January 1, 1997): 165–75. http://dx.doi.org/10.1042/bj3210165.
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The cAMP phosphodiesterase (PDE) 3 and PDE4 isoforms provide the major cAMP-hydrolysing PDE activities in Jurkat T-cells, with additional contributions from the PDE1 and PDE2 isoforms. Challenge of cells with the adenylate cyclase activator forskolin led to a rapid, albeit transient, increase in PDE3 activity occurring over the first 45 min, followed by a sustained increase in PDE3 activity which began after ∼3 h and continued for at least 24 h. Only this second phase of increase in PDE3 activity was blocked by the transcriptional inhibitor actinomycin D. After ∼3 h of exposure to forskolin, PDE4 activity had increased, via a process that could be inhibited by actinomycin D, and it remained elevated for at least a 24 h period. Such actions of forskolin were mimicked by cholera toxin and 8-bromo-cAMP. Forskolin increased intracellular cAMP concentrations in a time-dependent fashion and its action was enhanced when PDE induction was blocked with actinomycin D. Reverse transcription (RT)-PCR analysis, using generic primers designed to detect transcripts representing enzymically active products of the four PDE4 genes, identified transcripts for PDE4A and PDE4D but not for PDE4B or PDE4C in untreated Jurkat T-cells. Forskolin treatment did not induce transcripts for either PDE4B or PDE4C; however, it reduced the RT-PCR signal for PDE4A transcripts and markedly enhanced that for PDE4D transcripts. Using RT-PCR primers for PDE4 splice variants, a weak signal for PDE4D1 was evident in control cells whereas, in forskolin-treated cells, clear signals for both PDE4D1 and PDE4D2 were detected. RT-PCR analysis of the PDE4A species indicated that it was not the PDE4A isoform PDE-46 (PDE4A4B). Immunoblotting of control cells for PDE4 forms identified a single PDE4A species of ∼118 kDa, which migrated distinctly from the PDE4A4B isoform PDE-46, with immunoprecipitation analyses showing that it provided all of the PDE4 activity in control cells. Forskolin treatment led to a marked decrease of this novel PDE4A species and allowed the detection of a strong signal for an ∼67 kDa PDE4D species, suggested to be PDE4D1, but did not induce PDE4B and PDE4C isoforms. Elevation of intracellular cAMP concentrations in Jurkat T-cells thus exerts a highly selective effect on the transcriptional activity of the genes encoding the various PDE4 isoforms. This leads to the down-regulation of a novel PDE4A splice variant and the induction of PDE4D1 and PDE4D2 splice variants, leading to a net increase in the total PDE4 activity of Jurkat T-cells.
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Wang, Huanchen, Ming-Sheng Peng, Yi Chen, Jie Geng, Howard Robinson, Miles D. Houslay, Jiwen Cai, and Hengming Ke. "Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors." Biochemical Journal 408, no. 2 (November 14, 2007): 193–201. http://dx.doi.org/10.1042/bj20070970.
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PDE4 (phosphodiesterase-4)-selective inhibitors have attracted much attention as potential therapeutics for the treatment of both depression and major inflammatory diseases, but their practical application has been compromised by side effects. A possible cause for the side effects is that current PDE4-selective inhibitors similarly inhibit isoforms from all four PDE4 subfamilies. The development of PDE4 subfamily-selective inhibitors has been hampered by a lack of structural information. In the present study, we rectify this by providing the crystal structures of the catalytic domains of PDE4A, PDE4B and PDE4D in complex with the PDE4 inhibitor NVP {4-[8-(3-nitrophenyl)-[1,7]naphthyridin-6-yl]benzoic acid} as well as the unliganded PDE4C structure. NVP binds in the same conformation to the deep cAMP substrate pocket and interacts with the same residues in each instance. However, detailed structural comparison reveals significant conformational differences. Although the active sites of PDE4B and PDE4D are mostly comparable, PDE4A shows significant displacements of the residues next to the invariant glutamine residue that is critical for substrate and inhibitor binding. PDE4C appears to be more distal from other PDE4 subfamilies, with certain key residues being disordered. Our analyses provide the first structural basis for the development of PDE4 subfamily-selective inhibitors.
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Boyd, Abigail, Ileana V. Aragon, Lina Abou Saleh, Dylan Southers, and Wito Richter. "The cAMP-phosphodiesterase 4 (PDE4) controls β-adrenoceptor- and CFTR-dependent saliva secretion in mice." Biochemical Journal 478, no. 10 (May 24, 2021): 1891–906. http://dx.doi.org/10.1042/bcj20210212.
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Saliva, while often taken for granted, is indispensable for oral health and overall well-being, as inferred from the significant impairments suffered by patients with salivary gland dysfunction. Here, we show that treatment with several structurally distinct PAN-PDE4 inhibitors, but not a PDE3 inhibitor, induces saliva secretion in mice, indicating it is a class-effect of PDE4 inhibitors. In anesthetized mice, while neuronal regulations are suppressed, PDE4 inhibition potentiates a β-adrenoceptor-induced salivation, that is ablated by the β-blocker Propranolol and is absent from homozygous ΔF508-CFTR mice lacking functional CFTR. These data suggest that PDE4 acts within salivary glands to gate saliva secretion that is contingent upon the cAMP/PKA-dependent activation of CFTR. Indeed, PDE4 contributes the majority of total cAMP-hydrolytic capacity in submandibular-, sublingual-, and parotid glands, the three major salivary glands of the mouse. In awake mice, PDE4 inhibitor-induced salivation is reduced by CFTR deficiency or β-blockers, but also by the muscarinic blocker Atropine, suggesting an additional, central/neuronal mechanism of PDE4 inhibitor action. The PDE4 family comprises four subtypes, PDE4A-D. Ablation of PDE4D, but not PDE4A-C, produced a minor effect on saliva secretion, implying that while PDE4D may play a predominant role, PDE4 inhibitor-induced salivation results from the concurrent inactivation of multiple (at least two) PDE4 subtypes. Taken together, our data reveal a critical role for PDE4/PDE4D in controlling CFTR function in an in vivo model and in inducing salivation, hinting at a therapeutic potential of PDE4 inhibition for cystic fibrosis and conditions associated with xerostomia.
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Xu, Man, Xiaowen Yu, Xia Meng, Songming Huang, Yue Zhang, Aihua Zhang, and Zhanjun Jia. "Inhibition of PDE4/PDE4B improves renal function and ameliorates inflammation in cisplatin-induced acute kidney injury." American Journal of Physiology-Renal Physiology 318, no. 3 (March 1, 2020): F576—F588. http://dx.doi.org/10.1152/ajprenal.00477.2019.
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Nephrotoxicity is a known clinical complication of cisplatin that limits the use of this potent antitumor drug. Cyclic nucleotide phosphodiesterases (PDEs) play complex roles in physiology and pathology. PDE4, which is a member of the PDE family, has four subtypes (PDE4A–PDE4D), and PDE4B plays an important role in inflammation. Thus, in the present study, we investigated the effect of PDE4/PDE4B inhibition on renal function and inflammation in a cisplatin nephrotoxicity model. In mice, cisplatin enhanced mRNA and protein expression of PDE4B in renal tubules. After treatment with the PDE4 inhibitor cilomilast, cisplatin-induced renal dysfunction, renal tubular injury, tubular cell apoptosis, and inflammation were all improved. Next, after silencing PDE4B in vivo, we observed a protective effect against cisplatin nephrotoxicity similar to that of the PDE4 inhibitor. In vitro, cisplatin-induced renal tubular cell death was strikingly ameliorated by the PDE4 inhibitor and PDE4B knockdown along with the blockade of the inflammatory response. Considering the known roles of some cell survival pathways in antagonizing insults, we examined levels of PDE4-associated proteins sirtuin 1, phosphatidylinositol 3-kinase, and phosphorylated AKT in cisplatin-treated renal tubular cells with or without cilomilast treatment. Strikingly, cisplatin treatment downregulated the expression of the above proteins, and this effect was largely abolished by the PDE4 inhibitor. Together, these findings indicate the beneficial role of PDE4/PDE4B inhibition in treating cisplatin nephrotoxicity, possibly through antagonizing inflammation and restoring cell survival signaling pathways.
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Abusnina, Abdurazzag, Thérèse Keravis, Qingwei Zhou, Hélène Justiniano, Annelise Lobstein, and Claire Lugnier. "Tumour growth inhibition and anti-angiogenic effects using curcumin correspond to combined PDE2 and PDE4 inhibition." Thrombosis and Haemostasis 113, no. 02 (March 2015): 319–28. http://dx.doi.org/10.1160/th14-05-0454.
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SummaryVascular 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. We have previously reported that PDE2 and PDE4 up-regulations in human umbilical vein endothelial cells (HUVECs) are implicated in VEGF-induced angiogenesis and that inhibition of PDE2 and PDE4 activities prevents the development of the in vitro angiogenesis by increasing cAMP level, as well as the in vivo chicken embryo angiogenesis. We have also shown that polyphenols are able to inhibit PDEs. The curcumin having anti-cancer properties, the present study investigated whether PDE2 and PDE4 inhibitors and curcumin could have similar in vivo anti-tumour properties and whether the anti-angiogenic effects of curcumin are mediated by PDEs. Both PDE2/PDE4 inhibitor association and curcumin significantly inhibited in vivo tumour growth in C57BL/6N mice. In vitro, curcumin inhibited basal and VEGF-stimulated HUVEC proliferation and migration and delayed cell cycle progression at G0/G1, similarly to the combination of selective PDE2 and PDE4 inhibitors. cAMP levels in HUVECs were significantly increased by curcumin, similarly to rolipram (PDE4 inhibitor) and BAY-60–550 (PDE2 inhibitor) association, indicating cAMP-PDE inhibitions. Moreover, curcumin was able to inhibit VEGF-induced cAMP-PDE activity without acting on cGMP-PDE activity and to modulate PDE2 and PDE4 expressions in HUVECs. The present results suggest that curcumin exerts its in vitro anti-angiogenic and in vivo antitumour properties through combined PDE2 and PDE4 inhibition.
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Favot, Laure, Thérèse Keravis, Vincent Holl, Alain Bec, and Claire Lugnier. "VEGF-induced HUVEC migration and proliferation are decreased by PDE2 and PDE4 inhibitors." Thrombosis and Haemostasis 90, no. 08 (2003): 334–43. http://dx.doi.org/10.1160/th03-02-0084.
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SummaryMigration 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. The purpose of this study was to evaluate the effect of PDE inhibitors on in vitro and in vivo angiogenesis, using human umbilical vein endothelial cell (HUVEC) and chick chorioallantoic membrane (CAM) models respectively. Here, we report that: 1) PDE2, PDE3, PDE4 and PDE5 are expressed in HUVEC; 2) EHNA (20 µM), PDE2 selective inhibitor, and RP73401 (10 µM), PDE4 selective inhibitor, are able to increase the intracellular cAMP level in HUVEC; 3) EHNA and RP73401 are able to inhibit proliferation, cell cycle progression and migration of HUVEC stimulated by VEGF; 4) these in vitro effects can be mimic by treating HUVEC with the cAMP analogue, 8-Br-cAMP (600 µM); 5) only the association of EHNA and RP73401 inhibits in vivo angiogenesis, indicating that both migration and proliferation must be inhibited. These data strongly suggest that PDE2 and PDE4 represent new potential therapeutic targets in pathological angiogenesis.
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Ivey, F. Douglas, Lili Wang, Didem Demirbas, Christina Allain, and Charles S. Hoffman. "Development of a Fission Yeast-Based High-Throughput Screen to Identify Chemical Regulators of cAMP Phosphodiesterases." Journal of Biomolecular Screening 13, no. 1 (November 26, 2007): 62–71. http://dx.doi.org/10.1177/1087057107312127.
