The PDE4 inhibitor CHF6001 affects keratinocyte proliferation via cellular redox pathways

Woodby, Brittany; Sticozzi, Claudia; Pambianchi, Erika; Villetti, Gino; Civelli, Maurizio; Valacchi, Giuseppe; Facchinetti, Fabrizio

doi:10.1016/j.abb.2020.108355

Cited by 14 publications

(8 citation statements)

References 47 publications

(63 reference statements)

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“…We next aimed to utilize this lung organoid model to evaluate the efficacy of existing COPD therapeutics. Increasing evidence 10,11 has linked phosphodiesterase (PDE) 4 inhibition to the therapeutic management of respiratory diseases, and roflumilast has been used as an oral medication in COPD patients with a prior history of hospitalization for an acute exacerbation (GOLD 2021). This led us to explore whether the classic PDE4 inhibitor, rolipram, was able to rescue the CS-induced reduction in organoid formation by alveolar progenitors.…”

Section: Resultsmentioning

confidence: 99%

A transcriptomics-guided drug target discovery strategy identifies novel receptor ligands for lung regeneration

Bos

Conlon

et al. 2021

Preprint

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Currently, there is no pharmacological treatment targeting defective tissue repair in chronic disease. Here we utilized a transcriptomics-guided drug target discovery strategy using gene signatures of smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke, identifying druggable targets expressed in alveolar epithelial progenitors of which we screened the function in lung organoids. We found several drug targets with regenerative potential of which EP and IP prostanoid receptor ligands had the most significant therapeutic potential in restoring cigarette smoke-induced defects in alveolar epithelial progenitors in vitro and in vivo. Mechanistically, we discovered by using scRNA-sequencing analysis that circadian clock and cell cycle/apoptosis signaling pathways were enriched in alveolar epithelial progenitor cells in COPD patients and in a relevant model of COPD, which was prevented by PGE2 or PGI2 mimetics. Conclusively, specific targeting of EP and IP receptors offers therapeutic potential for injury to repair in COPD.

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Section: Resultsmentioning

confidence: 99%

A transcriptomics-guided drug target discovery strategy identifies novel receptor ligands for lung regeneration

Bos

Conlon

et al. 2021

Preprint

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“…Phosphodiesterase-4(PDE4) inhibitors are currently approved for the treatment of psoriasis. Brittany et al have found that PDE4 inhibitors can reduce oxidative stress through the inactivation of the NADPH oxidase ( Woodby et al, 2020 ). Recently, Liang et al also found that PDE4 inhibitors can improve the redox imbalance by reducing ROS and MDA production ( Liang et al, 2021 ).…”

Section: Novel Therapeutic Approaches For Inflammatory Skin Diseasesmentioning

confidence: 99%

Oxidative Stress and Gut Microbiome in Inflammatory Skin Diseases

Zhang

et al. 2022

Front. Cell Dev. Biol.

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Oxidative stress plays a dominant role in inflammatory skin diseases. Emerging evidence has shown that the close interaction occurred between oxidative stress and the gut microbiome. Overall, in this review, we have summarized the impact of oxidative stress and gut microbiome during the progression and treatment for inflammatory skin diseases, the interactions between gut dysbiosis and redox imbalance, and discussed the potential possible role of oxidative stress in the gut-skin axis. In addition, we have also elucidated the promising gut microbiome/redox-targeted therapeutic strategies for inflammatory skin diseases.

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“…51 Clinically used oral PDE4 inhibitors, such as apremilast, are very effective, but are still associated with gastrointestinal and neurological adverse effects. 48,52,53 Several small molecule PDE4 inhibitors for topical use are currently at various stages of development. For example, CHF6001 is a potent PDE4 inhibitor administered by inhalation, and used for inflammatory pulmonary diseases.…”

Section: Discussionmentioning

confidence: 99%

“…54 Preclinical studies have shown that CHF6001 interferes with NF-kB nuclear translocation and reduces oxidative stress in cultured epidermal keratinocytes, although its cutaneous antiinflammatory effects in vivo have yet to be reported. 53 E6005, another novel PDE4 inhibitor developed for topical use, suppressed proinflammatory cytokine production in human lymphocytes in vitro, exhibited anti-inflammatory effects in mouse models of atopic dermatitis, and showed acceptable tolerability in randomized controlled trials. 55 Crisaborole is a potent boron-based PDE4 and TNFα release inhibitor in PBMC (IC 50 = 0.49--5.0 μM).…”

Section: Discussionmentioning

confidence: 99%

DRM02, a novel phosphodiesterase-4 inhibitor with cutaneous anti-inflammatory activity

2020

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Chronic inflammatory skin disorders are frequently associated with impaired skin barrier function. Selective phosphodiesterase-4 (PDE4) inhibition constitutes an effective therapeutic strategy for the treatment of inflammatory skin diseases. We now report the pharmacological antiinflammatory profile of DRM02, a novel pyrazolylbenzothiazole derivative with selective in vitro inhibitory activity toward PDE4 isoforms A, B and D. DRM02 treatment of cultured primary human and mouse epidermal keratinocytes interfered with pro-inflammatory cytokine production elicited by interleukin-1α and tumor necrosis factor-α. Similarly, DRM02 inhibited the production of proinflammatory cytokines by human peripheral blood mononuclear cells ex vivo and cultured THP-1 monocyte-like cells, with IC 50 values of 0.6-14 µM. These anti-inflammatory properties of DRM02 were associated with dose-dependent repression of nuclear factor-κB (NF-κB) transcriptional activity. In skin inflammation in vivo mouse models, topically applied DRM02 inhibited the acute response to phorbol ester and induced Th2-type contact hypersensitivity reactivity. Further, DRM02 also decreased cutaneous clinical changes and expression of Th17 immune pathway cytokines in a mouse model of psoriasis evoked by repeated topical imiquimod application. Thus, the overall pharmacological profiling of the PDE4 inhibitor DRM02 has revealed its potential as a topical therapy for inflammatory skin disorders and restoration of skin homeostasis.

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The PDE4 inhibitor CHF6001 affects keratinocyte proliferation via cellular redox pathways

Cited by 14 publications

References 47 publications

A transcriptomics-guided drug target discovery strategy identifies novel receptor ligands for lung regeneration

A transcriptomics-guided drug target discovery strategy identifies novel receptor ligands for lung regeneration

Oxidative Stress and Gut Microbiome in Inflammatory Skin Diseases

DRM02, a novel phosphodiesterase-4 inhibitor with cutaneous anti-inflammatory activity

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