FNF-12, a novel benzylidene-chromanone derivative, attenuates inflammatory response in in vitro and in vivo asthma models mediated by M2-related Th2 cytokines via MAPK and NF-kB signaling
FNF-12, a novel benzylidene-chromanone derivative, attenuates inflammatory response in in vitro and in vivo asthma models mediated by M2-related Th2 cytokines via MAPK and NF-kB signaling
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DOI：
10.1007/s43440-021-00325-0
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发表时间：
2021-09-01
影响因子：
4.4
通讯作者：
Rajagopalan, Prasanna
中科院分区：
文献类型：
--
作者：
Abohassan, Mohammad;Al Shahrani, Mesfer;Rajagopalan, Prasanna
背景与目的本研究评价了一种新型亚苄基-色满酮衍生物FNF-12在体外和体内哮喘模型中的疗效。方法采用大鼠嗜碱性粒细胞白血病(RBL-2H3)和急性单核细胞白血病(THP-1)来源的M2巨噬细胞。使用人全血来源的中性粒细胞和嗜碱性粒细胞。用流式细胞术研究关键信号蛋白。采用血小板活化因子(PAF)诱导的豚鼠哮喘模型进行体内研究。结果FNF-12的化学结构经核磁共振和质谱学确证。FnF-12可抑制RBL-2H3细胞脱颗粒，IC50值为123.7 nM，并以剂量效应方式抑制肿瘤坏死因子-α的释放。该化合物有效地控制了中性粒细胞的迁移和弹性蛋白酶的释放。Fc epsilon RI-嗜碱性粒细胞活化实验的IC50值为205 nM。在THP-1来源的M2巨噬细胞中，FNF-12抑制内毒素(LPS)诱导的IL-10、I-309/CCL1和MDC/CCL22的释放。抑制脂多糖诱导的细胞丝裂原活化蛋白激酶(MAPK)-p-p38和核因子-kB-p-p65的表达。在PAF诱导的动物模型中，总白细胞、嗜酸性粒细胞、中性粒细胞和巨噬细胞的积聚呈剂量依赖性减少。结论FNF-12在体内外哮喘模型中均能控制炎症反应，其机制可能与通过MAPK和NF-kB信号途径调控M2相关的Th2细胞因子有关。图形摘要
Background and aim This study evaluates a novel benzylidene-chromanone derivative, FNF-12, for efficacy in in vitro and in vivo asthma models. Methods Rat basophilic leukemia (RBL-2H3) and acute monocytic leukemia (THP-1)-derived M2 macrophages were used. Human whole blood-derived neutrophils and basophils were employed. Flow cytometry was used for studying key signalling proteins. Platelet activation factor (PAF)-induced asthma model in guinea pigs was used for in vivo studies. Results The chemical structure of FNF-12 was confirmed with proton-nuclear mass resonance (NMR) and mass spectroscopy. FNF-12 controlled degranulation in RBL-2H3 cells with an IC50 value of 123.7 nM and inhibited TNF-alpha release from these cells in a dose-responsive way. The compound effectively controlled the migration and elastase release in activated neutrophils. IC50 value in the Fc epsilon RI-basophil activation assay was found to be 205 nM. FNF-12 controlled the release of lipopolysaccharide (LPS)-induced interleukin-10, I-309/CCL1 and MDC/CCL22 in THP-1 derived M2 macrophages. The compound suppressed LPS-induced mitogen activated protein kinase (MAPK)-p-p38 and nuclear factor kappa B(NF-kB)-p-p65 expression in these cells. A dose-dependent decrease in the accumulation of total leucocytes, eosinophils, neutrophils and macrophages was observed in PAF-induced animal models. Conclusion FNF-12 was able to control the inflammatory responses in in vitro and in vivo asthma models, which may be driven by controlling M2-related Th2 cytokines via MAPK and NF-kB signaling. Graphic abstract