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Keywords = cyclic AMP phosphodiesterases

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12 pages, 2241 KiB  
Article
PDE Inhibitors and Autophagy Regulators Modulate CRE-Dependent Luciferase Activity in Neuronal Cells from the Mouse Suprachiasmatic Nucleus
by Erik Maronde and Abdelhaq Rami
Molecules 2025, 30(15), 3229; https://doi.org/10.3390/molecules30153229 - 1 Aug 2025
Viewed by 169
Abstract
Background: Signaling pathways like those depending on cAMP/PKA, calcium/calmodulin/CaMK, MEK-1/MAPK or PI3K/Akt have been described to modulate suprachiasmatic nucleus (SCN) neuronal signaling via influencing transcription factors like CREB. Here, we analyzed the effect of cyclic nucleotide phosphodiesterase inhibitors and structurally similar substances commonly [...] Read more.
Background: Signaling pathways like those depending on cAMP/PKA, calcium/calmodulin/CaMK, MEK-1/MAPK or PI3K/Akt have been described to modulate suprachiasmatic nucleus (SCN) neuronal signaling via influencing transcription factors like CREB. Here, we analyzed the effect of cyclic nucleotide phosphodiesterase inhibitors and structurally similar substances commonly used as autophagy modulators on a cell line stably expressing a cyclic nucleotide element-driven luciferase reporter. Methods: We used an SCN cell line stably transfected with a CRE-luciferase reporter (SCNCRE) to evaluate signaling and vitality responses to various isoform-selective PDE inhibitors and autophagy modulators to evaluate the mechanism of action of the latter. Results: In this study the different impacts of common PDE inhibitors and autophagy modulators on CRE-luciferase activity applied alone and in combination with known CRE-luciferase activating agents showed that (1) PDE3, 4 and 5 are present in SCNCRE cells, with (2) PDE3 being the most active and (3) the autophagy inhibitor 3-Methyladenin (3-MA) displaying PDE inhibitor-like behavior. Conclusions: Experiments provide evidence that, in addition to the extracellular signaling pathways components shown before to be involved in CRE-luciferase activity regulation like cAMP analogs, adenylate cyclase activators and beta-adrenoceptor agonists, cyclic nucleotide metabolism as realized by phosphodiesterase activity, or molecule/agents influencing processes like autophagy or inflammation, modulate transcriptional CRE-dependent activity in these cells. Specifically, we provide evidence that the autophagy inhibitor 3-MA, given that PDEs are expressed, may also act as a PDE inhibitor and inducer of CRE-mediated transcriptional activity. Full article
(This article belongs to the Special Issue Exploring Bioactive Organic Compounds for Drug Discovery, 2nd Edition)
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22 pages, 1370 KiB  
Review
Roles of Cyclic Nucleotide Phosphodiesterases in Signal Transduction Pathways in the Nematode Caenorhabditis elegans
by Kranti K. Galande and Rick H. Cote
Cells 2025, 14(15), 1174; https://doi.org/10.3390/cells14151174 - 30 Jul 2025
Viewed by 689
Abstract
Cyclic nucleotide signaling pathways play essential roles in the physiology of the nematode Caenorhabditis elegans, influencing processes such as reproduction, environmental sensing, and cellular homeostasis. The intracellular levels of cAMP and cGMP are tightly regulated by their synthesis by adenylyl and guanylyl [...] Read more.
