Publications

2022
Lihi Bar-Lev Schleider, Raphael Mechoulam, Inbal Sikorin, Timna Naftali, and Victor Novack. 2022. “Adherence, Safety, and Effectiveness of Medical Cannabis and Epidemiological Characteristics of the Patient Population: A Prospective Study.” Frontiers in medicine, 9, Pp. 827849. Abstract
BACKGROUND: Despite the absence of rigorous prospective studies, there has been an increase in the use of cannabis-based medicinal products. During the study period, the use of medical cannabis in Israel was tightly regulated by national policy. Through a prospective study of approximately 10,000 patients, we aimed to characterize the medical cannabis patient population as well as to identify treatment adherence, safety, and effectiveness. METHODS AND FINDINGS: In this study of prescribed medical cannabis patients, adherence, safety, and effectiveness were assessed at 6 months. Treatment adherence was assessed by the proportion of patients purchasing the medication out of the total number of patients (excluding deceased cases and patients transferred to another cannabis clinic). Safety was assessed by the frequency of the side-effects, while effectiveness was defined as at least moderate improvement in the patient condition without treatment cessation or serious side-effects. The most frequent primary indications requiring therapy were cancer (49.1%), followed by non-specific pain (29.3%). The average age was 54.6 ± 20.9 years, 51.1% males; 30.2% of the patients reported prior experience with cannabis. During the study follow-up, 1,938 patients died (19.4%) and 1,735 stopped treatment (17.3%). Common side-effects, reported by 1,675 patients (34.2%), were: dizziness (8.2%), dry mouth (6.7%), increased appetite (4.7%), sleepiness (4.4%), and psychoactive effect (4.3%). Overall, 70.6% patients had treatment success at 6 months. Multivariable logistic regression analysis revealed that the following factors were associated with treatment success: cigarette smoking, prior experience with cannabis, active driving, working, and a young age. The main limitation of this study was the lack of data on safety and effectiveness of the treatment for patients who refused to undergo medical assessment even at baseline or died within the first 6 months. CONCLUSIONS: We observed that supervised medical-cannabis treatment is associated with high adherence, improvement in quality of life, and a decrease in pain level with a low incidence of serious adverse events.
Antibiotic resistance has become an increasing challenge in the treatment of various infectious diseases, especially those associated with biofilm formation on biotic and abiotic materials. There is an urgent need for new treatment protocols that can also target biofilm-embedded bacteria. Many secondary metabolites of plants possess anti-bacterial activities, and especially the phytocannabinoids of the Cannabis sativa L. varieties have reached a renaissance and attracted much attention for their anti-microbial and anti-biofilm activities at concentrations below the cytotoxic threshold on normal mammalian cells. Accordingly, many synthetic cannabinoids have been designed with the intention to increase the specificity and selectivity of the compounds. The structurally unrelated endocannabinoids have also been found to have anti-microbial and anti-biofilm activities. Recent data suggest for a mutual communication between the endocannabinoid system and the gut microbiota. The present review focuses on the anti-microbial activities of phytocannabinoids and endocannabinoids integrated with some selected issues of their many physiological and pharmacological activities.
