Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
Eur J Pharmacol. 2022 Sep 5;930:175156. doi: 10.1016/j.ejphar.2022.175156. Epub 2022 Jul 19.
The maturation and secretion of interleukin-1β (IL-1β) mediated by NLRP3 inflammasome activation plays an important role in the progression of many inflammatory diseases. Inhibition of NLRP3 inflammasome activation may be a promising strategy to treat these inflammation-driven diseases, such as psoriasis. As a broad-spectrum antifungal agent, ciclopirox (CPX) is widely used in the treatment of dermatomycosis. Although CPX has been reported to have anti-inflammatory effects in many studies, there has been little research into its underlying mechanisms. In our study, CPX reduced lipopolysaccharide (LPS)/nigericin-induced NLRP3 inflammasome activation (IC: 1.684 μM). Mechanistically, CPX upregulated peroxisome proliferator-activated receptor-γ coactivator-1α expression (by 82.7% at 5 μM and 87.5% at 10 μM) to protect mitochondria. Our studies showed that CPX reduced mitochondrial reactive oxygen species production, increased mitochondrial membrane potential, elevated mitochondrial biosynthesis, and up-regulated intracellular adenosine triphosphate level. Furthermore, treatment with CPX promoted the up-regulation of mRNA expression, which involved mitochondrial biosynthesis (NRF1, NRF2, TFAM) and antioxidation (SOD1 and CAT). In addition, CPX ameliorated inflammatory response in imiquimod-induced psoriasis mice. This study provides a potential pharmacological mechanism for CPX to treat psoriasis and other NLRP3-driven inflammatory diseases.
NLRP3 炎性小体激活介导的白细胞介素-1β（IL-1β）的成熟和分泌在许多炎症性疾病的进展中起着重要作用。抑制 NLRP3 炎性小体的激活可能是治疗这些炎症驱动性疾病（如银屑病）的一种有前途的策略。环吡酮（CPX）作为一种广谱抗真菌剂，广泛用于治疗皮肤真菌病。尽管 CPX 在许多研究中已被报道具有抗炎作用，但对其潜在机制的研究甚少。在我们的研究中，CPX 降低了脂多糖（LPS）/ Nigericin 诱导的 NLRP3 炎性小体激活（IC：1.684 μM）。从机制上讲，CPX 上调过氧化物酶体增殖物激活受体-γ 共激活物-1α 的表达（在 5 μM 时增加 82.7%，在 10 μM 时增加 87.5%）以保护线粒体。我们的研究表明，CPX 减少了线粒体活性氧的产生，增加了线粒体膜电位，提高了线粒体生物合成，并上调了细胞内三磷酸腺苷水平。此外，CPX 促进了与线粒体生物合成（NRF1、NRF2、TFAM）和抗氧化（SOD1 和 CAT）相关的 mRNA 表达的上调。此外，CPX 改善了咪喹莫特诱导的银屑病小鼠的炎症反应。这项研究为 CPX 治疗银屑病和其他 NLRP3 驱动的炎症性疾病提供了一个潜在的药理机制。