Cyclic nucleotide signaling pathways play essential roles in the physiology of the nematode Caenorhabditis elegans, influencing processes such as reproduction, environmental sensing, and cellular homeostasis. The intracellular levels of cAMP and cGMP are tightly regulated by their synthesis by adenylyl and guanylyl cyclases and their degradation catalyzed by 3′,5′-cyclic nucleotide phosphodiesterases (PDEs). Mammals possess eleven PDE families (PDE1 through PDE11), whereas nematode genomes contain six PDE genes orthologous to six of the mammalian PDE families. Despite their evolutionary conservation, the signaling pathways, regulatory mechanisms, and enzymatic properties of nematode PDEs remain incompletely understood. This review synthesizes current knowledge on the regulation of cyclic nucleotide levels in C. elegans, highlighting how dysregulation of nematode PDEs affects a wide range of physiological and behavioral processes, including sensory transduction, development, and locomotion. Full article
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20 pages, 1116 KiB  
Review
Repurposing Terbutaline and Milrinone for Cancer Therapy: A Comprehensive Review
by Eduarda Ribeiro and Nuno Vale
Future Pharmacol. 2025, 5(3), 38; https://doi.org/10.3390/futurepharmacol5030038 - 11 Jul 2025
Viewed by 324
Abstract
Cancer remains a leading cause of mortality worldwide, necessitating innovative therapeutic strategies. Drug repurposing offers a cost-effective approach to cancer treatment by identifying new anticancer applications for existing drugs. Terbutaline, a β2-adrenergic receptor agonist, and Milrinone, a phosphodiesterase-3 inhibitor, are traditionally used as [...] Read more.
Cancer remains a leading cause of mortality worldwide, necessitating innovative therapeutic strategies. Drug repurposing offers a cost-effective approach to cancer treatment by identifying new anticancer applications for existing drugs. Terbutaline, a β2-adrenergic receptor agonist, and Milrinone, a phosphodiesterase-3 inhibitor, are traditionally used as positive inotropic agents but have shown potential anticancer effects. This review explores their mechanisms of action in cancer, focusing on their roles in modulating cyclic adenosine monophosphate (cAMP) levels, oxidative stress, and the tumor microenvironment. Terbutaline influences β2-adrenergic signaling, impacting cell proliferation, angiogenesis, and immune evasion. Milrinone, through PDE3 inhibition, elevates cAMP, promoting apoptosis and reducing tumor growth. Both agents exhibit anti-inflammatory and anti-angiogenic properties, suggesting their potential as adjuvant therapies in oncology. Despite promising preclinical data, clinical validation is required to confirm their efficacy and safety in cancer patients. This review highlights the therapeutic promise of repurposing Terbutaline and Milrinone, emphasizing the need for further research to optimize their application in cancer therapy. Full article
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15 pages, 2238 KiB  
Article
The Phosphodiesterase 4 Inhibitor Roflumilast Protects Microvascular Endothelial Cells from Irradiation-Induced Dysfunctions
by Nathalie Guitard, Florent Raffin and François-Xavier Boittin
Cells 2025, 14(13), 1017; https://doi.org/10.3390/cells14131017 - 3 Jul 2025
Viewed by 378
Abstract
In endothelial cells, high-dose irradiation induces numerous dysfunctions including alteration in junctional proteins such as VE-Cadherin, apoptosis and enhanced adhesiveness linked to overexpression of adhesion molecules like Intercellular Adhesion Molecule 1 (ICAM-1). Such endothelial dysfunctions can lead to altered tissue perfusion, development of [...] Read more.
