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<table><caption>Table 1: Human cancers with driver mutations in genes that encode elements of cAMP-signaling pathways.</caption><thead><tr><th>Tissue</th><th>Cancer type</th><th>Pathway element</th><th>Gene name</th></tr></thead><tbody><tr><td rowspan="6">Adrenal cortex</td><td rowspan="6">Adenoma</td><td>G protein alpha subunit</td><td>GNAS</td></tr><tr><td>Phosphodiesterase</td><td>PDE8B</td></tr><tr><td>Phosphodiesterase</td><td>PDE11A</td></tr><tr><td>PKA regulatory subunit</td><td>PRKARA1</td></tr><tr><td>PKA catalytic subunit</td><td>PRKACA</td></tr><tr><td>PKA catalytic subunit</td><td>PRKACB</td></tr><tr><td>Thyroid</td><td>Adenoma</td><td>GPCR</td><td>TSHR</td></tr><tr><td>Parathyroid</td><td>Adenoma</td><td>G protein alpha subunit</td><td>GNAS</td></tr><tr><td rowspan="2">Pituitary</td><td rowspan="2">Somatotropinoma</td><td>GPCR</td><td>GPR101</td></tr><tr><td>PKA regulatory subunit</td><td>PRKARA1</td></tr><tr><td>Testis Sertoli cell</td><td>LCCSCT</td><td>PKA regulatory subunit</td><td>PRKARA1</td></tr><tr><td>Testis Leydig/Sertoli cell</td><td>Germ cell tumors</td><td>Phosphodiesterase</td><td>PDE11A</td></tr><tr><td>Testis germ cell</td><td>Germ cell tumors</td><td>Phosphodiesterase</td><td>PDE11A</td></tr><tr><td>Liver</td><td>Fibrolamellar HCC</td><td>PKA catalytic subunit</td><td>PRKACA</td></tr><tr><td>Abdominal soft tissue and CNS</td><td>FET-CREB fusion tumors</td><td>Transcription factor</td><td>CREB</td></tr></tbody></table>

Abbreviations: HCC, hepatocellular cancer; LCCSCT, large-cell calcifying Sertoli cell tumors; all other abbreviations are defined in the text.
<table><caption>Table 2: The Clinical Potential of Combining Exisulind or Sildenafil with Chemotherapeutic Drugs</caption><thead><tr><td>Inhibitor</td><td>Combined with; outcome</td><td>Cancer type</td><td>References</td></tr></thead><tbody><tr><td>Exisulind</td><td>Cisplatin and paclitaxel; synergistic inhibition of cancer cell growth in culture</td><td>Lung cancer</td><td>(Soriano et al., 1999)</td></tr><tr><td>Exisulind</td><td>Docetaxel; induced apoptosis, reduced tumor growth and metastasis and improved survival in mouse orthotopic model</td><td>Lung cancer</td><td>(Bunn Jr et al., 2002; Soriano et al., 1999; Whitehead et al., 2003a)</td></tr><tr><td>Exisulind</td><td>Capecitabine; combination well tolerated in breast cancer patients, but synergism appeared to be modest</td><td>Breast cancer</td><td>(Pusztai et al., 2003a)</td></tr><tr><td>Sildenafil</td><td>Pemetrexed; suppressed tumor growth in mice that was enhanced with the mTOR inhibitor temsirolimus</td><td>Lung cancer</td><td>(Booth et al., 2017)</td></tr><tr><td>Sildenafil</td><td>Pemetrexed and sorafenib; enhanced activity in multiple cancer cell lines and mouse xenograft models</td><td>Lung cancer</td><td>(Booth et al., 2017)</td></tr><tr><td>Sildenafil</td><td>Doxorubicin; enhanced apoptosis and antitumor efficacy in mouse xenograft models, while attenuating doxorubicin cardiotoxic effects</td><td>Prostate cancer</td><td>(Das et al., 2010)</td></tr><tr><td>Sildenafil</td><td>OSU-03012 (non-COX inhibitor of celecoxib) and sorafenib; synergism to kill cancer cells in vitro and in vivo</td><td>Glioblastoma</td><td>(Booth et al., 2015)</td></tr><tr><td>Sildenafil</td><td>Doxorubicin; enhanced apoptosis and ROS production in rhabdomyosarcoma cell lines</td><td>Rhabdomyosarcoma</td><td>(Urla et al., 2023)</td></tr></tbody></table>

