Background: Dietary oils differ in their fatty acid composition and the presence of additional microcompo-nents (antioxidants, etc.). These differences are thought to invoke different biochemical pathways, thus affecting fats and carbohydrates metabolism differently. Olive oil (OO) and soybean oil (SO) are common vegetable oils in the local cuisine. Peanuts oils of local varieties are viewed as potential sources of dietary vegetable oils, especially in the food industry. Objective: We examined the effect of four different dietary vegetable oils on carbohydrate and lipid metabolism in mice. The selected oils were OO, high in oleic acid, extracted from cultivated high oleic acid peanut (C-PO), regular peanut oil (PO), and SO. Design: In this study, 32 male C57BL/6J mice were randomly divided into four groups (n = 8 in each group) and were fed with four different diets enriched with 4% (w/w) dietary vegetable oils (OO, C-PO, PO, or SO). After 10 weeks, the mice were sacrificed. Western blot was used to examine proteins such as phospho-AMP-activated protein kinase (p-AMPK), ace-tyl-CoA carboxylase (ACC), cluster of differentiation 36 (CD36), and Sirtuin 1 (SIRT1), whereas real-time polymerase chain reaction (PCR) was used to examine the expression of sterol regulatory element-binding protein-1c (SREBP-1C), fatty acid synthase (FAS), glucose-6-phosphatase (G6Pase), and CD36 transcripts. Results: In mice-fed SO, lipid accumulation was predominately in adipose tissue, accompanied a tendency decrease in insulin sensitivity. Mice-fed OO had lower plasma triglycerides (TG) and increased hepatic CD36 gene expression. The C-PO group presented lower messenger RNA (mRNA) levels in the liver for all examined genes: SREBP-1c, FAS, G6Pase, and CD36. There were no significant differences in weight gain, plasma cholesterol and high-density lipoprotein (HDL) cholesterol levels, hepatic ACC, SIRT1, AMPK, and CD36 protein levels or in liver function among the diets. Discussion: It seems that as long as fat is consumed in moderation, oil types may play a lesser role in the metabolism of healthy individuals. Conclusion: This finding has the potential to increase flexibility in choosing oil types for consumption. © 2020 Anna Altberg et al.

Systemic cyclosporine A (CsA) therapy shows efficacy in the treatment of recalcitrant severe atopic dermatitis (AD) but elicits severe side-effects. Thus, a topical formulation of CsA nanocapsules (NCs), able to potentially bypass these drawbacks, was developed. CsA-NCs were shown to enhance drug penetration into the various layers of porcine ear skin. Furthermore, the encapsulated CsA was biologically active, as shown in vitro on mouse splenocytes, reflected by inhibition of both cell proliferation and of interleukin (IL)-2 secretion. Ex-vivo efficacy was demonstrated on human skin organ culture by markedly reducing pro-inflammatory cytokines secretion. Finally, CsA-NCs topical formulation elicited improved efficacy in terms of better preservation of the skin barrier integrity, a decrease of the systemic pro-inflammation markers and reduced skin inflammation. The overall results suggest that this original topical platform may provide a novel therapeutic tool of clinical significance compared to the existing topical therapeutic drugs in AD. © 2019 Elsevier Inc.

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.

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. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

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.

In the last decade, we have observed an increased public and scientific interest in the clinical applications of medical cannabis. Currently, the application of cannabinoids in cancer patients is mainly due to their analgesic and anti-emetic effects. The direct effects of phyto-cannabinoids on cancer cells are under intensive research, and the data remain somewhat inconsistent. Although anti-proliferative properties were observed in vitro, conclusive data from animal models and clinical trials are lacking. Since immunotherapy of malignant diseases and bone marrow transplantation are integral approaches in hemato-oncology, the immuno-modulatory characteristic of cannabinoids is a fundamental aspect for consideration. The effect of cannabinoids on the immune system is presently under investigation, and some evidence for its immunoregulatory properties has been shown. In addition, the interaction of cannabinoids and classical cytotoxic agents is a subject for further investigation. Here we discuss the current knowledge of cannabinoid-based treatments in preclinical models and the limited data in oncological patients. Particularly, we address the possible contradiction between the direct anti-tumor and the immune-modulatory effects of cannabinoids. Better understanding of the mechanism of cannabinoids influence is essential to design therapies that will allow cannabinoids to be incorporated into the clinic. © 2020 Gonen and Amital. 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.

