GW0742 activates miR-17-5p and inhibits TXNIP/NLRP3-mediated inflammation after hypoxic-ischaemic injury in rats and in PC12 cells.
GW0742 activates miR-17-5p and inhibits TXNIP/NLRP3-mediated inflammation after hypoxic-ischaemic injury in rats and in PC12 cells.
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DOI：
10.1111/jcmm.15698
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发表时间：
2020-11
影响因子：
5.3
通讯作者：
Zhang JH
中科院分区：
文献类型：
--
作者：
Gamdzyk M;Doycheva DM;Kang R;Tang H;Travis ZD;Tang J;Zhang JH
本研究旨在探讨过氧化物酶体增殖物激活受体-β/δ（PPAR -β/δ）受体激动剂GW0742对缺氧缺血（HI）大鼠模型以及糖氧剥夺（OGD）模型中的PC12细胞神经炎症的影响。通过结扎颈总动脉并诱导缺氧150分钟来诱导HI。免疫荧光用于定量小胶质细胞激活以及确定PPAR -β/δ的细胞定位。通过蛋白质印迹法测量蛋白质的表达。通过双荧光素酶报告基因检测评估GW0742对PC12细胞中miR - 17 - 5p的激活作用。HI后，TXNIP、NLRP3、裂解的半胱天冬酶 - 1和白细胞介素 - 1β（IL - 1β）的内源性表达增加。GW0742治疗显著减少了HI后同侧大脑半球中激活的促炎小胶质细胞的数量。从机制上讲，GW0742显著降低了TXNIP、NLRP3、白细胞介素 - 6（IL - 6）和肿瘤坏死因子 - α（TNF - α）的表达。PPAR -β/δ拮抗剂GSK3787、miR - 17 - 5p抑制剂或TXNIP基因编辑激活剂（CRISPR activation）均可消除GW0742的抗炎作用。GW0742激活PPAR -β/δ可激活PC12细胞中miR - 17 - 5p的表达，并提高OGD后的细胞活力，同时伴有TXNIP表达降低以及白细胞介素 - 1β和肿瘤坏死因子 - α分泌减少。总之，GW0742可能是治疗HI患者的一种有前景的神经治疗药物。
This study aimed to investigate the effects of PPAR‐β/δ receptor agonist GW0742 on neuroinflammation in a rat model of hypoxia‐ischaemia (HI) and in PC12 cells in OGD model. HI was induced by ligating the common carotid artery and inducing hypoxia for 150 minutes. Immunofluorescence was used for quantification of microglia activation and for determining cellular localization of PPAR‐β/δ. Expression of proteins was measured by Western blot. Activation of miR‐17‐5p by GW0742 was assessed in PC12 cells by Dual‐Luciferase Reporter Gene Assay. The endogenous expression of TXNIP, NLRP3, cleaved caspase‐1 and IL‐1β was increased after HI. GW0742 treatment significantly reduced the number of activated pro‐inflammatory microglia in ipsilateral hemisphere after HI. Mechanistically, GW0742 significantly decreased the expression of TXNIP, NLRP3, IL‐6 and TNF‐α. Either PPAR‐β/δ antagonist GSK3787, miR‐17‐5p inhibitor, or TXNIP CRISPR activation abolished the anti‐inflammatory effects of GW0742. Activation of PPAR‐β/δ by GW0742 activated miR‐17‐5p expression in PC12 cells and increased cell viability after OGD, which was accompanied by decreased expression of TXNIP and reduced secretion of IL‐1β and TNF‐α. In conclusion, GW0742 may be a promising neurotherapeutic for the management of HI patients.
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影响因子：
3.6
作者：
Hagberg, H;Gilland, E;Soder, O
通讯作者：
Soder, O
新生儿神经保护和神经性护理的治疗进展。
影响因子：
48
作者：
Johnston, Michael V.;Fatemi, Ali;Wilson, Mary Ann;Northington, Frances
通讯作者：
Northington, Frances
影响因子：
4.7
作者：
Dharap A;Pokrzywa C;Murali S;Kaimal B;Vemuganti R
通讯作者：
Vemuganti R
DOI：
10.1007/978-3-7091-0693-8_15
发表时间：
2011-01-01
期刊：
INTRACEREBRAL HEMORRHAGE RESEARCH: FROM BENCH TO BEDSIDE
影响因子：
--
作者：
Fathali, Nancy;Khatibi, Nikan H.;Zhang, John H.
通讯作者：
Zhang, John H.
影响因子：
6.7
作者：
Haskova, Z.;Hoang, B.;Kilgore, K. S.
通讯作者：
Kilgore, K. S.