Background and Objectives: Colorectal cancer (CRC) is the most frequently diagnosed malignant disease of the gastrointestinal system, and new diagnostic and prognostic markers are needed to elucidate the complete tumor profile. Materials and Methods: We used CRC tumor tissues (Dukes\' A-D) and adjacent noncancerous tissues of 43 patients. Immunohistochemistry was used to examine the expression of phosphodiesterase 4B (PDE4B), phosphodiesterase 4D (PDE4D), and secreted frizzled related protein 5 (SFRP5) markers. We also analyzed the expression levels of PDE4B, PDE4D, and SFRP5 in CRC tissues compared to control tissues using RNA-sequencing data from the UCSC Xena browser. Results: In CRC stages, the distribution of PDE4B-positive cells varied, with differing percentages between epithelium and lamina propria. Statistically significant differences were found in the number of PDE4B-positive epithelial cells between healthy controls and all CRC stages, as well as between different CRC stages. Similarly, significant differences were observed in the number of PDE4B-positive cells in the lamina propria between healthy controls and all CRC stages, as well as between different CRC stages. CRC stage Dukes\' C exhibited a significantly higher number of PDE4B-positive cells in the lamina propria compared to CRC stage Dukes\' B. Significant differences were noted in the number of PDE4D-positive epithelial cells between healthy controls and CRC stages Dukes\' A, B, and D, as well as between CRC stage Dukes\' C and stages A, B, and D. CRC stage Dukes\' A had significantly more PDE4D-positive cells in the lamina propria compared to stage D. Significant differences were also observed in the number of SFRP5-positive cells in the lamina propria between healthy controls and all CRC stages, as well as between CRC stages Dukes\' A and D. While the expression of PDE4D varied across CRC stages, the expression of SFRP5 remained consistently strong in both epithelium and lamina propria, with significant differences noted mainly in the lamina propria. The expression levels of PDE4B, PDE4D, and SFRP5 reveal significant differences in the expression of these genes between CRC patients and healthy controls, with notable implications for patient prognosis. Namely, our results demonstrate that PDE4B, PDE4D, and SFRP5 are significantly under-expressed in CRC tissues compared to control tissues. The Kaplan-Meier survival analysis and the log-rank (Mantel-Cox) test revealed distinct prognostic implications where patients with lower expression levels of SFRP5 exhibited significantly longer overall survival. The data align with our immunohistochemical results and might suggest a potential tumor-suppressive role for these genes in CRC. Conclusions: Considering significantly lower gene expression, aligned with our immunohistochemical data in tumor tissue in comparison to the control tissue, as well as the significantly poorer survival rate in the case of its higher expression, we can hypothesize that SFRP5 is the most promising biomarker for CRC out of the observed proteins. These findings suggest alterations in PDE4B, PDE4D, and SFRP5 expression during CRC progression, as well as between different stages of CRC, with potential implications for understanding the molecular mechanisms involved in CRC development and progression.

UNASSIGNED: It has been reported that Runx1 engaged in IS progression, but the detailed mechanism of Runx1 in IS is still unclear.
UNASSIGNED: Mice and HT22 cells were subjected to the process of middle cerebral artery occlusion and reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R), respectively. Infract volume was tested using TTC staining. The levels of inflammatory cytokines were investigated using ELISA assay. Cell viability was examined utilizing MTS. Apoptosis rate was evaluated using flow cytometry and TUNEL. The productions of SOD and MDA were monitored by means of commercial kits. The correlations among Runx1, miR-203-3p and Pde4d were ascertained using dual luciferase reporter gene, ChIP and RNA-RNA pull-down assays.
UNASSIGNED: Runx1 and Pde4d were abnormally elevated, while miR-203-3p was notably declined in MCAO/R mice and OGD/R-induced HT22 cells. OGD/R treatment suppressed cell viability and facilitated cell apoptosis, inflammation and oxidative stress, which were compromised by Runx1 knockdown or miR-203-3p upregulation. Runx1 bound to miR-203-3p promoter, thus decreasing miR-203-3p expression. MiR-203-3p inhibited Pde4d expression via targeting Pde4d mRNA. Runx1 deficiency-induced protection effects on OGD/R-treated HT22 cells were offset by miR-203-3p downregulation.
UNASSIGNED: Runx1 aggravated neuronal injury caused by IS through mediating miR-203-3p/Pde4d axis.