Abbreviations: mTOR; Mammalian target of rapamycin, COX; Cyclooxygenase, ROS, Reactive oxygen species.
<caption>Table 3. Summary of PDE isoform expression and function in immune cells.</caption>

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<table><thead><tr><th>Immune cell subpopulation</th><th>PDE gene expression</th><th>PDE protein expression /activity</th><th>PDE activity and methods</th><th>Results</th></tr></thead><tbody><tr><td>Dendritic cells</td><td></td><td>PDE1, PDE3 membrane bound, PDE4, PDE7<br>PDE4B<br>PDE4b</td><td>PDE isoenzyme activity<br>PDE isoenzyme activity<br>PDE4 inhibitor studies<br>PDE4B gene knockout studies</td><td>Pro-inflammatory cytokine production<br>DC mediated Th2 dependent immunopathology<br>Selective suppression of Th2 polarization of T cell subpopulations in vivo</td></tr><tr><td>Granulocytes</td><td></td><td></td><td>PDE4 inhibitor studies</td><td>In vitro suppression of neutrophil functions<br>Suppression of chemotaxis, inflammation, neutrophil and eosinophil infiltration in vivo<br>Basophils</td></tr><tr><td></td><td>PDE4A, D</td><td>PDE4A, D</td><td>PDE4A and D expression studies</td><td></td></tr></tbody></table>
<table><tr><td>NK cells</td><td></td><td>PDE3 and 4</td><td>PDE3 and 4 inhibitor studies</td><td></td></tr><tr><td></td><td></td><td>PDE4</td><td>PDE4 inhibitor studies</td><td>Suppression of TNF-alpha production</td></tr><tr><td></td><td></td><td>IBMX sensitive PDEs</td><td>Broad PDE inhibitor studies</td><td>Suppression of IFN-gamma production</td></tr><tr><td>Monocytes and macrophages</td><td></td><td>PDE1<br>PDE3<br>PDE4</td><td>PDE isoenzyme activity, inhibitor studies</td><td>Suppression of TNF-release through PDE4 +/-PDE3 inhibition</td></tr><tr><td>Macrophages</td><td>Pde4 deficient mice</td><td>Pde4 deficient mice global</td><td></td><td>Suppression of cytokine production<br>Protection from LPS-induced shock<br>Promotion of susceptibility to HIV-1 infection</td></tr><tr><td></td><td>PDE8A</td><td>PDE8A</td><td></td><td>Altered cytokine and chemokine production</td></tr><tr><td></td><td></td><td>PDE10A</td><td>Inhibition of PDE10, PDE10A deficient mice</td><td>Suppression of cytokine expression,</td></tr><tr><td>Microglia</td><td></td><td>PDE1</td><td>Inhibition of PDE1 activity</td><td></td></tr></table>
<table><tr><td></td><td></td><td></td><td></td><td>Inhibition of cytokine release, suppression of cytokine gene expression, suppression of motility</td></tr></table>
<table><tr><td rowspan="10">CD4+ T cells</td><td>PDE1</td><td>PDE1</td><td>PDE1 activity</td><td>Upregulation under mitogen stimulation</td></tr><tr><td>PDE2</td><td>PDE2</td><td>PDE2 expression and activity</td><td>Expressed in mouse T cells but not human T cells</td></tr><tr><td>PDE2A</td><td>PDE2A</td><td>PDE2 facilitates T cell activation</td><td>Mouse T cell activation</td></tr><tr><td>PDE3</td><td>PDE3, PDE3B</td><td>Membrane bound PDE3B activity,</td><td>Foxp3 repression of PDE3B in Treg cells</td></tr><tr><td>Pde3b</td><td>Pde3b</td><td>Pde3b deficient mice</td><td>Reduced PDE3B expression permits normal Treg cell homoeostasis and Treg cell-specific gene expression</td></tr><tr><td>Pde4b</td><td>PDE4A</td><td>PDE activity and inhibition</td><td>T cell activation and functions</td></tr><tr><td>PDE4b</td><td>PDE4B</td><td>PDE activity and inhibition, PDE4B deficient mice</td><td>T cell activation and functions, Th subset polarization</td></tr><tr><td>PDE4b</td><td>PDE4D</td><td>PDE activity and inhibition</td><td>T cell activation and functions</td></tr><tr><td>PDE4b</td><td>PDE4</td><td>PDE activity, binding, overexpression and inhibition</td><td>Modulation of signal transduction through the T cell receptor</td></tr><tr><td>PDE4b</td><td>PDE4</td><td>PDE activity, binding, overexpression and inhibition</td><td>Regulation of full T cell activation</td></tr></table>
<table><tr><td></td><td>PDE7<br>PDE7A1, A3</td><td>PDE7<br>PDE7A1, A3</td><td>Expression and anti-sense inhibition studies</td><td>Upregulation of PDE8A1 after polyclonal T cell activation</td></tr><tr><td>Mitogen-activated splenocytes, anti-CD3 activated CD4<sup>+</sup> T cells, antigen exposed naïve and memory CD4<sup>+</sup> T cells</td><td>PDE8A1<br>Pde8a</td><td>PDE8A1<br>PDE8A</td><td>Induction of PDE8A expression in response to stimulus, PDE8 inhibition<br>Induction of PDE8A expression in response to stimulus, PDE8 inhibition via enzymatic inhibitor and peptide disruptor, in vivo suppression of EAE</td><td>Induction of PDE8A expression in response to stimulus, Association of PDE8A expression and accumulation of sensitized T cells in draining lymph node of in an animal model of allergic airway disease AAD</td></tr><tr><td>CD4<sup>+</sup> effector Teff cells</td><td>PDE8A</td><td>PDE8A</td><td>PDE expression</td><td>PDE8A inhibition by enzymatic inhibitor or a PDE8A-Raf-1 kinase</td></tr></table>
<table><tr><td>CD4+ regulatory Treg cells</td><td>Pde1a, Pde1b, Pde2a, Pde3b, Pde4b, Pde5a, Pde7a Pde8a PDE8A</td><td>PDE1A, B PDE2A PDE3B PDE4B PDE5A PDE8A</td><td>High cAMP levels in T cells</td></tr></table>
<table><tr><td><b>B cells</b></td><td><i>PDE4A, B, D</i><br/><i>PDE7B</i></td><td><i>PDE4A, B, D</i><br/><i>PDE7B</i></td><td>Expression<br/>PDE7 inhibition</td><td>Induction of apoptosis through<br/>PDE7 inhibition</td></tr></table>

