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Cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis

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Abstract

Cannabinoids from cannabis (Cannabis sativa) are anti-inflammatory and have inhibitory effects on the proliferation of a number of tumorigenic cell lines, some of which are mediated via cannabinoid receptors. Cannabinoid (CB) receptors are present in human skin and anandamide, an endogenous CB receptor ligand, inhibits epidermal keratinocyte differentiation. Psoriasis is an inflammatory disease also characterised in part by epidermal keratinocyte hyper-proliferation. We investigated the plant cannabinoids Delta-9 tetrahydrocannabinol, cannabidiol, cannabinol and cannabigerol for their ability to inhibit the proliferation of a hyper-proliferating human keratinocyte cell line and for any involvement of cannabinoid receptors. A keratinocyte proliferation assay was used to assess the effect of treatment with cannabinoids. Cell integrity and metabolic competence confirmed using lactate-dehydrogenase and adenosine tri-phosphate assays. To determine the involvement of the receptors, specific agonist and antagonist were used in conjunction with some phytocannabinoids. Western blot and RT-PCR analysis confirmed presence of CB1 and CB2 receptors. The cannabinoids tested all inhibited keratinocyte proliferation in a concentration-dependent manner. The selective CB2 receptor agonists JWH015 and BML190 elicited only partial inhibition, the non-selective CB agonist HU210 produced a concentration-dependent response, the activity of theses agonists were not blocked by either CB1/CB2 antagonists. The results indicate that while CB receptors may have a circumstantial role in keratinocyte proliferation, they do not contribute significantly to this process. Our results show that cannabinoids inhibit keratinocyte proliferation, and therefore support a potential role for cannabinoids in the treatment of psoriasis.

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... Rheumatoid arthritis CB2 receptor agonists [14,15] Analgesic, anti-inflammatory and immunomodulatory effect [14,15] Psoriasis and Psoriatic Arthritis CB1/CB2 receptor agonists [24] Analgesic, anti-inflammatory, immunomodulatory, antiproliferative and proapoptotic effect [24,25] Fibromyalgia CB1 agonists [46] Analgesic and sleep-enhancing effect [28,29] Osteoarthritis CB1, CB2, GRP55 и PPAR-gamma agonists [31] Analgesic, anti-inflammatory effect, Chondroprotective effect [30,31] Osteoporosis CB2 agonists [35] Promoters of bone formation and inhibitors of bone resorption [32,33,34] Dermatomyositis CB2 agonists ḉ inhibitors of the production of key proinflammatory cytokines by T-cells [22,23] Anti-inflammatory and immunomodulatory effect [22,23] Progressive systemic sclerosis CB2 и PPAR-gamma agonists ḉinhibitors of the release of growth factors responsible for the collagen synthesis [18,19] Anti-inflammatory and antifibrotic effect [18,19] Multiple Sclerosis CB1 и CB2 receptor agonists [4] Anti-inflammatory, Immunomodulatory, Analgesic, antispasmolytic and neuroprotective effect [4,5] Parkinson's disease CB1 agonists mainly and to a lesser extent CB2 agonists [42,43] Neuroprotecive effect and effect on motor disorders [42,43] Alzheimer's disease CB1 agonists, preventing aggregation of amyloid-betapeptide aggregation [44] Neuroprotective, anti-inflammatory effect [44] Chronic pain CB1 и CB2 аagonists [38] Suppression of the perception of nociceptive stimuli, blocking the transmission of impulses from afferent sensory neurons to the spinal cord and brain; Work synergistically with opioid drugs to relieve chronic pain [3,38] Insomnia CB1 и CB2 agonists [57] Accelerating the time needed to get into deep sleep as well as extending its duration [57] Diabetes Inhibition of CB1 receptors and activation of CB2 receptors [47] Improving the function of insulin-producing beta cells in pancreas and increasing insulin sensitivity in peripheral tissues [47] Glaucoma CB1 agonists [49] Reducing high intraocular pressure, Neuroprotective and antioxidant effect [50,51] Neoplastic diseases CB1/ CB2 depending on the expression of corresponding receptors in tumor cells [55] Inhibition of cancer cell proliferation, Appetite stimulation, Antiemetic effect in patients on chemotherapy [55] and macrophages, and inhibits the release of proinflammatory cytokines from immune cells [10]. Thus CB2 activation results in suppression of T-cells and amelioration of the negative impact of autoreactive immune cells [10,11,12]. ...
... Rheumatoid arthritis CB2 receptor agonists [14,15] Analgesic, anti-inflammatory and immunomodulatory effect [14,15] Psoriasis and Psoriatic Arthritis CB1/CB2 receptor agonists [24] Analgesic, anti-inflammatory, immunomodulatory, antiproliferative and proapoptotic effect [24,25] Fibromyalgia CB1 agonists [46] Analgesic and sleep-enhancing effect [28,29] Osteoarthritis CB1, CB2, GRP55 и PPAR-gamma agonists [31] Analgesic, anti-inflammatory effect, Chondroprotective effect [30,31] Osteoporosis CB2 agonists [35] Promoters of bone formation and inhibitors of bone resorption [32,33,34] Dermatomyositis CB2 agonists ḉ inhibitors of the production of key proinflammatory cytokines by T-cells [22,23] Anti-inflammatory and immunomodulatory effect [22,23] Progressive systemic sclerosis CB2 и PPAR-gamma agonists ḉinhibitors of the release of growth factors responsible for the collagen synthesis [18,19] Anti-inflammatory and antifibrotic effect [18,19] Multiple Sclerosis CB1 и CB2 receptor agonists [4] Anti-inflammatory, Immunomodulatory, Analgesic, antispasmolytic and neuroprotective effect [4,5] Parkinson's disease CB1 agonists mainly and to a lesser extent CB2 agonists [42,43] Neuroprotecive effect and effect on motor disorders [42,43] Alzheimer's disease CB1 agonists, preventing aggregation of amyloid-betapeptide aggregation [44] Neuroprotective, anti-inflammatory effect [44] Chronic pain CB1 и CB2 аagonists [38] Suppression of the perception of nociceptive stimuli, blocking the transmission of impulses from afferent sensory neurons to the spinal cord and brain; Work synergistically with opioid drugs to relieve chronic pain [3,38] Insomnia CB1 и CB2 agonists [57] Accelerating the time needed to get into deep sleep as well as extending its duration [57] Diabetes Inhibition of CB1 receptors and activation of CB2 receptors [47] Improving the function of insulin-producing beta cells in pancreas and increasing insulin sensitivity in peripheral tissues [47] Glaucoma CB1 agonists [49] Reducing high intraocular pressure, Neuroprotective and antioxidant effect [50,51] Neoplastic diseases CB1/ CB2 depending on the expression of corresponding receptors in tumor cells [55] Inhibition of cancer cell proliferation, Appetite stimulation, Antiemetic effect in patients on chemotherapy [55] and macrophages, and inhibits the release of proinflammatory cytokines from immune cells [10]. Thus CB2 activation results in suppression of T-cells and amelioration of the negative impact of autoreactive immune cells [10,11,12]. ...
... As for the effects of cannabinoids in patients with Psoriasis and Psoriatic arthritis (PsA), it has been reported that they have an important role in suppressing joint pain by inhibiting the activity of multiple proinflammatory cytokines and angiogenic growth factors. In addition, they can also delay the excessive proliferation of the epidermis and reduce the prevalence and severity of skin psoriasis [24,25]. ...
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Терапевтичният потенциал на канабиноидите е обект на засилен научен интерес през последните десетилетия. От дълбока древност се използват лечебните им свойства, но непознаването на механизмите, по които въздействат на органите и системите в човешкото тяло и наблюдаваните странични ефекти, ограничават навлизането им в клиничната практика. Все още остават неизяснени патогенетичните механизми, чрез които канабиноидите повлияват на толкова голям спектър от различни по своята същност заболявания. Натрупват се все повече доказателства за тяхното противовъзпалително и антифибротично действие, участват в регулацията на свръхактивирания имунен отговор и могат да се използват като симптоматично средство за лечение на хронична болка. В настоящия обзор се разглежда физиологичната и патофизиологична роля на ендоканабиноидната система, терапевтичните възможности на канабиса и синтетичните канабиноидни аналози, приложението им при различни ревматологични и автоимунни заболявания и потенциалните рискове от провеждането на такъв тип лечение.
... Like CBG (12), CBN (10) inhibits the proliferation of keratinocytes in vitro. The mechanism of this effect is unknown, but CB1 and CB2 receptors do not appear to play any part in it (Wilkinson and Williamson 2007). Like other cannabinoids (e.g., CBDV (13)), CBN (10) stimulates the transfer of mesenchymal stem cells from the bone marrow to damaged bone tissue, thus contributing to faster healing of fractures (Scutt and Williamson 2007). ...
... This pathway has often been associated with reduction of the D 6 double bond, leading to the formation of 8-hydroxy-6,7-dihydro-CBG. Another common route by which 12 is metabolized is epoxidation at the D 6 double bond and subsequent hydrolysis to give 6,7-dihydroxy-6,7-dihydro-CBG (Harvey and Brown 1990). CBG (12) has potential in the treatment of glaucoma (Colasanti 1990), psoriasis (Wilkinson and Williamson 2007), and pain (De Petrocellis et al. 2008). ...
... A strong ability to inhibit the proliferation of human keratinocytes was observed in in vitro assays. This activity, thanks to which 12 could in the future be used in the treatment of psoriasis, for example, is not mediated through CB1 or CB2 receptors (Wilkinson and Williamson 2007). CBG (12) can inhibit electrically induced contractions of vas deferens cells (in vitro) and stimulate the binding of GTP to brain cell membranes (in vivo). ...
Article
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Cannabis spp. are some of the most controversial medicinal plants in the world. They contain great amounts of biologically active secondary metabolites, including the typical phenolic compounds called cannabinoids. Because of their low toxicity and complex biological activities, cannabinoids can be useful in the therapy of various diseases, but adverse psychological effects (of Δ9-THC in particular) raise concerns. This review summarizes the current knowledge of selected active C. indica compounds and their therapeutic potential. We summarize the main compounds contained in cannabis, the mechanisms of their effects, and their potential therapeutic applications. Further, we mention some of the clinical tests used to evaluate the efficacy of cannabinoids in therapy.
... 9 For example, CBD alone is not particularly active at the classic CB receptors, however may antagonize CB1 in the presence of CB1 agonists (eg THC), or may context-dependently activate CB1 through the inhibition of breakdown enzymes and resulting passive increase in CB1 tone. 7,9,24 CB receptors have also been noted to exhibit biased agonism, whereby their choice of intracellular effector pathway differs from agonist to agonist. 9 CB1 and CB2 have also been observed to form heteromers, which affects their ligand affinity. ...
... Wilkinson and team found that proliferation of HPV16 e6/e7 transformed hyperproliferative keratinocytes was inhibited by the pCBs THC, CBD, CBN and CBG. 24 Cannabidiol and CBG exhibited the greatest overall activity, with CBD boasting the highest potency. 24 Furthermore, the anti-proliferative effects of these compounds were not abrogated by the addition of CB receptor-specific antagonists, suggesting a non-classic CB receptor-based mechanism. ...
... 24 Cannabidiol and CBG exhibited the greatest overall activity, with CBD boasting the highest potency. 24 Furthermore, the anti-proliferative effects of these compounds were not abrogated by the addition of CB receptor-specific antagonists, suggesting a non-classic CB receptor-based mechanism. 24 Neither CBD nor CBG is very active at CB receptors which further supports this hypothesis. ...
