Targeting phosphodiesterase 4 as a therapeutic strategy for cognitive improvement

Wei, Xuemei; Yu, Guoqi; Shen, Hualiang; Luo, Yanjuan; Shang, Tianbo; Shen, Runpu; Xi, Meiyang; Sun, Haopeng

doi:10.1016/j.bioorg.2022.106278

Cited by 8 publications

(3 citation statements)

References 167 publications

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“…In addition to ferroptosis, whether cuproptosis involved in VTN-mediated impaired cell differentiation in IBD remained to be confirmed in future work. cAMP is the classic second messager, which could activate PKA/CREB cascade pathway or be hydrolyzed into AMP by PDE4 [42]. Recently, the serial work suggested PDE4 could be a promising therapeutic target for various diseases, such as nephrotic syndrome [43], acute myeloid leukemia [44], idiopathic pulmonary fibrosis [45], heart failure [46], and colitis [8].…”

Section: Discussionmentioning

confidence: 99%

Vitronectin Destroyed Intestinal Epithelial Cell Differentiation through Activation of PDE4-Mediated Ferroptosis in Inflammatory Bowel Disease

Pan

Liang

et al. 2023

Mediators of Inflammation

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Objective. Vitronectin (VTN) has been reported to trigger cell pyroptosis to aggravate inflammation in our previous study. However, the function of VTN in inflammatory bowel disease (IBD) remains to be addressed. Methods. Real-time PCR and western blotting were performed to analyze VTN-regulated intestinal epithelial cell (IEC) differentiation through ferroptosis, and immunofluorescence (IF), luciferase, and chromatin immunoprecipitation were used to identify whether VTN-modulated ferroptosis is dependent on phosphodiesterase 4 (PDE4)/protein kinase A (PKA)/cyclic adenosine monophosphate-response element-binding protein (CREB) cascade pathway. In vivo experiment in mice and a pilot study in patients with IBD were used to confirm inhibition of PDE4-alleviated IECs ferroptosis, leading to cell differentiation during mucosal healing. Results. Herein, we found that caudal-related homeobox transcription factor 2-mediated IECs differentiation was impaired in response to VTN, which was attributed to enhanced ferroptosis characterized by decreased glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 expression. Inhibition of ferroptosis in IECs rescued the inhibitory effect of VTN on cell differentiation. Further analysis showed that VTN triggered phosphorylation of PDE4, leading to inhibit PKA/CREB activation and CREB nuclear translocation, which further reduced GPX4 transactivation. Endogenous PKA interacted with CREB, and this interaction was destroyed in response to VTN stimulation. What is more, overexpression of CREB in CaCO2 cells overcame the promotion of VTN on ferroptosis. Most importantly, inhibition of PDE4 by roflumilast or dipyridamole could alleviate dextran sulfate sodium-induced colitis in mice and in a pilot clinical study confirmed by IF. Conclusions. These findings demonstrated that highly expressed VTN disrupted IECs differentiation through PDE4-mediated ferroptosis in IBD, suggesting targeting PDE4 could be a promising therapeutic strategy for patients with IBD.

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Section: Discussionmentioning

confidence: 99%

Vitronectin Destroyed Intestinal Epithelial Cell Differentiation through Activation of PDE4-Mediated Ferroptosis in Inflammatory Bowel Disease

Pan

Liang

et al. 2023

Mediators of Inflammation

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“…On the other hand, PDE4 inhibitors were promising to a great extent. 95 HT-0712, a 3,5-disubstituted piperidinone (Fig. 8), has completed a phase II study, showing enhancement in the long-term memory of patients with age-related memory impairment.…”

Section: Phosphodiesterase Inhibitors (Pdeis)mentioning

confidence: 99%

Review on anti-alzheimer drug development: approaches, challenges and perspectives

Abdallah

2024

RSC Adv.

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“…These small-molecule compounds, such as the first-generation inhibitor rolipram, and the second-generation inhibitor roflumilast and cilomilast, have shown extensive pharmacological effects in vitro and in vivo . These include anti-inflammatory and immunomodulatory effects ( Kim et al, 2021 ), antidepressant and antipsychotic effects ( Martinez et al, 2021 ), and cognitive enhancement ( Wei et al, 2023 ). These findings clearly demonstrate the critical functions of PDE4 in cells and physiology.…”

Section: Anti-inflammatory Effects Of Pde4 Inhibitorsmentioning

confidence: 99%

PDE4 inhibitors: potential protective effects in inflammation and vascular diseases

Fan,

Wang,

Wang

et al. 2024

Front. Pharmacol.

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Phosphodiesterase 4 (PDE4) inhibitors are effective therapeutic agents for various inflammatory diseases. Roflumilast, apremilast, and crisaborole have been developed and approved for the treatment of chronic obstructive pulmonary disease psoriatic arthritis, and atopic dermatitis. Inflammation underlies many vascular diseases, yet the role of PDE4 inhibitors in these diseases remains inadequately explored. This review elucidates the clinical applications and anti-inflammatory mechanisms of PDE4 inhibitors, as well as their potential protective effects on vascular diseases. Additionally, strategies to mitigate the adverse reactions of PDE4 inhibitors are discussed. This article emphasizes the need for further exploration of the therapeutic potential and clinical applications of PDE4 inhibitors in vascular diseases.

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Targeting phosphodiesterase 4 as a therapeutic strategy for cognitive improvement

Cited by 8 publications

References 167 publications

Vitronectin Destroyed Intestinal Epithelial Cell Differentiation through Activation of PDE4-Mediated Ferroptosis in Inflammatory Bowel Disease

Vitronectin Destroyed Intestinal Epithelial Cell Differentiation through Activation of PDE4-Mediated Ferroptosis in Inflammatory Bowel Disease

Review on anti-alzheimer drug development: approaches, challenges and perspectives

PDE4 inhibitors: potential protective effects in inflammation and vascular diseases

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