Cell:Caspase-2酶抑制剂可以改善脂肪肝疾病

2018-09-21 佚名 生物通

加州大学圣地亚哥分校医学院的研究人员通过小鼠和人类临床标本发现,caspase-2这种蛋白水解酶,是非酒精性脂肪性肝炎(NASH)的一个关键驱动因素,后者是一种慢性和侵袭性的肝脏疾病。

加州大学圣地亚哥分校医学院的研究人员通过小鼠和人类临床标本发现,caspase-2这种蛋白水解酶,是非酒精性脂肪性肝炎(NASH)的一个关键驱动因素,后者是一种慢性和侵袭性的肝脏疾病。



研究人员通过鉴定caspase-2的关键作用,指出这种酶的抑制剂可以提供一种有效的方法来阻止导致NASH的致病进展,甚至逆转早期症状。

这篇题为“ER Stress Drives Lipogenesis and Steatohepatitis via Caspase-2 Activation of S1P”的研究成果公布在9月13日的Cell杂志上。

“我们的研究结果显示,caspase-2是NASH发病机制的关键因素,不仅在小鼠中,而且在人类中也是如此,”加州大学圣地亚哥分校医学院药理学杰出教授Michael Karin博士说,“在解释NASH如何发生的同时,我们的研究结果也为治疗或预防这种破坏性疾病提供了一种简单而有效的方法。”

最具侵袭性的非酒精性脂肪性肝病

NASH是最具侵袭性的非酒精性脂肪性肝病(NAFLD),包括一系列慢性肝病,目前已成为肝脏移植的主要原因。 NAFLD和NASH的发生原因仍然是一个谜,但研究人员认为,使得良性NAFLD进展为侵袭性NASH的一个因素在于肝内蛋白质错误折叠引起的内质网(ER)应激升高。这导致肝组织中胆固醇和甘油三酯的过度累积。

在最新研究中,研究人员首先通过结合肝脏特异性ER应激和高脂肪饮食来激发NASH样疾病,复制人体NASH的主要特征,包括肝细胞中脂肪堆积,肝脏损伤等,从而确定参与NASH发病机制的分子。研究人员利用该模型发现,NASH的发病与caspase-2的表达增加有关。

之后,Karin和团队检查了从良性NAFLD或侵袭性NASH患者收集的人肝脏标本,结果发现确认人体内caspase-2的表达也升高。他们敲除了肝脏ER应激和高脂肪饮食小鼠中的caspase-2基因,或用特异性caspase-2抑制剂治疗小鼠,发现caspase-2负责NASH的各个方面,包括脂滴积聚,肝脏损伤,炎症和疤痕。

“我们现在发现,通过阻止caspase-2表达或抑制其活性,NASH的生物标志物得到缓解,”Karin实验室高级研究员兼主要作者Juyoun Kim博士说,“这很令人兴奋,因为现在我们不仅了解了caspase-2在疾病中的作用,而且还有一条新途径可以找到潜在的药物治疗方法。”

Caspase-2如何发挥作用

通过这项研究,Karin和研究小组还发现,caspase-2在激活SREBP1和SREBP2脂肪生成的主要调节因子中具有关键作用。

脂肪生成是一种发生在肝脏中的过程,其中碳水化合物等营养成分转化为脂肪酸,甘油三酯和胆固醇。研究发现Caspase-2通过切割另一种称为site-1 protease的酶来控制SREBP1和2的活化。

“在无NASH的个体中,SREBP1和SREBP2的活性得到控制,这对于防止肝脏中过多的脂质积聚至关重要,”Karin说,“然而,在NASH患者中出现问题,肝脏继续产生过量的甘油三酯和胆固醇。这与SREBP1和SREBP2活性升高以及caspase-2表达增加有关。”

未来,Karin和团队希望开发更有效的caspase-2抑制剂,可用于预防NASH,并最终提供用于临床治疗。

“这项研究向前迈出了一大步,不仅能够了解其病理,而且也为NASH和NAFLD患者探索可能的新疗法,”共同作者,加州大学圣地亚哥分校NAFLD研究中心主任Rohit Loomba说,“我们希望最终使用更大规模的人类受试者来验证这些研究结果。”

原始出处:Kim JY, Garcia-Carbonell R, Yamachika S, et al. ER Stress Drives Lipogenesis and Steatohepatitis via Caspase-2 Activation of S1P. Cell. 2018 Aug 31. 