In endothelial cells, high-dose irradiation induces numerous dysfunctions including alteration in junctional proteins such as VE-Cadherin, apoptosis and enhanced adhesiveness linked to overexpression of adhesion molecules like Intercellular Adhesion Molecule 1 (ICAM-1). Such endothelial dysfunctions can lead to altered tissue perfusion, development of tissue inflammation through increased endothelial permeability, and ultimately organ damage. As intracellular cyclic AMP (cAMP) levels are known to control intercellular junctions or apoptosis in the endothelium, we investigated here the effect of the Phosphodiesterase 4 inhibitor Roflumilast, a drug increasing cAMP levels, on irradiation-induced endothelial dysfunctions in human pulmonary microvascular endothelial cells (HPMECs). Using continuous impedance measurements in confluent endothelial cell monolayers, Roflumilast was found to rapidly reinforce the endothelial barrier and to prevent irradiation-induced barrier disruption. In accordance, irradiation-induced alteration in membrane VE-Cadherin-composed adherens junctions was prevented by Roflumilast treatment after irradiation, which was correlated with its protective effect of the actin cytoskeleton. Post-irradiation treatment with Roflumilast also protected HPMECs from irradiation-induced late apoptosis, but was without effect on irradiation-induced ICAM-1 overexpression. Overall, our results indicate that the beneficial effects of Roflumilast after irradiation are linked to the strengthening/protection of the endothelial barrier and reduced apoptosis, suggesting that this medicine may be useful for the treatment of endothelial damages after exposure to a high dose of radiation. Full article
(This article belongs to the Section Cellular Pathology)
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29 pages, 1484 KiB  
Review
Adenylyl Cyclases as Therapeutic Targets in Neuroregeneration
by Julia Tomczak, Agnieszka Kapsa and Tomasz Boczek
Int. J. Mol. Sci. 2025, 26(13), 6081; https://doi.org/10.3390/ijms26136081 - 25 Jun 2025
Viewed by 844
Abstract
Adenylyl cyclases (ACs) are key regulators of cyclic adenosine monophosphate (cAMP) signaling—a pathway critical for neuroregeneration, synaptic plasticity, and neuronal survival. In both the central and peripheral nervous systems, injury-induced activation of ACs promotes axonal outgrowth and functional recovery through the stimulation of [...] Read more.
Adenylyl cyclases (ACs) are key regulators of cyclic adenosine monophosphate (cAMP) signaling—a pathway critical for neuroregeneration, synaptic plasticity, and neuronal survival. In both the central and peripheral nervous systems, injury-induced activation of ACs promotes axonal outgrowth and functional recovery through the stimulation of protein kinase A (PKA), exchange proteins directly activated by cAMP (Epac), and cAMP-response element-binding protein (CREB). Among the various AC isoforms, calcium-sensitive AC1, AC8, and AC5, as well as bicarbonate-responsive soluble AC (sAC), have emerged as crucial mediators of neuroplasticity and axon regeneration. These isoforms coordinate diverse cellular responses—including gene transcription, cytoskeletal remodeling, and neurotransmitter release—to metabolic, synaptic, and injury-related signals. Dysregulation of AC activity has been implicated in the pathophysiology of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, as well as in chronic pain syndromes. Pharmacological modulation of cAMP levels through AC activation, phosphodiesterase (PDE) inhibition, or pituitary adenylyl cyclase-activating polypeptide (PACAP) receptor signaling has shown therapeutic promise in preclinical models by enhancing neurogenesis, remyelination, and synaptic repair. Conversely, targeted inhibition of specific AC isoforms, particularly AC1, has demonstrated efficacy in reducing maladaptive plasticity and neuropathic pain. This review highlights the diverse roles of ACs in neuronal function and injury response and discusses emerging strategies for their therapeutic targeting. Full article
(This article belongs to the Special Issue Latest Review Papers in Molecular Neurobiology 2025)
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24 pages, 1312 KiB  
Review
Targeting Phosphodiesterase 4 in Gastrointestinal and Liver Diseases: From Isoform-Specific Mechanisms to Precision Therapeutics
by Can Chen, Mei Liu and Xiang Tao
Biomedicines 2025, 13(6), 1285; https://doi.org/10.3390/biomedicines13061285 - 23 May 2025
Viewed by 834
Abstract
Phosphodiesterase 4 (PDE4) serves as a crucial regulator of cyclic adenosine monophosphate (cAMP) signaling and has been identified as a significant therapeutic target for inflammatory and metabolic disorders impacting the gastrointestinal (GI) tract and liver. Although pan-PDE4 inhibitors hold therapeutic promise, their clinical [...] Read more.
