Publications

2021
Saja Baraghithy, Yael Soae, Dekel Assaf, Liad Hinden, Shiran Udi, Adi Drori, Yankel Gabet, and Joseph Tam. 2021. “Renal Proximal Tubule Cell Cannabinoid-1 Receptor Regulates Bone Remodeling and Mass via a Kidney-to-Bone Axis.” Cells, 10, 2. Abstract
The renal proximal tubule cells (RPTCs), well-known for maintaining glucose and mineral homeostasis, play a critical role in the regulation of kidney function and bone remodeling. Deterioration in RPTC function may therefore lead to the development of diabetic kidney disease (DKD) and osteoporosis. Previously, we have shown that the cannabinoid-1 receptor (CB1R) modulates both kidney function as well as bone remodeling and mass via its direct role in RPTCs and bone cells, respectively. Here we employed genetic and pharmacological approaches that target CB1R, and found that its specific nullification in RPTCs preserves bone mass and remodeling both under normo- and hyper-glycemic conditions, and that its chronic blockade prevents the development of diabetes-induced bone loss. These protective effects of negatively targeting CB1R specifically in RPTCs were associated with its ability to modulate erythropoietin (EPO) synthesis, a hormone known to affect bone mass and remodeling. Our findings highlight a novel molecular mechanism by which CB1R in RPTCs remotely regulates skeletal homeostasis via a kidney-to-bone axis that involves EPO.
Samantha M Ayoub, Fabiana Piscitelli, Cristoforo Silvestri, Cheryl L Limebeer, Erin M Rock, Reem Smoum, Mathew Farag, Hannah de Almeida, Megan T Sullivan, Sébastien Lacroix, Besma Boubertakh, Nayudu Nallabelli, Aron H Lichtman, Francesco Leri, Raphael Mechoulam, Vincenzo Di Marzo, and Linda A Parker. 2021. “Spontaneous and Naloxone-Precipitated Withdrawal Behaviors From Chronic Opiates are Accompanied by Changes in N-Oleoylglycine and N-Oleoylalanine Levels in the Brain and Ameliorated by Treatment With These Mediators.” Frontiers in pharmacology, 12, Pp. 706703. Abstract
Rationale: The endocannabinoidome mediators, N-Oleoylglycine (OlGly) and N-Oleoylalanine (OlAla), have been shown to reduce acute naloxone-precipitated morphine withdrawal affective and somatic responses. Objectives: To determine the role and mechanism of action of OlGly and OlAla in withdrawal responses from chronic exposure to opiates in male Sprague-Dawley rats. Methods: Opiate withdrawal was produced: 1) spontaneously 24 h following chronic exposure to escalating doses of morphine over 14 days (Experiments 1 and 2) and steady-state exposure to heroin by minipumps for 12 days (Experiment 3), 2) by naloxone injection during steady-state heroin exposure (Experiment 4), 3) by naloxone injection during operant heroin self-administration (Experiment 5). Results: In Experiment 1, spontaneous morphine withdrawal produced somatic withdrawal reactions. The behavioral withdrawal reactions were accompanied by suppressed endogenous levels of OlGly in the nucleus accumbens, amygdala, and prefrontal cortex, N-Arachidonylglycerol and OlAla in the amygdala, 2-arachidonoylglycerol in the nucleus accumbens, amygdala and interoceptive insular cortex, and by changes in colonic microbiota composition. In Experiment 2, treatment with OlAla, but not OlGly, reduced spontaneous morphine withdrawal responses. In Experiment 3, OlAla attenuated spontaneous steady-state heroin withdrawal responses at both 5 and 20 mg/kg; OlGly only reduced withdrawal responses at the higher dose of 20 mg/kg. Experiment 4 demonstrated that naloxone-precipitated heroin withdrawal from steady-state exposure to heroin (7 mg/kg/day for 12 days) is accompanied by tissue-specific changes in brain or gut endocannabinoidome mediator, including OlGly and OlAla, levels and colonic microbiota composition, and that OlAla (5 mg/kg) attenuated behavioural withdrawal reactions, while also reversing some of the changes in brain and gut endocannabinoidome and gut microbiota induced by naloxone. Experiment 5 demonstrated that although OlAla (5 mg/kg) did not interfere with operant heroin self-administration on its own, it blocked naloxone-precipitated elevation of heroin self-administration behavior. Conclusion: These results suggest that OlAla and OlGly are two endogenous mediators whose brain concentrations respond to chronic opiate treatment and withdrawal concomitantly with changes in colon microbiota composition, and that OlAla may be more effective than OlGly in suppressing chronic opiate withdrawal responses.
