Identification and characterization of a novel adiponectin receptor agonist adipo anti-inflammation agonist and its anti-inflammatory effects in vitro and in vivo.
Identification and characterization of a novel adiponectin receptor agonist adipo anti-inflammation agonist and its anti-inflammatory effects in vitro and in vivo.
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DOI：
10.1111/bph.15277
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发表时间：
2021-01
影响因子：
7.3
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Qiu W;Wu H;Hu Z;Wu X;Tu M;Fang F;Zhu X;Liu Y;Lian J;Valverde P;Van Dyke T;Steffensen B;Dong LQ;Tu Q;Zhou X;Chen J
脂联素（Adiponectin， APN）是一种由脂肪细胞分泌的脂肪因子，与APN受体AdipoR1和AdipoR2结合，发挥抗炎作用，其机制尚不完全清楚。需要开发能够激活AdipoR1和AdipoR2的小分子，用于抑制脂多糖（LPS）诱导的内毒素血症和其他炎症性疾病的炎症反应。我们设计了10种新的AdipoRon （APR）的结构类似物，并评估了它们的抗炎特性。从小鼠体内分离骨髓源性巨噬细胞（BMMs）和腹腔巨噬细胞（PEMs）。采用逆转录和实时定量聚合酶链反应（qRT-PCR）、酶联免疫吸附试验（ELISA）和芯片技术检测lps诱导的内毒素血症小鼠和饮食诱导的肥胖（DIO）小鼠的促炎细胞因子水平。Western blotting、免疫组织化学（IHC）、siRNA干扰和免疫沉淀检测信号通路。一种新型APN受体激动剂adipo anti-inflammation agonist （AdipoAI）在DIO和内毒素血症小鼠以及培养的巨噬细胞中强烈抑制炎症。我们还发现，AdipoAI通过髓系分化标志物88 （MyD88）信号通路减弱AdipoR1和APPL1的关联，从而抑制核因子κB （NF-κB）、丝裂原活化蛋白激酶（MAPK）和c-Maf通路的激活，并限制lps诱导的巨噬细胞中促炎细胞因子的产生。AdipoAI是一种有希望的替代APN和APR的治疗方法，可以通过不同的信号通路抑制lps诱导的内毒素血症和其他炎症性疾病的炎症。
Adiponectin (APN) is an adipokine secreted from adipocytes that binds to APN receptors AdipoR1 and AdipoR2 and exerts an anti-inflammatory response through mechanisms not fully understood. There is a need to develop small molecules that activate AdipoR1 and AdipoR2 and to be used to inhibit the inflammatory response in lipopolysaccharide (LPS)-induced endotoxemia and other inflammatory disorders. We designed 10 new structural analogues of an AdipoR agonist, AdipoRon (APR), and assessed their anti-inflammatory properties. Bone marrow-derived macrophages (BMMs) and peritoneal macrophages (PEMs) were isolated from mice. Levels of pro-inflammatory cytokines were measured by reverse transcription and real-time quantitative polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and microarray in LPS-induced endotoxemia mice and diet-induced obesity (DIO) mice in which systemic inflammation prevails. Western blotting, immunohistochemistry (IHC), siRNA interference and immunoprecipitation were used to detect signalling pathways. A novel APN receptor agonist named adipo anti-inflammation agonist (AdipoAI) strongly suppresses inflammation in DIO and endotoxemia mice, as well as in cultured macrophages. We also found that AdipoAI attenuated the association of AdipoR1 and APPL1 via myeloid differentiation marker 88 (MyD88) signalling, thus inhibiting activation of nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and c-Maf pathways and limiting the production of pro-inflammatory cytokines in LPS-induced macrophages. AdipoAI is a promising alternative therapeutic approach to APN and APR to suppress inflammation in LPS-induced endotoxemia and other inflammatory disorders via distinct signalling pathways.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
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