Publications

2022
Liad Hinden, Aviram Kogot-Levin, Joseph Tam, and Gil Leibowitz. 2022. “Pathogenesis of diabesity-induced kidney disease: role of kidney nutrient sensing.” The FEBS journal, 289, 4, Pp. 901–921. Abstract
Diabetes kidney disease (DKD) is a major healthcare problem associated with increased risk for developing end-stage kidney disease and high mortality. It is widely accepted that DKD is primarily a glomerular disease. Recent findings however suggest that kidney proximal tubule cells (KPTCs) may play a central role in the pathophysiology of DKD. In diabetes and obesity, KPTCs are exposed to nutrient overload, including glucose, free-fatty acids and amino acids, which dysregulate nutrient and energy sensing by mechanistic target of rapamycin complex 1 and AMP-activated protein kinase, with subsequent induction of tubular injury, inflammation, and fibrosis. Pharmacological treatments that modulate nutrient sensing and signaling in KPTCs, including cannabinoid-1 receptor antagonists and sodium glucose transporter 2 inhibitors, exert robust kidney protective effects. Shedding light on how nutrients are sensed and metabolized in KPTCs and in other kidney domains, and on their effects on signal transduction pathways that mediate kidney injury, is important for understanding the pathophysiology of DKD and for the development of novel therapeutic approaches in DKD and probably also in other forms of kidney disease.
2021
Shreya Banerjee, Ronit Vogt Sionov, Mark Feldman, Reem Smoum, Raphael Mechoulam, and Doron Steinberg. 2021. “Anandamide alters the membrane properties, halts the cell division and prevents drug efflux in multidrug resistant Staphylococcus aureus.” Scientific reports, 11, 1, Pp. 8690. Abstract
Antibiotic resistance is a serious public health problem throughout the world. Overcoming methicillin and multidrug-resistant Staphylococcus aureus (MRSA/MDRSA) infections has become a challenge and there is an urgent need for new therapeutic approaches. We have previously demonstrated that the endocannabinoid Anandamide (AEA) can sensitize MRSA to antibiotics. Here we have studied the mechanism of action using a MDRSA clinical isolate that are sensitized by AEA to methicillin and norfloxacin. We found that AEA treatment halts the growth of both antibiotic-sensitive and antibiotic-resistant S. aureus. The AEA-treated bacteria become elongated and the membranes become ruffled with many protrusions. AEA treatment also leads to an increase in the percentage of bacteria having a complete septum, suggesting that the cell division is halted at this stage. The latter is supported by cell cycle analysis that shows an accumulation of bacteria in the G2/M phase after AEA treatment. We further observed that AEA causes a dose-dependent membrane depolarization that is partly relieved upon time. Nile red staining of the bacterial membranes indicates that AEA alters the membrane structures. Importantly, 4'-6-diamidino-2-phenylindole (DAPI) accumulation assay and ethidium bromide efflux (EtBr) assay unveiled that AEA leads to a dose-dependent drug accumulation by inhibiting drug efflux. In conclusion, our study demonstrates that AEA interferes with cell division, alters the membrane properties of MDRSA, and leads to increased intracellular drug retention, which can contribute to the sensitization of MDRSA to antibiotics.
Muna Aqawi, Ronit Vogt Sionov, Ruth Gallily, Michael Friedman, and Doron Steinberg. 2021. “Anti-Bacterial Properties of Cannabigerol Toward Streptococcus mutans.” Frontiers in microbiology, 12, Pp. 656471. Abstract
Streptococcus mutans (S. mutans) is a gram-positive facultatively anaerobic bacterium and the most common pathogen associated with tooth caries. The organism is acid tolerant and can undergo physiological adaptation to function effectively in acid environments such as carious dental plaque. Some cannabinoids have been found to have potent anti-microbial activity against gram-positive bacteria. One of these is the non-psychoactive, minor phytocannabinoid Cannabigerol (CBG). Here we show that CBG exhibits anti-bacterial activities against S. mutans. CBG halts the proliferation of planktonic growing S. mutans, which is affected by the initial cell density. High-resolution scanning electron microscopy showed that the CBG-treated bacteria become swollen with altered membrane structures. Transmission electron microscopy provided data showing that CBG treatment leads to intracellular accumulation of membrane structures. Nile red, DiOC2(3) and laurdan staining demonstrated that CBG alters the membrane properties, induces membrane hyperpolarization, and decreases the membrane fluidity. CBG-treated bacteria showed increased propidium iodide uptake and reduced calcein AM staining, suggesting that CBG increases the membrane permeability and reduces the metabolic activity. Furthermore, CBG prevented the drop in pH caused by the bacteria. In summary, we present here data showing the mechanisms by which CBG exerts its anti-bacterial effect against S. mutans.
