Cell Metabolism:上海药物所柳红/黄河团队发布新型降血脂药物1期临床数据

2022-04-18 王聪 “生物世界”公众号

低密度脂蛋白(LDL),是一种富含胆固醇的脂蛋白,当其过量时,它携带的胆固醇便积存在动脉壁上,容易引起动脉硬化等心血管疾病。因此 LDL 也被称为“坏胆固醇”。

高脂血症以胆固醇和甘油三酯水平升高为特征,是动脉粥样硬化等心血管疾病的主要危险因素。据世界卫生组织(WHO)统计,在过去的20年里,心血管疾病一直是人类死亡的首要原因,是人类健康的第一杀手。

低密度脂蛋白(LDL),是一种富含胆固醇的脂蛋白,当其过量时,它携带的胆固醇便积存在动脉壁上,容易引起动脉硬化等心血管疾病。因此 LDL 也被称为“坏胆固醇”。

尽管目前批准上市的降血脂药物(如他汀类药物)可以降低血液中的低密度脂蛋白胆固醇(LDL-C),但大约20%的高 LDL-C 水平的患者对此类治疗没有反应,或表现出他汀类药物不耐受。因此,非常有必要开发基于非他汀类药物的降血脂药物。

之前的研究证实,PCSK9 和 ANGPTL3 这两个基因表达的蛋白可以与低密度脂蛋白受体(LDLR)结合并使其降解,从而升高血液中低密度脂蛋白胆固醇(LDL-C)水平。因此,抑制这两个基因的表达,就可以降低 LDL-C 水平,实现治疗高脂血症的效果,预防心血管疾病的发生。

2022年4月14日,中科院上海药物所柳红团队和黄河团队合作,在 Cell Metabolism 期刊发表了题为:Identification and evaluation of a lipid-lowering small compound in preclinical models and in a Phase I trial 的研究论文。

临床前研究显示,小分子 DC371739 在多种动物模型中能够同时显着降低血浆中总胆固醇、低密度脂蛋白胆固醇和甘油三酯水平,并且在1期临床试验(NCT04927221)中显示出初步阳性效果和良好的耐受性。

从机制上来说,DC371739 与其他已知的降血脂药物不同,它是通过直接与 HNF-1α 结合来组织 PCSK9 和 ANGPTL3 的转录,从而发挥降血脂作用。其独特的作用机制是的它可以与阿托伐他汀等他汀类药物联合使用,提供更好的降血脂效果,也为那些他汀类药物不耐受患者提供潜在的替代治疗方法。

从中药紫堇中提取的四氢原小檗碱同类物(THPBs)具有多种生物活性,具有药物开发潜力。研究团队对其进行了一系列化学修饰,构建了一个小型化合物库。

上海药物所蒋华良院士团队通过计算机辅助药物设计策略,发现 PCSK9 是 THPBs 的新型作用靶标。柳红团队对上述化合物库进行筛选,构建了结构多样性四氢异喹啉类化合物库,同时开展多轮结构改造和成药性优化。王逸平团队开展系统的体内外活性筛选和药效学评价,最终发现了候选药物 DC371739。2020年7月,该候选药物获得国家药品监督管理局批准进行临床试验治疗高胆固醇血症。

王逸平研究员长期从事心血管系统疾病的新药研发,创建了完整的心血管系统药物体内外药效学筛选评价体系。2018年4月11日,王逸平研究员因病在办公室离世,年仅55岁。DC371739 也是王逸平研究员生前潜心研究的又一候选新药。

临床前研究显示,DC371739 能够显着降低高脂饮食诱导的高脂血症仓鼠和自发性高脂血症恒河猴的血液中总胆固醇及低密度脂蛋白胆固醇水平

鉴于这些有希望的降血脂效果,研究团队开展了1期临床试验(NCT04927221),初步临床试验结果显示,20 名高脂血症参与者在每天40毫克 DC371739 治疗28天后,与安慰剂组相比,治疗组血清总胆固醇和低密度脂蛋白胆固醇水平显着降低了18.75%和19.12%,血清甘油三酯和ApoB水平也显着降低了27.07%和25.30%。

该研究还指出,DC371739 的作用机制不同于已知的小分子降血脂药物,DC371739 通过直接与转录因子 HNF-1α 结合,从而阻碍 PCSK9 和 ANGPTL3 这两个关键基因的转录。因此,DC371739 能够同时抑制 PCSK9 和 ANGPTL3 的转录,是一种很有前途的降血脂候选药物。

