Writing in Redox Biology, researchers from Spain and Scotland conducted a study* investigating the molecular level effects of cannabidiol (CBD) on epidermal cells. The research was co-funded by a European Regional Development Fund and grant from the EU Ministry of Economy and Competitiveness (MINECO).
Using a combination of two analytical methods – RNA sequencing (RNA-Seq) and sequential window acquisition of all theoretical mass spectrometry (SWATCH-MS) – the researchers characterised how CBD effected primary human keratinocytes – the largest collection of cells on the outer skin layer. The researchers said such work plugged a current research gap in understanding CBD’s true potential in skin care.
A closer, molecular look…
The researchers said CBD had attracted “great attention” for its therapeutic potential against different pathologies, including skin diseases, and its efficacy and clinical benefits had been “extensively demonstrated”. However, the molecular mechanism(s) and targets responsible for these effects were “as yet, unknown”, they added. More specifically, CBD’s mechanism of action on different skin cell types was also not yet understood.
Findings in the current study showed that CBD regulated major pathways in human primary keratinocytes involved in keratinocyte differentiation, skin development and epidermal cell differentiation, among other processes.
Importantly, results demonstrated how this was achieved: through upregulation of the gene heme oxygenase 1 (HMOX1) and degradation of the transcriptional repressor BACH1. Importantly, this occurred independently from the NRF2 pathway – part of a group of nuclear receptors that released antioxidative genes and proteins when under oxidative stress.
“We show for the first time that CBD is a BACH1 inhibitor and a weak NRF2 activator. Furthermore, we reveal that in keratinocytes, HMOX1 expression is regulated by BACH1 in a NRF2-independent manger. Finally, we show that topical CBD application in mice increased the levels of HMOX1 in the epidermis (in agreement with our results in cells) and induced the expression of wound-repair and proliferation associated keratins 16 and 17.”
A molecular target and scientific rationale
The researchers said findings had clearly identified BACH1 as a “molecular target for CBD in keratinocytes”. Results also set the basis for use of topical CBD for the treatment of different skin diseases, including atopic dermatitis and keratin disorders.
“Our study demonstrated for the first time a biochemical target for CBD and provides a scientific rationale for its use as a treatment for some skin conditions,” they said.
HMOX1 was an “important cytoprotective enzyme” in skin, with antioxidant, anti-inflammatory and anti-apoptotic properties which proved useful in inflammatory- or oxidative stress-associated skin conditions, the researchers said.
“In these scenarios, BACH1 inhibitors might be very useful, due to their potent activity as HMOX1 inducers. Our validation of CBD as an BACH1 inhibitor suggests that CBD treatment would a: protect the skin against external insults, e.g. against UVA-irradiation-induced damage; and b: be greatly beneficial in a variety of skin conditions, e.g. eczema or atopic dermatitis.”
The researchers noted that long-term BACH1 deficiency and associated sustained HMOX1 upregulation had not shown any detrimental effect under normal conditions in mice, suggesting acute BACH1 inhibition would not have any systemic deteriorative effect.
In vivo topical CBD treatment was tested with concentrations that aligned with current commercial products – 0.1-1%.
*The current study has pre-proof status. It has been peer reviewed and accepted for publication by the Editorial Board of the journal but may undergo ‘enhancements, such as formatting for readability and the addition of a cover page and metadata.
Source: Redox Biology
Published online ahead of print, September 5, 2019. Doi: j.redox.2019.101321
Title: “Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1”
Authors: L. Casares, V. Garcia et al.
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