cAMP-PKA signaling pathway and anxiety: Where do we go next?

Cellular Signalling, Год журнала: 2024, Номер 122, С. 111311 - 111311

Опубликована: Июль 24, 2024

Язык: Английский

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PDE4D: A Multipurpose Pharmacological Target

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(15), С. 8052 - 8052

Опубликована: Июль 24, 2024

Phosphodiesterase 4 (PDE4) enzymes catalyze cyclic adenosine monophosphate (cAMP) hydrolysis and are involved in a variety of physiological processes, including brain function, monocyte macrophage activation, neutrophil infiltration. Among different PDE4 isoforms, Phosphodiesterases 4D (PDE4Ds) play fundamental role cognitive, learning memory consolidation processes cancer development. Selective PDE4D inhibitors (PDE4Dis) could represent an innovative valid therapeutic strategy for the treatment various neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s, Lou Gehrig’s but also stroke, traumatic spinal cord injury, mild cognitive impairment, all demyelinating diseases multiple sclerosis. In addition, small molecules able to block isoforms have been recently studied specific types, particularly hepatocellular carcinoma breast cancer. This review overviews PDE4DIsso far identified provides useful information, from medicinal chemistry point view, development novel series compounds with improved pharmacological properties.

Язык: Английский

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Cyclic nucleotide phosphodiesterases as drug targets

Pharmacological Reviews, Год журнала: 2025, Номер 77(3), С. 100042 - 100042

Опубликована: Янв. 22, 2025

Cyclic nucleotides are synthesized by adenylyl and/or guanylyl cyclase, and downstream of this synthesis, the cyclic nucleotide phosphodiesterase families (PDEs) specifically hydrolyze nucleotides. PDEs control adenosine-3',5'monophosphate (cAMP) guanosine-3',5'-monophosphate (cGMP) intracellular levels mediating their quick return to basal steady state levels. This often takes place in subcellular nanodomains. Thus, govern short-term protein phosphorylation, long-term expression, even epigenetic mechanisms modulating Consequently, involvement both health disease is extensively investigated. PDE inhibition has emerged as a promising clinical intervention method, with ongoing developments aiming enhance its efficacy applicability. In comprehensive review, we look into intricate landscape biochemistry, exploring diverse roles various tissues. Furthermore, outline underlying different pathophysiological conditions. Additionally, review application related diseases, shedding light on current advancements future prospects for intervention. SIGNIFICANCE STATEMENT: Regulating critical checkpoint numerous (patho)physiological However, despite development several inhibitors aimed at controlling overactivated PDEs, applicability settings poses challenges. context, our focus pharmacodynamics structure activity illustrate how selectivity can be optimized. points preclinical evidence that depicts optimization efforts indications.

Язык: Английский

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Molecular Properties of Phosphodiesterase 4 and Its Inhibition by Roflumilast and Cilomilast

Molecules, Год журнала: 2025, Номер 30(3), С. 692 - 692

Опубликована: Фев. 4, 2025

Phosphodiesterase 4 (PDE4) catalyzes cyclic adenosine monophosphate (cAMP) hydrolysis, playing a crucial role in the cAMP signaling pathway. is secondary messenger involved numerous physiological functions, such as inflammatory responses, immune neural activity, learning, and memory. PDE4 inhibition important for controlling anti-inflammatory neuroprotective effects. In this review, we provide comprehensive overview of molecular functions properties human PDE4s. The study presents detailed sequence information isoforms structural catalytic domain members family. We also review inhibitory effects inhibitors roflumilast cilomilast related to respiratory diseases PDE4. crystal structures complex with are analyzed. This provides useful future design novel inhibitors.

