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Pulmonary fibrosis (PF) is a progressive, fatal lung disease lacking effective treatments. Autotaxin (ATX) plays a crucial role in exacerbating inflammation and fibrosis, making it a promising target for fibrosis therapies. Herein, starting from PAT-409 (Cudetaxestat), a series of novel ATX inhibitors bearing 1 H -indole-3-carboxamide, 4,5,6,7-tetrahydro-7 H -pyrazolo[3,4- c ]pyridin-7-one, or 4,5,6,7-tetrahydro-1 H -pyrazolo[4,3- c ]pyridine cores were designed based on the structure of ATX hydrophobic tunnel. The optimal 31 and 35 inhibited ATX with IC 50 values of 2.8 and 0.7 nM, respectively. In a bleomycin-induced mouse PF model, both compounds significantly reduced fibrosis by regulating the TGF-β/Smad signaling pathway and downregulating collagen deposition. Furthermore, 35 exhibited both negligibly low hERG channel inhibition (IC 50 > 30 μM) and remarkable microsomal stability. Notably, 35 was characterized by favorable pharmacokinetic properties ( F = 69.5%) and excellent safety in vivo . Overall, 35 turned out to be a well-characterized potent and safe ATX inhibitor warranting further investigation for the treatment of PF.

Phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze cyclic nucleotides. While the 11 PDE subfamilies share common features, key differences confer signaling specificity. The differences include substrate selectivity, enzymatic activity regulation, tissue expression, and subcellular localization. Selective inhibitors of each subfamily have elucidated the protean role of PDEs in normal cell function. PDEs are also linked to diseases, some of which affect the immune, cardiac, and vascular systems. Selective PDE inhibitors are clinically used to treat these specific disorders. Ongoing preclinical studies and clinical trials are likely to lead to the approval of additional PDE-targeting drugs for therapy in human disease. In this review, we discuss the structure and function of PDEs and examine current and evolving therapeutic uses of PDE inhibitors, highlighting their mechanisms and innovative applications that could further leverage this crucial family of enzymes in clinical settings.

Renal fibrosis is closely related to the prognosis of chronic kidney disease (CKD). The increase in cGMP reduces renal fibrosis. Soluble guanylate cyclase (sGC) and phosphodiesterase (PDE) are key enzymes that maintain cGMP levels. BAY 41-8543 (1 mg/kg/day) and/or BAY 73-6691 (1 mg/kg/day) were used to treat 5/6 nephrectomized rats for 13 weeks. 5/6 Nephrectomy caused an increase in cystatin C, proteinuria and glomerulosclerosis and renal interstitial fibrosis. Neither sGC stimulation nor PDE9 inhibition alone improved kidney function and morphology, whereas BAY 41-8543 in combination with BAY 73-6691 attenuated renal interstitial fibrosis. This beneficial effect could not be explained by alterations in blood pressure and the renal immune system. BAY 41-8543 in combination with BAY 73-6691 had no effect on renal macrophage, CD4 + T-cell and CD8 + T-cell in the late-stage of 5/6 nephrectomy. RNA sequencing revealed BAY 41-8543 in combination with BAY 73-6691 down-regulated the expression of fibrosis-related genes such as Collagen Type I Alpha 1, Collagen Type III Alpha 1 Chain and Collagen Type XIV Alpha 1 Chain. sGC stimulator combined with PDE9 inhibitor attenuated renal fibrosis in 5/6 nephrectomized rats by down-regulating fibrosis-related gene expression. This novel approach of using low-dose combination therapies to minimize side effects while maintaining therapeutic efficacy offers a promising strategy for the treatment of CKD., (© 2024 The Author(s). Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

MK-8189 is a novel phosphodiesterase 10A (PDE10A) inhibitor being evaluated in clinical studies for the treatment of schizophrenia. PDE10A is a cyclic nucleotide phosphodiesterase enzyme highly expressed in medium spiny neurons of the striatum. MK-8189 exhibits subnanomolar potency on the PDE10A enzyme and has excellent pharmaceutical properties. Oral administration of MK-8189 significantly increased cyclic guanosine monophosphate and phospho glutamate receptor 1 in rat striatal tissues. Activation of the dopamine D1 direct and D2 indirect pathways was demonstrated by detecting significant elevation of mRNA encoding substance P and enkephalin after MK-8189 administration. The PDE10A tracer [ 3 H]MK-8193 was used to determine the PDE10A enzyme occupancy (EO) required for efficacy in behavioral models. In the rat-conditioned avoidance responding assay, MK-8189 significantly decreased avoidance behavior at PDE10A EO greater than ∼48%. MK-8189 significantly reversed an MK-801-induced deficit in prepulse inhibition at PDE10A EO of ∼47% and higher. Target engagement of MK-8189 in rhesus monkeys was examined with [ 11 C]MK-8193 in positron emission tomography studies, and plasma concentrations of 127 nM MK-8189 yielded ∼50% EO in the striatum. The impact of MK-8189 on cognitive symptoms was evaluated using the objective retrieval task in rhesus monkeys. MK-8189 significantly attenuated a ketamine-induced deficit in object retrieval performance at exposure that yielded ∼29% PDE10A EO. These findings demonstrate the robust impact of MK-8189 on striatal signaling and efficacy in preclinical models of symptoms associated with schizophrenia. Data from these studies were used to establish the relationship between preclinical efficacy, plasma exposures, and PDE10A EO to guide dose selection of MK-8189 in clinical studies. SIGNIFICANCE STATEMENT: We describe the primary pharmacology of MK-8189, a phosphodiesterase 10A (PDE10A) inhibitor under evaluation for the treatment of schizophrenia. We report efficacy in preclinical models that have been used to characterize other PDE10A inhibitors and atypical antipsychotics. The PDE10A occupancy achieved by MK-8189 in behavioral studies was used to support dose selection in clinical trials. This work provides evidence to support exploration of higher levels of PDE10A occupancy in clinical trials to determine if this translates to improved efficacy in patients., Competing Interests: Conflict of interest All authors are employees and stockholders in Merck & Co, Inc., (Copyright © 2024 American Society for Pharmacology and Experimental Therapeutics. Published by Elsevier Inc. All rights reserved.)