Constantin Itin, Abraham J. Domb, and Amnon Hoffman. 2021. “On the Suitability of Porcine Labial Mucosa as a Model for Buccal Mucosal Drug Delivery Research.” Journal of Pharmaceutical Sciences, 110, 4, Pp. 1863–1864. Abstract
Contrary to human, porcine mucosa of the inner side of the lip is parakeratinized. Thus, although desirable due to its large surface area, it does not closely resemble human buccal mucosa to be considered a suitable model for systemic drug delivery research. Nevertheless, it can be utilized for comparative screening of topical or systemic delivery of bioactive agents, mostly lipophilic such as cannabinoids.
Erin M Rock, Cheryl L Limebeer, Roger G Pertwee, Raphael Mechoulam, and Linda A Parker. 2021. “Therapeutic Potential of Cannabidiol, Cannabidiolic Acid, and Cannabidiolic Acid Methyl Ester as Treatments for Nausea and Vomiting.” Cannabis and cannabinoid research, 6, 4, Pp. 266–274. Abstract
Introduction: Nausea and vomiting are the most distressing symptoms reported by oncology patients undergoing anticancer treatment. With the currently available treatments, vomiting and especially nausea remain problematic, highlighting the need for alternative treatments. Discussion: Here we review in vitro and in vivo evidence for the effectiveness of the nonpsychoactive cannabinoid cannabidiol (CBD) in managing nausea and vomiting. In addition, we also review the evidence for CBD's acidic precursor, cannabidiolic acid (CBDA), and a methylated version of CBDA (CBDA-ME) in these phenomena. Finally, we explore the potential role of CBD in the treatment of cannabinoid hyperemesis syndrome. Conclusions: CBD has demonstrated efficacy in reducing nausea and vomiting, with CBDA and CBDA-ME being more potent. The data suggest a need for these compounds to be evaluated in clinical trials for their ability to reduce nausea and/or vomiting.
2020
E.M. Rock, S.M. Ayoub, C.L. Limebeer, A. Gene, K.L. Wills, M.V. DeVuono, R. Smoum, V. Di Marzo, A.H. Lichtman, R. Mechoulam, and L.A. Parker. 2020. “Acute naloxone-precipitated morphine withdrawal elicits nausea-like somatic behaviors in rats in a manner suppressed by N-oleoylglycine.” Psychopharmacology, 237, 2, Pp. 375-384. Abstract
Rationale: Acute naloxone-precipitated morphine withdrawal (MWD) produces a conditioned place aversion (CPA) in rats even after one or two exposures to high-dose (20 mg/kg, sc) morphine followed 24-h later by naloxone (1 mg/kg, sc). However, the somatic withdrawal reactions produced by acute naloxone-precipitated MWD in rats have not been investigated. A recently discovered fatty acid amide, N-oleoylglycine (OlGly), which has been suggested to act as a fatty acid amide hydrolase (FAAH) inhibitor and as a peroxisome proliferator-activated receptor alpha (PPARα) agonist, was previously shown to interfere with a naloxone-precipitated MWD-induced CPA in rats. Objectives: The aims of these studies were to examine the somatic withdrawal responses produced by acute naloxone-precipitated MWD and determine whether OlGly can also interfere with these responses. Results: Here, we report that following two exposures to morphine (20 mg/kg, sc) each followed by naloxone (1 mg/kg, sc) 24 h later, rats display nausea-like somatic reactions of lying flattened on belly, abdominal contractions and diarrhea, and display increased mouthing movements and loss of body weight. OlGly (5 mg/kg, ip) interfered with naloxone-precipitated MWD-induced abdominal contractions, lying on belly, diarrhea and mouthing movements in male Sprague–Dawley rats, by both a cannabinoid 1 (CB1) and a PPARα mechanism of action. Since these withdrawal reactions are symptomatic of nausea, we evaluated the potential of OlGly to interfere with lithium chloride (LiCl)-induced and MWD-induced conditioned gaping in rats, a selective measure of nausea; the suppression of MWD-induced gaping reactions by OlGly was both CB1 and PPARα mediated. Conclusion: These results suggest that the aversive effects of acute naloxone-precipitated MWD reflect nausea, which is suppressed by OlGly. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
T. Stark, M. Di Bartolomeo, R. Di Marco, E. Drazanova, C.B.M. Platania, F.A. Iannotti, J. Ruda-Kucerova, C. D'Addario, L. Kratka, V. Pekarik, F. Piscitelli, Z. Babinska, J. Fedotova, G. Giurdanella, S. Salomone, A. Sulcova, C. Bucolo, C.T. Wotjak, Jr Starcuk, Z., F. Drago, R. Mechoulam, V. Di Marzo, and V. Micale. 2020. “Altered dopamine D3 receptor gene expression in MAM model of schizophrenia is reversed by peripubertal cannabidiol treatment.” Biochemical Pharmacology, 177. Abstract
Gestational methylazoxymethanol acetate (MAM) treatment produces offspring with adult phenotype relevant to schizophrenia, including positive- and negative-like symptoms, cognitive deficits, dopaminergic dysfunction, structural and functional abnormalities. Here we show that adult rats prenatally treated with MAM at gestational day 17 display significant increase in dopamine D3 receptor (D3) mRNA expression in prefrontal cortex (PFC), hippocampus and nucleus accumbens, accompanied by increased expression of dopamine D2 receptor (D2) mRNA exclusively in the PFC. Furthermore, a significant change in the blood perfusion at the level of the circle of Willis and hippocampus, paralleled by the enlargement of lateral ventricles, was also detected by magnetic resonance imaging (MRI) techniques. Peripubertal treatment with the non-euphoric phytocannabinoid cannabidiol (30 mg/kg) from postnatal day (PND) 19 to PND 39 was able to reverse in MAM exposed rats: i) the up-regulation of the dopamine D3 receptor mRNA (only partially prevented by haloperidol 0.6 mg/kg/day); and ii) the regional blood flow changes in MAM exposed rats. Molecular modelling predicted that cannabidiol could bind preferentially to dopamine D3 receptor, where it may act as a partial agonist according to conformation of ionic-lock, which is highly conserved in GPCRs. In summary, our results demonstrate that the mRNA expression of both dopamine D2 and D3 receptors is altered in the MAM model; however only the transcript levels of D3 are affected by cannabidiol treatment, likely suggesting that this gene might not only contribute to the schizophrenia symptoms but also represent an unexplored target for the antipsychotic activity of cannabidiol. © 2020 Elsevier Inc.
