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Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes
Abstract
The endocannabinoid system (ECS) regulates multiple physiological processes, including cutaneous cell growth and differentiation. Here, we explored the effects of the major nonpsychotropic phytocannabinoid of Cannabis sativa, (-)-cannabidiol (CBD), on human sebaceous gland function and determined that CBD behaves as a highly effective sebostatic agent. Administration of CBD to cultured human sebocytes and human skin organ culture inhibited the lipogenic actions of various compounds, including arachidonic acid and a combination of linoleic acid and testosterone, and suppressed sebocyte proliferation via the activation of transient receptor potential vanilloid-4 (TRPV4) ion channels. Activation of TRPV4 interfered with the prolipogenic ERK1/2 MAPK pathway and resulted in the downregulation of nuclear receptor interacting protein-1 (NRIP1), which influences glucose and lipid metabolism, thereby inhibiting sebocyte lipogenesis. CBD also exerted complex antiinflammatory actions that were coupled to A2a adenosine receptor-dependent upregulation of tribbles homolog 3 (TRIB3) and inhibition of the NF-κB signaling. Collectively, our findings suggest that, due to the combined lipostatic, antiproliferative, and antiinflammatory effects, CBD has potential as a promising therapeutic agent for the treatment of acne vulgaris.
... SZ95 sebocytes were originated from human facial sebaceous glands [9]. The cells were provided by Prof. Christos C. Zouboulis [12][13][14][15][16][17][18][19]. The medium was renewed every other day, and cells were subcultured at 60-70% confluence. ...
... Over the past years, several members of the TRP ion channel superfamily were shown to be expressed on human sebocytes, including TRPV1 [16,[37][38][39], TRPV2 [16], TRPV3 [17] and TRPV4 [16], whereas mRNA expression of TRPA1 and TRPM8 was found to be below the detection limit [16]. Regarding their functional role, the mostly Ca 2+ -permeable TRPV1, TRPV3 and TRPV4 were all shown to negatively regulate sebaceous lipogenesis [16,17,38], and activation of TRPV3 was also linked to pro-inflammatory effects [17]. ...
... Over the past years, several members of the TRP ion channel superfamily were shown to be expressed on human sebocytes, including TRPV1 [16,[37][38][39], TRPV2 [16], TRPV3 [17] and TRPV4 [16], whereas mRNA expression of TRPA1 and TRPM8 was found to be below the detection limit [16]. Regarding their functional role, the mostly Ca 2+ -permeable TRPV1, TRPV3 and TRPV4 were all shown to negatively regulate sebaceous lipogenesis [16,17,38], and activation of TRPV3 was also linked to pro-inflammatory effects [17]. ...
Transient receptor potential melastatin 5 (TRPM5) ion channel is expressed in human hair follicles, where its spontaneous activity contributes to the maintenance of the growing, anagen phase of the hair cycle. Because adjacent sebaceous glands also exhibited TRPM5 immunopositivity, topically applied TRPM5 modulators administered to influence hair growth may also affect sebaceous glands. Hence, we aimed to assess expression of TRPM5 as well as effects of TRPM5 modulators [activators: 2,5‐dimethylpyrazine, 2‐heptanone; antagonist: triphenylphosphine oxide (TPPO)] on human SZ95 sebocytes, i.e., on the best available in vitro model to study human sebaceous glands. First, using complementary methods [RNA‐Seq, RT‐qPCR, western blot, siRNA‐mediated gene silencing and fluorescent Na ⁺ ‐ (SBFI AM) and Ca ²⁺ ‐measurements (Fura‐2 AM)], we found that TRPM5 is not expressed in human sebocytes in a functionally active form. Importantly, while non‐cytotoxic (MTT‐assay) concentrations of the activators were ineffective, TPPO promoted sebaceous lipogenesis (Nile Red labelling). This effect was TRPM5‐independent and was found to be mediated in an Akt‐ and epidermal growth factor receptor (EGFR)‐dependent manner, most likely via the Akt‐induced up‐regulation of diacylglycerol O‐acyltransferase (DGAT)‐2. Moreover, TPPO up‐regulated interleukin (IL)‐6 in an EGFR‐ and p38α MAPK‐dependent manner (RT‐qPCR), whereas it decreased the release of IL‐8 (ELISA), and down‐regulated additional pro‐inflammatory cytokines [chemokine (C‐X‐C motif) ligand [CXCL]‐1, CXCL2, CXCL6, colony‐stimulating factor 2, IL‐32; RNA‐Seq]. Collectively, specific TRPM5 modulators are unlikely to exert direct sebaceous gland‐related side effects, while safe TPPO analogues may induce beneficial moderate lipogenic and anti‐inflammatory effects in dry skin dermatoses.
... It modulates skin homeostasis by influencing key signaling pathways involved in skin cell proliferation and differentiation. Also, it has demonstrated efficacy in regulating the production of sebum in sebocytes and in reducing inflammation in keratinocytes, making it a promising candidate for the treatment of acne vulgaris and other inflammatory skin conditions [19,20]. Previous studies reported that in keratinocytes, the pCBs, CBD, CBG and CBC, were able to reduce the inflammation [21,22]. ...
... Keratinocytes are the predominant cell type in the epidermis and play a significant role in the skinʹs response to injury and inflammation. Cannabinoid research using HaCaT has shown that pCBs can exert anti-inflammatory effects by modulating cytokine production and promote wound healing by enhancing keratinocyte migration [1,20]. This migration is a vital step in the re-epithelialization process during wound repair, thus restoring the skinʹs barrier function. ...
... To assess skin recovery and regeneration quantitatively, a panel of 14 subjects (comprising both genders, aged [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] participated in the study. Controlled skin irritation was induced using Sodium Lauryl Sulphate (SLS) exposure, followed by the daily application of the regenerator cream for 28 days. ...
Background: Recent advancements have highlighted the potential of cannabis and its phy-tocannabinoids (pCBs) in skin health applications. These compounds, through their interac-tion with the endocannabinoid system (ECS), show promise for skin health products. Their ability to regulate inflammation, oxidative stress, and cellular proliferation makes them bene-ficial in addressing skin issues like inflammation, scarring, healing, acne, and aging, posi-tioning them as valuable tools for innovative skincare solutions. Methods: We investigated the cellular and molecular effects of proprietary pCB-based for-mulations on ECS modulation, inflammation, and skin regeneration. Using human dermal fibroblasts (HDF) and keratinocytes (HaCat), we assessed the formulations in both pre-treatment and treatment scenarios following exposure to stress-inducing agents. Key molecular markers were analyzed to tackle their efficacy in mitigating inflammation and promoting structural integrity and regeneration. Results: Our findings show that these formulations significantly reduce inflammation, pro-mote skin regeneration, and improve structural functions. In vivo studies confirmed that the formulations were well-tolerated and led to noticeable improvements in skin health, including enhanced barrier function. Conclusions: This study demonstrates the safety and efficacy of pCB-based formulations for cosmeceutical applications. By combining molecular analysis with in vivo testing, our research provides new insights into the therapeutic potential of pCBs for managing various skin con-ditions.
... The endogenous endocannabinoids (ECBs) are involved in the maintenance of homeostatic sebum production in the human sebaceous glands (Dobrosi et al., 2019). Several studies confirm that CBD could play an important role in the treatment of acne due to its effect on acne-related factors (Oláh et al., 2014). An important study was conducted to test the anti-inflammatory effect of CBD on human sebocytes (Oláh A et al., 2014). ...
... Several studies confirm that CBD could play an important role in the treatment of acne due to its effect on acne-related factors (Oláh et al., 2014). An important study was conducted to test the anti-inflammatory effect of CBD on human sebocytes (Oláh A et al., 2014). The study suggests that CBD is not limited to a direct ECS interaction, but has a more generalized effect. ...
... More importantly, CBD not only acts as a lipid-lowering agent but also stabilizes lipid imbalance by normalizing lipogenesis (Jin and Lee, 2018). In addition, CBD has been shown to reduce overall cell proliferation at some relevant doses (Oláh et al., 2014). The same research group has tested the anti-inflammatory potential of CBD and demonstrated its effect (Oláh et al., 2014). ...
Cannabis contains more than 140 cannabinoid compounds, of which cannabidiol and tetrahydrocannabinol are the most exposed ones, as they have the potential for numerous applications in various fields of health and medicine. Many scientific findings and numerous clinical studies over the last decade report results related to pain relief, treatment of chronic diseases and certain neurological disorders in human medicine. In line with the growing trend of research and application in human medicine, the research and application potential in veterinary medicine is also increasing. Of the biologically active molecules contained in the plant, cannabidiol has attracted the most interest. The cultivation of cannabis for medical and pharmaceutical purposes requires, among other things, compliance with legal regulations. An analysis of the legal acts regulating the use for medical and pharmaceutical purposes shows that the current regulation at state level is complex and should be amended. Keywords: Cannabis, Cannabinoids, Human medicine, Veterinary medicine, Inflammation, Legal Regulation
... Alternative targets with which cannabinoids can interact are Transient Receptor Potential (TRP) ion channels and Peroxisome Proliferator-Activated Receptors (PPARs) [4,5]. Through the interaction with these receptors, cannabinoids, in general, and cannabidiol (CBD), in particular, hold promise for the treatment of disorders, such as acne vulgaris [6][7][8][9][10], allergic contact dermatitis [7,10,11], asteatotic dermatitis [12], atopic dermatitis [4,[13][14][15][16], hidradenitis suppurativa [17], Kaposi sarcoma [10,18,19], pain [20][21][22][23][24], pruritus [7,12,[25][26][27][28][29][30][31][32], psoriasis [7,33], skin pigmentation disorders [34], and skin cancer [7,35], and can serve to improve skin protection, barrier function [36][37][38][39][40], and wound healing outcomes [41][42][43]. CBD is thought to act primarily as a modulator of inflammatory processes in the skin [44] and can reduce itching [45]. ...
... Alternative targets with which cannabinoids can interact are Transient Receptor Potential (TRP) ion channels and Peroxisome Proliferator-Activated Receptors (PPARs) [4,5]. Through the interaction with these receptors, cannabinoids, in general, and cannabidiol (CBD), in particular, hold promise for the treatment of disorders, such as acne vulgaris [6][7][8][9][10], allergic contact dermatitis [7,10,11], asteatotic dermatitis [12], atopic dermatitis [4,[13][14][15][16], hidradenitis suppurativa [17], Kaposi sarcoma [10,18,19], pain [20][21][22][23][24], pruritus [7,12,[25][26][27][28][29][30][31][32], psoriasis [7,33], skin pigmentation disorders [34], and skin cancer [7,35], and can serve to improve skin protection, barrier function [36][37][38][39][40], and wound healing outcomes [41][42][43]. CBD is thought to act primarily as a modulator of inflammatory processes in the skin [44] and can reduce itching [45]. ...
... Alternative targets with which cannabinoids can interact are Transient Receptor Potential (TRP) ion channels and Peroxisome Proliferator-Activated Receptors (PPARs) [4,5]. Through the interaction with these receptors, cannabinoids, in general, and cannabidiol (CBD), in particular, hold promise for the treatment of disorders, such as acne vulgaris [6][7][8][9][10], allergic contact dermatitis [7,10,11], asteatotic dermatitis [12], atopic dermatitis [4,[13][14][15][16], hidradenitis suppurativa [17], Kaposi sarcoma [10,18,19], pain [20][21][22][23][24], pruritus [7,12,[25][26][27][28][29][30][31][32], psoriasis [7,33], skin pigmentation disorders [34], and skin cancer [7,35], and can serve to improve skin protection, barrier function [36][37][38][39][40], and wound healing outcomes [41][42][43]. CBD is thought to act primarily as a modulator of inflammatory processes in the skin [44] and can reduce itching [45]. ...
The objective of this study was to investigate the cutaneous delivery of cannabidiol (CBD) from aqueous formulations developed for the targeted local treatment of dermatological conditions. CBD was formulated using a proprietary colloidal drug delivery system (VESIsorb®) into an aqueous colloidal solution at 2% (ACS 2%) and two colloidal gels (CG 1% and CG 2%, which contained 1% and 2% CBD, respectively). Two basic formulations containing CBD (5% in propylene glycol (PG 5%) and a 6.6% oil solution (OS 6.6%)) and two marketed CBD products (RP1 and RP2, containing 1% CBD) were used as comparators. Cutaneous delivery and cutaneous biodistribution experiments were performed using human abdominal skin (500–700 µm) under infinite- and finite-dose conditions with 0.5% Tween 80 in the PBS receiver phase. The quantification of CBD in the skin samples was performed using a validated UHPLC-MS/MS method and an internal standard (CBD-d3). The cutaneous deposition of CBD under finite-dose conditions demonstrated the superiority of CG 1%, CG 2%, and ACS 2% over the marketed products; CG 1% had the highest delivery efficiency (5.25%). Cutaneous biodistribution studies showed the superiority of the colloidal systems in delivering CBD to the viable epidermis, and the upper and lower papillary dermis, which are the target sites for the treatment of several dermatological conditions.
... Several preclinical findings regarding the effect of cannabinoids on acne have been reported. In a study conducted by Oláh et al. (2014) [91], CBD performed a unique "trinity of cellular anti-acne actions", emphasizing its potential in this regard. In this study, the authors used human sebocytes and human skin organ cultures (hSOC) to replicate the function of sebaceous glands in vivo and evaluate the effects of CBD. ...
... Several preclinical findings regarding the effect of cannabinoids on acne have been reported. In a study conducted by Oláh et al. (2014) [91], CBD performed a unique "trinity of cellular anti-acne actions", emphasizing its potential in this regard. In this study, the authors used human sebocytes and human skin organ cultures (hSOC) to replicate the function of sebaceous glands in vivo and evaluate the effects of CBD. ...
... Lipogenesis refers to the metabolic pathway through which these cells produce and accumulate lipids in order to produce sebum. CBD also exhibited an antiproliferative effect on sebocyte cells, reducing their excessive cell growth without inducing apoptosis; and anti-inflammatory properties by decreasing the levels of pro-inflammatory cytokines [91]. Additionally, this study demonstrated that the antiproliferative and lipostatic effects of CBD were mediated through the activation of the TRPV4 ion channels, which resulted in an increase in Ca 2+ concentration [91]. ...
Acne vulgaris is a prevalent dermatological disorder that impacts the quality of life for millions of people around the world. The multifactorial nature of this disorder requires innovative and effective treatment strategies. Over time, there has been a growing interest regarding the use of natural topical therapies, with cannabinoids emerging as a promising group of compounds for investiga-tion. In the context of acne treatment, cannabinoids are of particular interest due to their anti-acne properties, namely, lipostatic, anti-inflammatory, antiproliferative, and antimicrobial activities. Among these bioactive compounds, cannabidiol stands out as a notable derivative, exhibiting a promising spectrum of therapeutic actions. Pre-clinical and clinical studies have proven its ability to modulate sebum production, reduce inflammation, and inhibit bacterial proliferation - all of which are critical components in the pathogenesis of this dermatosis. This review provides a comprehen-sive overview of cannabinoids' potential as a novel and holistic approach to acne vulgaris treatment and summarizes recent developments in this area.