Hana Golan, Raphael Mechoulam, Reem Smoum, Efrat Cohen-Zada, Sara Pri-Chen, Sapir Wiener, Igor Grinberg, Dekel D Bar-Lev, Christeeneh G Haj, Tamar Fisher, and Amos Toren. 2022. “Anti-Tumorigenic Effect of a Novel Derivative of 2-Hydroxyoleic Acid and the Endocannabinoid Anandamide on Neuroblastoma Cells.” Biomedicines, 10, 7. Abstract
Modulation of the endogenous cannabinoid system has been suggested as a potential anticancer strategy. In the search for novel and less toxic therapeutic options, structural modifications of the endocannabinoid anandamide and the synthetic derivative of oleic acid, Minerval (HU-600), were done to obtain 2-hydroxy oleic acid ethanolamide (HU-585), which is an HU-600 derivative with the anandamide side chain. We showed that treatment of SK-N-SH neuroblastoma cells with HU-585 induced a better anti-tumorigenic effect in comparison to HU-600 as evidenced by 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide assay, colony-forming assay, and migration assay. Moreover, HU-585 demonstrated pro-apoptotic properties shown by increased levels of activated caspase-3 following treatment and a better senescence induction effect in comparison to HU-600, as demonstrated by increased activity of lysosomal $\beta$-galactosidase. Finally, we observed that combined treatment of HU-585 with the senolytic drugs ABT-263 in vitro, and ABT-737 in vivo resulted in enhanced anti-proliferative effects and reduced neuroblastoma xenograft growth in comparison to treatment with HU-585 alone. Based on these results, we suggest that HU-585 is a pro-apoptotic and senescence-inducing compound, better than HU-600. Hence, it may be a beneficial option for the treatment of resistant neuroblastoma especially when combined with senolytic drugs that enhance its anti-tumorigenic effects.
Irena Voinsky, Yazeed Zoabi, Noam Shomron, Moria Harel, Hanoch Cassuto, Joseph Tam, Shannon Rose, Adrienne C Scheck, Mohammad A Karim, Richard E Frye, Adi Aran, and David Gurwitz. 2022. “Blood RNA Sequencing Indicates Upregulated BATF2 and LY6E and Downregulated ISG15 and MT2A Expression in Children with Autism Spectrum Disorder.” International journal of molecular sciences, 23, 17. Abstract
Mutations in over 100 genes are implicated in autism spectrum disorder (ASD). DNA SNPs, CNVs, and epigenomic modifications also contribute to ASD. Transcriptomics analysis of blood samples may offer clues for pathways dysregulated in ASD. To expand and validate published findings of RNA-sequencing (RNA-seq) studies, we performed RNA-seq of whole blood samples from an Israeli discovery cohort of eight children with ASD compared with nine age- and sex-matched neurotypical children. This revealed 10 genes with differential expression. Using quantitative real-time PCR, we compared RNAs from whole blood samples of 73 Israeli and American children with ASD and 26 matched neurotypical children for the 10 dysregulated genes detected by RNA-seq. This revealed higher expression levels of the pro-inflammatory transcripts BATF2 and LY6E and lower expression levels of the anti-inflammatory transcripts ISG15 and MT2A in the ASD compared to neurotypical children. BATF2 was recently reported as upregulated in blood samples of Japanese adults with ASD. Our findings support an involvement of these genes in ASD phenotypes, independent of age and ethnicity. Upregulation of BATF2 and downregulation of ISG15 and MT2A were reported to reduce cancer risk. Implications of the dysregulated genes for pro-inflammatory phenotypes, immunity, and cancer risk in ASD are discussed.
