Blood:miR-146a类似物可治疗NF-kB驱动的炎症和白血病进展

2019-12-09 QQY MedSci原创

NF-κB是炎症和癌症进展的主要调控因子,在白血病发生过程中具有重要的作用。虽然NF-kB具有治疗潜力,但用药物靶向抑制NF-κB还是具有一定挑战性。近日,研究人员合成了一种髓细胞选择性NF-kB抑制剂,即将miR146a类似的寡核苷酸结合到一个清道夫受体(SR)/Toll样受体9(TLR9)激动剂(C-miR146a)上。与未结合的miR-146a不同,C-miR146a可被迅速内化并传递到靶髓

NF-κB是炎症和癌症进展的主要调控因子,在白血病发生过程中具有重要的作用。虽然NF-kB具有治疗潜力,但用药物靶向抑制NF-κB还是具有一定挑战性。

近日,研究人员合成了一种髓细胞选择性NF-kB抑制剂,即将miR146a类似的寡核苷酸结合到一个清道夫受体(SR)/Toll样受体9(TLR9)激动剂(C-miR146a)上。与未结合的miR-146a不同,C-miR146a可被迅速内化并传递到靶髓细胞和白血病细胞的细胞质中。C-miR146a可减少经典miR-146a靶点(IRAK1和TRAF6)的表达,从而阻断NF-κB激活靶细胞。

给miR-146缺陷性小鼠静脉注射C-miR146a类似物可预防髓细胞的NF-κB过度活化,进而减轻骨髓增生和小鼠对细菌的超敏反应。重要的是,在嵌合抗原受体(CAR) T细胞诱导的细胞因子释放综合征(CRS)的临床相关模型中,C-miR146a还显示了抑制重度炎症的功效。在不影响CD19特异性CAR T细胞抗肿瘤活性的情况下,系统应用C-miR146a寡核苷酸可减轻异种移植B细胞淋巴瘤模型中的人单核细胞依赖性的IL-1和IL-6释放。

除了抗炎作用,miR146a还是一种已知的肿瘤抑制因子,在人类髓系白血病中,常见miR146a缺失或表达水平降低。通过TCGA AML的数据集,研究人员发现miR-146水平与NF-κB-相关性基因和患者的生存呈负相关性。相应地,在体外,C-miR146a可诱导人MDSL、HL-60和MV4-11白血病细胞的细胞毒性作用。反复静脉予以C-miR146a可抑制NF-κB靶基因的表达,从而抑制的浸润性HL-60白血病的进展。

本研究结果显示,髓细胞靶向的miR146a类似物具有治疗炎症和骨髓增生性疾病的潜力。

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    2020-02-12 smallant2002
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    2020-08-28 feifers
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    2019-12-11 jichang
  4. [GetPortalCommentsPageByObjectIdResponse(id=1930746, encodeId=58bc1930e4617, content=<a href='/topic/show?id=22f61180211' target=_blank style='color:#2F92EE;'>#miR#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=41, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11802, encryptionId=22f61180211, topicName=miR)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=0a27288, createdName=smallant2002, createdTime=Wed Feb 12 20:09:00 CST 2020, time=2020-02-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2036292, encodeId=3f592036292f9, content=<a href='/topic/show?id=07f11183151' target=_blank style='color:#2F92EE;'>#miR-146a#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11831, encryptionId=07f11183151, topicName=miR-146a)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1f1d390, createdName=feifers, createdTime=Fri Aug 28 20:09:00 CST 2020, time=2020-08-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1536960, encodeId=ae861536960e5, content=<a href='/topic/show?id=f1c512e304f' target=_blank style='color:#2F92EE;'>#NF-kB#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=54, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12730, encryptionId=f1c512e304f, topicName=NF-kB)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=e2ca12754731, createdName=jichang, createdTime=Wed Dec 11 14:09:00 CST 2019, time=2019-12-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=376820, encodeId=420a3e682024, content=好文章,学习了!, beContent=null, objectType=article, channel=null, level=null, likeNumber=85, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=43a21971117, createdName=njwbhuang, createdTime=Wed Dec 11 09:45:02 CST 2019, time=2019-12-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=376761, encodeId=94363e6761a8, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=111, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6d551998554, createdName=1e1c07bdm01(暂无匿称), createdTime=Tue Dec 10 06:49:10 CST 2019, time=2019-12-10, status=1, ipAttribution=)]
    2019-12-11 njwbhuang

    好文章,学习了!

    0

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