Article
The increasing legalization of Cannabis for recreational and medicinal purposes in the United States has spurred renewed interest in the therapeutic potential of cannabinoids (CBs) for human disease. The skin has its own endocannabinoid system (eCS) which is a key regulator of various homeostatic processes, including those necessary for normal physiologic wound healing. Data on the use of CBs for wound healing are scarce. Compelling pre‐clinical evidence supporting the therapeutic potential of CBs to improve wound healing by modulating key molecular pathways is herein reviewed. These findings merit further exploration in basic science, translational and clinical studies.
... Endocannabinoids have been implicated in the pathogenesis of psoriasis. They (AEA, 2-AG) have been found to be expressed in the skin (Wilkinson & Williamson, 2007). AEA inhibits keratinocytes proliferation and promotes cell death through CB1 and TRPV1 activation and Ca influx (Toth et al., 2011). ...
... AEA has also shown to downregulate the expression of keratins K6 and K16, which are over-expressed in psoriasis (Ramot et al., 2013). THC and cannabinoids have been shown to reduce the proliferation of keratinocytes (Wilkinson & Williamson, 2007). ...
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Objectives: Cannabinoids have gained popularity recently with special emphasis on their use for chronic pain. Although NICE guidelines advise against their usage for management of chronic pain, almost all rheumatologists encounter a few patients in their daily practice who either use them or are curious about them. We reviewed the mechanism of action of cannabinoids, current knowledge about their role in rheumatology and potential drug interactions with common drugs used in Rheumatology. We attempted to answer the question "If cannabinoids are friend, foe or just a mere bystander?" Methods: We adhered to a search strategy for writing narrative reviews as per available guidelines. We searched PubMed with the search terms "Cannabinoids", "Rheumatology" and "Chronic pain" for published articles and retrieved 613 articles. The abstracts and titles of these articles were screened to identify relevant studies focusing on mechanism of actions, adverse effects and drug interactions. We also availed the services of a musculoskeletal librarian. Results: Despite the NHS guidelines against the usage of cannabinoids and associated significant stigma, cannabinoids are increasingly used for the management of pain in rheumatology without prescription. Cannabinoids act through two major receptors CB1 and CB2, which are important modulators of the stress response with potential analgesic effects. Their role in various rheumatological diseases including Rheumatoid arthritis, Osteoarthritis and Fibromyalgia have been explored with some benefits. However, in addition to the adverse effects, cannabinoids also have some potential interactions with common drugs used in rheumatology, which many users are unaware of. Conclusion: While the current studies and patient reported outcomes suggest cannabinoids to be a "friend" of rheumatology, their adverse events and drug interactions prove to be a "Foe". We were unable to arrive at a definite answer for our question posed, however on the balance of probabilities we can conclude cannabinoids to be a "foe". Under these circumstances, a disease and drug focussed research is need of the hour to answer the unresolved question.
... In the clinical settings, CBD has shown promising results for both, psoriasis, and atopic dermatitis (Palmieri et al., 2019;Pleńkowska et al., 2020;Wilkinson and Williamson, 2007). On the other hand, selfinitiated topical administration of CBD oil has been reported to have been useful in the management of epidermolysis bullosa (Chelliah et al., 2018). ...
... Cannabidiol is an antioxidant, and it reduces hyperproliferation of keratinocytes in the epidermis. (Maccarrone et al., 2003;Wilkinson and Williamson, 2007) Higher amount of drug in epidermis is desirable, specially for localized action in case of the treatment of psoriasis. A study conducted on human epidermal keratinocytes reported cannabidiol to have shown anti-inflammatory effect in atopic dermatitis models (Miltner et al., 2018). ...
Article
Cannabidiol, a non-psychoactive constituent of cannabis, has garnered much attention after United States Food and Drug Administration approved Epidiolex® for oral use. Although therapeutic effect of cannabidiol after systemic absorption has been investigated extensively, its therapeutic potential in treating skin disorders after local delivery still needs further exploration. Our study has investigated the effect of cannabidiol concentration, chemical enhancers, and essential oils on percutaneous absorption of cannabidiol. In vitro permeation tests were conducted on human skin. The 24 h study results suggest no significant difference in amount of drug absorbed into skin, between 5% (242.41±12.17 µg/cm²) and 10% (232.79±20.82 cm²) cannabidiol solutions. However, 1% delivered (23.02±4.74 µg/cm²) significantly lower amount of drug into skin than 5% and 10%. Transcutol and isopropyl myristate did not enhance delivery of cannabidiol. However, oleic acid was found to be useful as chemical enhancer. Oleic acid (43.07±10.11 µg/cm²) had significantly higher cannabidiol delivery into skin than the group without oleic acid (10.98±3.40 µg/cm²) after a 4 h in vitro permeation study. Essential oils at concentrations tested had lower total cannabidiol delivery when compared to control. This study's findings will help guide future research on the pharmacological effect of percutaneously delivered cannabidiol on inflammatory skin disorders.
... Inhibition of cell proliferation, concentration-dependent and independent of CB1R/CB2R. [82] In vitro and in situ lab research ...
... The inhibition of keratinocyte proliferation by several CNBs (THC, CBD, CBN and CBG) was reported by Wilkinson et al. [82] in an in vitro study using a hyper-proliferating human keratinocyte cell line. The results showed proliferation inhibition in a concentrationdependent manner, independent of CBR activation, with the authors suggesting a mechanism involving the PPAR receptor. ...
Article
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The use of natural products in dermatology is increasingly being pursued due to sustainability and ecological issues, and as a possible way to improve the therapeutic outcome of chronic skin diseases, relieving the burden for both patients and healthcare systems. The legalization of cannabis by a growing number of countries has opened the way for researching the use of cannabinoids in therapeutic topical formulations. Cannabinoids are a diverse class of pharmacologically active compounds produced by Cannabis sativa (phytocannabinoids) and similar molecules (endocannabinoids, synthetic cannabinoids). Humans possess an endocannabinoid system involved in the regulation of several physiological processes, which includes naturally-produced endocannabinoids, and proteins involved in their transport, synthesis and degradation. The modulation of the endocannabinoid system is a promising therapeutic target for multiple diseases, including vascular, mental and neurodegenerative disorders. However, due to the complex nature of this system and its crosstalk with other biological systems, the development of novel target drugs is an ongoing challenging task. The discovery of a skin endocannabinoid system and its role in maintaining skin homeostasis, alongside the anti-inflammatory actions of cannabinoids, has raised interest in their use for the treatment of skin inflammatory diseases, which is the focus of this review. Oral treatments are only effective at high doses, having considerable adverse effects; thus, research into plant-based or synthetic cannabinoids that can be incorporated into high-quality, safe topical products for the treatment of inflammatory skin conditions is timely. Previous studies revealed that such products are usually well tolerated and showed promising results for example in the treatment of atopic dermatitis, psoriasis, and contact dermatitis. However, further controlled human clinical trials are needed to fully unravel the potential of these compounds, and the possible side effects associated with their topical use.
... In human trials, Palmieri et al. found that topical application of CBD improved skin lesions in the course of psoriasis, e.g., reduction of Psoriasis Area Severity Index, atopic eczema, and tissue scarring, as well as increased skin hydration and elasticity [9]. Likewise, Wilkinson showed that CBD acts on psoriasis in cultured human epidermal keratinocytes [10]. ...
... CBD was shown to inhibit the proliferation of hyperproliferative keratinocytes [10] and it was demonstrated to possess remarkable antibacterial activity [21]. ...
Article
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Hemp fiber variety, Bialobrzeskie, contains phenolic acids in its chemical composition giving it inherent antioxidant and antibacterial activity. The use of this raw material in fabric manufacture allows the creation of functional clothing with a positive effect on human skin. The aim of the study was to develop biologically active functional clothing made of pure industrial hemp raw materials, where cannabidiol (CBD) extract applied on the fabric surface strengthened the fiber bioactivity. The design of the clothing technology was focused on keeping the hemp inherent properties on a steady level and avoiding the use of chemicals in each stage of the value chain from plant cultivation up to garment manufacture. The research covered the evaluation of phenolic acids content and The Ferric Ion Reducing Antioxidant Power FRAP antioxidant activity of the hemp fabric. The hemp fabric enriched with CBD was used for clothing preparation. The human trials covered wearing of the clothing by 15 volunteers for six weeks and evaluation of hemp garment effect on human skin. The skin parameters were tested twice, before and after six weeks of clothing wearing, according to the own methodology that included measurements of skin biophysical properties including tests of skin moisture, transepidermal water loss, and sebum. Also, the effect of the active substances present on the fabrics on the in vitro culture of human keratinocytes was evaluated. Results of the research proved, that the wearing of developed functional hemp clothing with CBD extracts applied on the fabric surface was safe and caused improvement of skin condition, which can have an influence on slowing down of skin aging. The invention covering the pure hemp functional clothing with hybrid bioactivity resulting from the joined activity of fiber and cannabidiol was applied for a patent, Patent Application No: P.438388, 2021.
... In accordance with this, it is known that pCBs, such as CBD and CBDV, are able to alter in vitro mitochondrial metabolic rates and DNA syntheses at μM concentrations in both cancerous and normal human cells [45]. Moreover, Δ 9 -THC, CBD and CBG have been shown to inhibit the proliferation of transformed human keratinocytes, which are notably different from HaCaT cells in that are under hyperproliferative conditions [46]. Previously, our group showed that CBD and CBG, at μM concentrations, act as transcriptional repressors in the skin, where they control cell proliferation and differentiation by modulating key proteins (keratins 1 and 10, involucrin and transglutaminase 5) through the DNA methylation of their genes [38]. ...
... In accordance with this, it is known that pCBs, such as CBD and CBDV, are able to alter in vitro mitochondrial metabolic rates and DNA syntheses at µM concentrations in both cancerous and normal human cells [45]. Moreover, ∆ 9 -THC, CBD and CBG have been shown to inhibit the proliferation of transformed human keratinocytes, which are notably different from HaCaT cells in that are under hyperproliferative conditions [46]. Previously, our group showed that CBD and CBG, at µM concentrations, act as transcriptional repressors in the skin, where they control cell proliferation and differentiation by modulating key proteins (keratins 1 and 10, involucrin and transglutaminase 5) through the DNA methylation of their genes [38]. ...
Article
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The decriminalization and legalization of cannabis has paved the way for investigations into the potential of the use of phytocannabinoids (pCBs) as natural therapeutics for the treatment of human diseases. This growing interest has recently focused on rare (less abundant) pCBs that are non-psychotropic compounds, such as cannabigerol (CBG), cannabichromene (CBC), Δ9-tetrahydrocannabivarin (THCV) and cannabigerolic acid (CBGA). Notably, pCBs can act via the endocannabinoid system (ECS), which is involved in the regulation of key pathophysiological processes, and also in the skin. In this study, we used human keratinocytes (HaCaT cells) as an in vitro model that expresses all major ECS elements in order to systematically investigate the effects of CBG, CBC, THCV and CBGA. To this end, we analyzed the gene and protein expression of ECS components (receptors: CB1, CB2, GPR55, TRPV1 and PPARα/γ/δ; enzymes: NAPE-PLD, FAAH, DAGLα/β and MAGL) using qRT-PCR and Western blotting, along with assessments of their functionality using radioligand binding and activity assays. In addition, we quantified the content of endocannabinoid(-like) compounds (AEA, 2-AG, PEA, etc.) using UHPLC-MS/MS. Our results demonstrated that rare pCBs modulate the gene and protein expression of distinct ECS elements differently, as well as the content of endocannabinoid(-like) compounds. Notably, they all increased CB1/2 binding, TRPV1 channel stimulation and FAAH and MAGL catalytic activity. These unprecedented observations should be considered when exploring the therapeutic potential of cannabis extracts for the treatment of human skin diseases.