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme that plays a crucial role in repairing DNA lesions caused by the entrapment of DNA topoisomerase IB (TOP1)-DNA break-associated crosslinks. TDP1 inhibitors exhibit synergistic effects with TOP1 inhibitors in cancer cells, effectively overcoming resistance to TOP1 inhibitors. Therefore, this approach presents a promising strategy for reversing tumor resistance to TOP1 inhibitors. This review comprehensively outlines the structural and biological features of TDP1, the substrates involved in its catalytic hydrolysis, and its potential as a therapeutic target in oncology. Additionally, we summarize the various screening methods used to identify TDP1 inhibitors, alongside the latest advancements in TDP1 inhibitor research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Brain injury develops from a complex series of pathophysiological phases, resulting in acute necrotic or delayed apoptotic cell death after traumatic brain injury (TBI). Inhibition of apoptotic cell death is critical for the treatment of acute neurodegenerative disorders, such as TBI. Here, we investigated the role of phosphodiesterase 10A (PDE10A) in the development of neuronal injury, particularly in apoptotic cell death. Using the PDE10A inhibitor TAK-063, we found that PDE10A inhibition is associated with decreased brain injury, brain swelling, and blood brain barrier disruption 48 h after cold-induced TBI. Furthermore, a particularly notable result was observed with 3 mg/kg TAK-063, which reduced disseminated neuronal injury. Protein abundance analysis revealed that PDE10A inhibition activates survival kinases AKT and ERK-1/-2, which were associated with the decreased activation of MMP-9 and PTEN. Additionally, iNOS and nNOS levels significantly reduced in the TAK-063 group, playing roles in inflammation and apoptosis. A planar surface immunoassay was performed for in-depth analyses of the apoptotic signaling pathways. We observed that inhibition of PDE10A resulted in the decreased expression of TNFRSF1A, TNFRSF10B, and TNFRSF6 receptors, particularly inducing apoptotic cell death. Moreover, these findings correlated with reduced levels of pro-apoptotic proteins, including PTEN, p27, Cytochrome-c, cleaved Caspase-3, Bad, and p53. Interestingly, TAK-063 treatment reduced levels of anti-apoptotic proteins or enzymes, including XIAP, Claspin, and HIF1α, without affecting Bcl-x, MCL-1, SMAC, HO-1, HO-2, HSP27, HSP60, and HSP70. The findings suggest that PDE10A regulates cellular signaling predominantly pro-apoptotic pathways, and inhibition of this protein is a promising approach for the treatment of acute brain injury., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ertugrul Kilic reports financial support was provided by Turkish Academy of Sciences. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: Atrial fibrillation (AF) poses a significant therapeutic challenge with drug interventions showing only limited success. Phosphodiesterases (PDE) regulate cardiac electrical stability and may represent an interesting target. Recently, PDE8 inhibition was proposed as an antiarrhythmic intervention by increasing L-type Ca 2+ current (I Ca,L ) and action potential duration (APD). However, the effect size of PDE8 inhibition on I Ca,L and APD seems discrepant and effects on force are unknown. We investigated the impact of PDE8 inhibition on force using PF-04957325 in right atrial appendages, obtained from patients in sinus rhythm (SR) and with persistent AF (peAF) undergoing cardiac surgery. A computational model was used to predict the effects of PDE8 inhibition on APD in SR and peAF. Results showed no increase in force after exposure to increasing concentrations of the PDE8 inhibitor PF-04957325 in either SR or peAF tissues. Furthermore, PDE8 inhibition did not affect the potency or efficacy of norepinephrine-induced inotropic effects in either group. Arrhythmic events triggered by norepinephrine were observed in both SR and peAF, but their frequency remained unaffected by PF-04957325 treatment. Computational modeling predicted that the reported increase in I Ca,L induced by PDE8 inhibition would lead to substantial APD prolongation at all repolarization states, particularly in peAF. Our findings indicate that PDE8 inhibition does not significantly impact force or arrhythmogenicity in human atrial tissue., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Hepatic fibrosis, a widespread pathological process observed across various liver diseases, is acknowledged as a potentially reversible condition. In recent years, liver fibrosis has garnered extensive research attention, with a primary emphasis on developing drugs that can directly block or reverse this condition. This paper presents a comprehensive review of the design strategies for various anti-hepatic fibrosis agents that have been many efficacious small-molecule drugs. This review encompasses the synthesis and design of nuclear receptor ligands (such as VDR and Nurr7), kinase inhibitors (including ALK5 and JAK1), selective PDE inhibitors, small-molecule monomers derived from natural products, and other small molecules. The aim of this review is to provide promising avenues and valuable insights for the continued development of anti-hepatic fibrosis drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Masson SAS. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no ideal drugs. Our previous research demonstrated that phosphodiesterase 1 (PDE1) could be a promising target for the treatment of IPF. However, only a few selective PDE1 inhibitors are available, and the mechanism of recognition between inhibitors and the PDE1 protein is not fully understood. This study carried out a step-by-step optimization of a dihydropyrimidine hit Z94555858 . By targeting the metal pocket of PDE1, a lead compound 3f was obtained, exhibiting an IC 50 value of 11 nM against PDE1, moderate selectivity over other PDEs, and significant anti-fibrotic effects in bleomycin-induced pulmonary fibrosis rats. The structure-activity relationship study aided by molecular docking revealed that forming halogen bonds with water in the metal pocket greatly enhanced the PDE1 inhibition, providing a novel strategy for further rational design of PDE1 inhibitors.

Purpose: Urolithiasis and symptomatic ureterolithiasis represent diseases known to be on the increase in most westernized countries. The present article aims to give an overview on some drug principles assumed to target signalling systems involved in modulating ureter smooth muscle contractility and to present background to their potential use or prospects in ureter stone disease., Methods: The article reviews drugs that have been evaluated over the last decades in vitro, in vivo and/or in clinical settings with regard to their properties to achieve spontaneous passage of (distal) ureteral stones and relieve colic pain. Among these drugs are alpha- and beta-adrenoceptor antagonists, calcium channel blocking agents, Rho kinase inhibitors, nitric oxide (NO) donor drugs, selective inhibitors of cyclic nucleotide phosphodiesterase enzymes (PDEs), as well as potassium channel openers., Results: Based on the recent scientific information on agents targeting different pathways, antagonists of alpha 1-adrenoceptors, inhibitors of the PDE isoenzymes PDE4 and PDE5 (affecting cyclic AMP- or NO/cyclic GMP-mediated signals that facilitate relaxation of ureter smooth muscle), as well as the combination of certain drugs (for example, PDE5/PDE4 inhibitor plus alpha 1-AR antagonist) seem to be intriguing pharmacological approaches to medical expulsion therapy (MET) in the overall population of patients., Conclusion: While NO donors, calcium channel antagonists and potassium channel openers may be limited for further development for medical expulsion therapy (MET) due to their systemic effects and a lack of effect on stone clearance, Rho kinase inhibitors should be explored further as a future pharmacological principle in ureteral stone disease., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Chronic fatigue stress (CFS) is a multisystem disorder which exhibits multiple signs of neurological complications like brain fog, cognitive deficits and oxidative stress with no specific treatment. Doxophylline, a non-selective phosphodiesterase inhibitor (PDEI), has anti-inflammatory properties with enhanced blood-brain barrier penetration and tissue specificity. We have evaluated the neuroprotective potential of doxophylline in a murine model of forced swim test (FST) induced CFS and in H 2 O 2 (hydrogen peroxide) induced oxidative stress in PC12 cells. An FST model to induce a state of CFS in mice was induced by forcing them to swim daily for 6 min for 15 days. The drug was administered daily 30 min prior to FST. The immobility period was compared for day 1 and day 15. Animals were sacrificed on day 16 for biochemical, mitochondrial, and histopathological estimations in the brain. Cytotoxicity assay, reactive oxygen species (ROS) and nuclear morphology determination were carried out in PC12 cells. A significant increase in immobility has been observed on the 15th day in CFS-induced mice compared to doxophylline treated group. Neurobehavioral studies revealed hypo locomotion, anxiety, motor incoordination, and memory deficit. Biochemical analysis showed a significant change in oxidative stress markers (superoxide dismutase (SOD), reduced glutathione (GSH), catalase, lipid peroxidation (LPO) and nitrite levels) and acetylcholinesterase enzyme activity (AChE) in brain homogenates. Doxophylline pre-treatment protects against these impairments. In PC12 cell lines, doxophylline exhibits alleviation against H 2 O 2 -induced oxidative stress, intracellular ROS generation, and changes in nuclear morphology. Doxophylline could be promising and possess therapeutic potential in CFS treatment. Further research is needed to test if doxophylline can be repurposed for neurological disorders., Competing Interests: Declarations. Ethics Approval: All protocols for animal experimentation were approved by Institutional Animal Ethics Committee (IAEC) of Panjab University, Chandigarh-160014, India against approval no. (PU/45/99/CPCSEA/IAEC/2022/706) and conducted in accordance with CCSEA guidelines for use & care of experimental animals. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory condition often complicated by cardiovascular disease (CVD) due to shared inflammatory pathways. This review explores the cardiovascular impacts of emerging anti-inflammatory therapies in COPD. Phosphodiesterase (PDE) inhibitors may offer anti-inflammatory effects with improved lung function but pose potential risks for arrhythmias when PDE3 is inhibited although PDE4 inhibitors reduce cardiovascular events by improving endothelial function and reducing thrombosis. Similarly, p38 mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) inhibitors target COPD-related inflammation and may benefit COPD patients with CVD. p38 MAPK inhibitors reduce cardiac fibrosis, enhance contractility and lower the risk of arrhythmia. PI3K inhibitors target the PI3K/Akt pathway, which drives atherosclerosis and cardiac fibrosis, and thus potentially mitigate both plaque instability and fibrosis. Biologic therapies, including monoclonal antibodies that inhibit IL-5, IL-13/IL-4, thymic stromal lymphopoietin, IL-33, and IL-17A, show promise in reducing exacerbations but require close cardiovascular monitoring due to their immunomodulatory effects. Single-target inhibitors of neutrophil elastase or matrix metalloproteinases show limited efficacy in COPD but may aid cardiovascular patients by stabilizing atherosclerotic plaques through promoting vascular smooth muscle cell proliferation. However, their tendency to degrade the extracellular matrix and attract immune cells may heighten plaque rupture risk, contraindicating use in CVD. Alpha-1 antitrypsin replacement therapy holds promise, potentially reducing COPD exacerbations and providing cardiovascular protection, especially in myocardial injury. Understanding the influence of these innovative therapies on CVD is vital, making it imperative to examine these molecules in COPD patients with CVD at an early stage., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Cazzola et al.)