O. Ostersetzer-Biran and L. Klipcan. 2020. “Aminoacyl-tRNA synthetases and translational quality control in plant mitochondria.” Mitochondrion, 54, Pp. 15-20. Abstract
Gene expression involves the transfer of information stored in the DNA to proteins by two sequential key steps: transcription and translation. Aminoacyl-tRNA synthetases (aaRSs), an ancient group of enzymes, are key to these processes as they catalyze the attachment of each of the 20 amino acids to their corresponding tRNA molecules. Yet, in addition to the 20 canonical amino acids, plants also produce numerous non-proteogenic amino acids (NPAAs), some of which are erroneously loaded into tRNAs, translated into non-functional or toxic proteins and may thereby disrupt essential cellular processes. While many studies have been focusing on plant organelle RNA metabolism, mitochondrial translation still lags behind its characterization in bacterial and eukaryotic systems. Notably, plant mitochondrial aaRSs generally have a dual location, residing also within the chloroplasts or cytosol. Currently, little is known about how mitochondrial aaRSs distinguish between amino acids and their closely related NPAAs. The organelle translation machineries in plants seem more susceptible to NPAAs due to protein oxidation by reactive oxygen species (ROS) and high rates of protein turnover. We speculate that plant organellar aaRSs have acquired high-affinities to their cognate amino acid substrates to reduce cytotoxic effects by NPAAs. © 2020 Elsevier B.V. and Mitochondria Research Society
Ronit Vogt Sionov, Mark Feldman, Reem Smoum, Raphael Mechoulam, and Doron Steinberg. 2020. “Anandamide prevents the adhesion of filamentous Candida albicans to cervical epithelial cells.” Scientific reports, 10, 1, Pp. 13728. Abstract
Candidiasis is a fungal infection caused by Candida species that have formed a biofilm on epithelial linings of the body. The most frequently affected areas include the vagina, oral cavity and the intestine. In severe cases, the fungi penetrate the epithelium and cause systemic infections. One approach to combat candidiasis is to prevent the adhesion of the fungal hyphae to the epithelium. Here we demonstrate that the endocannabinoid anandamide (AEA) and the endocannabinoid-like N-arachidonoyl serine (AraS) strongly prevent the adherence of C. albicans hyphae to cervical epithelial cells, while the endocannabinoid 2-arachidonoylglycerol (2-AG) has only a minor inhibitory effect. In addition, we observed that both AEA and AraS prevent the yeast-hypha transition and perturb hyphal growth. Real-time PCR analysis showed that AEA represses the expression of the HWP1 and ALS3 adhesins involved in Candida adhesion to epithelial cells and the HGC1, RAS1, EFG1 and ZAP1 regulators of hyphal morphogenesis and cell adherence. On the other hand, AEA increased the expression of NRG1, a transcriptional repressor of filamentous growth. Altogether, our data show that AEA and AraS have potential anti-fungal activities by inhibiting hyphal growth and preventing hyphal adherence to epithelial cells.
R.V. Sionov, M. Feldman, R. Smoum, R. Mechoulam, and D. Steinberg. 2020. “Anandamide prevents the adhesion of filamentous Candida albicans to cervical epithelial cells.” Scientific Reports, 10, 1. Abstract
Candidiasis is a fungal infection caused by Candida species that have formed a biofilm on epithelial linings of the body. The most frequently affected areas include the vagina, oral cavity and the intestine. In severe cases, the fungi penetrate the epithelium and cause systemic infections. One approach to combat candidiasis is to prevent the adhesion of the fungal hyphae to the epithelium. Here we demonstrate that the endocannabinoid anandamide (AEA) and the endocannabinoid-like N-arachidonoyl serine (AraS) strongly prevent the adherence of C. albicans hyphae to cervical epithelial cells, while the endocannabinoid 2-arachidonoylglycerol (2-AG) has only a minor inhibitory effect. In addition, we observed that both AEA and AraS prevent the yeast-hypha transition and perturb hyphal growth. Real-time PCR analysis showed that AEA represses the expression of the HWP1 and ALS3 adhesins involved in Candida adhesion to epithelial cells and the HGC1, RAS1, EFG1 and ZAP1 regulators of hyphal morphogenesis and cell adherence. On the other hand, AEA increased the expression of NRG1, a transcriptional repressor of filamentous growth. Altogether, our data show that AEA and AraS have potential anti-fungal activities by inhibiting hyphal growth and preventing hyphal adherence to epithelial cells. © 2020, The Author(s).}, funding_text 1=his study was partially supported by Agriculture Ministry of Israel. We are grateful to Dr. Yael Feinstein-Rotkopf for operating the Nikon spinning scan microscope at our Interdepartment Core Research Facility. We thank Muna Aqawi and Sarah Gingichashvili for their support.