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    2019-05-09 马龙
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topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/eiadcQaiaZ4fUvicZKEbibPBA2otZ0yzMeAVET5icsaS77W0Tvo3ibFMibzxTVRPsg62xJu0GicwBCvAlPMyu7TB6j86ug/132, createdBy=d64c1981665, createdName=一一一多, createdTime=Sun Sep 23 21:10:40 CST 2018, time=2018-09-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1624893, encodeId=909b162489391, content=<a href='/topic/show?id=0333412062' target=_blank style='color:#2F92EE;'>#Cas#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=20, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4120, encryptionId=0333412062, topicName=Cas)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=411420689333, createdName=yaanren, createdTime=Sat Sep 22 15:10:00 CST 2018, time=2018-09-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=345978, encodeId=77783459e831, content=学习谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4Nd44v3xHnnictn9UpctwtH62EPQ59TMdI9lnqHMgQ16nH7GmGCfpzicsHgjibYVk6vwSpXrC86gMibRkoaIzf5HwSz7/0, createdBy=78cc1691107, createdName=龙胆草, createdTime=Fri Sep 21 08:21:25 CST 2018, time=2018-09-21, status=1, ipAttribution=)]
    2019-09-03 jklm09
  4. 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createdBy=ba58436, createdName=马龙, createdTime=Thu May 09 21:10:00 CST 2019, time=2019-05-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1851790, encodeId=d51d1851e9031, content=<a href='/topic/show?id=f0a254918f0' target=_blank style='color:#2F92EE;'>#抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54918, encryptionId=f0a254918f0, topicName=抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Tue Sep 03 02:10:00 CST 2019, time=2019-09-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1961140, encodeId=dbc419611405e, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, 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replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c2531680715, createdName=1de33e15m69(暂无匿称), createdTime=Sat Dec 22 23:46:27 CST 2018, time=2018-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2034014, encodeId=57d220340145e, content=<a href='/topic/show?id=b8d74135dd' target=_blank style='color:#2F92EE;'>#Caspase#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4135, encryptionId=b8d74135dd, topicName=Caspase)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ca20190, createdName=wushaoling, createdTime=Tue May 21 12:10:00 CST 2019, time=2019-05-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=346326, encodeId=3e37346326d8, content=重要的结论, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/eiadcQaiaZ4fUvicZKEbibPBA2otZ0yzMeAVET5icsaS77W0Tvo3ibFMibzxTVRPsg62xJu0GicwBCvAlPMyu7TB6j86ug/132, createdBy=d64c1981665, createdName=一一一多, createdTime=Sun Sep 23 21:10:40 CST 2018, time=2018-09-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1624893, encodeId=909b162489391, content=<a href='/topic/show?id=0333412062' target=_blank style='color:#2F92EE;'>#Cas#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=20, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4120, encryptionId=0333412062, topicName=Cas)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=411420689333, createdName=yaanren, createdTime=Sat Sep 22 15:10:00 CST 2018, time=2018-09-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=345978, encodeId=77783459e831, content=学习谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4Nd44v3xHnnictn9UpctwtH62EPQ59TMdI9lnqHMgQ16nH7GmGCfpzicsHgjibYVk6vwSpXrC86gMibRkoaIzf5HwSz7/0, createdBy=78cc1691107, createdName=龙胆草, createdTime=Fri Sep 21 08:21:25 CST 2018, time=2018-09-21, status=1, ipAttribution=)]