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Cyclic nucleotide phosphodiesterases (PDEs) comprise a superfamily of enzymes that serve as drug targets in many human diseases. There is a continuing need to identify high-specificity inhibitors that affect individual PDE families or even subtypes within a single family. The authors describe a fission yeast-based high-throughput screen to detect inhibitors of heterologously expressed adenosine 3′,5′-cyclic monophosphate (cAMP) PDEs. The utility of this system is demonstrated by the construction and characterization of strains that express mammalian PDE2A, PDE4A, PDE4B, and PDE8A and respond appropriately to known PDE2A and PDE4 inhibitors. High-throughput screens of 2 bioactive compound libraries for PDE inhibitors using strains expressing PDE2A, PDE4A, PDE4B, and the yeast PDE Cgs2 identified known PDE inhibitors and members of compound classes associated with PDE inhibition. The authors verified that the furanocoumarin imperatorin is a PDE4 inhibitor based on its ability to produce a PDE4-specific elevation of cAMP levels. This platform can be used to identify PDE activators, as well as genes encoding PDE regulators, which could serve as targets for future drug screens. ( Journal of Biomolecular Screening 2008:62-71)
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Yougbare, Issaka, Caroline Morin, Farid Yannick Senouvo, Chantal Sirois, Roula Albadine, Claire Lugnier, and Eric Rousseau. "NCS 613, a potent and specific PDE4 inhibitor, displays anti-inflammatory effects on human lung tissues." American Journal of Physiology-Lung Cellular and Molecular Physiology 301, no. 4 (October 2011): L441—L450. http://dx.doi.org/10.1152/ajplung.00407.2010.
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Chronic inflammation is a hallmark of pulmonary diseases, which leads to lung parenchyma destruction (emphysema) and obstructive bronchiolitis occurring in both chronic obstructive pulmonary disease and asthma. Inflammation is strongly correlated with low intracellular cAMP levels and increase in specific cAMP hydrolyzing activity. The aim of the present study was to investigate the role of the cyclic phosphodiesterase type 4 (PDE4) in human lung and to determine the effects of NCS 613, a new PDE4 inhibitor, on lung inflammation and bronchial hyperresponsiveness. High cAMP-PDE activities were found in the cytosoluble fractions from human lung parenchyma and distal bronchi. PDE4 (rolipram sensitive) represented 40% and 56% of total cAMP-PDE activities in the above-corresponding tissues. Moreover, PDE4A, PDE4B, PDE4C, and PDE4D isoforms were detected in all three subcellular fractions (cytosolic, microsomal, and nuclear) with differential distributions according to specific variants. Pharmacological treatments with NCS 613 significantly decreased PDE4 activity and reduced IκBα degradation in cultured parenchyma, both of which are usually correlated with a lower inflammation status. Moreover, NCS 613 pretreatment potentiated isoproterenol-induced relaxations in human distal bronchi, while reducing TNF-α-induced hyperresponsiveness in cultured bronchi, as assessed in the presence of methacholine, U-46619, or histamine. This reducing effect of NCS 613 on human bronchi hyperresponsiveness triggered by TNF-α was related to a lower expression level of PDE4B and PDE4C, as well as a downregulation of the phosphorylated forms of p38-MAPK, CPI-17, and MYPT-1, which are known to control tone. In conclusion, specific PDE4 inhibitors, such as NCS 613, may represent an alternative and isoform-specific approach toward reducing human lung inflammation and airway overreactivity.
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Boyd, Abigail, Ileana Aragon, Justin Rich, Will McDonough, Marianna Oditt, Daniel Irelan, Edward Fiedler, Lina Abou Saleh, and Wito Richter. "Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice." Biology 10, no. 12 (December 20, 2021): 1355. http://dx.doi.org/10.3390/biology10121355.
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Treatment with PAN-PDE4 inhibitors has been shown to produce hypothermia in multiple species. Given the growing body of evidence that links nausea and emesis to disturbances in thermoregulation in mammals, we explored PDE4 inhibitor-induced hypothermia as a novel correlate of nausea in mice. Using knockout mice for each of the four PDE4 subtypes, we show that selective inactivation of individual PDE4 subtypes per se does not produce hypothermia, which must instead require the concurrent inactivation of multiple (at least two) PDE4 subtypes. These findings contrast with the role of PDE4s in shortening the duration of α2-adrenoceptor-dependent anesthesia, a behavioral surrogate previously used to assess the emetic potential of PDE4 inhibitors, which is exclusively affected by inactivation of PDE4D. These different outcomes are rooted in the distinct molecular mechanisms that drive these two paradigms; acting as a physiologic α2-adrenoceptor antagonist produces the effect of PDE4/PDE4D inactivation on the duration of α2-adrenoceptor-dependent anesthesia, but does not mediate the effect of PDE4 inhibitors on body temperature in mice. Taken together, our findings suggest that selective inhibition of any individual PDE4 subtype, including inhibition of PDE4D, may be free of nausea and emesis.
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Murthy, Karnam S., Huiping Zhou, and Gabriel M. Makhlouf. "PKA-dependent activation of PDE3A and PDE4 and inhibition of adenylyl cyclase V/VI in smooth muscle." American Journal of Physiology-Cell Physiology 282, no. 3 (March 1, 2002): C508—C517. http://dx.doi.org/10.1152/ajpcell.00373.2001.
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Regulation of adenylyl cyclase type V/VI and cAMP-specific, cGMP-inhibited phosphodiesterase (PDE) 3 and cAMP-specific PDE4 by cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG) was examined in gastric smooth muscle cells. Expression of PDE3A but not PDE3B was demonstrated by RT-PCR and Western blot. Basal PDE3 and PDE4 activities were present in a ratio of 2:1. Forskolin, isoproterenol, and the PKA activator 5,6-dichloro-1-β-d-ribofuranosyl benzimidazole 3′,5′-cyclic monophosphate, SP-isomer, stimulated PDE3A phosphorylation and both PDE3A and PDE4 activities. Phosphorylation of PDE3A and activation of PDE3A and PDE4 were blocked by the PKA inhibitors [protein kinase inhibitor (PKI) and H-89] but not by the PKG inhibitor (KT-5823). Sodium nitroprusside inhibited PDE3 activity and augmented forskolin- and isoproterenol-stimulated cAMP levels; PDE3 inhibition was reversed by blockade of cGMP synthesis. Forskolin stimulated adenylyl cyclase phosphorylation and activity; PKI blocked phosphorylation and enhanced activity. Stimulation of cAMP and inhibition of inositol 1,4,5-trisphosphate-induced Ca2+release and muscle contraction by isoproterenol were augmented additively by PDE3 and PDE4 inhibitors. The results indicate that PKA regulates cAMP levels in smooth muscle via stimulatory phosphorylation of PDE3A and PDE4 and inhibitory phosphorylation of adenylyl cyclase type V/VI. Concurrent generation of cGMP inhibits PDE3 activity and augments cAMP levels.
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Fang, Qiuhong, Yingmin Ma, Jing Wang, Joel Michalski, Stephen I. Rennard, and Xiangde Liu. "PGE2Desensitizesβ-Agonist Effect on Human Lung Fibroblast-Mediated Collagen Gel Contraction through Upregulating PDE4." Mediators of Inflammation 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/145197.
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In the current study, we investigated the effect of a long-actingβ-agonist (salmeterol) and a phosphodiesterase 4 (PDE4) inhibitor (cilomilast) on human lung fibroblast-mediated collagen gel contraction. Higher concentrations of salmeterol (10−7and 10−6 M) inhibited fibroblast-mediated collagen gel contraction. No effect was observed with cilomilast alone (up to 10−5 M). In the presence of 10−8 M salmeterol, however, cilomilast could significantly inhibit fibroblast-mediated collagen gel contraction in a concentration-dependent manner (10−7~10−5 M). Blockade of endogenous PGE2by indomethacin further potentiated the inhibitory effect of salmeterol on fibroblast-mediated collagen gel contraction, but it did not affect cilomilast's effect. Pretreatment with PGE2abolished the inhibitory effect of salmeterol, but it potentiated the inhibitory effect of cilomilast on fibroblast-mediated collagen gel contraction. Finally, indomethacin slightly inhibited PDE4C expression, while PGE2stimulated the expression of PDE4A and -4C in human lung fibroblasts. These findings suggest that long-actingβ-agonist and PDE4 inhibitor have a synergistic effect in regulating fibroblast tissue repair functions and that PGE2can modulate the effect ofβ-agonist and PDE4 inhibitor at least in part through the mechanism of regulating PDE4 expression.
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Sarfati, Marika, Véronique Mateo, Sylvie Baudet, Manuel Rubio, Christine Fernandez, Fréderic Davi, Jacques-Louis Binet, Jozo Delic, and Hélène Merle-Béral. "Sildenafil and vardenafil, types 5 and 6 phosphodiesterase inhibitors, induce caspase-dependent apoptosis of B-chronic lymphocytic leukemia cells." Blood 101, no. 1 (January 1, 2003): 265–69. http://dx.doi.org/10.1182/blood-2002-01-0075.
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Abstract Type 4 phosphodiesterase (PDE4) inhibitors reportedly induce apoptosis in chronic lymphocytic leukemia (CLL) cells. Following clinical improvement of one previously untreated CLL patient with sildenafil therapy, we evaluated the in vitro induction of apoptosis in CLL cells by 4 PDE5/6 inhibitors, including sildenafil, vardenafil, zaprinast, and methoxyquinazoline (MQZ). After 24 hours of culture, the various PDE inhibitors differed in their ability to induce apoptosis, with zaprinast displaying no killing effect. Normal B cells isolated from control donors were totally resistant to PDE-induced apoptosis. Vardenafil was 3 and 30 times more potent an inducer of apoptosis than sildenafil and MQZ, respectively. Both vardenafil and sildenafil failed to elevate adenosine 3′5′ cyclic monophosphate (cAMP) levels, largely excluding an inhibitory effect on cAMP-PDE3, -PDE4, and -PDE7. Vardenafil- or sildenafil-treated B-CLL cells displayed up to 30% intracellular active caspase 3. Drug-induced apoptosis was inhibited by the caspase inhibitor z-VAD.fmk, prevented by interleukin-4 (IL-4), and significantly reduced by stromal-derived factor1-α (SDF-1α). We conclude that vardenafil and sildenafil induce caspase-dependent apoptosis of B-CLL cells in vitro and thus might be considered in the treatment of CLL patients. However, further in vivo investigations should be warranted.
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Suzuki, Osamu, Taiji Goto, Toshiharu Yoshino, Satoshi Nakamura, and Hiroaki Maeda. "The role of phosphodiesterase 4B in IL-8/LTB4-induced human neutrophil chemotaxis evaluated with a phosphodiesterase 4B inhibitor." Acta Pharmaceutica 65, no. 2 (June 1, 2015): 191–97. http://dx.doi.org/10.1515/acph-2015-0016.
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Abstract PDE4B was previously shown to be a dominant PDE4 subtype of neutrophils. However, its physiological role in the neutrophil function has not been evaluated. In this study, the inhibitory effects of a phosphodiesterase 4B (PDE4B)- selective inhibitor (compound A) and subtype non-selective PDE4 inhibitors (roflumilast and cilomilast) were evaluated in human peripheral blood cells. Compound A, roflumilast and cilomilast in a similar manner inhibited TNF-α production by LPS-stimulated human mononuclear cells. However, the inhibitory effect of compound A on IL-8 or LTB4-induced chemotactic response of neutrophils was modest even at the highest concentration (10 μmol L-1), whereas roflumilast and cilomilast inhibited IL-8 or LTB4-induced neutrophil chemotaxis. Our results suggest that PDE4B does not play an important role during the chemotactic response of human neutrophils.
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Ahmad, Faiyaz, Guang Gao, Ling Mei Wang, Tova Rahn Landstrom, Eva Degerman, Jacalyn H. Pierce, and Vincent C. Manganiello. "IL-3 and IL-4 Activate Cyclic Nucleotide Phosphodiesterases 3 (PDE3) and 4 (PDE4) by Different Mechanisms in FDCP2 Myeloid Cells." Journal of Immunology 162, no. 8 (April 15, 1999): 4864–75. http://dx.doi.org/10.4049/jimmunol.162.8.4864.