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4 Abbreviations: see abbreviation table.

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Figures caption:

**Figure 1. Timeline of PDEs in medicinal history.** Henry Hyde Salter's discovery of caffeine's bronchodilator effects contributed to the exploration of PDEs, though the effect of caffeine is more likely to occur through adenosine receptors. In the mid-20th century, the discovery of phosphodiesterases (PDEs) as enzymes degrading cyclic nucleotides like cAMP and cGMP marked the beginning of their history. Early research by scientists such as Earl W. Sutherland Jr. elucidated their roles in cellular signaling, flag stoned the way for drug development. These inhibitors have since evolved to treat conditions like pulmonary arterial hypertension and erectile dysfunction. Over time, research continued, uncovering new isoforms and therapeutic possibilities, extending the application of PDE inhibitors beyond cardiovascular diseases to conditions like cognitive dysfunction and fibrosis. "Created with BioRender.com".

**Figure 2. Phosphodiesterase (PDE) superfamily structure.** PDEs are enzymes categorized into cAMP-specific, cGMP-specific, and dual-substrate families based on their affinity for cyclic nucleotides. Each of the 11 families possesses a catalytic domain at the COOH terminal. These isoforms also exhibit specific structural domains such as REC (Signal regulatory domain), PAS (PerARNT-Sim), UCR (upstream conversed region), PAT-7 (7-residue nuclear localization signal), and GAF (cGMP-binding ubiquitous motif), which play roles in regulating enzymatic activity, sensing cellular signals, influencing localization, and binding to cyclic nucleotides. lines indicate the length of the amino acid sequence of a representative member of each family. Adapted from (Baillie et al., 2019a). "Created with BioRender.com".

