Modulation of Redox and Inflammatory Signaling in Human Skin Cells Using Phytocannabinoids Applied after UVA Irradiation: In Vitro Studies

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“UVA exposure disturbs the metabolism of skin cells, often inducing oxidative stress and inflammation. Therefore, there is a need for bioactive compounds that limit such consequences without causing undesirable side effects.

The aim of this study was to analyse in vitro the effects of the phytocannabinoids cannabigerol (CBG) and cannabidiol (CBD), which differ in terms of biological effects. Furthermore, the combined use of both compounds (CBG+CBD) has been analysed in order to increase their effectiveness in human skin fibroblasts and keratinocytes protection against UVA-induced alternation.

The results obtained indicate that the effects of CBG and CBD on the redox balance might indeed be enhanced when both phytocannabinoids are applied concurrently. Those effects include a reduction in NOX activity, ROS levels, and a modification of thioredoxin-dependent antioxidant systems. The reduction in the UVA-induced lipid peroxidation and protein modification has been confirmed through lower levels of 4-HNE-protein adducts and protein carbonyl groups as well as through the recovery of collagen expression. Modification of antioxidant signalling (Nrf2/HO-1) through the administration of CBG+CBD has been proven to be associated with reduced proinflammatory signalling (NFκB/TNFα).

Differential metabolic responses of keratinocytes and fibroblasts to the effects of the UVA and phytocannabinoids have indicated possible beneficial protective and regenerative effects of the phytocannabinoids, suggesting their possible application for the purpose of limiting the harmful impact of the UVA on skin cells.”

https://pubmed.ncbi.nlm.nih.gov/38891097/

“The results presented in this manuscript indicate that the concurrent use of the two phytocannabinoids (CBG and CBD), acting as both a protective and regenerative system, may have a beneficial effect on the redox balance in human keratinocytes and skin fibroblasts, even if they were applied after UVA irradiation. The tested phytocannabinoids also counteract proinflammatory reactions, which, consequently, contribute to the development of various pathological conditions. The obtained results suggest the combined use of CBG and CBD as a potential preventive and regenerative method for skin cells, especially those damaged by UV radiation, which may be used for the purpose of both prevention and therapy.”

https://www.mdpi.com/2073-4409/13/11/965

Cannabidiol exerts multitarget immunomodulatory effects on PBMCs from individuals with psoriasis vulgaris

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“Introduction: The involvement of endocannabinoid system (ECS) in the inflammatory cascade, and the ability of phytocannabinoids, endocannabinoids and their synthetic analogues to modulate it has become an interesting research area for new therapeutic approaches in inflammatory skin diseases. Cannabidiol (CBD) appears to be the most promising among phytocannabinoids, due to the lack of psychotropic effects and low toxicity profile. Its anti-inflammatory action has been highlighted in different preclinical models, ranging from experimental colitis to arthritis and neuroinflammation. Our aim was to evaluate CBD immune-modulatory effects in peripheral blood mononuclear cells (PBMC) of psoriasis individuals with particular attention to both innate and adaptative immune arms.

Methods: We performed in vitro immune functional experiments to analyze CBD action on various immune cells active in psoriatic lesions.

Results: The results showed that CBD produced a shift from Th1 to Th2 response, while boosting cytotoxic activity of Natural Killer (NK) cells. Furthermore, it also exerted a potent action on monocyte differentiation as, after CBD treatment, monocytes from psoriatic individuals were unable to migrate in response to inflammatory stimuli and to fully differentiate into mature dendritic cells. Finally, a M2 skewing of monocyte-derived macrophages by CBD also contributed to the fine tuning of the magnitude of immune responses.

Conclusions: These data uncover new potential immunomodulatory properties of this cannabinoid suggesting a possible therapeutic action in the treatment of multiple inflammatory skin diseases.”

https://pubmed.ncbi.nlm.nih.gov/38601151/

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1373435/full

Cannabidiol Mediates In Vitro Attenuation of Proinflammatory Cytokine Responses in Psoriatic Disease

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“Background: Cannabidiol (CBD), a substance that belongs to the phytocannabinoids, appears to exert antioxidant, neuroprotective, antipsychotic, anticonvulsant, and anticancer properties. Recent evidence supports the immunoregulatory effect of CBD on autoimmune and/or inflammatory disease. Psoriasis is a chronic skin disease. The main immune cell population involved in the pathogenesis of the disease is the interleukin- (IL-) 17-producing T helper (Th) 17 subset. Other subpopulations, such as interferon-γ (IFNγ) -producing Th1 and T cytotoxic (Tc) 1, IL-17-producing Tc17, as well as natural killer (NK) and natural killer T cells (NKT) have been implicated in psoriasis development. 

