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

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.

A combination of three antioxidants decreases the impact of rural particulate pollution in Normal human keratinocytes

“…A recent review of sun protection noted that extract of Glycyrrhiza inflata root acts to inhibit UV‐induced ROS generation by activating NRF2 in primary human fibroblasts [34]. In addition, a recent report suggested that NRF2 activation can reverse the deleterious action of air pollution [21]. Those findings reported for NRF2 involvement in the response to environmental stress are reinforced by the observations in this study.…”

“…It is known that PM exposure causes a set of proinflammatory signalling in human epidermal skin cells. Therefore, because damage from PM 2.5 is associated with ROS generation and expression or release of inflammatory and remodelling mediators such as IL-6, NRF2, MMP1 and CYP1A1 [13,15,[19][20][21], we used those endpoints to monitor the efficacy of the AOx to block these signs of damage. CXCL10 was also used as an endpoint because of its association with inflammatory skin conditions [14,18,31].…”

“…The NRF2 pathway is a key mediator in the response to oxidative stress [19,20]. Interestingly, exposure to various pollutants has been linked to both induction and suppression, as well as nuclear translocation of NRF2 [13], however at least one report has shown that two pharmacological agents (SK-119 and SH-29) depend on activation of NRF2 to protect against damage to HaCat cells from particulates [21].…”

Development of an Effective Acne Treatment Based on CBD and Herbal Extracts: Preliminary In Vitro, Ex Vivo, and Clinical Evaluation

“…The experiments were conducted with the approval of the IRB Committee of the Soroka Medical Center, Beer Sheva, Israel (#0258-19-SOR, approval protocol scrc20016; 29.06.2020). The tissue was processed and maintained in an air/liquid interface with the dermal side submerged, as previously detailed [ 13 , 14 ].…”

NRF2 in dermatological disorders: Pharmacological activation for protection against cutaneous photodamage and photodermatosis

“…The authors have recently used a computer-aided in silico approach to design and synthesize oxopyrrolidine-based class of NRF2 activators ( Fig. 4 ) [ 199 ], and after in vitro examination, a lead compound SK-119 was generated [ 200 , 201 ]. The compound interacts with the arginine-rich area in the Kelch domain of Keap1 using the same binding mode as the NRF2–ETGE motif.…”