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Abstract In FDCP2 myeloid cells, IL-4 activated cyclic nucleotide phosphodiesterases PDE3 and PDE4, whereas IL-3, granulocyte-macrophage CSF (GM-CSF), and phorbol ester (PMA) selectively activated PDE4. IL-4 (not IL-3 or GM-CSF) induced tyrosine phosphorylation of insulin-receptor substrate-2 (IRS-2) and its association with phosphatidylinositol 3-kinase (PI3-K). TNF-α, AG-490 (Janus kinase inhibitor), and wortmannin (PI3-K inhibitor) inhibited activation of PDE3 and PDE4 by IL-4. TNF-α also blocked IL-4-induced tyrosine phosphorylation of IRS-2, but not of STAT6. AG-490 and wortmannin, not TNF-α, inhibited activation of PDE4 by IL-3. These results suggested that IL-4-induced activation of PDE3 and PDE4 was downstream of IRS-2/PI3-K, not STAT6, and that inhibition of tyrosine phosphorylation of IRS molecules might be one mechnism whereby TNF-α could selectively regulate activities of cytokines that utilized IRS proteins as signal transducers. RO31-7549 (protein kinase C (PKC) inhibitor) inhibited activation of PDE4 by PMA. IL-4, IL-3, and GM-CSF activated mitogen-activated protein (MAP) kinase and protein kinase B via PI3-K signals; PMA activated only MAP kinase via PKC signals. The MAP kinase kinase (MEK-1) inhibitor PD98059 inhibited IL-4-, IL-3-, and PMA-induced activation of MAP kinase and PDE4, but not IL-4-induced activation of PDE3. In FDCP2 cells transfected with constitutively activated MEK, MAP kinase and PDE4, not PDE3, were activated. Thus, in FDCP2 cells, PDE4 can be activated by overlapping MAP kinase-dependent pathways involving PI3-K (IL-4, IL-3, GM-CSF) or PKC (PMA), but selective activation of PDE3 by IL-4 is MAP kinase independent (but perhaps IRS-2/PI3-K dependent).
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Germain, Nöella, Elisabeth Boichot, Jean-Michel Planquois, and Vincent Lagente. "Reduced Airway Hyperresponsiveness by Phosphodiesterase 3 and 4 Inhibitors in Guinea-Pigs." Mediators of Inflammation 8, no. 3 (1999): 153–57. http://dx.doi.org/10.1080/09629359990487.
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The aim of the present study was to compare the effects of selective phosphodiesterase (PDE) 3, 4 and 5 inhibitors on antigen-induced airway hyperresponsiveness in sensitized guinea-pigs. When the sensitized guinea-pigs were orally pre-treated with the selective PDE4 inhibitor, Ro 20-1724 (30 mg/kg), and studied 48 h after OA, a significant reduction (p<0.01) of the leftward shift of the dose-response curve to ACh was noted, whereas it was ineffective at the lower dose (10 mg/kg). Administration of the selective PDE3 inhibitor, milrinone (30 mg/kg) also elicited a significant reduction (p<0.01) of the airway hyperresponsiveness, whereas the PDE5 inhibitor zaprinast (30 mg/kg) was ineffective. These results show that both PDE3 and PDE4 inhibitors are able to inhibit the antigen-induced airway hyperresponsiveness in sensitized guinea-pigs and support the potential utility of selective PDE inhibitors in the treatment of asthma.
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Kolosionek, Ewa, Rajkumar Savai, Hossein Ardeschir Ghofrani, Norbert Weissmann, Andreas Guenther, Friedrich Grimminger, Werner Seeger, Gamal Andre Banat, Ralph Theo Schermuly, and Soni Savai Pullamsetti. "Expression and Activity of Phosphodiesterase Isoforms during Epithelial Mesenchymal Transition: The Role of Phosphodiesterase 4." Molecular Biology of the Cell 20, no. 22 (November 15, 2009): 4751–65. http://dx.doi.org/10.1091/mbc.e09-01-0019.
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Epithelial–mesenchymal transition (EMT) has emerged as a critical event in the pathogenesis of organ fibrosis and cancer and is typically induced by the multifunctional cytokine transforming growth factor (TGF)-β1. The present study was undertaken to evaluate the potential role of phosphodiesterases (PDEs) in TGF-β1-induced EMT in the human alveolar epithelial type II cell line A549. Stimulation of A549 with TGF-β1 induced EMT by morphological alterations and by expression changes of the epithelial phenotype markers E-cadherin, cytokeratin-18, zona occludens-1, and the mesenchymal phenotype markers, collagen I, fibronectin, and α-smooth muscle actin. Interestingly, TGF-β1 stimulation caused twofold increase in total cAMP-PDE activity, contributed mostly by PDE4. Furthermore, mRNA and protein expression demonstrated up-regulation of PDE4A and PDE4D isoforms in TGF-β1-stimulated cells. Most importantly, treatment of TGF-β1 stimulated epithelial cells with the PDE4-selective inhibitor rolipram or PDE4 small interfering RNA potently inhibited EMT changes in a Smad-independent manner by decreasing reactive oxygen species, p38, and extracellular signal-regulated kinase phosphorylation. In contrast, the ectopic overexpression of PDE4A and/or PDE4D resulted in a significant loss of epithelial marker E-cadherin but did not result in changes of mesenchymal markers. In addition, Rho kinase signaling activated by TGF-β1 during EMT demonstrated to be a positive regulator of PDE4. Collectively, the findings presented herein suggest that TGF-β1 mediated up-regulation of PDE4 promotes EMT in alveolar epithelial cells. Thus, targeting PDE4 isoforms may be a novel approach to attenuate EMT-associated lung diseases such as pulmonary fibrosis and lung cancer.
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Ma, Jingyi, Virender Kumar, and Ram I. Mahato. "Nanoparticle Delivery of Novel PDE4B Inhibitor for the Treatment of Alcoholic Liver Disease." Pharmaceutics 14, no. 9 (September 7, 2022): 1894. http://dx.doi.org/10.3390/pharmaceutics14091894.
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The incidence of alcoholic liver disease (ALD) is increasing worldwide while no effective treatment has been approved. The progression of ALD has proven to be related to the upregulation of phosphodiesterase 4 (PDE4) expression, and PDE4 inhibitors showed potential to improve ALD. However, the application of PDE4 inhibitors is limited by the gastrointestinal side effects due to PDE4D inhibition. Therefore, we used a novel PDE4B inhibitor KVA-D88 as the therapeutic for ALD treatment. KVA-D88 inhibited inflammatory response, promoted β-oxidation, increased the level of antioxidants in the hepatocytes, and suppressed hepatic stellate cell (HSC) activation in vitro. To improve the solubility and availability in vivo, KVA-D88 was encapsulated into mPEG-b-P(CB-co-LA) nanoparticles (NPs) by solvent evaporation, with a mean particle size of 135 nm and drug loading of 4.2%. We fed the male C57BL/6 mice with a Lieber–DeCarli liquid diet containing 5% (v/v) ethanol for 6 weeks to induce ALD. Systemic administration of KVA-D88 free drug and KVA-D88-loaded NPs at 5 mg/kg significantly improved the ALD in mice. KVA-D88 significantly ameliorated alcohol-induced hepatic injury and inflammation. KVA-D88 also markedly reduced steatosis by promoting fatty acid β-oxidation. Liver fibrosis and reactive oxygen species (ROS)-caused cellular damage was observed to be alleviated by KVA-D88. KVA-D88-loaded NPs proved better efficacy than free drug in the animal study. In conclusion, the novel PDE4B inhibitor KVA-D88-loaded NPs have the potential to treat ALD in mice
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Balasubramaniam, Ambikaipakan, Sulaiman Sheriff, Lou Ann Friend, and J. Howard James. "Phosphodiesterase 4B knockout prevents skeletal muscle atrophy in rats with burn injury." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 315, no. 2 (August 1, 2018): R417—R421. http://dx.doi.org/10.1152/ajpregu.00042.2018.
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The phosphodiesterase 4 (PDE4)-cAMP pathway plays a predominant role in mediating skeletal muscle proteolysis in burn injury. The present investigations to determine the PDE4 isoform(s) involved in this action revealed that burn injury increased the expression of rat skeletal muscle PDE4B mRNA by sixfold but had little or no effect on expression of other PDE4 isoforms. These observations led us to study the effects of burn in PDE4B knockout (KO) rats. As reported by us previously, burn injury significantly increased extensor digitorum longus (EDL) muscle total and myofibrillar proteolysis in wild-type (WT) rats, but there were no significant effects on either total or myofibrillar protein breakdown in EDL muscle of PDE4B KO rats with burn injury. Moreover, burn injury increased PDE4 activity in the skeletal muscle of WT rats, but this was reduced by >80% in PDE4B KO rats. Also, burn injury decreased skeletal muscle cAMP concentration in WT rats but had no significant effects in the muscles of PDE4B KO rats. Incubation of the EDL muscle of burn-PDE4B KO rats with an inhibitor of the exchange factor directly activated by cAMP, but not with a protein kinase A inhibitor, eliminated the protective effects of PDE4B KO on EDL muscle proteolysis and increased muscle proteolysis to the same extent as in the EDL of burn-WT rats. These novel findings confirm a major role for PDE4B in skeletal muscle proteolysis in burn injury and suggest that an innovative therapy based on PDE4B-selective inhibitors could be developed to treat skeletal muscle cachexia in burn injury without the fear of causing emesis, which is associated with PDE4D inhibition.
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Bloom, Timothy J. "Cyclic nucleotide phosphodiesterase isozymes expressed in mouse skeletal muscle." Canadian Journal of Physiology and Pharmacology 80, no. 12 (December 1, 2002): 1132–35. http://dx.doi.org/10.1139/y02-149.
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To understand changes in cyclic nucleotide metabolism in muscle disease states, the expression of phosphodiesterase (PDE) isozymes in normal mouse leg muscle was examined. Four subcellular fractions were generated by differential centrifugation at 10 000 × g and 100 000 × g. cAMP PDE activity was found predominately in the soluble fractions, while cGMP PDE activity was more evenly distributed amongst soluble and particulate fractions. Pharmacological inhibitors demonstrate that PDE4 represents the major cAMP hydrolyzing activity and PDE2 represents the major cGMP hydrolyzing activity in mouse leg muscle. PDE1 is expressed at low levels, while PDE3 and PDE5 are intermediate. Between 20 and 40% of total PDE activity remained in the presence of inhibitors for PDE1PDE5, indicating that other PDE families contribute to the total PDE pool. Reverse-transcription PCR with family-specific primers showed expression of mRNA for PDE7PDE9, supporting this conclusion. Total PDE activity was found to be elevated in tissue extracts from a mouse model of Duchenne's muscular dystrophy.Key words: cyclic nucleotide, phosphodiesterase, skeletal muscle, pharmacological inhibitors, muscular dystrophy.
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MACKENZIE, Simon J., and Miles D. HOUSLAY. "Action of rolipram on specific PDE4 cAMP phosphodiesterase isoforms and on the phosphorylation of cAMP-response-element-binding protein (CREB) and p38 mitogen-activated protein (MAP) kinase in U937 monocytic cells." Biochemical Journal 347, no. 2 (April 10, 2000): 571–78. http://dx.doi.org/10.1042/bj3470571.
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U937 monocytic cells are shown here to express a range of PDE4, cAMP-specific phosphodiesterase (PDE) isoenzymes: the long isoenzymes, PDE4A4, PDE4D5 and PDE4D3, plus the short isoenzyme, PDE4B2. These isoenzymes provide around 76% of the total cAMP PDE activity of U937 cells. The specific activities of the total PDE4A, PDE4B and PDE4D activities were 0.63±0.09, 8.8±0.2 and 34.4±2.9 pmol/min per mg of protein respectively. The PDE4 selective inhibitor, rolipram, inhibited immunopurified PDE4B and PDE4D activities similarly, with IC50 values of approx. 130 nM and 240 nM respectively. In contrast, rolipram inhibited immunopurified PDE4A activity with a dramatically lower IC50 value of around 3 nM. Rolipram increased phosphorylation of cAMP-response-element-binding protein (CREB) in U937 cells in a dose-dependent fashion, which implied the presence of both high affinity (IC50 value approx. 1 nM) and low affinity (IC50 value approx. 120 nM) components. Rolipram dose-dependently inhibited the interferon-γ (IFN-γ)-stimulated phosphorylation of p38 mitogen-activated protein (MAP) kinase in a simple monotonic fashion with an IC50 value of approx. 290 nM. On this basis, it is suggested that rolipram inhibition of PDE4A4 is involved in regulating CREB phosphorylation but not IFN-γ-stimulated p38 MAP kinase phosphorylation. PDE4A4 was also selectively activated by challenge of U937 cells with either bacterial lipopolysaccharide (LPS) or IFN-γ through a process which was attenuated by both wortmannin and rapamycin. It is proposed that the PDE4A4 isoform is involved in compartmentalized cAMP signalling responses in U937 monocytes.
