1.Doxycycline诱导细胞凋亡及其机制 2.GDNF修饰的人羊膜上皮细胞在大鼠MCAO模型中的治疗作用
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摘要
强力霉素(Doxycycline, Dc)诱导肿瘤细胞凋亡及其在肿瘤动物模型中的治疗作用已有报道,其治疗作用主要是通过抑制细胞金属基质蛋白酶表达及细胞色素c氧化酶活力来抑制细胞转移、诱导细胞凋亡,但Dc诱导细胞凋亡的机制还不清楚。本章研究了线粒体,calpain和caspase在Dc诱导HeLa细胞凋亡过程中的作用。通过细胞形态学及DNA ladder分析证明Dc能够诱导HeLa细胞发生显著凋亡,并且这一过程具有药物浓度和时间依赖性。广泛性caspase(半胱氨酸天冬氨酸特异蛋白酶)抑制剂(zVAD-fmk)及caspase-8,-9特异抑制剂(zIETD-fmk, zLEHD-fmk)抑制分析表明,Dc诱导的凋亡具有caspase活力依赖性。Western blot检测到caspase-3,-9,-8及calpain I(钙依赖蛋白酶I)发生了活化,但caspase-2活化没有被检测到。在胞浆蛋白中可以检测到从线粒体中释放的细胞色素c(Cyt c)和Smac,并且这两种蛋白的释放不能被zVAD-fmk和zIETD-fmk所抑制。进一步通过使用各种蛋白酶抑制剂,结合Western blot和细胞凋亡分析证明,caspase-9可能作为起始caspase通过线粒体途径活化,而caspase-8主要通过caspase-9和calpain途径活化。Caspase-8和-9的特异抑制剂对caspase-3的活化都有抑制作用,但前者抑制作用更强,这一结果与凋亡抑制分析结果一致。抑制caspase-8活力后检测细胞凋亡率及caspase-3活化,结果证明在Dc诱导的HeLa细胞凋亡过程中caspase-8起重要的作用。
滑膜成纤维细胞是类风湿关节炎(RA)发病过程中一种重要的炎症细胞。在RA病人关节中滑膜成纤维细胞(SFB)发生增生,分泌多种炎症因子并且参与了诱导软骨细胞凋亡和关节损伤。Doxycycline具有抑制细胞增殖,抑制金属基质蛋白酶表达及诱导细胞凋亡的功能。本章研究了Doxycycline诱导大鼠RA模型中膝关节SFB(RA-SFB)细胞凋亡的功能。流式细胞检测表明Dc诱导的RA-SFB细胞凋亡具有药物浓度和处理时间依赖性;Dc可以诱导RA-SFB细胞发生显著的凋亡并且产生DNA Ladder。透射电镜下观察到Dc处理后线粒体发生明显的膨胀,线粒体嵴消失,胞质出现大量的空泡;线粒体膜电位(MMP)在Dc处理48 h内发生显著降低,所以线粒体参与了Dc诱导的RA-SFB细胞凋亡。Western blot分析证明caspase-3和calpain I在Dc诱导后发生活化;抗凋亡蛋白XIAP在Dc处理后部分被降解。本章研究为Doxycycline诱导RA中SFB细胞凋亡提供一定的依据,并且Doxycycline联合其它药物或基因通过凋亡的途径来治疗RA具有潜在的可能性。
人羊膜上皮细胞(hAECs)具有胚胎干细胞及多能干细胞的特征,在一定条件下能够分化成不同组织的细胞,GDNF具有抗缺血后神经元凋亡的功能。本章中以慢病毒为载体,分别将GDNF和EGFP转染到hAECs中,得到稳定表达EGFP和GDNF的hAECs-EGFP和hAECs-GDNF细胞。分别将这两种细胞移植到脑中动脉阻塞(MCAO)缺血损伤的大鼠脑内。移植后第7天可以检测到GFAP(体外培养的hAECs表达的胶质细胞标志蛋白)的表达;移植后第21天仍可以检测到植入区EGFP的高表达;并且移植到体内以后,少部分hAECs可以被诱导表达神经元标志蛋白MAP2。两种细胞对脑缺血后大鼠行为学指标都有显著的改善作用,并且在移植后早期hAECs-GDNF治疗组比hAECs-EGFP治疗组恢复更明显。Western blot检测证明:在靠近hAECs移植部位的缺血区组织内,caspase-3活化基本被抑制。此外hAECs治疗后,缺血损伤区体积也明显减小。由于hAECs来源广泛,道德和伦理学问题较少,且免疫原性低,因此以hAECs为载体进行细胞基因治疗是一种潜在的、具有广阔应用前景的生物治疗方法。
Doxycycline (Dc) has been demonstrated to inhibit cell growth and induce apoptosis in tumor cells, although its mechanism of action is not fully understood. The present study demonstrates that apoptosis can be induced in HeLa cells by Dc, and that process was concentration and time dependent. Western blot data demonstrated that cytochrome c (Cyt c), Smac (the second mitochondria-derived activator of caspase), calpain I, caspase-9, -3 and -8 were all involved in the apoptotic process, while the pan caspase inhibitor zVAD-fmk almost completely inhibited Dc-induced apoptosis. We further demonstrated that the release of mitochondrial proteins and the activation of calpain occurred upstream of the caspase cascade, in which caspase-9 was activated in response to the release of Cyt c, caspase-8 activation was caspase- and calpain-dependent, and caspase-3 was activated mainly by caspase-8 and -9. Caspase-8 played important roles in the activation of caspase-3 and induction of apoptosis, while the role of the caspase-9 was limited.
