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Molecular Advances on Cannabinoid and Endocannabinoid Research 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (28 February 2024) | Viewed by 6785

Special Issue Editor

Department of Movement and Wellness Sciences, Parthenope University of Naples, I-80133 Naples, Italy
Interests: endocannabinoid system; endocannabinoids–GnRH–steroids crosstalk; kisspeptins; reproduction; HPG axis; spermatogenesis; spermatozoa; endocrine disruptors; epigenetics
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Special Issue Information

Dear Colleagues,

Marijuana has been used for recreational and medical use since ancient times. In 1964, Raphael Mechoulam and Yechiel Gaoni, two pioneers of cannabinoid research, first reported the structure of Δ9-tetrahydrocannabinol (Δ9-THC), the main psychotropic phytocannabinoid in Cannabis L. sativa, revealing the pharmacological and therapeutic potential of plant-derived cannabinoids. Studies on Δ9-THC were pivotal to the discovery of cannabinoid receptors and endogenous cannabinoids (i.e., endocannabinoids), revealing the existence of a conserved endogenous signaling system that is involved in many biological functions. Endocannabinoids and endocannabinoid-like substances, canonical and non-canonical cannabinoid receptors, biosynthetic/hydrolyzing enzymes and transporters have been discovered in biological systems, and the endocannabinoid system (ECS) has a recognized role in synaptic plasticity, learning and memory, neuroinflammation, pain control, stress response, mood and behavior, energy homeostasis, food intake and metabolism, reproduction, fertility and pregnancy, immune response, cardiac functions, cancer progression, etc. Furthermore, the isolation of several psychotropic and non-psychotropic plant-derived cannabinoids in parallel to the development of agonists/antagonists/inhibitors of the ECS has gathered attention with regard to the development of cannabinoid-based therapies. Recreational/medical use of cannabinoids is gaining traction and legitimacy in many countries, but the large distribution of cannabinoid receptors in biological systems and the pleiotropic activity of the ECS require further investigation.

This Special Issue aims to update knowledge of the molecular advances in cannabinoid and endocannabinoid research in physiological and pathological conditions, with a focus on molecular and epigenetic regulatory mechanisms and possible therapeutic exploitation. Experimental studies in in vitro and in vivo models, review articles, and clinical studies are all welcome.

Prof. Dr. Rosaria Meccariello
Guest Editor

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Published Papers (5 papers)