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Adderley, Shaquria P., Meera Sridharan, Elizabeth A. Bowles, Alan H. Stephenson, Mary L. Ellsworth, and Randy S. Sprague. "Protein kinases A and C regulate receptor-mediated increases in cAMP in rabbit erythrocytes." American Journal of Physiology-Heart and Circulatory Physiology 298, no. 2 (February 2010): H587—H593. http://dx.doi.org/10.1152/ajpheart.00975.2009.
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Activation of the β-adrenergic receptor (β-AR) or the prostacyclin receptor (IPR) results in increases in cAMP and ATP release from erythrocytes. cAMP levels depend on a balance between synthesis via adenylyl cyclase and hydrolysis by phosphodiesterases (PDEs). Previously, we reported that cAMP increases associated with activation of the β-AR and IPR in rabbit and human erythrocytes are tightly regulated by distinct PDEs ( 1 ). Importantly, inhibitors of these PDEs potentiated both increases in cAMP and ATP release. It has been shown that increases in protein kinase (PK) activity can activate PDE3 and PDE4. Both PKA and PKC are present in the erythrocyte and can phosphorylate and activate these PDEs. Here we investigate the hypothesis that PKA regulates PDE activity associated with the β-AR and both PKA and PKC regulate the PDE activity associated with the IPR in rabbit erythrocytes. Pretreatment of erythrocytes with the PKA inhibitor, H89 (10 μM), in the presence of the PDE4 inhibitor, rolipram (10 μM), augmented isoproterenol (1 μM)-induced cAMP increases. In contrast, in the presence of the PDE3 inhibitor, cilostazol (10 μM), pretreatment of erythrocytes with either H89 (1 μM) or two chemically dissimilar inhibitors of PKC, calphostin C (1 μM) or GFX109203X (1 μM), potentiated iloprost (1 μM)-induced cAMP increases. Furthermore, pretreatment of erythrocytes with both H89 and GFX109203X in the presence of cilostazol augmented the iloprost-induced increases in cAMP to a greater extent than either PK inhibitor individually. These results support the hypothesis that PDEs associated with receptor-mediated increases in cAMP in rabbit erythrocytes are regulated by kinases specific to the receptor's signaling pathway.
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DAY, Jonathan P., Julian A. T. DOW, Miles D. HOUSLAY, and Shireen-A. DAVIES. "Cyclic nucleotide phosphodiesterases in Drosophila melanogaster." Biochemical Journal 388, no. 1 (May 10, 2005): 333–42. http://dx.doi.org/10.1042/bj20050057.
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Cyclic nucleotide PDEs (phosphodiesterases) are important enzymes that regulate intracellular levels of cAMP and cGMP. In the present study, we identify and characterize novel PDEs in the genetic model, Drosophila melanogaster. The Drosophila genome encodes five novel PDE genes in addition to dunce. Predicted PDE sequences of Drosophila show highly conserved critical domains when compared with human PDEs. Thus PDE-encoding genes of D. melanogaster are CG14940-PDE1C, CG8279-PDE6β, CG5411-PDE8A, CG32648-PDE9 and CG10231-PDE11. Reverse transcriptase–PCRs of adult tissues reveal widespread expression of PDE genes. Drosophila Malpighian (renal) tubules express all the six PDEs: Drosophila PDE1, dunce (PDE4), PDE6, PDE8, PDE9 and PDE11. Antipeptide antibodies were raised against PDE1, PDE6, PDE9 and PDE11. Verification of antibody specificity by Western blotting of cloned and expressed PDE constructs allowed the immunoprecipitation studies of adult Drosophila lysates. Biochemical characterization of immunoprecipitated endogenous PDEs showed that PDE1 is a dual-specificity PDE (Michaelis constant Km for cGMP: 15.3±1 μM; Km cAMP: 20.5±1.5 μM), PDE6 is a cGMP-specific PDE (Km cGMP: 37±13 μM) and PDE11 is a dual-specificity PDE (Km cGMP: 6±2 μM; Km cAMP: 18.5±5.5 μM). Drosophila PDE1, PDE6 and PDE11 display sensitivity to vertebrate PDE inhibitors, zaprinast (IC50 was 71±39 μM for PDE1, 0.65±0.015 μM for PDE6 and 1.6±0.5 μM for PDE11) and sildenafil (IC50 was 1.3±0.9 μM for PDE1, 0.025±0.005 μM for PDE6 and 0.12±0.06 μM for PDE11). We provide the first characterization of a cGMP-specific PDE and two dual-specificity PDEs in Drosophila, and show a high degree of similarity in structure and function between human and Drosophila PDEs.
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Shih, Chung-Hung, Tzu-Jung Huang, Chien-Ming Chen, Yun-Lian Lin, and Wun-Chang Ko. "S-Petasin, the Main Sesquiterpene ofPetasites formosanus, Inhibits Phosphodiesterase Activity and Suppresses Ovalbumin-Induced Airway Hyperresponsiveness." Evidence-Based Complementary and Alternative Medicine 2011 (2011): 1–14. http://dx.doi.org/10.1093/ecam/nep088.
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S-Petasin is the main sesquiterpene ofPetasites formosanus, a traditional folk medicine used to treat hypertension, tumors and asthma in Taiwan. The aim of the present study was to investigate its inhibitory effects on phosphodiesterase (PDE) 1–5, and on ovalbumin (OVA)-induced airway hyperresponsiveness (AHR) in a murine model of allergic asthma.S-Petasin concentration-dependently inhibited PDE3 and PDE4 activities with 50% inhibitory concentrations (IC50) of 25.5, and 17.5 μM, respectively. According to the Lineweaver-Burk analysis,S-petasin competitively inhibited PDE3 and PDE4 activities with respective dissociation constants for inhibitor binding (Ki) of 25.3 and 18.1 μM, respectively. Both IC50andKivalues for PDE3 were significantly greater than those for PDE4.S-Petasin (10–30 μmol/kg, administered subcutaneously (s.c.)) dose-dependently and significantly attenuated the enhanced pause (Penh) value induced by methacholine (MCh) in sensitized and challenged mice. It also significantly suppressed the increases in total inflammatory cells, lymphocytes, neutrophils, eosinophils and levels of cytokines, including interleukin (IL)-2, IL-4 and IL-5, tumor necrosis factor (TNF)-α and interferon (IFN)-γ in bronchoalveolar lavage fluid (BALF) of these mice. In addition,S-petasin (10–30 μmol/kg, s.c.) dose-dependently and significantly attenuated total and OVA-specific immunoglobulin E (IgE) levels in the serum and BALF, and enhanced the IgG2alevel in serum of these mice. The PDE4Hvalue ofS-petasin was >300 μM; therefore, its PDE4H/PDE4Lvalue was calculated to be >17. In conclusion, the present results forS-petasin at least partially explain whyPetasites formosanusis used as a folk medicine to treat asthma in Taiwan.
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Cheng, Jingfei, Michael A. Thompson, Henry J. Walker, Catherine E. Gray, Montserrat M. Diaz Encarnacion, Gina M. Warner, and Joseph P. Grande. "Differential regulation of mesangial cell mitogenesis by cAMP phosphodiesterase isozymes 3 and 4." American Journal of Physiology-Renal Physiology 287, no. 5 (November 2004): F940—F953. http://dx.doi.org/10.1152/ajprenal.00079.2004.
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Mesangial cell (MC) mitogenesis is regulated through “negative cross talk” between cAMP-PKA and ERK signaling. Although it is widely accepted that cAMP inhibits mitogenesis through PKA-mediated phosphorylation of Raf-1, recent studies have indicated that cAMP-mediated inhibition of mitogenesis may occur independently of Raf-1 phosphorylation or without inhibiting ERK activity. We previously showed that MCs possess functionally compartmentalized intracellular pools of cAMP that are differentially regulated by cAMP phosphodiesterases (PDE); an intracellular pool directed by PDE3 but not by PDE4 suppresses mitogenesis. We therefore sought to determine whether there was a differential effect of PDE3 vs. PDE4 inhibitors on the Ras-Raf-MEK-ERK pathway in cultured MC. Although PDE3 and PDE4 inhibitors activated PKA and modestly elevated cAMP levels to a similar extent, only PDE3 inhibitors suppressed MC mitogenesis (−57%) and suppressed Raf-1 kinase and ERK activity (−33 and −68%, respectively). Both PDE3 and PDE4 inhibitors suppressed B-Raf kinase activity. PDE3 inhibitors increased phosphorylation of Raf-1 on serine 43 and serine 259 and decreased phosphorylation on serine 338; PDE4 inhibitors were without effect. Overexpression of a constitutively active MEK-1 construct reversed the antiproliferative effect of PDE3 inhibitors. PDE3 inhibitors also reduced cyclin A levels (−27%), cyclin D and cyclin E kinase activity (−30 and −50%, respectively), and induced expression of the cell cycle inhibitor p21 (+90%). We conclude that the antiproliferative effects of PDE3 inhibitors are mechanistically related to inhibition of the Ras-Raf-MEK-ERK pathway. Additional cell cycle targets of PDE3 inhibitors include cyclin A, cyclin D, cyclin E, and p21.
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Kistemaker, Loes E. M., Tjitske A. Oenema, Hoeke A. Baarsma, I. Sophie T. Bos, Martina Schmidt, Fabrizio Facchinetti, Maurizio Civelli, Gino Villetti, and Reinoud Gosens. "The PDE4 inhibitor CHF-6001 and LAMAs inhibit bronchoconstriction-induced remodeling in lung slices." American Journal of Physiology-Lung Cellular and Molecular Physiology 313, no. 3 (September 1, 2017): L507—L515. http://dx.doi.org/10.1152/ajplung.00069.2017.
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Combination therapy of PDE4 inhibitors and anticholinergics induces bronchoprotection in COPD. Mechanical forces that arise during bronchoconstriction may contribute to airway remodeling. Therefore, we investigated the impact of PDE4 inhibitors and anticholinergics on bronchoconstriction-induced remodeling. Because of the different mechanism of action of PDE4 inhibitors and anticholinergics, we hypothesized functional interactions of these two drug classes. Guinea pig precision-cut lung slices were preincubated with the PDE4 inhibitors CHF-6001 or roflumilast and/or the anticholinergics tiotropium or glycopyorrolate, followed by stimulation with methacholine (10 μM) or TGF-β1 (2 ng/ml) for 48 h. The inhibitory effects on airway smooth muscle remodeling, airway contraction, and TGF-β release were investigated. Methacholine-induced protein expression of smooth muscle-myosin was fully inhibited by CHF-6001 (0.3–100 nM), whereas roflumilast (1 µM) had smaller effects. Tiotropium and glycopyrrolate fully inhibited methacholine-induced airway remodeling (0.1–30 nM). The combination of CHF-6001 and tiotropium or glycopyrrolate, in concentrations partially effective by themselves, fully inhibited methacholine-induced remodeling in combination. CHF-6001 did not affect airway closure and had limited effects on TGF-β1-induced remodeling, but rather, it inhibited methacholine-induced TGF-β release. The PDE4 inhibitor CHF-6001, and to a lesser extent roflumilast, and the LAMAs tiotropium and glycopyrrolate inhibit bronchoconstriction-induced remodeling. The combination of CHF-6001 and anticholinergics was more effective than the individual compounds. This cooperativity might be explained by the distinct mechanisms of action inhibiting TGF-β release and bronchoconstriction.
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Neumann, Joachim, Rafaela Voss, Ulrich Laufs, Christian Werner, and Ulrich Gergs. "Phosphodiesterases 2, 3 and 4 can decrease cardiac effects of H2-histamine-receptor activation in isolated atria of transgenic mice." Naunyn-Schmiedeberg's Archives of Pharmacology 394, no. 6 (February 12, 2021): 1215–29. http://dx.doi.org/10.1007/s00210-021-02052-y.