Mark Feldman, Ronit Vogt Sionov, Raphael Mechoulam, and Doron Steinberg. 2021. “Anti-biofilm activity of cannabidiol against candida albicans.” Microorganisms, 9, 2, Pp. 1–17. Abstract
Candida albicans is a common fungal pathogen in humans. Biofilm formation is an important virulence factor of C. albicans infections. We investigated the ability of the plant-derived cannabidiol (CBD) to inhibit the formation and removal of fungal biofilms. Further, we evaluated its mode of action. Our findings demonstrate that CBD exerts pronounced time-dependent inhibitory effects on biofilm formation as well as disruption of mature biofilm at a concentration range below minimal inhibitory and fungicidal concentrations. CBD acts at several levels. It modifies the architecture of fungal biofilm by reducing its thickness and exopolysaccharide (EPS) production accompanied by downregulation of genes involved in EPS synthesis. It alters the fungal morphology that cor-related with upregulation of yeast-associated genes and downregulation of hyphae-specific genes. Importantly, it represses the expression of C. albicans virulence-associated genes. In addition, CBD increases ROS production, reduces the intracellular ATP levels, induces mitochondrial membrane hyperpolarization, modifies the cell wall, and increases the plasma membrane permeability. In conclusion, we propose that CBD exerts its activity towards C. albicans biofilm through a multi-target mode of action, which differs from common antimycotic agents, and thus can be explored for further development as an alternative treatment against fungal infections.
Eric Murillo-Rodríguez, Diana Millán-Aldaco, Gloria Arankowsky-Sandoval, Tetsuya Yamamoto, Roger G Pertwee, Linda Parker, and Raphael Mechoulam. 2021. “Assessing the treatment of cannabidiolic acid methyl ester: a stable synthetic analogue of cannabidiolic acid on c-Fos and NeuN expression in the hypothalamus of rats.” Journal of cannabis research, 3, 1, Pp. 31. Abstract
BACKGROUND: Cannabidiol (CBD), the non-psychotropic compound from Cannabis sativa, shows positive results on controlling several health disturbances; however, comparable data regarding additional chemical from C. sativa, such as cannabidiolic acid (CBDA), is scarce due to its instability. To address this limitation, a stable CBDA analogue, CBDA methyl ester (HU-580), was synthetized and showed CBDA-like effects. Recently, we described that HU-580 increased wakefulness and wake-related neurochemicals. OBJECTIVE: To extend the comprehension of HU-580´s properties on waking, the c-Fos and NeuN expression in a wake-linked brain area, the hypothalamus was evaluated. METHODS: c-Fos and NeuN expression in hypothalamic sections were analyzed after the injections of HU-580 (0.1 or 100 $μ$g/kg, i.p.). RESULTS: Systemic administrations of HU-580 increased c-Fos and neuronal nuclei (NeuN) expression in hypothalamic nuclei, including the dorsomedial hypothalamic nucleus dorsal part, dorsomedial hypothalamic nucleus compact part, and dorsomedial hypothalamic nucleus ventral part. CONCLUSION: HU-580 increased c-Fos and NeuN immunoreactivity in hypothalamus nuclei suggesting that this drug might modulate the sleep-wake cycle by engaging the hypothalamus.