Background: The treatment of vitiligo is a persistent challenge in dermatology. New treatments are being offered and studied in this field for those resistant to or intolerant of classical therapies., Aims: In this systematic review, we study the use of prostaglandin analogues (PGAs) and phosphodiesterase inhibitors (PDEIs) in the treatment of vitiligo, as they are known for their pigmentation inducing effects through activating melanocytes., Methods: We searched four main online databases with the keywords "Vitiligo", "Prostaglandin analogue" and "Phosphodiesterase inhibitor"., Results: A total of 42 articles were included, with 1027 cases, studying drugs like bimatoprost, latanoprost, travoprost, dinoprostone, apremilast, crisaborole, etc. Among the included studies, the treatment regimens are commonly once or twice daily for 12-48 weeks, with a mean of 20.61 weeks, and the routes of administration are mainly topical gels or ophthalmic solutions and oral tablets. Side effects are mild and tolerable, namely erythema, itching or burning sensations at application site for topicals, or gastrointestinal problems with apremilast. Repigmentation results are significant in both adult and pediatric patients and progressive or stable vitiligo. PGAs and PDEIs outperform many classical therapies, for example, narrowband ultraviolet B phototherapy (NB-UVB), tacrolimus, mometasone or methylprednisolone mini-pulse. PGAs or PDEIs are usually used in combination therapies to either cause synergism or increase drug delivery, and almost always enhance repigmentation, for example, with NB-UVB, fractional CO 2 laser, microneedling, and mometasone., Conclusion: Monotherapy or add-on PGAs and PDEIs can be considered effective treatments for vitiligo and promising last resorts for those resistant to other therapies., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

ENPP1 acts as a negative regulator of the cGAS-STING pathway through the hydrolysis of 2'3'-cGAMP. Inhibitors of ENPP1 are regarded as promising agents for stimulating the immune response in cancer immunotherapy. This study describes the identification and optimization of imidazo[1,2- a ]pyrazine derivative 7 as a highly potent and selective ENPP1 inhibitor. Compound 7 demonstrated substantial inhibitory activity against ENPP1 with an IC 50 value of 5.70 or 9.68 nM while showing weak inhibition against ENPP2 and ENPP3. Furthermore, compound 7 was shown to enhance the mRNA expression of cGAMP-induced STING pathway downstream target genes, such as IFNB1 , CXCL10 , and IL 6. In vivo pharmacokinetic and antitumor studies showed promising results, with 7 not only exhibiting efficient pharmacokinetic properties but also enhancing the antitumor efficacy of the anti-PD-1 antibody. Treatment with 7 (80 mg/kg) combined with anti-PD-1 antibody achieved a tumor growth inhibition rate of 77.7% and improved survival in a murine model.

Introduction: Chronic obstructive pulmonary disease (COPD) is a common syndrome associated with smoking and environmental exposures coupled with genetic susceptibility. Recent major advancements in the treatment of COPD patients have become available., Areas Covered: New data on the role of classic bronchodilators, including short-acting and long-acting beta2-agonists and anti-muscarinic antagonists, in the treatment of COPD patients are discussed. Data promoting a more targeted approach to inhaled and systemic corticosteroid use in COPD are reviewed. Phosphodiesterase (PDE) inhibitors, including the recently approved PDE 3/4 inhibitor inhaled ensifentrine, are noted. Selective use of antibiotics can play a role in complex COPD patients. COPD patients with evidence of asthma-COPD overlap syndrome and type-two lymphocytic inflammatory-mediated airway constriction appear to respond to biologics, particularly the anti-IL-4/IL-3 antagonist monoclonal antibody, dupilumab., Expert Opinion: New therapeutic options have made the approach and treatment of the COPD patient much more complicated. These options tend to be very expensive. Attention to identifying the endotype and phenotype will help direct the pharmacotherapy.

Purpose: Retinal ischemia-reperfusion (RIR) injury is implicated in various retinal diseases, leading to retinal ganglion cells (RGCs) degeneration. Microglial senescence exacerbates inflammation, contributing to neurodegeneration. This study aimed to investigate the potential therapeutic role of Roflumilast (Roflu) in ameliorating microglial senescence and neuroinflammation following RIR injury., Methods: C57BL/6J mice underwent RIR surgery, and Roflu treatment was administered intraperitoneally. BV2 microglial cells were subjected to oxygen-glucose deprivation and reoxygenation (OGD/R) to simulate ischemic conditions in vitro. SA-β-gal staining was used to detect cellular senescence. Quantitative PCR and ELISA were used to examine the levels of senescence-associated secretory phenotype (SASP) factors. Hematoxylin and eosin (H&E) staining was performed on retinal sections to assess retinal morphology and thickness. Surviving RGCs were labeled and quantified in retinal whole-mounts using immunofluorescence (IF). Furthermore, Western blot and IF staining were used to quantify the proteins associated with the cell cycle and NLRP3 inflammasomes., Results: Roflu treatment reduced microglial senescence, ROS production, and secretion of pro-inflammatory cytokines in OGD/R-exposed BV2 cells. It also restored cell proliferation capacity and reversed OGD/R-induced cell cycle arrest. In vivo, Roflu alleviated retinal senescence, preserved retinal thickness, and protected against RGCs death in the RIR mouse model. Mechanistically, Roflu inhibited the NLRP3 inflammasome activation and suppressed DNA damage signaling pathway in microglia., Conclusions: Roflu exerts neuroprotective effects by mitigating microglial senescence and inflammation via inhibition of the NLRP3 inflammasome in RIR injury. These findings suggest that Roflu may serve as a promising therapeutic strategy for retinal diseases associated with ischemic injury by targeting microglial senescence.

Chronic kidney disease (CKD) is characterized by a steady decline in kidney function and affects roughly 10% of the world's population. This review focuses on the critical function of cyclic adenosine monophosphate (cAMP) signaling in CKD, specifically how it influences both protective and pathogenic processes in the kidney. cAMP, a critical secondary messenger, controls a variety of cellular functions, including transcription, metabolism, mitochondrial homeostasis, cell proliferation, and apoptosis. Its compartmentalization inside cellular microdomains ensures accurate signaling. In kidney physiology, cAMP is required for hormone-regulated activities, particularly in the collecting duct, where it promotes water reabsorption through vasopressin signaling. Several illnesses, including Fabry disease, renal cell carcinoma, nephrogenic diabetes insipidus, Bartter syndrome, Liddle syndrome, diabetic nephropathy, autosomal dominant polycystic kidney disease, and renal tubular acidosis, have been linked to dysfunction in the cAMP system. Both cAMP analogs and phosphodiesterase inhibitors have the potential to improve kidney function and reduce kidney damage. Future research should focus on developing targeted PDE inhibitors for the treatment of CKD.