Phosphodiesterase 4 (PDE4) serves as a crucial regulator of cyclic adenosine monophosphate (cAMP) signaling and has been identified as a significant therapeutic target for inflammatory and metabolic disorders impacting the gastrointestinal (GI) tract and liver. Although pan-PDE4 inhibitors hold therapeutic promise, their clinical use has been constrained by dose-dependent adverse effects. Recent progress in the development of isoform-specific PDE4 inhibitors, such as those selective for PDE4B/D, alongside targeted delivery systems like liver-targeting nanoparticles and probiotic-derived vesicles, is reshaping the therapeutic landscape. This review consolidates the latest insights into PDE4 biology, highlighting how the structural characterization of isoforms informs drug design. We conduct a critical evaluation of preclinical and clinical data across various diseases, including inflammatory bowel diseases (IBDs), alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), liver fibrosis, and digestive tract tumors, with an emphasis on mechanisms extending beyond cAMP modulation, such as microbiota remodeling and immune reprogramming. Additionally, we address challenges in clinical translation, including biomarker discovery and the heterogeneity of trial outcomes, and propose a roadmap for future research directions. Full article
(This article belongs to the Section Drug Discovery, Development and Delivery)
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16 pages, 2970 KiB  
Article
PDE10A Inhibition Reduces NLRP3 Activation and Pyroptosis in Sepsis and Nerve Injury
by Bradford C. Berk, Camila Lage Chávez and Chia George Hsu
Int. J. Mol. Sci. 2025, 26(10), 4498; https://doi.org/10.3390/ijms26104498 - 8 May 2025
Viewed by 929
Abstract
Cell death and inflammation are key innate immune responses, but excessive activation can cause tissue damage. The NLRP3 inflammasome is a promising target for reducing inflammation and promoting recovery. Immunometabolism regulates NLRP3 responses in neurological and inflammatory diseases through cyclic nucleotide signaling. Targeting [...] Read more.
Cell death and inflammation are key innate immune responses, but excessive activation can cause tissue damage. The NLRP3 inflammasome is a promising target for reducing inflammation and promoting recovery. Immunometabolism regulates NLRP3 responses in neurological and inflammatory diseases through cyclic nucleotide signaling. Targeting phosphodiesterases (PDEs), which hydrolyze cAMP and cGMP, offer a novel approach to mitigate inflammation. While 14 PDE inhibitors are FDA-approved, PDE10A’s role in NLRP3 inflammasome activation remains unclear. This study investigates the effects of PDE10A inhibition on inflammasome-driven inflammation using two PDE10A inhibitors, MP-10 and TP-10, in macrophage and animal models of sepsis and traumatic nerve injury. Our results show that PDE10A inhibition reduces inflammasome activation by preventing ASC speck formation and by lowering levels of cleaved caspase-1, gasdermin D, and IL-1β, which are key mediators of pyroptosis. In the sepsis model, MP-10 significantly reduced inflammation, decreased plasma IL-1β, alleviated thrombocytopenia, and improved organ damage markers. In the nerve injury model, PDE10A inhibition enhanced motor function recovery and reduced muscle atrophy-related gene expression. These findings suggest that PDE10A inhibition could be a promising therapeutic approach for inflammatory and neuromuscular injuries. Given MP-10’s established safety in human trials, Phase 2 clinical studies for sepsis and nerve injury are highly promising. Full article
(This article belongs to the Special Issue Roles of Inflammasomes in Inflammatory Responses and Human Diseases)
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27 pages, 7160 KiB  
Review
Inhibitors of Cyclic Dinucleotide Phosphodiesterases and Cyclic Oligonucleotide Ring Nucleases as Potential Drugs for Various Diseases
by Christopher S. Vennard, Samson Marvellous Oladeji and Herman O. Sintim
Cells 2025, 14(9), 663; https://doi.org/10.3390/cells14090663 - 30 Apr 2025
Viewed by 671
Abstract
The phosphodiester linkage is found in DNA, RNA and many signaling molecules, such as cyclic mononucleotide, cyclic dinucleotides (CDNs) and cyclic oligonucleotides (cONs). Enzymes that cleave the phosphodiester linkage (nucleases and phosphodiesterases) play important roles in cell persistence and fitness and have therefore [...] Read more.