Язык: Английский

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The multifaceted role of phosphodiesterase 4 in tumor: from tumorigenesis to immunotherapy

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Март 10, 2025

Phosphodiesterase 4 (PDE4) is an enzyme that specifically hydrolyzes the second messenger cAMP and has a critical role in regulation of variety cellular functions. In recent years, PDE4 attracted great interest cancer research, its tumorigenesis development been gradually elucidated. Research indicates abnormal expression or heightened activity associated with initiation progression multiple cancers, including lung, colorectal, hematological by facilitating cell proliferation, migration, invasion, anti-apoptosis. Moreover, also influences tumor immune microenvironment, significantly evasion suppressing anti-tumor responses, reducing T-cell activation, promoting polarization tumor-associated macrophages toward pro-tumorigenic phenotype. However, family may have both oncogenic tumor-suppressive effects, which could depend on specific type grade tumor. inhibitors garnered substantial as potential anti-cancer therapeutics, directly inhibiting growth restoring surveillance capabilities to enhance clearance cells. Several are currently under investigation aim exploring their therapy, particularly combination strategies checkpoint inhibitors, improve therapeutic efficacy mitigate side effects conventional chemotherapy. This review provides overview tumorigenesis, drug resistance, immunotherapy, actions intending guide exploration new target therapy.

Язык: Английский

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PDE7 as a Precision Target: Bridging Disease Modulation and Potential PET Imaging for Translational Medicine

ACS Medicinal Chemistry Letters, Год журнала: 2025, Номер unknown

Опубликована: Апрель 15, 2025

Язык: Английский

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Pharmacological potential of cyclic nucleotide signaling in immunity

Pharmacology & Therapeutics, Год журнала: 2024, Номер 258, С. 108653 - 108653

Опубликована: Апрель 26, 2024

Язык: Английский

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Disorder of neuroplasticity aggravates cognitive impairment via neuroinflammation associated with intestinal flora dysbiosis in chronic heart failure

Aging, Год журнала: 2024, Номер unknown

Опубликована: Июль 1, 2024

Chronic heart failure (CHF) impairs cognitive function, yet its effects on brain structure and underlying mechanisms remain elusive. This study aims to explore the behind impairment.

Язык: Английский

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Molecular docking and DFT study of 4-difluoromethyl pyrazole derivatives as cyclooxygenase-2 inhibitor

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Март 25, 2024

Abstract We applied molecular docking simulations and DFT to examine the binding interactions of 4-difluoromethyl pyrazole derivatives ( 3a-3h ). assessed potential mechanisms strengths within receptor's site. By methodical simulations, we elucidated characteristics towards capacities. Proposed compounds were subjected with major protease PDB:3LN1 ) assess affinities. In designed ), 3a 3f show highest score, leading high affinity toward 3LN1 . An energy score -6.9765 Cal/mol ligand 3g suggests a strong advantageous affinity, negative number indicating stability. The reactivity parameters, FMO, MEP drugs estimated by calculations. was attributed existence three hydrogen bonds several hydrophobic between drug essential amino acid residues receptor. Ultimately, findings illustrated using molecule electrostatic data DFT. All these showed varying degrees influence on active protein locations.

Язык: Английский

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Rabeprazole suppressed gastric intestinal metaplasia through activation of GPX4-mediated ferroptosis

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Ноя. 7, 2024

Background Gastric intestinal metaplasia is a common pathological feature in patients with Helicobacter pylori ( H. ) infection. Rabeprazole was widely used as the first-line regimen for infectious treatment. The objective of this study to explore mechanism rabeprazole gastric Methods Real-time PCR, Western blotting (WB) and ROS analysis were conducted confirm that could induce ferroptosis suppress metaplasia. Cellular fraction, luciferase chromatin immunoprecipitation (ChIP) identify underlying modulated ferroptosis. Results Herein, we found treatment led inhibit CDX2 MUC2 expression, alleviating metaplasia, which attributed enhanced characterized by decreased GPX4 expression. Inhibition ferrostatin-1 (Fer-1) reverse expression caused rabeprazole. Mechanically, CREB phosphorylation nuclear translocation, further binding promoter, reducing transactivity. Moreover, endogenous PKA interacted CREB, interaction drastically destroyed response Most importantly, observed pylori- infected comparison HC control. Conclusion These findings suggested induced reduce epithelial cells through PKA/CREB cascade signaling, implying targeting be promising strategy improving during -infected patients.

Язык: Английский

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