Elyad M Davidson, Noa Raz, and Aharon M Eyal. 2020. “Anesthetic considerations in medical cannabis patients.” Current opinion in anaesthesiology, 33, 6, Pp. 832–840. Abstract
PURPOSE OF REVIEW: Growing numbers of patients, consuming cannabinoids admitted to surgery, create a challenge to anesthesia providers. This review provides a summary of recent literature related to cannabis and anesthesia, with specific recommendations to the anesthetic management of medical cannabis consumers. RECENT FINDINGS: At present, cannabis has found its way to public consensus in many countries and is penetrating slower to different medical fields. We relate and discuss recent findings investigating effects of cannabis consumption on the various aspects including perioperative measures, post-operative pain, PONV, cardiovascular stability, and anesthesia monitoring. SUMMARY: Recent surveys estimate that 10-20% of adult populations have consumed cannabis in the past year. Medical cannabis consumers are a newer group of cannabis users. Anesthesia providers have to update their knowledge on cannabis and possible anesthetic interaction. It is unreasonable to make recommendations that apply to the whole heterogeneous group of cannabis users, but is easier with the more homogenous group of Medical cannabis users, characterized by frequent use and relatively high cannabis doses, combined with good knowledge of administered composition and protocol, as well as adverse and withdrawal effects. Anesthesia providers have to know the effects and modify anesthetic plan accordingly. We provide perioperative anesthetic recommendations related to medical cannabis consumers. Collecting information of the effects of medical cannabis use in perioperative setting will further create a highly useful database for anesthetics in the close future.
E.M. Davidson, N. Raz, and A.M. Eyal. 2020. “Anesthetic considerations in medical cannabis patients.” Current opinion in anaesthesiology, 33, 6, Pp. 832-840. Abstract
PURPOSE OF REVIEW: Growing numbers of patients, consuming cannabinoids admitted to surgery, create a challenge to anesthesia providers. This review provides a summary of recent literature related to cannabis and anesthesia, with specific recommendations to the anesthetic management of medical cannabis consumers. RECENT FINDINGS: At present, cannabis has found its way to public consensus in many countries and is penetrating slower to different medical fields. We relate and discuss recent findings investigating effects of cannabis consumption on the various aspects including perioperative measures, post-operative pain, PONV, cardiovascular stability, and anesthesia monitoring. SUMMARY: Recent surveys estimate that 10-20% of adult populations have consumed cannabis in the past year. Medical cannabis consumers are a newer group of cannabis users. Anesthesia providers have to update their knowledge on cannabis and possible anesthetic interaction. It is unreasonable to make recommendations that apply to the whole heterogeneous group of cannabis users, but is easier with the more homogenous group of Medical cannabis users, characterized by frequent use and relatively high cannabis doses, combined with good knowledge of administered composition and protocol, as well as adverse and withdrawal effects. Anesthesia providers have to know the effects and modify anesthetic plan accordingly. We provide perioperative anesthetic recommendations related to medical cannabis consumers. Collecting information of the effects of medical cannabis use in perioperative setting will further create a highly useful database for anesthetics in the close future.
Michal Eger, Miaad Bader, Dara Bree, Rivka Hadar, Alina Nemirovski, Joseph Tam, Dan Levy, Chaim G Pick, and Yankel Gabet. 2020. “Author Correction: Bone Anabolic Response in the Calvaria Following Mild Traumatic Brain Injury is Mediated by the Cannabinoid-1 Receptor.”. Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
P. Pacher, N.M. Kogan, and R. Mechoulam. 2020. “Beyond THC and endocannabinoids.” Annual Review of Pharmacology and Toxicology, 60, Pp. 637-659. Abstract
Research in the cannabinoid field, namely on phytocannabinoids, the endogenous cannabinoids anandamide and 2-arachidonoyl glycerol and their metabolizing and synthetic enzymes, the cannabinoid receptors, and anandamide-like cannabinoid compounds, has expanded tremendously over the last few years. Numerous endocannabinoid-like compounds have been discovered. The Cannabis plant constituent cannabidiol (CBD) was found to exert beneficial effects in many preclinical disease models ranging from epilepsy, cardiovascular disease, inflammation, and autoimmunity to neurodegenerative and kidney diseases and cancer. CBD was recently approved in the United States for the treatment of rare forms of childhood epilepsy. This has triggered the development of many CBD-based products for human use, often with overstated claims regarding their therapeutic effects. In this article, the recently published research on the chemistry and biological effects of plant cannabinoids (specifically CBD), endocannabinoids, certain long-chain fatty acid amides, and the variety of relevant receptors is critically reviewed. Copyright © 2020 by Annual Reviews. All rights reserved.
