Cell :中风治疗新篇章-抑制细胞铁死亡

2019-05-31 佚名 转化医学网

研究发现神经元通过诱导硒蛋白(包括谷胱甘肽过氧化物酶4(GPX4))对铁死亡相关刺激做出反应。硒(Se)可在铁死亡过程中增强GPX4和其它基因的转录,通过共激活转录因子TFAP2c和Sp1来保护神经元,在中风的营养和治疗中有重要意义。

研究发现神经元通过诱导硒蛋白(包括谷胱甘肽过氧化物酶4(GPX4))对铁死亡相关刺激做出反应。硒(Se)可在铁死亡过程中增强GPX4和其它基因的转录,通过共激活转录因子TFAP2c和Sp1来保护神经元,在中风的营养和治疗中有重要意义。

铁死亡(ferroptosis)是2012年Dixon发现的一种的铁依赖性的程序性细胞死亡形式,在形态学、生化、基因水平上不同于凋亡、自噬、焦亡等已知的细胞死亡形式。铁死亡可由癌症中的氧化应激、植物热应激以及出血性中风触发,目前对于铁死亡相关的信号调节网络所知甚少。该研究发现神经元通过诱导硒蛋白(包括谷胱甘肽过氧化物酶4(GPX4))对铁死亡相关刺激做出反应。硒(Se)可在铁死亡过程中增强GPX4和其它基因的转录,通过共激活转录因子TFAP2c和Sp1来保护神经元,在中风的营养和治疗中有重要意义。

脑出血(Intracerebral hemorrhage,ICH)是一种中风亚型,往往由高血压、大脑淀粉样血管病、动静脉畸形和抗凝血剂的使用等因素引起。尽管脑出血发病率和致死率都很高,目前依然没有有效的治疗手段。而关注的重点在于降低脑中风后的继发损害。继发损害,如神经元死亡,发生在初次出血后的数小时至数天,并可由溶血产生的血红蛋白和富含铁的氧化形式的亚铁血红素引起。

近期研究证实脑出血后继发细胞死亡并非由铁催化的氧化剂对一些大分子的随机破坏引起,而是由一种非凋亡的程序性细胞死亡-铁死亡引起。铁死亡由一些脂质的过氧化产物诱发,可被选择性脂质过氧化抑制剂(如ferrostatin)阻断。此前研究表明,除了在脑出血中的作用,铁死亡还与肿瘤抑制、缺血-再灌注损伤、创伤性脑损伤、帕金森氏病、植物热应激等有关。

在大脑皮质神经元中,铁死亡引起转录激活因子4(ATF4)的转录激活,以及与细胞死亡相关基因(如CHOP、TRIB3、CHAC1)的表达上调。体外实验中,生殖系缺失ATF4基因的神经元可抵抗同型半胱氨酸(homocysteic acid,HCA)诱导的铁死亡,转入野生型ATF4后可恢复对铁死亡的敏感性,如果转入DNA结合区突变的ATF4则不能恢复敏感性。后续研究也表明在神经元中铁螯合剂也可抑制谷氨酸盐或氯高铁血红素诱导的铁死亡,这种抑制作用是通过靶向铁依赖酶家族-缺氧诱导因子(HIF) 脯氨酰羟化酶,进而影响ATF4依赖性的基因转录发挥作用。在弹性蛋白诱导的肿瘤细胞铁死亡中也观察到ATF4依赖性的基因表达。

前期研究表明p53可通过抑制SLC7A11的转录来诱导铁死亡,这与通过药物(如弹性蛋白、谷氨酸盐、HCA)抑制SCL7A11可诱导铁死亡的结果一致。在一些动物实验中,p53乙酰化缺陷突变导致对细胞死亡不敏感,可以通过强制性表达SCL7A11来实现对肿瘤细胞的抑制效果。这些研究表明p53在抑制肿瘤过程中有多种作用,包括通过抑制SLC7A11转录来激活铁死亡。相反,p53依赖性的p21(waf1/cip1)转录或p53依赖性的DPP4的细胞核积累通过维持氧化还原平衡来抑制铁死亡,表明p53在铁死亡和细胞周期抑制中具有多种作用,并根据压力或损伤的水平而发挥不同的调节作用。除了p53,Nrf-2也可以在肿瘤细胞或神经元中抑制铁死亡。