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AbstractHistamine exerts cAMP-dependent positive inotropic effects (PIE) and positive chronotropic effects (PCE) on isolated left and right atria, respectively, of transgenic mice which overexpress the human H2-receptor in the heart (=H2-TG). To determine whether these effects are antagonized by phosphodiesterases (PDEs), contractile studies were done in isolated left and right atrial preparations of H2-TG. The contractile effects of histamine were tested in the additional presence of the PDE-inhibitorserythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA, 1 μM, PDE2-inhibitor) or cilostamide (1 μM, PDE3-inhibitor), rolipram (10 μM, a PDE4-inhibitor), and their combinations. Cilostamide (1 μM) and EHNA (1 μM), rolipram (1 μM), and EHNA (1 μM) and the combination of rolipram (0.1 μM) and cilostamide (1 μM) each increased the potency of histamine to elevate the force of contraction (FOC) in H2-TG. Cilostamide (1 μM) and rolipram (10 μM) alone increased and EHNA (1 μM) decreased alone, and their combination increased the potency of histamine to increase the FOC in H2-TG indicating that PDE3 and PDE4 regulate the inotropic effects of histamine in H2-TG. The PDE inhibitors (EHNA, cilostamide, rolipram) alone did not alter the potency of histamine to increase the heart beat in H2-TG whereas a combination of rolipram, cilostamide, and EHNA, or of rolipram and EHNA increased the potency of histamine to act on the beating rate. In summary, the data suggest that the PCE of histamine in H2-TG atrium involves PDE 2 and 4 activities, whereas the PIE of histamine are diminished by activity of PDE 3 and 4.
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Tarpey, Siobhán B., Darrell R. Sawmiller, Claire Kelly, W. Joseph Thompson, and Mary I. Townsley. "Phosphodiesterase 3 activity is reduced in dog lung following pacing-induced heart failure." American Journal of Physiology-Lung Cellular and Molecular Physiology 284, no. 5 (May 1, 2003): L766—L773. http://dx.doi.org/10.1152/ajplung.00373.2002.
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We hypothesized that decreases in expression and/or activity of cAMP-specific phosphodiesterases (PDE) contribute to protective adaptations observed in lung after heart failure. In this study, we compared PDE activity in lung parenchyma isolated from control dogs and those paced to heart failure by assaying cyclic nucleotide hydrolysis in fractions of homogenate supernatant eluted from DEAE-Trisacryl columns. Cyclic nucleotide hydrolysis due to PDE3, PDE4, and PDE5 isoforms was predominant in both control and paced groups. The ratio of PDE3 activity to total cAMP PDE activity was decreased in the paced group compared with control ( P< 0.05), whereas PDE4 or PDE5 activity ratios were not different between the two groups. With the use of RT-PCR, message expression for PDE3A or PDE3B did not differ between the two groups. Cilostamide, a selective PDE3 inhibitor, and forskolin, a nonspecific agonist for adenylyl cyclase, both inhibited thapsigargin-induced increases in endothelial permeability in control lung. We conclude that PDE3 activity, but not mRNA expression, is reduced in lung from dogs paced to heart failure, a change that could contribute to heart failure-induced attenuation of the lung endothelial permeability response to injury.
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Basole, Chaitali P., Rebecca K. Nguyen, Katie Lamothe, Puja Billis, Mai Fujiwara, Amanda G. Vang, Robert B. Clark, Paul M. Epstein, and Stefan Brocke. "Treatment of Experimental Autoimmune Encephalomyelitis with an Inhibitor of Phosphodiesterase-8 (PDE8)." Cells 11, no. 4 (February 14, 2022): 660. http://dx.doi.org/10.3390/cells11040660.
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After decades of development, inhibitors targeting cyclic nucleotide phosphodiesterases (PDEs) expressed in leukocytes have entered clinical practice for the treatment of inflammatory disorders, with three PDE4 inhibitors being in clinical use as therapeutics for psoriasis, psoriatic arthritis, chronic obstructive pulmonary disease and atopic dermatitis. In contrast, the PDE8 family that is upregulated in pro-inflammatory T cells is a largely unexplored therapeutic target. We have previously demonstrated a role for the PDE8A-Raf-1 kinase complex in the regulation of myelin oligodendrocyte glycoprotein peptide 35–55 (MOG35–55) activated CD4+ effector T cell adhesion and locomotion by a mechanism that differs from PDE4 activity. In this study, we explored the in vivo treatment of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS) induced in mice immunized with MOG using the PDE8-selective inhibitor PF-04957325. For treatment in vivo, mice with EAE were either subcutaneously (s.c.) injected three times daily (10 mg/kg/dose), or were implanted subcutaneously with Alzet mini-osmotic pumps to deliver the PDE8 inhibitor (15.5 mg/kg/day). The mice were scored daily for clinical signs of paresis and paralysis which were characteristic of EAE. We observed the suppression of the clinical signs of EAE and a reduction of inflammatory lesion formation in the CNS by histopathological analysis through the determination of the numbers of mononuclear cells isolated from the spinal cord of mice with EAE. The PDE8 inhibitor treatment reduces the accumulation of both encephalitogenic Th1 and Th17 T cells in the CNS. Our study demonstrates the efficacy of targeting PDE8 as a treatment of autoimmune inflammation in vivo by reducing the inflammatory lesion load.
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Irelan, Daniel, Abigail Boyd, Edward Fiedler, Peter Lochmaier, Will McDonough, Ileana V. Aragon, Lyudmila Rachek, Lina Abou Saleh, and Wito Richter. "Acute PDE4 Inhibition Induces a Transient Increase in Blood Glucose in Mice." International Journal of Molecular Sciences 24, no. 4 (February 7, 2023): 3260. http://dx.doi.org/10.3390/ijms24043260.
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cAMP-phosphodiesterase 4 (PDE4) inhibitors are currently approved for the treatment of inflammatory diseases. There is interest in expanding the therapeutic application of PDE4 inhibitors to metabolic disorders, as their chronic application induces weight loss in patients and animals and improves glucose handling in mouse models of obesity and diabetes. Unexpectedly, we have found that acute PDE4 inhibitor treatment induces a temporary increase, rather than a decrease, in blood glucose levels in mice. Blood glucose levels in postprandial mice increase rapidly upon drug injection, reaching a maximum after ~45 min, and returning to baseline within ~4 h. This transient blood glucose spike is replicated by several structurally distinct PDE4 inhibitors, suggesting that it is a class effect of PDE4 inhibitors. PDE4 inhibitor treatment does not reduce serum insulin levels, and the subsequent injection of insulin potently reduces PDE4 inhibitor-induced blood glucose levels, suggesting that the glycemic effects of PDE4 inhibition are independent of changes in insulin secretion and/or sensitivity. Conversely, PDE4 inhibitors induce a rapid reduction in skeletal muscle glycogen levels and potently inhibit the uptake of 2-deoxyglucose into muscle tissues. This suggests that reduced glucose uptake into muscle tissue is a significant contributor to the transient glycemic effects of PDE4 inhibitors in mice.
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Alaamery, Manal A., Arlene R. Wyman, F. Douglas Ivey, Christina Allain, Didem Demirbas, Lili Wang, Ozge Ceyhan, and Charles S. Hoffman. "New Classes of PDE7 Inhibitors Identified by a Fission Yeast-Based HTS." Journal of Biomolecular Screening 15, no. 4 (March 12, 2010): 359–67. http://dx.doi.org/10.1177/1087057110362100.
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Studies of the phosphodiesterase PDE7 family are impeded by there being only one commercially available PDE7 inhibitor, BRL50481. The authors have employed a high-throughput screen of commercial chemical libraries, using a fission yeast-based assay, to identify PDE7 inhibitors that include steroids, podocarpanes, and an unusual heterocyclic compound, BC30. In vitro enzyme assays measuring the potency of BC30 and 2 podocarpanes, in comparison with BRL50481, produce data consistent with those from yeast-based assays. In other enzyme assays, BC30 stimulates the PDE4D catalytic domain but not full-length PDE4D2, suggesting an allosteric site of action. BC30 significantly enhances the anti-inflammatory effect of the PDE4 inhibitor rolipram as measured by release of tumor necrosis factor α from activated monocytes. These studies introduce several new PDE7 inhibitors that may be excellent candidates for medicinal chemistry because of the requirements for drug-like characteristics placed on them by the nature of the yeast-based screen.
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Okatan, Esma N., and Belma Turan. "The contribution of phosphodiesterases to cardiac dysfunction in rats with metabolic syndrome induced by a high-carbohydrate diet." Canadian Journal of Physiology and Pharmacology 97, no. 11 (November 2019): 1064–72. http://dx.doi.org/10.1139/cjpp-2019-0006.
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Metabolic syndrome (MetS) is a cluster of risk factors, including insulin resistance among others, underlying the development of diabetes and (or) cardiovascular diseases. Studies show a close relationship between cardiac dysfunction and abnormal cAMP catabolism, which contributes to pathological remodelling. Stimulating the synthesis of cAMP via suppression of phosphodiesterases (PDEs) has positive therapeutic effects. Therefore, we examined the role of PDEs on cardiac dysfunction in high-carbohydrate diet-induced MetS rats. We first demonstrated significantly high expression levels of PDE3 and PDE4, the most highly expressed subtypes, together with depressed cAMP levels in heart tissue from MetS rats. Second, we demonstrated the activity of these PDEs by using either their basal or PDE inhibitor-induced intracellular levels of cAMP and Ca2+, the transient intracellular Ca2+ changes under electrical stimulation, isometric contractions in papillary muscle strips and some key signalling proteins (such as RyR2, PLN, PP1A, and PKA) are responsible for the Ca2+ homeostasis in isolated cardiomyocytes from MetS rats. The clear recovery in decreased basal cAMP levels, increased protein expression levels of PDE3 and PDE4, and positive responses in the altered Ca2+ homeostasis to PDE inhibitors as seen in our study can provide important insights about the roles of activated PDEs in depressed contractile activity in hearts from MetS rats.
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Favot, Laure, Thérèse Keravis, and Claire Lugnier. "Modulation of VEGF-induced endothelial cell cycle protein expression through cyclic AMP hydrolysis by PDE2 and PDE4." Thrombosis and Haemostasis 92, no. 09 (2004): 634–45. http://dx.doi.org/10.1160/th03-12-0768.
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SummaryEndothelial 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 p21waf1/cip1 and p27kip1 expressions; 3) EHNA (20 µM), a selective PDE2 inhibitor, RP73401 (10 µM), 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 p27kip1 expressions; 5) EHNA, contrary to RP73401, enhanced the VEGF-induced increase of cyclin A and decrease of p27kip1. EHNA and RP73401 together blocked the VEGF-induced increase in cyclin D1 and decrease in p21waf1/cip1 expressions; 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. Consequently, PDE2 and PDE4 inhibitions were able to inhibit VEGF-induced endothelial cell proliferation by restoring cell cycle key protein expression, and might thus be useful in excessive angiogenesis. Furthermore, the differences between PDE2 and PDE4 effects may suggest compartmentalized effects.
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Sasseville, M., F. K. Albuz, F. J. Richard, and R. B. Gilchrist. "254. Evidences for a novel cAMP-phosphodiesterase expressed in the bovine ovarian follicle." Reproduction, Fertility and Development 20, no. 9 (2008): 54. http://dx.doi.org/10.1071/srb08abs254.
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3′5’-Cyclic adenosine monophosphate (cAMP) is an important second messenger in the mammalian ovarian follicle implicated in gonadotrophin signalling as well as oocyte meiotic arrest. Cyclic AMP-degrading phosphodiesterases (PDE) modulate cAMP levels in the ovarian follicle, but the specific PDE subtypes responsible for this degradation in the different cellular compartments within the bovine follicle remain unknown. The current dogma, established principally in rodent, presents PDE3A as the ‘oocyte PDE’, while PDE4D is the ‘granulosa/cumulus PDE’. Our PDE activity measurements suggested that a PDE3 (cilostamide-sensitive, 10µM) was representing 79% of the total cAMP-PDE activity in the bovine oocyte, in agreement with the dogma. However, our results suggested that PDE4 (rolipram-sensitive, 10µM) is representing only 19% of the cAMP-PDE activity in the cumulus cells, while 65% of the activity was due to PDE8 (IBMX-insensitive, 500µM), a result in direct opposition with the accepted PDE distribution in the ovarian follicle. Mural granulosa cells were displaying equal amounts of PDE4 (31%) and PDE8 (30%) cAMP-PDE activities. Interestingly, cAMP-PDE activities were not varying during the first 9 h of IVM in the bovine cumulus-oocyte complexes (COC), as seen in rat. COCs treated with an adenylyl cyclase stimulator (forkolin 100µM) in combinaison with the only known inhibitor for the PDE8 family, dipyridamole, are showing a dose-dependant increase of cAMP levels and a significant delay nuclear maturation, whereas a potent PDE4 inhibitor, rolipram (up to 100µM), was ineffective. This study provides the first insight into subtype-specific PDE cAMP degrading activities in the bovine ovarian follicle, especially around oocyte nuclear maturation. It demonstrates dramatic differential PDE subtype compartmentalisation between ovarian somatic cells and the germ cell, including the important contribution of a new PDE family member in the ovarian follicle, PDE8. PDE8 could be a novel pharmacological target to improve bovine oocyte IVM conditions and to increase developmental competence.