... In the present experiment, we employed a cell culture model using bovine, primary REC to first determine if there is a cytotoxic effect of CBD, and to investigate both the potential therapeutic and prophylactic effects of CBD under LPSinduced inflammatory conditions. While CBD has been utilized in previous cell culture models [28,29], a recent review of the literature [30] suggests that viability of cells may be affected in a dosedependent manner when exposed to CBD. The degree of cytotoxicity also appears to be influenced by the cell type. ...
... This effect was not observed when the cells were incubated with the vehicle alone, suggesting that the CBD was solely responsible for the reduction in viability. These results are consistent with Olah et al. [29], where a CBD concentration of 50 μM resulted in apoptosisdriven cytotoxicity in human sebocytes. While negative effects of high doses of CBD have been reported in several studies [32,33], other studies indicate that 10 μM or less does not affect cell viability [30]. ...
... These data suggest a preventative effect of CBD. This is consistent with Olah et al. [29] showing that CBD prevented the inflammatory response related to acne development in human sebocytes. Moreover, in a model of colitis in mice, a synthetic cannabinoid, AM841, was effective at both a preventative and a treatment for colitis-related inflammation [13]. ...
Background
Ruminant livestock experience a number of challenges, including high concentrate diets, weaning and transport, which can increase their risk of disorders such as ruminal acidosis, and the associated inflammation of the ruminal epithelium. Cannabidiol (CBD), a phytochemical from hemp ( Cannabis sativa ), is a promising target as a therapy for gastrointestinal inflammation, and may be extremely valuable as either a treatment or prophylactic. However, the effects of CBD in the the ruminant gastrointestinal tract have not been explored, in part due to the restrictions on feeding hemp to livestock. Therefore, the objective of this study was to investigate the immunomodulatory properties of CBD using a model of inflammation in primary ruminal epithelial cells (REC). In addition, CBD dose was evaluated for possible cytotoxic effects.
Results
Negative effects on cell viability were not observed when REC were exposed to 10 μM CBD. However, when the dose was increased to 50 μM for 24 h, there was a significant cytotoxic effect. When 10 μM CBD was added to culture media as treatment for inflammation induced with lipopolysaccharide (LPS), expression of genes encoding for pro-inflammatory cytokine IL1B was less compared to LPS exposure alone, and CBD resulted in a down-regulation of IL6 . As a pre-treatment, prior to LPS exposure, REC had decreased expression of IL6 and CXCL10 while CBD was present in the media, but not when it was removed prior to addition of LPS.
Conclusions
Results suggest that CBD may reduce cytokine transcription both during LPS-induced inflammation and when used preventatively, although these effects were dependent on its continued presence in the culture media. Overall, these experiments provide evidence of an immunomodulatory effect by CBD during a pro-inflammatory response in primary REC in culture.
... It showed antiacne activity by controlling sebum production and sebocyte lipogenesis (Peyravian et al. 2022). For instance, Oláh et al. (2014) investigated the consequences of cannabidiol on the functioning of the human sebaceous gland and found that it functions as a very potent sebostatic agent. Inhibition of lipogenic actions of arachidonic acid and a combination of linoleic acid and testosterone and suppression of sebocyte proliferation via the triggering of transient receptor potential vanilloid-4 (TRPV4) ion channels were observed with cannabidiol in cultured human sebocytes and human skin organ culture. ...
... Additionally, cannabidiol displayed intricate anti-inflammatory attributes that suppressed NF-κB signaling and the upregulated A2a adenosine receptor-dependent tribbles homolog 3 (TRIB3). They concluded that as cannabidiol simultaneously demonstrates lipostatic, antiproliferative, and nti-inflammatory properties, it could be an effective remedy for acne vulgaris (Oláh et al. 2014). ...
Acne is a skin disease that impacts 9.4% of the world's population. Available treatments for managing acne include retinoid-like drugs, antibiotics, corticosteroids, photo, and radiotherapy. Howevere, the aforementioned treatments have certain limitations such as possibility of developing skin cancer from tetracycline, doxycycline, and corticosteroids, microbial resistance to antibiotics , and deadly side effects, and so forth. Repurposing of existing therapeutics having excellent safety profile can be promising way to treat acne efficiently. The repurposed drugs and phytoceuticals from diverse classes have demonstrated promising effects in treating acne. These repurposed drugs have displayed antiacne effectiveness by targeting single or multiple signaling pathways. Various repurposed therapeutics undergoing clinical trials at different phases demonstrated their safety and efficacy in treating acne. Despite being a very good, safe, and less time-consuming strategy, drug repurposing (DR) faces multiple challenges such as lack of regulatory guidelines, preservation of intellectual property, and clinical validation of claimed therapeutic indication. DR appears to be a viable approach and is likely to offer effective treatment at a reasonable cost in alleviating acne.
... It modulates skin homeostasis by influencing key signaling pathways involved in skin cell proliferation and differentiation. Also, it has demonstrated efficacy in regulating the production of sebum in sebocytes and in reducing inflammation in keratinocytes, making it a promising candidate for the treatment of acne vulgaris and other inflammatory skin conditions [19,20]. Previous Int. ...
... Keratinocytes are the predominant cell type in the epidermis and play a key role in the skin's response to injury and inflammation. Cannabinoid research shows that pCBs enhance keratinocyte migration and modulate cytokine production, exerting anti-inflammatory effects and restoring the skin barrier [1,20]. This migration is a vital step in the re-epithelialization process during wound repair, thus restoring the skin's barrier function. ...
Recent advancements have highlighted the potential of cannabis and its phytocannabinoids (pCBs) in skin health applications. These compounds, through their interaction with the endocannabinoid system (ECS), show promise for skin health products. Their ability to regulate inflammation, oxidative stress and cell proliferation makes them useful in addressing skin problems such as inflammation, scarring, healing, acne and aging, positioning them as valuable tools for innovative skincare solutions. In the present work, the cellular and molecular effects of proprietary pCB-based formulations on ECS modulation, inflammation and skin regeneration were investigated. Using human dermal fibroblasts (HDF) and keratinocytes (HaCaT), the effect of formulations in both pre-treatment and treatment scenarios following exposure to stress-inducing agents was assessed. Key molecular markers were analyzed to tackle their efficacy in mitigating inflammation and promoting structural integrity and regeneration. In vitro results showed that these formulations significantly reduced inflammation, promoted skin regeneration and improved structural functions. In vivo studies confirmed that the formulations were well-tolerated and led to noticeable improvements in skin health, including enhanced barrier function. This study demonstrates the safety and efficacy of pCB-based formulations for cosmeceutical applications. By combining molecular analysis with in vivo testing, this research provides new insights into the therapeutic potential of pCBs for managing various skin conditions.
... It is worth pointing out that in patients with psoriasis, when there is an increase in oxidative stress in granulocytes and serum, CBD tends to increase the oxidative status, which may suggest its potential use as an antioxidant [43,79,80]. Another impact of CBD, which has an anti-inflammatory effect, suggests its usefulness in acne treatment [81,82]. Studies show that CBD was able to inhibit excessive lipid synthesis (lipogenesis) in sebocyte cultures and reduce concentrations of inflammatory cytokine TNF-α [81,82]. ...
... Another impact of CBD, which has an anti-inflammatory effect, suggests its usefulness in acne treatment [81,82]. Studies show that CBD was able to inhibit excessive lipid synthesis (lipogenesis) in sebocyte cultures and reduce concentrations of inflammatory cytokine TNF-α [81,82]. ...
This review provides an overview of cannabis-based phytocannabinoids, focusing on their mechanisms of action, therapeutic applications, and production processes, along with the environmental factors that affect their quality and efficacy. Phytocannabinoids such as THC (∆⁹-tetrahydrocannabinol), CBD (cannabidiol), CBG (cannabigerol), CBN (cannabinol), and CBC (cannabichromene) exhibit significant therapeutic potential in treating various physical and mental health conditions, including chronic pain, epilepsy, neurodegenerative diseases, skin disorders, and anxiety. The cultivation of cannabis plays a crucial role in determining cannabinoid profiles, with indoor cultivation offering more control and consistency than outdoor methods. Environmental factors such as light, water, temperature, humidity, nutrient management, CO2, and the drying method used are key to optimizing cannabinoid content in inflorescences. This review outlines the need for broader data transfer between the health industry and technological production, especially in terms of what concentration and cannabinoid ratios are effective in treatment. Such data transfer would provide cultivators with information on what environmental parameters should be manipulated to obtain the required final product.
... TRPV4 activation interfered with the pro-lipogenic ERK1/2 MAPK pathway, leading to the down-regulation of nuclear receptor interacting protein-1 and subsequent inhibition of sebocyte lipogenesis. Additionally, CBD exerted anti-inflammatory actions via A 2A adenosine receptor-dependent up-regulation of tribbles homolog 3 and inhibition of the NF-κB signaling pathway [83]. In addition to excessive sebaceous gland activity, a skin microbiome imbalance may mediate the pathogenesis of acne. ...
... A recent study also demonstrated that CBD selectively killed a subset of Gram-negative bacteria, supporting the anti-microbial properties of CBD [86]. Regarding the concentration of CBD, Oláh et al. showed that CBD significantly reduced the overall proliferation of sebocytes at 1-10 μM doses, while higher doses of CBD (50 μM) resulted in apoptosis-driven cytotoxicity [83]. A recent study by Cohen et al. also examined the effect of CBD at different concentrations (0.3125-10 µg/mL) on C. acnes growth and demonstrated that concentrations of 5 and 10 μg/mL of CBD specifically attenuated C. acnes growth [87]. ...
Cannabidiol (CBD) is a non-psychotropic cannabinoid with multiple pharmacological properties. Cannabidiol has attracted growing attention in the cosmetic industry, with an increasing number of CBD-containing skincare products on the market in recent years. The aim of this review is to evaluate the current evidence on the use of CBD for cosmetic purposes. Following an overview of CBD and the endocannabinoid system in the skin, we summarize pre-clinical and clinical studies that address the potential of CBD in cosmetic dermatology. Available in vitro and in vivo evidence suggests that CBD has anti-oxidant, anti-inflammatory, moisturizing, anti-acne, wound-healing, and anti-aging properties. However, only a few clinical studies have been conducted on the use of CBD in the skin. In addition, there is a critical need to develop an efficient drug-delivery system for topical/transdermal application of CBD. Further research, including clinical and pharmacokinetic studies, are needed to fully evaluate the role of CBD in cosmetic dermatology.
... This unique lipid-modulating effect is significant, as sebum overproduction is a hallmark of acne and contributes to pore blockages. Previous study on cultured human sebocytes demonstrated that activating transient receptor potential vanilloid-4 (TRPV4) ion channels resulted in the downregulation of nuclear receptor interacting protein-1 (NRIP1), which influences glucose and lipid metabolism [6]. While there isn't a direct and well-established p-ERK, phosphorylated ERK. ...
... The data presented in this study are available on request from the corresponding author. LPS-induced acne-like context exhibited decreased levels of TNF-α, IL-1β, and IL-6 [6]. ...
Cannabidiol (CBD), which is derived from hemp, is gaining recognition because of its anti-inflammatory and lipid-modulating properties that could be utilized to treat acne. We conducted experiments to quantitatively assess the effects of CBD on acne-related cellular pathways. SEB-1 sebocytes and HaCaT keratinocytes were exposed to various CBD concentrations. CBD exhibited a concentration-dependent impact on cell viability and notably reduced SEB-1 viability; furthermore, it induced apoptosis and a significant increase in the apoptotic area at higher concentrations. Additionally, CBD remarkably reduced pro-inflammatory cytokines, including CXCL8, IL-1α, and IL-1β. Additionally, it inhibited lipid synthesis by modulating the AMPK-SREBP-1 pathway and effectively reduced hyperkeratinization-related protein keratin 16. Simultaneously, CBD stimulated the synthesis of elastin, collagen 1, and collagen 3. These findings emphasize the potential of CBD for the management of acne because of its anti-inflammatory, apoptotic, and lipid-inhibitory effects. Notably, the modulation of the Akt/AMPK-SREBP-1 pathway revealed a novel and promising mechanism that could address the pathogenesis of acne.
... In vitro study on cultured human sebocytes [32] UV photoprotection Cytoprotection after the UVA irradiation of the cells Primary cultures of human skin fibroblasts and the immortalized human keratinocyte cell line (HaCaT) [10] moisturizing effect Increase in expression of aquaporin-3, which contributes to skin water retention ...
... Moreover, anti-inflammatory activity can be explained by binding to A2a receptors, activating the production of cAMP, and, consequently, inhibiting the NF-κB pathway. Also, CBD can suppress sebocyte proliferation by activating transient receptor potential vanilloid-4 (TRPV4) ion channels and by downregulating nuclear receptor interacting protein-1 (NRIP1) [32]. The vitality of sebocytes can be changed by smaller doses of phytocannabinoids (up to 10 µm), while higher doses (≥50 µm) can lead to sebocyte apoptosis [38]. ...
Known for its natural bio-compounds and therapeutic properties, hemp is being utilized in the development of skin products. These products offer a wide range of applications and benefits in the fields of natural bio-compounds, pharmaceutical technology, topical delivery systems, and cosmeceuticals. This manuscript deals with hemp actives, such as cannabinoids, terpenes, and flavonoids, and their diverse biological properties relative to topical application, including anti-inflammatory, antimicrobial, and antioxidant effects. Also, the paper reviews strategies to overcome poor penetration of hemp actives, as well as the integration of hemp actives in cosmeceuticals that provide natural and sustainable alternatives to traditional skincare products offering a range of benefits, including anti-aging, moisturizing, and soothing properties. The review aims to provide a comprehensive understanding of the development and manufacturing processes of skin products containing hemp actives. By delving into the science behind hemp-based products, the paper provides valuable insights into the potential of hemp as a versatile ingredient in the pharmaceutical and cosmetic industries. The utilization of hemp in these innovative products not only offers therapeutic benefits but also promotes natural and sustainable approaches to skincare.
... Specifically, CBD exhibits sebostatic properties, effectively inhibiting the lipogenic actions of compounds like arachidonic acid and a combination of linoleic acid and testosterone. It also suppresses sebocyte proliferation through the activation of transient receptor potential vanilloid-4 (TRPV4) ion channels [301][302][303][304][305]. Given these properties, CBD is a promising candidate for the treatment of acne. ...
... [ [299][300][301][302][303][304][305] Biologic treatments (e.g., TNF-α inhibitors like adalimumab; IL-17 and IL-23 inhibitors like secukinumab) ...
Acne vulgaris is a common dermatological condition that can present across different ages but predominantly affects adolescents and young adults. Characterized by various lesion types, the pathogenesis of acne is complex, involving genetic, hormonal, microbial, and inflammatory factors. This review comprehensively addresses current and emerging acne management strategies, emphasizing both topical and systemic treatments, procedural therapies, and dietary modifications. Key topical agents include retinoids, benzoyl peroxide, antibiotics, and other specialized compounds. Systemic options like antibiotics, hormonal therapies, and retinoids offer significant therapeutic benefits, particularly for moderate to severe cases. Procedural treatments such as laser devices, photodynamic therapy, chemical peels, and intralesional injections present viable alternatives for reducing acne symptoms and scarring. Emerging therapies focus on novel biologics, bacteriophages, probiotics, and peptides, providing promising future options. This review underscores the importance of personalized approaches to treatment due to the multifaceted nature of acne, highlighting the potential of innovative therapies for improving patient outcomes.