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Research

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19 pages, 5965 KiB  
Article
Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected Macrophages
by Lester J. Rosario-Rodríguez, Yadira M. Cantres-Rosario, Kelvin Carrasquillo-Carrión, Ana E. Rodríguez-De Jesús, Luz J. Cartagena-Isern, Luis A. García-Requena, Abiel Roche-Lima and Loyda M. Meléndez
Int. J. Mol. Sci. 2024, 25(6), 3246; https://doi.org/10.3390/ijms25063246 - 13 Mar 2024
Viewed by 451
Abstract
HIV-associated neurocognitive disorders (HAND) affect 15–55% of HIV-positive patients and effective therapies are unavailable. HIV-infected monocyte-derived macrophages (MDM) invade the brain of these individuals, promoting neurotoxicity. We demonstrated an increased expression of cathepsin B (CATB), a lysosomal protease, in monocytes and post-mortem brain [...] Read more.
HIV-associated neurocognitive disorders (HAND) affect 15–55% of HIV-positive patients and effective therapies are unavailable. HIV-infected monocyte-derived macrophages (MDM) invade the brain of these individuals, promoting neurotoxicity. We demonstrated an increased expression of cathepsin B (CATB), a lysosomal protease, in monocytes and post-mortem brain tissues of women with HAND. Increased CATB release from HIV-infected MDM leads to neurotoxicity, and their secretion is associated with NF-κB activation, oxidative stress, and lysosomal exocytosis. Cannabinoid receptor 2 (CB2R) agonist, JWH-133, decreases HIV-1 replication, CATB secretion, and neurotoxicity from HIV-infected MDM, but the mechanisms are not entirely understood. We hypothesized that HIV-1 infection upregulates the expression of proteins associated with oxidative stress and that a CB2R agonist could reverse these effects. MDM were isolated from healthy women donors (n = 3), infected with HIV-1ADA, and treated with JWH-133. After 13 days post-infection, cell lysates were labeled by Tandem Mass Tag (TMT) and analyzed by LC/MS/MS quantitative proteomics bioinformatics. While HIV-1 infection upregulated CATB, NF-κB signaling, Nrf2-mediated oxidative stress response, and lysosomal exocytosis, JWH-133 treatment downregulated the expression of the proteins involved in these pathways. Our results suggest that JWH-133 is a potential alternative therapy against HIV-induced neurotoxicity and warrant in vivo studies to test its potential against HAND. Full article
(This article belongs to the Special Issue Molecular Advances on Cannabinoid and Endocannabinoid Research 2.0)
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21 pages, 5841 KiB  
Article
Targeting Fatty Acid Amide Hydrolase Counteracts the Epithelial-to-Mesenchymal Transition in Keratinocyte-Derived Tumors
by Daniela Kovacs, Enrica Flori, Emanuela Bastonini, Sarah Mosca, Emilia Migliano, Carlo Cota, Marco Zaccarini, Stefania Briganti and Giorgia Cardinali
Int. J. Mol. Sci. 2023, 24(24), 17379; https://doi.org/10.3390/ijms242417379 - 12 Dec 2023
Viewed by 690
Abstract
The endocannabinoid system regulates physiological processes, and the modulation of endogenous endocannabinoid (eCB) levels is an attractive tool to contrast the development of pathological skin conditions including cancers. Inhibiting FAAH (fatty acid amide hydrolase), the degradation enzyme of the endocannabinoid anandamide (AEA) leads [...] Read more.
The endocannabinoid system regulates physiological processes, and the modulation of endogenous endocannabinoid (eCB) levels is an attractive tool to contrast the development of pathological skin conditions including cancers. Inhibiting FAAH (fatty acid amide hydrolase), the degradation enzyme of the endocannabinoid anandamide (AEA) leads to the increase in AEA levels, thus enhancing its biological effects. Here, we evaluated the anticancer property of the FAAH inhibitor URB597, investigating its potential to counteract epithelial-to-mesenchymal transition (EMT), a process crucially involved in tumor progression. The effects of the compound were determined in primary human keratinocytes, ex vivo skin explants, and the squamous carcinoma cell line A431. Our results demonstrate that URB597 is able to hinder the EMT process by downregulating mesenchymal markers and reducing migratory potential. These effects are associated with the dampening of the AKT/STAT3 signal pathways and reduced release of pro-inflammatory cytokines and tumorigenic lipid species. The ability of URB597 to contrast the EMT process provides insight into effective approaches that may also include the use of FAAH inhibitors for the treatment of skin cancers. Full article
(This article belongs to the Special Issue Molecular Advances on Cannabinoid and Endocannabinoid Research 2.0)
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14 pages, 2764 KiB  
Article
The Anti-Tumorigenic Role of Cannabinoid Receptor 2 in Non-Melanoma Skin Cancer
by Jennifer Ana Iden, Bitya Raphael-Mizrahi, Aaron Naim, Albert Kolomansky, Tamar Liron, Drorit Neumann, Marilena Vered and Yankel Gabet
Int. J. Mol. Sci. 2023, 24(9), 7773; https://doi.org/10.3390/ijms24097773 - 24 Apr 2023
Viewed by 1851
Abstract
Five million non-melanoma skin cancers occur globally each year, and it is one of the most common malignant cancers. The dysregulation of the endocannabinoid system, particularly cannabinoid receptor 2 (CB2), is implicated in skin cancer development, progression, and metastasis. Comparing wildtype (WT) to [...] Read more.
Five million non-melanoma skin cancers occur globally each year, and it is one of the most common malignant cancers. The dysregulation of the endocannabinoid system, particularly cannabinoid receptor 2 (CB2), is implicated in skin cancer development, progression, and metastasis. Comparing wildtype (WT) to systemic CB2 knockout (CB2-/-) mice, we performed a spontaneous cancer study in one-year old mice, and subsequently used the multi-stage chemical carcinogenesis model, wherein cancer is initiated by 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). We found that aging CB2-/- mice have an increased incidence of spontaneous cancerous and precancerous skin lesions compared to their WT counterparts. In the DMBA/TPA model, CB2-/- developed more and larger papillomas, had decreased spontaneous regression of papillomas, and displayed an altered systemic immune profile, including upregulated CD4+ T cells and dendritic cells, compared to WT mice. Immune cell infiltration in the tumor microenvironment was generally low for both genotypes, although a trend of higher myeloid-derived suppressor cells was observed in the CB2-/- mice. CB2 expression in carcinogen-exposed skin was significantly higher compared to naïve skin in WT mice, suggesting a role of CB2 on keratinocytes. Taken together, our data show that endogenous CB2 activation plays an anti-tumorigenic role in non-melanoma skin carcinogenesis, potentially via an immune-mediated response involving the alteration of T cells and myeloid cells coupled with the modulation of keratinocyte activity. Full article
(This article belongs to the Special Issue Molecular Advances on Cannabinoid and Endocannabinoid Research 2.0)
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18 pages, 4391 KiB  
Article
Novel Cannabinoid Receptor 2 (CB2) Low Lipophilicity Agonists Produce Distinct cAMP and Arrestin Signalling Kinetics without Bias
by Raahul Sharma, Sameek Singh, Zak M. Whiting, Maximilian Molitor, Andrea J. Vernall and Natasha L. Grimsey
Int. J. Mol. Sci. 2023, 24(7), 6406; https://doi.org/10.3390/ijms24076406 - 29 Mar 2023
Cited by 4 | Viewed by 1610
Abstract
Cannabinoid Receptor 2 (CB2) is a promising target for treating inflammatory diseases. We designed derivatives of 3-carbamoyl-2-pyridone and 1,8-naphthyridin-2(1H)-one-3-carboxamide CB2-selective agonists with reduced lipophilicity. The new compounds were measured for their affinity (radioligand binding) and ability to elicit cyclic adenosine monophosphate (cAMP) signalling [...] Read more.
Cannabinoid Receptor 2 (CB2) is a promising target for treating inflammatory diseases. We designed derivatives of 3-carbamoyl-2-pyridone and 1,8-naphthyridin-2(1H)-one-3-carboxamide CB2-selective agonists with reduced lipophilicity. The new compounds were measured for their affinity (radioligand binding) and ability to elicit cyclic adenosine monophosphate (cAMP) signalling and β-arrestin-2 translocation with temporal resolution (BRET-based biosensors). For the 3-carbamoyl-2-pyridone derivatives, we found that modifying the previously reported compound UOSS77 (also known as S-777469) by appending a PEG2-alcohol via a 3-carbomylcyclohexyl carboxamide (UOSS75) lowered lipophilicity, and preserved binding affinity and signalling profile. The 1,8-naphthyridin-2(1H)-one-3-carboxamide UOMM18, containing a cis configuration at the 3-carboxamide cyclohexyl and with an alcohol on the 4-position of the cyclohexyl, had lower lipophilicity but similar CB2 affinity and biological activity to previously reported compounds of this class. Relative to CP55,940, the new compounds acted as partial agonists and did not exhibit signalling bias. Interestingly, while all compounds shared similar temporal trajectories for maximal efficacy, differing temporal trajectories for potency were observed. Consequently, when applied at sub-maximal concentrations, CP55,940 tended to elicit sustained (cAMP) or increasing (arrestin) responses, whereas responses to the new compounds tended to be transient (cAMP) or sustained (arrestin). In future studies, the compounds characterised here may be useful in elucidating the consequences of differential temporal signalling profiles on CB2-mediated physiological responses. Full article
(This article belongs to the Special Issue Molecular Advances on Cannabinoid and Endocannabinoid Research 2.0)
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Review