Nicole Rodrigues Silva, Francisco Isaac Fernandes Gomes, Alexandre Hashimoto Pereira Lopes, Isadora Lopes Cortez, Jéssica Cristina dos Santos, Conceição Elidianne Aníbal Silva, Raphael Mechoulam, Felipe Villela Gomes, Thiago Mattar Cunha, and Francisco Silveira Guimarães. 2022. “The Cannabidiol Analog PECS-101 Prevents Chemotherapy-Induced Neuropathic Pain via PPAR$\gamma$ Receptors.” Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 19, 1, Pp. 434–449. Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is the main dose-limiting adverse effect of chemotherapy drugs such as paclitaxel (PTX). PTX causes marked molecular and cellular damage, mainly in the peripheral nervous system, including sensory neurons in the dorsal root ganglia (DRG). Several studies have shown the therapeutic potential of cannabinoids, including cannabidiol (CBD), the major non-psychotomimetic compound found in the Cannabis plant, to treat peripheral neuropathies. Here, we investigated the efficacy of PECS-101 (former HUF-101), a CBD fluorinated analog, on PTX-induced neuropathic pain in mice. PECS-101, administered after the end of treatment with PTX, did not reverse mechanical allodynia. However, PECS-101 (1 mg/kg) administered along with PTX treatment caused a long-lasting relief of the mechanical and cold allodynia. These effects were blocked by a PPAR$\gamma$, but not CB1 and CB2 receptor antagonists. Notably, the effects of PECS-101 on the relief of PTX-induced mechanical and cold allodynia were not found in macrophage-specific PPAR$\gamma$-deficient mice. PECS-101 also decreased PTX-induced increase in Tnf, Il6, and Aif1 (Iba-1) gene expression in the DRGs and the loss of intra-epidermal nerve fibers. PECS-101 did not alter motor coordination, produce tolerance, or show abuse potential. In addition, PECS-101 did not interfere with the chemotherapeutic effects of PTX. Thus, PECS-101, a new fluorinated CBD analog, could represent a novel therapeutic alternative to prevent mechanical and cold allodynia induced by PTX potentially through the activation of PPAR$\gamma$ in macrophages.
José Alexandre S Crippa, Julia Cozar Pacheco, Antonio W Zuardi, Francisco S Guimarães, Alline Cristina Campos, Flávia Lima de Osório, Sonia Regina Loureiro, Rafael G Dos Santos, José Diogo S Souza, Juliana Mayumi Ushirohira, Rafael Rinaldi Ferreira, Karla Cristinne Mancini Costa, Davi Silveira Scomparin, Franciele Franco Scarante, Isabela Pires-Dos-Santos, Raphael Mechoulam, Flávio Kapczinski, Benedito AL Fonseca, Danillo LA Esposito, Afonso Dinis Costa Passos, Amaury Lelis Dal Fabbro, Fernando Bellissimo-Rodrigues, Eurico Arruda, Sandro Scarpelini, Maristela Haddad Andraus, Julio Cesar Nather Junior, Danilo Tadao Wada, Marcel Koenigkam-Santos, Antonio Carlos Santos, Geraldo Busatto Filho, and Jaime EC Hallak. 2022. “Cannabidiol for COVID-19 Patients with Mild to Moderate Symptoms (CANDIDATE Study): A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.” Cannabis and cannabinoid research, 7, 5, Pp. 658–669. Abstract
{Importance: Owing to its anti-inflammatory properties and antiviral "in vitro" effect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cannabidiol (CBD) has been proposed as a potential treatment for coronavirus disease 2019 (COVID-19). Objective: To investigate the safety and efficacy of CBD for treating patients with mild to moderate COVID-19. Design: Randomized, parallel-group, double-blind, placebo-controlled clinical trial conducted between July 7 and October 16, 2020, in two sites in Brazil. Setting: Patients were recruited in an emergency room. Participants: Block randomized patients (1:1 allocation ratio-by a researcher not directly involved in data collection) with mild and moderate COVID-19 living in Ribeirão Preto, Brazil, seeking medical consultation, and those who voluntarily agreed to participate in the study. Interventions: Patients received 300 mg of CBD or placebo added to standard symptomatic care during 14 days. Main Outcome and Measure: The primary outcome was reduction or prevention of the deterioration in clinical status from mild/moderate to severe/critical measured with the COVID-19 Scale or the natural course of the resolution of typical clinical symptoms. Primary study outcome was assessed on days 14, 21, and 28 after enrollment. Results: A total of 321 patients were recruited and assessed for eligibility, and 105 were randomly allocated either in CBD (n=49) or in placebo (n=42) group. Ninety-one participants were included in the analysis of efficacy. There were no baseline between-group differences regarding disease severity ($\chi$(2)=0.025
Muna Aqawi, Doron Steinberg, Osnat Feuerstein, Michael Friedman, and Sarah Gingichashvili. 2022. “Cannabigerol Effect on Streptococcus mutans Biofilms-A Computational Approach to Confocal Image Analysis.” Frontiers in microbiology, 13, Pp. 880993. Abstract
Biofilms are complex bacterial structures in which bacterial cells thrive as a community. Many bacterial species, including pathogens, form biofilms of high complexity and adaptability to a wide range of environmental conditions. One example of these is Streptococcus mutans, a gram-positive bacterium that has been associated with caries. Cannabigerol, a non-psychoactive cannabinoid, has been shown to affect S. mutans biofilms. In order to better characterize the effect of cannabigerol on biofilms of S. mutans, this paper provides a series of computational assays for biofilm analysis, applied on confocal images of S. mutans biofilms treated with cannabigerol. Confocal images are ubiquitous in biofilm analysis-they are often used to visualize the complex structure and molecular composition of biofilm macrocolonies. In this article, we demonstrate how confocal imaging data can be used to reveal more comprehensive insights into biofilm structure and measure specific anti-biofilm effects. This is accomplished by a series of computational assays, each focusing on a different aspect of biofilm structure.