... Recently, CBD has also attracted the attention of the cosmetic industry, mainly due to its anti-inflammatory, analgesic, hydrating, moisturizing, and wrinkle-reducing properties [15]. CBD also acts as a sebostatic agent, inhibiting the proliferation of sebocytes and sebum, making it a promising therapeutic agent for the treatment of acne vulgaris [16]. ...
... Because of its many uses and applications, researchers have focused on the thermal and photochemical stability of cannabinoids. The first attempt at photochemical studies on CBD is to be attributed to Loewe in 1950 [16], which was followed by a serial of seminal papers by Shani and Mechoulam [17]. The nature of the products resulting from the UVinduced decomposition of CBD has recently been discussed [6,18,19] and its possible photochemical conversion into Δ 9 -THC is a moot point. ...
THC, the psychotropic cannabinoid in Cannabis sativa L., for many years has been the focus of all the pharmacological attention as the main promising principle of the plant. Recently, however, cannabidiol (CBD) has brought a sudden change in the scenario, exponentially increasing the interest in pharmacology as the main non-psychotropic cannabinoid with potential therapeutic, cosmetical and clinical applications. Although the reactivity of CBD and Δ ⁹ - THC has been considered, little attention has been paid to the possible photodegradation of these cannabinoids in the vegetal matrix and the data available in the literature are, in some cases, contradictory. The aim of the present work is to provide a characterization of the photochemical behaviour of CBD and Δ ⁹ - THC in three cannabis chemotypes, namely I (Δ ⁹ - THC 2.50% w/w ), II (CBD:Δ ⁹ - THC 5.82% w/w :3.19% w/w ) and III (CBD 3.02% w/w ).
Graphical abstract
... As mentioned above, phytocannabinoids were shown to greatly influence biological activity of various skin cells, including epidermal keratinocytes and sebocytes 16,[44][45][46][47] . Thus, we decided to investigate two lead compounds in each group (CBD derivatives: 8 and 9; CBG derivatives: 16a and 21b) along with the respective mother molecules Table 2). ...
... likely due to the aforementioned cytotoxic effect (Fig. 6c). Notably, in a perfect agreement with our previously reported data 44 , CBD could completely prevent the lipogenic effect of the "acne-mimicking" pro-inflammatory lipid mediator arachidonic acid (AA) 48,51 (Fig. 7b). Importantly, both compounds 8 and 9 could mimic this www.nature.com/scientificreports/ ...
Cannabidiol (CBD) and (−)-cannabigerol (CBG) are two major non-psychotropic phytocannabinoids that have many beneficial biological properties. However, due to their low water solubility and prominent first-pass metabolism, their oral bioavailability is moderate, which is unfavorable for medicinal use. Therefore, there is a great need for appropriate chemical modifications to improve their physicochemical and biological properties. In this study, Mannich-type reaction was used for the synthetic modification of CBD and CBG for the first time, and thus fifteen new cannabinoid derivatives containing one or two tertiary amino groups were prepared. Thereafter the antiviral, antiproliferative and antibacterial properties of the derivatives and their effects on certain skin cells were investigated. Some modified CBD derivatives showed remarkable antiviral activity against SARS-CoV-2 without cytotoxic effect, while synthetic modifications on CBG resulted in a significant increase in antiproliferative activity in some cases compared to the parent compound.
... Targeting neuronal pathways to improve ceramide synthesis, Certain neuropeptides, such as skinasensyl, have been shown to stimulate the production of barrier lipids, which include ceramides [27]. Regulation of neurotransmitters to control sebum's activity, Compounds that interact with the human endocannabinoid system, like cannabidiol, were found to regulate sebum's production and improve the appearance of acne-prone skin [28]. Neuropeptides like copper tripeptide-1 Glycyl Histidyl Lysine-Cu (GHK-Cu), have been shown to improve skin hydration and reduce transepidermal water loss by promoting glycosaminoglycan production [29]. ...
The review on this fast-evolving field of neuro cosmetics, at the intersection of neuroscience and cosmetic science, has interestingly led to innovative skincare treatment approaches. The paper progresses from a basic discovery of neurogenic inflammation made by substance P in 1996 the more recent skin-brain axis of 2015 to its applications. The review focuses on neurotransmitters such as acetylcholine and serotonin, neuropeptides such as substance P and Calcitonin Gene-Related Peptide (CGRP), and the neuroendocrine cells, Merkel, and Langerhans cells, to achieve skin homeostasis, inflammation control, and aging. The article looks at neurocosmetic applications such as anti-aging, skin barrier enhancement, and pigmentation management to active ingredients such as acetyl hexapeptide-8, niacinamide, and cannabidiol. Also reviewed are delivery systems including nanoencapsulation, microneedle technology, and iontophoresis in enhancing bioavailability and penetration of neuroactive compounds. A meta-analysis of clinical trials is shown. One study, which lasted up to 24 w, registered a 27% decrease in wrinkles and an 18% increase in elasticity with the peptide complex; the second one described a 45% decrease in rosacea erythema with Alpha-Melanocyte Stimulating Hormone (α-MSH) and Transient Receptor Potential Vanilloid (TRPV1) antagonists. In this review, emerging areas for future research are AI-driven personalized neurocosmetics, interventions of the gut-brain-skin axis, chronocosmetics, epigenetic modulation, smart nanocarriers, and bioelectronic skin therapies. Safety and regulatory issues that arise are commented on, emphasizing long-term studies and standardized approaches. The review is apt for any researcher or dermatologist looking for a comprehensive overview of how neurocosmetics hold transformative promise in topical peptide formulations.
... Anti-acne phytochemicals such as curcumin [117], quercetin [118], curcuminoids [119], neem oil [74], α-terpineol [120], cannabidiol [121] and cinnamon oil [122] were loaded for improving skin permeation, drug solubility and stability enhancement properties in the topical treatments of skin acne. ...
... However, there are few reports concerning the clinical application of endocannabimimetics as cosmetic ingredients. Based on previous studies suggesting the therapeutic benefits of CBD or hemp seed-derived cannabinoids on acne [18,23,24], the clinical efficacy of sunflower oil 1-aminopropanol amide on skin function was assessed in healthy volunteers with acne-prone skin. The participants were administered 0.1% of sunflower oil 1-aminopropanol amide-containing cream product on the facial and volar arm areas once a day for 4 weeks. ...
Despite the potential benefits of cannabidiol as a skin-soothing ingredient, its regulatory status hampers its general use in cosmetic products in many countries. To develop an alternative to cannabidiol, fatty acid amide molecules mimicking the chemical structure of endocannabinoids were manufactured using a lipase-catalyzed process. A mixture of fatty acid amides from sunflower oil and 1-amino propan-3-ol was synthesized using an immobilized lipase reaction, and the activation of cannabinoid receptor 1 (CB1R) was measured using a cAMP assay. The anti-inflammatory activity of the endocannabimimetic ingredients was evaluated in cultured human monocytes and ex vivo human skin explant models. A clinical study was conducted to address the skin hydration, skin barrier function, and skin redness, and the ratio of the interleukin-1-receptor antagonist (IL1-RA) to IL-1⍺ in corneocytes, as a marker for skin sensitivity, were also measured. As a result, the activation of CB1R by endocannabimimetic ingredients was observed in cAMP assays, and a reduction in inflammatory responses by human monocytes induced by lipopolysaccharide treatment were also observed. External stress-induced inflammatory responses were reduced in ex vivo human skin explants. Improvements in skin hydration and barrier function were observed in a clinical study. A significant decrease in skin redness and the IL-1RA to IL-1⍺ ratio was also observed. Endocannabimimetic ingredients, as alternatives to cannabidiol, can be used in skin-soothing cosmetics to increase skin hydration, improve skin barrier function, and reduce skin sensitivity.
... En 2016, Oláh y colaboradores estudiaron la influencia de distintos fitocannabinoides como el cannabidiol (CBD), cannabicromeno (CBC), cannabidivarina (CBDV), tetrahidrocannabivarina (THCV), cannabigerol (CBG) y cannabigerovarina (CBGV) sobre una línea celular de sebocitos (SZ95), reportando efectos sobre la lipogénesis en estas células (Figura 4), agrupándose de la siguiente manera (Oláh et al., 2016): el CBG y el CBGV fueron considerados como "pro-lipogénicos", el CBDV como "neutrales" ya que no causaba una diferencia significativa en la producción de lípidos con respecto al grupo control. Por su parte el cannabicromeno (CBC) y la tetrahidrocannabivarina (THCV) mostraron efectos "lipostáticos" (ver Tabla 2) (Nast et al., 2016;Oláh et al., 2016): Otro estudio realizado por Oláh y colaboradores en 2014, mostró que la administración de CBD en sebocitos SZ95 presentó un efecto sebostático, antiinflamatorio y antiproliferativo sobre este tipo celular (Oláh et al., 2014). ...
El acné es una afección compleja que afecta a millones de personas en todo el mundo, está constituida por unidades pilosebáceas de la piel y aparece tanto en forma inflamatoria como no inflamatoria. Dada su naturaleza multifactorial, el tratamiento del acné a menudo implica una variedad de terapias integrales, que pueden aumentar los costos. Objetivo: realizar una investigación teórica sobre la fisiopatología del acné y sus características para enfocar dicho conocimiento en el establecimiento de nuevas dianas terapéuticas como el sistema endocannabinoide que mejore el entendimiento para el desarrollo potencial de tratamientos más efectivos contra este padecimiento. Métodos. Se utilizaron plataformas para la búsqueda de la información, considerando algunas palabras clave como: "Endocannabinoid System", "sebaceous glands" and "acne vulgaris". Resultados: Se encontraron alrededor de 3,242 artículos, en el buscador de PubMed, "Acne vulgaris" (1,588), "Endocannabinoid System" (812), "sebaceous glands" (842). En el Google schoolar, se encontraron alrededor de 199,000, 93,800 y 135,000 artículos respectivamente. Los principales hallazgos mencionan que entre los años 1990 – 2022, los estudios epidemiológicos en Europa y Reino Unido mostraron prevalenciea de la cepa Cutibacterium acnes resistente a distintos antibióticos como la eritromicina y clindamicina, siendo los sebocitos, queranocitos cutáneas y mastocitos, las células que presentan componentes del sistema endocannabinoide; reportándose algunos cannabinoides con efecto sobre la lipogénesis de éstas células. Conclusión: El sistema endocannabinoide se considera una diana terapéutica potencial para el tratamiento del acné debido a que las glándulas sebáceas muestran relación con este sistema, presentando efectos antiinflamatorios y antiproliferativos sobre células dérmicas. Millions of people worldwide suffer from acne, a complicated disorder that can be either inflammatory or non-inflammatory and affects the skin's pilosebaceous units. Because acne is complex, treating it frequently entails using a range of integrative therapies, which might raise expenses. Aim: To conduct theoretical research on acne pathophysiology and its features to concentrate that knowledge on identifying novel therapeutic targets, such as the endocannabinoid system, which advances our understanding of the condition and may lead to the creation of more potent treatments. Methods: Information was found using platforms that took into account keywords like "Endocannabinoid System," "sebaceous glands", and "acne vulgaris". Findings: The PubMed search engine yielded about 3,242 articles about "Acne vulgaris" (1,588), "Endocannabinoid System" (812), and "sebaceous glands" (842). Google Scholar yielded about 199,000, 93,800, and 135,000 articles, respectively. The main findings mention that between the years 1990 - 2022, epidemiological studies in Europe and the United Kingdom showed the prevalence of Cutibacterium acnes strain resistant to different antibiotics such as erythromycin and clindamycin, with sebocytes, skin keranocytes and mast cells being the cells that present components of the endocannabinoid system. Therefore, some cannabinoids have been reported to affect the lipogenesis of these cells. Conclusion: Because of its association with the sebaceous glands and its anti-inflammatory and antiproliferative effects on dermal cells, the endocannabinoid system is thought to be a promising therapeutic target for acne treatment.
... Estudos sobre acne buscam ativos dermatológicos que possam atuar em suas múltiplas etapas patogênicas, como a superprodução de sebo, a proliferação de sebócitos e a inflamação, sem causar efeitos colaterais durante o tratamento (Oláh et al., 2014). A descoberta de novas propriedades biológicas e farmacológicas dos canabinoides tópicos sugere indicações terapêuticas para a pele, com base na capacidade desses compostos de modular a resposta inflamatória, demonstrando eficácia no tratamento de diversas condições dermatológicas, incluindo a acne (Casiraghi et al., 2020). ...
A acne é uma condição inflamatória multifatorial, com prevalência significativa, associada à atividade da bactéria Cutibacterium acnes. Esse estudo revisa o potencial sebostático, anti-inflamatório e antimicrobiano do canabidiol (CBD) no tratamento dessa condição. A revisão integrativa da literatura foi realizada nas bases SciELO, PubMed e ScienceDirect, com artigos publicados entre 2008 e 2024. Foram selecionados 12 estudos que investigam o CBD e seus efeitos na produção de sebo, inflamação e controle de C. acnes. Resultados sugerem que o CBD atua como modulador do sistema endocanabinoide, influenciando a produção de sebo e a resposta inflamatória por meio da inibição de vias de sinalização como Proteína Cinase Ativada por Mitógenos (MAPK) e Fator Nuclear kappa B de realce de cadeias leves em linfócitos B ativados (NF-κB), além de modular receptores como Receptor Canabinoide 2 (CB2R) e Receptor Potencial Transitório Vaniloide 1 (TRPV1). Esses efeitos reduzem a proliferação de sebócitos e a inflamação associada à acne. Embora os estudos in vitro e in vivo apresentem resultados promissores, evidências clínicas são limitadas. No entanto, cremes tópicos com CBD mostraram melhorias significativas em pacientes com acne. Conclui-se que o CBD possui potencial terapêutico como agente sebostático e anti-inflamatório no tratamento da acne, com necessidade de mais ensaios clínicos para confirmar sua eficácia.
... Furthermore, CBD has been shown to modulate the formation of neutrophil extracellular traps (NETs), contributing to psoriatic inflammation [5]. While CBD's antiinflammatory effects are well-documented, such as its ability to regulate oil-producing sebocytes [6], its broader role in managing skin conditions like psoriasis is promising. One study emphasized CBD's capacity to modulate TH1 and TH2 cytokine profiles, which are central in psoriasis pathology [2]. ...