... Several authors performed a biological comparison among different cannabinoids within the same experimental setting. Due to their common anti-inflammatory properties, cannabinoids were investigated for their potential application in inflammatory-based skin diseases [77][78][79]. However, Petrosino et al. [79] observed different behaviors in poly(I : C)-activated keratinocytes, an immunogenic model that mimics viral infection and hypersensitivity through TLR3 and IFNγ induction. ...
... Regarding the context of psoriasis, Wilkinson et al. [78] demonstrated that phytocannabinoids (Δ 9 -THC, CBD, CBG, CBN) may counteract the proliferation of human HPV 16-transformed keratinocytes. The effect was independent from TRPV1 or CB 1/2 agonism and was slightly superior for nonpsychotropic cannabinoids (IC 50 ranging from 2.0 and 2.3 µM) than for THC (IC 50 = 2.9 µM). ...
Article
The use of Cannabis sativa is currently recognized to ease certain types of chronic pain, reduce chemotherapy-induced nausea, and improve anxiety. Nevertheless, few studies highlighted the therapeutic potential of C. sativa extracts and related phytocannabinoids for a variety of widespread skin disorders including acne, atopic dermatitis, psoriasis, pruritus, and pain. This review summarized the current evidence on the effects of phytocannabinoids at the cutaneous level through the collection of in vitro, in vivo, and clinical studies published on PubMed, Scopus, Embase, and Web of Science until October 2020. Phytocannabinoids have demonstrated potential anti-inflammatory, antioxidant, anti-aging, and anti-acne properties by various mechanisms involving either CB1/2-dependent and independent pathways. Not only classical immune cells, but also several skin-specific actors, such as keratinocytes, fibroblasts, melanocytes, and sebocytes, may represent a target for phytocannabinoids. Cannabidiol, the most investigated compound, revealed photoprotective, antioxidant, and anti-inflammatory mechanisms at the cutaneous level, while the possible impact on cell differentiation, especially in the case of psoriasis, would require further investigation. Animal models and pilot clinical studies supported the application of cannabidiol in inflammatory-based skin diseases. Also, one of the most promising applications of non-psychotropic phytocannabinoids is the treatment of seborrheic disorders, especially acne. In conclusion, the incomplete knowledge of the role of the endocannabinoid system in skin disorders emerged as an important limit for pharmacological investigations. Moreover, the limited studies conducted on C. sativa extracts suggested a higher potency than single phytocannabinoids, thus stimulating new research on phytocannabinoid interaction.
... Endocannabinoid ligand signalling by these two 'classical' cannabinoid receptors are known to trigger different pathways in the pathogenesis of some cancers, such as those of the liver and breast (Pisanti et al. 2013). Additionally, cancers such as those of the bladder, pancreas and small intestine and prostate cancer, keratinocyte and neuroblastoma cell lines (Brown 2007) respond to endocannabinoid-like ligands in a non-CB1/CB2-dependent manner (Ayakannu et al. 2013), indicating other potential cellular targets for endocannabinoids in tumours involving cells of this type (Wilkinson and Williamson 2007). ...
... 15 Synthetic cannabinoid receptor agonists can also have anti-histamine effects. Through manipulation of these inflammatory and cytokine pathways, cannabis has been hypothesized to decrease toll-like receptor activation, 19 decrease proliferation of cultured human epidermal keratinocytes, increase apoptotic reactions, 20 and to have potential utility for treatment of inflammatory conditions such as acne vulgaris, encephalomyelitis, and multiple sclerosis. 21 Beyond potential implications for wound healing, cannabis also affects the respiratory and cardiovascular systems. ...
Article
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Cannabis use is increasingly prevalent. Cannabinoid receptors regulate pro-inflammatory cytokines, and compounds in marijuana exert diverse physiologic effects. As more patients use cannabis, clinicians should recognize implications of perioperative cannabis use. Although the role of cannabis use in perioperative pain control has been explored, little is known about its effect on perioperative wound healing or on hematologic, pulmonary, and cardiovascular physiology. Methods: We searched PubMed for English-language articles related to cannabis (ie, marijuana, cannabidiol oil, and tetrahydrocannabinol) and wound healing, cardiovascular, pulmonary, or hematologic outcomes, and surgery. Titles and abstracts were reviewed, and relevant articles were analyzed. Human, animal, and pathology studies were included. Editorials, case reports, and review articles were excluded. Results: In total, 2549 wound healing articles were identified; 5 human studies and 8 animal/pathology studies were included. Results were conflicting. An estimated 2900 articles related to cardiovascular effects were identified, of which 2 human studies were included, which showed tetrahydrocannabinol and marijuana caused tachycardia. A total of 142 studies regarding pulmonary effects were identified. Three human studies were included, which found no difference in respiratory complications. In total, 114 studies regarding hematologic effects were identified. The 3 included human studies found conflicting venous thromboembolism risks. The overall study quality was poor. Information about dose/duration, administration route, and follow-up was reported with variable completeness. Conclusions: Surgeons should consider effects of cannabis in the perioperative setting. Little is known about its perioperative effects on wound healing, or on cardiovascular, pulmonary, and hematologic physiology. Further research should elucidate the effects of administration route, dose, and timing of cannabis use among surgical patients.
... As such, PEA could be a potential therapeutic target of CBD that can be used in phototherapy. Moreover, it is known that CBD activates PPARγ/GPR55 receptors or increases DNA methylation in human keratinocytes in order to inhibit their proliferation [55,56]. ...
Article
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There is a great need for compounds with antioxidant and anti-inflammatory properties for protection against UV radiation, which is the most prooxidative physical factor that skin cells are exposed to everyday. Therefore, the aim of the study was to evaluate the mechanism of phytocannabinoid-cannabidiol (CBD) action in vivo on lipid metabolism in keratinocytes of rat skin exposed to UVA/UVB radiation. Our results show that CBD protects keratinocytes against the effects of UVA/UVB radiation by reducing lipid peroxidation products: 4-HNE and 8-isoPGF2α. In addition, CBD significantly increases the level of endocannabinoids, such as anandamide, 2-arachidonylglycerol, and palmitoylethanolamide, and the activation of their receptors CB1/2 or TRPV1. The above changes are due to the protective effect of CBD against the UVA/UVB-induced decrease in the level/activity of superoxide dismutase and the components of the thioredoxin and glutathione systems. CBD also increases the in vivo transcriptional activity of Nrf2 and the expression of its Bach1 inhibitor as well as preventing the UVA/UVB-induced increase in the expression of Nrf2 activators p21, p62, p38, and KAP1 and proinflammatory factors such as NFκB and TNFα. By counteracting oxidative stress and changes in lipid structure in keratinocytes, CBD prevents cellular metabolic disturbances, protecting the epidermis against UV damage.
... Some of these phytocannabinoids (mainly THC and CBD) have been tested as a treatment against various skin conditions (see Table 3). [113] Psoriasis THC and CBD In vitro (human-skin keratinocytes) Inhibition of keratinocytes proliferation [114] CBD and CBG Human trial (2 subjects) 16-33% reduction of lesions after 6 weeks [115] Cannabinoids exhibit frequently antioxidant, antimicrobial activity, and less frequently a photoprotectant (see Table 4). [123] Because of its wide range of effects, formulation technologies are being developed to ensure better topical delivery of CBD for medical and cosmetic use [124][125][126][127][128]. ...
Article
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Cannabis sativa L. plant is currently attracting increasing interest in cosmetics and dermatology. In this review, the biologically active compounds of hemp are discussed. Particularly the complex interactions of cannabinoids with the endocannabinoid system of the skin to treat various conditions (such as acne, allergic contact dermatitis, melanoma, and psoriasis) with clinical data. Moreover, the properties of some cannabinoids make them candidates as cosmetic actives for certain skin types. Hemp seed oil and its minor bioactive compounds such as terpenes, flavonoids, carotenoids, and phytosterols are also discussed for their added value in cosmetic formulation.
... In psoriasis, the administration of Δ 9 -THC and CBD inhibits the proliferation of keratinocyte and modulate associated inflammation by promoting the conversion of Th1 lymphocytes to the anti-inflammatory Th2 phenotype [125]. These effects, however, are independent of CB receptors, and appear to be mediated predominantly by PPAR-γ [126]. Arachidonoyl-chloro-ethanolamide, a synthetic CB 1 agonist, decreases both keratinocyte cell proliferation in situ in human skin cultures, and the expression of K6 and K16 in organ cultured human skin samples [127]. ...
Article
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The discovery of endogenous cannabinoid receptors CB1 and CB2 and their endogenous ligands has generated interest in the endocannabinoid system and has contributed to the understanding of the role of the endocannabinoid system. Its role in the normal physiology of the body and its implication in pathological states such as cardiovascular diseases, neoplasm, depression and pain have been subjects of scientific interest. In this review the authors focus on the endogenous cannabinoids, and the critical role of cannabinoid receptor signaling in neurodegeneration and other inflammatory responses such as gut, joint and skin inflammation. This review also discusses the potential of endocannabinoid pathways as drug targets in the amelioration of some inflammatory conditions. Though the exact role of the endocannabinoid system is not fully understood, the evidence found much clearly points to a great potential in exploiting both its central and peripheral pathways in disease management. Cannabinoid therapy has proven promising in several preclinical and clinical trials.
... Mechanistically, CBD can inhibit the NF-κB signaling pathway and activate JAK/STAT kinase [18]. Therefore, CBD is used in a variety of diseases such as autoimmune encephalitis [19], rheumatoid arthritis [20], colitis [21], diabetes [22], and psoriasis [23], as well as Alzheimer's [24], Parkinson's [25], and Huntington's Disease [26]. It has also anticonvulsant [14,[27][28][29], antipsychotic [14,27,30], antiemetic [14,27], anticarcinogenic [31,32], and antidepressant [14,33] effects. ...
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Cannabidiol supplements (CBD) are increasingly consumed by athletes to improve regeneration. However, the evidence for the pro-regenerative effects of CBD in sports is quite limited. There-fore, our aim was to investigate the effects of a single CBD supplementation in a six-arm place-bo-controlled crossover study after resistance training on performance and muscle damage. Be-fore and after the resistance training, one-repetition maximum in the back squat (1RM BS), countermovement jump (CMJ), and blood serum concentrations of creatine kinase (CK) and myoglobin (Myo) were measured in healthy, well-trained participants. Sixteen of 21 participants completed the study and were included in the analysis. In 1RM BS, a significant decrease was observed after 24 h (p < 0 .01) but not 48 or 72 h. A significant group difference was detected after 72 h (p < 0.05; ES = 0.371). In CMJ, no significant changes were observed. The CK and Myo concentrations increased significantly after 24 h (CK: p < 0.001; Myo: p < 0.01), 48 h (CK: p < 0.001; Myo: p < 0.01) and 72 h (CK: p < 0.001; Myo: p < 0.001). After 72 h, a significant group difference was observed in both muscle damage biomarkers (CK: p < 0.05 ES = 0.236; Myo: p < 0.05; ES = 0.214). The results show small and significant effects on muscle damage and recovery of squat performance after 72 h. However, more data are necessary for clearer statements about the pro-regenerative effects of CBD supplementation after resistance training.
... Endocannabinoid ligand signalling by these two 'classical' cannabinoid receptors are known to trigger different pathways in the pathogenesis of some cancers, such as those of the liver and breast (Pisanti et al. 2013). Additionally, cancers such as those of the bladder, pancreas and small intestine and prostate cancer, keratinocyte and neuroblastoma cell lines (Brown 2007) respond to endocannabinoid-like ligands in a non-CB1/CB2-dependent manner (Ayakannu et al. 2013), indicating other potential cellular targets for endocannabinoids in tumours involving cells of this type (Wilkinson and Williamson 2007). ...
