Plants for Human Health Institute, Animal Sciences Dept., NC Research Campus, NC State University, NC, USA.
Department of Biomedical and Specialist Surgical Sciences, University of Ferrara, Ferrara, Italy.
Arch Biochem Biophys. 2020 May 30;685:108355. doi: 10.1016/j.abb.2020.108355. Epub 2020 Apr 5.
Psoriasis is a skin disease characterized by abnormal keratinocyte proliferation and inflammation. Currently, there are no cures for this disease, so the goal of treatment is to decrease inflammation and slow down the associated rapid cell growth and shedding. Recent advances have led to the usage of phosphodiesterase 4 (PDE4) inhibitors for treatment of this condition. For example, apremilast is an oral, selective PDE4 inhibitor that is able to reduce skin inflammation and is Food and Drug Administration (FDA)-approved to treat adults with moderate to severe psoriasis and/or psoriatic arthritis. However, common target-related adverse events, including diarrhea, nausea, headache, and insomnia limit the usage of this drug. To circumvent these effects, the usage of PDE4 inhibitors specifically designed for topical treatment, such as CHF6001, may combine local anti-inflammatory activity with limited systemic exposure, improving tolerability. In this study, we showed that CHF6001, currently undergoing clinical development for COPD, suppresses human keratinocyte proliferation as assessed via BrdU incorporation. We also observed decreased re-epithelialization in a scratch-wound model after CHF6001 treatment. At the molecular level, CHF6001 inhibited translocation of phosphorylated NF-κB subunit p65, promoting loss of nuclear cyclin D1 accumulation and an increase of cell cycle inhibitor p21. Furthermore, CHF6001 decreased oxidative stress, measured by assessing lipid peroxidation (4-HNE adduct formation), through the inactivation of the NADPH oxidase. These results suggest that CHF6001 has the potential to treat skin disorders associated with hyperproliferative keratinocytes, such as psoriasis by targeting oxidative stress, abnormal re-epithelization, and inflammation.
银屑病是一种以角质形成细胞异常增殖和炎症为特征的皮肤疾病。目前，这种疾病还没有治愈方法，因此治疗的目标是减轻炎症并减缓相关的快速细胞生长和脱落。最近的进展导致了磷酸二酯酶 4（PDE4）抑制剂被用于治疗这种疾病。例如，阿普司特是一种口服、选择性 PDE4 抑制剂，能够减轻皮肤炎症，已被美国食品和药物管理局（FDA）批准用于治疗成人中度至重度银屑病和/或银屑病关节炎。然而，常见的与靶点相关的不良反应，包括腹泻、恶心、头痛和失眠，限制了该药物的使用。为了避免这些影响，可使用专门设计用于局部治疗的 PDE4 抑制剂，如 CHF6001，它可能将局部抗炎活性与有限的全身暴露相结合，从而提高耐受性。在这项研究中，我们表明，CHF6001（目前正在开发用于治疗 COPD）通过 BrdU 掺入抑制人角质形成细胞增殖。我们还观察到在 CHF6001 治疗后划痕模型中再上皮化减少。在分子水平上，CHF6001 抑制磷酸化 NF-κB 亚基 p65 的易位，促进核 cyclin D1 积累的丧失和细胞周期抑制剂 p21 的增加。此外，CHF6001 通过失活 NADPH 氧化酶减少氧化应激，通过评估脂质过氧化（4-HNE 加合物形成）来测量。这些结果表明，CHF6001 通过靶向氧化应激、异常再上皮化和炎症，有可能治疗与角质形成细胞过度增殖相关的皮肤疾病，如银屑病。