**Figure 3. The catalytic domain of PDE4B2B in complex with NPV.** This folding is conserved in the catalytic domains of all PDE families. The catalytic domain (Pfam: PF00233) typically consists of 16 α-helices that bind two divalent metals, Zn²⁺ and (typically) Mg²⁺ that are essential for
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the catalysis of cAMP and cGMP to their linear form. The ten-membered ring of NPV stacks against the benzyl ring of Phe446 on one side and
interacts with hydrophobic residues of Ile410 and Phe414 on another side; adapted from (Wang et al., 2007b).

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**Figure 4. Structures of PDE4.** (A) Ribbon model of catalytic domain of PDE4D in complex with 5'-AMP (PDB code of 1PTW; adapted from (Huai et al., 2003; Wang et al., 2008c)). Grey and pink spheres are zinc and magnesium, respectively. Sticks represent 5'-AMP. (B). Interaction of metal ions with 5'-AMP. (C) Surface representation of the active site of D201N PDE4D mutant in complex with substrate cAMP (PDB code, 2PW3; adapted from (Wang et al., 2007b)). Phe372 on one side of the purine ring and Phe230 and Ile336 on another side form the “hydrophobic clamp”. The invariant Gln369 forms a hydrogen bond with substrate cAMP.

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**Figure 5. Structure of PDE2.** (A) Dimer of PDE2A3 adapted from (Pandit et al., 2009). Catalytic subunits are shown in green and cyan. (B) Superposition of the unliganded nearly full-length PDE2 (green and cyan) over the PDE2 catalytic domain (yellow) complexed with inhibitor Bay60-7550 (red sticks; adapted from (Zhu et al., 2013)). The H-loop conformations are shown for the PDE2-Bay60-7550 structure (blue) and the unliganded structure (pink). (C) A unique hydrophobic pocket may aid in the future design of PDE2 inhibitors with high affinity and selectivity.

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**Figure 6. Conformational changes in the catalytic domain of PDE5 upon binding of inhibitors.** (A) Dramatic conformational changes in the H-loop of the PDE5 catalytic domain upon binding of IBMX (blue), sildenafil (gold), icarisid II (green) or in the unliganded state (purple). (B) Superposition of PDE5 structures in complex with sildenafil (gold ribbons and sticks) and vardenafil (cyan), duplicated from Wang et al., 2008. The shared structural elements of PDE5 are shown in green.

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**Figure 7. Binding of the natural product evodiamine to PDE5.** Evodiamine occupies an allosteric effector site that adjoins the active site of PDE; adapted from (Zhang et al., 2020c). (A). Surface representation of the allosteric effector site in the catalytic domain that is filled with a bundle of water molecules (red spheres) in the unliganded state. (B). Surface representation of the binding of evodiamine. The purple mesh shows the electron density of the binding; vardenafil occupies the active site of PDE5. (C). Ribbon presentation of the conformational changes in the H-loop upon binding of vardenafil (green sticks) and evodiamine (cyan sticks); adapted from (Zhang et al., 2020c).

**Figure 8. The structures of PDE4D in complex with the allosteric inhibitor D155871.** (A) Ribbon presentation of the PDE4D catalytic domain (cyan) with a helix from the UCR2 region (residues 191-201 of PDE4D7, green) interacting with the inhibitor D155871 (yellow sticks); NC and CC, N- and C-termini, respectively, of the catalytic domain. Note that residues 204-254 that connect UCR2 helix and the catalytic domain have disordered conformations and are not traceable. (B) Surface representation of D155871 binding in the absence (panel B) and presence (panel C) of the UCR2 helix; adapted from (Burgin et al., 2010b).