The phosphodiester linkage is found in DNA, RNA and many signaling molecules, such as cyclic mononucleotide, cyclic dinucleotides (CDNs) and cyclic oligonucleotides (cONs). Enzymes that cleave the phosphodiester linkage (nucleases and phosphodiesterases) play important roles in cell persistence and fitness and have therefore become targets for various diseased states. While various inhibitors have been developed for nucleases and cyclic mononucleotide phosphodiesterases, and some have become clinical successes, there is a paucity of inhibitors of the recently discovered phosphodiesterases or ring nucleases that cleave CDNs and cONs. Inhibitors of bacterial c-di-GMP or c-di-AMP phosphodiesterases have the potential to be used as anti-virulence compounds, while compounds that inhibit the degradation of 3′,3′-cGAMP, cA3, cA4, cA6 could serve as antibiotic adjuvants as the accumulation of these second messengers leads to bacterial abortive infection. In humans, 2′3′-cGAMP plays critical roles in antiviral and antitumor responses. ENPP1 (the 2′3′-cGAMP phosphodiesterase) or virally encoded cyclic dinucleotide phosphodiesterases, such as poxin, however, blunt this response. Inhibitors of ENPP1 or poxin-like enzymes have the potential to be used as anticancer and antiviral agents, respectively. This review summarizes efforts made towards the discovery and development of compounds that inhibit CDN phosphodiesterases and cON ring nucleases. Full article
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17 pages, 514 KiB  
Review
Advancing Obstructive Airway Disease Treatment: Dual PDE3/4 Inhibition as a Therapeutic Strategy
by Rinzhin T. Sherpa, Cynthia J. Koziol-White and Reynold A. Panettieri
Cells 2025, 14(9), 659; https://doi.org/10.3390/cells14090659 - 30 Apr 2025
Viewed by 1487
Abstract
Obstructive airway diseases, including asthma and chronic obstructive pulmonary disease (COPD), evoke significant global health concerns manifested by airway inflammation and obstruction. Despite their differing origins, shared pathophysiological features and responses to therapeutic interventions highlight common molecular mechanisms. Standard treatments include inhaled bronchodilators, [...] Read more.
Obstructive airway diseases, including asthma and chronic obstructive pulmonary disease (COPD), evoke significant global health concerns manifested by airway inflammation and obstruction. Despite their differing origins, shared pathophysiological features and responses to therapeutic interventions highlight common molecular mechanisms. Standard treatments include inhaled bronchodilators, with combination therapies offering enhanced symptom control. Cyclic AMP (cAMP) plays a crucial role in airway relaxation. Phosphodiesterase (PDE) decreases cAMP levels, thereby attenuating the relaxation of airway smooth muscle, making it a promising therapeutic target. The balance between cAMP production and degradation is essential for regulating airway tone and function. PDE inhibitors for the treatment of obstructive airway diseases have suffered challenges, with adverse side effects of prospective inhibitors causing clinical failures. Efforts to develop PDE inhibitors with an improved safety profile could prove to be beneficial as an add-on treatment for severe asthma and COPD. The recent FDA approval of Ensifentrine, a dual PDE3/4 inhibitor, can significantly advance COPD management by improving bronchodilation, reducing inflammation, and lowering exacerbation rates with favorable safety outcomes. Full article
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22 pages, 5209 KiB  
Review
Diverse Roles of the Multiple Phosphodiesterases in the Regulation of Cyclic Nucleotide Signaling in Dictyostelium
by Pundrik Jaiswal and Alan R. Kimmel
Cells 2025, 14(7), 522; https://doi.org/10.3390/cells14070522 - 1 Apr 2025
Viewed by 765
Abstract
Dictyostelium is a unique model used to study the complex and interactive cyclic nucleotide signaling pathways that regulate multicellular development. Dictyostelium grow as individual single cells, but in the absence of nutrients, they initiate a multicellular developmental program. Central to this is secreted [...] Read more.