Psoriasis, a chronic inflammatory skin condition, has traditionally been managed with topical and systemic therapies, but emerging interest in alternative treatments has highlighted the potential of Cannabidiol (CBD) oil. This comprehensive analysis explores the efficacy of CBD oil as an adjunct therapy for psoriasis, investigating its anti-inflammatory and immunomodulatory mechanisms. The novelty of this research lies in its multi-faceted approach, combining clinical trials, in vitro studies, and biochemical analyses to understand further how CBD oil interacts with psoriasis pathology, including its effects on keratinocyte proliferation and cytokine release. Findings indicate that CBD oil may offer significant benefits in reducing psoriatic lesions and improving patient-reported outcomes, potentially through modulation of the endocannabinoid system and suppressing proinflammatory pathways. However, regulatory challenges, including variability in product quality and legal restrictions, present hurdles for broader implementation. Future research should focus on standardizing CBD formulations, establishing optimal dosages, and addressing regulatory barriers to integrating CBD oil into mainstream psoriasis treatment protocols. CBD oil holds promise as a valuable adjunct therapy for psoriasis, offering a novel mechanism of action and the potential for enhanced management of this complex condition.
... 103 The antioxidant and anti-inflammatory activity of CBD is regulated via NF-E2-related factor 2 (Nrf2)-target genes, including Heme Oxygenase 1 (HMOX1) but via a mechanism independent of Nrf2. 104 On the other hand, retinol tends to suppress the expression of Nrf2-target antioxidative genes. 105 By incorporating CBD, there is a potential to restore the antioxidative effects that may be inhibited by retinol, while still retaining the skin-strengthening properties. ...
Background
Retinoids, defined as synthetic or natural derivatives of vitamin A, have been extensively studied as anti‐aging molecules that are widely applied in cosmetics. However, due to their physicochemical property, retinoids are highly unstable and extremely sensitive to light, oxygen, and temperature. Moreover, topical application of retinoids often leads to cutaneous irritation. These instabilities and irritant properties of retinoids limit their application in cosmetic and pharmaceutical products.
Aim
Our study aimed to provide a systematic review to summarize the mechanisms underlying the instability and irritant properties of retinoids, as well as recent developments in addressing these challenges.
Methods
A comprehensive PubMed search was conducted using the following keywords: retinoids, chemical instability, skin irritation, retinoid derivatives, nano lipid‐based carriers, liposomes, penetration‐enhancer vesicles, ethosomes, niosomes, nanoemulsions, solid lipid nanoparticles, vitamins, soothing and hydrating agents, antioxidants and metal chelator and retinol combinations. Relevant researches published between 1968 and 2023 and studies related to these reports were reviewed.
Results
The development of new retinoid derivatives, the utilization of new delivery systems like nano lipid‐based carriers and the combination with other compounds like vitamins, soothing agents, antioxidants and metal chelator have been explored to improve the stability, bioavailability, and toxicity of the retinoid family.
Conclusions
Through advancements in formulation techniques, structure modification of retinoid derivatives and development of novel nano lipid‐based carriers, the chemical instability and skin irritation of retinoids has been mitigated, ensuring their efficacy and potency over extended periods.
... It has been shown to modulate the Wnt/β-catenin pathway, which is crucial for regulating keratinocyte proliferation and differentiation. 63 CBD can also affect mitogen-activated protein kinase (MAPK) signaling pathways, including the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK pathways, which are involved in keratinocyte proliferation and inflammation. 57 Furthermore, CBD's impact on epigenetic regulation, such as histone modifications and DNA methylation, may contribute to the modulation of keratinocyte functions. ...
Psoriasis is a chronic skin condition that can significantly impact the quality of life of those affected. As an autoimmune disease, it can lead to itchy, painful, and scaly patches on the skin. Although various treatments, including topical creams, phototherapy, and systemic medications, are currently available, they may not always offer effective relief and can have side effects. Researchers have thus been exploring the potential benefits of non-psychoactive compounds such as CBD, found in Cannabis sativa plants, for treating psoriasis. CBD treatment may reduce inflammation, oxidative stress, itching, abnormal proliferation of keratinocytes, and may increase hydration. This review aims to provide an overview of the existing literature on the potential uses of CBD for psoriasis treatment.
... Whether cannabinoids have the same effect is currently unknown but as de- PRL has been demonstrated in mice (74,129,130), and a similar effect was observed af- have shown both a reduction of circulating PRL levels (127) and no clear trends (128) 430 after THC administration. ...
Cannabis use has increased sharply in the last 20 y among adults, including reproductive-aged women. Its recent widespread legalization is associated with a decrease in risk perception of cannabis use during breastfeeding. However, the effect of cannabis use (if any) on milk production and milk composition is not known. This narrative review summarizes current knowledge related to maternal cannabis use during breastfeeding and provides an overview of possible pathways whereby cannabis might affect milk composition and production. Several studies have demonstrated that cannabinoids and their metabolites are detectable in human milk produced by mothers who use cannabis. Due to their physicochemical properties, cannabinoids are stored in adipose tissue, can easily reach the mammary gland, and can be secreted in milk. Moreover, cannabinoid receptors are present in adipocytes and mammary epithelial cells. The activation of these receptors directly modulates fatty acid metabolism, potentially causing changes in milk fatty acid profiles. Additionally, the endocannabinoid system is intimately connected to the endocrine system. As such, it is probable that interactions of exogenous cannabinoids with the endocannabinoid system might modify release of critical hormones (e.g., prolactin and dopamine) that regulate milk production and secretion. Nonetheless, few studies have investigated effects of cannabis use (including on milk production and composition) in lactating women. Additional research utilizing robust methodologies are needed to elucidate whether and how cannabis use affects human milk production and composition.
... Também é sabido que o CBD pode ser absorvido por via transcutânea, o que é consistente com a observação de que a pele humana possui receptores nativos para canabinoides. Os canabinoides como o CBD, portanto, são uma grande promessa para o tratamento de problemas de pele como acne e eczema e outras condições relacionadas, conforme mostram os resultados apontados no estudo (Oláh et al., 2014). São fornecidas composições formuladas como cremes, pomadas, soros ou loções para uso em cuidados com a pele, particularmente como cremes antienvelhecimento, antirrugas e hidratantes. ...
A Cannabis sativa produz uma variedade de metabólitos secundários com potenciais usos farmacológicos, como antisséptico e anti-inflamatório. Além disso, produtos derivados dessa planta são comumente utilizados em cosméticos. Este artigo teve como objetivo realizar uma análise de patentes relacionadas a cosméticos à base de Cannabis sativa, buscando identificar as principais tendências e inovações nessa área. Foram realizadas buscas em bases de dados como WIPO, INPI, USPTO e Espacenet, utilizando termos como "Cannabis ", "indústria cosmética", "cosmético" e "produtos de cuidado pessoal". Foram identificadas 33 patentes relacionadas a formulações cosméticas para cuidados com a pele, cabelo, maquiagem e unhas. A China foi o país com o maior número de patentes depositadas (45%). Essas patentes demonstram o potencial da Cannabis sativa como ingrediente ativo em cosméticos, oferecendo novas possibilidades de produtos ao mercado.
... CBD suppressed lipogenesis in sebocytes, and these sebostatic actions of CBD are mediated by the TRPV4 ion channel. Also, they found that the downstream signaling pathway is the ERK 1/2 MAPK pathway, which is a prolipogenic signaling pathway in sebocytes ( Figure 5) [65]. ...
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.
... ábra) (6). Ennek további feltárása és az erre épülő lehetséges terápiás megoldások azonosítása (85,86) kétséget kizáróan további érdekes eredményeket rejt felvetve, hogy a pattanásos bőr kezelésén túl további gyulladásos bőrbetegségek is befolyásolhatóak lehetnek a faggyúmirigy működésének modulálásán keresztül. ...
Sebaceous glands are not only producing lipids to contribute to the lipid barrier but are important in maintaining the homeostasis of the skin as well, which is greatly related to their immune competence. Our aim with this review is to present key studies on their possible involvement in inflammation and their crosstalk with various cell types of the immune system that altogether led to the introduction of “sebaceous-immunobiology” as a novel field in dermatology. With a focus on diseases considered to be related to sebaceous glands, such as acne, rosacea, seborrheic dermatitis, atopic dermatitis, psoriasis, lichen planopilaris, eosinophilic pustular folliculitis, and hidradenitis suppurativa, we also aim to put forward that sebaceous glands are not only innocent bystanders but active contributors in disease development.
... TRPV4 is expressed in different cells, including sensory neurons and endothelial, immune, and epithelial cells, and it contributes to different physiological processes [9,10]. Although TRPV4 is involved in different skin diseases, such as barrier-related conditions, acne, rosacea, and different types of malignant tumors [11][12][13][14], its role in cutaneous wound healing is unclear. Recent reports have shown that TRPV4 is involved in cell migration ability and fibroblasts proliferation and differentiation, which are important for wound healing [6,15,16]. ...
... [11][12][13][14] Modulation of the activity of the ECS may influence several types of skin disease, including atopic dermatitis, psoriasis, acne and skin tumours, according to the aetiology of the diseases. [15][16][17][18] Furthermore, cannabis has been found to possess anti-inflammatory and anti-pruritic properties, 13 19-21 as well as a few more uncommon ones like antihydrosis. 22 This makes the cannabinoids and ...
Introduction
Following the discovery of various effects on skin function by modifying endocannabinoid systems, multiple preclinical studies have revealed the promise of cannabis and cannabinoids in the treatment of a variety of skin diseases. However, its clinical efficacy is still debated.
Methods and analysis
The protocol has been prepared using the Preferred Items for Systematic Review and Meta-analysis Protocols guidelines. A systematic search will be conducted using PubMed, EMBASE, SCOPUS, the Cochrane Central Register of Controlled Trials and Web of Science. We will include randomised controlled trials and observational studies investigating alterations to dermatological characteristics following administration of cannabis and cannabinoids for dermatological diseases and disorders. The two reviewers will perform both the title and abstract and full-text screenings. The Cochrane Risk-of-Bias 2 and ROBINS-1 tools will be used to evaluate the risk of bias. If a group of comparable studies for each quantitative outcome can be discovered, we will conduct a random effects meta-analysis. We will investigate heterogeneity using a combination of visual inspection of the forest plot, the Cochran’s Q test and Higgins’ test [I2]. Sensitivity analyses will be performed to assess the statistical robustness of the primary outcome. To evaluate a publication bias, the Egger’s regression asymmetry test and funnel plots will be considered.
Ethics and dissemination
This study does not require ethical approval because no original data will be collected. The findings will be presented at conferences and published in peer-reviewed journals.
PROSPERO registration number
CRD42023397189.
Context: Acne is a prevalent inflammatory condition affecting individuals globally, particularly during adolescence, and has a significant psychosocial impact. Its pathogenesis involves sebaceous hypersecretion, follicular hyperkeratinization, and microbial dysbiosis, primarily associated with Cutibacterium acnes. Conventional acne treatments, including topical and systemic therapies, often cause adverse effects, highlighting the need for new, safer options. Cannabidiol (CBD), a non-psychoactive compound from Cannabis sativa, has emerged as a promising candidate due to its anti-inflammatory and antioxidant properties. This review discusses acne pathophysiology and examines CBD's therapeutic potential alongside global regulatory perspectives on its use in cosmetics. Evidence Acquisition: A literature search was conducted for articles on acne pathogenesis, endocannabinoid systems, and CBD's pharmacological effects. Results: Acne’s inflammatory nature is driven by androgen-induced sebum production, follicular hyperkeratinization, and microbial imbalance, mainly involving C. acnes. Androgens activate receptors in sebaceous glands, increasing sebum production and contributing to pore blockages and inflammatory responses. Although effective, conventional treatments such as retinoids and antibiotics often have undesirable side effects, driving interest in plant-based alternatives. The CBD shows potential as an acne treatment by modulating inflammation through CB2 receptor and TRPV1 channel activation, which directly helps reduce the inflammatory response that contributes to acne severity. It also reduces sebocyte proliferation, addressing the hyperkeratinization that leads to clogged pores, and inhibits cytokines like TNF-α, reducing the inflammatory processes that exacerbate acne lesions. The CBD also acts as an antioxidant, mitigating oxidative stress associated with acne-related inflammation. Furthermore, CBD’s lipophilic nature facilitates its accumulation in the stratum corneum, enabling prolonged skin interaction with minimal systemic absorption. A review of regulations reveals varying levels of acceptance for CBD in cosmetics, with North America and Europe allowing its use under specific guidelines, while restrictions remain stricter in other regions. Conclusions: The CBD represents a multi-targeted, safer alternative for acne management, addressing key mechanisms of acne pathogenesis, such as inflammation, sebocyte activity, and oxidative stress, without the adverse effects of conventional treatments. Further studies are necessary to validate these findings in clinical settings and establish standardized guidelines for the safe inclusion of CBD in skincare products.
Ovarian cancer (OC) is the most deadly gynecological tumor. OC cells utilize cellular metabolic reprogramming to gain a survival advantage, particularly through aberrant lipid metabolic process. As the primary ingredient in exogenous cannabinoids, cannabidiol (CBD) has been shown to exert anticancer effects in several cancers. However, it is still unclear whether CBD can disrupt fatty acid metabolism and induce apoptosis in OC cells. In this study, we have demonstrated that CBD significantly inhibits the proliferation of OCs through a dependence on cannabinoid receptor type 1 (CB1R). Lipidomics and flow cytometry analysis revealed that CBD has the ability to decrease fatty acid levels and significantly suppress the transcription of genes involved in fatty acid uptake and synthesis in ES-2 cells. In addition, the analysis from RNA-seq and real-time RT-PCR revealed that CBD activated the endoplasmic reticulum (ER) stress pathway. Conversely, by supplementation with unsaturated fatty acid or blocking CB1R, ER stress or reactive oxygen species (ROS) signals with specific inhibitors could significantly relieve CBD induced a dose-dependent ER stress associated apoptosis, G0-G1 phase arrest, and mitochondrial dysfunction. Taken collectively, these data indicate that CBD may disrupt lipid metabolism, and lead to ER stress-related apoptosis in OCs. Our findings may provide a theoretical mechanism for anti-ovarian cancer using CBD.
Cannabinol (CBN) is a secondary metabolite of cannabis whose beneficial activity on inflammatory diseases of human skin has attracted increasing attention. Here, we sought to investigate the possible modulation by CBN of the major elements of the endocannabinoid system (ECS), in both normal and lipopolysaccharide‐inflamed human keratinocytes (HaCaT cells). CBN was found to increase the expression of cannabinoid receptor 1 (CB 1 ) at gene level and that of vanilloid receptor 1 (TRPV1) at protein level, as well as their functional activity. In addition, CBN modulated the metabolism of anandamide (AEA) and 2‐arachidonoylglicerol (2‐AG), by increasing the activities of N ‐acyl phosphatidylethanolamines‐specific phospholipase D (NAPE‐PLD) and fatty acid amide hydrolase (FAAH)—the biosynthetic and degradative enzyme of AEA—and that of monoacylglycerol lipase (MAGL), the hydrolytic enzyme of 2‐AG. CBN also affected keratinocyte inflammation by reducing the release of pro‐inflammatory interleukin (IL)‐8, IL‐12, and IL‐31 and increasing the release of anti‐inflammatory IL‐10. Of note, the release of IL‐31 was mediated by TRPV1. Finally, the mitogen‐activated protein kinases (MAPK) signaling pathway was investigated in inflamed keratinocytes, demonstrating a specific modulation of glycogen synthase kinase 3β (GSK3β) upon treatment with CBN, in the presence or not of distinct ECS‐directed drugs. Overall, these results demonstrate that CBN modulates distinct ECS elements and exerts anti‐inflammatory effects—remarkably via TRPV1—in human keratinocytes, thus holding potential for both therapeutic and cosmetic purposes.
