Abstract
Air pollution has been repeatedly linked to numerous health-related disorders, including skin sensitization, oxidative imbalance, premature extrinsic aging, skin inflammation, and increased cancer prevalence. Nrf2 is a key player in the endogenous protective mechanism of the skin. We hypothesized that pharmacological activation of Nrf2 might reduce the deleterious action of diesel particulate matter (DPM), evaluated in HaCaT cells. SK-119, a recently synthesized pharmacological agent as well as 2,2′-((1E,1′E)-(1,4-phenylenebis(azaneylylidene))bis(methaneylylidene))bis(benzene-1,3,5-triol) (SH-29) were first evaluated in silico, suggesting a potent Nrf2 activation capacity that was validated in vitro. In addition, both compounds were able to attenuate key pathways underlying DPM damage, including cytosolic and mitochondrial reactive oxygen species (ROS) generation, tested by DC-FDA and MitoSOX fluorescent dye, respectively. This effect was independent of the low direct scavenging ability of the compounds. In addition, both SK-119 and SH-29 were able to reduce DPM-induced IL-8 hypersecretion in pharmacologically relevant concentrations. Lastly, the safety of both compounds was evaluated and demonstrated in the ex vivo human skin organ culture model. Collectively, these results suggest that Nrf2 activation by SK-119 and SH-29 can revert the deleterious action of air pollution.
Highlights
The synthesized compound SH-29 was designed based on the structure of SK-119 [27]. These two compounds differ in polyphenolic rings; SK-119 has one triphenolate ring, whereas compound SH-29 has a double triphenolate ring
In our previous in silico studies, SK-119 was shown to interact with the arginine-rich area in the Kelch domain of Kelch-like ECH-associated protein 1 (Keap1) using the same mode as the nuclear factor erythroid 2-related factor 2 (Nrf2)-ETGT motif through hydrophobic and electrostatic interactions: two π–π stacking interactions between the compound and protein side chains (TYR 334 and TYR 572) and several hydrogen bonding (H-bond) with the side chains (ARG 415, ARG 483, SER 508, SER 555, and TYR 334)
It was shown that SK-119 was able to attenuate skin inflammatory and UVB-induced damage by Nrf2 activation
Summary
The European health agency still considers air pollution as the largest environmental health risk, causing cardiovascular and respiratory diseases that might lead to premature deaths [2,3,4]. Environmental pollutants such as polycyclic aromatic hydrocarbons, volatile organic compounds, heavy metals, ozone (O3 ), cigarette smoke, and particulate matter (PM) were repeatedly linked to respiratory and systemic disorders as well as an increase in the prevalence of cutaneous inflammatory diseases [5,6,7]. PM in ambient air is strongly related to the progression of atopic dermatitis in children
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