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Although the expression of the putative cannabinoid receptor GPR55 has been shown to be involved in the growth of various tumours and is increased in a number of cancers, its expression has not been examined in patients with endometrial cancer (EC). Quantitative RT-PCR (for mRNA levels) and immunohistochemistry (for protein levels) were used to measure GPR55 expression in patients with Type 1 and Type 2 EC and correlated against cannabinoid receptor (CB1 and CB2) protein levels using non-cancerous endometrium as the control tissue. The data indicated that GPR55 transcript and GPR55 protein levels were significantly ( p < 0.002 and p < 0.0001, respectively) higher in EC tissues than in control tissues. The levels of immunoreactive GPR55 protein were correlated with GPR55 transcript levels, but not with the expression of CB1 receptor protein, and were inversely correlated with CB2 protein expression, which was significantly decreased. It can be concluded that GPR55 expression is elevated in women with EC, and thus could provide a potential novel biomarker and therapeutic target for this disease.
... In addition, shorter and bulkier alkyl substituents at C-3 improved the affinity for the CB2 receptor [37,38]. Cannabinoids have also shown immunomodulatory properties in the treatment of psoriasis [39], antinociceptive properties related to their capacity to induce vasorelaxation and release neuropeptides [40,41], and antineoplastic activity on Lewis lung tumors [33]. ...
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The natural products pulchrol and pulchral, isolated from the roots of the Mexican plant Bourreria pulchra, have previously been shown to possess antiparasitic activity towards Trypanosoma cruzi, Leishmania braziliensis and L. amazonensis, which are protozoa responsible for Chagas disease and leishmaniasis. These infections have been classified as neglected diseases, and still require the development of safer and more efficient alternatives to their current treatments. Recent SARs studies, based on the pulchrol scaffold, showed which effects exchanges of its substituents have on the antileishmanial and antitrypanosomal activity. Many of the analogues prepared were shown to be more potent than pulchrol and the current drugs used to treat leishmaniasis and Chagas disease (miltefosine and benznidazole, respectively), in vitro. Moreover, indications of some of the possible interactions that may take place in the binding sites were also identified. In this study, 12 analogues with modifications at two or three different positions in two of the three rings were prepared by synthetic and semi-synthetic procedures. The molecules were assayed in vitro towards T. cruzi epimastigotes, L. braziliensis promastigotes, and L. amazonensis promastigotes. Some compounds had higher antiparasitic activity than the parental compound pulchrol, and in some cases even benznidazole and miltefosine. The best combinations in this subset are with carbonyl functionalities in the A-ring and isopropyl groups in the C-ring, as well as with alkyl substituents in both the A- and C-rings combined with a hydroxyl group in position 1 (C-ring). The latter corresponds to cannabinol, which indeed was shown to be potent towards all the parasites.
... In a 2020 study on CBG antibacterial activity against methicillin-resistant S. aureus (MRSA), it was found that, in vitro, CBG acts through the disruption of the cytoplasmatic membrane of MRSA. Using an in vivo model of systemic MRSA infection in mice, CBG was shown to express antibacterial action comparable to vancomycin, at a non-toxic dose of 100 mg/kg, suggesting that CBG could be a less toxic alternative for the treatment of methicillin-resistant Gram-negative bacteria [129]. ...
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The most important discoveries in pharmacology, such as certain classes of analgesics or chemotherapeutics, started from natural extracts which have been found to have effects in traditional medicine. Cannabis, traditionally used in Asia for the treatment of pain, nausea, spasms, sleep, depression, and low appetite, is still a good candidate for the development of new compounds. If initially all attention was directed to the endocannabinoid system, recent studies suggest that many of the clinically proven effects are based on an intrinsic chain of mechanisms that do not necessarily involve only cannabinoid receptors. Recent research has shown that major phytocannabinoids and their derivatives also interact with non-cannabinoid receptors such as vanilloid receptor 1, transient receptor ankyrin 1 potential, peroxisome proliferator-activated receptor-gamma or glitazone receptor, G55 protein-coupled receptor, and nuclear receptor, producing pharmacological effects in diseases such as Alzheimer’s, epilepsy, depression, neuropathic pain, cancer, and diabetes. Nonetheless, further studies are needed to elucidate the precise mechanisms of these compounds. Structure modulation of phytocannabinoids, in order to improve pharmacological effects, should not be limited to the exploration of cannabinoid receptors, and it should target other courses of action discovered through recent research.
... The proliferation of keratinocytes was inhibited by CBG in a concentration-dependent manner, indicating therapeutic potential for the treatment of an inflammatory condition known as psoriasis (Wilkinson and Williamson 2007). The major question arising from this study was the mechanism through which the keratinocytes are inhibited. ...
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Cannabigerol (CBG) is one of the major phytocannabinoids present in Cannabis sativa L. but is presumed to be an artefact or degradation product of cannabigerolic acid (CBGA), the principal precursor of several cannabinoids. The growing interest in CBG has been attributed to its non-psychotropic properties, low cannabinoid receptor potency and relative abundance in some commercial Cannabis varieties. A broad pharmacological profile has been described, where CBG is reported to exhibit anti-inflammatory, anticancer, anti-oxidant, antimicrobial, neuroprotective and appetite-enhancing properties, among others. Previous reviews on CBG have been limited to either the pharmacological potential of the molecule, with little detail on the chemistry, or to advances in the analytical tools used to explore CBG content in a wide range of biological samples. The current review seeks to highlight the chemistry, biosynthesis, pharmacology and safety aspects of the molecule. Additionally, we provide new insights into, and critical evaluation of, the pharmacological interactions of CBG via different receptor sites based on in silico predictions, using retrieved 3D structures of alpha-2 adrenergic receptors from the Protein Data Bank (PDB). For the first time, a bibliometric overview of the literature was performed, and with the aid of scientometric tools it was possible to present a visual overview of the research trends over the years, assess research performance of countries, and delineate the research output trajectory, hotspots and voids. In-depth analysis of the published literature revealed that clinical trials establishing the efficacy, safety and side-effects of CBG therapy in specific disease conditions are limited, as well as industry-friendly quality control procedures for CBG-enriched cannabis extracts.
... Some in vitro studies have shown that CBD inhibits differentiation in immortalized HaCaT cells 138 and also exerts antiproliferative actions on transformed human keratinocytes (HPV16). 139 On the contrary, a study by Casares et al indicated that the role of CBD in treating psoriasis should be approached with caution due to its proliferative effects for keratins 16 and 17. 42 Thus, more robust experimentation is needed to determine the use of treatment for psoriatic lesions. ...
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Though there is limited research confirming the purported topical benefits of cannabinoids, it is certain that cutaneous biology is modulated by the human endocannabinoid system (ECS). Receptors from the ECS have been identified in the skin and systemic abuse of synthetic cannabinoids, and their analogs, have also been associated with the manifestation of dermatological disorders, indicating the effects of the ECS on cutaneous biology. In particular, cannabidiol (CBD), a non-psychoactive compound from the cannabis plant, has garnered significant attention in recent years for its anecdotal therapeutic potential for various pathologies, including skin and cosmetic disorders. Though a body of preclinical evidence suggests topical application of CBD may be efficacious for some skin disorders, such as eczema, psoriasis, pruritis, and inflammatory conditions, confirmed clinical efficacy and elucidation of underlying molecular mechanisms have yet to be fully identified. This article provides an update on the advances in CBD research to date and the potential areas of future exploration.
... While they are not considered to have anti-inflammatory effect per se, cannabinoids have demonstrated the ability to inhibit keratinocyte cell proliferation, thus limiting the pro-inflammatory roles of these cells [170]. Wilkinson et al. showed that THC, cannabinol (CBN), CBD and CBG inhibit the proliferation of human papillomavirus (HPV)-16 E6/E7 transformed human skin keratinocytes in an in vitro model for psoriasis [171]. The synthetic CB1 agonist ACEA inhibited the upregulation of keratins K6 and K16 in isolated human skin samples of psoriasis lesions [172]. ...
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Recent studies have identified great similarities and interferences between the epithelial layers of the digestive tract, the airways and the cutaneous layer. The relationship between these structures seems to implicate signaling pathways, cellular components and metabolic features, and has led to the definition of a gut-lung-skin barrier. Inflammation seems to involve common features in these tissues; therefore, analyzing the similarities and differences in the modulation of its bi-omarkers can yield significant data promoting a better understanding of the particularities of specific signaling pathways and cellular effects. Cannabinoids are well known for a wide array of beneficial effects, including anti-inflammatory properties. This paper aims to explore the effects of natural and synthetic cannabinoids, including the components of the endocannabinoid system, in relation to the inflammation of the gut-lung-skin barrier epithelia. Recent advancements in the use of cannabinoids as anti-inflammatory substances in various disorders of the gut, lungs and skin are detailed. Some studies have reported mixed or controversial results, and these have also been addressed in our paper.
... CBD inhibited the proliferation of a hyper-proliferating human keratinocyte cell line in a concentration-dependent manner, thus demonstrating a therapeutic potential for the treatment of psoriasis. This process was not through a cannabinoid receptors mechanism [105]. It may be a consequence of CBD/PPARγ interactions, as the PPARγ receptor has been shown to be yet another cannabinoid receptor [106]. ...
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The pathophysiology of psoriasis is complex and has not been completely elucidated. Better understanding of the pathogenesis may contribute to further improvement of our therapeutic strategies controlling psoriasis. Emerging evidence points to a causative relationship between altered activity of peroxisome proliferator-activated receptor γ (PPARγ) and psoriasis. The present review focuses on deeper understanding of the possible role of PPARγ in the pathogenesis of psoriasis and the potential of PPARγ agonist to improve the treatment of psoriasis. PPARγ is decreased in psoriasis. PPARγ possibly has effects on the multiple aspects of the pathogenesis of psoriasis, including abnormal lipid metabolism, insulin resistance, immune cells, pro-inflammatory cytokines, keratinocytes, angiogenesis, oxidative stress, microRNAs and nuclear factor kappa B. As defective activation of PPARγ is involved in psoriasis development, PPARγ agonists may be promising agents for treatment of psoriasis. Pioglitazone appears an effective and safe option in the treatment of patients with psoriasis, but there are still concerns about its potential side effects. Research effort has recently been undertaken to explore the PPARγ-activating potential of natural products. Among them some have been studied clinically or preclinically for treatment of psoriasis with promising results.
... Its use by humans dates back to 5,000 years ago, and it represents one of the oldest plant sources of food and textile fiber (Russo, 2014). The therapeutic use of Cannabis includes the treatment of cancer-related pain, multiple sclerosis, rheumatoid arthritis, epilepsy, anorexia, anxiety, inflammatory bowel, and skin disease (Ahmed & Katz, 2016; Wilkinson & Williamson, 2007). THC, the main active ingredient, can induce transient cognitive and behavioral effects similar to those seen in endogenous psychoses. ...
... Previous data suggest that this agent could modulate skin biology and modify inflammatory processes. 1,2 However, the data from clinical trials are still lacking. To the best of our knowledge, this is the first randomized study, which aims to elucidate the efficacy and safety of CBD ointment in the treatment of psoriasis. ...
... CBC has also been shown to relieve pain in mice by augmenting the analgesic effects of THC when the two are co-administered (Davis & Hatoum, 1983;Maione et al., 2011;, and can increase concentrations and prolong the duration of endocannabinoids like anandamide through its interactions with TRP channels (Shinjyo & Di Marzo, 2013;De Petrocellis et al., 2011. CBN is being investigated for several topical therapeutic targets for skin conditions like psoriasis, burns, and MRSA infections, via inhibition of keratinocyte proliferation, TRPV2 agonism, and direct antimicrobial activity, respectively (Wilkinson & Williamson, 2007;Appendio et al., 2008;Qin et al., 2008;Russo, 2014). In addition, CBN is an important marker compound of THC degradation in plant material, an artifact that occurs naturally with storage and may be expedited by high heat exposure as the oxidation byproduct of THC (Upton et al., 2013). ...
