Frantz Marie-Céline, Rozot Roger, Marrot Laurent
Advanced Research, L'OREAL Research & Innovation, Aulnay-sous-Bois, France.
Biofactors. 2023 Jan;49(1):32-61. doi: 10.1002/biof.1907. Epub 2022 Oct 18.
The skin is the organ that is most susceptible to the impact of the exposome. Located at the interface with the external environment, it protects internal organs through the barrier function of the epidermis. It must adapt to the consequences of the harmful effects of solar radiation, the various chemical constituents of atmospheric pollution, and wounds associated with mechanical damage: oxidation, cytotoxicity, inflammation, and so forth. In this biological context, a capacity to adapt to the various stresses caused by the exposome is essential; otherwise, more or less serious conditions may develop accelerated aging, pigmentation disorders, atopy, psoriasis, and skin cancers. Nrf2-controlled pathways play a key role at this level. Nrf2 is a transcription factor that controls genes involved in oxidative stress protection and detoxification of chemicals. Its involvement in UV protection, reduction of inflammation in processes associated with healing, epidermal differentiation for barrier function, and hair regrowth, has been demonstrated. The modulation of Nrf2 in the skin may therefore constitute a skin protection or care strategy for certain dermatological stresses and disorders initiated or aggravated by the exposome. Nrf2 inducers can act through different modes of action. Keap1-dependent mechanisms include modification of the cysteine residues of Keap1 by (pro)electrophiles or prooxidants, and disruption of the Keap1-Nrf2 complex. Indirect mechanisms are suggested for numerous phytochemicals, acting on upstream pathways, or via hormesis. While developing novel and safe Nrf2 modulators for skin care may be challenging, new avenues can arise from natural compounds-based molecular modeling and emerging concepts such as epigenetic regulation.
皮肤是最易受暴露组影响的器官。它位于与外部环境的界面处，通过表皮的屏障功能保护内部器官。它必须适应太阳辐射的有害影响、大气污染的各种化学成分以及与机械损伤相关的伤口所带来的后果：氧化、细胞毒性、炎症等等。在这种生物学背景下，适应暴露组引起的各种应激的能力至关重要；否则，可能会出现或多或少严重的情况，如加速衰老、色素沉着紊乱、特应性、银屑病和皮肤癌。Nrf2 控制的途径在这一水平上起着关键作用。Nrf2 是一种转录因子，它控制参与氧化应激保护和化学物质解毒的基因。它在紫外线防护、与愈合相关过程中的炎症减轻、屏障功能的表皮分化以及毛发再生中的作用已得到证实。因此，调节皮肤中的 Nrf2 可能构成一种针对由暴露组引发或加重的某些皮肤病学应激和疾病的皮肤保护或护理策略。Nrf2 诱导剂可以通过不同的作用方式起作用。依赖 Keap1 的机制包括（前）亲电试剂或促氧化剂对 Keap1 半胱氨酸残基的修饰，以及 Keap1-Nrf2 复合物的破坏。对于许多植物化学物质，提出了间接机制，它们作用于上游途径或通过应激适应作用。虽然开发用于皮肤护理的新型安全 Nrf2 调节剂可能具有挑战性，但基于天然化合物的分子建模和表观遗传调控等新兴概念可能会带来新的途径。
