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.

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.

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.

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.

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

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.

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.

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.

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.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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.

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.

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.

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.

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.

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.

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.

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.

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. © 2020 Ritter 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.

The Cannabis plant contains numerous components, including cannabinoids and other active molecules. The phyto-cannabinoid activity is mediated by the endocannabinoid system. Cannabinoids affect the nervous system and play significant roles in the regulation of the immune system. While Cannabis is not yet registered as a drug, the potential of cannabinoid-based medicines for the treatment of various conditions has led many countries to authorize their clinical use. However, the data from basic and medical research dedicated to medical Cannabis is currently limited. A variety of pathological conditions involve dysregulation of the immune system. For example, in cancer, immune surveillance and cancer immuno-editing result in immune tolerance. On the other hand, in autoimmune diseases increased immune activity causes tissue damage. Immuno-modulating therapies can regulate the immune system and therefore the immune-regulatory properties of cannabinoids, suggest their use in the therapy of immune related disorders. In this contemporary review, we discuss the roles of the endocannabinoid system in immunity and explore the emerging data about the effects of cannabinoids on the immune response in different pathologies. In addition, we discuss the complexities of using cannabinoid-based treatments in each of these conditions.