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“Hemp” refers to non-intoxicating, low delta-9 tetrahydrocannabinol (Δ9-THC) cultivars of Cannabis sativa L. “Marijuana” refers to cultivars with high levels of Δ9-THC, the primary psychoactive cannabinoid found in the plant and a federally controlled substance used for both recreational and therapeutic purposes. Although marijuana and hemp belong to the same genus and species, they differ in terms of chemical and genetic composition, production practices, product uses, and regulatory status. Hemp seed and hemp seed oil have been shown to have valuable nutritional capacity. Cannabidiol (CBD), a non-intoxicating phytocannabinoid with a wide therapeutic index and acceptable side effect profile, has demonstrated high medicinal potential in some conditions. Several countries and states have facilitated the use of THC-dominant medical cannabis for certain conditions, while other countries continue to ban all forms of cannabis regardless of cannabinoid profile or low psychoactive potential. Today, differentiating between hemp and marijuana in the laboratory is no longer a difficult process. Certain thin layer chromatography (TLC) methods can rapidly screen for cannabinoids, and several gas and liquid chromatography techniques have been developed for precise quantification of phytocannabinoids in plant extracts and biological samples. Geographic regulations and testing guidelines for cannabis continue to evolve. As they are improved and clarified, we can better employ the appropriate applications of this uniquely versatile plant from an informed scientific perspective.
... e unique therapeutic effects of cannabis are hypothesized to be achieved through a complex synergy between the multiple phytocannabinoids and many other secondary compounds of the plant, including terpenes and flavonoids [6,7]. Cannabinoids are the subject of ongoing active research in the field of natural pharmaceutical agents, with evidence implying their potential effectiveness for the treatment of inflammation, cancer, and cardiovascular disorders [8][9][10]. Furthermore, cannabis usage is associated with a reduced risk for metabolic diseases such as obesity [11], diabetes [12,13], and NAFLD [14,15]. ...
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Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver abnormalities and has been linked with metabolic syndrome hallmarks. Unfortunately, current treatments are limited. This work aimed to elucidate the effects of three cannabis extracts on metabolic alteration and gut microbiota composition in a mouse model of NAFLD and obesity. Male mice were fed with a high-fat diet (HFD) for 12 weeks. Following the establishment of obesity, the HFD-fed group was subdivided into HFD or HFD that was supplemented with one of three cannabis extracts (CN1, CN2, and CN6) for additional 8 weeks. Metabolic parameters together with intestinal microbiota composition were evaluated. Except for several minor changes in gene expression, no profound metabolic effect was found due to cannabis extracts addition. Nevertheless, marked changes were observed in gut microbiota diversity and composition, with CN1 and CN6 exhibiting microbial abundance patterns that are associated with more beneficial outcomes. Taken together, specific cannabis extracts’ addition to an HFD results in more favorable modifications in gut microbiota. Although no marked metabolic effect was disclosed, longer treatments duration and/or higher extracts concentrations may be needed. More research is required to ascertain this conjecture and to establish the influence of various cannabis extracts on host health in general and NAFLD in particular.
... On the other hand, cannabidiol (CBD) comes from the Cannabaceae family [25]. CBD is a biologically active cannabinoid with anticonvulsant [26], spasmolytic [27] and anticancer [28] effects that is indicated in the treatment of various diseases [29][30][31]. Its biological activity is due to the interaction with the endocannabidoid system, which includes two cannabinoid receptors coupled to G proteins (CB1, located in the central nervous system, and CB2, located in the lymph nodes) and two endogenous (anandamide and 2-arachidonoylglycerol) compounds [32][33][34]. ...
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The use of supplements containing herbal active ingredients in sport has increased in recent years. Their consumption is explained by the benefits they may provide and because their natural origin do not involve health complications, from the point of view of the consumers. The aim of this study is to analyze the availability of four supplements (caffeine, turmeric, ginseng, cannabidiol) on the internet and understand the nature of these websites. A descriptive, observational, and cross-sectional study design was used. A detailed search was carried out with specifically developed software. The searches and data evaluation took 10 days. The websites consulted correspond to those that sell supplements, or some sport websites in the case of the Spanish ones, whereas those in English belong to pharmacies, parapharmacies, or herbalists. It is concluded that the websites do not provide adequate information to ensure proper consumption and lack advice on the choices of supplements and their administration guidelines.
... In psoriasis, the administration of Δ 9 -THC and CBD inhibit the proliferation of keratinocyte and modulate associated inflammation by promoting the conversion of Th1 lymphocytes to the anti-inflammatory Th2 phenotype (Sheriff et al., 2019). These effects, however, are independent of CB receptors, and appears to be mediated predominantly by PPARγ (Wilkinson and Williamson, 2007). Arachidonoyl-chloro-ethanolamide, a synthetic CB 1 agonist, decreases both keratinocyte cell proliferation in situin human skin cultures, and the expression of K6 and K16 in organ cultured human skin samples (Ramot et al., 2013). ...
... Thus, CBG could be investigated as a potential treatment for MS and possibly other neuroinflammatory diseases [151]. Given CBG's antioxidant and anti-inflammatory effects seen in in vivo studies, it could also be investigated as a potential treatment for inflammatory conditions like colitis [89], IBD [123], 'acne-like condition,' dry skin syndrome [134], and psoriasis [152]. Given its inhibitory effects on growth of colorectal cells, it could also be developed for the prevention and treatment of colorectal and other cancers including breast cancer [123,153]. ...
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Purpose of review There have been many debates, discussions, and published writings about the therapeutic value of cannabis plant and the hundreds of cannabinoids it contains. Many states and countries have attempted, are attempting, or have already passed bills to allow legal use of cannabinoids, especially cannabidiol (CBD), as medicines to treat a wide range of clinical conditions without having been approved by a regulatory body. Therefore, by using PubMed and Google Scholar databases, we have reviewed published papers during the past 30 years on cannabinoids as medicines and comment on whether there is sufficient clinical evidence from well-designed clinical studies and trials to support the use of CBD or any other cannabinoids as medicines. Recent findings Current research shows that CBD and other cannabinoids currently are not ready for formal indications as medicines to treat a wide range of clinical conditions as promoted except for several exceptions including limited use of CBD for treating two rare forms of epilepsy in young children and CBD in combination with THC for treating multiple-sclerosis-associated spasticity. Summary Research indicates that CBD and several other cannabinoids have potential to treat multiple clinical conditions, but more preclinical, and clinical studies and clinical trials, which follow regulatory guidelines, are needed to formally recommend CBD and other cannabinoids as medicines.
... A recent study by Jin et al. (2020) found that leaves are rich in cannabinoids, terpenes and sesquiterpenoids, but also contain significant quantities of flavonoids and sterols. They all have anti-inflammatory, anti-bacterial and anti-fungal properties that can promote wound healing and can help with different skin problems (Andre et al., 2016;Kupczyk et al., 2009;Wilkinson and Williamson, 2007;Wright et al., 2005). Another system category with which leaf use is significantly associated was circulatory system and blood disorders (p = 0.005) ( Fig. 2 and Supplementary data Table S4). ...
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Ethnopharmacological relevance: Cannabis is one of the most versatile genera in terms of plant use and has been exploited by humans for millennia. Nowadays, Cannabis is the centre of many scientific studies, most of them focusing on chemical composition and medicinal values. While new and varied applications are continuously being developed, the knowledge surrounding less common uses of the plant is slowly disappearing. Aim of the review: We have analysed diversity of global data of Cannabis traditional uses, to investigate if certain plant parts are significantly associated with particular Cannabis use. We wanted to uncover potential associations between the plant parts used for the treatment of different body systems and ailments. Materials and methods: We have analysed the extensive database of Cannabis traditional uses (CANNUSE). This database contains 2330 data entries of Cannabis ethnobotanical uses from over 40 countries across the world. The dataset was divided into five general groups based on the type of use: medicinal, alimentary, psychoactive, fibre and other uses. Given the abundance of human medicinal uses, detailed analysis was done on the subset of 1167 data entries. We analysed the relationship between 16 body system categories and ailments treated with Cannabis plant parts. We used a Pearson's chi-square and Fisher's exact test, to determine which Cannabis parts are characteristic of treatment for specific ailments. Results: In this dataset, the majority of reports were represented by medicinal (75.41%), followed by psychoactive (8.35%) and alimentary (7.29%) use. The most commonly used plant parts were leaf (50.51%), seed (15.38%) and inflorescence (11.35%). We found that different Cannabis plant parts were significantly associated with different uses; the leaf was typically used for medicinal, seed for alimentary and inflorescence for psychoactive use. Regarding the human medicinal uses, most common were reports for treatments of the digestive system and nutritional disorders (17.66%), nervous system and mental disorders (16.24%), followed by pain and inflammations (12.21%). We found a significant relationship between the use of certain Cannabis parts and treatment of ailments and body systems categories; leaf was significantly associated with treatment of two categories: skin and subcutaneous tissue disorders and circulatory system and blood disorders; seed use was associated with musculoskeletal system disorders and traumas; while inflorescence use shows a statistical support for treatment of nervous system and mental disorders. Conclusion: Several pharmaceutical companies are intensely working on developing new drugs with isolated chemical compounds or crude extracts, almost exclusively from Cannabis inflorescences. However, our review revealed that use of leaf or seed in traditional medicine is often more important than use of inflorescence for the treatment of certain ailments. A review of traditional medicine provides a body of knowledge and an initial pathway to identify landraces and plant parts that could have an important role in future medicinal research. We are confident that traditional medicine still has a large potential for modern medicine. As more information on Cannabis diversity (genetics, biochemistry, and clinical studies) becomes available, ethnobotanical data are poised to be of much greater significance.
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Geçmişte pek çok bitki, bitki parçası, meyvesi, tohumu ve bunlardan hazırlanan ürünler (iksirler ve karışımlar) tedavi amaçlı olarak kullanılmıştır. Bugün farmasötik sanayide gelinen aşamadan dolayı geçmişe bakıldığında, kullanılan birçok iksirlerin ve karışımların işe yaramadığı, hatta bazılarının zararlı bile olduğu bilinmektedir. Bununla birlikte, bazı bitkilerin bazı hastalıklara farklı mekanizmalarla olumlu etkileri olabildiği bilimsel olarak kanıtlanırken aynı zamanda bir kısmı ilaç etken maddesi olarak eczanelerde de yer alabilmektedir. Bu bitkilerden biri olan kenevir, insanlar tarafından yüzyıllar boyunca tekstil lifi, ilaç, keyif verici madde, tıbbı tedavi amaçlı olarak ve dini ritüellerde günlük adanma işlemleri sırasında kullanılmıştır.
Chapter
Medical marijuana and the promise of medical advances with cannabinoids is a controversial topic. This book provides clinicians with credible, peer-reviewed science to advise patients on the use of cannabinoids in practice. From the history of cannabis to the recent discoveries, chapters include the science of cannabinoids, changes in the legal and regulatory landscape, and the emerging area of endocannabinoids. The book differentiates approved cannabinoids from cannabis and medical marijuana and stimulates clinicians to think about the risks and benefits of these two drugs. It provides the factual background for clinicians to lead the discussion on the continued use of marijuana, ongoing areas of research and future advances and development of new medications for treatment. An invaluable guide for all specialists in the pharmaceutical sciences, toxicologists, biochemists, neurologists, psychiatrists, addiction specialists, as well as primary care physicians, nurse practitioners, and regulators and policymakers.