Purpose: The aim of the present study was to evaluate the in vitro effect of CBD on the aforementioned subpopulations isolated from patients with psoriasis using flow cytometry. 

Methods: Cells were stimulated in the presence or absence of CBD, stained and examined using surface and intracellular markers. 

Results: CBD decreased IL-17 production within the CD3, Th, and NKT cell compartments and IFNγ production within the CD3 compartment in cells isolated from patients with psoriasis. Interestingly, CBD supplementation did not inhibit production of proinflammatory cytokines in cells isolated from healthy individuals. On the contrary, IFNγ-producing Th, Tc, and NK cells increased after CBD supplementation. 

Conclusion: CBD provides anti-inflammatory effects in T cells isolated from patients with psoriasis. Our results could be the impetus for future investigations regarding the immunomodulatory properties of CBD and its utilization for development of CBD-containing antipsoriatic agents.”

https://pubmed.ncbi.nlm.nih.gov/38181167/

Cannabinoids and Their Receptors in Skin Diseases

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“The therapeutic application of cannabinoids has gained traction in recent years. Cannabinoids interact with the human endocannabinoid system in the skin. A large body of research indicates that cannabinoids could hold promise for the treatment of eczema, psoriasis, acne, pruritus, hair disorders, and skin cancer. However, most of the available data are at the preclinical stage. Comprehensive, large-scale, randomized, controlled clinical trials have not yet been fully conducted. In this article, we describe new findings in cannabinoid research and point out promising future research areas.”

https://pubmed.ncbi.nlm.nih.gov/38003712/

“In recent years, some components of cannabis, also known as marijuana, have been studied. Cannabis has been used for various purposes throughout history, including recreational, medicinal, and industrial uses. In recent years, cannabinoid components are emerging as therapeutic alternatives for patients with a variety of illnesses and conditions. In particular, their anti-inflammatory properties have piqued the interest of dermatologists [1]. Given the growing number of pre-clinical and clinical studies exploring the potential of cannabinoids to treat dermatologic conditions, we here summarize reports of cannabinoid use in dermatologic therapy.”

https://www.mdpi.com/1422-0067/24/22/16523

Analgesic and Anti-Inflammatory Effects of 1% Tropical Cannabidiol Gel in Animal Models

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“Introduction: Cannabidiol (CBD), a phytocannabinoid isolated from cannabis plants, is an interesting candidate for studying its anti-inflammatory effects, especially in the pre-clinical and animal models. Its anti-inflammatory effects, such as reduction of edema and arthritis, have been demonstrated in animal models. However, topical CBD administration requires further evaluation of CBD dosage and efficacy in animal models and clinical settings. 

Methods: This in vivo study investigated the anti-inflammatory effects of topical CBD administration in an animal model. Scientific experiments, including the formalin test, writhing test, carrageenan-induced edema, histopathological examination, and detection of various proinflammatory mediators, were performed. 

Results: The anti-inflammatory effects in vivo after inflammation induction, represented by decreased times of paw licking, degree of paw edema, and decreased writhing response, showed that 1% of tropical CBD use had significantly comparable or better anti-inflammatory effects when compared with tropical diclofenac, an anti-inflammatory agent. Moreover, the anti-inflammatory effects were significant compared with the placebo. In addition, the histopathological examination showed that topical CBD drastically reduced leukocyte infiltration and the degree of inflammation. This study also showed that the levels of various proinflammatory mediators in the plasma of mice treated with topical CBD did not differ from those treated with diclofenac. 

Conclusions: The topical administration of 1% CBD gel is a potentially effective candidate for an anti-inflammatory agent. Candidate for an anti-inflammatory agent.”

https://pubmed.ncbi.nlm.nih.gov/37669453/

https://www.liebertpub.com/doi/10.1089/can.2023.0070

Therapeutic Potential of Minor Cannabinoids in Dermatological Diseases-A Synthetic Review