Members of the phosphodiesterase 4 (PDE4) enzyme family regulate the availability of the secondary messenger cyclic adenosine monophosphate (cAMP) and, by doing so, control cellular processes in health and disease. In particular, PDE4D has been associated with Alzheimer\'s disease and the intellectual disability seen in fragile X syndrome. Furthermore, single point mutations in critical PDE4D regions cause acrodysostosis type 2(ACRDYS2, also referred to as inactivating PTH/PTHrP signalling disorder 5 or iPPSD5), where intellectual disability is seen in ∼90% of patients alongside the skeletal dysmorphologies that are characteristic of acrodysostosis type 1 (ACRDYS1/iPPSD4) and ACRDYS2. Two contrasting mechanisms have been proposed to explain how mutations in PDE4D cause iPPSD5. The first mechanism, the \'over-activation hypothesis\', suggests that cAMP/PKA (cyclic adenosine monophosphate/protein kinase A) signalling is reduced by the overactivity of mutant PDE4D, whilst the second, the \'over-compensation hypothesis\' suggests that mutations reduce PDE4D activity. That reduction in activity is proposed to cause an increase in cellular cAMP, triggering the overexpression of other PDE isoforms. The resulting over-compensation then reduces cellular cAMP and the levels of cAMP/PKA signalling. However, neither of these proposed mechanisms accounts for the fine control of PDE activation and localization, which are likely to play a role in the development of iPPSD5. This review will draw together our understanding of the role of PDE4D in iPPSD5 and present a novel perspective on possible mechanisms of disease.

BACKGROUND: Canine atopic dermatitis (CAD) is a common genetically predisposed, inflammatory, and pruritic skin disorder that affects dogs globally. To date, there are no specific biomarkers available to diagnose CAD, and the current diagnosis is based on a combination of criteria including patient history, clinical signs, and exclusion of other relevant differential diagnoses.
RESULTS: We examined the gene expression of phosphodiesterase 4D (PDE4D) in peripheral blood mononuclear cells (PBMCs), as well as miR-203 and miR-483 in plasma, in three groups: healthy dogs, CAD dogs, and other inflammatory pruritic skin diseases (OIPSD) such as pemphigus foliaceus, scabies, cutaneous lymphoma, and dermatophytosis. Our results showed that PDE4D gene expression in the CAD group is statistically higher compared to those in the healthy and OIPSD groups, suggesting PDE4D may be a specific marker for CAD. Nevertheless, no correlation was found between PDE4D gene expression levels and the lesion severity gauged by CAD severity index-4 (CADESI-4). We also showed that miR-203 is a generic marker for clinical dermatitis and differentiates both CAD and OIPSD inflammatory conditions from healthy controls.
CONCLUSIONS: We show that PDE4D is a potential marker to differentiate CAD from non-atopic healthy and OIPSD while miR-203 may be a potential marker for general dermatologic inflammation. Future study of PDE4D and miR-203 on a larger scale is warranted.