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Psoriasis, an incurable autoimmune skin disease, is one of the most common immune-mediated disorders. Presently, numerous clinical research studies are underway, and treatment options are available. However, these treatments focus on improving symptoms of the disease and fail to achieve a radical cure; they also have certain toxic side effects. In recent years, natural products have increasingly gained attention because of their high efficiency and low toxicity. Despite their obvious therapeutic effects, natural products’ biological activity was limited by their instability, poor solubility, and low bioavailability. Novel drug delivery systems, including liposomes, lipospheres, nanostructured lipid carriers, niosomes, nanoemulsions, nanospheres, microneedles, ethosomes, nanocrystals, and foams could potentially overcome the limitations of poor water solubility and permeability in traditional drug delivery systems. Thus, to achieve a therapeutic effect, the drug can reach the epidermis and dermis in psoriatic lesions to interact with the immune cells and cytokines.
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University of Conneticut School of Medicine The public and health care providers are increasingly curious about the potential medical benefits of Cannabis. In vitro and in vivo studies of Cannabis have suggested it has favorable effects on regulating pain, pruritus, and inflammation, making it a potentially attractive therapeutic agent for many dermatologic conditions. The body of literature reporting on the role of cannabinoids in dermatology is in its infancy but growing. We review the current research, possible cutaneous adverse effects, and future directions for cannabinoids and their use in skin cancer, acne, psoriasis, pruritus, dermatitis, scleroderma, dermatomyositis, cutaneous lupus erythematous, epidermolysis bullosa, pain, and wound healing.
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The impact of aging on the integrity of the outermost layer of our tissue, the epithelium, predisposes the older adult to dysfunction in these tissues found in the skin, lungs, eyes, and hair. As the foundation of health, the health status of the gut lining directs the status of other epithelial tissues due to the impact of nutritional deficiencies from malabsorption as well as the impact of the microbiome that exists on all of these external-facing surfaces. Both environments, the skin and the gut, host microbiomes of immense and diverse proportions. On its own, the gut performs innumerable functions, including but not limited to vitamin production, immune regulation, protection from pathogens, serum lipid modulation, and metabolism of xenobiotics and food components (Ellis et al. Microorganisms 7:550, 2019). The skin serves to maintain the cutaneous immune system. (Ellis et al. Microorganisms 7:550, 2019). Although the mechanisms are not fully elucidated, there are a few prevailing theories. Changes in gut flora due to stress, injury, or inflammation increase epithelial permeability in the gut, which triggers T-cell activation, disrupts tolerance, and leads to systemic inflammation that disturbs cutaneous homeostasis (Arck et al. Exp Dermatol 19:401–5, 2010). Another theory suggests increased gut permeability allows for direct migration of inflammatory products into systemic circulation (Cani et al. Diabetes 56:1761–72, 2007). The connection warrants further research but is likely due to a combination of both neurologic and immunologic responses to environmental changes (Ellis et al. Microorganisms 7:550, 2019). In this chapter, we highlight the most common concerns related to the skin, lungs, eyes, and hair for the older adult: xerosis, psoriasis, eczema, chronic obstructive pulmonary disease, macular degeneration, and alopecia.
Chapter
Cannabis refers to a genus of flowering plants and includes three major species Cannabis sativa, Cannabis indica, and Cannabis ruderalis. Phytocannabinoids (plant-based cannabinoids) include cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC). Endocannabinoids are endogenous chemicals which act on the cannabinoid receptors (CBR). Synthetic medications such as nabilone, dronabinol, and rimonabant are also commercially available. The phytocannabinoids are chemicals extracted from the cannabis plant either interacting directly with cannabinoid receptors or sharing chemical similarity with endocannabinoids or both. While Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most studied phytocannabinoids, other phytocannabinoids that require special mention include cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), and tetrahydrocannabivarin (THCV). These minor cannabinoids have demonstrated anticonvulsant, anti-inflammatory, antibacterial, and antidepressant properties apart from showing promise in pain relief and muscle relaxation. Evidence of anticancer and cytotoxic properties on human epithelioid carcinoma and breast cancer in basic research models highlights the need for further research in this arena, to validate their use.
Article
Psoriasis is one of the most common human skin diseases, although its development is not limited to one tissue, but is associated with autoimmune reactions throughout the body. Overproduction of pro-inflammatory cytokines and growth factors systemically stimulates the proliferation of skin cells, which manifests as excessive exfoliation of the epidermis, and/or arthritis, as well as other comorbidities such as insulin resistance, metabolic syndrome, hypertension, and depression. Thus, there is a great need for a thorough analysis of the pathophysiology of psoriatic patients, including classical methods, such as spectrophotometry, chromatography, or Western blot, and also novel omics approaches such as lipidomics and proteomics. Moreover, the extensive pathophysiology forces increased research examining biological changes in both skin cells, and systemically. A wide range of techniques involved in lipidomic research based on a combination of mass spectrometry and different types of chromatography (RP-LC-QTOF-MS/MS, HILIC-QTOF-MS/MS or RP-LC-QTRAP-MS/MS), have allowed comprehensive assessment of lipid modification in psoriatic skin and provided new insight into the role of lipids and their mechanism of action in psoriasis. Moreover, proteomic analysis using gel-nanoLC-OrbiTrap-MS/MS, as well as MALDI-TOF/TOF techniques facilitates the description of panels of enzymes involved in lipidome modifications, and the response of the endocannabinoid system to metabolic changes. Psoriasis is known to alter the expression of proteins that are involved in the inflammatory and antioxidant response, as well as protein biosynthesis, degradation, as well as cell proliferation and apoptosis. Knowledge of changes in the lipidomic and proteomic profile will not only allow the understanding of psoriasis pathophysiology, but also facilitate proper and early diagnosis and effective pharmacotherapy.
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Introduction: Cannabigerol (CBG), and its precursor before decarboxylation, cannabigerolic acid is sometimes labeled the "mother of all cannabinoids." The purpose of the present study was to investigate reasons for use and self-reported therapeutic effects in CBG-predominant cannabis users. Usage patterns and adverse effects, including withdrawal symptoms were also explored. Methods: Cannabidiol-predominant cannabis users were recruited online to complete an online survey assessing CBG use patterns, conditions treated with CBG-predominant cannabis (containing >50% CBG), perceived efficacy, associated adverse events, and withdrawal symptoms. One hundred twenty-seven eligible participants (U.S. residents ages 21+ who reported using CBG-predominant cannabis in the past 6 months) completed the survey. Results: Most of the samples (n=65; 51.2%) reported use of CBG-predominant products solely for medical purposes (n=46; 36.2% reported use for medical and recreational purposes; n=8; 6.3% reported recreational use only, and n=8 were missing). The most common conditions the complete sample reported using CBG to treat were anxiety (51.2%), chronic pain (40.9%), depression (33.1%), and insomnia/disturbed sleep (30.7%). Efficacy was highly rated, with the majority reporting their conditions were "very much improved" or "much improved" by CBG. Furthermore, 73.9% claimed superiority of CBG-predominant cannabis over conventional medicines for chronic pain, 80% for depression, 73% for insomnia, and 78.3% for anxiety. Forty-four percent of CBG-predominant cannabis users reported no adverse events, with 16.5% noting dry mouth, 15% sleepiness, 11.8% increased appetite, and 8.7% dry eyes. Around 84.3% reported no withdrawal symptoms, with sleep difficulties representing the most frequently endorsed withdrawal symptom (endorsed by two respondents). Conclusions: This is the first patient survey of CBG-predominant cannabis use to date, and the first to document self-reported efficacy of CBG-predominant products, particularly for anxiety, chronic pain, depression, and insomnia. Most respondents reported greater efficacy of CBG-predominant cannabis over conventional pharmacotherapy, with a benign adverse event profile and negligible withdrawal symptoms. This study establishes that humans are employing CBG and suggests that CBG-predominant cannabis-based medicines should be studied in randomized controlled trials.
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Synthetic Cannabinoids (CBs) are a novel class of psychoactive substances that have rapidly evolved around the world with the addition of diverse structural modifications to existing molecules which produce new structural analogues that can be associated with serious adverse health effects. Synthetic CBs represent the largest class of drugs detected by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) with a total of 207 substances identified from 2008 to October 2020, and 9 compounds being reported for the first time. Synthetic CBs are sprayed on natural harmless herbs with an aim to mimic the euphoric effect of Cannabis. They are sold under different brand names including Black mamba, spice, K2, Bombay Blue, etc. As these synthetic CBs act as full agonists at the CB receptors, they are much more potent than natural Cannabis and have been increasingly associated with acute to chronic intoxications and death. Due to their potential toxicity and abuse, the US government has listed some synthetic CBs under schedule 1 classification. The present review aims to provide a focused overview of the literature concerning the development of synthetic CBs, their abuse, and potential toxicological effects including renal toxicity, respiratory depression, hyperemesis syndrome, cardiovascular effects, and a range of effects on brain function.
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Topical therapy is a mainstay of dermatological treatment and holds many advantages, including ease of use, relative lack of systemic side effects, and patient-directed application. In hidradenitis suppurativa (HS), topical therapeutics are often used for early-stage lesions or as adjunct therapy to systemic or surgical treatments. The four categories of disease-modifying topical therapies for sHS include antibiotics, antiseptics, keratolytics, and bathing additives (each of which will be discussed in this chapter), while topical therapies aimed at symptom-control such as analgesics and antipruritics are reviewed in Chapter 19. Unfortunately, there is a lack of robust evidence supporting the use of most topical therapies in HS. Thus, in the absence of rigorous data, the decision regarding which topical treatment to use is often made at the clinician’s discretion as well as the patient’s preference. This chapter will provide an overview of topical therapies, including their dosing schedules, mechanisms of action, contraindications, and recommendations for use to better inform these decisions.
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Cannabidiol (CBD) is one of the main active ingredients in hemp. It shows a number of valuable biological properties, such as anti-cancer, anti-depressant or anti-inflammatory. The aim of the article was to present the most importantproperties of cannabidiol and its possible application in cosmetology and dermatology. The wide therapeutic potential of CBD makes it possible to use in the treatment of, not only cancer or mental disorders, but also many dermatoses.
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The Chemistry inside Spices & Herbs: Research and Development brings comprehensive information about the chemistry of spices and herbs with a focus on recent research in this field. The book is an extensive 2-part collection of 20 chapters contributed by experts in phytochemistry with the aim to give the reader deep knowledge about phytochemical constituents in herbal plants and their benefits. The contents include reviews on the biochemistry and biotechnology of spices and herbs, herbal medicines, biologically active compounds and their role in therapeutics among other topics. Chapters which highlight natural drugs and their role in different diseases and special plants of clinical significance are also included. Part II continues from the previous part with chapters on the treatment of skin diseases and oral problems. This part focuses on clinically important herbs such as turmeric, fenugreek, ashwagandha (Indian winter cherry), basil, Terminalia chebula (black myrobalan). In terms of phytochemicals, this part presents chapters that cover resveratrol, piperine and circumin. Audience: This book is an ideal resource for scholars (in life sciences, phytomedicine and natural product chemistry) and general readers who want to understand the importance of herbs, spices and traditional medicine in pharmaceutical and clinical research.