Dictyostelium is a unique model used to study the complex and interactive cyclic nucleotide signaling pathways that regulate multicellular development. Dictyostelium grow as individual single cells, but in the absence of nutrients, they initiate a multicellular developmental program. Central to this is secreted cAMP, a primary GPCR-response signal. Activated cAMP receptors at the cell surface direct a number of downstream signaling pathways, including synthesis of the intracellular second messengers cAMP and cGMP. These, in turn, activate a series of downstream targets that direct chemotaxis within extracellular cAMP gradients, multicellular aggregation, and, ultimately, cell-specific gene expression, morphogenesis, and cytodifferentiation. Extracellular cAMP and intracellular cAMP and cGMP exhibit rapid fluctuations in concentrations and are, thus, subject to exquisite regulation by both synthesis and degradation. The Dictyostelium genome encodes seven phosphodiesterases (PDEs) that degrade cyclic nucleotides to nucleotide 5’-monophosphates. Each PDE has a distinct structure, substrate specificity, regulatory input, cellular localization, and developmentally regulated expression pattern. The intra- or extra-cellular localizations and enzymatic specificities for cAMP or cGMP are essential for degradative precision at different developmental stages. We discuss the diverse PDEs, the nucleotide cyclases, and the target proteins for cAMP and cGMP in Dictyostelium. We further outline the major molecular, cellular, and developmental events regulated by cyclic nucleotide signaling, with emphasis on the input of each PDE and consequence of loss-of-function mutations. Finally, we relate the structures and functions of the Dictyostelium PDEs with those of humans and in the context of potential therapeutic understandings. Full article
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20 pages, 7827 KiB  
Article
Neuroprotective Effects of Cilomilast and Chlorogenic Acid Against Scopolamine-Induced Memory Deficits via Modulation of the cAMP/PKA–CREB–BDNF Pathway
by Esraa M. Mosalam, Soha M. Atya, Noha M. Mesbah, Shady Allam and Eman T. Mehanna
Int. J. Mol. Sci. 2025, 26(7), 3108; https://doi.org/10.3390/ijms26073108 - 28 Mar 2025
Cited by 1 | Viewed by 814
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline, neuroinflammation and neuronal damage. This study aimed to investigate the neuroprotective effects of cilomilast (CILO), a phosphodiesterase-4 (PDE4) inhibitor, alone and in combination with chlorogenic acid (CGA), a natural polyphenol, against scopolamine [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline, neuroinflammation and neuronal damage. This study aimed to investigate the neuroprotective effects of cilomilast (CILO), a phosphodiesterase-4 (PDE4) inhibitor, alone and in combination with chlorogenic acid (CGA), a natural polyphenol, against scopolamine (SCOP)-induced cognitive impairment in mice. Forty male albino mice were divided into five groups: normal control, SCOP control, CGA + SCOP, CILO + SCOP and CILO + CGA + SCOP. Behavioral assessments, including the Y-maze and pole climbing tests, demonstrated that SCOP significantly impaired cognition, while treatment with CILO and CGA reversed these deficits, with the combination group showing the greatest improvement. Histopathological analyses revealed that CILO and CGA reduced neuronal damage and amyloid beta (Aβ) accumulation. Immunohistochemical and biochemical assessments confirmed a decrease in neuroinflammatory markers, including tumor necrosis factor-alpha (TNF-α) and nuclear factor kappa B (NF-κB). Molecular analyses showed that CILO restored cyclic adenosine monophosphate (cAMP) levels, leading to activation of protein kinase A (PKA), cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), key regulators of neuronal plasticity and survival. CGA enhanced these effects by further inhibiting PDE4, amplifying the neuroprotective response. These findings suggest that PDE4 inhibitors, particularly in combination with CGA, may represent promising therapeutic strategies for AD-related cognitive impairment. Full article
(This article belongs to the Section Molecular Neurobiology)
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25 pages, 1414 KiB  
Review
The Impact of the Exposome on Alzheimer’s Disease: The Influence of Nutrition
by Martina Monaco, Carola Torazza, Ernesto Fedele and Massimo Grilli
Int. J. Mol. Sci. 2025, 26(7), 3015; https://doi.org/10.3390/ijms26073015 - 26 Mar 2025
Viewed by 1024