Background: Diabetic kidney disease (DKD) is associated with a higher risk of cardiovascular disease (CVD). Pentoxifylline (PTF), a nonselective phosphodiesterase inhibitor with anti-inflammatory, antiproliferative, and antifibrotic actions, has demonstrated renal benefits in both clinical trials and meta-analyses. The present work aimed to study the effects of PTF on the progression of subclinical atherosclerosis (SA) in a population of patients with diabetes and moderate to severe chronic kidney disease (CKD)., Methods: In this open-label, randomized controlled, prospective single-center pilot study the evolution of carotid intima-media thickness (CIMT) and ankle-brachial index (ABI) were determined in 102 patients with type 2 diabetes mellitus and CKD assigned to PTF, aspirin or control groups during 18 months. We also determined the variations in the levels of inflammatory markers and Klotho (KL), a protein involved in maintaining cardiovascular health, and their relationship with the progression of SA., Results: Patients treated with PTF presented a better evolution of CIMT, increased KL mRNA levels in peripheral blood cells (PBCs) and reduced the inflammatory state. The progression of CIMT values was inversely related to variations in KL both in serum and mRNA expression levels in PBCs. Multiple regression analysis demonstrated that PTF treatment and variations in mRNA KL expression in PBCs, together with changes in HDL, were significant determinants for the progression of CIMT (adjusted R 2  = 0.24, P < 0.001) independently of traditional risk factors. Moreover, both variables constituted protective factors against a worst progression of CIMT [OR: 0.103 (P = 0.001) and 0.001 (P = 0.005), respectively]., Conclusions: PTF reduced SA progression assessed by CIMT variation, a beneficial effect related to KL gene expression in PBCs., Trial Registration: The study protocol code is PTF-AA-TR-2009 and the trial was registered on the European Union Drug Regulating Authorities Clinical Trials (EudraCT #2009-016595-77). The validation date was 2010-03-09., (© 2024. The Author(s).)

Background: PDE10A inhibition represents a potential mechanism for treating schizophrenia. PDE10A inhibitors increase cyclic nucleotides in striatal neurons, thereby mimicking the effects of dopamine receptor D2 antagonists and D1 agonists. We evaluated the PDE10A inhibitor MK-8189 for treating schizophrenia., Methods: Randomized, double-blind, placebo and active-controlled, phase 2a, multicenter, inpatient trial in adults experiencing an acute episode of schizophrenia. Participants were randomized 2:2:1 to once-daily MK-8189 12 mg, placebo, or risperidone 6 mg (active control) for 4-weeks. The primary outcome was change-from-baseline in total score on the Positive and Negative Syndrome Scale (PANSS) at 4 weeks., Results: The number of treated participants was 90 for MK-8189, 89 for placebo, and 45 for risperidone. MK-8189 demonstrated a trend towards improvement versus placebo for change-from-baseline in PANSS total score after 4 weeks (difference = -4.7 [95 % CI: -9.8,0.5], P = 0.074). The active control risperidone was superior to placebo on PANNS total score (difference = -7.3 [95 % CI: -14.0,-0.6], P = 0.033), demonstrating assay sensitivity, while MK-8189 and risperidone did not significantly differ (difference = 2.6 [95 % CI: -4.0,9.2], P = 0.440). MK-8189 had a nominally significant effect on PANSS positive subscale score compared to placebo (difference = -2.2 [95 % CI: -3.8,-0.5], P = 0.011). Discontinuation of MK-8189 treatment due to an adverse event was low (<10 %). Extrapyramidal symptoms occurred with MK-8189 but were mostly mild and transient. Compared with placebo, MK-8189 reduced body weight while risperidone increased weight., Conclusions: These findings suggest that PDE10A inhibition may produce antipsychotic effects and associated weight loss and that further trials with PDE10A inhibitors are warranted., Trial Registration: Clinicaltrials.gov identifier: NCT03055338., Competing Interests: Declaration of competing interest Mukai, Lupinacci, Snow-adami, Voss, Smith, and Egan are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, NJ, USA (MSD) and own stock/stock options in Merck & Co., Inc., Rahway, NJ, USA. Marder has acted as a consultant for MSD., (Copyright © 2024. Published by Elsevier B.V.)

Objective: The purpose of this study was to analyze the available evidence regarding the efficacy of iPDE5 in the treatment of female sexual dysfunction (FSD)., Methods: A comprehensive literature search was conducted in March 2023 through the main scientific databases., Results: A total of 53 articles were identified, out of which, 6 met the predefined inclusion criteria. All of these were randomized controlled trials. Among the included studies, 4 demonstrated the effectiveness of sildenafil in improving sexual response and addressing FSD, while 2 studies failed to establish its efficacy in this context., Conclusion: Overall, the efficacy of sildenafil in the treatment of FSD remains controversial and inconclusive based on the available evidence. Further research is necessary to clarify the therapeutic potential of iPDE5 in addressing FSD and to better understand the factors that influence treatment outcomes., Competing Interests: Conflicts to interest: none to declare.

Background: Tourette syndrome is a neurodevelopmental movement disorder involving basal ganglia dysfunction. PDE10A inhibitors modulate signaling in the striatal basal ganglia nuclei and are thus of interest as potential therapeutics in treating Tourette syndrome and other movement disorders., Methods: The preclinical pharmacology and toxicology, human safety and tolerability, and human PET striatal enzyme occupancy data for the PDE10A inhibitor EM-221 are presented., Results: EM-221 inhibited PDE10A with an in vitro IC50 of 9 pM and was >100,000 selective vs. other PDEs and other CNS receptors and enzymes. In rats, at doses of 0.05-0.50 mg/kg, EM-221 reduced hyperlocomotion and the disruption of prepulse inhibition induced by MK-801, attenuated conditioned avoidance, and facilitated novel object recognition, consistent with PDE10A's inhibition. EM-221 displayed no genotoxicity and was well tolerated up to 300 mg/kg in rats and 100 mg/kg in dogs. In single- and multiple-day ascending dose studies in healthy human volunteers, EM-221 was well tolerated up to 10 mg, with a maximum tolerated dose of 15 mg. PET imaging indicated that a PDE10A enzyme occupancy of up to 92.8% was achieved with a ~24 h half-life., Conclusions: The preclinical and clinical data presented here support the study of EM-221 in phase 2 trials of Tourette syndrome and other movement disorders.

Autotaxin (ATX) is a member of the ectonucleotide pyrophosphate/phosphodiesterase ( ENPP ) family; it is encoded by the ENPP2 gene. ATX is a secreted glycoprotein and catalyzes the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is responsible for the transduction of various signal pathways through the interaction with at least six G protein-coupled receptors, LPA Receptors 1 to 6 (LPAR1-6). The ATX-LPA axis is involved in various physiological and pathological processes, such as angiogenesis, embryonic development, inflammation, fibrosis, and obesity. However, significant research also reported its connection to carcinogenesis, immune escape, metastasis, tumor microenvironment, cancer stem cells, and therapeutic resistance. Moreover, several studies suggested ATX and LPA as relevant biomarkers and/or therapeutic targets. In this review of the literature, we aimed to deepen knowledge about the role of the ATX-LPA axis as a promoter of cancer development, progression and invasion, and therapeutic resistance. Finally, we explored its potential application as a prognostic/predictive biomarker and therapeutic target for tumor treatment.

Neurodegenerative diseases (NDs) cause progressive loss of neuron structure and ultimately lead to neuronal cell death. Since the available drugs show only limited symptomatic relief, NDs are currently considered as incurable. This review will illustrate the principal roles of the signaling systems of cyclic adenosine and guanosine 3',5'-monophosphates (cAMP and cGMP) in the neuronal functions, and summarize expression/activity changes of the associated enzymes in the ND patients, including cyclases, protein kinases, and phosphodiesterases (PDEs). As the sole enzymes hydrolyzing cAMP and cGMP, PDEs are logical targets for modification of neurodegeneration. We will focus on PDE inhibitors and their potentials as disease-modifying therapeutics for the treatment of Alzheimer's disease, Parkinson's disease, and Huntington's disease. For the overlapped but distinct contributions of cAMP and cGMP to NDs, we hypothesize that dual PDE inhibitors, which simultaneously regulate both cAMP and cGMP signaling pathways, may have complementary and synergistic effects on modifying neurodegeneration and thus represent a new direction on the discovery of ND drugs., (© 2024 Wiley Periodicals LLC.)