此外,由于作用机制不同,DC371739 可以与他汀类药物联合使用,大鼠实验显示,DC371739 与阿托伐他汀联用可以产生更好的降血脂效果。这为他汀类药物不耐受患者提供了潜在的替代治疗方法。

近年来,针对 PCSK9 和 ANGPTL3 的降血脂研究有很多,例如诺华公司开发的针对 PCSK9 的 siRNA 药物、赛诺菲开发的针对 PCSK9 的单抗、Verve 公司正在研发的基因编辑 PCSK9 的疗法,以及再生元公司开发的针对 ANGPTL3 的单抗等等。但这些药物或疗法,无疑会有非常高的价格,且需要注射给药,与他汀类药物相比很难有优势。

而 DC371739 作为一种可口服的小分子候选药物,易于给药且成本更低,能同时作用于 PCSK9 和 ANGPTL3,产生良好的降血脂效果,且可以与他汀类药物联用,进一步增强治疗效果,有望成为一种非常理想的替代性治疗药物。

原始出处:

Wang J, Zhao J, Yan C, et al. Identification and evaluation of a lipid-lowering small compound in preclinical models and in a Phase I trial. Cell Metabolism, 2022.

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objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11584, encryptionId=d56611584ec, topicName=Meta)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d8f4110, createdName=guojianrong, createdTime=Mon Jan 30 11:12:24 CST 2023, time=2023-01-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1872412, encodeId=3b9018e2412c1, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Mon Dec 05 08:12:24 CST 2022, time=2022-12-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2016770, encodeId=7b962016e703a, content=<a href='/topic/show?id=75a2228481a' target=_blank style='color:#2F92EE;'>#临床数据#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=22848, encryptionId=75a2228481a, topicName=临床数据)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=fa4f352, createdName=chenlianhui, createdTime=Mon Jan 30 01:12:24 CST 2023, time=2023-01-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1962738, encodeId=199d1962e382a, 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, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Thu Dec 15 18:12:24 CST 2022, time=2022-12-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1212419, encodeId=ea9512124191a, content=期待。, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210703/9c448fe1b3b54fd7bc9477662f4861bb/4bdadad22bfd46f2921aabb4c40265d3.jpg, createdBy=a8d81938466, createdName=weigq, createdTime=Tue Apr 19 09:09:01 CST 2022, time=2022-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1577289, encodeId=e99715e7289be, content=<a href='/topic/show?id=d86d1159e36' target=_blank style='color:#2F92EE;'>#Metabolism#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11597, encryptionId=d86d1159e36, topicName=Metabolism)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1a6516392333, createdName=1249859em43(暂无昵称), createdTime=Sun Apr 17 10:12:24 CST 2022, time=2022-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1598166, encodeId=03d4159816699, content=<a href='/topic/show?id=6c6f1e62c5' target=_blank style='color:#2F92EE;'>#ABO#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1762, encryptionId=6c6f1e62c5, topicName=ABO)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b6c918580135, createdName=闆锋旦, createdTime=Sun Apr 17 10:12:24 CST 2022, time=2022-04-17, status=1, ipAttribution=)]
    2022-07-28 一闲
  4. [GetPortalCommentsPageByObjectIdResponse(id=1993004, encodeId=f0ea19930041b, content=<a href='/topic/show?id=29c598209ca' target=_blank style='color:#2F92EE;'>#降血脂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=98209, encryptionId=29c598209ca, topicName=降血脂)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTIW7uIr5ebYvJohUq0dkkVV05uF9jPpeyCrlcx904mUdMI9UKqpO3bt4GkgYBNdv485qT2NsVE27w/132, createdBy=023c2500122, createdName=ms8543593053280928, createdTime=Fri Nov 25 09:12:24 CST 2022, time=2022-11-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1972192, encodeId=661e19e219275, content=<a href='/topic/show?id=1212199e12e' target=_blank style='color:#2F92EE;'>#上海药物所#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, 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content=<a href='/topic/show?id=75a2228481a' target=_blank style='color:#2F92EE;'>#临床数据#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=22848, encryptionId=75a2228481a, topicName=临床数据)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=fa4f352, createdName=chenlianhui, createdTime=Mon Jan 30 01:12:24 CST 2023, time=2023-01-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1962738, encodeId=199d1962e382a, 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, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Thu Dec 15 18:12:24 CST 2022, time=2022-12-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1212419, encodeId=ea9512124191a, content=期待。, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210703/9c448fe1b3b54fd7bc9477662f4861bb/4bdadad22bfd46f2921aabb4c40265d3.jpg, createdBy=a8d81938466, createdName=weigq, createdTime=Tue Apr 19 09:09:01 CST 2022, time=2022-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1577289, encodeId=e99715e7289be, content=<a href='/topic/show?id=d86d1159e36' target=_blank style='color:#2F92EE;'>#Metabolism#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11597, encryptionId=d86d1159e36, topicName=Metabolism)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1a6516392333, createdName=1249859em43(暂无昵称), createdTime=Sun Apr 17 10:12:24 CST 2022, time=2022-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1598166, encodeId=03d4159816699, content=<a href='/topic/show?id=6c6f1e62c5' target=_blank style='color:#2F92EE;'>#ABO#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1762, encryptionId=6c6f1e62c5, topicName=ABO)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b6c918580135, createdName=闆锋旦, createdTime=Sun Apr 17 10:12:24 CST 2022, time=2022-04-17, status=1, ipAttribution=)]
