Micro-ribonucleic acid-23a-3p prevents the onset of type 2 diabetes mellitus by suppressing the activation of nucleotide-binding oligomerization-like receptor family pyrin domain containing 3 inflammatory bodies-caused pyroptosis through negatively regulating NIMA-related kinase 7.
Micro-ribonucleic acid-23a-3p prevents the onset of type 2 diabetes mellitus by suppressing the activation of nucleotide-binding oligomerization-like receptor family pyrin domain containing 3 inflammatory bodies-caused pyroptosis through negatively regulating NIMA-related kinase 7.
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DOI：
10.1111/jdi.13396
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发表时间：
2021-03
影响因子：
3.2
通讯作者：
Qi K
中科院分区：
文献类型：
--
作者：
Chang H;Chang H;Cheng T;Lee GD;Chen X;Qi K
微核糖核酸（micro-ribonucleacids，miRNAs）在控制2型糖尿病相关代谢方面具有重要作用。本研究旨在探讨miR-23 a-3 p在核巧酸结合寡聚化样受体家族pyrin domain containing 3（NLRP 3）炎性小体激活引起的细胞焦亡中的作用，从而降低2型糖尿病的发生。检测2型糖尿病患者和大鼠模型中miR-23 a-3 p和NIMA相关激酶7（NEK 7）的表达。双荧光素酶报告基因实验用于验证miR-23 a-3 p和NEK 7之间的靶向关系。用miR-23 a-3 p模拟物、miR-23 a-3 p抑制剂或短发夹NEK 7转染骨髓源性巨噬细胞，并用NLRP 3炎性小体的特异性激活剂（脂多糖+腺苷-5 ′-三磷酸）处理，以评价细胞中NEK 7、miR-23 a-3 p、gasdermin D p30、caspase-1原和caspase-1以及上清液中白细胞介素-1 β和肿瘤坏死因子-α的表达。采用2型糖尿病大鼠模型，观察miR-23 a-3 p、NEK 7和NLRP 3炎性小体对体内细胞凋亡和2型糖尿病的影响。在2型糖尿病患者和大鼠模型中，NEK 7过表达，而miR-23 a-3 p表达不足。NEK 7是miR-23 a-3 p的靶基因。在骨髓源性巨噬细胞中加入脂多糖+腺苷-5 ′-三磷酸后，miR-23 a-3 p的表达随后下降。此外，加入脂多糖+腺苷-5 ′-三磷酸可增加骨髓源性巨噬细胞中NEK 7、NLRP 3、pro-caspase-1、cle-caspase-1和gasdermin D p30的表达，并增加上清液中白细胞介素-1 β和肿瘤坏死因子-α的水平，同时伴有明显的细胞凋亡，这在miR-23 a-3 p过表达和NEK 7沉默后逆转。miR-23 a-3 p过表达可减轻2型糖尿病大鼠的肝肾损伤，并减少NLRP 3诱导的细胞凋亡。通过miR-23 a-3 p靶向NEK 7可以减少NLRP 3诱导的2型糖尿病大鼠的细胞凋亡，并减轻肝脏和肾脏损伤。靶向NIMA相关激酶7的微核糖核酸可减轻NOD-、LRR-和pyrin domain containing protein 3诱导的2型糖尿病大鼠肝细胞凋亡，减轻肝、肾损伤。
Micro‐ribonucleic acids (miRNAs) possess crucial functions in governing metabolisms associated with type 2 diabetes mellitus. This study aimed to investigate the role of miR‐23a‐3p in pyroptosis caused by nucleotide‐binding oligomerization‐like receptor family pyrin domain containing 3 (NLRP3) inflammatory body activation, thereby reducing the occurrence of type 2 diabetes mellitus. miR‐23a‐3p and NIMA‐related kinase 7 (NEK7) expression in type 2 diabetes mellitus patients and rat models was examined. Dual‐luciferase reporter gene experiments were used to verify the targeting relationship between miR‐23a‐3p and NEK7. Bone marrow‐derived macrophages were transfected with miR‐23a‐3p mimic, miR‐23a‐3p inhibitor or short hairpin NEK7 and were treated with a specific activator of NLRP3 inflammatory body (lipopolysaccharide + adenosine‐5′‐triphosphate) to evaluate expression of NEK7, miR‐23a‐3p, gasdermin D p30, pro‐caspase‐1 and caspase‐1 in cells, and interleukin‐1β and tumor necrosis factor‐α in supernatant. Type 2 diabetes mellitus rat models were used to observe the influences of miR‐23a‐3p, NEK7 and NLRP3 inflammatory body on pyroptosis and type 2 diabetes mellitus in vivo. NEK7 was overexpressed, whereas miR‐23a‐3p was underexpressed in patients and rat models with type 2 diabetes mellitus. NEK7 was a target gene of miR‐23a‐3p. After the addition of lipopolysaccharide + adenosine‐5′‐triphosphate in bone marrow‐derived macrophages, the expression of miR‐23a‐3p subsequently declined. Furthermore, the addition of lipopolysaccharide + adenosine‐5′‐triphosphate elevated NEK7, NLRP3, pro‐caspase‐1, cle‐caspase‐1 and gasdermin D p30 expressions in bone marrow‐derived macrophages, and enhanced levels of interleukin‐1β and tumor necrosis factor‐α in the supernatant, accompanied with conspicuous cell pyroptosis, which was reversed after miR‐23a‐3p overexpression and NEK7 silencing. miR‐23a‐3p overexpression alleviated liver and kidney damage in type 2 diabetes mellitus rats, and reduced NLRP3‐induced pyroptosis. Targeting NEK7 by miR‐23a‐3p could reduce NLRP3‐induced pyroptosis, and assuage liver and kidney injuries in type 2 diabetes mellitus rats. Targeting NIMA‐related kinase 7 by micro‐ribonucleic acid could reduce NOD‐, LRR‐ and pyrin domain‐containing protein 3‐induced pyroptosis, and assuage liver and kidney injuries in type 2 diabetes mellitus rats.
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影响因子：
64.8
作者：
Shi, Jianjin;Zhao, Yue;Shao, Feng
通讯作者：
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影响因子：
12.8
作者：
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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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通讯作者：
DiStefano, PS
影响因子：
4
作者：
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通讯作者：
Natarajan V