Cefradine blocks solar-ultraviolet induced skin inflammation through direct inhibition of T-LAK cell-originated protein kinase.
Cefradine blocks solar-ultraviolet induced skin inflammation through direct inhibition of T-LAK cell-originated protein kinase.
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头孢拉定通过直接抑制 T-LAK 细胞来源的蛋白激酶来阻断太阳紫外线引起的皮肤炎症。
DOI：
10.18632/oncotarget.8260
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发表时间：
2016-04-26
期刊：
影响因子：
--
通讯作者：
Zhu F
中科院分区：
文献类型：
--
作者：
Fan X;Duan Q;Ke C;Zhang G;Xiao J;Wu D;Zeng X;Chen J;Guo J;Zhou J;Shi F;Zhu F
过量的太阳紫外线（SUV）引起的皮肤炎症和皮肤癌对人类健康构成了极大的威胁。SUV通过激活p38丝裂原活化蛋白激酶（p38）和c-Jun N-末端激酶（JNKs）诱导皮肤炎症反应。T-LAK细胞源性蛋白激酶（TOPK）在此过程中起重要作用。临床资料显示TOPK、磷酸化p38、磷酸化JNKs在日光性皮炎中高表达。体外研究表明，SUV以剂量和时间依赖性方式诱导HaCat和JB 6细胞中p38和JNK的磷酸化。分子对接模型表明，头孢拉定，FDA批准的头孢菌素类抗生素，直接结合TOPK。体外结合实验结果证实头孢拉定可与TOPK直接结合。体外激酶实验结果表明，头孢拉定能抑制TOPK活性。体外研究进一步显示，头孢拉定可通过抑制TOPK活性，抑制SUV诱导的p38、JNKs和H2 AX磷酸化水平，并呈剂量和时间依赖性;头孢拉定可抑制HaCat和JB 6细胞分泌IL 6和TNF-α。体内研究表明，头孢拉定可下调SUV诱导的Babl/c小鼠p38、JNKs和H2 AX的磷酸化，抑制IL 6和TNF-α的分泌。提示头孢拉定可通过阻断TOPK信号通路抑制SUV所致的皮肤炎症反应，TOPK是抑制SUV所致皮肤炎症反应的有效靶点。
Skin inflammation, and skin cancer induced by excessive solar ultraviolet (SUV) is a great threat to human health. SUV induced skin inflammation through activating p38 mitogen-activated protein kinase (p38) and c-Jun N-termeinal kinases (JNKs). T-LAK cell-originated protein kinase (TOPK) plays an important role in this process. Herein, the clinical data showed TOPK, phospho-p38, phospho-JNKs were highly expressed in human solar dermatitis. Ex vivo studies showed that SUV induced the phosphorylation of p38 and JNKs in HaCat and JB6 cells in a dose and time dependent manner. Molecule docking model indicated cefradine, an FDA-approved cephalosporin antibiotic, directly binds with TOPK. The result of in vitro binding assay verified cefradine can directly bind with TOPK. In vitro kinase results showed cefradine can inhibit TOPK activity. Ex vivo studies further showed cefradine inhibited SUV-induced the phosphorylation level of p38, JNKs and H2AX through inhibiting TOPK activity in a dose and time dependent manner, and cefradine inhibited the secretion of IL6 and TNF-α in HaCat and JB6 cells. In vivo studies showed that cefradine down-regulated SUV-induced the phosphorylation of p38, JNKs and H2AX and inhibited the secretion of IL6 and TNF-α in Babl/c mice. These results indicated that cefradine can inhibit SUV-induced skin inflammation by blocking TOPK signaling pathway, and TOPK is an effective target for suppressing inflammation induced by SUV irradiation.
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影响因子：
1.7
作者：
Coondoo A;Phiske M;Verma S;Lahiri K
通讯作者：
Lahiri K
DOI：
10.1016/j.bbapap.2005.08.017
发表时间：
2005-12-30
影响因子：
3.2
作者：
Kaminska, B
通讯作者：
Kaminska, B
影响因子：
11.2
作者：
Kim, Dong Joon;Li, Yan;Dong, Zigang
通讯作者：
Dong, Zigang
DOI：
10.1126/stke.2003.167.re2
发表时间：
2003-01-28
期刊：
Science's STKE : signal transduction knowledge environment
影响因子：
--
作者：
Bode, Ann M;Dong, Zigang
通讯作者：
Dong, Zigang
DOI：
10.1002/prot.340230306
发表时间：
1995-11-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
SALI, A;POTTERTON, L;KARPLUS, M
通讯作者：
KARPLUS, M