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27 pages, 1925 KiB  
Review
The Role of the Endocannabinoid System in Binge Eating Disorder
by Romain Bourdy and Katia Befort
Int. J. Mol. Sci. 2023, 24(11), 9574; https://doi.org/10.3390/ijms24119574 - 31 May 2023
Cited by 5 | Viewed by 1795
Abstract
Eating disorders are multifactorial disorders that involve maladaptive feeding behaviors. Binge eating disorder (BED), the most prevalent of these in both men and women, is characterized by recurrent episodes of eating large amounts of food in a short period of time, with a [...] Read more.
Eating disorders are multifactorial disorders that involve maladaptive feeding behaviors. Binge eating disorder (BED), the most prevalent of these in both men and women, is characterized by recurrent episodes of eating large amounts of food in a short period of time, with a subjective loss of control over eating behavior. BED modulates the brain reward circuit in humans and animal models, which involves the dynamic regulation of the dopamine circuitry. The endocannabinoid system plays a major role in the regulation of food intake, both centrally and in the periphery. Pharmacological approaches together with research using genetically modified animals have strongly highlighted a predominant role of the endocannabinoid system in feeding behaviors, with the specific modulation of addictive-like eating behaviors. The purpose of the present review is to summarize our current knowledge on the neurobiology of BED in humans and animal models and to highlight the specific role of the endocannabinoid system in the development and maintenance of BED. A proposed model for a better understanding of the underlying mechanisms involving the endocannabinoid system is discussed. Future research will be necessary to develop more specific treatment strategies to reduce BED symptoms. Full article
(This article belongs to the Special Issue Molecular Advances on Cannabinoid and Endocannabinoid Research 2.0)
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