**Figure 9. The M-pocket of PDE9 binds the inhibitor C33.** (A) Surface representation of the PDE9 M-pocket occupied with C33 (yellow sticks). (B) Superposition of PDE9 (green ribbons) with PDE5 (light cyan) and PDE8A (salmon) showing structural conservation of the M-pocket. (C) Sequence alignment around the M-pocket of PDEs. The green color highlights helices H14 and H15 which are connected by the M-loop. Two residues (red) gate the pocket. Duplicated from (Huang et al., 2015)

**Figure 10. Mapping the tissue localization of Phosphodiesterases (PDEs).** This figure illustrates the diverse tissue localization of PDEs, enzymes crucial for regulating cyclic nucleotide levels. PDE expression patterns vary among species and can be altered in pathological conditions,
influencing various physiological processes such as cardiovascular function, neuronal signaling, immune responses, and reproductive function. In
cases where the precise tissue localization of PDEs is unknown, their representation is depicted vertically adjacent to the respective tissue name.
Abbreviations: M:Macrophages; T:T-cells; L:Lymphocytes; E:Endothelial cells; P:Platelet; S: Smooth muscle cells; b1:Cerebral cortex/temporal
lobe; b2:Ocipital lobe; b3:Temporal lobe. "Created with BioRender.com".

**Figure 11. Modulatory role of PDEs on cAMP/cGMP signaling in cardiomyocytes.** In this figure, the red area denotes the presence of cAMP, while the blue area signifies the contribution and subcellular localization of cGMP PDEs. Each PDE sub-family is represented as small colored circles on the PDE enzyme. Under normal physiological conditions, cardiac function is finely tuned by two intracellular cyclic nucleotides with opposing effects: cAMP, influenced by beta-adrenergic stimulation and protein kinase A signaling, and cGMP, stimulated by nitric oxide (NO) and natriuretic peptides (NPs) production. However, in pathological conditions such as heart failure, chronic elevation of catecholamines due to sympathetic over activation further stimulates beta-adrenergic receptors, leading to maladaptive remodeling, including hypertrophy and cardiac fibrosis. Conversely, elevated levels of NO and NPs exhibit anti-hypertrophic and anti-fibrotic effects. The question marks denote uncertainty regarding whether specific PDEs play preventive roles in these processes. "Created with BioRender.com".

**Figure 12. The importance of PDEs regulation in vasculature.** Vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) constitute the primary vascular cell types, with pericytes taking over the role of VSMCs in the microvasculature, alongside macrophages and other supporting cells. The regulatory influence of phosphodiesterases (PDEs) on cAMP has been implicated in endothelial permeability. Additionally, PDEs play a role in proliferation and cell migration, processes typically mediated by VEGF signaling and Rac1, leading to an increase in ROS produced by
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NADPH oxidase. PDE inhibitors have demonstrated promising effects in preventing aneurysm formation, a critical aspect of vascular remodeling disorders. Nevertheless, the precise mechanisms through which cyclic nucleotides balance each other to regulate arterial wall thickening/thinning remain unclear. Question marks indicate that the precise role of PDE in that specific pathway remains unknown. “Created with BioRender.com”.

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**Figure 13. Involvement of PDEs in liver fibrosis and hepatocyte damage.** Several factors, including alcohol, viruses, and high-fat diets, can instigate damage to hepatocytes and fibrosis. Injured hepatocytes release inflammatory mediators leading to the recruitment of peripheral immune cells and activation of resident macrophages consequently, triggering the activation of hepatic stellate cells (HSCs). Activated HSCs transdifferentiate into pro-inflammatory and profibrogenic myofibroblasts and release excessive amount of extracellular matrix proteins (ECM), which in long-term leads to liver fibrosis. Elevated phosphodiesterase (PDE) activity mediates some of these pathological changes, thus presenting as potential pharmacological targets for treating liver disorders. “Created with BioRender.com”.

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**Figure 14. Role of PDEs in Pathophysiology of Neurodevelopmental Disorders.** Phosphodiesterases (PDEs) inhibitors increases activation of Protein Kinase A (PKA), leading to increased activation of CREB transcription. This process contributes to the prevention of formation and toxicity of amyloid beta plaques in neurodegenerative disorders like Alzheimer's disease. Additionally, changes in PDE expression can affect neuroinflammation and reduces cerebral glucose uptake which as a primary energy source for brain could lead to development of neurodegenerative disorders. Red arrows indicates the effect of PDE inhibitors. Question marks imply the unknown role of these PDE subtypes in neurodevelopmental disorders. “Created with BioRender.com”.