V. Stoeger, A.-K. Holik, K. Hölz, T. Dingjan, J. Hans, J.P. Ley, G.E. Krammer, M.Y. Niv, M.M. Somoza, and V. Somoza. 2020. “Bitter-Tasting Amino Acids l-Arginine and l -Isoleucine Differentially Regulate Proton Secretion via T2R1 Signaling in Human Parietal Cells in Culture.” Journal of Agricultural and Food Chemistry, 68, 11, Pp. 3434-3444. Abstract
This study aimed at identifying whether the bitter-tasting amino acids l-arginine (l-ARG) and l-isoleucine (l-ILE) differentially regulate mechanisms of gastric acid secretion in human parietal cells (HGT-1 cells) via activation of bitter taste sensing receptors (T2Rs). In a first set of experiments, involvement of T2Rs in l-ARG and l-ILE-modulated proton secretion was demonstrated by co-treatment of HGT-1 cells with T2R antagonists. Subsequent whole genome screenings by means of cDNA arrays revealed T2R1 as a prominent target for both amino acids. Next, the functional role of T2R1 was verified by means of a T2R1 CRISPR-Cas9 knock-out approach. Here, the effect of l-ARG on proton secretion decreased by 65.7 ± 21.9% and the effect of l-ILE increased by 93.2 ± 24.1% in HGT-1 T2R1 ko versus HGT-1 wt cells (p < 0.05). Overall, our results indicate differential effects of l-ARG and l-ILE on proton secretion in HGT-1 cells and our molecular docking studies predict distinct binding for these amino acids in the binding site of T2R1. Further studies will elucidate whether the mechanism of differential effects involves structure-specific ligand-biased signaling of T2R1 or additional cellular targets. Copyright © 2019 American Chemical Society.
D. Robinson, S. Ritter, L. Zadik-Weiss, H. Ounallah-Saad, N. Abu-Ahmad, R. Kashkoosh, M. Yassin, and R. Or. 2020. “Bridging the accessibility gap of cannabinoid medicine and Arabic culture.” Rambam Maimonides Medical Journal, 11, 1. Abstract
Arabs are a large minority group in the Israeli society. With the increasing use of medical cannabis throughout Israel due to changing governmental policies, the interactions of the Arab society with medical cannabis becomes of scientific and medical relevance. Recreational cannabis use is considered haram (forbidden) in Islam. However, most religious scholars agree that medical cannabis usage might be justified as zarurat (emergency and life-saving, therefore allowed) use. Obstacles to medical cannabis use within the Arabic population may relate to language barrier and/or cultural barriers. There are few Arabic-speaking web-based medical-cannabis support groups, and little official information about it is available in the Arabic language. In order for the full benefits of medical cannabis to reach the entire Israeli population, a government-sponsored web-based educational program is necessary in Hebrew and Arabic, both of which are among the nation's official languages, thereby contributing to the equalization of health resource accessibility. © 2020 Robinson et al. This is an open-access article. All its content, except where otherwise noted, is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Muna Aqawi, Ruth Gallily, Ronit Vogt Sionov, Batya Zaks, Michael Friedman, and Doron Steinberg. 2020. “Cannabigerol Prevents Quorum Sensing and Biofilm Formation of Vibrio harveyi.” Frontiers in microbiology, 11, Pp. 858. Abstract
Cannabigerol (CBG) is a non-psychoactive cannabinoid naturally present in trace amounts in the Cannabis plant. So far, CBG has been shown to exert diverse activities in eukaryotes. However, much less is known about its effects on prokaryotes. In this study, we investigated the potential role of CBG as an anti-biofilm and anti-quorum sensing agent against Vibrio harveyi. Quorum sensing (QS) is a cell-to-cell communication system among bacteria that involves small signaling molecules called autoinducers, enabling bacteria to sense the surrounding environment. The autoinducers cause alterations in gene expression and induce bioluminescence, pigment production, motility and biofilm formation. The effect of CBG was tested on V. harveyi grown under planktonic and biofilm conditions. CBG reduced the QS-regulated bioluminescence and biofilm formation of V. harveyi at concentrations not affecting the planktonic bacterial growth. CBG also reduced the motility of V. harveyi in a dose-dependent manner. We further observed that CBG increased LuxO expression and activity, with a concomitant 80% downregulation of the LuxR gene. Exogenous addition of autoinducers could not overcome the QS-inhibitory effect of CBG, suggesting that CBG interferes with the transmission of the autoinducer signals. In conclusion, our study shows that CBG is a potential anti-biofilm agent via inhibition of the QS cascade.