Plants and algae play a crucial role in the earth's ecosystems. Through photosynthesis they convert light energy into chemical energy, capture CO2 and produce oxygen and energy-rich organic compounds. Photosynthetic organisms are primary producers and synthesize the essential omega 3 and omega 6 fatty acids. They have also unique and highly diverse complex lipids, such as glycolipids, phospholipids, triglycerides, sphingolipids and phytosterols, with nutritional and health benefits. Plant and algal lipids are useful in food, feed, nutraceutical, cosmeceutical and pharmaceutical industries but also for green chemistry and bioenergy. The analysis of plant and algal lipidomes represents a significant challenge due to the intricate and diverse nature of their composition, as well as their plasticity under changing environmental conditions. Optimization of analytical tools is crucial for an in-depth exploration of the lipidome of plants and algae. This review highlights how lipidomics analytical tools can be used to establish a complete mapping of plant and algal lipidomes. Acquiring this knowledge will pave the way for the use of plants and algae as sources of tailored lipids for both industrial and environmental applications. This aligns with the main challenges for society, upholding the natural resources of our planet and respecting their limits.
Acne is a chronic inflammatory disease of the pilosebaceous unit. Its pathophysiology includes increased secretion of sebum, abnormal follicular keratinization, Propionibacterium acnes proliferation in the pilosebaceous unit and inflammation. In fact, there is much more behind the known pathogenesis that has to be highlighted for better understanding and more successful treatment. Insulin-like growth factor (IGF)-1, diet, vitamin D and stress are some of the factors affecting the sebaceous gland. Cutaneous microbiome equilibrium with dysbiosis, the process leading to a disturbed skin barrier and disequilibrium of the cutaneous microbiome, resulting in the proliferation of P. acnes strains, is another important process that triggers acne. Inflammation and inflammatory products (TNF, IL8 and more) have a different explanations at the pathogenesis.
Polycystic kidney disease (PKD), a disease characterized by enlargement of the kidney through cystic growth is the fourth leading cause of end-stage kidney disease world-wide. TRPV4, a calcium-permeable TRP, channel participates in kidney cell physiology and since TRPV4 forms complexes with another channel whose malfunction is associated to PKD, TRPP2 (or PKD2), we sought to determine whether patients with PKD, exhibit previously unknown mutations in TRPV4. Here, we report the presence of mutations in the TRPV4 gene in patients diagnosed with PKD and determine that they produce gain-of-function (GOF). Mutations in the sequence of the TRPV4 gene have been associated to a broad spectrum of neuropathies and skeletal dysplasias but not PKD, and their biophysical effects on channel function have not been elucidated. We identified and examined the functional behavior of a novel E6K mutant and of the previously known S94L and A217S mutant TRVP4 channels. The A217S mutation has been associated to mixed neuropathy and/or skeletal dysplasia phenotypes, however, the PKD carriers of these variants had not been diagnosed with these reported clinical manifestations. The presence of certain mutations in TRPV4 may influence the progression and severity of PKD through GOF mechanisms. PKD patients carrying TRVP4 mutations are putatively more likely to require dialysis or renal transplant as compared to those without these mutations.
In recent years, there have been significant growth and interest in cannabinoid-based drugs for a wide range of medical conditions, some of which are neurogenic diseases, pain control, and seizures. As there is an increased demand for cannabinoid-based drugs, it is necessary to adapt biotechnological techniques to develop new traits for the sophisticated and selective breeding of Cannabis plants aimed for cannabinoid production.
Despite Biotech companies aspiring to replace cannabis plants with heterologous hosts, genome editing for precision cannabis breeding is yet to be embraced. The availability of genome-editing technologies might herald a new dawn in breeding yielding new varieties with improved profiles of bioactive cannabinoids and terpenes. In this review, we highlight novel breeding approaches such as marker-assisted selection (MAS), mutation breeding, micropropagation, transgenic breeding, and CRISPR/Cas-based editing techniques aimed for enhanced cannabinoid production.
Endocrine disorders can exert major effects on the human skin, leading to different signs and symptoms, including skin dryness, hair loss or excessive hair growth, pruritus, pigmentary changes and hyperhidrosis. This chapter reviews these changes and provides a practical approach to patients with suspected underlying endocrinological disorders. The chapter also discusses the latest findings showing that the skin serves as a complex (neuro‐) endocrine organ by itself, and thus possesses important practical implications for future dermatological therapy.
Background
The treatment of diverse diseases using plant-derived products is actively encouraged. In the past few years, cannabidiol (CBD) has emerged as a potent cannabis-derived drug capable of managing various debilitating neurological infections, diseases, and their associated complications. CBD has demonstrated anti-inflammatory and curative effects in neuropathological conditions, and it exhibits therapeutic, apoptotic, anxiolytic, and neuroprotective properties. However, more information on the reactions and ability of CBD to alleviate brain-related disorders and the neuroinflammation that accompanies them is needed.
Main body
This narrative review deliberates on the therapeutic and remedial prospects of CBD with an emphasis on neurological and neuropsychiatric disorders. An extensive literature search followed several scoping searches on available online databases such as PubMed, Web of Science, and Scopus with the main keywords: CBD, pro-inflammatory cytokines, and cannabinoids. After a purposive screening of the retrieved papers, 170 (41%) of the articles (published in English) aligned with the objective of this study and retained for inclusion.
Conclusion
CBD is an antagonist against pro-inflammatory cytokines and the cytokine storm associated with neurological infections/disorders. CBD regulates adenosine/oxidative stress and aids the downregulation of TNF-α, restoration of BDNF mRNA expression, and recovery of serotonin levels. Thus, CBD is involved in immune suppression and anti-inflammation. Understanding the metabolites associated with response to CBD is imperative to understand the phenotype. We propose that metabolomics will be the next scientific frontier that will reveal novel information on CBD’s therapeutic tendencies in neurological/neuropsychiatric disorders.
Cannabidiol (CBD) is a high-value natural compound of Cannabis Sativa plant. It is a non-psychotropic phytocannabinoid, attracting significant attention as a multifunctional active ingredient for topical applications. Although it is...
Acne vulgaris is a prevalent dermatological disorder that impacts the quality of life for millions of people around the world. The multifactorial nature of this disorder requires innovative and effective treatment strategies. Over time, there has been a growing interest regarding the use of natural topical therapies, with cannabinoids emerging as a promising group of compounds for investigation. In the context of acne treatment, cannabinoids are of particular interest due to their anti-acne properties, namely, lipostatic, anti-inflammatory, antiproliferative, and antimicrobial activities. Among these bioactive compounds, cannabidiol stands out as a notable derivative, exhibiting a promising spectrum of therapeutic actions. Pre-clinical and clinical studies have proven its ability to modulate sebum production, reduce inflammation, and inhibit bacterial proliferation—all of which are critical components in the pathogenesis of this dermatosis. This review provides a comprehensive overview of cannabinoids’ potential as a novel and holistic approach to acne vulgaris treatment and summarizes recent developments in this area.
Background
Seborrheic dermatitis (SD) affects 18.6%-59% of persons with Parkinson disease (PD), and recent studies provide evidence that oral cannabidiol (CBD) therapy could reduce sebum production in addition to improving motor and psychiatric symptoms in PD. Therefore, oral CBD could be useful for improving symptoms of both commonly co-occurring conditions.
Objective
This study investigates whether oral CBD therapy is associated with a decrease in SD severity in PD.
Methods
Facial photographs were collected as a component of a randomized (1:1 CBD vs placebo), parallel, double-blind, placebo-controlled trial assessing the efficacy of a short-term 2.5 mg per kg per day oral sesame solution CBD-rich cannabis extract (formulated to 100 mg/mL CBD and 3.3 mg/mL THC) for reducing motor symptoms in PD. Participants took 1.25 mg per kg per day each morning for 4 ±1 days and then twice daily for 10 ±4 days. Reviewers analyzed the photographs independently and provided a severity ranking based on the Seborrheic Dermatitis Area and Severity Index (SEDASI) scale. Baseline demographic and disease characteristics, as well as posttreatment SEDASI averages and the presence of SD, were analyzed with 2-tailed t tests and Pearson χ2 tests. SEDASI was analyzed with longitudinal regression, and SD was analyzed with generalized estimating equations.
Results
A total of 27 participants received a placebo and 26 received CBD for 16 days. SD severity was low in both groups at baseline, and there was no treatment effect. The risk ratio for patients receiving CBD, post versus pre, was 0.69 (95% CI 0.41-1.18; P=.15), compared to 1.20 (95% CI 0.88-1.65; P=.26) for the patients receiving the placebo. The within-group pre-post change was not statistically significant for either group, but they differed from each other (P=.07) because there was an estimated improvement for the CBD group and an estimated worsening for the placebo group.
Conclusions
This study does not provide solid evidence that oral CBD therapy reduces the presence of SD among patients with PD. While this study was sufficiently powered to detect the primary outcome (efficacy of CBD on PD motor symptoms), it was underpowered for the secondary outcomes of detecting changes in the presence and severity of SD. Multiple mechanisms exist through which CBD can exert beneficial effects on SD pathogenesis. Larger studies, including participants with increased disease severity and longer treatment periods, may better elucidate treatment effects and are needed to determine CBD’s true efficacy for affecting SD severity.
Trial Registration
ClinicalTrials.gov NCT03582137; https://clinicaltrials.gov/ct2/show/NCT03582137
Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel activated by various stimuli, such as heat. A recent study reported that high expression of TRPV4 predicted a poor prognosis in ovarian cancer patients. This study demonstrated that TRPV4 was highly expressed in ovarian cancer and had the ability to promote proliferation and migration. Through RNA-seq and related experiments, we confirmed that the oncogenic pathway of TRPV4 in ovarian cancer may be related to the fatty acid synthesis. By correlation analysis and RNA-seq, we demonstrated that SREBP1 and mTORC1 were inseparably related to that. Therefore, we used inhibitors to perform experiments. Calcium fluorescent probe experiments suggest that the change of calcium content in ovarian cancer cells was related to the downstream mTORC1 signaling pathway and fatty acid synthesis. These results confirmed that TRPV4 affected the fatty acid synthesis through the calcium-mTOR/SREBP1 signaling pathway, thereby promoting ovarian cancer progression.
Introduction_Cannabis sativa L. is an annual, dioecious, herbaceous, monotypic genus of blooming plants, synthetically rich in the natural constituents of complex compounds including terpenophenolic chemicals such as phytocannabinoids. Thus, cannabis is gaining a distinct fascination in the pharmaceutical research under its medicinal properties despite being prohibited in many countries. This study aims to provide overview of cannabis's phytochemical and pharmacological qualities as well as its cannabinoids synthesis. Methods_Between 2011 and April 2022, the literature was reviewed by searching Medline, Scopus, Google Scholar, ScienceDirect, Web of Knowledge, PubMed, and SpringerLink databases. The accompanying vital terms were utilized: ‘Cannabis sativa L.’, ‘Chemical constituents’, ‘Biosynthesis’, ‘Pharmacological aspects’, ‘Phytocannabinoids’, and ‘Terpenes’. Results_More than 588 bioactive compounds have been extracted and characterized into various classes of cannabinoids and non-cannabinoids (i.e., terpenes, alkaloids, hydrocarbons etc.). Overall, 20 studies show to exhibit diversified implications of cannabis in arrays of diseases, especially cancer and neurological disorders, because of its analgesic, antidiabetic, antioxidant, anti-inflammatory, anticancer, sedative, spasmolytic, antimicrobial, and expectorant effects. Conclusion_This investigation suggests that the cannabinoids from Cannabis sativus can be employed to treat different serious ailments.
Sativex(®), a cannabis extract oromucosal spray containing Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), is currently in phase III trials as an adjunct to opioids for cancer pain treatment, and recently received United Kingdom approval for treatment of spasticity. There are indications that CBD modulates THC's effects, but it is unclear if this is due to a pharmacokinetic and/or pharmacodynamic interaction.
Cannabis smokers provided written informed consent to participate in this randomized, controlled, double-blind, double-dummy institutional review board-approved study. Participants received 5 and 15 mg synthetic oral THC, low-dose (5.4 mg THC and 5.0 mg CBD) and high-dose (16.2 mg THC and 15.0 mg CBD) Sativex, and placebo over 5 sessions. CBD, THC, 11-hydroxy-THC, and 11-nor- 9-carboxy-THC were quantified in plasma by 2-dimensional GC-MS. Lower limits of quantification were ≤0.25 μg/L.
Nine cannabis smokers completed all 5 dosing sessions. Significant differences (P < 0.05) in maximum plasma concentrations (C(max)) and areas under the curve from 0-10.5 h postdose (AUC(0→10.5)) for all analytes were found between low and high doses of synthetic THC and Sativex. There were no statistically significant differences in C(max), time to maximum concentration or in the AUC(0→10.5) between similar oral THC and Sativex doses. Relative bioavailability was calculated to determine the relative rate and extent of THC absorption; 5 and 15 mg oral THC bioavailability was 92.6% (13.1%) and 98.8% (11.0%) of low- and high-dose Sativex, respectively.
These data suggest that CBD modulation of THC's effects is not due to a pharmacokinetic interaction at these therapeutic doses.
Marijuana (Cannabis sativa) has long been known to contain antibacterial cannabinoids, whose potential to address antibiotic resistance has not yet been investigated. All five major cannabinoids (cannabidiol (1b), cannabichromene (2), cannabigerol (3b), Delta (9)-tetrahydrocannabinol (4b), and cannabinol (5)) showed potent activity against a variety of methicillin-resistant Staphylococcus aureus (MRSA) strains of current clinical relevance. Activity was remarkably tolerant to the nature of the prenyl moiety, to its relative position compared to the n-pentyl moiety (abnormal cannabinoids), and to carboxylation of the resorcinyl moiety (pre-cannabinoids). Conversely, methylation and acetylation of the phenolic hydroxyls, esterification of the carboxylic group of pre-cannabinoids, and introduction of a second prenyl moiety were all detrimental for antibacterial activity. Taken together, these observations suggest that the prenyl moiety of cannabinoids serves mainly as a modulator of lipid affinity for the olivetol core, a per se poorly active antibacterial pharmacophore, while their high potency definitely suggests a specific, but yet elusive, mechanism of activity.