Gil Zandani, Sarit Anavi-Cohen, Tal Assa-Glazer, Jonathan Gorelick, Abraham Nyska, Noa Sela, Nirit Bernstein, and Zecharia Madar. 2022. “Cannabis Extract Effects on Metabolic Parameters and Gut Microbiota Composition in a Mice Model of NAFLD and Obesity.” Evidence-based complementary and alternative medicine : eCAM, 2022, Pp. 7964018. Abstract
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.
Raphael Mechoulam. 2022. “A Delightful Trip Along the Pathway of Cannabinoid and Endocannabinoid Chemistry and Pharmacology.” Annual review of pharmacology and toxicology. Abstract
After a traumatic childhood in Europe during the Second World War, I found that scientific research in Israel was a pleasure beyond my expectations. Over the last 65 year, I have worked on the chemistry and pharmacology of natural products. During the last few decades, most of my research has been on plant cannabinoids, the endogenous cannabinoids arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol, and endogenous anandamide-like compounds, all of which are involved in a wide spectrum of physiological reactions. Two plant cannabinoids, $Δ$(9)-tetrahydrocannabinol and cannabidiol, are approved drugs. However, the endogenous cannabinoids and the anandamide-like constituents have not yet been well investigated in humans. For me, intellectual freedom-the ability to do research based on my own scientific interests-has been the most satisfying part of my working life. Looking back over the 91 years of my long life, I conclude that I have been lucky, very lucky, both personally and scientifically. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 63 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Phytocannabinoids possess a wide range of immune regulatory properties, mediated by the endocannabinoid system. Monocyte/macrophage innate immune cells express endocannabinoid receptors. Dysregulation of macrophage function is involved in the pathogenesis of different inflammatory diseases, including inflammatory bowel disease. In our research, we aimed to evaluate the effects of the phytocannabinoids D9 tetrahydrocannabinol (THC) and cannabidiol (CBD) on macrophage activation. Macrophages from young and aged C57BL/6 mice were activated in vitro in the presence of pure cannabinoids or cannabis extracts. The phenotype of the cells, nitric oxide (NO•) secretion, and cytokine secretion were examined. In addition, these treatments were administered to murine colitis model. The clinical statuses of mice, levels of colon infiltrating macrophages, and inflammatory cytokines in the blood, were evaluated. We demonstrated inhibition of macrophage NO• and cytokine secretion and significant effects on expression of cell surface molecules. In the murine model, clinical scores were improved and macrophage colon infiltration reduced following treatment. We identified higher activity of cannabis extracts as compared with pure cannabinoids. Each treatment had a unique effect on cytokine composition. Overall, our results establish that the effects of cannabinoid treatments differ. A better understanding of the reciprocal relationship between cannabinoids and immunity is essential to design targeted treatment strategies.