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The use of cannabinoids in veterinary medicine has been increasing exponentially recently and there is little information regarding the pharmacokinetics of cannabinoids except for cannabidiol (CBD) and tetrahydrocannabinol (THC), with even more sparse information related to their native acid forms found in cannabis. Cannabigerol (CBG) is the precursor molecule to cannabinoid formation in the cannabis plant which may have medicinal properties as well, yet there are no publications related to CBG or the native cannabigerolic acid (CBGA) in companion animal species. The aim of this study was to investigate similar dosing of CBG and CBGA from hemp plants that have been used for cannabidiol pharmacokinetic studies. Administration in the fed and fasted state was performed to better understand absorption and retention of these unique hemp‐derived cannabinoids in dogs. Results suggest that when providing a hemp‐derived CBG/CBGA formulation in equal quantities, CBGA is absorbed approximately 40‐fold better than CBG regardless of being given to fed or fasted dogs. After twice daily dosing for two weeks at 2 mg/kg in the fasted and then fed state, no differences in the mean serum CBG (5 ng/ml) or CBGA (250 ng/ml) serum concentrations were observed between states. Importantly, physical examination, complete blood counts, and serum chemistry evaluations over the two weeks suggest no adverse events during this short‐term dosing trial.
Chapter
The Chemistry inside Spices and Herbs: Research and Development brings comprehensive information about the chemistry of spices and herbs with a focus on recent research in this field. The book is an extensive 2-part collection of 20 chapters contributed by experts in phytochemistry with the aim to give the reader deep knowledge about phytochemical constituents in herbal plants and their benefits. The contents include reviews on the biochemistry and biotechnology of spices and herbs, herbal medicines, biologically active compounds and their role in therapeutics among other topics. Chapters which highlight natural drugs and their role in different diseases and special plants of clinical significance are also included. Part II continues from the previous part with chapters on the treatment of skin diseases and oral problems. This part focuses on clinically important herbs such as turmeric, fenugreek, ashwagandha (Indian winter cherry), basil, Terminalia chebula (black myrobalan). In terms of phytochemicals, this part presents chapters that cover resveratrol, piperine and circumin.
Article
Ethnopharmacological relevance Skin diseases are among the most common human health affections. A healthy skin promotes a healthy body that can be achieved through modern, allopathic and natural medicines. Therefore, medicinal plants can be a reliable therapy in treating skin diseases in humans through a diverse range of bioactive molecules they contain. Aim of the study This review aims to provide for the first-time scientific evidence related to the dermatological properties of Morocco's medicinal plants and it aims to provide a baseline for the discovery of new drugs having activities against skin issues. Methods This review involved an investigation with different search engines for Moroccan ethnobotanical surveys published between 1991 and 2021. The plants used to treat skin diseases have been determined. Information regarding pharmacological effects, phytochemical, and clinical trials related to the plants listed in this review was collected from different scientific databases like PubMed, Science Direct, Google Scholar, Web of Science and Scopus. The data were analyzed and summarized in the review. Results A total of 401 plants belonging to 86 families mainly represented by Asteraceae, Lamiaceae, Fabaceae, and Apiaceae which have been documented to be in common use by Moroccans for managing skin diseases. Among those plants recorded, the most commonly used are Allium cepa L, Chamaeleon gummifer (L.) Cass and Salvia rosmarinus Schleid. Mill. Leaves were the most commonly used plant part, while powder and decoction were the most common method of traditional drug preparation. 107 of the 401 plants (27%) have undergone pharmacological validation. A total of 44 compounds isolated from 27 plants were investigated to treat different types of skin diseases, and 25 plants have been clinically studied for their activities against skin diseases. Conclusion The beneficial effects of using Moroccan medicinal plants to treat skin diseases, according to traditional practices, have been proven in numerous scientific studies. Therefore, other studies should focus on isolating and identifying specific bioactive compounds from plant extracts, revealing more valuable therapeutic properties. Furthermore, additional reliable clinical trials are needed to confirm their beneficial effect on patients with skin diseases.
Article
Objectives Evidence suggests that cannabinoids may provide therapeutic benefit to patients with dermatologic conditions. The recommendation behaviors of dermatologists with regards to recommending medical cannabis are unknown. We administered a pilot survey to evaluate dermatologists’ recommendation behaviors including dermatologic indications and formulation preferences. Design A cross-sectional study was done to sample dermatologists using a 24-question survey. Setting Online survey through SurveyMonkey® that was distributed via Orlando Dermatology Aesthetic and Clinical Conference’s mailing list, including thousands of practicing dermatologists. Main outcome measures Descriptive data of dermatologists’ recommendation behaviors of medical cannabis are described. Fisher’s exact test and Chi-Square tests were used to compare recommendation behaviors by gender, age, years in practice, and residency legality. Results The survey was sent to 7176 individuals; of the 28.7 % who opened the email, 2.2 % completed the survey (N = 145). 91 % of dermatologists were in support of medical cannabis use and 13.8 % have recommended it for a dermatologic condition. Atopic dermatitis (45 %) and psoriasis (40 %) were the most common. The most common form of administration was topical (75 %). The main reasons for not recommending medical cannabis were limited knowledge (56 %) and lack of experience (48 %). Conclusions Cutaneous inflammatory and pruritic conditions such as psoriasis and atopic dermatitis were the most common reasons dermatologists recommended medical cannabis in our survey. Respondents’ recommendation patterns may have been limited by limited by lack of knowledge or experience with medical cannabis. The small sample size of our survey limits generalizability to the dermatology field and warrants further investigation.
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We have developed a rapid, sensitive, and inexpensive method for measuring the cellular protein content of adherent and suspension cultures in 96-well microtiter plates. The method is suitable for ordinary laboratory purposes and for very large-scale applications, such as the National Cancer Institute's disease-oriented in vitro anticancer-drug discovery screen, which requires the use of several million culture wells per year. Cultures fixed with trichloroacetic acid were stained for 30 minutes with 0.4% (wt/vol) sulforhodamine B (SRB) dissolved in 1% acetic acid. Unbound dye was removed by four washes with 1% acetic acid, and protein-bound dye was extracted with 10 mM unbuffered Tris base [tris (hydroxymethyl)aminomethane] for determination of optical density in a computer-interfaced, 96-well microtiter plate reader. The SRB assay results were linear with the number of cells and with values for cellular protein measured by both the Lowry and Bradford assays at densities ranging from sparse subconfluence to multilayered supraconfluence. The signal-to-noise ratio at 564 nm was approximately 1.5 with 1,000 cells per well. The sensitivity of the SRB assay compared favorably with sensitivities of several fluorescence assays and was superior to those of both the Lowry and Bradford assays and to those of 20 other visible dyes. The SRB assay provides a colorimetric end point that is nondestructive, indefinitely stable, and visible to the naked eye. It provides a sensitive measure of drug-induced cytotoxicity, is useful in quantitating clonogenicity, and is well suited to high-volume, automated drug screening. SRB fluoresces strongly with laser excitation at 488 nm and can be measured quantitatively at the single-cell level by static fluorescence cytometry.
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Nonmelanoma skin cancer is one of the most common malignancies in humans. Different therapeutic strategies for the treatment of these tumors are currently being investigated. Given the growth-inhibiting effects of cannabinoids on gliomas and the wide tissue distribution of the two subtypes of cannabinoid receptors (CB(1) and CB(2)), we studied the potential utility of these compounds in anti-skin tumor therapy. Here we show that the CB(1) and the CB(2) receptor are expressed in normal skin and skin tumors of mice and humans. In cell culture experiments pharmacological activation of cannabinoid receptors induced the apoptotic death of tumorigenic epidermal cells, whereas the viability of nontransformed epidermal cells remained unaffected. Local administration of the mixed CB(1)/CB(2) agonist WIN-55,212-2 or the selective CB(2) agonist JWH-133 induced a considerable growth inhibition of malignant tumors generated by inoculation of epidermal tumor cells into nude mice. Cannabinoid-treated tumors showed an increased number of apoptotic cells. This was accompanied by impairment of tumor vascularization, as determined by altered blood vessel morphology and decreased expression of proangiogenic factors (VEGF, placental growth factor, and angiopoietin 2). Abrogation of EGF-R function was also observed in cannabinoid-treated tumors. These results support a new therapeutic approach for the treatment of skin tumors.
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Studies on the effects of marijuana smoking have evolved into the discovery and description of the endocannabinoid system. To date, this system is composed of two receptors, CB1 and CB2, and endogenous ligands including anandamide, 2-arachidonoyl glycerol, and others. CB1 receptors and ligands are found in the brain as well as immune and other peripheral tissues. Conversely, CB2 receptors and ligands are found primarily in the periphery, especially in immune cells. Cannabinoid receptors are G protein-coupled receptors, and they have been linked to signaling pathways and gene activities in common with this receptor family. In addition, cannabinoids have been shown to modulate a variety of immune cell functions in humans and animals and more recently, have been shown to modulate T helper cell development, chemotaxis, and tumor development. Many of these drug effects occur through cannabinoid receptor signaling mechanisms and the modulation of cytokines and other gene products. It appears the immunocannabinoid system is involved in regulating the brain-immune axis and might be exploited in future therapies for chronic diseases and immune deficiency.
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Psoriasis vulgaris is a common skin disorder characterised by focal formation of inflamed, raised plaques that constantly shed scales derived from excessive growth of skin epithelial cells. The disease is defined by a series of linked cellular changes in the skin: hyperplasia of epidermal keratinocytes, vascular hyperplasia and ectasia, and infiltration of T lymphocytes, neutrophils, and other types of leucocyte in affected skin. In a relatively short period, psoriasis vulgaris has been conceptualised as a T lymphocyte mediated autoimmune disease and new biological therapies that target T cells have just entered routine clinical practice. Similarly, rapid progress has been made towards dissecting cellular and molecular pathways of inflammation that contribute to disease pathogenesis. This short review presents current pathogenic concepts that have emerged from genetic, genomic, and cellular information obtained in basic studies and from clinical studies of selective immune targeting drugs.
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Anandamide (AEA), a prominent member of the endogenous ligands of cannabinoid receptors (endocannabinoids), is known to affect several functions of brain and peripheral tissues. A potential role for AEA in skin pathophysiology has been proposed, yet its molecular basis remains unknown. Here we report unprecedented evidence that spontaneously immortalized human keratinocytes (HaCaT) and normal human epidermal keratinocytes (NHEK) have the biochemical machinery to bind and metabolize AEA, i.e. a functional type-1 cannabinoid receptor (CB1R), a selective AEA membrane transporter (AMT), an AEA-degrading fatty acid amide hydrolase (FAAH), and an AEA-synthesizing phospholipase D (PLD). We show that, unlike CB1R and PLD, the activity of AMT and the activity and expression of FAAH increase while the endogenous levels of AEA decrease in HaCaT and NHEK cells induced to differentiate in vitro by 12-O-tetradecanoylphorbol 13-acetate (TPA) plus calcium. We also show that exogenous AEA inhibits the formation of cornified envelopes, a hallmark of keratinocyte differentiation, in HaCaT and NHEK cells treated with TPA plus calcium, through a CB1R-dependent reduction of transglutaminase and protein kinase C activity. Moreover, transient expression in HaCaT cells of the chloramphenicol acetyltransferase reporter gene under control of the loricrin promoter, which contained a wild-type or mutated activating protein-1 (AP-1) site, showed that AEA inhibited AP-1 in a CB1R-dependent manner. Taken together, these data demonstrate that human keratinocytes partake in the peripheral endocannabinoid system and show a novel signaling mechanism of CB1 receptors, which may have important implications in epidermal differentiation and skin development.