    2019-07-06 维他命
  5. 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replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c2531680715, createdName=1de33e15m69(暂无匿称), createdTime=Sat Dec 22 23:46:27 CST 2018, time=2018-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2034014, encodeId=57d220340145e, content=<a href='/topic/show?id=b8d74135dd' target=_blank style='color:#2F92EE;'>#Caspase#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4135, encryptionId=b8d74135dd, topicName=Caspase)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ca20190, createdName=wushaoling, createdTime=Tue May 21 12:10:00 CST 2019, time=2019-05-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=346326, encodeId=3e37346326d8, content=重要的结论, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/eiadcQaiaZ4fUvicZKEbibPBA2otZ0yzMeAVET5icsaS77W0Tvo3ibFMibzxTVRPsg62xJu0GicwBCvAlPMyu7TB6j86ug/132, createdBy=d64c1981665, createdName=一一一多, createdTime=Sun Sep 23 21:10:40 CST 2018, time=2018-09-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1624893, encodeId=909b162489391, content=<a href='/topic/show?id=0333412062' target=_blank style='color:#2F92EE;'>#Cas#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=20, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4120, encryptionId=0333412062, topicName=Cas)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=411420689333, createdName=yaanren, createdTime=Sat Sep 22 15:10:00 CST 2018, time=2018-09-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=345978, encodeId=77783459e831, content=学习谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4Nd44v3xHnnictn9UpctwtH62EPQ59TMdI9lnqHMgQ16nH7GmGCfpzicsHgjibYVk6vwSpXrC86gMibRkoaIzf5HwSz7/0, createdBy=78cc1691107, createdName=龙胆草, createdTime=Fri Sep 21 08:21:25 CST 2018, time=2018-09-21, status=1, ipAttribution=)]
    2019-05-27 gostraight
  6. 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replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c2531680715, createdName=1de33e15m69(暂无匿称), createdTime=Sat Dec 22 23:46:27 CST 2018, time=2018-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2034014, encodeId=57d220340145e, content=<a href='/topic/show?id=b8d74135dd' target=_blank style='color:#2F92EE;'>#Caspase#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4135, encryptionId=b8d74135dd, topicName=Caspase)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ca20190, createdName=wushaoling, createdTime=Tue May 21 12:10:00 CST 2019, time=2019-05-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=346326, encodeId=3e37346326d8, content=重要的结论, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/eiadcQaiaZ4fUvicZKEbibPBA2otZ0yzMeAVET5icsaS77W0Tvo3ibFMibzxTVRPsg62xJu0GicwBCvAlPMyu7TB6j86ug/132, createdBy=d64c1981665, createdName=一一一多, createdTime=Sun Sep 23 21:10:40 CST 2018, time=2018-09-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1624893, encodeId=909b162489391, content=<a href='/topic/show?id=0333412062' target=_blank style='color:#2F92EE;'>#Cas#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=20, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4120, encryptionId=0333412062, topicName=Cas)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=411420689333, createdName=yaanren, createdTime=Sat Sep 22 15:10:00 CST 2018, time=2018-09-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=345978, encodeId=77783459e831, content=学习谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4Nd44v3xHnnictn9UpctwtH62EPQ59TMdI9lnqHMgQ16nH7GmGCfpzicsHgjibYVk6vwSpXrC86gMibRkoaIzf5HwSz7/0, createdBy=78cc1691107, createdName=龙胆草, createdTime=Fri Sep 21 08:21:25 CST 2018, time=2018-09-21, status=1, ipAttribution=)]
    2018-12-22 1de33e15m69(暂无匿称)