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“Dermatological diseases pose a significant burden on the quality of life of individuals and can be challenging to treat effectively. In this aspect, cannabinoids are gaining increasing importance due to their therapeutic potential in various disease entities including skin diseases. In this synthetic review, we comprehensively analyzed the existing literature in the field of potential dermatological applications of a lesser-known subgroup of cannabinoids, the so-called minor cannabinoids, such as cannabidivarin (CBDV), cannabidiforol (CBDP), cannabichromene (CBC), tetrahydrocannabivarin (THCV), cannabigerolic acid (CBGA), cannabigerol (CBG), cannabielsoin (CBE), cannabimovone (CBM) or cannabinol (CBN), while drawing attention to their unique pharmacological properties. We systematically searched the available databases for relevant studies and analyzed the data to provide an overview of current thematic knowledge. We looked through the full-text, bibliographic and factographic databases, especially Scopus, Web of Science, PubMed, Polish Scientific Journals Database, and selected the most relevant papers. Our review highlights that minor cannabinoids exhibit diverse pharmacological activities, including anti-inflammatory, analgesic, antimicrobial, and anti-itch properties. Several studies have reported their efficacy in mitigating symptoms associated with dermatological diseases such as psoriasis, eczema, acne, and pruritus. Furthermore, minor cannabinoids have shown potential in regulating sebum production, a crucial factor in acne pathogenesis. The findings of this review suggest that minor cannabinoids hold therapeutic promise in the management of dermatological diseases. Further preclinical and clinical investigations are warranted to elucidate their mechanisms of action, determine optimal dosage regimens, and assess long-term safety profiles. Incorporating minor cannabinoids into dermatological therapies could potentially offer novel treatment options of patients and improve their overall well-being.”

https://pubmed.ncbi.nlm.nih.gov/37630401/

https://www.mdpi.com/1420-3049/28/16/6149

Cannabidiol and Cannabigerol Modify the Composition and Physicochemical Properties of Keratinocyte Membranes Exposed to UVA

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“The action of UVA radiation (both that derived from solar radiation and that used in the treatment of skin diseases) modifies the function and composition of keratinocyte membranes. Therefore, this study aimed to assess the effects of phytocannabinoids (CBD and CBG), used singly and in combination, on the contents of phospholipids, ceramides, lipid rafts and sialic acid in keratinocyte membranes exposed to UVA radiation, together with their structure and functionality. The phytocannabinoids, especially in combination (CBD+CBG), partially prevented increased levels of phosphatidylinositols and sialic acid from occurring and sphingomyelinase activity after the UVA exposure of keratinocytes. This was accompanied by a reduction in the formation of lipid rafts and malondialdehyde, which correlated with the parameters responsible for the integrity and functionality of the keratinocyte membrane (membrane fluidity and permeability and the activity of transmembrane transporters), compared to UVA-irradiated cells. This suggests that the simultaneous use of two phytocannabinoids may have a protective effect on healthy cells, without significantly reducing the therapeutic effect of UV radiation used to treat skin diseases such as psoriasis.”

https://pubmed.ncbi.nlm.nih.gov/37569799/

“Since UVA radiation modifies the composition, structure and functionality of the lipid bilayer of keratinocyte membranes, the use of natural compounds, especially lipophilic compounds such as phytocannabinoids, is important for maintaining the proper condition of the skin and, consequently, for the proper functioning of the skin over the entire human body. “

https://www.mdpi.com/1422-0067/24/15/12424

Rare Phytocannabinoids Exert Anti-Inflammatory Effects on Human Keratinocytes via the Endocannabinoid System and MAPK Signaling Pathway

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“Increasing evidence supports the therapeutic potential of rare cannabis-derived phytocannabinoids (pCBs) in skin disorders such as atopic dermatitis, psoriasis, pruritus, and acne. However, the molecular mechanisms of the biological action of these pCBs remain poorly investigated.

In this study, an experimental model of inflamed human keratinocytes (HaCaT cells) was set up by using lipopolysaccharide (LPS) in order to investigate the anti-inflammatory effects of the rare pCBs cannabigerol (CBG), cannabichromene (CBC), Δ9-tetrahydrocannabivarin (THCV) and cannabigerolic acid (CBGA). To this aim, pro-inflammatory interleukins (IL)-1β, IL-8, IL-12, IL-31, tumor necrosis factor (TNF-β) and anti-inflammatory IL-10 levels were measured through ELISA quantification. In addition, IL-12 and IL-31 levels were measured after treatment of HaCaT cells with THCV and CBGA in the presence of selected modulators of endocannabinoid (eCB) signaling. In the latter cells, the activation of 17 distinct proteins along the mitogen-activated protein kinase (MAPK) pathway was also investigated via Human Phosphorylation Array.

Our results demonstrate that rare pCBs significantly blocked inflammation by reducing the release of all pro-inflammatory ILs tested, except for TNF-β. Moreover, the reduction of IL-31 expression by THCV and CBGA was significantly reverted by blocking the eCB-binding TRPV1 receptor and by inhibiting the eCB-hydrolase MAGL. Remarkably, THCV and CBGA modulated the expression of the phosphorylated forms (and hence of the activity) of the MAPK-related proteins GSK3β, MEK1, MKK6 and CREB also by engaging eCB hydrolases MAGL and FAAH.