Cannabidiol (CBD) is a non-psychoactive plant cannabinoid that inhibits cell proliferation and induces cell death of cancer cells and activated immune cells. It is not an agonist of the classical CB1/CB2 cannabinoid receptors and the mechanism by which it functions is unknown. Here, we studied the effects of CBD on various mitochondrial functions in BV-2 microglial cells. Our findings indicate that CBD treatment leads to a biphasic increase in intracellular calcium levels and to changes in mitochondrial function and morphology leading to cell death. Density gradient fractionation analysis by mass spectrometry and western blotting showed colocalization of CBD with protein markers of mitochondria. Single-channel recordings of the outer-mitochondrial membrane protein, the voltage-dependent anion channel 1 (VDAC1) functioning in cell energy, metabolic homeostasis and apoptosis revealed that CBD markedly decreases channel conductance. Finally, using microscale thermophoresis, we showed a direct interaction between purified fluorescently labeled VDAC1 and CBD. Thus, VDAC1 seems to serve as a novel mitochondrial target for CBD. The inhibition of VDAC1 by CBD may be responsible for the immunosuppressive and anticancer effects of CBD. Cell Death and Disease (2013) 4, e949; doi:10.1038/cddis.2013.471; published online 5 December 2013
Hyperseborrhoea has been considered as a major aetiopathogenetic factor of acne. However, changes in sebaceous gland activity not only correlate with seborrhoea but also with alterations in sebum fatty acid composition. Current findings indicate that sebum lipid fractions with proinflammatory properties and inflammatory tissue cascades are associated in the process of the development of acne lesions. The oxidant/antioxidant ratio of the skin surface lipids and alterations of lipid composition are the main players in the induction of acne inflammation. Nutrition may influence the development of seborrhoea, the fractions of sebum lipids and acne. Acne is an inflammatory disease probably triggered, among others, by proinflammatory sebum lipid fractions.
Acne pathogenesis has recently been linked to decreased nuclear FoxO1 levels and increased mTORC1 activity. This hypothesis postulates that antiacne agents either enhance nuclear FoxO activity or inhibit mTORC1. Benzoyl peroxide (BPO), by activation of oxidative stress-inducible kinases, increases nuclear FoxO levels promoting Sestrin3-mediated AMPK activation. Furthermore, BPO-derived ROS may activate AMPK via ataxia-telangiectasia mutated. Isotretinoin and all-trans retinoic acid may stimulate FoxO gene expression. Doxycycline may enhance FoxOs nuclear retention by inhibiting the expression of exportin 1. Suppression of TNFα signalling by tetracyclines, erythromycin and other macrolides may attenuate IKKβ-TSC1-mediated mTORC1 activation. Erythromycin attenuates ERK1/2 activity and thereby increases TSC2. Azelaic acid may decrease mTORC1 by inhibiting mitochondrial respiration, increasing cellular ROS and nuclear FoxO levels. Antiandrogens may attenuate mTORC1 by suppressing mTORC2-mediated Akt/TSC2 signalling. This hypothesis unmasks a common mode of action of antiacne agents as either FoxO enhancers or mTORC1 inhibitors and thus provides a rational approach for the development of new antiacne agents.
Summary The Gene Expression Omnibus (GEO) project was initiated at NCBI in 1999 in response to the growing demand for a public repository for data generated from high-throughput microarray experiments. GEO has a flexible and open design that allows the submission, storage, and retrieval of many types of data sets, such as those from high-throughput gene expression, genomic hybridization, and antibody array experiments. GEO was never intended to replace lab-specific gene expression databases or laboratory information management systems (LIMS), both of which usually cater to a particular type of data set and analytical method. Rather, GEO complements these resources by acting as a central, molecular abundance-data distribution hub. GEO is available on the World Wide Web at http://www.ncbi.nih.gov/geo (http://www.ncbi.nih.gov/geo).
Cannabinoids are known to exert immunosuppressive activities. However, the mechanisms which contribute to these effects are unknown. Using lipopolysaccharide (LPS) to activate BV-2 microglial cells, we examined how Δ(9)-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, and cannabidiol (CBD) the non-psychoactive component, modulate the inflammatory response. Microarray analysis of genome-wide mRNA levels was performed using Illumina platform and the resulting expression patterns analyzed using the Ingenuity Pathway Analysis to identify functional subsets of genes, and the Ingenuity System Database to denote the gene networks regulated by CBD and THC. From the 5338 transcripts that were differentially expressed across treatments, 400 transcripts were found to be upregulated by LPS, 502 by CBD+LPS and 424 by THC+LPS, while 145 were downregulated by LPS, 297 by CBD+LPS and 149 by THC+LPS, by 2-fold or more (p≤0.005). Results clearly link the effects of CBD and THC to inflammatory signaling pathways and identify new cannabinoid targets in the MAPK pathway (Dusp1, Dusp8, Dusp2), cell cycle related (Cdkn2b, Gadd45a) as well as JAK/STAT regulatory molecules (Socs3, Cish, Stat1). The impact of CBD on LPS-stimulated gene expression was greater than that of THC. We attribute this difference to the fact that CBD highly upregulated several genes encoding negative regulators of both NFκB and AP-1 transcriptional activities, such as Trib3 and Dusp1 known to be modulated through Nrf2 activation. The CBD-specific expression profile reflected changes associated with oxidative stress and glutathione depletion via Trib3 and expression of ATF4 target genes. Furthermore, the CBD affected genes were shown to be controlled by nuclear factors usually involved in regulation of stress response and inflammation, mainly via Nrf2/Hmox1 axis and the Nrf2/ATF4-Trib3 pathway. These observations indicate that CBD, and less so THC, induce a cellular stress response and that this response underlies their high immunosuppressant activities.
P. acnes, Propionibacterium acnes; RT-PCR, reverse transcriptase-PCR; S. aureus, Staphylococcus aureus
Biphasic effects of cannabinoids have been shown in processes such as feeding behavior, motor activity, motivational processes and anxiety responses. Using two different tests for the characterization of anxiety-related behavior (elevated plus-maze and holeboard), we first identified in wild-type C57BL/6N mice, two doses of the synthetic CB1 cannabinoid receptor agonist CP-55,940 with anxiolytic (1 μg/kg) and anxiogenic properties (50 μg/kg), respectively. To clarify the role of CB1 receptors in this biphasic effect, both doses were applied to two different conditional CB1 receptor knockout (KO) mouse lines, GABA-CB1-KO (CB1 receptor inactivation in forebrain GABAergic neurons) and Glu-CB1-KO (CB1 receptor inactivation in cortical glutamatergic neurons). We found that the anxiolytic-like effects of the low dose of cannabinoids are mediated via the CB1 receptor on cortical glutamatergic terminals, because this anxiolytic-like response was abrogated only in Glu-CB1-KO mice. On the contrary, the CB1 receptor on the GABAergic terminals is required to induce an anxiogenic-like effect under a high-dose treatment because of the fact that this effect was abolished specifically in GABA-CB1-KO mice. These experiments were carried out in both sexes, and no differences occurred with the doses tested in the mutant mice. Interestingly, the positive allosteric modulation of GABA(B) receptor with GS-39783 was found to largely abrogate the anxiogenic-like effect of the high dose of CP-55,940. Our results shed new light in further understanding the biphasic effects of cannabinoids at the molecular level and, importantly, pave the way for the development of novel anxiolytic cannabinoid drugs, which may have favorable effect profiles targeting the CB1 receptor on glutamatergic terminals.
Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL -1. They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant.
In the current study, we aimed at identifying the functional role of transient receptor potential vanilloid-3 (TRPV3) ion channel in the regulation of human hair growth. Using human organ-cultured hair follicles (HFs) and cultures of human outer root sheath (ORS) keratinocytes, we provide the first evidence that activation of TRPV3 inhibits human hair growth. TRPV3 immunoreactivity was confined to epithelial compartments of the human HF, mainly to the ORS. In organ culture, TRPV3 activation by plant-derived (e.g., eugenol, 10-1,000 μM) or synthetic (e.g., 2-aminoethoxydiphenyl borate, 1-300 μM) agonists resulted in a dose-dependent inhibition of hair shaft elongation, suppression of proliferation, and induction of apoptosis and premature HF regression (catagen). Human ORS keratinocytes also expressed functional TRPV3, whose stimulation induced membrane currents, elevated intracellular calcium concentration, inhibited proliferation, and induced apoptosis. Of great importance, these effects on ORS keratinocytes were all mediated by TRPV3, as small interfering RNA-mediated silencing of TRPV3 effectively abrogated the cellular actions of the above agonists. These findings collectively support the concept that TRPV3 signaling is a significant player in human hair growth control. Therefore, TRPV3 and the related intracellular signaling mechanism might function as a promising target for pharmacological manipulations of clinically relevant hair growth disorders.
Sebum is a complex lipid mixture that is synthesized in sebaceous glands and excreted on the skin surface. The purpose of this study was the comprehensive detection of the intact lipids that compose sebum. These lipids exist as a broad range of chemical structures and concentrations. Sebum was collected with SebuTape(TM) from the foreheads of healthy donors, and then separated by HPLC on a C8 stationary phase with sub 2 µm particle size. This HPLC method provided high resolution and excellent reproducibility of retention times (RT). Compound mining was performed with time of flight (TOF) and triple quadrupole (QqQ) mass spectrometers (MS), which allowed for the classification of lipids according to their elemental composition, degree of unsaturation, and MS/MS fragmentation. The combination of the two MS systems detected 95 and 29 families of triacylglycerols (TAG) and diacylglycerols (DAG), respectively. Assignment was carried out regardless of positional isomerism. Among the wax esters (WE), 28 species were found to contain the 16:1 fatty acyl moiety. This method was suitable for the simultaneous detection of squalene and its oxygenated derivative. A total of 9 cholesterol esters (CE) were identified and more than 48 free fatty acids (FFA) were detected in normal sebum. The relative abundance of each individual lipid within its own chemical class was determined for 12 healthy donors. In summary, this method provided the first characterization of the features and distribution of intact components of the sebum lipidome.
Cannabinoids have been shown to exert anti-inflammatory activities in various in vivo and in vitro experimental models as well as ameliorate various inflammatory degenerative diseases. However, the mechanisms of these effects are not completely understood. Using the BV-2 mouse microglial cell line and lipopolysaccharide (LPS) to induce an inflammatory response, we studied the signaling pathways engaged in the anti-inflammatory effects of cannabinoids as well as their influence on the expression of several genes known to be involved in inflammation. We found that the two major cannabinoids present in marijuana, Delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), decrease the production and release of proinflammatory cytokines, including interleukin-1beta, interleukin-6, and interferon (IFN)beta, from LPS-activated microglial cells. The cannabinoid anti-inflammatory action does not seem to involve the CB1 and CB2 cannabinoid receptors or the abn-CBD-sensitive receptors. In addition, we found that THC and CBD act through different, although partially overlapping, mechanisms. CBD, but not THC, reduces the activity of the NF-kappaB pathway, a primary pathway regulating the expression of proinflammatory genes. Moreover, CBD, but not THC, up-regulates the activation of the STAT3 transcription factor, an element of homeostatic mechanism(s) inducing anti-inflammatory events. Following CBD treatment, but less so with THC, we observed a decreased level of mRNA for the Socs3 gene, a main negative regulator of STATs and particularly of STAT3. However, both CBD and THC decreased the activation of the LPS-induced STAT1 transcription factor, a key player in IFNbeta-dependent proinflammatory processes. In summary, our observations show that CBD and THC vary in their effects on the anti-inflammatory pathways, including the NF-kappaB and IFNbeta-dependent pathways.
Autophagy can promote cell survival or cell death, but the molecular basis underlying its dual role in cancer remains obscure. Here we demonstrate that delta(9)-tetrahydrocannabinol (THC), the main active component of marijuana, induces human glioma cell death through stimulation of autophagy. Our data indicate that THC induced ceramide accumulation and eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation and thereby activated an ER stress response that promoted autophagy via tribbles homolog 3-dependent (TRB3-dependent) inhibition of the Akt/mammalian target of rapamycin complex 1 (mTORC1) axis. We also showed that autophagy is upstream of apoptosis in cannabinoid-induced human and mouse cancer cell death and that activation of this pathway was necessary for the antitumor action of cannabinoids in vivo. These findings describe a mechanism by which THC can promote the autophagic death of human and mouse cancer cells and provide evidence that cannabinoid administration may be an effective therapeutic strategy for targeting human cancers.
To understand pathways mediating the inflammatory responses of human aortic endothelial cells to oxidized phospholipids, we previously used a combination of genetics and genomics to model a coexpression network encompassing >1000 genes. CHAC1 (cation transport regulator-like protein 1), a novel gene regulated by ox-PAPC (oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycero-phosphorylcholine), was identified in a co-regulated group of genes enriched for components of the ATF4 (activating transcription factor 4) arm of the unfolded protein response pathway. Herein, we characterize the role of CHAC1 and validate the network model. We first define the activation of CHAC1 mRNA by chemical unfolded protein response-inducers, but not other cell stressors. We then define activation of CHAC1 by the ATF4-ATF3-CHOP (C/EBP homologous protein), and not parallel XBP1 (X box-binding protein 1) or ATF6 pathways, using siRNA and/or overexpression plasmids. To examine the subset of genes downstream of CHAC1, we used expression microarray analysis to identify a list of 227 differentially regulated genes. We validated the activation of TNFRSF6B (tumor necrosis factor receptor superfamily, member 6b), a FASL decoy receptor, in cells treated with CHAC1 small interfering RNA. Finally, we showed that CHAC1 overexpression enhanced apoptosis, while CHAC1 small interfering RNA suppressed apoptosis, as determined by TUNEL, PARP (poly(ADP-ribose) polymerase) cleavage, and AIF (apoptosis-inducing factor) nuclear translocation.
Intracellular calcium ([Ca(2+)](i)) modulates adipocyte lipid metabolism and inhibits the early stages of murine adipogenesis. Consequently, we evaluated effects of increasing [Ca(2+)](i) in early and late stages of human adipocyte differentiation. Increasing [Ca(2+)](i) with either thapsigargin or A23187 at 0-1 h of differentiation markedly suppressed differentiation, with a 40-70% decrease in triglyceride accumulation and glycerol-3 phosphate dehydrogenase (GPDH) activity (P < 0.005). However, a 1-h pulse of either agent at 47-48 h only modestly inhibited differentiation. Sustained, mild stimulation of Ca(2+) influx with either agouti protein or 10 mM KCl-induced depolarization during 0-48 h of differentiation inhibited triglyceride accumulation and GPDH activity by 20-70% (P < 0.05) and markedly suppressed peroxisome proliferator-activated receptor gamma (PPARgamma) expression. These effects were reversed by Ca(2+) channel antagonism. In contrast, Ca(2+) pulses late in differentiation (71-72 h or 48-72 h) markedly increased these markers of differentiation. Thus increasing [Ca(2+)](i) appears to exert a biphasic regulatory role in human adipocyte differentiation, inhibiting the early stages while promoting the late stage of differentiation and lipid filling.
The transient receptor potential (TRP) ion channels are encoded by ?30 distinct genes in mammals. TRP channels may be generally described as cation channels that increase intracellular Ca 2+ levels. They are activated by diverse stimuli such as changes in temperature, pH, and osmolarity, and are modulated by growth factor and G-protein-coupled receptor pathways. TRPs thus integrate multiple concomitant stimuli as cellular sensors. They are grouped into six subfamilies, named C, V, M, A, P, and ML, on the basis of amino acid sequence homology: canonical, vanilloid, melastatin, ankyrin repeat, polycystins, and mucolipins, respectively.