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Houslay, M. D., and G. S. Baillie. "Phosphodiesterase-4 gates the ability of protein kinase A to phosphorylate G-protein receptor kinase-2 and influence its translocation." Biochemical Society Transactions 34, no. 4 (July 21, 2006): 474–75. http://dx.doi.org/10.1042/bst0340474.
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Challenge of the β2Ar (β2-adrenergic receptor) with isoprenaline in HEK-293β2 cells (human embryonic kidney cells stably overexpressing a FLAG- and green fluorescent protein-tagged β2Ar) results in the PKA (cAMP-dependent protein kinase) phosphorylation of GRK2 (G-protein receptor kinase-2). This response was enhanced when PDE4 (phosphodiesterase-4) activity was attenuated using either rolipram, a PDE4-selective inhibitor, or with siRNA (small interfering RNA) knockdown of both PDE4B and PDE4D. Rolipram also facilitated GRK2 recruitment to the membrane and phosphorylation of the β2Ar by GRK2 in response to isoprenaline challenge of cells. In resting cells, rolipram treatment alone is sufficient to promote PKA phosphorylation of GRK2, with consequential effects on GRK2 translocation and GRK2 phosphorylation of the β2Ar. Similar effects are observed in cardiac myocytes. We propose that PDE4 activity protects GRK2 from inappropriate phosphorylation by PKA in resting cells that might have occurred through fluctuations in basal cAMP levels. Thus PDE4 gates the action of PKA to phosphorylate GRK2.
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Lerner, Adam, Hongli Dong, Lewis Weintraub, Paul M. Epstein, and Sanjay Tiwari. "PDE4 Inhibitors Augment Glucocorticoid-Mediated Apoptosis in B-CLL Cells in the Absence of Exogenous Adenylyl Cyclase Stimulation." Blood 104, no. 11 (November 16, 2004): 4793. http://dx.doi.org/10.1182/blood.v104.11.4793.4793.
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Abstract cAMP-mediated signaling potentiates glucocorticoid-mediated apoptosis in lymphoid cells, but an effective means by which to take advantage of this observation in the treatment of lymphoid malignancies has not been identified. The PDE4 enzyme family regulates the catabolism of cAMP to AMP in a wide range of tissues. PDE4 inhibitors have recently been submitted for approval for use in asthma and COPD. In leukemic samples from 11 B-CLL patients, rolipram and RO20-1724, two structurally unrelated PDE4 inhibitors, synergized with either hydrocortisone or dexamethasone in inducing B-CLL but not T cell apoptosis. Dose titration studies demonstrated that addition of a PDE4 inhibitor augmented B-CLL apoptosis even when maximally effective doses of either glucocorticoid were utilized. In five patients so analyzed, 10 uM rolipram augmented the induction of apoptosis by 100 uM hydrocortisone by 40 +/− 18%. Using transient transfection of a GRE-luciferase construct with an Amaxa nucleofector technique, we determined that treatment with PDE4 inhibitors augmented glucocorticoid receptor (GR)-mediated GRE transactivation in primary B-CLL cells. Strikingly, inhibition of PKA with the cAMP antagonist Rp-8Br-cAMPS inhibited glucocorticoid-induced apoptosis by 86 +/− 14% in 6 patients so tested and GRE transactivation by 83% in 8 patients so tested. Similarly, treatment with Ht31 peptide, a 23 residue peptide derived from an AKAP that binds with 4.0 nM dissociation constant to PKA RII subunits, also reduced hydrocortisone-induced transactivation. These studies suggest that PKA activity is required for both the ability of glucocorticoids to induce apoptosis and GRE transactivation in B-CLL cells. CCRF-CEM cells, a well-studied model of glucocorticoid and cAMP-induced apoptosis, differed from B-CLL cells in that stimulation of adenylyl cyclase with the diterpene forskolin was required to increase both glucocorticoid-mediated apoptosis and GRE activation, while PDE4 inhibition had no effect. We isolated both dexamethasone-sensitive and dexamethasone-resistant CCRF-CEM clones for these studies and demonstrated that forskolin induced glucocorticoid sensitivity even in the initially dexamethasone resistant clone. 1,9 dideoxyforskolin, a forskolin analogue that does not activate adenylyl cyclase, failed to augment glucocorticoid sensitivity in CCRF-CEM cells. Given the marked discrepancy in the sensitivity of B-CLL cells and CCRF-CEM cells to PDE4 inhibitor-induced augmentation of glucocorticoid apoptosis and GRE transactivation, we next examined the cAMP response and PDE4 isoforms in these two cell types. Inhibition of PDE4 induced cAMP elevation in B-CLL but not CCRF-CEM cells, while forskolin augmented cAMP levels in CCRF-CEM but not B-CLL cells. While rolipram but not forskolin treatment up-regulated 63 and 68 kDa forms of PDE4B (most likely PDE4B2) in B-CLL, forskolin but not rolipram treatment up-regulated 67 and 72 kDa forms of PDE4D (most likely PDE4D1/D2) in CCRF-CEM cells. These studies suggest that PKA is required for and enhances glucocorticoid-induced apoptosis in B-CLL by modulating GR signal transduction and that inhibition of PDE4 in the absence of exogenous adenylyl cyclase activation is a clinically tenable means by which to achieve such PKA activation. Clinical trials that examine whether PDE4 inhibitors enhance the efficacy of glucocorticoid-containing chemotherapy regimens in B-CLL and other lymphoid malignancies are indicated.
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Yakovleva, O. A., A. I. Semenenko, and O. Yu Hoina-Kardasevich. "New targets of pharmacotherapy of bronchial obstruction." Infusion & Chemotherapy, no. 3.1 (October 11, 2020): 87–88. http://dx.doi.org/10.32902/2663-0338-2020-3.1-73.
Full textAbstract:
Objective. To assess the prospects for scientific development of new classes of bronchodilators for respiratory diseases with obstructive syndrome, taking into account future molecular targets.
Materials and methods. The analysis of international English scientific information in the systems of surveys and search on the Internet for the last 5 years is carried out.
Results and discussion. Currently, there is an increasing interest in the development of new directions for pharmacological correction of the mechanisms of bronchial obstruction. The proposed international protocols are based on several groups of correctors: short-acting and prolonged-acting β-agonists, anticholinergics, methylxanthines, antileukotriene drugs and their combinations, but their safety limits their use in the age aspect. Therefore, the search for new targets for influencing bronchial tone remains relevant in respiratory pathology. There are nine potential new classes of bronchodilators that are being studied.
Selective phosphodiesterase inhibitors (PDE) were already known as roflumilast for the treatment of chronic obstructive pulmonary disease (COPD), but the genetic polymorphism of PDE isoenzymes, their different localization in subcellular microdomains, a complex signaling network and their selectivity for cyclic AMP or GMP all make it difficult to obtain and develop effective pharmacological action. Dual PDE3/PDE4 inhibitors are being developed taking into account that the PDE4 isoenzyme – the main one in most inflammatory cells involved in the pathogenesis of bronchial asthma (BA) and COPD, predominates in the smooth muscles (SM) of the bronchi; its inhibition leads to their relaxation, especially when interacting with stimulation of β2-adrenergic receptors. The double inhibition exposure can undoubtedly contribute to bronchodilator and anti-inflammatory activity. Evaluation of zardaverine, benzafentrin, tolafentrin and pumafentrin was carried out in volunteers, but without introduction into the clinic. Nevertheless, ensifenthrin, as the only dual PDE3/PDE4 inhibitor, has been proposed for the stage of clinical development in the treatment of BA, COPD, and cystic fibrosis, taking into account its high affinity for PDE3 (3440 times more against PDE4), mainly with a bronchodilatory effect, more effective in a synergistic combination with β2-agonists or anticholinergics. Dual inhibitors of PDE4/PDE7: these isozymes are expressed in immune cells through the control of cAMP, their double inhibition reduces bronchial hypersensitivity, production of proinflammatory interleukins in the experiment, which retains interest in a number of compounds – PDE4/PDE7 inhibitors. Dual PDE4/PDE5 inhibitors: especially attractive for their multilevel effect on bronchi, reduction of pulmonary hypertension and inflammation, lung remodeling. Thus, the combination of a PDE5 inhibitor (tadalafil) and PDE4 (roflumilast) improves these parameters in preclinical data, but their clinical development is questionable.
Agonists of bitter taste receptors – a group of 25 proteins – in addition to the tongue, are found in the respiratory epithelium and in the SM, where their three subtypes (10, 14 and 31) are highly expressed. The activation effect exceeds the relaxation of β-agonists by 2 times, with a high concentration of Ca2+ and relaxation, the search for agonists of this class against the background of a small amount of clinical data continues. Agonists of the E-prostanoid receptor-4 (PGE2): activation of the PGE2 receptor stimulates cAMP, the synthesis of several compounds of this type can relax the bronchi and in histamine spasm, can be interpreted as its key role, when administered orally, although it has not been tested in humans.
Inhibitors of Rh0 kinase: these protein kinases are highly represented in contractile SM, the RhoA/ROCK pathway regulates phosphatases of myosin light chains, two molecules have been proposed for clinical use – fasudil and ripasudil (Japan, China), but they have not yet been used in pulmonology for obstruction. Calcilytics: the G-protein receptor (guanine nucleotide) is associated with extracellular Ca2+, regulates the contraction in asthma and is elevated in sputum, also potential bronchodilators for the strategy. Among the new targets, PPAR-agonists should be named, although they affect lipid and glucose metabolism, are able to relax SM in asthma, their effects are debated. Agonists of the receptor relaxin-1 or -2 (studies of serelaxin) as a dilator and antifibrotic drug have demonstrated the generation of relaxing epithelial factors, but T1/2 only 10-20 min requires continuous infusion of 48 h, their conjugation with fatty acids creates a long-acting relaxin-2 analogue. NO donors can be useful, but the release of NO activates superoxide, induces tolerance, therefore these mechanisms are clarified in the experiment. Pepducins – lipidated peptides, through binding to G-proteins or arrestins, can also offer new strategies for signaling responses (biased agonists).
Conclusions. New possibilities for the development of bronchodilators are in the preclinical phase, but they can become an addition to the modern optimal therapy for bronchial obstruction.
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Yougbare, Issaka. "Alterations of cAMP/cGMP Signaling Pathways in Lupus Nephritis." Journal of Nephrological Science 3, no. 2 (June 8, 2021): 8–12. http://dx.doi.org/10.29245/2767-5149/2021/2.1112.
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Systemic lupus erythematosus (SLE) is an autoimmune disease with a broad spectrum of clinical manifestations, but its pathogenesis remains fairly understood. Cyclic nucleotide signaling pathways in immune cells and kidney are emerging as cellular mechanisms governing SLE disease progression. Upregulations of cGMP/cAMP metabolism lead to lupus nephritis and abnormal kidney remodeling/hypertrophy. PDE4 family remains the major cAMP hydrolyzing enzyme as PDE1 is responsible for cGMP breakdown in kidney. SLE disease progression to lupus nephritis is correlated with increase PDE1 and PDE4 activities resulting in lower cyclic nucleotide levels in kidney. Administration of Nimodipine, a PDE1 inhibitor prevents the lymphoproliferative phenotype and exert anti-proliferative effects on mesangial cells while PDE4 inhibitor NCS 613 prevents inflammatory cytokines release, immune complex deposition, and nephritis in MRL/lpr lupus prone mice. In this review, we highlight recent findings of alterations of cyclic nucleotide signaling pathways in lupus nephritis. Given the role of cAMP/cGMP signaling in kidney function, dual inhibition of PDE1 and PDE4 may represent a promising therapeutic approach to tackle lupus nephritis.
