24 ANTI-POLLUTION


Figure 3: Regulation of Nrf2. A) Nrf2 is


constitutively synthesised and it is bound by Keap1 that allows for its ubiquitination. Once ubiquitinated, both proteins are separated and while Nrf2 is degraded in the proteasome, Keap1 is recycled and binds a newly synthesised protein of Nrf2. B) In the presence of an activator such as Sulforaphane or Redivine, the complex Keap1/Nrf2 is stabilised hence preventing both Nrf2 proteasomal degradation and Keap1 recycling. Because of the absence of active Keap1, neosynthesised Nrf2 is capable of translocating in the nucleus and to stimulate the expression and antioxidant-coding genes.


Additionally, while indoor, we are constantly exposed to artificial light from light bulbs and/or computers. Overexposure to these artificial lights may also affect skin and cause premature ageing. In line with several recent reports3,4 a blue light was used for these experiments.


BaP detoxification endogenous mechanisms


When skin is exposed to pollutants such as BaP, a defensive mechanism is triggered: the xenobiotic response element (XRE) (Fig 1). When BaP gets to a skin cell, it


A.


specifically binds the aryl hydrocarbon receptor (AhR). This transcription factor will then undergo a nuclear translocation and bind DNA to stimulate the expression of several genes including CYP1A1. This gene codes for a protein capable of metabolising BaP.5


However, during this metabolisation


process, mutagenic end-products together with large amounts of free radicals, especially reactive oxygen species (ROS), are being produced.6


This resulting


oxidative stress is responsible for reduced cell viability and DNA damage (Fig 5). The BaP-induced oxidative stress is then


Control B.


125 100 75 50 25 0


Sulforaphane * Redivine (0.075%)


+25% **


C.


175 150 125 100 75 50 25 0


Control Sulforaphane (10µM)


Redivine (0.075%)


Control Sulforaphane (10µM)


300 250 200 150 100 50 0


*** *** +153%


quenched by another defensive mechanism: the antioxidant response element (ARE) which is orchestrated by the transcription factor Nrf2.7 Nrf2 is a sensor of free radicals. During an oxidative stress, it will promote the neosynthesis of antioxidants such as glutathione and NQO1 (Fig 2). Nrf2 is a constitutive protein that is constantly inactivated by another protein Keap1. Indeed, Keap1 binds Nrf2 and allows for its ubiquitination that leads to Nrf2 proteosomal degradation, and the recycling of Keap1 (Fig 3A). During an oxidative stress, or because of


Control Sulforaphane (10µM)


Redivine (0.075%)


+47%


the presence of an inducer, the complex Keap1-Nrf2 is stabilised hence sequestrating Keap1 to Nrf2 (which is also not degraded). Bound to Nrf2, Keap1 is prevented from being recycled in order to handle the de novo-synthesised Nrf2 (Fig 3B). Freed from Keap1-mediated degradation, stabilised Nrf2 will relocate in the nucleus and bind DNA in order to activate the expression of antioxidant- coding genes. These neosynthesised anti- oxidants will in turn neutralise the free radicals responsible the oxidative stress.


Redivine (0.075%)


Figure 4: Redivine activates Nrf2 and is therefore responsible for an increased antioxidant synthesis. A) Immunfluorescence pictures of keratinocytes treated with sulforaphane or Redivine (0.075%). In the presence of either sulforaphane or Redivine, Nrf2 (in green) is relocated to the nucleus (in blue, DAPI). Quantification of nuclear Nrf2 was assessed by immunostaining. B) Quantification of glutathione synthesis was performed using fluorimetry. C) Quantification of NQO1 synthesis was performed using western blot. (vs. control: *p-value<0.05 ; ** p-value<0.01 ; ***p-value<0.005).


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Results Red Vine Leaf Extract as a strong anti- oxidant, directly fights the oxidative stress In order to assess Red Vine Leaf Extract’s ability to directly scavenge and neutralise free radicals, several tests (DPPH, ABTS, PNBT) were performed (Table 1). All these assays show that Red Vine Leaf Extract has strong anti-oxidant properties and can efficiently directly fight an oxidative stress.


November 2018


Glutathione synthesis (% of comtrol)


NQO1 synthesis (% of comtrol)


Nuclear Nrf2 (% of comtrol)


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