Natalya M Kogan, Maximilian Peters, and Raphael Mechoulam. 2021. “Cannabinoid Quinones-A Review and Novel Observations.” Molecules (Basel, Switzerland), 26, 6. Abstract
A cannabinoid anticancer para-quinone, HU-331, which was synthesized by our group five decades ago, was shown to have very high efficacy against human cancer cell lines in-vitro and against in-vivo grafts of human tumors in nude mice. The main mechanism was topoisomerase II$\alpha$ catalytic inhibition. Later, several groups synthesized related compounds. In the present presentation, we review the publications on compounds synthesized on the basis of HU-331, summarize their published activities and mechanisms of action and report the synthesis and action of novel quinones, thus expanding the structure-activity relationship in these series.
Adi Aran, Moria Harel, Hanoch Cassuto, Lola Polyansky, Aviad Schnapp, Nadia Wattad, Dorit Shmueli, Daphna Golan, and Xavier F Castellanos. 2021. “Cannabinoid treatment for autism: a proof-of-concept randomized trial.” Molecular autism, 12, 1, Pp. 6. Abstract
BACKGROUND: Endocannabinoid dysfunction in animal models of autism spectrum disorder (ASD) and accumulating, albeit anecdotal, evidence for efficacy in humans motivated this placebo-controlled double-blind comparison of two oral cannabinoid solutions in 150 participants (age 5-21 years) with ASD. METHODS: We tested (1) BOL-DP-O-01-W, a whole-plant cannabis extract containing cannabidiol and $Δ$9-tetrahydrocannabinol at a 20:1 ratio and (2) BOL-DP-O-01, purified cannabidiol and $Δ$9-tetrahydrocannabinol at the same ratio. Participants (N = 150) received either placebo or cannabinoids for 12-weeks (testing efficacy) followed by a 4-week washout and predetermined cross-over for another 12 weeks to further assess tolerability. Registered primary efficacy outcome measures were improvement in behavioral problems (differences between whole-plant extract and placebo) on the Home Situation Questionnaire-ASD (HSQ-ASD) and the Clinical Global Impression-Improvement scale with disruptive behavior anchor points (CGI-I). Secondary measures were Social Responsiveness Scale (SRS-2) and Autism Parenting Stress Index (APSI). RESULTS: Changes in Total Scores of HSQ-ASD (primary-outcome) and APSI (secondary-outcome) did not differ among groups. Disruptive behavior on the CGI-I (co-primary outcome) was either much or very much improved in 49% on whole-plant extract (n = 45) versus 21% on placebo (n = 47; p = 0.005). Median SRS Total Score (secondary-outcome) improved by 14.9 on whole-plant extract (n = 34) versus 3.6 points after placebo (n = 36); p = 0.009). There were no treatment-related serious adverse events. Common adverse events included somnolence and decreased appetite, reported for 28% and 25% on whole-plant extract, respectively (n = 95); 23% and 21% on pure-cannabinoids (n = 93), and 8% and 15% on placebo (n = 94). Limitations Lack of pharmacokinetic data and a wide range of ages and functional levels among participants warrant caution when interpreting the results. CONCLUSIONS: This interventional study provides evidence that BOL-DP-O-01-W and BOL-DP-O-01, administrated for 3 months, are well tolerated. Evidence for efficacy of these interventions are mixed and insufficient. Further testing of cannabinoids in ASD is recommended. Trial registration ClinicalTrials.gov: NCT02956226. Registered 06 November 2016, https://clinicaltrials.gov/ct2/show/NCT02956226.
Elyad M Davidson, Noa Raz, and Aharon M Eyal. 2021. “Concerns About Recommendations for Perioperative Cannabis Use.” JAMA surgery, 156, 10, Pp. 988–989.