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Freund, Yvonne, Chen Dong, Charlotte Virtucio-Frates, Fernando Rock, Yvonne Mak, Yasheen Zhou, Lee Zane, and Kurt Jarnagin. "AN2728, a new boron-based topical anti-inflammatory agent, inhibits phosphodiesterase 4 (IRC4P.611)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 57.28. http://dx.doi.org/10.4049/jimmunol.194.supp.57.28.
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Abstract The novel boron-containing compound, AN2728, is being investigated in phase 3 trials for atopic dermatitis treatment. It exerts its anti-inflammatory effect by inhibiting phosphodiesterase-4 (PDE4), which catalyzes the breakdown of cAMP to AMP. AN2728 competes with cAMP to inhibit the PDE4B1-catalytic domain with Ki of 173±26 nM; thus AN2728 interacts at the enzyme-active site. The X-ray structure of PDE4B-catalytic domain with AN2728 and its structural relative AN2898 reveals that the boron atom interacts with the bimetal center and occupies a position in the catalytic site similar to that of the cAMP phosphate. AN2728 has good affinity across PDE4 gene products A-D. Its selective affinity for PDE4 is 4-10-fold greater than its affinity for PDE1, 2, 3A, 6, or 7B. It is inactive on PDE3B, 5, 7A1, and 8-11. AN2728 activity increases intracellular cAMP and activates PKA, followed by phosphorylation and negative regulation of various cytokine transcription factors. AN2728 inhibits production of specific cytokines with a pattern similar to that of other established PDE4 inhibitors and distinct from those of a glucocorticoid and calcineurin inhibitor. To investigate reactivity against other targets, AN2728 was tested against a set of 50 receptors and ligand-gated ion channels for inhibition at 10 µM. Inhibition was <25% for all receptors; thus, AN2728 is specific for PDE4 and appears to exert an anti-inflammatory effect through inhibition of inflammatory cytokine production.
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Matsumoto, Takayuki, Tsuneo Kobayashi, and Katsuo Kamata. "Alterations in EDHF-type relaxation and phosphodiesterase activity in mesenteric arteries from diabetic rats." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 1 (July 2003): H283—H291. http://dx.doi.org/10.1152/ajpheart.00954.2002.
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In isolated superior mesenteric artery rings from age-matched control rats and streptozotocin (STZ)-induced diabetic rats, we investigated the role of cAMP in endothelium-derived hyperpolarizing factor (EDHF)-type relaxation. The ACh-induced EDHF-type relaxation was significantly weaker in STZ-induced diabetic rats than in control rats, and in both groups of rats it was attenuated by 18α-glycyrrhetinic acid (18α-GA), an inhibitor of gap junctions, and enhanced by IBMX, a cAMP-phosphodiesterase (PDE) inhibitor. These enhanced EDHF-type responses were very similar in magnitude between diabetic and age-matched control rats. The EDHF-type relaxation was enhanced by cilostamide, a PDE3-selective inhibitor, but not by Ro 20–1724, a PDE4-selective inhibitor. The expression levels of the mRNAs and proteins for two cAMP PDEs (PDE3A, PDE3B) were significantly increased in STZ-induced diabetic rats, but those for PDE4D were not. We conclude that the impairment of EDHF-type relaxations in STZ-induced diabetic rats may be attributed to a reduction in the action of cAMP via increased PDE activity.
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Cedervall, Peder, Ann Aulabaugh, Kieran F. Geoghegan, Thomas J. McLellan, and Jayvardhan Pandit. "Engineered stabilization and structural analysis of the autoinhibited conformation of PDE4." Proceedings of the National Academy of Sciences 112, no. 12 (March 9, 2015): E1414—E1422. http://dx.doi.org/10.1073/pnas.1419906112.
Full textAbstract:
Phosphodiesterase 4 (PDE4) is an essential contributor to intracellular signaling and an important drug target. The four members of this enzyme family (PDE4A to -D) are functional dimers in which each subunit contains two upstream conserved regions (UCR), UCR1 and -2, which precede the C-terminal catalytic domain. Alternative promoters, transcriptional start sites, and mRNA splicing lead to the existence of over 25 variants of PDE4, broadly classified as long, short, and supershort forms. We report the X-ray crystal structure of long form PDE4B containing UCR1, UCR2, and the catalytic domain, crystallized as a dimer in which a disulfide bond cross-links cysteines engineered into UCR2 and the catalytic domain. Biochemical and mass spectrometric analyses showed that the UCR2-catalytic domain interaction occurs in trans, and established that this interaction regulates the catalytic activity of PDE4. By elucidating the key structural determinants of dimerization, we show that only long forms of PDE4 can be regulated by this mechanism. The results also provide a structural basis for the long-standing observation of high- and low-affinity binding sites for the prototypic inhibitor rolipram.
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Varona, Saray, Lídia Puertas, María Galán, Mar Orriols, Laia Cañes, Silvia Aguiló, Mercedes Camacho, et al. "Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAA." Antioxidants 10, no. 3 (March 16, 2021): 460. http://dx.doi.org/10.3390/antiox10030460.
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Abdominal aortic aneurysm (AAA) is a common life-threatening condition characterized by exacerbated inflammation and the generation of reactive oxygen species. Pharmacological treatments to slow AAA progression or to prevent its rupture remain a challenge. Targeting phosphodiesterase 4 (PDE4) has been verified as an effective therapeutic strategy for an array of inflammatory conditions; however, no studies have assessed yet PDE4 in AAA. Here, we used angiotensin II (AngII)-infused apolipoprotein E deficient mice to study the involvement of the PDE4 subfamily in aneurysmal disease. PDE4B but not PDE4D was upregulated in inflammatory cells from both experimental and human AAA. The administration of the PDE4 selective inhibitor rolipram (3 mg/kg/day) to AngII-challenged mice (1000 ng/kg bodyweight/min) protected against AAA formation, limiting the progressive increase in the aortic diameter without affecting the blood pressure. The drug strongly attenuated the rise in vascular oxidative stress (superoxide anion) induced by AngII, and decreased the expression of inflammatory markers, as well as the recruitment of macrophages (MAC3+), lymphocytes (CD3+), and neutrophils (ELANE+) into the vessel wall. Rolipram also normalized the vascular MMP2 expression and MMP activity, preserving the elastin integrity and improving the vascular remodelling. These results point to PDE4B as a new therapeutic target for AAA.
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Phillips, Peter G., Lu Long, Martin R. Wilkins, and Nicholas W. Morrell. "cAMP phosphodiesterase inhibitors potentiate effects of prostacyclin analogs in hypoxic pulmonary vascular remodeling." American Journal of Physiology-Lung Cellular and Molecular Physiology 288, no. 1 (January 2005): L103—L115. http://dx.doi.org/10.1152/ajplung.00095.2004.
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We investigated the effects of prostacyclin analogs and isoform-selective phosphodiesterase (PDE) inhibitors, alone and in combination, on pulmonary vascular remodeling in vitro and in vivo. Vascular smooth muscle cells (VSMC) isolated from pulmonary (proximal and distal) and systemic circulations demonstrated subtle variations in expression of PDE isoform mRNA. However, using biochemical assays, we found PDE3 and PDE4 isoforms to be responsible for the majority of cAMP hydrolysis in all VSMC. In growth assays, the prostacyclin analogs cicaprost and iloprost inhibited mitogen-induced proliferation of VSMC in a cAMP-dependent manner. In addition, isoform-selective antagonists of PDEs 1, 3, or 4 inhibited VSMC proliferation, an effect that synergized with the effect of prostacyclin analogs. The inhibitory effects were greater in cells isolated from pulmonary circulation. In an in situ perfused rat lung preparation, administration of prostacyclin analogs or the PDE inhibitors vinpocetine (PDE1), cilostamide (PDE3), or rolipram (PDE4), but not EHNA (PDE2), attenuated acute hypoxic vasoconstriction (HPV). Combinations of agents led to a greater reduction in HPV. Furthermore, during exposure to hypoxia for 13 days, Wistar rats were treated with iloprost, rolipram, cilostamide, or combinations of these agents. Compared with normoxic controls, hypoxic animals developed pulmonary hypertension and distal pulmonary artery muscularization. These parameters were attenuated by iloprost+cilostamide, iloprost+rolipram, and cilostamide+rolipram but were not significantly affected by single agents. Together, these findings provide a greater understanding of the role of cAMP PDEs in VSMC proliferation and provide rationale for combined use of prostacylcin analogs plus PDE3/4 inhibitors in treatment of pulmonary vascular remodeling.
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HOUSLAY, Miles D., and David R. ADAMS. "PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization." Biochemical Journal 370, no. 1 (February 15, 2003): 1–18. http://dx.doi.org/10.1042/bj20021698.
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cAMP is a second messenger that controls many key cellular functions. The only way to inactivate cAMP is to degrade it through the action of cAMP phosphodiesterases (PDEs). PDEs are thus poised to play a key regulatory role. PDE4 cAMP-specific phosphodiesterases appear to have specific functions with selective inhibitors serving as potent anti-inflammatory agents. The recent elucidation of the structure of the PDE4 catalytic unit allows for molecular insight into the mode of catalysis as well as substrate and inhibitor selectivity. The four PDE4 genes encode over 16 isoforms, each of which is characterized by a unique N-terminal region. PDE4 isoforms play a pivotal role in controlling functionally and spatially distinct pools of cAMP by virtue of their unique intracellular targeting. Targeting occurs by association with proteins, such as arrestins, SRC family tyrosyl kinases, A-kinase anchoring proteins ('AKAPs') and receptor for activated C kinase 1 ('RACK1'), and, in the case of isoform PDE4A1, by a specific interaction (TAPAS-1) with phosphatidic acid. PDE4 isoforms are ‘designed’ to be regulated by extracellular-signal-related protein kinase (ERK), which binds to anchor sites on the PDE4 catalytic domain that it phosphorylates. The upstream conserved region 1 (UCR1) and 2 (UCR2) modules that abut the PDE4 catalytic unit confer regulatory functions by orchestrating the functional outcome of phosphorylation by cAMP-dependent protein kinase ('PKA') and ERK. PDE4 enzymes stand at a crossroads that allows them to integrate various signalling pathways with that of cAMP in spatially distinct compartments.
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Liang, Cheng-Guang, Li-Jun Huo, Zhi-Sheng Zhong, Da-Yuan Chen, Heide Schatten, and Qing-Yuan Sun. "Cyclic Adenosine 3′,5′-Monophosphate-Dependent Activation of Mitogen-Activated Protein Kinase in Cumulus Cells Is Essential for Germinal Vesicle Breakdown of Porcine Cumulus-Enclosed Oocytes." Endocrinology 146, no. 10 (October 1, 2005): 4437–44. http://dx.doi.org/10.1210/en.2005-0309.
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MAPK plays an important role during meiotic maturation in mammalian oocytes, whereas the necessity of MAPK during meiotic resumption in porcine oocytes is still controversial. Here, by applying the method of ultracentrifugation to move the opaque lipid droplets to the edge of the oocyte, therefore allowing clear visualization of porcine germinal vesicles, oocytes just before germinal vesicle breakdown (GVBD) and those that had just undergone GVBD were selected for the assay of MAPK activation. Our results showed that phosphorylation of MAPK in oocytes occurred after GVBD in all three different culture models: spontaneous maturation model, inhibition-induction maturation model, and normal maturation model. Moreover, we found that activation of MAPK in cumulus cells but not in oocytes was essential for GVBD in cumulus-enclosed oocytes. Then the cross-talk between cAMP and MAPK in cumulus cells was investigated by using cell-type-specific phosphodiesterase (PDE) isoenzyme inhibitors. Our results showed that PDE3 subtype existed in oocytes, whereas PDE4 subtype existed in cumulus cells. PDE3 inhibitor prevented meiotic resumption of oocytes, whereas PDE4 inhibitor enhanced the ability of FSH or forskolin to activate MAPK in cumulus cells. We propose that increased cAMP resulting from inhibition of PDE3 in oocytes blocks GVBD, whereas increased cAMP resulting from inhibition of PDE4 activates MAPK pathway in cumulus cells, which is essential for GVBD induction.
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Nunez, Francisco J., Nancy A. Schulte, David M. Fogel, Joel Michalski, Stephen I. Rennard, Raymond B. Penn, Myron L. Toews, and Rennolds S. Ostrom. "Agonist-specific desensitization of PGE2-stimulated cAMP signaling due to upregulated phosphodiesterase expression in human lung fibroblasts." Naunyn-Schmiedeberg's Archives of Pharmacology 393, no. 5 (December 28, 2019): 843–56. http://dx.doi.org/10.1007/s00210-019-01800-5.