Synovial fibroblast cell (SFB cell) is one of the most important inflammatory cells in rheumatoid arthritis (RA) and its hyperplasia could induce joints damage. Recent works have shown that Doxycycline (Dc) is a pluripotent drug that affects many mammalian cell functions including proliferation, apoptosis, and matrix remodeling. It has been reported that Dc has therapeutic function on rheumatoid arthritis. In this paper we focus our interest on the functions of Dc to induce SFB cells apoptosis. SFB cells separated from knee joints of male Lewis rats having RA (RA-SFB cells) were used. The apoptosis rate of Dc-induced RA-SFB cells is concentration- and time- dependent. Its apoptosis rate was significantly increased after treatment with Dc (45μg/ml) for 3 days. Transmission electron microscope observation showed that mitochondria were swelled and the critaes were dispeared, compared with control. More over, mitochiodria membrane potential was decreased significantly after treatement with Dc for 48 h. Western blot analysis showed that caspase-3, calpain I were activated and XIAP was partially degraded, during treatment with Dc.
Human amniotic epithelial cells (hAECs), with the characteristics of both embryonic stem cell and pluripotent stem cell, have the potential to differentiate into various tissues. EGFP and GDNF were transferred into the hAECs by using lentivirus vector, respectively. Intracerebral graft of hAECs-EGFP and hAECs-GDNF into ischemic rats prepared by middle cerebral artery occlusion (MCAO) could significantly ameliorate behavioral dysfunction, and reduce the infarct volume. Furthermore, neuronal marker MAP2 and astrocytic marker GFAP were detected in the transplanted hAECs. Meanwhile, the activation of caspase-3 was prevented in the vicinity of graft area. In addition, the low antigenic nature of hAECs and the immuno-privileged characteristic of brain favor no immunosuppressor treatment during the transplantation therapy. Being easily obtained with less ethical arguments gives hAECs the advantage for cell therapy. As both hAECs and lentiviral vectors are low antigenic, lentiviral transfected hAECs can be used as an effective transfer vehicle for GDNF in ischemia treatment. Moreover, lentivirus modified hAECs may have the potential to be used for cell-mediated gene therapy in the future.
