慢性阻塞性肺疾病(COPD)是全球死亡的主要原因,有效的治疗方法有限。Sirtuins(SIRT)是参与调节氧化还原和炎症稳态的组蛋白脱乙酰酶。因此,本研究旨在探讨SIRT-2在COPD小鼠模型中调节炎症的作用.
■通过香烟烟雾(CS)暴露60天,建立了小鼠的COPD,和AK-7用作特异性SIRT-2抑制剂。在CS暴露前1小时鼻内施用AK-7(100μg/kg和200μg/kg体重)。进行分子对接以分析不同炎性蛋白与AK-7的结合亲和力。
■免疫细胞分析显示,巨噬细胞(F4/80)数量显着增加,中性粒细胞(Gr-1),和淋巴细胞(CD4+,CD8+,和CD19+)在COPD中,组和他们的人口被AK-7给药减少。总活性氧,总诱导型一氧化氮合酶,炎性介质,如中性粒细胞弹性蛋白酶,C反应蛋白,组胺,IL-4、IL-6、IL-17和TNF-α等细胞因子在COPD组升高,在AK-7组下降。然而,IL-10显示代表抗炎效力的反向结果。AK-7通过抑制SIRT-2降低了p-NF-κB的表达,p-P38,p-Erk,和p-JNK并增加Nrf-2的表达。此外,AK-7还通过抑制炎症来减轻肺损伤,实质破坏,肺气肿,胶原蛋白,俱乐部细胞,和Kohn毛孔.AK-7还显示与炎性蛋白的良好结合亲和力。
■当前的研究表明,SIRT-2抑制可缓解COPD严重程度并增强肺部治疗干预措施,提示AK-7是COPD药物开发的潜在治疗分子。
UNASSIGNED: Chronic obstructive pulmonary disease (COPD) is a major global cause of mortality with limited effective treatments. Sirtuins (SIRT) are histone deacetylases that are involved in the regulation of redox and inflammatory homeostasis. Hence, the present study aims to investigate the role of SIRT-2 in modulating inflammation in a murine model of COPD.
UNASSIGNED: COPD in mice was established by cigarette smoke (CS) exposure for 60 days, and AK-7 was used as the specific SIRT-2 inhibitor. AK-7 (100 µg/kg and 200 µg/kg body weight) was administered intranasally 1 h before CS exposure. Molecular docking was performed to analyze the binding affinity of different inflammatory proteins with AK-7.
UNASSIGNED: Immune cell analysis showed a significantly increased number of macrophages (F4/80), neutrophils (Gr-1), and lymphocytes (CD4+, CD8+, and CD19+) in the COPD, group and their population was declined by AK-7 administration. Total reactive oxygen species, total inducible nitric oxide synthase, inflammatory mediators such as neutrophil elastase, C-reactive protein, histamine, and cytokines as IL4, IL-6, IL-17, and TNF-α were elevated in COPD and declined in the AK-7 group. However, IL-10 showed reverse results representing anti-inflammatory potency. AK-7 administration by inhibiting SIRT-2 decreased the expression of p-NF-κB, p-P38, p-Erk, and p-JNK and increased the expression of Nrf-2. Furthermore, AK-7 also declined the lung injury by inhibiting inflammation, parenchymal destruction, emphysema, collagen, club cells, and Kohn pores. AK-7 also showed good binding affinity with inflammatory proteins.
UNASSIGNED: The current study reveals that SIRT-2 inhibition mitigates COPD severity and enhances pulmonary therapeutic interventions, suggesting AK-7 as a potential therapeutic molecule for COPD medication development.