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AbstractPulmonary fibrosis is characterized by fibroblasts persisting in an activated form, producing excessive fibrous material that destroys alveolar structure. The second messenger molecule cyclic 3′,5′-adenosine monophosphate (cAMP) has antifibrotic properties, and prostaglandin E2 (PGE2) can stimulate cAMP production through prostaglandin E (EP)2 and EP4 receptors. Although EP receptors are attractive therapeutic targets, the effects of long-term exposure to PGE2 have not been characterized. To determine the effects of long-term exposure of lung fibroblasts to PGE2, human fetal lung (HFL)-1 cells were treated for 24 h with 100 nM PGE2 or other cAMP-elevating agents. cAMP levels stimulated by acute exposure to PGE2 were measured using a fluorescent biosensor. Pretreatment for 24 h with PGE2 shifted the concentration-response curve to PGE2 rightward by approximately 22-fold but did not affect responses to the beta-adrenoceptor agonist isoproterenol. Neither isoproterenol nor forskolin pretreatment altered PGE2 responses, implying that other cAMP-elevating agents do not induce desensitization. Use of EP2- and EP4-selective agonists and antagonists suggested that PGE2-stimulated cAMP responses in HFL-1 cells are mediated by EP2 receptors. EP2 receptors are resistant to classical mechanisms of agonist-specific receptor desensitization, so we hypothesized that increased PDE activity mediates the loss of signaling after PGE2 pretreatment. PGE2 treatment upregulated messenger RNA for PDE3A, PDE3B, PDE4B, and PDE4D and increased overall PDE activity. The PDE4 inhibitor rolipram partially reversed PGE2-mediated desensitization and PDE4 activity was increased, but rolipram did not alter responses to isoproterenol. The PDE3 inhibitor cilostazol had minimal effect. These results show that long-term exposure to PGE2 causes agonist-specific desensitization of EP2 receptor-stimulated cAMP signaling through the increased expression of PDE isozymes, most likely of the PDE4 family.
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Chao, Pin-Chun, and Kirk L. Hamilton. "Genistein stimulates electrogenic Cl− secretion via phosphodiesterase modulation in the mouse jejunum." American Journal of Physiology-Cell Physiology 297, no. 3 (September 2009): C688—C698. http://dx.doi.org/10.1152/ajpcell.00152.2009.
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Previously, we demonstrated that genistein stimulated Cl− secretion in the mouse jejunum (Baker MJ and Hamilton KL, Am J Physiol Cell Physiol 287: C1636–C1645, 2004); however, the mode of action of genistein still remains unclear. Here, we examined the activation of Cl− secretion by the modulation of phosphodiesterases (PDEs) by genistein (75 μM) in the mouse jejunum with the Ussing short-circuit current ( Isc) technique. Drugs tested included theophylline (10 mM), a nonspecific PDE inhibitor; 8-methoxymethyl-3-isobutyl-1-methylxanthine (8-MM-IBMX; 100 μM), erythro-9-(2-hydroxyl-3-nonyl)-adenine (EHNA; 40 μM), milrinone (100 μM), and rolipram (40 and 100 μM), which are specific inhibitors of PDE1–PDE4, respectively. Theophylline stimulated a bumetanide-sensitive Isc, indicative of Cl− secretion, and abolished genistein's stimulatory action on Isc. Neither 8-MM-IBMX nor EHNA altered the basal Isc nor did these PDE inhibitors affect the stimulatory action of genistein on the Isc of the mouse jejunum. Rolipram had no effect on basal Isc, but it reduced the genistein-stimulated Isc compared with time-matched control tissues. Milrinone stimulated a concentration-dependent increase in Isc. Bumetanide (10 μM) inhibited 60 ± 4% of milrinone-induced Isc. Pretreating tissues with milrinone prevented genistein from stimulating Isc, and pretreatment with genistein reduced the effect of milrinone on Isc. H89 (50 μM), a PKA inhibitor, reduced the milrinone-stimulated Isc. Likewise, H89 reduced the genistein-stimulated Isc. Here, we demonstrate, for the first time, that genistein activates Cl− secretion of the mouse jejunum via inhibition of a PDE3-dependent pathway.
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Yang, Fan, Rachita K. Sumbria, Dong Xue, Chuanhui Yu, Dan He, Shuo Liu, Annlia Paganini-Hill, and Mark Fisher. "Effects of PDE4 Pathway Inhibition in Rat Experimental Stroke." Journal of Pharmacy & Pharmaceutical Sciences 17, no. 3 (August 8, 2014): 362. http://dx.doi.org/10.18433/j3s02v.
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PURPOSE: The first genomewide association study indicated that variations in the phosphodiesterase 4D (PDE4D) gene confer risk for ischemic stroke. However, inconsistencies among the studies designed to replicate the findings indicated the need for further investigation to elucidate the role of the PDE4 pathway in stroke pathogenesis. Hence, we studied the effect of global inhibition of the PDE4 pathway in two rat experimental stroke models, using the PDE4 inhibitor rolipram. Further, the specific role of the PDE4D isoform in ischemic stroke pathogenesis was studied using PDE4D knockout rats in experimental stroke. METHODS: Rats were subjected to either the ligation or embolic stroke model and treated with rolipram (3mg/kg; i.p.) prior to the ischemic insult. Similarly, the PDE4D knockout rats were subjected to experimental stroke using the embolic model. RESULTS: Global inhibition of the PDE4 pathway using rolipram produced infarcts that were 225% (p<0.01) and 138% (p<0.05) of control in the ligation and embolic models, respectively. PDE4D knockout rats subjected to embolic stroke showed no change in infarct size compared to wild-type control. CONCLUSIONS: Despite increase in infarct size after global inhibition of the PDE4 pathway with rolipram, specific inhibition of the PDE4D isoform had no effect on experimental stroke. These findings support a role for the PDE4 pathway, independent of the PDE4D isoform, in ischemic stroke pathogenesis. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
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Li, Xiang, Suryakiran Vadrevu, Allan Dunlop, Jon Day, Noopur Advant, Jessica Troeger, Enno Klussmann, et al. "Selective SUMO modification of cAMP-specific phosphodiesterase-4D5 (PDE4D5) regulates the functional consequences of phosphorylation by PKA and ERK." Biochemical Journal 428, no. 1 (April 28, 2010): 55–65. http://dx.doi.org/10.1042/bj20091672.
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Enzymes from the PDE (phosphodiesterase) 4 cAMP-specific PDE family are crucial for the maintenance of compartmentalized cAMP responses in many cell types. Regulation of PDE activity can be achieved via post-translational modification such as phosphorylation by ERK (extracellular-signal-regulated kinase) MAPKs (mitogen-activated protein kinases) and PKA (protein kinase A). In the present paper, we report for the first time that PDE4 isoforms from the PDE4A and PDE4D subfamilies can be selectively modified by SUMO (small ubiquitin-related modifier). We have identified a single SUMO site within a consensus tetrapeptide motif, ΨKXE (where Ψ represents a hydrophobic residue), which lies in the catalytic unit of these enzymes. SUMO modification of PDE4 at this site was observed upon overexpression of the SUMO E3 ligase PIASy [protein inhibitor of activated STAT (signal transducer and activator of transcription) Y] in HEK (human embryonic kidney)-293 cells and we identify PIASy as a novel binding partner for long PDE4 isoforms. Site-directed mutagenesis of the acceptor lysine residue ablated conjugation of PDE4 with SUMO, suggesting the presence of a single SUMO site in the first subdomain of the conserved PDE4 catalytic unit. This observation was supported by both cell-free in vitro SUMOylation assays and analysis of SUMOylated spot-immobilized peptide arrays. SUMO modification of long PDE4 isoforms serves to augment their activation by PKA phosphorylation and repress their inhibition by ERK phosphorylation. Following ligation of β-adrenergic receptors, SUMOylation of PDE4 isoforms sufficiently amplified PKA-stimulated PDE4 activity to reduce markedly the PKA phosphorylation status of the β2-adrenergic receptor. These results highlight a new means whereby cells might achieve the selective regulation of the activity of cAMP-specific PDE4 enyzmes.
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Meyers, John, and Adam Lerner. "PDE4 Inhibitors Enhance DNA Damage-Induced Apoptosis In CLL." Blood 116, no. 21 (November 19, 2010): 2902. http://dx.doi.org/10.1182/blood.v116.21.2902.2902.
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Abstract Abstract 2902 Treatment of primary chronic lymphocytic leukemia (CLL) cells with PDE4 inhibitors induces apoptosis while comparable treatment of primary human T and B cells from healthy donors does not. PDE4 inhibitor treatment also augments glucocorticoid-induced apoptosis in CLL cells. We now report that PDE4 inhibitor treatment enhances CLL apoptosis induced by DNA damage. Using drug combination analysis, treatment with etoposide and rolipram resulted in a greater than additive apoptotic effect than predicted by a Loewe additivity model at many dose combinations. In order to directly address the role of DNA damage and rule out effects on drug uptake and efflux, we next examined the ability of PDE4 inhibitors to modulate gamma-irradiation-induced apoptosis in CLL. While most patients demonstrated in vitro sensitivity to rolipram and gamma irradiation, a small subset of patients, including those known to be p53 mutant, that lacked a substantial response to ionizing radiation also lacked sensitivity to rolipram (p < 0.01). Those patients with intact sensitivity to radiation, demonstrated at least an additive, or greater-than-additive at some doses, effect on apoptosis when PDE4 inhibitor treatment was combined with gamma irradiation treatment (p < 0.05 at 1 Gy and 20 mM rolipram). As judged by comet assays, gamma radiation-induced DNA double stranded breaks were repaired within one hour of induction regardless of exposure to rolipram. As judged by Western analysis and flow cytometry, the kinetics of gamma irradiation-induced H2AX phosphorylation, a marker for DNA damage, were not altered by addition of rolipram in a manner that correlated with apoptosis. Finally, rolipram treatment did not further augment levels of p53, p21cip, or phospho-Chk2. These results suggest that PDE4 inhibitors did not alter double strand DNA break repair nor alter upstream radiation-induced p53-mediated signaling events. As PDE4 inhibitors are known to induce CLL apoptosis through a mitochondrial pathway, our current studies are focused on identifying the mechanism by which DNA damage and PDE4 inhibitor signaling pathways converge at the mitochondrion to enhance apoptosis. Regardless of the precise mechanism by which these supra-additive apoptotic effects occur, our study adds credence to the concept that PDE4 inhibitors may prove to be important sensitizing adjuvants in the treatment of human B cell malignancies. Disclosures: No relevant conflicts of interest to declare.
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Świerczek, Artur, Krzysztof Pociecha, Hanna Plutecka, Marietta Ślusarczyk, Grażyna Chłoń-Rzepa, and Elżbieta Wyska. "Pharmacokinetic/Pharmacodynamic Evaluation of a New Purine-2,6-Dione Derivative in Rodents with Experimental Autoimmune Diseases." Pharmaceutics 14, no. 5 (May 19, 2022): 1090. http://dx.doi.org/10.3390/pharmaceutics14051090.
Full textAbstract:
Current treatment strategies of autoimmune diseases (ADs) display a limited efficacy and cause numerous adverse effects. Phosphodiesterase (PDE)4 and PDE7 inhibitors have been studied recently as a potential treatment of a variety of ADs. In this study, a PK/PD disease progression modeling approach was employed to evaluate effects of a new theophylline derivative, compound 34, being a strong PDE4 and PDE7 inhibitor. Activity of the studied compound against PDE1 and PDE3 in vitro was investigated. Animal models of multiple sclerosis (MS), rheumatoid arthritis (RA), and autoimmune hepatitis were utilized to assess the efficacy of this compound, and its pharmacokinetics was investigated in mice and rats. A new PK/PD disease progression model of compound 34 was developed that satisfactorily predicted the clinical score-time courses in mice with experimental encephalomyelitis that is an animal model of MS. Compound 34 displayed a high efficacy in all three animal models of ADs. Simultaneous inhibition of PDE types located in immune cells may constitute an alternative treatment strategy of ADs. The PK/PD encephalomyelitis and arthritis progression models presented in this study may be used in future preclinical research, and, upon modifications, may enable translation of the results of preclinical investigations into the clinical settings.