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline, memory loss, and behavioural changes. While genetic predispositions and pathological processes have been the traditional focus, this review highlights the fundamental role of environmental factors, particularly nutrition, within the exposome framework [...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline, memory loss, and behavioural changes. While genetic predispositions and pathological processes have been the traditional focus, this review highlights the fundamental role of environmental factors, particularly nutrition, within the exposome framework in modulating the risk and progression of AD. The exposome, which includes the totality of environmental exposures in an individual’s lifetime, provides a comprehensive approach to understanding the complex aetiology of AD. In this review, we explore the impact of dietary factors and cyclic nucleotide pathways (cAMP/cGMP) on AD, emphasizing the potential of dietary interventions as therapeutic strategies. We investigate key aspects of how nutrition affects the accumulation of β-amyloid, the aggregation of tau proteins, and neuroinflammation. We also examine the impact of specific nutrients on cognitive performance and the risk of AD. Additionally, we discuss the potential of nutraceuticals with anti-phosphodiesterase activity and the role of various animal models of AD (such as 5xFAD, 3xTg-AD, Tg2576, and APP/PS1 mice) in demonstrating the effects of dietary interventions on disease onset and progression. Full article
(This article belongs to the Special Issue Molecular Research of Alzheimer’s Disease and Nutrition Therapy)
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15 pages, 4198 KiB  
Article
Chemical Space Exploration and Machine Learning-Based Screening of PDE7A Inhibitors
by Yuze Li, Zhe Wang, Shengyao Ma, Xiaowen Tang and Hanting Zhang
Pharmaceuticals 2025, 18(4), 444; https://doi.org/10.3390/ph18040444 - 21 Mar 2025
Cited by 1 | Viewed by 608
Abstract
Background/Objectives: Phosphodiesterase 7 (PDE7), a member of the PDE superfamily, selectively catalyzes the hydrolysis of cyclic adenosine 3′,5′-monophosphate (cAMP), thereby regulating the intracellular levels of this second messenger and influencing various physiological functions and processes. There are two subtypes of PDE7, PDE7A [...] Read more.
Background/Objectives: Phosphodiesterase 7 (PDE7), a member of the PDE superfamily, selectively catalyzes the hydrolysis of cyclic adenosine 3′,5′-monophosphate (cAMP), thereby regulating the intracellular levels of this second messenger and influencing various physiological functions and processes. There are two subtypes of PDE7, PDE7A and PDE7B, which are encoded by distinct genes. PDE7 inhibitors have been shown to exert therapeutic effects on neurological and respiratory diseases. However, FDA-approved drugs based on the PDE7A inhibitor are still absent, highlighting the need for novel compounds to advance PDE7A inhibitor development. Methods: To address this urgent and important issue, we conducted a comprehensive cheminformatics analysis of compounds with potential for PDE7A inhibition using a curated database to elucidate the chemical characteristics of the highly active PDE7A inhibitors. The specific substructures that significantly enhance the activity of PDE7A inhibitors, including benzenesulfonamido, acylamino, and phenoxyl, were identified by an interpretable machine learning analysis. Subsequently, a machine learning model employing the Random Forest–Morgan pattern was constructed for the qualitative and quantitative prediction of PDE7A inhibitors. Results: As a result, six compounds with potential PDE7A inhibitory activity were screened out from the SPECS compound library. These identified compounds exhibited favorable molecular properties and potent binding affinities with the target protein, holding promise as candidates for further exploration in the development of potent PDE7A inhibitors. Conclusions: The results of the present study would advance the exploration of innovative PDE7A inhibitors and provide valuable insights for future endeavors in the discovery of novel PDE inhibitors. Full article
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28 pages, 3566 KiB  
Review
Role of PDE4 Family in Cardiomyocyte Physiology and Heart Failure
by Ivan Sherstnev, Aleksandra Judina, Giovanni Battista Luciani, Alessandra Ghigo, Emilio Hirsch and Julia Gorelik
Cells 2025, 14(6), 460; https://doi.org/10.3390/cells14060460 - 20 Mar 2025
Viewed by 1507
Abstract
Phosphodiesterase 4 (PDE4) is a key regulator of cyclic adenosine monophosphate (cAMP) signalling in cardiomyocytes, controlling contractility, calcium handling, and hypertrophic responses. PDE4 provides spatial and temporal precision to cAMP signalling, particularly under β-adrenergic stimulation, through its compartmentalised activity in subcellular nanodomains, including [...] Read more.