Martina Di Bartolomeo, Tibor Stark, Oriana Maria Maurel, Fabio Arturo Iannotti, Martin Kuchar, Jana Ruda-Kucerova, Fabiana Piscitelli, Samuele Laudani, Vladimir Pekarik, Salvatore Salomone, Beatrice Arosio, Raphael Mechoulam, Mauro Maccarrone, Filippo Drago, Carsten T Wotjak, Vincenzo Di Marzo, Matteo Vismara, Bernardo Dell'Osso, Claudio D'Addario, and Vincenzo Micale. 2021. “Crosstalk between the transcriptional regulation of dopamine D2 and cannabinoid CB1 receptors in schizophrenia: Analyses in patients and in perinatal $Δ$9-tetrahydrocannabinol-exposed rats.” Pharmacological research, 164, Pp. 105357. Abstract
Perinatal exposure to $Δ$(9)-tetrahydrocannabinol (THC) affects brain development and might increase the incidence of psychopathology later in life, which seems to be related to a dysregulation of endocannabinoid and/or dopaminergic systems. We here evaluated the transcriptional regulation of the genes encoding for the cannabinoid CB1 receptor (Cnr1) and the dopamine D2 receptor (Drd2) in perinatal THC-(pTHC) exposed male rats, focusing on the role of DNA methylation analyzed by pyrosequencing. Simultaneously, the molecular and behavioral abnormalities at two different time points (i.e., neonatal age and adulthood) and the potential preventive effect of peripubertal treatment with cannabidiol, a non-euphoric component of Cannabis, were assessed. The DRD2 methylation was also evaluated in a cohort of subjects with schizophrenia. We observed an increase in both Cnr1 and Drd2 mRNA levels selectively in the prefrontal cortex of adult pTHC-exposed rats with a consistent reduction in DNA methylation at the Drd2 regulatory region, paralleled by social withdrawal and cognitive impairment which were reversed by cannabidiol treatment. These adult abnormalities were preceded at neonatal age by delayed appearance of neonatal reflexes, higher Drd2 mRNA and lower 2-arachidonoylglycerol (2-AG) brain levels, which persisted till adulthood. Alterations of the epigenetic mark for DRD2 were also found in subjects with schizophrenia. Overall, reported data add further evidence to the dopamine-cannabinoid interaction in terms of DRD2 and CNR1 dysregulation which could be implicated in the pathogenesis of schizophrenia spectrum disorders, suggesting that cannabidiol treatment may normalize pTHC-induced psychopathology by modulating the altered dopaminergic activity.
Hagar Cohen, Uri Kramer, Moran Hausman-Kedem, Shimrit Uliel-Siboni, and Sara Eyal. 2021. “Dosage of cannabidiol-enriched cannabis in children and adults with epilepsy.”.
S. Udi, L. Hinden, M. Ahmad, A. Drori, M.R. Iyer, R. Cinar, and J. Tam. 2021. “Dual Inhibition of Cannabinoid-1 Receptor and iNOS Attenuates Obesity-induced Chronic Kidney Disease (vol 177, pg 110, 2020).” BRITISH JOURNAL OF PHARMACOLOGY, 178, 5, Pp. 1250.
José Alexandre S. Crippa, Antonio W. Zuardi, Francisco S. Guimarães, Alline Cristina Campos, Flávia de Lima Osório, Sonia Regina Loureiro, Rafael G. Dos Santos, José Diogo S. Souza, Juliana Mayumi Ushirohira, Julia Cozar Pacheco, Rafael Rinaldi Ferreira, Karla Cristinne Mancini Costa, Davi Silveira Scomparin, Franciele Franco Scarante, Isabela Pires-Dos-Santos, Raphael Mechoulam, Flávio Kapczinski, Benedito A.L. Fonseca, Danillo L.A. Esposito, Karina Pereira-Lima, Srijan Sen, Maristela Haddad Andraus, and Jaime E.C. Hallak. 2021. “Efficacy and Safety of Cannabidiol plus Standard Care vs Standard Care Alone for the Treatment of Emotional Exhaustion and Burnout among Frontline Health Care Workers during the COVID-19 Pandemic: A Randomized Clinical Trial.” JAMA Network Open, 4, 8. Abstract
