Nrf2 Pathway Involvement in the Beneficial Skin Effects of Moderate Ionic Osmotic Stress—The Case of The Dead Sea Water

Abstract

Objectives: Exposing skin to moderate ionic osmotic stress (MIOS) triggers several biochemical responses. The objective of this work is to reveal the mechanism triggered by MIOS on the skin surface. Furthermore, this work aims to study the involvement of the Nrf2 (nuclear factor erythroid-2-related factor 2) pathway, activated by MIOS, and its beneficial effect in protecting skin against stress via the stimulation of phase II enzymes. Methods: HaCaT cells and human skin organ culture were exposed to Dead Sea Water (DSW) as MIOS inducers and the induction of internal ROS elevation, Nrf2 translocation, mRNA gene expressions of the phase II enzymes, heme-oxygenase 1 (HO1), and Catalase (CAT) were determined. Results: Skin exposure to MIOS increases Nrf2 translocation to the nucleus, leading to increased levels of ROS, HO1, and CAT. Furthermore, exposing skin to MIOS promotes protection against UVB-related risks. This is demonstrated by attenuation of the expression of biomarkers, related to UVB-induced damage, Caspase-3, IL-8, and IL-1β. Conclusions: Skin exposure to MIOS leads to the activation of Nrf2 skin defense pathway and, therefore, could present beneficial advantages to human skin health, as demonstrated on human skin models. The beneficial effects of MIOS, induced by DSW are significantly superior to eq. NaCl brine, suggests that MIOS protection of skin against stress is partially related to specific mineral combinations.

Cutaneous Nrf2‐Keap1 pathway modulation by environmental factors: The Dead Sea area as a test case

“…This regulated antioxidant mechanism has been demonstrated to play a role in the treatment of several skin diseases 39 . In our previous study, we demonstrated that topical exposure of HSOC to DS water results in the induction of the Nrf2‐Keap1 pathway, likely due to the high mineral content of DS water acting as moderated ionic osmotic stress (MIOS) 16 . Here, we elucidate the effect of solar irradiation at the DS on cutaneous tissue.…”

“…39 In our previous study, we demonstrated that topical exposure of HSOC to DS water results in the induction of the Nrf2-Keap1 pathway, likely due to the high mineral content of DS water acting as moderated ionic osmotic stress (MIOS). 16 Here, we elucidate the effect of solar irradiation at the DS on cutaneous tissue. As shown in Figure 5 and Table 1, the UVB solar radiation (280-320 nm) intensity at the DS is lower than in Jerusalem by 5.4% due to the altitude difference between these locations, measured by our spectrophotometer instrument (UV-VIS Ocean Optics USB2000+ Extended Range Spectrophotometer, Largo, FL USA).…”

“…15 While intense stressors might induce massive oxidative damage in cutaneous tissue, moderate environmental stressors can activate the Nrf2-Keap1 pathway and provide protection rather than damage. 16,17 This mild stress often named eustress, describes a condition where moderate stress is beneficial rather than deleterious. [18][19][20] Therefore, it was hypothesized that exposure of skin to moderate stressors might be beneficial to cutaneous tissue and assist in coping with many pathological conditions via the enhanced activation of the protecting Nrf2 pathway.…”

“…We suggest the Dead Sea (DS) area as an example of a location with moderate environmental conditions (e.g., high water salinity, high atmospheric pressure, and unique irradiation). 16,21 The accumulation of these moderate stressors may elucidate partially the DS reputation as a beneficial area to treat many skin pathologies and other disorders. 22,23 The DS lake is located at the lowest terrestrial site on the planet at an altitude of 438 meters below sea level (in 2022).…”

“…Therefore, it was hypothesized that exposure of skin to moderate stressors might be beneficial to cutaneous tissue and assist in coping with many pathological conditions via the enhanced activation of the protecting Nrf2 pathway. We suggest the Dead Sea (DS) area as an example of a location with moderate environmental conditions (e.g., high water salinity, high atmospheric pressure, and unique irradiation) 16,21 . The accumulation of these moderate stressors may elucidate partially the DS reputation as a beneficial area to treat many skin pathologies and other disorders 22,23 …”