滑膜成纤维细胞是类风湿关节炎(RA)发病过程中一种重要的炎症细胞。在RA病人关节中滑膜成纤维细胞(SFB)发生增生,分泌多种炎症因子并且参与了诱导软骨细胞凋亡和关节损伤。Doxycycline具有抑制细胞增殖,抑制金属基质蛋白酶表达及诱导细胞凋亡的功能。本章研究了Doxycycline诱导大鼠RA模型中膝关节SFB(RA-SFB)细胞凋亡的功能。流式细胞检测表明Dc诱导的RA-SFB细胞凋亡具有药物浓度和处理时间依赖性;Dc可以诱导RA-SFB细胞发生显著的凋亡并且产生DNA Ladder。透射电镜下观察到Dc处理后线粒体发生明显的膨胀,线粒体嵴消失,胞质出现大量的空泡;线粒体膜电位(MMP)在Dc处理48 h内发生显著降低,所以线粒体参与了Dc诱导的RA-SFB细胞凋亡。Western blot分析证明caspase-3和calpain I在Dc诱导后发生活化;抗凋亡蛋白XIAP在Dc处理后部分被降解。本章研究为Doxycycline诱导RA中SFB细胞凋亡提供一定的依据,并且Doxycycline联合其它药物或基因通过凋亡的途径来治疗RA具有潜在的可能性。
人羊膜上皮细胞(hAECs)具有胚胎干细胞及多能干细胞的特征,在一定条件下能够分化成不同组织的细胞,GDNF具有抗缺血后神经元凋亡的功能。本章中以慢病毒为载体,分别将GDNF和EGFP转染到hAECs中,得到稳定表达EGFP和GDNF的hAECs-EGFP和hAECs-GDNF细胞。分别将这两种细胞移植到脑中动脉阻塞(MCAO)缺血损伤的大鼠脑内。移植后第7天可以检测到GFAP(体外培养的hAECs表达的胶质细胞标志蛋白)的表达;移植后第21天仍可以检测到植入区EGFP的高表达;并且移植到体内以后,少部分hAECs可以被诱导表达神经元标志蛋白MAP2。两种细胞对脑缺血后大鼠行为学指标都有显著的改善作用,并且在移植后早期hAECs-GDNF治疗组比hAECs-EGFP治疗组恢复更明显。Western blot检测证明:在靠近hAECs移植部位的缺血区组织内,caspase-3活化基本被抑制。此外hAECs治疗后,缺血损伤区体积也明显减小。由于hAECs来源广泛,道德和伦理学问题较少,且免疫原性低,因此以hAECs为载体进行细胞基因治疗是一种潜在的、具有广阔应用前景的生物治疗方法。
Doxycycline (Dc) has been demonstrated to inhibit cell growth and induce apoptosis in tumor cells, although its mechanism of action is not fully understood. The present study demonstrates that apoptosis can be induced in HeLa cells by Dc, and that process was concentration and time dependent. Western blot data demonstrated that cytochrome c (Cyt c), Smac (the second mitochondria-derived activator of caspase), calpain I, caspase-9, -3 and -8 were all involved in the apoptotic process, while the pan caspase inhibitor zVAD-fmk almost completely inhibited Dc-induced apoptosis. We further demonstrated that the release of mitochondrial proteins and the activation of calpain occurred upstream of the caspase cascade, in which caspase-9 was activated in response to the release of Cyt c, caspase-8 activation was caspase- and calpain-dependent, and caspase-3 was activated mainly by caspase-8 and -9. Caspase-8 played important roles in the activation of caspase-3 and induction of apoptosis, while the role of the caspase-9 was limited.
Synovial fibroblast cell (SFB cell) is one of the most important inflammatory cells in rheumatoid arthritis (RA) and its hyperplasia could induce joints damage. Recent works have shown that Doxycycline (Dc) is a pluripotent drug that affects many mammalian cell functions including proliferation, apoptosis, and matrix remodeling. It has been reported that Dc has therapeutic function on rheumatoid arthritis. In this paper we focus our interest on the functions of Dc to induce SFB cells apoptosis. SFB cells separated from knee joints of male Lewis rats having RA (RA-SFB cells) were used. The apoptosis rate of Dc-induced RA-SFB cells is concentration- and time- dependent. Its apoptosis rate was significantly increased after treatment with Dc (45μg/ml) for 3 days. Transmission electron microscope observation showed that mitochondria were swelled and the critaes were dispeared, compared with control. More over, mitochiodria membrane potential was decreased significantly after treatement with Dc for 48 h. Western blot analysis showed that caspase-3, calpain I were activated and XIAP was partially degraded, during treatment with Dc.
Human amniotic epithelial cells (hAECs), with the characteristics of both embryonic stem cell and pluripotent stem cell, have the potential to differentiate into various tissues. EGFP and GDNF were transferred into the hAECs by using lentivirus vector, respectively. Intracerebral graft of hAECs-EGFP and hAECs-GDNF into ischemic rats prepared by middle cerebral artery occlusion (MCAO) could significantly ameliorate behavioral dysfunction, and reduce the infarct volume. Furthermore, neuronal marker MAP2 and astrocytic marker GFAP were detected in the transplanted hAECs. Meanwhile, the activation of caspase-3 was prevented in the vicinity of graft area. In addition, the low antigenic nature of hAECs and the immuno-privileged characteristic of brain favor no immunosuppressor treatment during the transplantation therapy. Being easily obtained with less ethical arguments gives hAECs the advantage for cell therapy. As both hAECs and lentiviral vectors are low antigenic, lentiviral transfected hAECs can be used as an effective transfer vehicle for GDNF in ischemia treatment. Moreover, lentivirus modified hAECs may have the potential to be used for cell-mediated gene therapy in the future.
引文
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