Automatic synthesis of a phosphodiesterase 4B (PDE4B) radioligand and PET imaging in depression rodent models.

Myocardial ischemia/reperfusion (I/R) injury is a clinical challenge in the treatment of acute myocardial infarction (AMI). Phosphodiesterase 4B (PDE4B) expression is upregulated in AMI tissues. Thus, the present study aimed to investigate the role of PDE4B in myocardial I/R injury. H9c2 cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) to establish an in vitro myocardial I/R model. PDE4B expression was detected via reverse transcription-quantitative PCR (RT-qPCR) and western blotting before and after transfection with PDE4B interference plasmids in H/R-stimulated H9c2 cells. Cell viability and cytotoxicity were assessed using the Cell Counting Kit-8 and lactate dehydrogenase assays, respectively. Furthermore, oxidative stress was assessed using malondialdehyde, superoxide dismutase and glutathione/glutathione oxidized ratio detection kits. Cell apoptosis was detected via a TUNEL assay and western blotting. c-Jun dimerization protein 2 (JDP2) expression was also detected via RT-qPCR and western blotting. The dual luciferase reporter and chromatin immunoprecipitation assays were performed to verify the interaction between JDP2 and PDE4B. Following co-transfection with PDE4B interference plasmid and JDP2 overexpression plasmid, cell viability, cytotoxicity, oxidative stress and cell apoptosis were assessed. The results demonstrated that PDE4B knockdown reversed H/R-induced loss of viability and cytotoxicity of H9c2 cells. H/R-induced oxidative stress and cardiomyocyte apoptosis were also alleviated by PDE4B knockdown. In addition, the transcription factor JDP2 was expressed at high levels in H/R-stimulated H9c2 cells, and JDP2 overexpression upregulated PDE4B expression. Notably, JDP2 overexpression partly reversed the ameliorative effect of PDE4B knockdown on H/R-induced H9c2 injury. Taken together, the results of the present study suggested that JDP2-activated PDE4B contributed to H/R-induced H9c2 cell injury.

Phosphodiesterase 4B (PDE4B) is a key enzyme involved in regulating intracellular cyclic adenosine monophosphate levels and plays a significant role in the diagnosis, classification, treatment, and prognosis of various cancers. However, the role of PDE4B in gastric cancer (GC) remains unclear. We used the GEPIA2 (Gene Expression Profiling Interactive Analysis 2) database to analyze the differential expression level of PDE4B across tumor samples and verified our findings via qPCR and immunohistochemical analysis. We also analyzed the correlation between PDE4B expression levels and clinical pathological parameters, and prognosis, in the database. The effects of PDE4B on GC proliferation, migration, and invasion were evaluated through in vitro and in vivo experiments. Enrichment analysis was performed using bioinformatic tools, and results were validated by western blot analysis. The correlation between PDE4B expression and immune cell infiltration was investigated using bioinformatics tools. PDE4B is highly expressed in GC and is significantly associated with deep infiltration, distant metastasis, tumor, node, metastasis (TNM) stage, and preoperative CA199 levels. Over-expression of PDE4B promotes proliferation, clonal formation, migration, and invasion of GC cells and is associated with poor prognosis. PDE4B promotes the infiltration of immune cells into the tumor microenvironment (TME) and the phosphorylation of PI3K/AKT pathway, increasing MYC expression. PDE4B can serve as an independent prognostic biomarker for GC. We found that PDE4B can promote immune cell infiltration of the TME and mediate malignancy in gastric cancer through the PI3K/AKT/MYC pathway.

Control of the PI3K/AKT Pathway by Phosphodiesterase 4B Modulates Glucocorticoid Response in B-Cell Lymphomas.

PDE4B Activity Controls Glucorticoid and Rapamycin Effects in DLBCL.

Phosphodiesterase 4B is required for NLRP3 inflammasome activation by positive feedback with Nrf2 in the early phase of LPS- induced acute lung injury