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**Figure 15.** **PDE5 and PDE10 regulation of cancer cell proliferation and survival.** PDE5 and/or PDE10 regulate cGMP/PKG signaling to allow for β-catenin-dependent Tcf/Lef transcription and RAS/MAPK signaling resulting in the synthesis proteins essential for cancer cell proliferation and survival. Solid circles represent PDE5 and PDE10 that may be co-expressed whereby higher levels of PDE10 may compensate for the effects of a PDE5 isozyme specific inhibitor. Both COX-dependent and independent mechanisms are involved in anti-cancer activity of COX inhibitors. Red crosses symbolizes the impact of cGMP PDE and COX inhibitors. "Created with BioRender.com".

**Figure 16.** **The cAMP-PKA-PDE pathway in T cells.** An example of GPCR-mediated signaling through several receptors leading to activation of cAMP signaling in T cells. Here, ADO and PGE₂ serve as ligands for their cognate GPCRs A2AR/A2BR and EP2/EP4, respectively, allowing the activation of AC, which then catalyses the synthesis of cAMP from ATP. cAMP can bind to and activate the regulatory subunit of PKA, inducing the release of the active catalytic subunit, which enables dedicated pools of PKA anchored to several AKAPS to phosphorylate downstream proteins involved in immune regulation, including transcriptional programs. cAMP-specific PDEs, on the other hand, can hydrolyze cAMP to AMP in a feedback mechanism to attenuate the signal, thereby sculpting and compartmentalizing the cAMP pool. ADO and PGE₂ receptor antagonism as well as PDE inhibition, are current strategies for drug development.

**Figure 17.** **The opposing roles of PKA and PDE4 in proximal T cell signaling.** Inhibition of T cell activation by cAMP is facilitated by a signaling complex in lipid rafts, consisting of PKA, Ezrin, EBP50, Cbp/PAG. This complex works as an immunoregulatory pathway, hindering TCR-induced T-cell activation. In T cells, TCR activation through G-protein coupling to AC generates cAMP (I), allowing PKA activation (II). The membrane-bound cytoskeleton linker protein Ezrin then acts as an AKAP and positions PKA to phosphorylate Csk (III) through the PKA-
Ezrin-EBP50-Cbp/PAG-Csk complex, which in the absence of CD28 co-stimulation (IV), allows Csk to phosphorylate the Src family kinase Lck (V) at the C-terminal inhibitory site, hence, preventing full T cell activation (A). CD28 co-stimulation, however, increases TCR-induced signals by recruiting the PDE4/□-arrestin complex, resulting in cAMP degradation (IV), down-modulation of inhibitory signals, and facilitates full T cell activation (B).

**Figure 18. mRNA and protein isoforms encoded by the human PDE4D gene.** The *PDE4D* gene products are divided into “long” isoforms that contain UCR1, UCR2 and the catalytic region; “short” isoforms that lack UCR1, and “super-short” isoforms lacking UCR1 and a portion of UCR2. Also the C-terminal region (COOH), common to all PDE4D isoforms but not present in PDE4A, PDE4B or PDE4C isoforms. Dihydrotestosterone (DHT) act at the androgen receptor which is activated by phosphorylation by Protein kinase A. PKA is further regulated by cAMP signaling pathway. “Created with BioRender.com”.

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<figure><img src="image_2.png" /><figcaption>Figure 1. Timeline of PDEs in medicinal history</figcaption></figure>
<figure><img src="image_3.png" /><figcaption>Figure 2. Phosphodiesterase (PDE) superfamily structure.</figcaption></figure>
<figure><img src="image_4.png" /><figcaption>Figure 3. The catalytic domain of PDE4B2B in complex with NPV.</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>Figure 4. Structures of PDE4.</figcaption></figure>
<figure><img src="image_6.png" /><figcaption>Figure 5. Structure of PDE2.</figcaption></figure>
<figure><img src="image_7.png" /><figcaption>Figure 6. Conformational changes in the catalytic domain of PDE5 upon binding of inhibitors.</figcaption></figure>
<figure><img src="image_8.png" /><figcaption>Figure 7. Binding of the natural product evodiamine to PDE5.</figcaption></figure>
<figure><img src="image_9.png" /><figcaption>Figure 8. The structures of PDE4D in complex with the allosteric inhibitor D155871.</figcaption></figure>
<figure><img src="image_10.png" /><figcaption>Figure 9. The M-pocket of PDE9 binds the inhibitor C33.</figcaption></figure>
<figure><img src="image_11.png" /><figcaption>Figure 10. Mapping the tissue localization of Phosphodiesterases (PDEs).</figcaption></figure>
<figure><img src="image_12.png" /><figcaption>Figure 11. Modulatory role of PDEs on cAMP/cGMP signaling in cardiomyocytes.</figcaption></figure>
<figure><img src="image_13.png" /><figcaption>Figure 12. The importance of PDEs regulation in vasculature.</figcaption></figure>
Fibrosis and hepatocytes damage