Traumatic brain injury (TBI) is one of the main causes of death in young people for which currently no efficacious treatment exists. Recently, we have reported that mice with mild-TBI with a specific injury in the insula showed elevated levels of a little investigated N-acyl amino acid, N-oleoylglycine (OlGly). N-acyl amino acids have recently experienced an increased interest because of their important biological activities. They belong to the endocannabinoidome family of lipids with structural similarities with the endocannabinoids (eCBs). The aim of this study was to test the neuroprotective and antihyperalgesic actions of OlGly in a model of mouse mild-TBI (mTBI) and its effect on levels of eCBs and N-acylethanolamines at the end of treatment. Following mTBI, mice were administered a daily injection of OlGly (10-50-100 mg/kg i.p.) for 14 days. Treatment with OlGly normalized motor impairment and behavior in the light/dark box test, ameliorated TBI-induced thermal hyperalgesia and mechanical allodynia, and normalized aggressiveness and depression. Moreover, levels of eCBs and some N-acylethanolamines underwent significant changes 60 days after TBI, especially in the prefrontal cortex and hypothalamus, and OlGly reversed some of these changes. In conclusion, our findings reveal that OlGly ameliorates the behavioral alterations associated with mTBI in mice, while concomitantly modulating eCB and eCB-like mediator tone. © 2020 American Chemical Society.

Rationale: When acutely administered intraperitoneally, the non-psychoactive cannabinoid cannabidiol (CBD), its acidic precursor cannabidiolic acid (CBDA) and a stable methyl ester of CBDA (HU-580) reduce lithium chloride (LiCl)–induced conditioned gaping in male rats (a selective preclinical model of acute nausea) via activation of the serotonin 1A (5-HT1A) receptor. Objectives: To utilise these compounds to manage nausea in the clinic, we must determine if their effectiveness is maintained when injected subcutaneously (s.c) and when repeatedly administered. First, we compared the effectiveness of each of these compounds to reduce conditioned gaping following repeated (7-day) and acute (1-day) pretreatments and whether these anti-nausea effects were mediated by the 5-HT1A receptor. Next, we assessed whether the effectiveness of these compounds can be maintained when administered prior to each of 4 conditioning trials (once per week). We also evaluated the ability of repeated CBD (7 days) to reduce LiCl-induced vomiting in Suncus murinus. Finally, we examined whether acute CBD was equally effective in male and female rats. Results: Both acute and repeated (7 day) s.c. administrations of CBD (5 mg/kg), CBDA (1 μg/kg) and HU-580 (1 μg/kg) similarly reduced LiCl-induced conditioned gaping, and these effects were blocked by 5HT1A receptor antagonism. When administered over 4 weekly conditioning trials, the anti-nausea effectiveness of each of these compounds was also maintained. Repeated CBD (5 mg/kg, s.c.) maintained its anti-emetic efficacy in S. murinus. Acute CBD (5 and 20 mg/kg, s.c.) administration reduced LiCl-induced conditioned gaping similarly in male and female rats. Conclusion: When administered repeatedly (7 days), CBD, CBDA and HU-580 did not lose efficacy in reducing nausea and continued to act via agonism of the 5-HT1A receptor. When administered across 4 weekly conditioning trials, they maintained their effectiveness in reducing LiCl-induced nausea. Repeated CBD also reduced vomiting in shrews. Finally, CBD’s anti-nausea effects were similar in male and female rats. This suggests that these cannabinoids may be useful anti-nausea and anti-emetic treatments for chronic conditions, without the development of tolerance. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

Cannabidiolic acid methyl ester (HU-580) is a more stable compound than cannabidiolic acid (CBDA) which has been shown to be effective in reducing nausea, anxiety, depression behaviors in animal models. Here we extend the investigation of this compound to determine its effect on the sleep-wake cycle in male Wistar rats. HU-580 dose-dependently (0.1, 1.0 or 100 μg/Kg, i.p.) prolonged wakefulness (W) and decreased slow wave sleep (SWS) duration whereas rapid eye movement sleep (REMS) showed no statistical change. In addition, the brain microdialysis probes either placed at nucleus accumbens (NAc) or into the basal forebrain in freely moving animals were used to evaluate the effects of HU-580 treatment on neurotransmitters related to the sleep-wake cycle modulation. HU-580 enhanced extracellular levels of dopamine, serotonin collected from NAc while adenosine and acetylcholine were increased in basal forebrain. In summary, HU-580 seems to possess wake-promoting pharmacological properties and enhances the levels of wake-related neurochemicals. This is the first report of effects of HU-580 on sleep modulation expanding the very limited existent data on the neurobiological effects of HU-580 on rats. © 2019 Elsevier Inc.

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.