Leslie Rebibo, Marina Frušić-Zlotkin, Ron Ofri, Taher Nassar, and Simon Benita. 2022. “The dose-dependent effect of a stabilized cannabidiol nanoemulsion on ocular surface inflammation and intraocular pressure.” International journal of pharmaceutics, 617, Pp. 121627. Abstract
Cannabidiol (CBD) is a phytocannabinoid that has a great clinical therapeutic potential. Few studies have been published on its efficacy in ocular inflammations while its impact on intraocular pressure (IOP), a major risk factor for glaucoma, remains unclear. Moreover, due to its lability and high lipophilicity, its formulation within a prolonged stable topical ophthalmic solution or emulsion able to penetrate the highly selective corneal barrier is challenging. Therefore, various CBD nanoemulsions (NEs) were designed and evaluated for stability in accelerated conditions. Further, the optimal formulation was tested on a murine LPS-induced keratitis inflammation model. Lastly, increasing CBD concentrations were topically applied, for two weeks, on mice eyes, for IOP measurement. CBD NEs exhibited optimal physicochemical characteristics for ocular delivery. A specific antioxidant was required to obtain the stable, final, formulation. In vivo, 0.4 to 1.6% CBD w/v reduced the levels of key inflammatory cytokines, depending on the concentration applied. These concentrations decreased or did not affect the IOP. Our results showed that a well-designed CBD ocular dosage form can be stabilized for an extended shelf life. Furthermore, the significant decrease in inflammatory cytokines levels could be exploited, provided that an adequate therapeutic dosage regimen is identified in humans.
Erin M Rock, Cheryl L Limebeer, Reem Smoum, Raphael Mechoulam, and Linda A Parker. 2022. “Effect of oleoyl glycine and oleoyl alanine on lithium chloride induced nausea in rats and vomiting in shrews.” Psychopharmacology, 239, 2, Pp. 377–383. Abstract
RATIONALE: The fatty acid amide oleoyl glycine (OlGly) and its more stable methylated form oleoyl alanine (OlAla) reduce naloxone-precipitated morphine withdrawal (MWD)-induced conditioned gaping (nausea) responses in rats. In addition, OlGly has been shown to reduce lithium chloride (LiCl)-induced conditioned gaping in rats and vomiting in Suncus murinus (house musk shrews). OBJECTIVES: Here, we compared the potential of these fatty acid amides to maintain their anti-nausea/anti-emetic effect over a delay. The following experiments examined the potential of a wider dose range of OlGly and OlAla to interfere with (1) LiCl-induced conditioned gaping in rats and (2) LiCl-induced vomiting in shrews, when administered 20 or 70 min prior to illness. RESULTS: OlAla (1, 5, 20 mg/kg) reduced LiCl-induced conditioned gaping, with OlGly only effective at the high dose (20 mg/kg), with no effect of pretreatment delay time. At the high dose of 20 mg/kg, OlGly increased passive drips during conditioning suggesting a sedative effect. In shrews, both OlGly and OlAla (1, 5 mg/kg) suppressed LiCl-induced vomiting, with no effect of pretreatment delay. OlAla more effectively suppressed vomiting, with OlAla (5 mg/kg) also increasing the latency to the first vomiting reaction. CONCLUSIONS: OlAla was more effective than OlGly in reducing both LiCl-induced gaping in rats and LiCl-induced vomiting in shrews. These findings provide further evidence that these fatty acid amides may be useful treatments for nausea and vomiting, with OlAla demonstrating superior efficacy.