Taken together, the ability of rare pCBs to exert an anti-inflammatory effect in human keratinocytes through modifications of eCB and MAPK signaling opens new perspectives for the treatment of inflammation-related skin pathologies.”

https://pubmed.ncbi.nlm.nih.gov/36769042/

“Overall, this proof of concept, which shows that in inflamed human keratinocytes, rare pCBs can indeed interact with specific eCB system elements, opens new perspectives for possible treatments of inflammation-related skin diseases. Incidentally, such interactions between pCBs and eCB system seems to hold therapeutic potential well beyond the skin, such as possible treatments reported for autism spectrum disorders and cancer”

https://www.mdpi.com/1422-0067/24/3/2721

“Effects of Rare Phytocannabinoids on the Endocannabinoid System of Human Keratinocytes”

https://pubmed.ncbi.nlm.nih.gov/35628241/

Phytocannabinoids in the Pharmacotherapy of Psoriasis

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“Phytocannabinoids are naturally occurring compounds, the main source of which is Cannabis sativa L. Through direct action or interaction with G protein-coupled receptors, they affect ROS and pro-inflammatory cytokines levels and modify the effectiveness of transcription factor responsible for the biosynthesis of antioxidants which lead to oxidative stress and its consequences. Due to the modification of the redox balance and inflammation, phytocannabinoids are used in the treatment of various diseases, including autoimmune dermatoses, such as atopic dermatitis and psoriasis. Psoriasis is one of the most common dermatoses, and one of unknown etiology. A disturbed redox balance with a shift towards the oxidation leads to oxidative stress, resulting in oxidative modifications, mainly of lipids and proteins, and prolonged activation of immune cells and increased generation of pro-inflammatory cytokines, resulting in chronic inflammation. Given the biological activity of phytocannabinoids, they have become the focus of research as components of pharmacotherapy for psoriasis. Beneficial effects were shown by various representatives of phytocannabinoids, but the effect of cannabidiol (CBD) on skin cells (in vitro and ex vivo) and on blood cells from patients with psoriasis vulgaris and psoriatic arthritis has been most often evaluated in recent years.”

https://pubmed.ncbi.nlm.nih.gov/36770858/

https://www.mdpi.com/1420-3049/28/3/1192

Cannabidiol and Cannabigerol Exert Antimicrobial Activity without Compromising Skin Microbiota

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“Cannabidiol (CBD) and cannabigerol (CBG) are two pharmacologically active phytocannabinoids of Cannabis sativa L. Their antimicrobial activity needs further elucidation, particularly for CBG, as reports on this cannabinoid are scarce. We investigated CBD and CBG’s antimicrobial potential, including their ability to inhibit the formation and cause the removal of biofilms.

Our results demonstrate that both molecules present activity against planktonic bacteria and biofilms, with both cannabinoids removing mature biofilms at concentrations below the determined minimum inhibitory concentrations. We report for the first time minimum inhibitory and lethal concentrations for Pseudomonas aeruginosa and Escherichia coli (ranging from 400 to 3180 µM), as well as the ability of cannabinoids to inhibit Staphylococci adhesion to keratinocytes, with CBG demonstrating higher activity than CBD. The value of these molecules as preservative ingredients for cosmetics was also assayed, with CBG meeting the USP 51 challenge test criteria for antimicrobial effectiveness. Further, the exact formulation showed no negative impact on skin microbiota.

Our results suggest that phytocannabinoids can be promising topical antimicrobial agents when searching for novel therapeutic candidates for different skin conditions. Additional research is needed to clarify phytocannabinoids’ mechanisms of action, aiming to develop practical applications in dermatological use.”

https://pubmed.ncbi.nlm.nih.gov/36768709/

“This report compares CBD and CBG’s antimicrobial effectiveness and further cements phytocannabinoids’ potential to be used as antimicrobial agents. Both molecules’ antimicrobial capacity strongly depends on the target microorganism, namely whether it is Gram-negative or Gram-positive. Nonetheless, we were able to determine MICs for all tested strains, including S. pyogenesE. coli, and P. aeruginosa. It is of note that CBG revealed a stronger antimicrobial effect than CBD, particularly in the challenge test and in the antibiofilm assay. Further studies are needed to understand these discrepancies, as they may be connected to structural differences, receptor-binding affinity, or another mechanism other than a receptor-mediated one. Since no significant impact on the skin microbiota was observed and given its current widespread use, both CBD and CBG might be considered safe. Thus, we can assume that the development of topical formulations with active concentrations of CBG and/or CBD might represent a promising approach to tackle skin conditions where microorganisms and inflammation play a fundamental role, including psoriasis, atopic dermatitis, and acne.”

https://www.mdpi.com/1422-0067/24/3/2389