目的探究盐诱导激酶2(SIK2)对大鼠心脏缺血再灌注损伤的影响及机制。方法建立大鼠心肌缺血再灌注损伤模型,随机分为假手术组、缺血再灌注组、SIK2抑制剂组,5只/组(造模前24 h左股静脉注射博舒替尼10 mg/kg)。超声检测大鼠心功能,HE染色...目的探究盐诱导激酶2(SIK2)对大鼠心脏缺血再灌注损伤的影响及机制。方法建立大鼠心肌缺血再灌注损伤模型,随机分为假手术组、缺血再灌注组、SIK2抑制剂组,5只/组(造模前24 h左股静脉注射博舒替尼10 mg/kg)。超声检测大鼠心功能,HE染色观察大鼠心肌组织病理变化,透射电镜观察心肌细胞自噬情况,蛋白免疫印迹法检测各组大鼠心肌组织中SIK2和LC3B、Beclin-1、p62等自噬相关蛋白以及p-mTOR、mTOR、p-ULK1、ULK1相关通路蛋白含量。结果与假手术组比较,缺血再灌注组心肌组织病理损伤严重,自噬小体数量增加(P<0.05),同时SIK2蛋白表达增多(P<0.01);与缺血再灌注组相比,SIK2抑制剂组SIK2蛋白表达减少(P<0.01),心肌组织病理损伤较轻,自噬小体数量减少(P<0.05)。与假手术组相比,缺血再灌注组LVEF、FS值降低(79.33±3.40 vs 38.67±2.49,59.33±5.25 vs 19.33±1.25,P<0.001);与缺血再灌注组相比,SIK2抑制剂组LVEF、FS值升高(38.67±2.49 vs 59.33±3.40,19.33±1.25 vs 30.67±3.40,P<0.05),3组IVSDd、LVPWDd无明显差别(P>0.05)。与假手术组相比,缺血再灌注组LC3-Ⅱ/LC3-Ⅰ、Beclin-1蛋白表达增多,p62蛋白表达减少(P<0.01);与缺血再灌注组相比,SIK2抑制剂组LC3-Ⅱ/LC3-Ⅰ、Beclin-1蛋白表达减少,p62蛋白表达增多(P<0.05)。与假手术组相比,缺血再灌注组p-ULK1(Ser757)蛋白表达增多(P<0.01),p-mTOR蛋白表达减少(P<0.0001);与缺血再灌注组相比,SIK2抑制剂组p-ULK1(Ser757)蛋白表达减少(P<0.01),p-mTOR蛋白表达增多(P<0.05);各组mTOR、ULK1无明显差异(P>0.05)。结论SIK2可能通过mTOR/ULK1信号通路促进细胞自噬,对SIK2进行抑制,可以减少异常自噬,缓解心肌缺血再灌注损伤。展开更多
Salt-inducible kinase 2 (SIK2) is a member of the AMP-activated serine/threonine kinase family. It has been reported that inhibition of SIK2 can enhance the cytotoxicity of paclitaxel,1 promote premitotic apoptosis, a...Salt-inducible kinase 2 (SIK2) is a member of the AMP-activated serine/threonine kinase family. It has been reported that inhibition of SIK2 can enhance the cytotoxicity of paclitaxel,1 promote premitotic apoptosis, and lead to cell cycle arrest in the metaphase.2 Thus, targeting SIK2 may be a therapeutic strategy for cancers drug and radiotherapy resistance. Mitotic catastrophe is a type of abnormal mitosis leading to cell death characterized by the multipolar spindle and multinucleation, which was first discovered during an ionizing radiation (IR)-induced cell damage.3 However, the mechanism of mitotic catastrophe is not well understood. The present study aimed to assess the effect of the knockdown of SIK2 on IR-induced mitotic catastrophe.展开更多
Metastasis is the major cause of treatment failure in cancer patients and of cancer?related deaths.This editorial discusses how cancer metastasis may be better perceived and controlled.Based on big?data analyses,a col...Metastasis is the major cause of treatment failure in cancer patients and of cancer?related deaths.This editorial discusses how cancer metastasis may be better perceived and controlled.Based on big?data analyses,a collection of150 important pro?metastatic genes was studied.Using The Cancer Genome Atlas datasets to re?analyze the effect of some previously reported metastatic genes—e.g.,JAM2,PPARGC1A,SIK2,and TRAF6—on overall survival of patients with renal and liver cancers,we found that these genes are actually protective factors for patients with cancer.The role of epithelial–mesenchymal transition(EMT)in single?cell metastasis has been well?documented.However,in metastasis caused by cancer cell clusters,EMT may not be necessary.A novel role of epithelial marker E?cadherin,as a sensitizer for chemoresistant prostate cancer cells by inhibiting Notch signaling,has been found.This editorial also discusses the obstacles for developing anti?metastatic drugs,including the lack of high?throughput technologies for identifying metastasis inhibitors,less application of animal models in the pre?clinical evaluation of the leading com?pounds,and the need for adjustments in clinical trial design to better reflect the anti?metastatic efficacy of new drugs.We are confident that by developing more effective high?throughput technologies to identify metastasis inhibitors,we can better predict,prevent,and treat cancer metastasis.展开更多