Gitit Kra, Jayasimha Rayalu Daddam, Uzi Moallem, Hadar Kamer, Majdoleen Ahmad, Alina Nemirovski, Andres G Contreras, Joseph Tam, and Maya Zachut. 2022. “Effects of Environmental Heat Load on Endocannabinoid System Components in Adipose Tissue of High Yielding Dairy Cows.” Animals : an open access journal from MDPI, 12, 6. Abstract
{Environmental heat load (HL) adversely affects the performance of dairy cows. The endocannabinoid system (ECS) regulates metabolism and the stress response, thus we hypothesized that HL may affect the ECS of dairy cows. Our objective was to determine the levels of endocannabinoids (eCBs) and gene and protein expressions of the ECS components in adipose tissue (AT) and plasma of early postpartum (PP) and late-lactation cows. In addition, we examined eCBs in milk, and studied the interaction of eCBs with bovine cannabinoids receptors CB1 and CB2. In the first experiment, plasma and AT were sampled from cows calving during summer (S
Gitit Kra, Jayasimha Rayalu Daddam, Uzi Moallem, Hadar Kamer, Radka Kočvarová, Alina Nemirovski, Andres G Contreras, Joseph Tam, and Maya Zachut. 2022. “Effects of omega-3 supplementation on components of the endocannabinoid system and metabolic and inflammatory responses in adipose and liver of peripartum dairy cows.” Journal of animal science and biotechnology, 13, 1, Pp. 114. Abstract
BACKGROUND: Dietary supplementation of omega-3 fatty acids can reduce the activation of the endocannabinoid system (ECS) by decreasing the availability of arachidonic acid, thus lowering endocannabinoids (eCBs) levels. The ECS is a modulator of energy metabolism, stress response and inflammation in mammals, yet there is little information on the roles of the ECS in transition dairy cows. During the periparturient period, the adipose tissue and liver are the main metabolic organs that participate in the adaptations of dairy cows to onset of lactation; however, exceeded adipose tissue lipolysis and accumulation of lipids in the liver have adverse effects on cows' physiology. Here we aimed to examine whether omega-3 supplementation during the transition period will modulate ECS activation and affect metabolic and inflammatory indices in postpartum dairy cows, by supplementing twenty-eight transition Holstein dairy cows with either saturated fat (CTL) or encapsulated flaxseed oil (FLX). Components of the ECS, metabolic and inflammatory markers were measured in blood, liver, and subcutaneous adipose tissue. RESULTS: FLX supplementation reduced feed intake by 8.1% (P < 0.01) and reduced plasma levels of arachidonic acid (by 44.2%; P = 0.02) and anandamide (by 49.7%; P = 0.03) postpartum compared to CTL. The mRNA transcription levels of the cannabinoid receptor 1 (CNR1/CB1) tended to be lower (2.5 folds) in white blood cells of FLX than in CTL (P = 0.10), and protein abundance of ECS enzyme monoacylglycerol lipase was higher in peripheral blood mononuclear cells of FLX than in CTL (P = 0.04). In adipose tissue, palmitoylethanolamide levels were lower in FLX than in CTL (by 61.5%; P = 0.02), relative mRNA transcription of lipogenic genes were higher, and the protein abundance of cannabinoid receptor 2 (P = 0.08) and monoacylglycerol lipase (P = 0.10) tended to be higher in FLX compared to CTL. Hepatic 2-arachidonoylglycerol tended to be higher (by 73.1%; P = 0.07), and interlukin-6 mRNA transcription level was 1.5 folds lower in liver of FLX than in CTL (P = 0.03). CONCLUSIONS: Nutritional supplementation of omega-3 fatty acids seems to partly modulate ECS activation, which could be related to lower feed intake. The altered ECS components in blood, adipose tissue and liver are associated with moderate modulations in lipid metabolism in the adipose and inflammation in liver of peripartum dairy cows.