Phosphodiesterase 4 (PDE4) is a key regulator of cyclic adenosine monophosphate (cAMP) signalling in cardiomyocytes, controlling contractility, calcium handling, and hypertrophic responses. PDE4 provides spatial and temporal precision to cAMP signalling, particularly under β-adrenergic stimulation, through its compartmentalised activity in subcellular nanodomains, including the sarcoplasmic reticulum, plasma membrane and nuclear envelope. This review highlights the cardiac PDE4 isoforms PDE4A, PDE4B and PDE4D, focusing on their distinct localisation and contributions to cardiac physiology and pathophysiology, particularly in heart failure and arrhythmias. Although PDE4 plays a smaller role in overall cAMP hydrolysis in human hearts than in rodents, its compartmentalised function remains critical. Recent therapeutic advances have shifted from pan-PDE4 inhibitors to isoform-specific approaches to enhance efficacy while minimising systemic toxicity. We discuss the potential of selective PDE4 modulators, gene therapies and combination strategies in restoring cAMP compartmentation and preventing maladaptive cardiac remodelling. By integrating rodent and human studies, this review underscores the translational challenges and therapeutic opportunities surrounding PDE4, positioning it as both a key regulator of cardiac signalling and a promising target for heart failure therapies. Full article
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7 pages, 535 KiB  
Brief Report
PDE4 Inhibition Reduced Osteoclast Differentiation in Psoriatic Patients
by Annunziata Raimondo, Alessia Balestrino and Serena Lembo
Life 2025, 15(3), 467; https://doi.org/10.3390/life15030467 - 14 Mar 2025
Viewed by 526
Abstract
Background: Psoriatic skin inflammation has been linked to joint inflammation and bone structural alterations, contributing to a “pro-osteoclastogenic march.” Osteoclasts (OCs), responsible for bone resorption, originate from monocytes/macrophages and are regulated by the RANKL-RANK signaling pathway. The cyclic AMP (cAMP) pathway plays a [...] Read more.
Background: Psoriatic skin inflammation has been linked to joint inflammation and bone structural alterations, contributing to a “pro-osteoclastogenic march.” Osteoclasts (OCs), responsible for bone resorption, originate from monocytes/macrophages and are regulated by the RANKL-RANK signaling pathway. The cyclic AMP (cAMP) pathway plays a crucial role in OC maturation, and phosphodiesterases (PDEs) control its intracellular levels. Apremilast, a selective PDE4 inhibitor used for psoriasis (Pso) and psoriatic arthritis (PsA) treatment, may modulate osteoclastogenesis. Methods: Seventeen patients with moderate-to-severe psoriasis without arthritis, eligible for systemic apremilast therapy, were enrolled. Blood samples were collected at baseline and after 52 weeks of treatment to evaluate in vitro osteoclastogenesis from peripheral blood monocytes/macrophages and to measure serum RANKL levels. Results: After 52 weeks of apremilast treatment, OC and RANKL levels were significantly reduced in psoriatic patients compared to baseline. A sub-analysis was performed on two age- and sex-matched subgroups: a bionaïve group and a bioexperienced group. Bioexperienced patients exhibited lower OCP counts and reduced plasma RANKL levels compared to bionaïve patients. Conclusions: Our findings highlight the role of PDE4 in the pro-osteoclastogenic process in psoriasis and suggest that apremilast may counteract bone resorption by modulating RANKL levels and osteoclast differentiation, with potential clinical implications. Full article
(This article belongs to the Section Physiology and Pathology)
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