长期以来SCL7A11是细胞铁死亡转录调控研究的焦点,近期研究发现硒在调节铁死亡中扮演核心角色,硒通过在蛋白(如GPX4)翻译过程中掺入硒代半胱氨酸来调节铁死亡。然而,关于GPX4和其它的硒蛋白是否在转录水平被铁死亡刺激诱导所知甚少,而这种适应性平衡是否可用来抑制铁死亡也不清楚。该研究中,我们通过体内和体外实验证明了在神经系统中,铁死亡刺激可诱导硒蛋白(包括GPX4)转录。意外的是,我们发现超生理水平的硒通过TFAP2c和Sp1来上调硒蛋白的转录,进而抑制铁死亡和非铁死亡依赖的细胞死亡。通过将硒递送至脑室,含有硒代半胱氨酸的多肽可激活铁死亡相关的适应性转录反应,进而改善中风后大脑功能的恢复。



尤其是,在该研究构建的出血性中风的小鼠模型中,通过向大脑中递送单次剂量的硒就可以驱动抗氧化剂GPX4的表达,从而保护神经元,提升中风后小鼠的行为表现。

总之,我们发现硒作为药物可有效的抑制GPX4依赖的铁死亡,以及由过兴奋或ER压力诱导的GPX4依赖性的细胞死亡。在脑出血或中风后系统性的输注可通过血脑屏障的硒代多肽可激活转录,抑制细胞死亡,进而提升大脑功能。这些研究结果在脑出血的营养护理和后续治疗中具有重要的指导意义。

原始出处:Alim I1, Caulfield JT1, Chen Y1, et al .Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke. Cell. 2019 May 16;

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  1. [GetPortalCommentsPageByObjectIdResponse(id=367075, encodeId=f7a836e075e4, content=从坏调,到焦亡,再到铁死亡,会不会在发现更多的程序性死亡, beContent=null, objectType=article, channel=null, level=null, likeNumber=99, replyNumber=1, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=090d49833, createdName=LaserDermatol, createdTime=Sat Jun 01 00:58:42 CST 2019, time=2019-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1871312, encodeId=c2b118e131291, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Sat Sep 28 06:49:00 CST 2019, time=2019-09-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1961595, encodeId=b677196159533, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Thu Oct 03 10:49:00 CST 2019, time=2019-10-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2058579, encodeId=98f120585e90e, content=<a href='/topic/show?id=92e05858970' target=_blank style='color:#2F92EE;'>#新篇章#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=41, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=58589, encryptionId=92e05858970, topicName=新篇章)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1ce4238, createdName=dangious, createdTime=Mon Mar 30 12:49:00 CST 2020, time=2020-03-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1045865, encodeId=c886104586564, content=中风是俗称,应该称为缺血性卒中吧, beContent=null, objectType=article, channel=null, level=null, likeNumber=50, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=guging, createdTime=Sat Jun 01 02:49:00 CST 2019, time=2019-06-01, status=1, ipAttribution=)]
    2019-06-01 LaserDermatol