Background: Evidence indicates an association between immune dysregulation and major depressive disorder (MDD). Pentoxifylline (PTX), a phosphodiesterase inhibitor, has been shown to reduce pro-inflammatory activities. The aim of this study was to evaluate changes in depressive symptoms and pro-inflammatory markers after administration of PTX as an adjunctive agent to citalopram in patients with MDD., Methods: One hundred patients were randomly assigned to either citalopram (20 mg/day) plus placebo (twice daily) (n=50) or citalopram (20 mg/day) plus PTX (400 mg) (twice daily) (n=50). The Hamilton Depression Rating Scale-17 (HAM-D-17) scores at baseline, weeks 2, 4, 6, 8, 10, and 12 and serum levels of interleukin1-β (IL-1-β), tumor necrosis factor-α, C-reactive protein, IL-6, serotonin, IL-10, and brain-derived neurotrophic factor (BDNF) at baseline and week 12 were evaluated., Results: HAM-D-17 score in the PTX group significantly reduced in comparison to the control group after weeks 4, 6, 8,10, and 12 ((LSMD): - 2.193, p=0.021; - 2.597, p=0.036; - 2.916, p=0.019; - 4.336, p=0.005; and - 4.087, p=0.008, respectively). Patients who received PTX had a better response (83%) and remission rate (79%) compared to the placebo group (49% and 40%, p=0.006 and p=0.01, respectively). Moreover, the reduction in serum concentrations of pro-inflammatory factors and increase in serotonin and BDNF in the PTX group was significantly greater than in the placebo group (p<0.001)., Conclusion: These findings support the safety and efficacy of PTX as an adjunctive antidepressant agent with anti-inflammatory effects in patients with MDD., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Lysophosphatidic acid (LPA)-mediated activation of LPA receptor 1 (LPAR1) contributes to the pathophysiology of fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). These diseases are associated with high morbidity and mortality despite current treatment options. The LPA-producing enzyme autotaxin (ATX) and LPAR1 activation contribute to inflammation and mechanisms underlying fibrosis in preclinical fibrotic models. Additionally, elevated levels of LPA have been detected in bronchoalveolar lavage fluid from patients with IPF and in serum from patients with SSc. Thus, ATX and LPAR1 have gained considerable interest as pharmaceutical targets to combat fibrotic disease and inhibitors of these targets have been investigated in clinical trials for IPF and SSc. The goals of this review are to summarise the current literature on ATX and LPAR1 signalling in pulmonary fibrosis and to help differentiate the novel inhibitors in development. The mechanisms of action of ATX and LPAR1 inhibitors are described and preclinical studies and clinical trials of these agents are outlined. Because of their contribution to numerous physiologic events underlying fibrotic disease, ATX and LPAR1 inhibition presents a promising therapeutic strategy for IPF, SSc and other fibrotic diseases that may fulfil unmet needs of the current standard of care., Competing Interests: Conflict of interest: E.R. Volkmann has received consulting fees from Boehringer Ingelheim, CSL Behring, GSK and Roche; speaking fees (unbranded disease state lectures) from Boehringer Ingelheim; and grant support from Boehringer Ingelheim, Corbus, Forbius, Horizon Therapeutics (now Amgen, Inc), Kadmon and Prometheus. C.P. Denton has received research grants to his institution from Arxx Therapeutics, GSK, Horizon (now Amgen, Inc) and Servier; and consulting fees from Acceleron, Arxx Therapeutics, Bayer, Boehringer Ingelheim, CSL Behring, Galapagos, GSK, Janssen, Lilly, Roche and Sanofi. M. Kolb reports grants from Boehringer Ingelheim, the Canadian Institute for Health Research, Structure Therapeutics and United Therapeutics; and personal fees from AbbVie, Algernon, Bellerophon, Boehringer Ingelheim, Cipla, CSL Behring, DevPro Biopharma, European Respiratory Journal, Horizon (now Amgen, Inc), LabCorp, Nitto Denko, Pieris, Roche, Structure Therapeutics and United Therapeutics. M.S. Wijsenbeek-Lourens reports grants to her institution from AstraZeneca/Daiichi-Sankyo, Boehringer Ingelheim, the Dutch Lung Foundation, the Dutch Pulmonary Fibrosis Patients Association, Hoffmann-La Roche, The Netherlands Organisation for Health Research and Development, Sarcoidosis.nl and the Thorax Foundation; and consultancy fees paid to her institution from AstraZeneca, Boehringer Ingelheim, BMS, CSL Behring, Galapagos, Galecto, Hoffmann-La Roche, Horizon Therapeutics (now Amgen, Inc), Kinevant Sciences, Molecure, NeRRe, Novartis, PureTech, Thyron, Trevi and Vicore. C. Emson and K. Hudson are employees of Horizon Therapeutics (now Amgen, Inc) and own stock. A.J. Amatucci was employed at Horizon Therapeutics (now Amgen, Inc) during development of this manuscript. O. Distler has/had a consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last 3 calendar years: 4P-Pharma, AbbVie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Argenx, Arxx, AstraZeneca, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, Horizon, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Orion, Prometheus, Redxpharma, Roivant, Topadur and UCB; has a patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143); and is co-founder of CITUS AG. Y. Allanore has received consulting fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Janssen, Galderma, Medsenic and Prometheus. D. Khanna has received consulting fees from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Chemomab, CSL Behring, GSK, Merck, Novartis, Prometheus, Roche and UCB; and grant support from BMS, Boehringer Ingelheim, Horizon Therapeutics (now Amgen, Inc), Pfizer and Prometheus., (Copyright ©The authors 2024.)

Pentoxifylline (PTX), a non-selective phosphodiesterase inhibitor, has demonstrated protective effects against lung injury in animal models. Given the significance of pulmonary toxicity resulting from paraquat (PQ) exposure, the present investigation was designed to explore the impact of PTX on PQ-induced pulmonary oxidative impairment in male mice.Following preliminary studies, thirty-six mice were divided into six groups. Group 1 received normal saline, group 2 received a single dose of PQ (20 mg/kg; i.p.), and group 3 received PTX (100 mg/kg/day; i.p.). Additionally, treatment groups 4-6 were received various doses of PTX (25, 50, and 100 mg/kg/day; respectively) one hour after a single dose of PQ. After 72 hours, the animals were sacrificed, and lung tissue was collected.PQ administration caused a significant decrease in hematocrit and an increase in blood potassium levels. Moreover, a notable increase was found in the lipid peroxidation (LPO), nitric oxide (NO), and myeloperoxidase (MPO) levels, along with a notable decrease in total thiol (TTM) and total antioxidant capacity (TAC) contents, catalase (CAT) and superoxide dismutase (SOD) enzymes activity in lung tissue. PTX demonstrated the ability to improve hematocrit levels; enhance SOD activity and TTM content; and decrease MPO activity, LPO and NO levels in PQ-induced pulmonary toxicity. Furthermore, these findings were well-correlated with the observed lung histopathological changes.In conclusion, our results suggest that the high dose of PTX may ameliorate lung injury by improving the oxidant/antioxidant balance in animals exposed to PQ., Competing Interests: The authors declare that they have no conflicts of interest., (Thieme. All rights reserved.)

