Multiple-Purpose Connectivity Map Analysis Reveals the Benefits of Esculetin to Hyperuricemia and Renal Fibrosis.
Multiple-Purpose Connectivity Map Analysis Reveals the Benefits of Esculetin to Hyperuricemia and Renal Fibrosis.
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多用途连接图分析揭示了七叶亭对高尿酸血症和肾纤维化的益处
DOI：
10.3390/ijms21207695
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发表时间：
2020-10-18
影响因子：
5.6
通讯作者：
Zhou H
中科院分区：
文献类型：
--
作者：
Wang Y;Kong W;Wang L;Zhang T;Huang B;Meng J;Yang B;Xie Z;Zhou H
高尿酸血症（HUA）是慢性肾脏疾病（CKD）的危险因素。CKD 3-4期患者血清尿酸（SUA）水平与高尿酸血症肾病（HN）发病率密切相关。预防CKD需要新的尿酸（UA）降低策略。多用途连接图（CMAP）用于发现抗HUA和肾纤维化的潜在分子。我们用HUA和单侧输尿管闭塞（UUO）模型小鼠验证分子对肾脏的保护作用，并探讨相关机制。在UA诱导的HepG2和NRK-52E细胞中进行体外实验。Esculetin是得分最高的化合物，降低血清尿酸（SUA）水平，对UA排泄具有双重作用。黄皮素通过抑制肝脏黄嘌呤氧化酶（XO）的表达和活性，以及调节肾脏中UA转运蛋白发挥上述作用。esculetin抑制XO的机制与抑制己糖激酶2 （HK2）的核易位有关。黄皮素通过抑制TGF-β1激活的促纤维化信号，对HUA和UUO小鼠具有抗纤维化作用。内皮素对HUA小鼠的肾保护作用与降低SUA、减轻氧化应激和抑制纤维化有关。Esculetin是一种候选降尿酸药物，具有肾保护活性，能够抑制XO，促进UA排泄，保护氧化应激损伤，减少肾纤维化。
Hyperuricemia (HUA) is a risk factor for chronic kidney disease (CKD). Serum uric acid (SUA) levels in CKD stage 3–4 patients closely correlate with hyperuricemic nephropathy (HN) morbidity. New uric acid (UA)-lowering strategies are required to prevent CKD. The multiple-purpose connectivity map (CMAP) was used to discover potential molecules against HUA and renal fibrosis. We used HUA and unilateral ureteral occlusion (UUO) model mice to verify renoprotective effects of molecules and explore related mechanisms. In vitro experiments were performed in HepG2 and NRK-52E cells induced by UA. Esculetin was the top scoring compound and lowered serum uric acid (SUA) levels with dual functions on UA excretion. Esculetin exerted these effects by inhibiting expression and activity of xanthine oxidase (XO) in liver, and modulating UA transporters in kidney. The mechanism by which esculetin suppressed XO was related to inhibiting the nuclear translocation of hexokinase 2 (HK2). Esculetin was anti-fibrotic in HUA and UUO mice through inhibiting TGF-β1-activated profibrotic signals. The renoprotection effects of esculetin in HUA mice were associated with lower SUA, alleviation of oxidative stress, and inhibition of fibrosis. Esculetin is a candidate urate-lowering drug with renoprotective activity and the ability to inhibit XO, promote excretion of UA, protect oxidative stress injury, and reduce renal fibrosis.
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WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
DOI：
10.2147/dddt.s97959
发表时间：
2017
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Jones G;Panova E;Day R
通讯作者：
Day R
DOI：
10.1016/j.bbadis.2019.02.002
发表时间：
2019-06-01
影响因子：
6.2
作者：
Fang, Penghua;He, Biao;Bo, Ping
通讯作者：
Bo, Ping
影响因子：
37.3
作者：
Arora R;Sawney S;Saini V;Steffi C;Tiwari M;Saluja D
通讯作者：
Saluja D
影响因子：
8.2
作者：
Kim, So-hyung;Kang, Kyoung-ah;Hyun, Jin-won
通讯作者：
Hyun, Jin-won