    从坏调,到焦亡,再到铁死亡,会不会在发现更多的程序性死亡

    1

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  2. [GetPortalCommentsPageByObjectIdResponse(id=367075, encodeId=f7a836e075e4, content=从坏调,到焦亡,再到铁死亡,会不会在发现更多的程序性死亡, beContent=null, objectType=article, channel=null, level=null, likeNumber=99, replyNumber=1, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=090d49833, createdName=LaserDermatol, createdTime=Sat Jun 01 00:58:42 CST 2019, time=2019-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1871312, encodeId=c2b118e131291, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Sat Sep 28 06:49:00 CST 2019, time=2019-09-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1961595, encodeId=b677196159533, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Thu Oct 03 10:49:00 CST 2019, time=2019-10-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2058579, encodeId=98f120585e90e, content=<a href='/topic/show?id=92e05858970' target=_blank style='color:#2F92EE;'>#新篇章#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=41, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=58589, encryptionId=92e05858970, topicName=新篇章)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1ce4238, createdName=dangious, createdTime=Mon Mar 30 12:49:00 CST 2020, time=2020-03-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1045865, encodeId=c886104586564, content=中风是俗称,应该称为缺血性卒中吧, beContent=null, objectType=article, channel=null, level=null, likeNumber=50, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=guging, createdTime=Sat Jun 01 02:49:00 CST 2019, time=2019-06-01, status=1, ipAttribution=)]
  3. [GetPortalCommentsPageByObjectIdResponse(id=367075, encodeId=f7a836e075e4, content=从坏调,到焦亡,再到铁死亡,会不会在发现更多的程序性死亡, beContent=null, objectType=article, channel=null, level=null, likeNumber=99, replyNumber=1, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=090d49833, createdName=LaserDermatol, createdTime=Sat Jun 01 00:58:42 CST 2019, time=2019-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1871312, encodeId=c2b118e131291, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Sat Sep 28 06:49:00 CST 2019, time=2019-09-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1961595, encodeId=b677196159533, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Thu Oct 03 10:49:00 CST 2019, time=2019-10-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2058579, encodeId=98f120585e90e, content=<a href='/topic/show?id=92e05858970' target=_blank style='color:#2F92EE;'>#新篇章#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=41, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=58589, encryptionId=92e05858970, topicName=新篇章)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1ce4238, createdName=dangious, createdTime=Mon Mar 30 12:49:00 CST 2020, time=2020-03-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1045865, encodeId=c886104586564, content=中风是俗称,应该称为缺血性卒中吧, beContent=null, objectType=article, channel=null, level=null, likeNumber=50, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=guging, createdTime=Sat Jun 01 02:49:00 CST 2019, time=2019-06-01, status=1, ipAttribution=)]
    2019-10-03 维他命
  4. [GetPortalCommentsPageByObjectIdResponse(id=367075, encodeId=f7a836e075e4, content=从坏调,到焦亡,再到铁死亡,会不会在发现更多的程序性死亡, beContent=null, objectType=article, channel=null, level=null, likeNumber=99, replyNumber=1, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=090d49833, createdName=LaserDermatol, createdTime=Sat Jun 01 00:58:42 CST 2019, time=2019-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1871312, encodeId=c2b118e131291, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Sat Sep 28 06:49:00 CST 2019, time=2019-09-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1961595, encodeId=b677196159533, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Thu Oct 03 10:49:00 CST 2019, time=2019-10-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2058579, encodeId=98f120585e90e, content=<a href='/topic/show?id=92e05858970' target=_blank style='color:#2F92EE;'>#新篇章#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=41, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=58589, encryptionId=92e05858970, topicName=新篇章)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1ce4238, createdName=dangious, createdTime=Mon Mar 30 12:49:00 CST 2020, time=2020-03-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1045865, encodeId=c886104586564, content=中风是俗称,应该称为缺血性卒中吧, beContent=null, objectType=article, channel=null, level=null, likeNumber=50, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=guging, createdTime=Sat Jun 01 02:49:00 CST 2019, time=2019-06-01, status=1, ipAttribution=)]
  5. [GetPortalCommentsPageByObjectIdResponse(id=367075, encodeId=f7a836e075e4, content=从坏调,到焦亡,再到铁死亡,会不会在发现更多的程序性死亡, beContent=null, objectType=article, channel=null, level=null, likeNumber=99, replyNumber=1, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=090d49833, createdName=LaserDermatol, createdTime=Sat Jun 01 00:58:42 CST 2019, time=2019-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1871312, encodeId=c2b118e131291, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Sat Sep 28 06:49:00 CST 2019, time=2019-09-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1961595, encodeId=b677196159533, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Thu Oct 03 10:49:00 CST 2019, time=2019-10-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2058579, encodeId=98f120585e90e, content=<a href='/topic/show?id=92e05858970' target=_blank style='color:#2F92EE;'>#新篇章#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=41, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=58589, encryptionId=92e05858970, topicName=新篇章)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1ce4238, createdName=dangious, createdTime=Mon Mar 30 12:49:00 CST 2020, time=2020-03-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1045865, encodeId=c886104586564, content=中风是俗称,应该称为缺血性卒中吧, beContent=null, objectType=article, channel=null, level=null, likeNumber=50, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=guging, createdTime=Sat Jun 01 02:49:00 CST 2019, time=2019-06-01, status=1, ipAttribution=)]
    2019-06-01 guging

    中风是俗称,应该称为缺血性卒中吧

    0

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