Cyclic nucleotide phosphodiesterases (PDEs) modulate neurohormonal regulation of cardiac function by degrading cAMP and cGMP. In cardiomyocytes, multiple isoforms of PDEs with different enzymatic properties and subcellular locally regulate cyclic nucleotide levels and associated cellular functions. This organisation is severely disrupted during hypertrophy and heart failure (HF), which may contribute to disease progression. Clinically, PDE inhibition has been seen as a promising approach to compensate for the catecholamine desensitisation that accompanies heart failure. Although PDE3 inhibitors such as milrinone or enoximone can be used clinically to improve systolic function and relieve the symptoms of acute CHF, their chronic use has proved detrimental. Other PDEs, such as PDE1, PDE2, PDE4, PDE5, PDE9 and PDE10, have emerged as potential new targets for the treatment of HF, each with a unique role in local cyclic nucleotide signalling pathways. In this review, we describe cAMP and cGMP signalling in cardiomyocytes and present the different families of PDEs expressed in the heart and their modifications in pathological cardiac hypertrophy and HF. We also review results from preclinical models and clinical data indicating the use of specific PDE inhibitors or activators that may have therapeutic potential in CI., (© 2024 médecine/sciences – Inserm.)

Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet. Herein, compound AG-205/1186117 with the dihydropyrimidine scaffold was selected as the hit by virtual screening. A hit-to-lead structural modification led to a series of dihydropyrimidine derivatives. Lead 13h exhibited the IC 50 of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of 13h exerted significant anti-liver fibrotic effects in bile duct ligation-induced fibrosis rats, which also prevented TGF-β-induced myofibroblast differentiation in vitro, confirming that PDE1 could work as a potential target for liver fibrosis.

Phosphodiesterase (PDE) is a superfamily of enzymes that are responsible for the hydrolysis of two second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). PDE inhibition promotes the gene transcription by activating cAMP-response element binding protein (CREB), initiating gene transcription of brain-derived neurotrophic factor (BDNF). The procedure exerts neuroprotective profile, and motor and cognitive improving efficacy. From this point of view, PDE inhibition will provide a promising therapeutic strategy for treating neurodegenerative disorders. Herein, we summarized the PDE inhibitors that have entered the clinical trials or been discovered in recent five years. Well-designed clinical or preclinical investigations have confirmed the effectiveness of PDE inhibitors, such as decreasing Aβ oligomerization and tau phosphorylation, alleviating neuro-inflammation and oxidative stress, modulating neuronal plasticity and improving long-term cognitive impairment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze cyclic nucleotides, including cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both cyclic nucleotides are critical secondary messengers in the neurohormonal regulation in the cardiovascular system. PDEs precisely control spatiotemporal subcellular distribution of cyclic nucleotides in a cell- and tissue-specific manner, playing critical roles in physiological responses to hormone stimulation in the heart and vessels. Dysregulation of PDEs has been linked to the development of several cardiovascular diseases, such as hypertension, aneurysm, atherosclerosis, arrhythmia, and heart failure. Targeting these enzymes has been proven effective in treating cardiovascular diseases and is an attractive and promising strategy for the development of new drugs. In this review, we discuss the current understanding of the complex regulation of PDE isoforms in cardiovascular function, highlighting the divergent and even opposing roles of PDE isoforms in different pathogenesis.

T-cell activation is a pivotal process of the adaptive immune response with 3',5'-cyclic adenosine monophosphate (cAMP) as a key regulator of T-cell activation and function. It governs crucial control over T-cell differentiation and production of pro-inflammatory cytokines, such as IFN-γ. Intriguingly, levels of intracellular cAMP differ between regulatory (Treg) and conventional T-cells (Tcon). During cell-cell contact, cAMP is transferred via gap junctions between these T-cell subsets to mediate the immunosuppressive function of Treg. Moreover, the activation of T-cells via CD3 and CD28 co-stimulation leads to a transient upregulation of cAMP. Elevated intracellular cAMP levels are balanced precisely by phosphodiesterases (PDEs), a family of enzymes that hydrolyze cyclic nucleotides. Various PDEs play distinct roles in regulating cAMP and cyclic guanosine monophosphate (cGMP) in T-cells. Research on PDEs has gained growing interest due to their therapeutic potential to manipulate T-cell responses. So far, PDE4 is the best-described PDE in T-cells and the first PDE that is currently targeted in clinical practice to treat autoimmune diseases. But also, other PDE families harbor additional therapeutic potential. PDE2A is a dual-substrate phosphodiesterase which is selectively upregulated in Tcon upon activation. In this Mini-Review, we will highlight the impact of cAMP regulation on T-cell activation and function and summarize recent findings on different PDEs regulating intracellular cAMP levels in T-cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bielenberg, Kurelic, Frantz and Nikolaev.)

Apicomplexa encompasses a large number of intracellular parasites infecting a wide range of animals. Cyclic nucleotide signaling is crucial for a variety of apicomplexan life stages and cellular processes. The cyclases and kinases that synthesize and respond to cyclic nucleotides (i.e., 3',5'-cyclic guanosine monophosphate and 3',5'-cyclic adenosine monophosphate) are highly conserved and essential throughout the parasite phylum. Growing evidence indicates that phosphodiesterases (PDEs) are also critical for regulating cyclic nucleotide signaling via cyclic nucleotide hydrolysis. Here, we discuss recent advances in apicomplexan PDE biology and opportunities for therapeutic interventions, with special emphasis on the major human apicomplexan parasite genera Plasmodium , Toxoplasma , Cryptosporidium , and Babesia . In particular, we show a highly flexible repertoire of apicomplexan PDEs associated with a wide range of cellular requirements across parasites and lifecycle stages. Despite this phylogenetic diversity, cellular requirements of apicomplexan PDEs for motility, host cell egress, or invasion are conserved. However, the molecular wiring of associated PDEs is extremely malleable suggesting that PDE diversity and redundancy are key for the optimization of cyclic nucleotide turnover to respond to the various environments encountered by each parasite and life stage. Understanding how apicomplexan PDEs are regulated and integrating multiple signaling systems into a unified response represent an untapped avenue for future exploration., Competing Interests: The authors declare no conflict of interest.

Alcohol use disorder (AUD) requires new neurobiological targets. Problematic drinking involves underactive indirect pathway medium spiny neurons (iMSNs) that subserve adaptive behavioral selection vs. overactive direct pathway MSNs (dMSNs) that promote drinking, with a shift from ventromedial to dorsolateral striatal (VMS, DLS) control of EtOH-related behavior. We hypothesized that inhibiting phosphodiesterase 10A (PDE10A), enriched in striatal MSNs, would reduce EtOH self-administration in rats with a history of chronic intermittent ethanol exposure. To test this, Wistar rats ( n = 10/sex) with a history of chronic intermittent EtOH (CIE) vapor exposure received MR1916 (i.p., 0, 0.05, 0.1, 0.2, and 0.4 µmol/kg), a PDE10A inhibitor, before operant EtOH self-administration sessions. We determined whether MR1916 altered the expression of MSN markers ( Pde10a , Drd1 , Drd2 , Penk , and Tac1 ) and immediate-early genes (IEG) ( Fos , Fosb , Δ Fosb , and Egr1 ) in EtOH-naïve ( n = 5-6/grp) and post-CIE ( n = 6-8/grp) rats. MR1916 reduced the EtOH self-administration of high-drinking, post-CIE males, but increased it at a low, but not higher, doses, in females and low-drinking males. MR1916 increased Egr1 , Fos , and FosB in the DLS, modulated by sex and alcohol history. MR1916 elicited dMSN vs. iMSN markers differently in ethanol-naïve vs. post-CIE rats. High-drinking, post-CIE males showed higher DLS Drd1 and VMS IEG expression. Our results implicate a role and potential striatal bases of PDE10A inhibitors to influence post-dependent drinking.