M. Aqawi, R. Gallily, R.V. Sionov, B. Zaks, M. Friedman, and D. Steinberg. 2020. “Cannabigerol Prevents Quorum Sensing and Biofilm Formation of Vibrio harveyi.” Frontiers in Microbiology, 11. Abstract
Cannabigerol (CBG) is a non-psychoactive cannabinoid naturally present in trace amounts in the Cannabis plant. So far, CBG has been shown to exert diverse activities in eukaryotes. However, much less is known about its effects on prokaryotes. In this study, we investigated the potential role of CBG as an anti-biofilm and anti-quorum sensing agent against Vibrio harveyi. Quorum sensing (QS) is a cell-to-cell communication system among bacteria that involves small signaling molecules called autoinducers, enabling bacteria to sense the surrounding environment. The autoinducers cause alterations in gene expression and induce bioluminescence, pigment production, motility and biofilm formation. The effect of CBG was tested on V. harveyi grown under planktonic and biofilm conditions. CBG reduced the QS-regulated bioluminescence and biofilm formation of V. harveyi at concentrations not affecting the planktonic bacterial growth. CBG also reduced the motility of V. harveyi in a dose-dependent manner. We further observed that CBG increased LuxO expression and activity, with a concomitant 80% downregulation of the LuxR gene. Exogenous addition of autoinducers could not overcome the QS-inhibitory effect of CBG, suggesting that CBG interferes with the transmission of the autoinducer signals. In conclusion, our study shows that CBG is a potential anti-biofilm agent via inhibition of the QS cascade. © Copyright © 2020 Aqawi, Gallily, Sionov, Zaks, Friedman and Steinberg.
T. Assa-Glazer, J. Gorelick, N. Sela, A. Nyska, N. Bernstein, and Z. Madar. 2020. “Cannabis Extracts Affected Metabolic Syndrome Parameters in Mice Fed High-Fat/Cholesterol Diet.” Cannabis and Cannabinoid Research, 5, 3, Pp. 202-214. Abstract
Introduction: Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic syndrome, which often includes obesity, diabetes, and dyslipidemia. Several studies in mice and humans have implicated the involvement of the gut microbiome in NAFLD. While cannabis may potentially be beneficial for treating metabolic disorders such as NAFLD, the effects of cannabis on liver diseases and gut microbiota profile are yet to be addressed. In this study, we evaluated the therapeutic effects of cannabis strains with different cannabinoid profiles on NAFLD progression. Materials and Methods: NAFLD was induced by feeding mice a high-fat/cholesterol diet (HFCD) for 6 weeks. During this period, cannabis extracts were administrated orally at a concentration of 5 mg/kg every 3 days. Profile of lipids, liver enzymes, glucose tolerance, and gene expression related to carbohydrate lipid metabolism and liver inflammation were analyzed. The effect of cannabis strains on microbiota composition in the gut was evaluated. Results: A cannabidiol (CBD)-rich extract produced an increase in inflammatory related gene expression and a less diverse microbiota profile, associated with increased fasting glucose levels in HFCD-fed mice. In contrast, mice receiving a tetrahydrocannabinol (THC)-rich extract exhibited moderate weight gain, improved glucose response curves, and a decrease in liver enzymes. Conclusions: The results of this study indicate that the administration of cannabis containing elevated levels of THC may help ameliorate symptoms of NAFLD, whereas administration of CBD-rich cannabis extracts may cause a proinflammatory effect in the liver, linked with an unfavorable change in the microbiota profile. Our preliminary data suggest that these effects are mediated by mechanisms other than increased expression of the endocannabinoid receptors cannabinoid receptor 1 (CB1) and CB2. © Copyright 2020, Mary Ann Liebert, Inc., publishers 2020.
