Therapeutic effects of CO-releaser/Nrf2 activator hybrids (HYCOs) in the treatment of skin wound, psoriasis and multiple sclerosis
Therapeutic effects of CO-releaser/Nrf2 activator hybrids (HYCOs) in the treatment of skin wound, psoriasis and multiple sclerosis
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DOI：
10.1016/j.redox.2020.101521
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发表时间：
2020-07-01
期刊：
影响因子：
11.4
通讯作者：
Foresti, Roberta
中科院分区：
文献类型：
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作者：
El Ali, Zeina;Ollivier, Anthony;Foresti, Roberta
由血红素加氧酶-1 （HO-1）产生或CO-释放分子（CO- rm）传递的一氧化碳（CO）具有抗炎作用，应激反应的主要调节因子核因子红细胞2相关因子2 （Nrf2）也具有这一特性。我们最近开发了新的杂化分子（HYCOs），由CO-RMs偶联到富马酸酯，已知可激活Nrf2/HO-1。在这里，我们在体外和体内炎症模型中评估了锰（Mn）和钌（Ru）基HYCOs在人单核细胞和角质形成细胞中的生物活性。将HYCOs的作用与：a)富马酸二甲酯（DMF）进行比较，这是一种已知的临床使用的富马酸酯；b)单独的CO-RM；c)两种化合物的结合。Mn-HYCOs在体外比Ru-HYCOs更有效地捐献CO和上调Nrf2/HO-1。然而，不管金属是什么，在LPS刺激下单核细胞中抗炎标志物的强烈减少被观察到特异性HYCOs。单独使用DMF、CO-RM或两者联合使用均未观察到这种效应，这表明与单独使用HYCOs相比，HYCOs的效力增强。在多发性硬化症小鼠模型中，口服选定的HYCOs可加速皮肤伤口愈合，减少牛皮癣介导的炎症和相当于或超过DMF作用的疾病症状，并改善运动功能障碍。因此，HYCOs具有强大的抗炎活性，这在炎症是一个突出组成部分的疾病模型中得到了概括。动物对长时间每日给药HYCOs（长达40天）耐受良好。我们的研究结果清楚地证实，HYCOs具有双重作用模式，强调同时靶向Nrf2和CO递送可能是抗炎症的临床相关应用。
Carbon monoxide (CO) produced by heme oxygenase-1 (HO-1) or delivered by CO-releasing molecules (CO-RMs) exerts anti-inflammatory action, a feature also exhibited by the nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the stress response. We have recently developed new hybrid molecules (HYCOs) consisting of CO-RMs conjugated to fumaric esters known to activate Nrf2/HO-1. Here we evaluated the biological activities of manganese (Mn) and ruthenium (Ru)-based HYCOs in human monocytes and keratinocytes in vitro as well as in vivo models of inflammation. The effects of HYCOs were compared to: a) dimethyl fumarate (DMF), a known fumaric ester used in the clinic; b) a CO-RM alone; or c) the combination of the two compounds. Mn-HYCOs donated CO and up-regulated Nrf2/HO-1 in vitro more efficiently than Ru-HYCOs. However, irrespective of the metal, a strong reduction in anti-inflammatory markers in monocytes stimulated by LPS was observed with specific HYCOs. This effect was not observed with DMF, CO-RM alone or the combination of the two, indicating the enhanced potency of HYCOs compared to the separate entities. Selected HYCOs given orally to mice accelerated skin wound closure, reduced psoriasis-mediated inflammation and disease symptoms equalling or surpassing the effect of DMF, and ameliorated motor dysfunction in a mouse model of multiple sclerosis. Thus, HYCOs have potent anti-inflammatory activities that are recapitulated in disease models in which inflammation is a prominent component. Prolonged daily administration of HYCOs (up to 40 days) is well tolerated in animals. Our results clearly confirm that HYCOs possess a dual mode of action highlighting the notion that simultaneous Nrf2 targeting and CO delivery could be a clinically relevant application to combat inflammation.