Cancer immunotherapy, particularly with immune checkpoint inhibitors, has revolutionized the paradigm of cancer treatment. Nevertheless, the efficacy of cancer immunotherapy remains limited in most clinical settings due to the lack of a preexisting antitumor T-cell response in tumors. Therefore, the clinical outcomes of cancer immunotherapy must be improved crucially. With increased awareness of the importance of the innate immune response in the recruitment of T cells, as well as the onset and maintenance of the T cell response, great interest has been shown in activating the cGAS-STING signaling pathway to awaken the innate immune response, thereby orchestrating both innate and adaptive immune responses to induce tumor clearance. However, tumor cells have evolved to overexpress ectonucleotide pyrophosphate phosphodiesterase 1 (ENPP1), which degrades the immunotransmitter 2',3'-cGAMP and promotes the production of immune-suppressing adenosine, resulting in inhibition of the anticancer immune response in the tumor microenvironment. Clinically, ENPP1 overexpression is closely associated with poor prognosis in patients with cancer. Conversely, depleting or inhibiting ENPP1 has been verified to elevate extracellular 2',3'-cGAMP levels and inhibit the generation of adenosine, thereby reinvigorating the anticancer immune response for tumor elimination. A variety of ENPP1 inhibitors have recently been developed and have demonstrated significant promise for cancer immunotherapy. In this review, we provide an overview of ENPP1, dissect its immunosuppressive mechanisms, and discuss the development of ENPP1 inhibitors with the potential to further improve the efficacy of cancer immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Phosphodiesterase 1 (PDE1) is an enzyme entrusted with the hydrolysis of the second messengers cAMP and cGMP, thereby governing a plethora of metabolic processes, encompassing ion channel modulation and cellular apoptosis. Recent advancements in the realm of small molecule structural variations have greatly facilitated the exploration of innovative applications for PDE1. Remarkably, a recent series of PDE1 inhibitors (PDE1i) have been meticulously formulated and devised, showcasing enhanced selectivity and potency. Among them, ITI-214 has entered Phase II clinical trials, holding promise for the treatment of Parkinson's disease and heart failure. Nevertheless, the majority of current PDE1 inhibitors have encountered substantial side effects in clinical trials attributable to their limited selectivity, this predicament presents a formidable obstacle in the development of specific small molecule inhibitors targeting PDE1. This Perspective endeavors to illuminate the potential design approaches, structure-activity relationships, and biological activities of current PDE1i, aiming to offer support and insights for clinical practice and the development of novel PDE1i., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Cyclic adenosine monophosphates (cAMP) and cyclic guanosine monophosphate (cGMP) are two essential second messengers, which are hydrolyzed by phosphodiesterase's (PDEs), such as PDE-2. Pharmacological inhibition of PDE-2 (PDE2A) in the central nervous system improves cAMP and cGMP signaling, which controls downstream proteins related to neuropsychiatric, neurodegenerative, and neurodevelopmental disorders. Considering that there are no specific treatments for these disorders, PDE-2 inhibitors' development has gained more attention in the recent decade. There is high demand for developing new-generation drugs targeting PDE2 for treating diseases in the central nervous and peripheral systems. This review summarizes the relationship between PDE-2 with neuropsychiatric, neurodegenerative, and neurodevelopmental disorders as well as its possible treatment, mainly involving inhibitors of PDE2., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This Perspective provides an updated overview on the involvement of phosphodiesterase (PDE) isoforms and of the corresponding inhibitors in neurological disorders, including dementia, Parkinson's disease, multiple sclerosis, neuropsychiatric conditions and cerebral ischemia. Particular attention has been dedicated to natural and semi-synthetic compounds. Translation into the clinic of preclinical results, toxicity profile and bioavailability represent the challenging aspects in the development of PDE inhibitors. With the aim of providing the latest updates to the reader, the 2023 contributions in the field were considered for the preparation of this Perspective ., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Erectile dysfunction (ED) is one of the most common sexual disorders in males, which seriously affects the health of the patient and well-being of the family. The therapeutic strategy of ED is an individualized comprehensive treatment based on phosphodiesterase inhibitors. At present, as a new option for the treatment of ED, micro-energy medicine has attracted more and more attention in its therapeutic effects and advantages. This article presents an overview of the progress in the studies of micro-energy medicine in the treatment of ED.

Intracellular glucose concentration plays a crucial role in initiating the molecular secretory process of pancreatic β-cells through multiple messengers and signaling pathways. Cyclic nucleotides are key physiological regulators that modulate pathway interactions in β -cells. An increase of cyclic nucleotides is controled by hydrolysed phosphodiesterases (PDEs), which degrades cyclic nucleotides into inactive metabolites. Despite the undeniable therapeutic potential of PDE inhibitors, they are associated with several side effects. The treatment strategy for diabetes based on PDE inhibitors has been proposed for a long time. Hence, the world of natural antidiabetic medicinal plants represents an ideal source of phosphodiesterase inhibitors as a new strategy for developing novel agents to treat diabetes mellitus. This review highlights medicinal plants traditionally used in the treatment of diabetes mellitus that have been proven to have inhibitory effects on PDE activity. The contents of this review were sourced from electronic databases, including Science Direct, PubMed, Springer Link, Web of Science, Scopus, Wiley Online, Scifinder and Google Scholar. These databases were consulted to collect information without any limitation date. After comprehensive literature screening, this paper identified 27 medicinal plants that have been reported to exhibit anti-phosphodiesterase activities. The selection of these plants was based on their traditional uses in the treatment of diabetes mellitus. The review emphasizes the antiphosphodiesterase properties of 31 bioactive components derived from these plant extracts. Many phenolic compounds have been identified as PDE inhibitors: Brazilin, mesozygin, artonin I, chalcomaracin, norartocarpetin, moracin L, moracin M, moracin C, curcumin, gallic acid, caffeic acid, rutin, quercitrin, quercetin, catechin, kaempferol, chlorogenic acid, and ellagic acid. Moreover, smome lignans have reported as PDE inhibitors: (+)-Medioresinol di-O-β-d-glucopyranoside, (+)- Pinoresinol di-O-β-d-glucopyranoside, (+)-Pinoresinol-4-O-β-d-glucopyranosyl (1→6)-β-dglucopyranoside, Liriodendrin, (+)-Pinoresinol 4'-O-β-d-glucopyranoside, and forsythin. This review provides a promising starting point of medicinal plants, which could be further studied for the development of natural phosphodiesterase inhibitors to treat diabetes mellitus. Therefore, it is important to consider clinical studies for the identification of new targets for the treatment of diabetes., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Diabetic nephropathy (DN), the leading cause of end-stage renal disease, has no definite treatment so far. In fact, a combination of metabolic, hemodynamic, and immunological factors are involved in the pathogenesis of DN; therefore, effective disease management requires a holistic approach to all predisposing contributors. Due to the recent findings about the role of inflammation in the initiation and progression of kidney injury in diabetic patients and considerable advances in immunotherapy methods, it might be useful to revise and reconsider the current knowledge of the potential of immunomodulation in preventing and attenuating DN. In this review, we have summarized the findings of add-on therapeutic methods that have concentrated on regulating inflammatory responses in diabetic nephropathy, including phosphodiesterase inhibitors, nuclear factor-kB inhibitors, Janus kinase inhibitors, chemokine inhibitors, anti-cytokine antibodies, cell therapy, and vaccination., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Intracellular second messenger cyclic guanosine monophosphate (cGMP) mediates bioactivity of the natriuretic peptides and nitric oxide, and is key to circulatory homeostasis and protection against cardiovascular disease. Inhibition of cGMP-degrading phosphodiesterases (PDEs) PDE5 and PDE9 are emerging as pharmacological targets in heart failure (HF)., Objectives: The present study investigated dual enhancement of cGMP in experimental HF by combining inhibition of PDE-5 (P5-I) and PDE-9 (P9-I)., Methods: Eight sheep with pacing-induced HF received on separate days intravenous P5-I (sildenafil), P9-I (PF-04749982), P5-I+P9-I, and vehicle control, in counterbalanced order., Results: Compared with control, separate P5-I and P9-I significantly increased circulating cGMP concentrations in association with reductions in mean arterial pressure (MAP), left atrial pressure (LAP), and pulmonary arterial pressure (PAP), with effects of P5-I on cGMP, MAP, and PAP greater than those of P9-I. Only P5-I decreased pulmonary vascular resistance. Combination P5-I+P9-I further reduced MAP, LAP, and PAP relative to inhibition of either phosphodiesterase alone. P9-I and, especially, P5-I elevated urinary cGMP levels relative to control. However, whereas inhibition of either enzyme increased urine creatinine excretion and clearance, only P9-I induced a significant diuresis and natriuresis. Combined P5-I+P9-I further elevated urine cGMP with concomitant increases in urine volume, sodium and creatinine excretion, and clearance similar to P9-I alone, despite the greater MAP reductions induced by combination treatment., Conclusions: Combined P5-I+P9-I amalgamated the superior renal effects of P9-I and pulmonary effects of P5-1, while concurrently further reducing cardiac preload and afterload. These findings support combination P5-I+P9-I as a therapeutic strategy in HF., Competing Interests: Funding Support and Author Disclosures Financial support was provided by grants from the Heart Foundation of New Zealand (#1861) and the Canterbury Medical Research Foundation (#07-20). Dr Rademaker was named investigator on research grants from the Heart Foundation of New Zealand (#1861) and Canterbury Medical Research Foundation (#07-20). PF-04749982 and Sildenafil were provided by Pfizer via a Compound Transfer Agreement (CG#60248811 [WI215594]). Dr Scott was named investigator and received significant salary support from research grants from the Heart Foundation of New Zealand (#1861) and the Canterbury Medical Research Foundation (#07-20). Drs Charles and Richards were named investigators on research grants from the Heart Foundation of New Zealand (#1861) and the Canterbury Medical Research Foundation (#07-20)., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Phosphodiesterase 11A4 (PDE11A4) is a dual-acting cyclic nucleotide hydrolase expressed in neurons in the CA1, subiculum, amygdalostriatal transition area and amygdalohippocampal area of the extended hippocampal formation. PDE11A4 is the only PDE enzyme to emanate solely from hippocampal formation, a key brain region for the formation of long-term memory. PDE11A4 expression increases in the hippocampal formation of both humans and rodents as they age. Interestingly, PDE11A knockout mice do not show age-related deficits in associative memory and show no gross histopathology. This suggests that inhibition of PDE11A4 might serve as a therapeutic option for age-related cognitive decline. A novel, yeast-based high throughput screen previously identified moderately potent, selective PDE11A4 inhibitors, and this work describes initial efforts that improved potency more than 10-fold and improved some pharmaceutical properties of one of these scaffolds, leading to selective, cell-penetrant PDE11A4 inhibitors, one of which is 10-fold more potent compared to tadalafil in cell-based activity.