文摘目的探究盐诱导激酶2(SIK2)对大鼠心脏缺血再灌注损伤的影响及机制。方法建立大鼠心肌缺血再灌注损伤模型,随机分为假手术组、缺血再灌注组、SIK2抑制剂组,5只/组(造模前24 h左股静脉注射博舒替尼10 mg/kg)。超声检测大鼠心功能,HE染色观察大鼠心肌组织病理变化,透射电镜观察心肌细胞自噬情况,蛋白免疫印迹法检测各组大鼠心肌组织中SIK2和LC3B、Beclin-1、p62等自噬相关蛋白以及p-mTOR、mTOR、p-ULK1、ULK1相关通路蛋白含量。结果与假手术组比较,缺血再灌注组心肌组织病理损伤严重,自噬小体数量增加(P<0.05),同时SIK2蛋白表达增多(P<0.01);与缺血再灌注组相比,SIK2抑制剂组SIK2蛋白表达减少(P<0.01),心肌组织病理损伤较轻,自噬小体数量减少(P<0.05)。与假手术组相比,缺血再灌注组LVEF、FS值降低(79.33±3.40 vs 38.67±2.49,59.33±5.25 vs 19.33±1.25,P<0.001);与缺血再灌注组相比,SIK2抑制剂组LVEF、FS值升高(38.67±2.49 vs 59.33±3.40,19.33±1.25 vs 30.67±3.40,P<0.05),3组IVSDd、LVPWDd无明显差别(P>0.05)。与假手术组相比,缺血再灌注组LC3-Ⅱ/LC3-Ⅰ、Beclin-1蛋白表达增多,p62蛋白表达减少(P<0.01);与缺血再灌注组相比,SIK2抑制剂组LC3-Ⅱ/LC3-Ⅰ、Beclin-1蛋白表达减少,p62蛋白表达增多(P<0.05)。与假手术组相比,缺血再灌注组p-ULK1(Ser757)蛋白表达增多(P<0.01),p-mTOR蛋白表达减少(P<0.0001);与缺血再灌注组相比,SIK2抑制剂组p-ULK1(Ser757)蛋白表达减少(P<0.01),p-mTOR蛋白表达增多(P<0.05);各组mTOR、ULK1无明显差异(P>0.05)。结论SIK2可能通过mTOR/ULK1信号通路促进细胞自噬,对SIK2进行抑制,可以减少异常自噬,缓解心肌缺血再灌注损伤。
基金funded by grants from the National Natural Science Foundation of China(31470827,81773359,82073488,31870847 and 3127894).
文摘Salt-inducible kinase 2 (SIK2) is a member of the AMP-activated serine/threonine kinase family. It has been reported that inhibition of SIK2 can enhance the cytotoxicity of paclitaxel,1 promote premitotic apoptosis, and lead to cell cycle arrest in the metaphase.2 Thus, targeting SIK2 may be a therapeutic strategy for cancers drug and radiotherapy resistance. Mitotic catastrophe is a type of abnormal mitosis leading to cell death characterized by the multipolar spindle and multinucleation, which was first discovered during an ionizing radiation (IR)-induced cell damage.3 However, the mechanism of mitotic catastrophe is not well understood. The present study aimed to assess the effect of the knockdown of SIK2 on IR-induced mitotic catastrophe.
文摘Metastasis is the major cause of treatment failure in cancer patients and of cancer?related deaths.This editorial discusses how cancer metastasis may be better perceived and controlled.Based on big?data analyses,a collection of150 important pro?metastatic genes was studied.Using The Cancer Genome Atlas datasets to re?analyze the effect of some previously reported metastatic genes—e.g.,JAM2,PPARGC1A,SIK2,and TRAF6—on overall survival of patients with renal and liver cancers,we found that these genes are actually protective factors for patients with cancer.The role of epithelial–mesenchymal transition(EMT)in single?cell metastasis has been well?documented.However,in metastasis caused by cancer cell clusters,EMT may not be necessary.A novel role of epithelial marker E?cadherin,as a sensitizer for chemoresistant prostate cancer cells by inhibiting Notch signaling,has been found.This editorial also discusses the obstacles for developing anti?metastatic drugs,including the lack of high?throughput technologies for identifying metastasis inhibitors,less application of animal models in the pre?clinical evaluation of the leading com?pounds,and the need for adjustments in clinical trial design to better reflect the anti?metastatic efficacy of new drugs.We are confident that by developing more effective high?throughput technologies to identify metastasis inhibitors,we can better predict,prevent,and treat cancer metastasis.