Tal Assa-Glazer, Jonathan Gorelick, Noa Sela, Abraham Nyska, Nirit Bernstein, and Zecharia Madar. 2020. “Cannabis Extracts Affected Metabolic Syndrome Parameters in Mice Fed High-Fat/Cholesterol Diet.” Cannabis and cannabinoid research, 5, 3, Pp. 202–214. Abstract
Introduction: Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic syndrome, which often includes obesity, diabetes, and dyslipidemia. Several studies in mice and humans have implicated the involvement of the gut microbiome in NAFLD. While cannabis may potentially be beneficial for treating metabolic disorders such as NAFLD, the effects of cannabis on liver diseases and gut microbiota profile are yet to be addressed. In this study, we evaluated the therapeutic effects of cannabis strains with different cannabinoid profiles on NAFLD progression. Materials and Methods: NAFLD was induced by feeding mice a high-fat/cholesterol diet (HFCD) for 6 weeks. During this period, cannabis extracts were administrated orally at a concentration of 5 mg/kg every 3 days. Profile of lipids, liver enzymes, glucose tolerance, and gene expression related to carbohydrate lipid metabolism and liver inflammation were analyzed. The effect of cannabis strains on microbiota composition in the gut was evaluated. Results: A cannabidiol (CBD)-rich extract produced an increase in inflammatory related gene expression and a less diverse microbiota profile, associated with increased fasting glucose levels in HFCD-fed mice. In contrast, mice receiving a tetrahydrocannabinol (THC)-rich extract exhibited moderate weight gain, improved glucose response curves, and a decrease in liver enzymes. Conclusions: The results of this study indicate that the administration of cannabis containing elevated levels of THC may help ameliorate symptoms of NAFLD, whereas administration of CBD-rich cannabis extracts may cause a proinflammatory effect in the liver, linked with an unfavorable change in the microbiota profile. Our preliminary data suggest that these effects are mediated by mechanisms other than increased expression of the endocannabinoid receptors cannabinoid receptor 1 (CB1) and CB2.
Sivan Ritter, Lilach Zadik-Weiss, Osnat Almogi-Hazan, and Reuven Or. 2020. “Cannabis, One Health, and Veterinary Medicine: Cannabinoids' Role in Public Health, Food Safety, and Translational Medicine.” Rambam Maimonides medical journal, 11, 1. Abstract
Public health is connected to cannabis with regard to food, animal feed (feed), and pharmaceuticals. Therefore, the use of phytocannabinoids should be examined from a One Health perspective. Current knowledge on medical cannabis treatment (MCT) does not address sufficiently diseases which are of epidemiological and of zoonotic concern. The use of cannabinoids in veterinary medicine is illegal in most countries, mostly due to lack of evidence-based medicine. To answer the growing need of scientific evidence-based applicable medicine in both human and veterinary medicine, a new approach for the investigation of the therapeutic potential of cannabinoids must be adopted. A model that offers direct study of a specific disease in human and veterinary patients may facilitate development of novel therapies. Therefore, we urge the regulatory authorities-the ministries of health and agriculture (in Israel and worldwide)-to publish guidelines for veterinary use due to its importance to public health, as well as to promote One Health-related preclinical translational medicine studies for the general public health.

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