Stroke is a debilitating condition that often leads to disability and death. The increasing prevalence of stroke has drawn worldwide attention. Extensive evidence indicates a crucial role of genetic determinants in the occurrence and perpetuation of stroke. An Icelandic study identified a significant correlation of the phosphodiesterase 4D (PDE4D) single-nucleotide polymorphism (SNP) rs2910829 with stroke susceptibility. However, subsequent studies reported in Chinese populations were contradictory. We implemented a meta-analysis to inspect whether SNP rs2910829 is related to stroke susceptibility in Chinese populations and subsequently performed an in silico analysis to predict its potential functions. Finally, we analysed data from 24 studies comprising 7,484 Chinese stroke patients and 7,962 control individuals. Compared with the CC genotype, the TT genotype was associated with increased susceptibility to stroke (pooled odds ratio [OR] 1.28, 95% confidence interval [CI] 1.13-1.46, P < 0.001), whereas the CT genotype was not. Correspondingly, a significant association was detected under the recessive model (TT vs CT + CC: OR 1.30, 95% CI 1.15-1.47, P < 0.001). Similar results were obtained in large artery atherosclerosis (LAA) stroke but not in small vessel stroke. Bioinformatics analysis also revealed that SNP rs2910829 and its linked SNPs might be implicated in transcriptional regulation. This meta-analysis reveals significant relationships between the PDE4D SNP rs2910829 and susceptibility to stroke and subtype-LAA stroke in Chinese individuals, and further investigations are warranted to evaluate this effect.

Several studies have investigated the correlation between phosphodiesterase 4D (PDE4D) single nucleotide polymorphism (SNP) rs918592 and the risk of ischemic stroke (IS) in Chinese populations. But the results were inconsistent and inconclusive. Therefore, to resolve this conflict, we conducted a meta-analysis to further elucidate their relationship in Chinese populations.
Studies focused on SNP rs918592 and IS risk were electronic searched in the databases of PubMed, Embase, ISI Web of Science, Weipu, China National Knowledge Infrastructure (CNKI), Chinese Biomedical (CBM) and Wanfang. The association between SNP rs918592 and IS risk was expressed by odds ratio (OR) with its confidence interval (CI). Begg\'s and Egger\'s linear regression tests were used to assess publication bias. The meta-analysis was performed with STATA 11.0 statistical software. Two online prediction websites (HaploReg and RegulomeDB) were adopted to explore the functions of SNP rs918592.
The meta-analysis ultimately included 10 studies involving 2,348 cases and 2,289 controls. The results showed that there was a significant correlation between SNP rs918592 and IS risk in Chinese individuals. The G allele had reduced risk of developing IS compared to the A allele (OR 0.83, 95% CI 0.74-0.95, P = 0.005). HaploReg and RegulomeDB analyses suggested that SNP rs918592 and its strongly linked SNPs (e.g. rs34168777) might have regulatory functions.
This study shows that SNP rs918592 in PDE4D may be a contributor of IS risk in Chinese populations. It offers a good answer for the association of PDE4D SNP rs918592 with IS risk in Chinese populations for the first time.

BACKGROUND: Orismilast is a novel oral phosphodiesterase-4 (PDE4) B/D inhibitor being investigated as a potential treatment for moderate-to-severe psoriasis.
OBJECTIVE: To evaluate efficacy and safety of orismilast modified-release formulation in moderate-to-severe psoriasis.
METHODS: This multicenter, randomized (1:1:1:1 to 20, 30, 40 mg orismilast or placebo, twice daily), double-blinded, placebo-controlled, parallel-group, phase 2b, 16-week, dose-ranging study evaluated orismilast in adults with moderate-to-severe plaque psoriasis (NCT05190419). Efficacy end points were analyzed using multiple imputation.
RESULTS: Of 202 randomized patients, baseline characteristics were balanced across arms, except greater severe disease proportions for orismilast vs placebo. Orismilast showed significant improvements in the primary end point, percentage change in Psoriasis Area and Severity Index (PASI), from baseline to week 16 (orismilast -52.6% to -63.7% and placebo, -17.3%; all P <.001). Greater proportions receiving orismilast achieved PASI75 (39.5%-49.0%; P <.05) and PASI90 (22.0%-28.3%; P <.05 for 20 and 40 mg) vs placebo (PASI75, 16.5% and PASI90, 8.3%) at week 16. Safety findings were as expected with PDE4 inhibition; dose-dependent tolerability effects observed.
CONCLUSIONS: Small sample size, disease severity imbalance between groups, limited duration and diversity in study population.
CONCLUSIONS: Orismilast demonstrated greater efficacy vs placebo and a safety profile in line with PDE4 inhibition.

