Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1
Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1
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DOI：
10.1016/j.redox.2019.101321
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发表时间：
2020-01-01
期刊：
影响因子：
11.4
通讯作者：
Munoz, Eduardo
中科院分区：
文献类型：
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作者：
Casares, Laura;Garcia, Victor;Munoz, Eduardo
大麻二酚（CBD）是一种主要的非精神性植物大麻素，因其对包括皮肤病在内的不同病理的治疗潜力而引起了极大的关注。然而，尽管CBD在人类中的临床前模型和临床益处中的功效已被广泛证明，但负责这些效应的分子机制和靶点尚不清楚。本文中，我们使用RNA测序（RNA-Seq）和全理论质谱的连续窗口采集（SWATH-MS）的组合在分子水平上表征CBD对原代人角质形成细胞的影响。功能分析表明，CBD调节参与角质形成细胞分化，皮肤发育和表皮细胞分化等过程的途径。此外，CBD诱导了几种NRF 2靶基因的表达，其中血红素加氧酶1（HMOX 1）是CBD上调最多的基因和蛋白质。CRISPR/Cas9介导的基因组编辑、RNA干扰和生物化学研究表明，CBD介导的HMOX 1的诱导涉及转录阻遏物BACH 1的核输出和蛋白酶体降解。值得注意的是，我们发现BACH 1对角质形成细胞中HMOX 1表达的影响不依赖于NRF 2。体内研究表明，局部CBD增加了小鼠皮肤中HMOX 1以及增殖和伤口修复相关角蛋白16和17的水平。总而言之，我们的研究将BACH 1确定为角质形成细胞中CBD的分子靶点，并为使用局部CBD治疗包括特应性皮炎和角蛋白疾病在内的不同皮肤疾病奠定了基础。
Cannabidiol (CBD) is a major non-psychotropic phytocannabinoid that attracted a great attention for its therapeutic potential against different pathologies including skin diseases. However, although the efficacy in preclinical models and the clinical benefits of CBD in humans have been extensively demonstrated, the molecular mechanism(s) and targets responsible for these effects are as yet unknown. Herein we characterized at the molecular level the effects of CBD on primary human keratinocytes using a combination of RNA sequencing (RNA-Seq) and sequential window acquisition of all theoretical mass spectrometry (SWATH-MS). Functional analysis revealed that CBD regulated pathways involved in keratinocyte differentiation, skin development and epidermal cell differentiation among other processes. In addition, CBD induced the expression of several NRF2 target genes, with heme oxygenase 1 (HMOX1) being the gene and the protein most upregulated by CBD. CRISPR/Cas9-mediated genome editing, RNA interference and biochemical studies demonstrated that the induction of HMOX1 mediated by CBD, involved nuclear export and proteasomal degradation of the transcriptional repressor BACH1. Notably, we showed that the effect of BACH1 on HMOX1 expression in keratinocytes is independent of NRF2. In vivo studies showed that topical CBD increased the levels of HMOX1 and of the proliferation and wound-repair associated keratins 16 and 17 in the skin of mice. Altogether, our study identifies BACH1 as a molecular target for CBD in keratinocytes and sets the basis for the use of topical CBD for the treatment of different skin diseases including atopic dermatitis and keratin disorders.