SH-29 and SK-119 Attenuates Air-Pollution Induced Damage by Activating Nrf2 in HaCaT Cells

Shirin Kahremany, Lukas Hofmann, Noy Eretz-Kdosha, Eldad Silberstein, Arie Gruzman and Guy Cohen
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Shirin Kahremany: Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel
Lukas Hofmann: Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel
Noy Eretz-Kdosha: The Dead Sea and Arava Science Center, The Skin Research Institute, Masada 8691000, Israel
Eldad Silberstein: Department of Plastic Surgery, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva 8410100, Israel
Arie Gruzman: Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel
Guy Cohen: The Dead Sea and Arava Science Center, The Skin Research Institute, Masada 8691000, Israel

IJERPH, 2021, vol. 18, issue 23, 1-16

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.

Keywords: Nrf2; diesel particulate matter (DPM) (E)-5-oxo-1-(4-((2,4,6-trihydroxybenzylidene)amino)phenyl)pyrrolidine-3-carboxylic acid (SK-119); 2,2?-((1E,1?E)-(1,4-phenylenebis(azaneylylidene))bis(methaneylylidene))bis(benzene-1,3,5-triol (SH-29)); keratinocytes; pharmacological activators; ROS (search for similar items in EconPapers)
JEL-codes: I I1 I3 Q Q5 (search for similar items in EconPapers)
Date: 2021
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