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This study was undertaken to evaluate the effects of thiazolidinediones (TZD) on keratinocyte proliferation, motility, and matrix metalloproteinase (MMP) production. Rosiglitazone (a potent TZD) inhibited both proliferation and motility as well as elaboration of MMP-1 and MMP-9. Inhibition was obtained with keratinocytes in monolayer culture and human skin in organ culture. There were significant concentration-response differences in sensitivity of the three keratinocyte responses to treatment with rosiglitazone. In contrast to keratinocytes, dermal fibroblasts were resistant to the effects of rosiglitazone. Treatment of keratinocytes with rosiglitazone did not suppress epidermal growth factor receptor autophosphorylation, but inhibited signaling through the extracellular regulated kinase mitogen-activated protein kinase pathway without a concomitant effect on pathways that lead to c-jun activation. Pioglitazone, another TZD, also suppressed keratinocyte proliferation, although it was less effective than rosiglitazone. An experimental TZD (BP-1107) inhibited keratinocyte proliferation at a much lower concentration than either rosiglitazone or pioglitazone. Because enhanced keratinocyte motility and increased MMP production as well as increased keratinocyte proliferation are thought to contribute to the phenotype of psoriatic lesional skin, we propose that interference with these keratinocyte responses contributes to the previously reported antipsoriatic activity of TZD.
Article
A simple, economical method is described for determining ATP over the range 10−9 and 10−12 mole, by the firefly luciferin-luciferase system, using any liquid scintillation spectrometer of suitable performance. This procedure has been employed to determine ATP in perchloric acid extracts of biological material. A critical appraisal is made of the factors affecting the liquid scintillation spectrometer for this assay.
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Psoriasis is often treated with agents that activate nuclear hormone receptors for glucocorticoids, retinoids, and vitamin D. The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a related nuclear hormone receptor that can be activated by its ligands, including the thiazolidinediones. To assess whether treatment with troglitazone, a currently available thiazolidinedione used to treat diabetes mellitus, has an effect on psoriasis in normoglycemic patients and whether ligands for PPARgamma have an effect on models of psoriasis. Open-label administration of troglitazone in patients with psoriasis and evaluation of drug actions in cellular, organ, and transplant models of psoriasis. University and community hospital outpatient departments and university laboratories. Patients with chronic, stable plaque psoriasis and control subjects. Five patients with psoriasis received troglitazone (none withdrew); 10 different untreated patients and 10 controls provided tissue samples. Oral troglitazone therapy at various dosages in patients with psoriasis; also, use of troglitazone, ciglitazone, and 15-deoxy-delta-12,14-prostaglandinJ2 in psoriasis models. Investigator-determined clinical results in patients and cell counts and histological evidence in models. All patients' psoriasis improved substantially during troglitazone therapy. Peroxisome proliferator-activated receptor-gamma was expressed in human keratinocytes; ligands for PPARgamma inhibited the proliferation of normal and psoriatic human keratinocytes in culture. Troglitazone treatment normalized the histological features of psoriatic skin in organ culture and reduced the epidermal hyperplasia of psoriasis in the severe combined immunodeficient mouse and human skin transplant model of psoriasis (P<.05 compared with untreated controls). Peroxisome proliferator-activated receptor-gamma might be a useful intracellular target for the treatment of psoriasis; further study is needed to assess the clinical value of ligands for PPARgamma, including troglitazone.
Article
Over the past few years, considerable attention has focused on cannabidiol (CBD), a major nonpsychotropic constituent of cannabis. The authors present a review on the chemistry of CBD and discuss the anticonvulsive, antianxiety, antipsychotic, antinausea, and antirheumatoid arthritic properties of CBD. CBD does not bind to the known cannabinoid receptors, and its mechanism of action is yet unknown. It is possible that, in part at least, its effects are due to its recently discovered inhibition of anandamide uptake and hydrolysis and to its antioxidative effect.
Article
We have reported that injection of marijuana cannabinoids, such as Delta(9)-tetrahydrocannabinol (THC), into mice, followed by infection with Legionella pneumophila (Lp), suppresses the development of cell-mediated immunity T helper 1 (Th1) activity. These effects are accompanied by suppression of interleukin (IL)-12 and interferon (IFN) gamma production and enhancement of IL-4 production suggesting THC-induced T helper cell biasing. In the current report, other T helper cell biasing mechanisms were studied. Mice were injected with THC followed 18 h later by a challenge infection with Lp. Two-hour post-infection, spleens were removed and analyzed for mRNA to either IL-12Rbeta2 or GATA3 gene products. The results showed that THC suppressed IL-12Rbeta2 but increased GATA3. Receptor antagonists for CB1 (SR141716A, SR1) and CB2 (SR144528, SR2) were also injected to analyze the involvement of cannabinoid receptors. It was determined that SR1 attenuated the THC suppression of IL-12Rbeta2, while SR2 attenuated the increase in GATA3 mRNA. These results suggest that THC suppresses Th1 biasing activity such as IL-12Rbeta2 by a CB1 mediated mechanism and enhances the Th2 biasing activity, GATA3, by a CB2 mechanism. This dichotomy of receptor involvement might result from differential expression and/or signaling function of CB1 and CB2 on Th1 and Th2 cells.
Article
While psoriasis is upon the age of biological treatments, additional researches have led to other new therapies for psoriasis, including targets aimed at nuclear receptors. PPARs are members of the nuclear-hormone-receptor superfamily, including retinoid receptors and vitamin D receptors. Recent works have highlighted the role of PPARs, which transduce a wide variety of signals into a set of cellular responses at the level of gene transcription, as critical regulators of cutaneous homeostasis in regulating differentiation, proliferation, and inflammatory responses of the skin. PPAR agonists or antagonists may therefore, hold promise as interesting compounds for the treatment of various epidermal disorders characterized by inflammation, hyperproliferation and aberrant differentiation, such as psoriasis.
Article
Cannabidiol, a non-psychoactive constituent of cannabis, has been reported as a neuroprotectant. Cannabidiol and Delta(9)-tetrahydrocannabinol, the primary psychoactive constituent of cannabis, significantly decreased the infarct volume at 4 h in the mouse middle cerebral artery occlusion model. The neuroprotective effects of Delta(9)-tetrahydrocannabinol but not cannabidiol were inhibited by SR141716, a cannabinoid CB1 receptor antagonist, and were abolished by warming of the animals to the levels observed in the controls. Delta(9)-Tetrahydrocannabinol significantly decreased the rectal temperature, and the hypothermic effect was inhibited by SR141716. These results surely show that the neuroprotective effect of Delta(9)-tetrahydrocannabinol are via a CB1 receptor and temperature-dependent mechanisms whereas the neuroprotective effects of cannabidiol are independent of CB1 blockade and of hypothermia.
Article
We evaluated the ability of cannabidiol (CBD) to impair the migration of tumor cells stimulated by conditioned medium. CBD caused concentration-dependent inhibition of the migration of U87 glioma cells, quantified in a Boyden chamber. Since these cells express both cannabinoid CB1 and CB2 receptors in the membrane, we also evaluated their engagement in the antimigratory effect of CBD. The inhibition of cell was not antagonized either by the selective cannabinoid receptor antagonists SR141716 (CB1) and SR144528 (CB2) or by pretreatment with pertussis toxin, indicating no involvement of classical cannabinoid receptors and/or receptors coupled to Gi/o proteins. These results reinforce the evidence of antitumoral properties of CBD, demonstrating its ability to limit tumor invasion, although the mechanism of its pharmacological effects remains to be clarified. British Journal of Pharmacology (2005) 144, 1032–1036. doi:10.1038/sj.bjp.0706134
Article
In the nineteenth century, marijuana was prescribed by physicians for maladies ranging from eating disorders to rabies. However, as newer, more effective drugs were discovered and as the potential for abuse of marijuana was recognized, its use as a therapeutic became restricted, and only recently has its therapeutic potential been re-evaluated. Recent studies in animal models and in humans have produced promising results for the treatment of various disorders - such as obesity, cancer, and spasticity and tremor due to neuropathology - with drugs based on marijuana-derived cannabinoids. Moreover, as I discuss here, a wealth of information also indicates that these drugs have immunosuppressive and anti-inflammatory properties; therefore, on the basis of this mode of action, the therapeutic usefulness of these drugs in chronic inflammatory diseases is now being reassessed.
Article
An increasing number of cannabinoid actions are being reported that do not appear to be mediated by either CB1 or CB2, the known cannabinoid receptors. One such example is the synthetic analog ajulemic acid (AJA), which shows potent analgesic and anti-inflammatory effects in rodents and humans. AJA binds weakly to CB1 only at concentrations many fold higher than its therapeutic range, and is, therefore, completely free of psychotropic effects in both normal subjects and pain patients suggesting the involvement of a target site other than CB1. AJA as well as several other cannabinoids appear to have profound effects on cellular lipid metabolism as evidenced by their ability to transform fibroblasts into adipocytes where the accumulation of lipid droplets can be readily observed. Such transformations can be mediated by the activation of the nuclear receptor PPAR-gamma. A variety of small molecule ligands including AJA have been shown to induce the activation of PPAR-gamma and, in some cases this has led to the introduction of clinically useful agents. It is suggested that PPAR-gamma may serve a receptor function for certain actions of some cannabinoids.
Article
Psoriasis is a chronic inflammatory disorder of the skin that is mediated by T cells, dendritic cells and inflammatory cytokines. We now understand many of the cellular alterations that underlie this disease, and genomic approaches have recently been used to assess the alterations of gene expression in psoriatic skin lesions. Genetic susceptibility factors that contribute to predisposition to psoriasis are now also being identified. It is hoped that we will soon be able to correlate the cellular pathogenesis that occurs in psoriasis with these genetic factors. In this Review article, we describe what is known about genes that confer increased susceptibility to psoriasis, and we integrate this with what is known about the molecular and cellular mechanisms that occur in other inflammatory and autoimmune disorders.
Article
Marijuana has been used in medicine for millennia, but it was not until 1964 that delta9-tetrahydrocannabinol (delta9-THC), its major psychoactive component, was isolated in pure form and its structure was elucidated. Shortly thereafter it was synthesized and became readily available. However, it took another decade until the first report on its antineoplastic activity appeared. In 1975, Munson discovered that cannabinoids suppress Lewis lung carcinoma cell growth. The mechanism of this action was shown to be inhibition of DNA synthesis. Antiproliferative action on some other cancer cells was also found. In spite of the promising results from these early studies, further investigations in this area were not reported until a few years ago, when almost simultaneously two groups initiated research on the antiproliferative effects of cannabinoids on cancer cells: Di Marzo's group found that cannabinoids inhibit breast cancer cell proliferation, and Guzman's group found that cannabinoids inhibit the growth of C6 glioma cell. Other groups also started work in this field, and today, a wide array of cancer cell lines that are affected is known, and some mechanisms involved have been elucidated.
Article
Increasing evidence suggests that some cannabinoids mediate their effects independently of the known cannabinoid CB(1) and CB(2) receptors. Two recently published patents indicate that several cannabinoid receptor ligands also bind to the orphan G-protein-coupled receptor GPR55. This receptor is reported to be expressed in several tissues and might function in lipid or vascular biology. Thus, GPR55 might represent a new cannabinoid receptor.
Laboratory procedures in biotechnology
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Peroxisome proliferator-activated receptors as new molecular targets in psoriasis Rosiglitazone inhibits proliferation, motility, and matrix metalloproteinase production in keratinocytes
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Kuenzli S, Saurat JH. Peroxisome proliferator-activated receptors as new molecular targets in psoriasis. Curr Drug Targets Inflamm Allergy 2004;3(2):205-11. review. [18] Bhagavathula N, Nerusu KC, Lal A, et al. Rosiglitazone inhibits proliferation, motility, and matrix metalloproteinase production in keratinocytes. J Invest Dermatol 2004; 122(1):130-9.
Use of the liquid scintillation spectrometer for determining adenosine triphosphate by the luciferase enzyme.
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Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors
  • Casanova