This book is intended as a scientific resource for cannabinoid researchers carrying out animal and human experiments, and for those who are interested in learning about future directions in cannabinoid research. Additionally, this book may be of value to investigators currently working outside the field of cannabinoid research who have an interest in learning about these compounds and their atypical cannabinoid signalling. This book provides insight into the potential medical application of cannabinoids and their therapeutic development for the treatment of human disease. © Springer Science+Business Media New York 2013. All rights reserved.
Synopsis
Stratum corneum ( SC ) bilayer lipids, specifically fatty acids, ceramides and cholesterol, contribute to the permeability barrier function of the skin. Normal skin cleansing is associated with damage to the SC lipids because cleanser surfactants, in addition to providing the desired effect of solubilizing and facilitating the removal of sebum and skin soils, have a propensity to disrupt bilayer lipids by extracting endogenous skin lipids or intercalating into the bilayer. Disrupted SC lipids are associated with a variety of pathological skin conditions, as well as with dry skin induced by harsh cleansing. In an attempt to preserve the barrier and mitigate the damage caused by frequent normal cleansing, the incorporation of physiologically relevant lipids into skin cleansers has become common in leading cleansing products. It has been noted that fatty acids are more susceptible to surfactant‐induced removal than other lipids (eg, ceramides), an observation that may form the basis for a critically important strategy for replenishing SC lipids. This review will focus on the role of fatty acids in the structure and function of the SC , and the rationale for incorporation of stearic acid into moisturizing body cleansers to minimize their extraction by surfactants and replenish lost fatty acids to promote skin barrier preservation.
We have recently shown that lipid mediators of the emerging endocannabinoid system (ECS) are key players of growth control of the human pilosebaceous unit. In this study, we asked whether the prototypic endocannabinoid anandamide (N-arachidonoylethanolamine, AEA) has a role in growth and survival of epidermal keratinocytes (KCs). Using human cultured KCs and skin organ-culture models, and by employing combined pharmacological and molecular approaches, we provide early evidence that AEA markedly suppresses KC proliferation and induces cell death, both in vitro and in situ. Moreover, we present that these cellular actions are mediated by a most probably constitutively active signaling mechanism that involves the activation of the metabotropic cannabinoid receptor CB1 and a sequential engagement of the “ionotropic cannabinoid receptor” transient receptor potential vanilloid-1 (TRPV1). Finally, we demonstrate that the cellular effects of AEA are most probably due to a Ca2+ influx via the non-selective, highly Ca2+-permeable ion channel TRPV1, and the concomitant elevation of intracellular Ca2+ concentration. The data reported here may encourage one to explore whether the targeted manipulation of the above signaling pathway of the cutaneous ECS could become a useful adjunct treatment strategy for hyperproliferative human dermatoses such as psoriasis or KC-derived skin tumors.Abbreviations: AEA, N-arachidonoylethanolamine; [Ca2+]i, intracellular Ca2+ concentration; CAPS, capsaicin; ECS, endocannabinoid system; FLIPR, fluorescence image plate reader; G6PD, glucose-6-phosphate dehydrogenase; KC, keratinocyte; NHEK, normal human epidermal KC; RNAi, RNA interference; TRPV1, transient receptor potential vanilloid-1; TTP, time to peak
Structure and distribution Acne vulgaris Aetiology of acne Clinical features Treatment Uncommon associations with acne Severe acne variants Ectopic sebaceous glands Sebaceous gland hyperplasia, adenoma and carcinoma ‘Sebaceous’ (epidermoid) cysts and steatocystoma multiplex References
(−)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-inflammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA).
CBD and its enantiomer, (+)-CBD, together with seven analogues, obtained by exchanging the C-7 methyl group of CBD with a hydroxy-methyl or a carboxyl function and/or the C-5′ pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca2+ concentrations in cells over-expressing human VR1; (b) [14C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [14C]-AEA hydrolysis by rat brain membranes, which is catalysed by the fatty acid amide hydrolase.
Both CBD and (+)-CBD, but not the other analogues, stimulated VR1 with EC50=3.2 – 3.5 μM, and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67 – 70% of the effect obtained with ionomycin (4 μM). CBD (10 μM) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compounds were not additive.
(+)-5′-DMH-CBD and (+)-7-hydroxy-5′-DMH-CBD inhibited [14C]-AEA uptake (IC50=10.0 and 7.0 μM); the (−)-enantiomers were slightly less active (IC50=14.0 and 12.5 μM). CBD and (+)-CBD were also active (IC50=22.0 and 17.0 μM).
CBD (IC50=27.5 μM), (+)-CBD (IC50=63.5 μM) and (−)-7-hydroxy-CBD (IC50=34 μM), but not the other analogues (IC50>100 μM), weakly inhibited [14C]-AEA hydrolysis.
Only the (+)-isomers exhibited high affinity for CB1 and/or CB2 cannabinoid receptors.
These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological effects of CBD and its analogues. In view of the facile high yield synthesis, and the weak affinity for CB1 and CB2 receptors, (−)-5′-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent.
British Journal of Pharmacology (2001) 134, 845–852; doi:10.1038/sj.bjp.0704327
Sebocytes are highly specialized, sebum-producing epithelial cells that release their content by rupture of the cell membrane and cellular degradation (holocrine secretion). These cells are most commonly found in the skin in association with hair follicles (forming the pilosebaceous unit), where they arise from hair follicle keratinocytes, but there are also sebaceous glands (SGs) not associated with a hair follicle. The latter have special functions as secretion of pheromones or corneal protection. While the full range of sebum functions in human skin remains to be clarified, sebum forms an integral component of the epidermal barrier and the skin immune system. Sebocyte formation is controlled by multiple molecular pathways (e.g. Blimp1, Wnt, C-myc, Hedgehog) and sebum synthesis is strongly regulated by hormones, in particular by androgens. Excessive sebum production is seen in acne vulgaris, one of the most common skin diseases, while deregulated sebocyte differentiation characterizes some rare benign and malignant tumors.
Topical photodynamic therapy (PDT) with methyl-aminolevulinate (MAL) is a well-established treatment for precancerous skin lesions and non-melanoma skin cancer. Treatment outcomes are less effective for thick than for superficial lesions, which are presumed to be due to insufficient PpIX biodistribution in tumour tissue. Hexyl-aminolevulinate (HAL) is a more lipophilic photosensitizer precursor than MAL and may penetrate the skin to a greater depth and more homogeneously. We compared HAL- and MAL-induced PpIX accumulation in specific skin compartments using concentrations of 2%, 6% and 20% HAL and MAL on long-term UV-irradiated mouse skin. Furthermore, 20% HAL and 20% MAL were applied to non-irradiated skin. Porphyrin fluorescence was measured by fluorescence microscopy in selected skin regions: the epidermis, superficial dermis, deep dermis and sebaceous gland epithelium down to a depth of 1 mm. We found higher PpIX fluorescence intensities in epidermis and sebaceous gland epithelium from 2%, 6% and 20% HAL (median 72-104 au) than in corresponding concentrations of MAL (median 35-69 au) (P < 0.01). Fluorescence intensities in the superficial (35 au) and deep dermis (32 au) were similar for HAL and MAL (P = 0.51) and lower than epidermal fluorescence intensities (P < 0.001). Significantly, higher median PpIX fluorescence intensities (64 au) were found in 20% MAL-incubated skin irradiated with UV than in non-irradiated skin (48 au) (P < 0.001). HAL-induced fluorescence intensities did not depend on UV exposure (HAL 20%, UV: 72 au, non-UV: 70 au) (P = 0.87). In conclusion, HAL express high affinity for epidermis and sebaceous gland epithelium, and MAL for actinically damaged skin, which raises future perspectives for improved selectivity in PDT.
Acute lung injury is an inflammatory condition for which treatment is mainly supportive because effective therapies have not been developed. Cannabidiol, a non-psychotropic cannabinoid component of marijuana (Cannabis sativa), has potent immunosuppressive and anti-inflammatory properties. Therefore, we investigated the possible anti-inflammatory effect of cannabidiol in a murine model of acute lung injury. Analysis of total inflammatory cells and differential in bronchoalveolar lavage fluid was used to characterize leukocyte migration into the lungs; myeloperoxidase activity of lung tissue and albumin concentration in the bronchoalveolar lavage fluid were analyzed by colorimetric assays; cytokine/chemokine production in the bronchoalveolar lavage fluid was also analyzed by Cytometric Bead Arrays and Enzyme-Linked Immunosorbent Assay (ELISA). A single dose of cannabidiol (20mg/kg) administered prior to the induction of LPS (lipopolysaccharide)-induced acute lung injury decreases leukocyte (specifically neutrophil) migration into the lungs, albumin concentration in the bronchoalveolar lavage fluid, myeloperoxidase activity in the lung tissue, and production of pro-inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) 1, 2, and 4days after the induction of LPS-induced acute lung injury. Additionally, adenosine A(2A) receptor is involved in the anti-inflammatory effects of cannabidiol on LPS-induced acute lung injury because ZM241385 (4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol) (a highly selective antagonist of adenosine A(2A) receptor) abrogated all of the anti-inflammatory effects of cannabidiol previously described. Thus, we show that cannabidiol has anti-inflammatory effects in a murine model of acute lung injury and that this effect is most likely associated with an increase in the extracellular adenosine offer and signaling through adenosine A(2A) receptor.
Hyperhomocysteinemia (HHcy) has been shown to induce endothelial dysfunction, an early event in the progression of atherosclerosis. However, the underlying mechanism of endothelial cell injury in HHcy has not been clearly elucidated. In this study, we examined the effect of homocysteine on tribbles-related protein 3 (TRB3)-mediated cell-cycle arrest in human umbilical vein endothelial cells (HUVECs). Treatment of HUVECs with homocysteine (0-250 µmol/L) resulted in inhibition of cell proliferation assessed by [(3)H]-thymidine incorporation into DNA. Homocysteine induced cell-cycle arrest in the G1 phase by up-regulating the protein levels of p27(kip1). Under these conditions, homocysteine did not induce endoplasmic reticulum stress. However, homocysteine up-regulated the expression of TRB3, thus leading to the dephosphorylation of Akt (Thr308). Knock-down of endogenous TRB3 using siRNA significantly suppressed the inhibitory effect of homocysteine on the proliferation of HUVECs. Homocysteine-induced TRB3 expression was mediated by the cAMP/cAMP response element-binding protein (CREB) pathway. These results demonstrate that TRB3 is a critical molecule in the homocysteine-mediated cell-cycle arrest in endothelial cells.
Plant cannabinoids, like Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), activate/desensitize thermosensitive transient receptor potential (TRP) channels of vanilloid type-1 or -2 (TRPV1 or TRPV2). We investigated whether cannabinoids also activate/desensitize two other 'thermo-TRP's', the TRP channels of vanilloid type-3 or -4 (TRPV3 or TRPV4), and if the TRPV-inactive cannabichromene (CBC) modifies the expression of TRPV1-4 channels in the gastrointestinal tract.
TRP activity was assessed by evaluating elevation of [Ca(2+)](i) in rat recombinant TRPV3- and TRPV4-expressing HEK-293 cells. TRP channel mRNA expression was measured by quantitative RT-PCR in the jejunum and ileum of mice treated with vehicle or the pro-inflammatory agent croton oil.
(i) CBD and tetrahydrocannabivarin (THCV) stimulated TRPV3-mediated [Ca(2+)](i) with high efficacy (50-70% of the effect of ionomycin) and potency (EC(50∼) 3.7 μm), whereas cannabigerovarin (CBGV) and cannabigerolic acid (CBGA) were significantly more efficacious at desensitizing this channel to the action of carvacrol than at activating it; (ii) cannabidivarin and THCV stimulated TRPV4-mediated [Ca(2+)](i) with moderate-high efficacy (30-60% of the effect of ionomycin) and potency (EC(50) 0.9-6.4 μm), whereas CBGA, CBGV, cannabinol and cannabigerol were significantly more efficacious at desensitizing this channel to the action of 4-α-phorbol 12,13-didecanoate (4α-PDD) than at activating it; (iii) CBC reduced TRPV1β, TRPV3 and TRPV4 mRNA in the jejunum, and TRPV3 and TRPV4 mRNA in the ileum of croton oil-treated mice.
Cannabinoids can affect both the activity and the expression of TRPV1-4 channels, with various potential therapeutic applications, including in the gastrointestinal tract.
Acne is one of the most common dermatologic diseases in the developed regions of the world, affecting a large percentage of the population. Despite the great improvement in the number and quality of studies of the molecular etiology of this disease in the past 3 decades, the detailed molecular pathogenesis and the cause of the large individual variations in severity of skin symptoms remain unknown. The roles of genetic inheritance and special genetic susceptibility and protective factors have been suggested for over 100 years, but their identification and determination started only in the 1990s. To date, only a small number of genetic polymorphisms affecting the expression and/or function of a handful of genes have been investigated. This review surveys the major findings of the classic and molecular genetic studies that have been conducted in this field, draws conclusions, and indicates how the available data help our current understanding of the pathogenesis of this common skin disease.
We have recently shown that lipid mediators of the emerging endocannabinoid system (ECS) are key players of growth control of the human pilosebaceous unit. In this study, we asked whether the prototypic endocannabinoid anandamide (N-arachidonoylethanolamine, AEA) has a role in growth and survival of epidermal keratinocytes (KCs). Using human cultured KCs and skin organ-culture models, and by employing combined pharmacological and molecular approaches, we provide early evidence that AEA markedly suppresses KC proliferation and induces cell death, both in vitro and in situ. Moreover, we present that these cellular actions are mediated by a most probably constitutively active signaling mechanism that involves the activation of the metabotropic cannabinoid receptor CB(1) and a sequential engagement of the "ionotropic cannabinoid receptor" transient receptor potential vanilloid-1 (TRPV1). Finally, we demonstrate that the cellular effects of AEA are most probably due to a Ca(2+) influx via the non-selective, highly Ca(2+)-permeable ion channel TRPV1, and the concomitant elevation of intracellular Ca(2+) concentration. The data reported here may encourage one to explore whether the targeted manipulation of the above signaling pathway of the cutaneous ECS could become a useful adjunct treatment strategy for hyperproliferative human dermatoses such as psoriasis or KC-derived skin tumors.
Oxidative stress with reactive oxygen species generation is a key weapon in the arsenal of the immune system for fighting invading pathogens and initiating tissue repair. If excessive or unresolved, however, immune-related oxidative stress can initiate further increasing levels of oxidative stress that cause organ damage and dysfunction. Targeting oxidative stress in various diseases therapeutically has proven more problematic than first anticipated given the complexities and perversity of both the underlying disease and the immune response. However, growing evidence suggests that the endocannabinoid system, which includes the CB₁ and CB₂ G-protein-coupled receptors and their endogenous lipid ligands, may be an area that is ripe for therapeutic exploitation. In this context, the related nonpsychotropic cannabinoid cannabidiol, which may interact with the endocannabinoid system but has actions that are distinct, offers promise as a prototype for anti-inflammatory drug development. This review discusses recent studies suggesting that cannabidiol may have utility in treating a number of human diseases and disorders now known to involve activation of the immune system and associated oxidative stress, as a contributor to their etiology and progression. These include rheumatoid arthritis, types 1 and 2 diabetes, atherosclerosis, Alzheimer disease, hypertension, the metabolic syndrome, ischemia-reperfusion injury, depression, and neuropathic pain.