The cyclic AMP (adenosine monophosphate; cAMP)-hydrolyzing protein PDE4B (phosphodiesterase 4B) is a key negative regulator of cardiac β-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal Ca2+ handling and PDE4B is decreased in pressure overload hypertrophy, suggesting that increasing PDE4B in the heart is beneficial in heart failure. We measured PDE4B expression in human cardiac tissues and developed 2 transgenic mouse lines with cardiomyocyte-specific overexpression of PDE4B and an adeno-associated virus serotype 9 encoding PDE4B. Myocardial structure and function were evaluated by echocardiography, ECG, and in Langendorff-perfused hearts. Also, cAMP and PKA (cAMP dependent protein kinase) activity were monitored by Förster resonance energy transfer, L-type Ca2+ current by whole-cell patch-clamp, and cardiomyocyte shortening and Ca2+ transients with an Ionoptix system. Heart failure was induced by 2 weeks infusion of isoproterenol or transverse aortic constriction. Cardiac remodeling was evaluated by serial echocardiography, morphometric analysis, and histology. PDE4B protein was decreased in human failing hearts. The first PDE4B-transgenic mouse line (TG15) had a ≈15-fold increase in cardiac cAMP-PDE activity and a ≈30% decrease in cAMP content and fractional shortening associated with a mild cardiac hypertrophy that resorbed with age. Basal ex vivo myocardial function was unchanged, but β-adrenergic receptor stimulation of cardiac inotropy, cAMP, PKA, L-type Ca2+ current, Ca2+ transients, and cell contraction were blunted. Endurance capacity and life expectancy were normal. Moreover, these mice were protected from systolic dysfunction, hypertrophy, lung congestion, and fibrosis induced by chronic isoproterenol treatment. In the second PDE4B-transgenic mouse line (TG50), markedly higher PDE4B overexpression, resulting in a ≈50-fold increase in cardiac cAMP-PDE activity caused a ≈50% decrease in fractional shortening, hypertrophy, dilatation, and premature death. In contrast, mice injected with adeno-associated virus serotype 9 encoding PDE4B (1012 viral particles/mouse) had a ≈50% increase in cardiac cAMP-PDE activity, which did not modify basal cardiac function but efficiently prevented systolic dysfunction, apoptosis, and fibrosis, while attenuating hypertrophy induced by chronic isoproterenol infusion. Similarly, adeno-associated virus serotype 9 encoding PDE4B slowed contractile deterioration, attenuated hypertrophy and lung congestion, and prevented apoptosis and fibrotic remodeling in transverse aortic constriction. Our results indicate that a moderate increase in PDE4B is cardioprotective and suggest that cardiac gene therapy with PDE4B might constitute a new promising approach to treat heart failure.

Phosphodiesterase 4B activation exacerbates pulmonary hypertension induced by intermittent hypoxia by regulating mitochondrial injury and cAMP/PKA/p-CREB/PGC-1α signaling

The important role of phosphodiesterase 4B (PDE4B) inhibition on lipopolysaccharide (LPS)-induced ALI has been reported. However, the corresponding mechanisms remain unclear. In the present study, the relationship between PDE4B and phosphorylation of p65 (Ser468) in LPS-induced injury by in vivo and in vitro models was investigated. pde4b+/+ mice, inflammation was significantly up-regulated after LPS stimulation, including the highest number of immune cells, especially neutrophils, and the level of pro-inflammatory cytokines measured by ELISA, while all those were blunted in pde4b-/- mice. Moreover, pde4b-/- mice improved the expression of PKA in lung tissues and down-regulated the IKKα/β-NF-κB p65 signaling determined by western blotting. In vitro experiments in MH-S cells revealed that siRNA-mediated specific silence of PDE4B expression resulted in a decrease of inflammatory markers and phosphorylation of p65 at Ser468 after LPS treatment, but overexpressing PDE4B increased the inflammation and phosphorylation of p65 at Ser468. In MH-S cells, luciferase analysis indicated that PDE4B acts as a positive regulator of p65 in inflammation. PKA inhibitor (H-89) increased pP65 and PDE4B expression, while PKA activator (6-BZ-cAMP) showed the opposite effect in macrophages. More importantly, the proteasome-mediated degradation of cAMP effector was negatively correlated with the phosphorylation of p65 (Ser468) and PDE4B expression in MH-S cells. PDE4B plays a critical role in orchestrating LPS-induced acute lung inflammation by cAMP/PKA axis-mediated phosphorylation of p65.

Myopia is the most common cause of refractive error worldwide. High myopia is a severe type of myopia, which usually accompanies pathological changes in the fundus. To identify high myopia susceptibility genes, DNA-pooling based genome-wide association analysis was used to search for a correlation between single nucleotide polymorphisms and high myopia in a Han Chinese cohort (cases vs. controls in discovery stage: 507 vs. 294; replication stage 1: 991 vs. 1,025; replication stage 2: 1,021 vs. 52,708). Three variants (rs10889602T/G, rs2193015T/C, rs9676191A/C) were identified as being significantly associated with high myopia in the discovery, and replication stage. rs10889602T/G is located at the third intron of phosphodiesterase 4B (PDE4B), whose functional assays were performed by comparing the effects of rs10889602T/T deletion of this risk allele on PDE4B and COL1A1 gene and protein expression levels in the rs10889602T/Tdel/del, rs10889602T/Tdel/wt, and normal control A549 cell lines. The declines in the PDE4B and COL1A1 gene expression levels were larger in the rs10889602T/T deleted A549 cells than in the normal control A549 cells (one-way ANOVA, p < 0.001). The knockdown of PDE4B by siRNA in human scleral fibroblasts led to downregulation of COL1A1. This correspondence between the declines in rs10889602 of the PDE4B gene, PDE4B knockdown, and COL1A1 protein expression levels suggest that PDE4B may be a novel high myopia susceptibility gene, which regulates myopia progression through controlling scleral collagen I expression levels. More studies are needed to determine if there is a correlation between PDE4B and high myopia in other larger sample sized cohorts.