    2023-01-30 guojianrong
  5. [GetPortalCommentsPageByObjectIdResponse(id=1993004, encodeId=f0ea19930041b, content=<a href='/topic/show?id=29c598209ca' target=_blank style='color:#2F92EE;'>#降血脂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=98209, encryptionId=29c598209ca, topicName=降血脂)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTIW7uIr5ebYvJohUq0dkkVV05uF9jPpeyCrlcx904mUdMI9UKqpO3bt4GkgYBNdv485qT2NsVE27w/132, createdBy=023c2500122, createdName=ms8543593053280928, createdTime=Fri Nov 25 09:12:24 CST 2022, time=2022-11-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1972192, encodeId=661e19e219275, content=<a href='/topic/show?id=1212199e12e' target=_blank style='color:#2F92EE;'>#上海药物所#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, 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  6. [GetPortalCommentsPageByObjectIdResponse(id=1993004, encodeId=f0ea19930041b, content=<a href='/topic/show?id=29c598209ca' target=_blank style='color:#2F92EE;'>#降血脂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=98209, encryptionId=29c598209ca, topicName=降血脂)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTIW7uIr5ebYvJohUq0dkkVV05uF9jPpeyCrlcx904mUdMI9UKqpO3bt4GkgYBNdv485qT2NsVE27w/132, createdBy=023c2500122, createdName=ms8543593053280928, createdTime=Fri Nov 25 09:12:24 CST 2022, time=2022-11-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1972192, encodeId=661e19e219275, content=<a href='/topic/show?id=1212199e12e' target=_blank style='color:#2F92EE;'>#上海药物所#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, 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content=<a href='/topic/show?id=75a2228481a' target=_blank style='color:#2F92EE;'>#临床数据#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=22848, encryptionId=75a2228481a, topicName=临床数据)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=fa4f352, createdName=chenlianhui, createdTime=Mon Jan 30 01:12:24 CST 2023, time=2023-01-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1962738, encodeId=199d1962e382a, 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, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Thu Dec 15 18:12:24 CST 2022, time=2022-12-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1212419, encodeId=ea9512124191a, content=期待。, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210703/9c448fe1b3b54fd7bc9477662f4861bb/4bdadad22bfd46f2921aabb4c40265d3.jpg, createdBy=a8d81938466, createdName=weigq, createdTime=Tue Apr 19 09:09:01 CST 2022, time=2022-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1577289, encodeId=e99715e7289be, content=<a href='/topic/show?id=d86d1159e36' target=_blank style='color:#2F92EE;'>#Metabolism#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11597, encryptionId=d86d1159e36, topicName=Metabolism)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1a6516392333, createdName=1249859em43(暂无昵称), createdTime=Sun Apr 17 10:12:24 CST 2022, time=2022-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1598166, encodeId=03d4159816699, content=<a href='/topic/show?id=6c6f1e62c5' target=_blank style='color:#2F92EE;'>#ABO#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1762, encryptionId=6c6f1e62c5, topicName=ABO)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b6c918580135, createdName=闆锋旦, createdTime=Sun Apr 17 10:12:24 CST 2022, time=2022-04-17, status=1, ipAttribution=)]
  7. [GetPortalCommentsPageByObjectIdResponse(id=1993004, encodeId=f0ea19930041b, content=<a href='/topic/show?id=29c598209ca' target=_blank style='color:#2F92EE;'>#降血脂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=98209, encryptionId=29c598209ca, topicName=降血脂)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTIW7uIr5ebYvJohUq0dkkVV05uF9jPpeyCrlcx904mUdMI9UKqpO3bt4GkgYBNdv485qT2NsVE27w/132, createdBy=023c2500122, createdName=ms8543593053280928, createdTime=Fri Nov 25 09:12:24 CST 2022, time=2022-11-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1972192, encodeId=661e19e219275, content=<a href='/topic/show?id=1212199e12e' target=_blank style='color:#2F92EE;'>#上海药物所#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=19971, encryptionId=1212199e12e, topicName=上海药物所)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=03e7496, createdName=楚钟, createdTime=Wed Jun 15 02:12:24 CST 