Cannabidiol (CBD) and Δ(9) -tetrahydrocannabinol (THC) interact with transient receptor potential (TRP) channels and enzymes of the endocannabinoid system.
The effects of 11 pure cannabinoids and botanical extracts [botanical drug substance (BDS)] from Cannabis varieties selected to contain a more abundant cannabinoid, on TRPV1, TRPV2, TRPM8, TRPA1, human recombinant diacylglycerol lipase α (DAGLα), rat brain fatty acid amide hydrolase (FAAH), COS cell monoacylglycerol lipase (MAGL), human recombinant N-acylethanolamine acid amide hydrolase (NAAA) and anandamide cellular uptake (ACU) by RBL-2H3 cells, were studied using fluorescence-based calcium assays in transfected cells and radiolabelled substrate-based enzymatic assays. Cannabinol (CBN), cannabichromene (CBC), the acids (CBDA, CBGA, THCA) and propyl homologues (CBDV, CBGV, THCV) of CBD, cannabigerol (CBG) and THC, and tetrahydrocannabivarin acid (THCVA) were also tested.
CBD, CBG, CBGV and THCV stimulated and desensitized human TRPV1. CBC, CBD and CBN were potent rat TRPA1 agonists and desensitizers, but THCV-BDS was the most potent compound at this target. CBG-BDS and THCV-BDS were the most potent rat TRPM8 antagonists. All non-acid cannabinoids, except CBC and CBN, potently activated and desensitized rat TRPV2. CBDV and all the acids inhibited DAGLα. Some BDS, but not the pure compounds, inhibited MAGL. CBD was the only compound to inhibit FAAH, whereas the BDS of CBC > CBG > CBGV inhibited NAAA. CBC = CBG > CBD inhibited ACU, as did the BDS of THCVA, CBGV, CBDA and THCA, but the latter extracts were more potent inhibitors.
These results are relevant to the analgesic, anti-inflammatory and anti-cancer effects of cannabinoids and Cannabis extracts.
A selection of seven phytocannabinoids representative of the major structural types of classic cannabinoids and their corresponding cannabivarins was investigated for in vivo topical anti-inflammatory activity in the Croton oil mouse ear dermatitis assay. Differences in the terpenoid moiety were far more important for anti-inflammatory activity than those at the C-3 alkyl residue, suggesting the involvement not only of cannabinoid receptors, but also of other inflammatory end-points targeted by phytocannabinoids.
Acne is one of the most prevalent diseases in dermatology: Millions of people worldwide experience this distressing condition. To determine the appropriate therapeutic strategy, there is a strong need for a standardized classification system of acne. The exact molecular mechanism of action of isotretinoin is not completely understood; however, oral isotretinoin targets simultaneously at all major mechanisms of acne pathogenesis. Various mass media reports about the risk of teratogenicity and depression from isotretinoin usage as well as the creation of intense prevention programs have created an obstacle to the use of the most active available drug against acne, presenting isotretinoin as a very dangerous regimen. According to recommendations of several international experts, which we share, oral isotretinoin may be prescribed not only to patients with severe disease but indications should be broadened to also include patients with less severe forms of acne, especially in cases with scarring, significant psychologic stress, or failure to respond to conventional therapy.
It is the purpose of this viewpoint article to delineate the regulatory network of growth hormone (GH), insulin, and insulin-like growth factor-1 (IGF-1) signalling during puberty, associated hormonal changes in adrenal and gonadal androgen metabolism, and the impact of dietary factors and smoking involved in the pathogenesis of acne. The key regulator IGF-1 rises during puberty by the action of increased GH secretion and correlates well with the clinical course of acne. In acne patients, associations between serum levels of IGF-1, dehydroepiandrosterone sulphate, dihydrotestosterone, acne lesion counts and facial sebum secretion rate have been reported. IGF-1 stimulates 5alpha-reductase, adrenal and gonadal androgen synthesis, androgen receptor signal transduction, sebocyte proliferation and lipogenesis. Milk consumption results in a significant increase in insulin and IGF-1 serum levels comparable with high glycaemic food. Insulin induces hepatic IGF-1 secretion, and both hormones amplify the stimulatory effect of GH on sebocytes and augment mitogenic downstream signalling pathways of insulin receptors, IGF-1 receptor and fibroblast growth factor receptor-2b. Acne is proposed to be an IGF-1-mediated disease, modified by diets and smoking increasing insulin/IGF1-signalling. Metformin treatment, and diets low in milk protein content and glycaemic index reduce increased IGF-1 signalling. Persistent acne in adulthood with high IGF-1 levels may be considered as an indicator for increased risk of cancer, which may require appropriate dietary intervention as well as treatment with insulin-sensitizing agents.
Cannabinoids and their derivatives are group of more than 60 biologically active chemical agents, which have been used in natural medicine for centuries. The major agent of exogenous cannabinoids is Delta(9)-tetrahydrocannabinol (Delta(9)-THC), natural psychoactive ingredient of marijuana. However, psychoactive properties of these substances limited their use as approved medicines. Recent discoveries of endogenous cannabinoids (e.g. arachidonoylethanolamide, 2-arachidonoylglycerol or palmithyloethanolamide) and their receptors initiated discussion on the role of cannabinoid system in physiological conditions as well as in various diseases. Based on the current knowledge, it could be stated that cannabinoids are important mediators in the skin, however their role have not been well elucidated yet. In our review, we summarized the current knowledge about the significant role of the cannabinoid system in the cutaneous physiology and pathology, pointing out possible future therapeutic targets.
The newly discovered endocannabinoid system (ECS; comprising the endogenous lipid mediators endocannabinoids present in virtually all tissues, their G-protein-coupled cannabinoid receptors, biosynthetic pathways and metabolizing enzymes) has been implicated in multiple regulatory functions both in health and disease. Recent studies have intriguingly suggested the existence of a functional ECS in the skin and implicated it in various biological processes (e.g. proliferation, growth, differentiation, apoptosis and cytokine, mediator or hormone production of various cell types of the skin and appendages, such as the hair follicle and sebaceous gland). It seems that the main physiological function of the cutaneous ECS is to constitutively control the proper and well-balanced proliferation, differentiation and survival, as well as immune competence and/or tolerance, of skin cells. The disruption of this delicate balance might facilitate the development of multiple pathological conditions and diseases of the skin (e.g. acne, seborrhea, allergic dermatitis, itch and pain, psoriasis, hair growth disorders, systemic sclerosis and cancer).
Interest in sebaceous gland physiology and its diseases is rapidly increasing. We provide a summarized update of the current knowledge of the pathobiology of acne vulgaris and new treatment concepts that have emerged in the last 3 years (2005-2008). We have tried to answer questions arising from the exploration of sebaceous gland biology, hormonal factors, hyperkeratinization, role of bacteria, sebum, nutrition, cytokines and toll-like receptors (TLRs). Sebaceous glands play an important role as active participants in the innate immunity of the skin. They produce neuropeptides, excrete antimicrobial peptides and exhibit characteristics of stem cells. Androgens affect sebocytes and infundibular keratinocytes in a complex manner influencing cellular differentiation, proliferation, lipogenesis and comedogenesis. Retention hyperkeratosis in closed comedones and inflammatory papules is attributable to a disorder of terminal keratinocyte differentiation. Propionibacterium acnes, by acting on TLR-2, may stimulate the secretion of cytokines, such as interleukin (IL)-6 and IL-8 by follicular keratinocytes and IL-8 and -12 in macrophages, giving rise to inflammation. Certain P. acnes species may induce an immunological reaction by stimulating the production of sebocyte and keratinocyte antimicrobial peptides, which play an important role in the innate immunity of the follicle. Qualitative changes of sebum lipids induce alteration of keratinocyte differentiation and induce IL-1 secretion, contributing to the development of follicular hyperkeratosis. High glycemic load food and milk may induce increased tissue levels of 5alpha-dihydrotestosterone. These new aspects of acne pathogenesis lead to the considerations of possible customized therapeutic regimens. Current research is expected to lead to innovative treatments in the near future.
Preliminary data presented at conferences and in the patent literature introduced the possibility the orphan receptor GPR55 might account for some of the well-documented non-CB(1), non-CB(2) effects reported for certain cannabinoid ligands. Several peer-reviewed publications have recently emerged in which the pharmacology of the cannabinoids at GPR55 has been probed in more depth. Despite this, the classification of GPR55 as a cannabinoid receptor remains a contentious issue. The weight of evidence points to GPR55 as a receptor that is activated by certain cannabinoid ligands and by the bioactive lipid l-alpha-lysophosphatidylinsoitol. It couples to G(12) proteins, activates RhoA and mobilizes intracellular Ca(2+), possibly in an agonist- and tissue-dependant manner, thus displaying 'agonist functional selectivity'. Here, I review the recent literature in an effort to glean the key controversies and outstanding questions surrounding the interaction between cannabinoids and this orphan receptor.
Despite the wealth of information on cannabinoid-induced peripheral antihyperalgesic and antinociceptive effects in many pain models, the molecular mechanism(s) for these actions remains unknown. Although metabotropic cannabinoid receptors have important roles in many pharmacological actions of cannabinoids, recent studies have led to the recognition of a family of at least five ionotropic cannabinoid receptors (ICRs). The known ICRs are members of the family of transient receptor potential (TRP) channels and include TRPV1, TRPV2, TRPV4, TRPM8 and TRPA1. Cannabinoid activation of ICRs can result in desensitization of the TRPA1 and TRPV1 channel activities, inhibition of nociceptors and antihyperalgesia and antinociception in certain pain models. Thus, cannabinoids activate both metabotropic and ionotropic mechanisms to produce peripheral analgesic effects. Here, we provide an overview of the pharmacology of TRP channels as ICRs.
Transient receptor potential vanilloid-1 (TRPV1), originally described as a central integrator of nociception, is expressed on human epidermal and hair follicle keratinocytes and is involved in regulation of cell growth and death. In human pilosebaceous units, we had shown that TRPV1 stimulation inhibits hair shaft elongation and matrix keratinocyte proliferation, and induces premature hair follicle regression and keratinocyte apoptosis. In the current study, we have explored the role of TRPV1-mediated signaling in sebaceous gland (SG) biology, using a human sebocyte cell culture model (SZ95 sebocytes). Demonstrating that human skin SG in situ and SZ95 sebocytes in vitro express TRPV1, we show that the prototypic TRPV1 agonist, capsaicin, selectively inhibits basal and arachidonic acid-induced lipid synthesis in a dose-, time-, and extracellular calcium-dependent and a TRPV1-specific manner. Low-dose capsaicin stimulates cellular proliferation via TRPV1, whereas higher concentrations inhibit sebocyte growth and induce cell death independent of TRPV1. Moreover, capsaicin suppresses the expression of genes involved in lipid homeostasis and of selected proinflammatory cytokines. Collectively, these findings support the concept that TRPV1 signaling is a significant, previously unreported player in human sebocyte biology and identify TRPV1 as a promising target in the clinical management of inflammatory SG disorders (for example, acne vulgaris).
The importance of the transappendageal route on percutaneous absorption was assessed in the hairless rat. Skin permeation of two steroids, hydrocortisone and testosterone, was evaluated in vivo on normal and artificially damaged skin in which follicles and sebaceous glands disappeared during healing. The test compounds were applied for periods of 0.5, 2 and 6 h. Thereafter, the stratum corneum reservoir function, the epidermal and dermal distribution profiles, and systemic absorption were determined for both molecules. The results presented here show that the reservoir function of the stratum corneum of appendage-free (scar) skin is more pronounced than that of normal skin, whereas the concentration appearing in the epidermis and dermis was greater in normal skin. Moreover, sebaceous glands probably contribute to the penetration of hydrocortisone and testosterone. We show that the relative importance of the skin appendages depends on the intrinsic physical properties of the molecules tested, and the time of application.
To validate information on cannabis use, 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic (THC-COOH) was investigated in human hair. The identification of THC-COOH in hair would document cannabis use more effectively than the detection of the parent drug which might have come from environmental exposure in a smoky atmosphere. Samples (100 mg) were decontaminated with methylene chloride and destroyed by incubation in 1 mL of 1 N sodium hydroxide for 30 min at 95 degrees C in presence of 10 ng of THC-COOH-d3. After cooling, samples were extracted by n-hexane/ethyl acetate after acidification with acetic acid. After derivatization by PFPA-PFP-OH of the dry extract, drugs were separated on a HP1 capillary column, and detected by mass spectrometry (m/z 602) using negative chemical ionization with methane as reagent gas. Among 30 samples obtained from subjects deceased from fatal heroin overdose, 17 tested positive for THC-COOH, in the range 0.02-0.39 ng/mg, with an average of 0.12 ng/mg.
Human facial sebaceous gland cells were transfected with a PBR-322-based plasmid containing the coding region for the Simian virus-40 large T antigen. The resulting proliferating cell cultures have been passaged over 50 times to date, have been cloned, and show no signs of senescence after 4&DF;1 2 y in vitro, whereas normal human sebocytes can only be grown for three to six passages. The immortalized transfected cells, termed SZ95, expressed the Simian virus-40 large T antigen and presented an hyper-diploid-aneuploid karyotype with a modal chromosome number of 64.5. The SZ95 cell line exhibited epithelial, polymorphous characteristics with different cell sizes of up to 3.25-fold during proliferation and 6-fold at confluence, showing numerous cytoplasmic lipid droplets. The cells showed large cytoplasm profiles with abundant organelles, including vacuoles and myelin figures which indicated lipid synthesis. Lack of or only few desmosomal areas were observed. SZ95 cells expressed molecules typically associated with human sebocytes, such as keratins 7, 13, and 19, and several proteins of the polymorphous epithelial mucin family. Functional studies revealed synthesis of the sebaceous lipids squalene and wax esters as well as of triglycerides and free fatty acids, even after 25-40 passages; active lipid secretion; population doubling times of 52.4 +/- 1.6 h; reduced growth but maintenance of lipid synthesis under serum-free conditions; and retrieval of cell proliferation after addition of 5alpha-dihydrotestosterone. Retinoids significantly inhibited proliferation of certain SZ95 cell clones in the expected magnitude 13-cis-retinoic acid > all-trans-retinoic acid > > acitretin. Thus SZ95 is an immortalized human sebaceous gland cell line that shows the morphologic, phenotypic and functional characteristics of normal human sebocytes.
Isotretinoin (13-cis-retinoic acid) is a retinoid that has been used over the past 2 decades to treat a wide variety of dermatologic conditions, some with great success. Although it is beneficial in many skin conditions, the side effects and toxicities of oral retinoids require careful monitoring by experienced physicians. The clinical applications of oral retinoids continue to expand both within and beyond the field of dermatology.