    王京奇主任的四生汤(生黄芪,生山楂,生荷叶,生薏苡仁)治疗脂肪肝疗效确切,咋这么久了还没制成中成药大面积推广进行临床试验

    0

  7. 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createdBy=ba58436, createdName=马龙, createdTime=Thu May 09 21:10:00 CST 2019, time=2019-05-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1851790, encodeId=d51d1851e9031, content=<a href='/topic/show?id=f0a254918f0' target=_blank style='color:#2F92EE;'>#抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54918, encryptionId=f0a254918f0, topicName=抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Tue Sep 03 02:10:00 CST 2019, time=2019-09-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1961140, encodeId=dbc419611405e, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, 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replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c2531680715, createdName=1de33e15m69(暂无匿称), createdTime=Sat Dec 22 23:46:27 CST 2018, time=2018-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2034014, encodeId=57d220340145e, content=<a href='/topic/show?id=b8d74135dd' target=_blank style='color:#2F92EE;'>#Caspase#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4135, encryptionId=b8d74135dd, topicName=Caspase)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ca20190, createdName=wushaoling, createdTime=Tue May 21 12:10:00 CST 2019, time=2019-05-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=346326, encodeId=3e37346326d8, content=重要的结论, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/eiadcQaiaZ4fUvicZKEbibPBA2otZ0yzMeAVET5icsaS77W0Tvo3ibFMibzxTVRPsg62xJu0GicwBCvAlPMyu7TB6j86ug/132, createdBy=d64c1981665, createdName=一一一多, createdTime=Sun Sep 23 21:10:40 CST 2018, time=2018-09-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1624893, encodeId=909b162489391, content=<a href='/topic/show?id=0333412062' target=_blank style='color:#2F92EE;'>#Cas#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=20, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4120, encryptionId=0333412062, topicName=Cas)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=411420689333, createdName=yaanren, createdTime=Sat Sep 22 15:10:00 CST 2018, time=2018-09-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=345978, encodeId=77783459e831, 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  8. 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topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/eiadcQaiaZ4fUvicZKEbibPBA2otZ0yzMeAVET5icsaS77W0Tvo3ibFMibzxTVRPsg62xJu0GicwBCvAlPMyu7TB6j86ug/132, createdBy=d64c1981665, createdName=一一一多, createdTime=Sun Sep 23 21:10:40 CST 2018, time=2018-09-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1624893, encodeId=909b162489391, content=<a href='/topic/show?id=0333412062' target=_blank style='color:#2F92EE;'>#Cas#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=20, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4120, encryptionId=0333412062, topicName=Cas)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=411420689333, createdName=yaanren, createdTime=Sat Sep 22 15:10:00 CST 2018, time=2018-09-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=345978, encodeId=77783459e831, content=学习谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4Nd44v3xHnnictn9UpctwtH62EPQ59TMdI9lnqHMgQ16nH7GmGCfpzicsHgjibYVk6vwSpXrC86gMibRkoaIzf5HwSz7/0, createdBy=78cc1691107, createdName=龙胆草, createdTime=Fri Sep 21 08:21:25 CST 2018, time=2018-09-21, status=1, ipAttribution=)]
    2018-09-23 一一一多

    重要的结论

    0

  9. 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topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/eiadcQaiaZ4fUvicZKEbibPBA2otZ0yzMeAVET5icsaS77W0Tvo3ibFMibzxTVRPsg62xJu0GicwBCvAlPMyu7TB6j86ug/132, createdBy=d64c1981665, createdName=一一一多, createdTime=Sun Sep 23 21:10:40 CST 2018, time=2018-09-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1624893, encodeId=909b162489391, content=<a href='/topic/show?id=0333412062' target=_blank style='color:#2F92EE;'>#Cas#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=20, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4120, encryptionId=0333412062, topicName=Cas)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=411420689333, createdName=yaanren, createdTime=Sat Sep 22 15:10:00 CST 2018, time=2018-09-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=345978, encodeId=77783459e831, content=学习谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4Nd44v3xHnnictn9UpctwtH62EPQ59TMdI9lnqHMgQ16nH7GmGCfpzicsHgjibYVk6vwSpXrC86gMibRkoaIzf5HwSz7/0, createdBy=78cc1691107, createdName=龙胆草, createdTime=Fri Sep 21 08:21:25 CST 2018, time=2018-09-21, status=1, ipAttribution=)]
    2018-09-22 yaanren
  10. 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    2018-09-21 龙胆草

    学习谢谢分享

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