2022, time=2022-06-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1897008, encodeId=e5d4189e0087c, content=<a href='/topic/show?id=4a391158248' target=_blank style='color:#2F92EE;'>#MET#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11582, encryptionId=4a391158248, topicName=MET)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=18fc139, createdName=一闲, createdTime=Thu Jul 28 16:12:24 CST 2022, time=2022-07-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1888428, encodeId=99be18884287d, content=<a href='/topic/show?id=d56611584ec' target=_blank style='color:#2F92EE;'>#Meta#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11584, encryptionId=d56611584ec, topicName=Meta)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d8f4110, createdName=guojianrong, createdTime=Mon Jan 30 11:12:24 CST 2023, time=2023-01-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1872412, encodeId=3b9018e2412c1, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Mon Dec 05 08:12:24 CST 2022, time=2022-12-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2016770, encodeId=7b962016e703a, content=<a href='/topic/show?id=75a2228481a' target=_blank style='color:#2F92EE;'>#临床数据#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=22848, encryptionId=75a2228481a, topicName=临床数据)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=fa4f352, createdName=chenlianhui, createdTime=Mon Jan 30 01:12:24 CST 2023, time=2023-01-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1962738, encodeId=199d1962e382a, 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, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Thu Dec 15 18:12:24 CST 2022, time=2022-12-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1212419, encodeId=ea9512124191a, content=期待。, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210703/9c448fe1b3b54fd7bc9477662f4861bb/4bdadad22bfd46f2921aabb4c40265d3.jpg, createdBy=a8d81938466, createdName=weigq, createdTime=Tue Apr 19 09:09:01 CST 2022, time=2022-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1577289, encodeId=e99715e7289be, content=<a href='/topic/show?id=d86d1159e36' target=_blank style='color:#2F92EE;'>#Metabolism#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11597, encryptionId=d86d1159e36, topicName=Metabolism)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1a6516392333, createdName=1249859em43(暂无昵称), createdTime=Sun Apr 17 10:12:24 CST 2022, time=2022-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1598166, encodeId=03d4159816699, content=<a href='/topic/show?id=6c6f1e62c5' target=_blank style='color:#2F92EE;'>#ABO#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1762, encryptionId=6c6f1e62c5, topicName=ABO)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b6c918580135, createdName=闆锋旦, createdTime=Sun Apr 17 10:12:24 CST 2022, time=2022-04-17, status=1, ipAttribution=)]
    2022-12-15 维他命
  8. 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content=<a href='/topic/show?id=75a2228481a' target=_blank style='color:#2F92EE;'>#临床数据#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=22848, encryptionId=75a2228481a, topicName=临床数据)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=fa4f352, createdName=chenlianhui, createdTime=Mon Jan 30 01:12:24 CST 2023, time=2023-01-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1962738, encodeId=199d1962e382a, 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, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Thu Dec 15 18:12:24 CST 2022, time=2022-12-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1212419, encodeId=ea9512124191a, content=期待。, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210703/9c448fe1b3b54fd7bc9477662f4861bb/4bdadad22bfd46f2921aabb4c40265d3.jpg, createdBy=a8d81938466, createdName=weigq, createdTime=Tue Apr 19 09:09:01 CST 2022, time=2022-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1577289, encodeId=e99715e7289be, content=<a href='/topic/show?id=d86d1159e36' target=_blank style='color:#2F92EE;'>#Metabolism#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11597, encryptionId=d86d1159e36, topicName=Metabolism)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1a6516392333, createdName=1249859em43(暂无昵称), createdTime=Sun Apr 17 10:12:24 CST 2022, time=2022-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1598166, encodeId=03d4159816699, content=<a href='/topic/show?id=6c6f1e62c5' target=_blank style='color:#2F92EE;'>#ABO#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1762, encryptionId=6c6f1e62c5, topicName=ABO)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b6c918580135, createdName=闆锋旦, createdTime=Sun Apr 17 10:12:24 CST 2022, time=2022-04-17, status=1, ipAttribution=)]
    2022-04-19 weigq

    期待。

    0

  9. 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  10. 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    2022-04-17 闆锋旦

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