For decades, topical corticosteroids have been the mainstay of treatment for mild-to-moderate inflammatory skin diseases, even though only short-term use is approved for these agents and systemic inflammation is not addressed. Increased understanding of the immunopathogenesis of these conditions, especially for psoriasis and atopic dermatitis, has facilitated the development of antibody-based drugs that neutralize single key cytokines or their associated receptors, such as interleukin (IL)-17A/F, IL-23, and IL-17RA in psoriasis and IL-13 and IL-4Rα in atopic dermatitis. However, oral therapy is still preferred by many patients owing to the ease of use and needle-free administration. Phosphodiesterase 4 (PDE4) inhibitors have been approved for both oral and topical use for inflammatory skin diseases. In this review, we present a summary of an emerging class of selective PDE4B/D inhibitors under clinical development and compare the differences in selectivity of this new generation of PDE4 inhibitors with the less selective currently approved PDE4 inhibitors.

Alzheimer\'s disease cortical tau pathology initiates in the layer II cell clusters of entorhinal cortex, but it is not known why these specific neurons are so vulnerable. Aging macaques exhibit the same qualitative pattern of tau pathology as humans, including initial pathology in layer II entorhinal cortex clusters, and thus can inform etiological factors driving selective vulnerability. Macaque data have already shown that susceptible neurons in dorsolateral prefrontal cortex express a \"signature of flexibility\" near glutamate synapses on spines, where cAMP-PKA magnification of calcium signaling opens nearby potassium and hyperpolarization-activated cyclic nucleotide-gated channels to dynamically alter synapse strength. This process is regulated by PDE4A/D, mGluR3, and calbindin, to prevent toxic calcium actions; regulatory actions that are lost with age/inflammation, leading to tau phosphorylation. The current study examined whether a similar \"signature of flexibility\" expresses in layer II entorhinal cortex, investigating the localization of PDE4D, mGluR3, and HCN1 channels. Results showed a similar pattern to dorsolateral prefrontal cortex, with PDE4D and mGluR3 positioned to regulate internal calcium release near glutamate synapses, and HCN1 channels concentrated on spines. As layer II entorhinal cortex stellate cells do not express calbindin, even when young, they may be particularly vulnerable to magnified calcium actions and ensuing tau pathology.

To explore the role of PDE4D in diabetic nephropathy (DN) and investigate whether resveratrol protects against DN via inhibiting PDE4D. Diabetic db/db mouse and glomerular mesangial cell line (GMCs) were used to investigate the role of PDE4D and the protective effect of resveratrol on renal fibrosis under high glucose (HG) environment. Resveratrol alleviated the progress of DN via inhibiting mitochondrial fragmentation and restoring the expression of PDE4D, PKA, phosphorylated Drp1-Ser637 and Drp1 in kidney of db/db mice. In HG-exposed GMCs, resveratrol treatment decreased the expression of PDE4D, increased PKA level, and inhibited Drp1-mediated mitochondrial fission. In contrast, PDE4D over-expression blunted the inhibitory effects of resveratrol on Drp1 expression and mitochondrial fission. Moreover, PKA inhibitor H89 blunted the effects of resveratrol on phosphorylated Drp1-Ser637 expression and mitochondrial fission in HG-treated GMCs. Inhibition of mitochondrial fission with Drp1 inhibitor Mdivi-1 alleviated mitochondrial dysfunction in GMCs under HG. These findings indicate PDE4D plays an important role in the process of DN. Resveratrol attenuates the development of DN by preventing mitochondrial fission through inhibiting PDE4D, which regulates the expression of phosphorylated Drp1-Ser637 directly.