Protective effects of cannabidiol on the membrane proteins of skin keratinocytes exposed to hydrogen peroxide via participation in the proteostasis network

Abstract

Hydrogen peroxide (H 2 O 2 ) is widely used in clinical practice due to its antiseptic properties and its ability to heal wounds. However, due to its involvement in the formation of ROS, H 2 O 2 causes several side effects, including disorders of the metabolism of skin cells and the development of chronic inflammation mediated by oxidative stress. Therefore, this study evaluated the effects of cannabidiol (CBD), a phytocannabinoid known for its antioxidant and anti-inflammatory properties, on the proteome of keratinocyte membranes exposed to H 2 O 2 . Overall, the hydrogen peroxide caused the levels of several proteins to increase, while the treatment with CBD prevented these changes. Analysis of the protein-protein interaction network showed that the significant changes mainly involved proteins with important roles in the proteasomal activity, protein folding processes (regulatory subunit of the proteasome 26S 6A, beta proteasome subunit type 1, chaperonin 60 kDa), protein biosynthesis (40S ribosomal proteins S16, S2 and ubiquitin-S27a), regulation of the redox balance (carbonyl reductase [NADPH] 1 and NAD(P)H [quinone] 1 dehydrogenase) and cell survival (14-3-3 theta protein). Additionally, CBD reduced the total amount of MDA, 4-HNE and 4-ONE-protein adducts. Therefore, we conclude that CBD partially prevents the changes induced by hydrogen peroxide by reducing oxidative stress and maintaining proteostasis networks. Moreover, our results indicate that combination therapy with CBD may bring a promising approach in the clinical use of hydrogen peroxide by preventing its pro-oxidative and pro-inflammatory effect through potential participation of CBD in membrane mediated molecular signaling.

The molecular activity of cannabidiol in the regulation of Nrf2 system interacting with NF-κB pathway under oxidative stress

“…This situation demonstrates the importance of CBD's regulatory effect on the proteasomal degradation of Nrf2 which is a critical part of the regulation of Nrf2 activity. This may confirm that the regulatory effect of CBD on the proteostasis network has been demonstrated by CBD-mediated protection in the expression and oxidative modifications of proteins involved in proteasome activity and protein folding [ 24 ]. Moreover, several studies show the CBD-mediated regulation of p62 expression in both an increasing [ 69 ] and decreasing trend [ 70 ], in Sprague Dawley rats using CBD (100 mg/kg) [ 69 ] and in Sprague Dawley rats with hemorrhagic shock-induced brain injury using this phytocannabinoid (5 mg/kg) [ 70 ], respectively.…”

“…Also, another study in human umbilical vein endothelial cells demonstrated a significant increase in the level of HMOX1 mRNA and protein together with Nrf2 level caused by CBD action [ 17 ]. Moreover, CBD intervention to prevent excessive production of ROS protects cell metabolism against oxidative damage of other macromolecules such as lipids [ 22 , 23 ] and proteins leading to the maintenance of protein homeostasis [ 24 ] which are the critical targets for oxidative damages-associated pathology [ Fig. 1 ].…”

“…These products are recognized as markers of oxidative stress [ 26 ]. Under pro-oxidative conditions, CBD treatment has been also shown to prevent excessive adduct formation between lipid peroxidation products and proteins [ 24 , 27 ]. These adducts can change protein functions and ultimately intracellular signaling, which also affects biological pathways such as inflammation, differentiation, and cell death, in which these proteins are involved [ 28 ].…”

Phytocannabinoids in the Pharmacotherapy of Psoriasis

“…As a consequence, research on the effectiveness of the pharmacological action of phytocannabinoids is related to the assessment of the independent impact of these compounds on skin cells, as well as the effects after UV irradiation (in vitro or ex vivo examinations) on skin cells, or during its direct exposure to the skin (in vivo studies) [ 52 , 53 , 54 , 55 ]. The skin is also exposed to chemical agents (e.g., disinfectants such as hydrogen peroxide) and pathogens (bacteria/viruses) [ 56 , 57 ]. Exposing the skin/skin cells to the above-mentioned physicochemical and biological factors usually leads to oxidative stress and inflammation in the skin cells, which may result in pathological changes and the development of skin diseases [ 58 , 59 ].…”

Protective Effect of Cannabidiol on Hydrogen Peroxide‐Induced Oxidative Damage in Human Umbilical Vein Endothelial Cells (HUVECs)

“…[17] Besides, CBD could partially prevented the changes of the keratinocyte membranes proteome via maintaining proteostasis networks and reducing oxidative stress. [18] However, there is a lack of systematic studies about the antioxidant capacity of CBD at the cellular level and the molecular mechanism also remains to be elucidated. H 2 O 2 -induced oxidative damage model is one of the most commonly used cell models of oxidative stress, which can be employed to evaluate the antioxidant effect of active components at the cellular level.…”