Cyclic nucleotide phosphodiesterase 9 (PDE9), a specifically hydrolytic enzyme with the highest affinity for cyclic guanosine monophosphate (cGMP) among the phosphodiesterases family, plays a critical role in many biological processes. Consequently, the development of PDE9 inhibitors has received increasing attention in recent years, with several compounds undergoing clinical trials for the treatment of central nervous system (CNS) diseases such as Alzheimer's disease, schizophrenia, and psychotic disorders, as well as heart failure and sickle cell disease. This review analyzes the recent primary literatures and patents published from 2004 to 2023, focusing on the structure, pharmacophores, selectivity, and therapeutic potential of PDE9 inhibitors. It hoped to provide a comprehensive overview of the field's current state to inform the development of novel PDE9 inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Diabetic neuropathy (DN) is the most prevalent complication of diabetes. Pharmacological treatments for DN are often limited in efficacy, so the development of new agents to alleviate DN is essential. The aim of this study was to evaluate the effects of rolipram, a selective phosphodiesterase-4 inhibitor (PDE-4I), and pentoxifylline, a general PDE inhibitor, using a rat model of DN. In this study, a diabetic rat model was established by i.p. injection of STZ (55 mg/kg). Rats were treated with rolipram (1 mg/kg), pentoxifylline (100 mg/kg), and combination of rolipram (0.5 mg/kg) and pentoxifylline (50 mg/kg), orally for 5 weeks. After treatments, sensory function was assessed by hot plate test. Then rats were anesthetized and dorsal root ganglion (DRG) neurons isolated. Cyclic adenosine monophosphate (cAMP), adenosine triphosphate (ATP, adenosine diphosphate and mitochondrial membrane potential (MMP) levels, Cytochrome c release, Bax, Bcl-2, caspase-3 proteins expression in DRG neurons were assessed by biochemical and ELISA methods, and western blot analysis. DRG neurons were histologically examined using hematoxylin and eosin (H&E) staining method. Rolipram and/or pentoxifylline significantly attenuated sensory dysfunction by modulating nociceptive threshold. Rolipram and/or pentoxifylline treatment dramatically increased the cAMP level, prevented mitochondrial dysfunction, apoptosis and degeneration of DRG neurons, which appears to be mediated by inducing ATP and MMP, improving cytochrome c release, as well as regulating the expression of Bax, Bcl-2, and caspase-3 proteins, and improving morphological abnormalities of DRG neurons. We found maximum effectiveness with rolipram and pentoxifylline combination on mentioned factors. These findings encourage the use of rolipram and pentoxifylline combination as a novel experimental evidence for further clinical investigations in the treatment of DN., (© 2023 Wiley Periodicals LLC.)

Background: Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder, presenting with a variety of aetiological and phenotypical features. Ibudilast is known to produce beneficial effects in several neurological disorders including neuropathic pain, multiple sclerosis, etc. by displaying its neuroprotective and anti-inflammatory properties. Here, in our study, the pharmacological outcome of ibudilast administration was investigated in the prenatal valproic acid (VPA)-model of ASD in Wistar rats., Methods: Autistic-like symptoms were induced in Wistar male pups of dams administered with Valproic acid (VPA) on embryonic day 12.5. VPA-exposed male pups were administered with two doses of ibudilast (5 and10 mg/kg) and all the groups were evaluated for behavioral parameters like social interaction, spatial memory/learning, anxiety, locomotor activity, and nociceptive threshold. Further, the possible neuroprotective effect of ibudilast was evaluated by assessing oxidative stress, neuroinflammation (IL-1β, TNF-α, IL-6, IL-10) in the hippocampus, % area of Glial fibrillary acidic protein (GFAP)-positive cells and neuronal damage in the cerebellum., Key Findings: Treatment with ibudilast significantly attenuated prenatal VPA exposure associated social interaction and spatial learning/memory deficits, anxiety, hyperactivity, and increased nociceptive threshold, and it decreased oxidative stress markers, pro-inflammatory markers (IL-1β, TNF-α, IL-6), and % area of GFAP-positive cells and restored neuronal damage., Conclusions: Ibudilast treatment has restored crucial ASD-related behavioural abnormalities, potentially through neuroprotection. Therefore, benefits of ibudilast administration in animal models of ASD suggest that ibudilast may have therapeutic potential in the treatment of ASD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Phosphodiesterase 1 (PDE1) is a subfamily of PDE super enzyme families that can hydrolyze cyclic adenosine monophosphate and cyclic guanosine monophosphate simultaneously. Currently, the number of PDE1 inhibitors is relatively few, significantly limiting their application. Herein, a novel series of quinolin-2(1 H )-ones were designed rationally, leading to compound 10c with an IC 50 of 15 nM against PDE1C, high selectivity across other PDEs, and remarkable safety properties. Furthermore, we used the lead compound 10c as a chemical tool to explore whether PDE1 could work as a novel potential target for the treatment of inflammatory bowel disease (IBD), a disease which is a chronic, relapsing disorder of the gastrointestinal tract inflammation lacking effective treatment. Our results showed that administration of 10c exerted significant anti-IBD effects in the dextran sodium sulfate-induced mice model and alleviated the inflammatory response, indicating that PDE1 could work as a potent target for IBD.