PDE4B abrogation extenuates angiotensin II-induced endothelial dysfunction related to hypertension through up-regulation of AMPK/Sirt1/Nrf2/ARE signaling.

Introduction Phosphodiesterase 4B (PDE4B) is a crucial enzyme in the phosphodiesterases (PDEs), acting as a regulator of cyclic adenosine monophosphate (cAMP). It is involved in cancer process through PDE4B/cAMP signaling pathway. Cancer occurs and develops with the regulation of PDE4B in the body, suggesting that PDE4B is a promising therapeutic target. Areas covered This review covereed the function and mechanism of PDE4B in cancer. We summarized the possible clinical applications of PDE4B, and highlighted the possible ways to develop clinical applications of PDE4B inhibitors. We also discussed some common PDEs inhibitors, and expected the development of combined targeting PDE4B and other PDEs drugs in the future. Expert opinion The existing research and clinical data can strongly prove the role of PDE4B in cancer. PDE4B inhibition can effectively increase cell apoptosis, inhibit cell proliferation, transformation, migration, etc., indicating that PDE4B inhibition can effectively inhibit the development of cancer. Other PDEs may antagonize or coordinate this effect. As for the further study on the relationship between PDE4B and other PDEs in cancer, it is still a challenge to develop multi-targeted PDEs inhibitors.

PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia

Intervertebral disc degeneration disease (IDD) is one of the leading causes of disability, and current therapies are ineffective. Phosphodiesterase 4B (PDE4B) plays essential roles in regulating the activation of the NLRP3 inflammasome. However, whether PDE4B or NLRP3 is involved in the development of IDD is unclear. This study sought to explore the role of PDE4B in IDD pathogenesis by in vivo and in vitro experiments. This results showed that PDE4B and NLRP3 were significantly upregulated in nucleus pulposus (NP) tissues from IDD-related human patients. Deletion of PDE4B in the NP resulted in downregulated JNK and NLRP3. Aberrant PDE4B expression enhanced the phosphorylation of JNK and NLRP3 expression. Furthermore, genetic ablation of the pde4b gene delayed IDD pathogenesis, and PDE4 inhibitor also can reverse the IDD pathogenesis. Our study showed that aberrant PDE4B activation in NP tissues induces pathological changes in IDD, phosphorylation of JNK and NLRP3 are involved in this process, and inhibition of aberrant PDE4B activity is a potential therapeutic strategy for IDD.

Association study of PDE4B with panic disorder in the Japanese population

Prostate cancer is the most commonly diagnosed non-cutaneous cancer in American men. Unfortunately, few successful therapies for castration-resistant prostate cancer (CRPC) exist. The protein kinase A (PKA) pathway is a critical mediator of cellular proliferation and differentiation in various normal and cancerous cells. However, the PKA activity and the mechanism of regulation in CRPC remain unclear. Then, in this study, we intended to reveal the PKA activity and the mechanism of regulation in CRPC. Western blotting, quantitative real-time polymerase chain reaction, cytotoxicity analysis, and cell proliferation assay were used to resolve the regulatory role of PKA in prostate cancer cell line, LNCaP and their derivatives. cAMP-specific phosphodiesterase 4B (PDE4B) was downregulated and the PKA pathway was activated in castration-resistant LNCaP derivatives (CxR cells). Rolipram activated the PKA pathway via inhibition of PDE4B, resulting in AR transactivation while the PKA inhibitor, H89 reduced AR transactivation. In response to hydrogen peroxide and in hydrogen peroxide-resistant LNCaP derivatives (HPR50 cells) PDE4B was decreased and as a result PKA activity was increased. Moreover, PDE4B expression was reduced in advanced prostate cancer and PDE4B knockdown promoted castration-resistant growth of LNCaP cells. Oxidative stress may suppress PDE4B expression and activate the PKA pathway. The PDE4B/PKA pathway contributed to progression of androgen-dependent prostate cancer to CRPC. This pathway may represent an attractive therapeutic molecular target.