Noxa in rheumatic diseases: present understanding and future impact.
Noxa in rheumatic diseases: present understanding and future impact.
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DOI：
10.1093/rheumatology/ket408
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发表时间：
2014-09
期刊：
影响因子：
5.5
通讯作者：
Karissa E. Cottier;Elizabeth M. Fogle;D. Fox;Salahuddin Ahmed
中科院分区：
文献类型：
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作者：
Karissa E. Cottier;Elizabeth M. Fogle;D. Fox;Salahuddin Ahmed
受损的程序性细胞死亡是慢性炎症和自身免疫性疾病发展的重要机制。Bcl-2家族蛋白在这些疾病中的过表达导致了靶向抑制这些蛋白作为主要治疗策略的概念。然而，这种方法的有限成功促使药理学家关注硬币的另一面，目的是重新激活可能中和Bcl-2或其他抗凋亡分子的危险促凋亡蛋白。在这一努力中，BH 3-only蛋白作为使抗性细胞发生凋亡的致敏的内源性分子获得了最近的关注。在仅BH 3家族中，Noxa因其特异性结合Mcl-1和Bcl-2并钝化其生物学特性而脱颖而出。Noxa现在正在被测试为癌症生物学中有前途的治疗靶点。尽管如此，它的作用和临床应用仍然缺乏验证自身免疫性疾病，包括风湿性疾病。这部分归因于我们对其调节作用的理解以及如何在治疗上利用Noxa的过表达或BH 3模拟物的递送方面存在重大差距。在这篇综述中，我们强调了最近在RA，OA，SLE和SS的一些研究表明，Noxa可能被用作一个潜在的治疗靶点，以规避这些风湿性疾病的侵入性和组织破坏性过程。
Impaired programmed cell death is an important contributing mechanism in the development of chronic inflammatory and autoimmune diseases. Overexpression of Bcl-2 family proteins in such diseases has led to the concept of targeted suppression of these proteins as a primary therapeutic strategy. However, limited success with this approach has prompted pharmacologists to look at the other side of the coin, with the aim of reactivating jeopardized pro-apoptotic proteins that may neutralize Bcl-2 or other anti-apoptotic molecules. In this effort, BH3-only proteins have gained recent attention as endogenous molecules for the sensitization of resistant cells to undergo apoptosis. Among the BH3-only family, Noxa stands out as exceptional for its specificity to bind Mcl-1 and Bcl-2 and blunt their biological properties. Noxa is now being tested as a promising therapeutic target in cancer biology. Nonetheless, its role and clinical application still lack validation in autoimmune diseases, including rheumatic conditions. This is partly attributed to the significant gap in our understanding of its regulatory role and how either overexpression of Noxa or delivery of BH3 mimetics could be therapeutically exploited. In this review we highlight some recent studies in RA, OA, SLE and SS suggesting that Noxa may be used as a potential therapeutic target to circumvent invasive and tissue destructive processes in these rheumatic diseases.