Introduction: Cancer patients report nausea as a side effect of their chemotherapy treatment. Using the pre-clinical rodent model of acute nausea-lithium chloride (LiCl)-induced conditioned gaping-our group has demonstrated that exogenous cannabinoids may have antinausea potential. Materials and Methods: With the goal of evaluating the role of sex as a factor in pre-clinical research, we first compared the conditioned gaping reactions produced by varying doses of LiCl in male and female rats using the taste reactivity test (Experiment 1). Results: LiCl produced dose-dependent conditioned gaping similarly in male and female rats with the highest dose (127.2 mg/kg) producing robust conditioned gaping, with this dose used in subsequent experiments. Next, we examined the antinausea potential of THC (Experiment 2), CBD (Experiment 3), cannabidiolic acid (CBDA; Experiment 4) and oleoyl alanine (OlAla; Experiment 5) in both male and female rats. THC, CBD, CBDA, and OlAla dose dependently reduced conditioned gaping in both male and female rats in a similar manner. Conclusions: These results suggest that cannabinoids may be equally effective in treating nausea in both males and females.
Reem Smoum, Christeene Haj, Shira Hirsch, Alina Nemirovski, Zhannah Yekhtin, Benny Bogoslavsky, Gaganjyot Kaur Bakshi, Mukesh Chourasia, Ruth Gallily, Joseph Tam, and Raphael Mechoulam. 2022. “Fenchone Derivatives as a Novel Class of CB2 Selective Ligands: Design, Synthesis, X-ray Structure and Therapeutic Potential.” Molecules (Basel, Switzerland), 27, 4. Abstract
A series of novel cannabinoid-type derivatives were synthesized by the coupling of (1S,4R)-(+) and (1R,4S)-(-)-fenchones with various resorcinols/phenols. The fenchone-resorcinol derivatives were fluorinated using Selectfluor and demethylated using sodium ethanethiolate in dimethylformamide (DMF). The absolute configurations of four compounds were determined by X-ray single crystal diffraction. The fenchone-resorcinol analogs possessed high affinity and selectivity for the CB2 cannabinoid receptor. One of the analogues synthesized, 2-(2',6'-dimethoxy-4'-(2″-methyloctan-2″-yl)phenyl)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol (1d), had a high affinity (K(i) = 3.51 nM) and selectivity for the human CB2 receptor (hCB2). In the [(35)S]GTP$\gamma$S binding assay, our lead compound was found to be a highly potent and efficacious hCB2 receptor agonist (EC(50) = 2.59 nM, E((max)) = 89.6%). Two of the fenchone derivatives were found to possess anti-inflammatory and analgesic properties. Molecular-modeling studies elucidated the binding interactions of 1d within the CB2 binding site.
Samir Abu-Gazala, Michael Bergel, Yhara Arad, Liron Hefetz, Shira Azulai, Aaron Baker, Arnon Haran, Hadar Israeli, Doron Kleiman, Itia Samuel, Uria Tsubary, Anna Permyakova, Joseph Tam, Rachel Ben-Haroush Schyr, and Danny Ben-Zvi. 2022. “Generation and characterization of a mouse model for one anastomosis gastric bypass surgery.” American journal of physiology. Endocrinology and metabolism, 322, 5, Pp. E414–E424. Abstract
One anastomosis gastric bypass (OAGB) surgery became a common bariatric procedure in recent years. In this surgery, the distal stomach, duodenum, and proximal jejunum are bypassed, leading to weight loss, improvement in metabolic parameters, and a change in hormonal secretion. We sought to generate and characterize a mouse model for OAGB. Mice fed for 26 wk on a high-fat diet were assigned to OAGB, sham surgery, or caloric restriction and were followed for 50 more days on a high-fat diet. Physiological and histological parameters of the mice were compared during and at the end of the experiment. OAGB-operated mice lost weight and displayed low levels of plasma lipids, high insulin sensitivity, and rapid glucose metabolism compared with sham-operated mice. OAGB-operated mice had higher energy expenditure, higher levels of glucagon-like peptide (GLP-1), and lower albumin than weight-matched calorie-restricted mice. There was no difference in the histology of the endocrine pancreas. The livers of OAGB mice had little hepatic steatosis yet presented with a large number of phagocytic cells. The OAGB mouse model recapitulates many of the phenotypes described in patients that underwent OAGB and enables molecular and physiological studies on the outcome of this surgery.NEW & NOTEWORTHY A mouse model for one anastomosis gastric bypass (OAGB) surgery displays similar outcomes to clinical reports and enables to study the weight loss-dependent and -independent effects of this bariatric surgery.