<figure><img src="image_14.png" /><figcaption>Figure 13. Involvement of PDEs in liver fibrosis and hepatocyte damage.</figcaption></figure>
<figure><img src="image_15.png" /><figcaption>Figure 14. Role of PDEs in Pathophysiology of Neurodevelopmental Disorders.</figcaption></figure>
<figure><img src="image_16.png" /><figcaption>Figure 15. PDE5 and PDE10 regulation of cancer cell proliferation and survival.</figcaption></figure>
<figure><img src="image_17.png" /><figcaption>Figure 16. The cAMP-PKA-PDE pathway in T cells.</figcaption></figure>
<figure><img src="image_18.png" /></figure>

<figure><img src="image_19.png" /><figcaption>Figure 17. The opposing roles of PKA and PDE4 in proximal T cell signaling.</figcaption></figure>
<figure><img src="image_20.png" /><figcaption>Figure 18. mRNA and protein isoforms encoded by the human *PDE4D* gene.</figcaption></figure>
<figure><img src="image_21.png" /><figcaption>Figure 1. Timeline of PDEs in medicinal history</figcaption></figure>
<figure><img src="image_22.png" /><figcaption>Figure 2. Phosphodiesterase (PDE) superfamily structure.</figcaption></figure>
<figure><img src="image_23.png" /><figcaption>Figure 3. The catalytic domain of PDE4B2B in complex with NPV.</figcaption></figure>
<figure><img src="image_24.png" /><figcaption>Figure 4. Structures of PDE4.</figcaption></figure>
<figure><img src="image_25.png" /><figcaption>Figure 5. Structure of PDE2.</figcaption></figure>
<figure><img src="image_26.png" /><figcaption>Figure 6. Conformational changes in the catalytic domain of PDE5 upon binding of inhibitors.</figcaption></figure>
<figure><img src="image_27.png" /><figcaption>Figure 7. Binding of the natural product evodiamine to PDE5.</figcaption></figure>
<figure><img src="image_28.png" /><figcaption>Figure 8. The structures of PDE4D in complex with the allosteric inhibitor D155871.</figcaption></figure>
<figure><img src="image_29.png" /><figcaption>Figure 9. The M-pocket of PDE9 binds the inhibitor C33.</figcaption></figure>
<figure><img src="image_30.png" /><figcaption>Figure 10. Mapping the tissue localization of Phosphodiesterases (PDEs).</figcaption></figure>
<figure><img src="image_31.png" /><figcaption>Figure 11. Modulatory role of PDEs on cAMP/cGMP signaling in cardiomyocytes.</figcaption></figure>
<figure><img src="image_32.png" /><figcaption>Figure 12. The importance of PDEs regulation in vasculature.</figcaption></figure>
Fibrosis and hepatocytes damage

<figure><img src="image_33.png" /><figcaption>Figure 13. Involvement of PDEs in liver fibrosis and hepatocyte damage.</figcaption></figure>
<figure><img src="image_34.png" /><figcaption>Figure 14. Role of PDEs in Pathophysiology of Neurodevelopmental Disorders.</figcaption></figure>
<figure><img src="image_35.png" /><figcaption>Figure 15. PDE5 and PDE10 regulation of cancer cell proliferation and survival.</figcaption></figure>
<figure><img src="image_36.png" /><figcaption>Figure 16. The cAMP-PKA-PDE pathway in T cells.</figcaption></figure>
<figure><img src="image_37.png" /></figure>

<figure><img src="image_38.png" /><figcaption>Figure 17. The opposing roles of PKA and PDE4 in proximal T cell signaling.</figcaption></figure>
<figure><img src="image_39.png" /><figcaption>Figure 18. mRNA and protein isoforms encoded by the human *PDE4D* gene.</figcaption></figure>