Rationale: Oleoyl glycine, a little studied fatty acid amide similar in structure to anandamide, interferes with nicotine addiction in mice and acute naloxone-precipitated morphine withdrawal (MWD) in rats. Because endogenous oleoyl glycine is subject to rapid enzymatic deactivation, we evaluated the potential of more stable analogs to interfere with opiate withdrawal. Objectives: The potential of monomethylated oleoyl glycine (oleoyl alanine, HU595) to interfere with somatic and aversive effects of acute naloxone-precipitated MWD, its duration, and mechanism of action was assessed in male Sprague Dawley rats. The potential of dimethylated oleoyl glycine (HU596) to interfere with the aversive effects of naloxone-precipitated MWD was also investigated. Results: Oleoyl alanine (HU595) interfered with somatic and aversive effects produced by naloxone-precipitated MWD at equivalent doses (1 and 5 mg/kg, i.p.) as we have reported for oleoyl glycine; however, oleoyl alanine produced a longer lasting (60 min) interference, yet did not produce rewarding or aversive effects on its own and did not modify locomotor activity. HU596 was not effective. The interference with aversive effects of naloxone-precipitated MWD by oleoyl alanine was prevented by both a PPARα antagonist and a CB1 receptor antagonist. Accordingly, the compound was found to inhibit FAAH and activate PPARα in vitro. Finally, oleoyl alanine also reduced acute naloxone-precipitated MWD anhedonia, as measured by decreased saccharin preference. Conclusions: Oleoyl alanine (also an endogenous fatty acid) may be a more stable and effective treatment for opiate withdrawal than oleoyl glycine. © 2020, 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.

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.

Background and Purpose: Chronic neuropathic pain (NEP) is associated with growing therapeutic cannabis use. To promote quality of life without psychotropic effects, cannabinoids other than Δ9-tetrahydrocannabidiol, including cannabidiol and its precursor cannabidiolic acid (CBDA), are being evaluated. Due to its instability, CBDA has been understudied, particularly as an anti-nociceptive agent. Adding a methyl ester group (CBDA-ME) significantly enhances its stability, facilitating analyses of its analgesic effects in vivo. This study examines early treatment efficacy of CBDA-ME in a rat model of peripherally induced NEP and evaluates sex as a biological variable. Experimental Approach: After 14 consecutive days of intraperitoneal CBDA-ME administration at 0.01, 0.1 and 1 μg·kg−1, commencing 1 day after surgically implanting a sciatic nerve-constricting cuff to induce NEP, the anti-nociceptive efficacy of this cannabinoid was assessed in male and female Sprague–Dawley rats relative to vehicle-treated counterparts. In females, 2 and 4 μg·kg−1 daily doses of CBDA-ME were also evaluated. Behavioural tests were performed for hind paw mechanical and thermal withdrawal thresholds once a week for 8 weeks. At endpoint, in vivo electrophysiological recordings were obtained to characterize soma threshold changes in primary sensory neurons. Key Results: In males, CBDA-ME elicited a significant concentration-dependent chronic anti-hyperalgesic effect, also influencing both nociceptive and non-nociceptive mechanoreceptors, which were not observed in females at any of the concentrations tested. Conclusion and Implications: Initiating treatment of a peripheral nerve injury with CBDA-ME at an early stage post-surgery provides anti-nociception in males, warranting further investigation into potential sexual dimorphisms underlying this response. © 2020 The British Pharmacological Society

Recent developments in near-infrared (NIR) dyes and imaging modalities enable tumor fluorescent images in preclinical and clinical settings. However, NIR dyes have several drawbacks, and therefore, there is an unmet diagnostic need for NIR dye encapsulation in appropriate pharmaceutical nanocarriers with targeting abilities for the purpose of achieving effective diagnosis and image-guided surgeries. Because integrin receptors are established diagnostic targets, the cyclic Arg-Gly-Asp (RGD) peptides, recognizing the αVβ3 integrin, have been extensively investigated for radiology and bioimaging of tumors. However, the Lys(Arg)-Thr-Ser [K(R)TS] cyclic peptides, selective for collagen receptors α1β1/α2β1 integrins, which are overexpressed in many tumors, were not yet investigated and therefore used here for tumor bioimaging with a unique α2β1-integrin-targeted nanocarrier, encapsulating the indocyanine green NIR dye. We synthesized three kinds of peptides: two cyclic RTS peptides functional only in the cyclic conformation and a linear peptide lacking the cyclic cysteine constrained RTS loop. We used them for the preparation of integrin-targeted self-assembled nanocarriers (ITNCs), referred to as OF5 and OF27, and a nontargeted control nanocarrier, referred to as OF70. Their selective association was demonstrated with α2β1 integrin expressing cell cultures and three-dimensional tumor spheroids and by competition with a α2β1 selective disintegrin. Cytotoxicity experiments in vitro demonstrated the safety of the ITNCs. The targeting potential and the biodistribution of the ITNCs, applied intravenously in A431 tumor-bearing nude mice, were evaluated in vivo using NIR bioimaging. Time-dependent biodistributions indicated that the ITNC OF27 showed higher fluorescent signals in main tissues, with no cytotoxic effects to major organs, and presented higher accumulation in tumors. Cumulatively, these results highlight the potential of the ITNC OF27 as an optical and innovative pharmaceutical bioimaging system, suitable for integrin α2β1 receptor in vivo tumor targeting and visualization in the NIR region. © 2020 American Chemical Society.