Joshua Stokar, Irina Gurt, Einav Cohen-Kfir, Oran Yakubovsky, Noa Hallak, Hadar Benyamini, Natan Lishinsky, Neta Offir, Joseph Tam, and Rivka Dresner-Pollak. 2022. “Hepatic adropin is regulated by estrogen and contributes to adverse metabolic phenotypes in ovariectomized mice.” Molecular metabolism, 60, Pp. 101482. Abstract
{OBJECTIVE: Menopause is associated with visceral adiposity, hepatic steatosis and increased risk for cardiovascular disease. As estrogen replacement therapy is not suitable for all postmenopausal women, a need for alternative therapeutics and biomarkers has emerged. METHODS: 9-week-old C57BL/6 J female mice were subjected to ovariectomy (OVX) or SHAM surgery (n = 10 per group), fed a standard diet and sacrificed 6- & 12 weeks post-surgery. RESULTS: Increased weight gain, hepatic triglyceride content and changes in hepatic gene expression of Cyp17a1, Rgs16, Fitm1 as well as Il18, Rares2, Retn, Rbp4 in mesenteric visceral adipose tissue (VAT) were observed in OVX vs. SHAM. Liver RNA-sequencing 6-weeks post-surgery revealed changes in genes and microRNAs involved in fat metabolism in OVX vs. SHAM mice. Energy Homeostasis Associated gene (Enho) coding for the hepatokine adropin was significantly reduced in OVX mice livers and strongly inversely correlated with weight gain (r = -0.7 p < 0.001) and liver triglyceride content (r = -0.4
Shira Hirsch, Liad Hinden, Meital Naim-Ben-David, Saja Baraghithy, Anna Permyakova, Shahar Azar, Taher Nasser, Emma Portnoy, Majd Agbaria, Alina Nemirovski, Gershon Golomb, and Joseph Tam. 2022. “Hepatic targeting of the centrally active cannabinoid 1 receptor (CB(1)R) blocker rimonabant via PLGA nanoparticles for treating fatty liver disease and diabetes.” Journal of controlled release : official journal of the Controlled Release Society. Abstract
Over-activation of the endocannabinoid/CB(1)R system is a hallmark feature of obesity and its related comorbidities, most notably type 2 diabetes (T2D), and non-alcoholic fatty liver disease (NAFLD). Although the use of drugs that widely block the CB(1)R was found to be highly effective in treating all metabolic abnormalities associated with obesity, they are no longer considered a valid therapeutic option due to their adverse neuropsychiatric side effects. Here, we describe a novel nanotechnology-based drug delivery system for repurposing the abandoned first-in-class global CB(1)R antagonist, rimonabant, by encapsulating it in polymeric nanoparticles (NPs) for effective hepatic targeting of CB(1)Rs, enabling effective treatment of NAFLD and T2D. Rimonabant-encapsulated NPs (Rimo-NPs) were mainly distributed in the liver, spleen, and kidney, and only negligible marginal levels of rimonabant were found in the brain of mice treated by iv/ip administration. In contrast to freely administered rimonabant treatment, no CNS-mediated behavioral activities were detected in animals treated with Rimo-NPs. Chronic treatment of diet-induced obese mice with Rimo-NPs resulted in reduced hepatic steatosis and liver injury as well as enhanced insulin sensitivity, which were associated with enhanced cellular uptake of the formulation into hepatocytes. Collectively, we successfully developed a method of encapsulating the centrally acting CB(1)R blocker in NPs with desired physicochemical properties. This novel drug delivery system allows hepatic targeting of rimonabant to restore the metabolic advantages of blocking CB(1)R in peripheral tissues, especially in the liver, without the negative CB(1)R-mediated neuropsychiatric side effects.

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