Importance: Frontline health care professionals who work with patients with COVID-19 have an increased incidence of burnout symptoms. Cannabidiol (CBD) has anxiolytic and antidepressant properties and may be capable of reducing emotional exhaustion and burnout symptoms. Objective: To investigate the safety and efficacy of CBD therapy for the reduction of emotional exhaustion and burnout symptoms among frontline health care professionals working with patients with COVID-19. Design, Setting, and Participants: This prospective open-label single-site randomized clinical trial used a 1:1 block randomization design to examine emotional exhaustion and burnout symptoms among frontline health care professionals (physicians, nurses, and physical therapists) working with patients with COVID-19 at the Ribeirão Preto Medical School University Hospital in São Paulo, Brazil. Participants were enrolled between June 12 and November 12, 2020. A total of 214 health care professionals were recruited and assessed for eligibility, and 120 participants were randomized in a 1:1 ratio by a researcher who was not directly involved with data collection. Interventions: Cannabidiol, 300 mg (150 mg twice per day), plus standard care or standard care alone for 28 days. Main Outcomes and Measures: The primary outcome was emotional exhaustion and burnout symptoms, which were assessed for 28 days using the emotional exhaustion subscale of the Brazilian version of the Maslach Burnout Inventory-Human Services Survey for Medical Personnel. Results: A total of 120 participants were randomized to receive either CBD, 300 mg, plus standard care (treatment arm; n = 61) or standard care alone (control arm; n = 59) for 28 days. Of those, 118 participants (59 participants in each arm; 79 women [66.9%]; mean age, 33.6 years [95% CI, 32.3-34.9 years]) received the intervention and were included in the efficacy analysis. In the treatment arm, scores on the emotional exhaustion subscale of the Maslach Burnout Inventory significantly decreased at day 14 (mean difference, 4.14 points; 95% CI, 1.47-6.80 points; partial eta squared [$η$p2] = 0.08), day 21 (mean difference, 4.34 points; 95% CI, 0.94-7.73 points; $η$p2= 0.05), and day 28 (mean difference, 4.01 points; 95% CI, 0.43-7.59 points; $η$p2= 0.04). However, 5 participants, all of whom were in the treatment group, experienced serious adverse events: 4 cases of elevated liver enzymes (1 critical and 3 mild, with the mild elevations reported at the final 28-day assessment) and 1 case of severe pharmacodermia. In 2 of those cases (1 with critical elevation of liver enzymes and 1 with severe pharmacodermia), CBD therapy was discontinued, and the participants had a full recovery. Conclusions and Relevance: In this study, CBD therapy reduced symptoms of burnout and emotional exhaustion among health care professionals working with patients during the COVID-19 pandemic. However, it is necessary to balance the benefits of CBD therapy with potential undesired or adverse effects. Future double-blind placebo-controlled clinical trials are needed to confirm the present findings. Trial Registration: ClinicalTrials.gov Identifier: NCT04504877.
Shelly Tartakover Matalon, Shahar Azar, David Meiri, Rivka Hadar, Alina Nemirovski, Narjes Abu Jabal, Fred Meir Konikoff, Liat Drucker, Joseph Tam, and Timna Naftali. 2021. “Endocannabinoid Levels in Ulcerative Colitis Patients Correlate With Clinical Parameters and Are Affected by Cannabis Consumption.” Frontiers in endocrinology, 12, Pp. 685289. Abstract
BACKGROUND: Inflammatory bowel diseases (IBDs) are chronic, idiopathic, inflammatory, gastrointestinal disorders. The endocannabinoid system may have a role in the pathogenesis of IBD. We aimed to assess whether cannabis treatment influences endocannabinoids (eCBs) level and clinical symptoms of IBD patients. METHODS: Blood samples and biopsies were taken from IBD patients treated by either cannabis or placebo for 8 weeks. Immunohistochemistry for N-acyl-phosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH) expression was done on colon biopsies, and sample levels of anandamide (AEA), eCB2-arachidonylglycerol (2-AG), arachidonic acid (AA), palmitoylethanolamine (PEA), and oleoylethanolamine (OEA) were measured in patient's sera before and after cannabis treatment. Caco-2 cells were cultured with extracts of cannabis with/without tetrahydrocannabinol (THC) and their proteins extracted, and Western blotting for NAPE-PLD and FAAH expression was done. RESULTS: Thirteen patients with Crohn's disease (CD) and nine patients with ulcerative colitis (UC) were treated with cannabis. Seventeen patients with CD and 10 with UC served as placebo groups. In all CD patients, the levels of eCBs remained unaltered during the treatment period. In UC patients treated with placebo, but not in those treated with cannabis, the levels of PEA, AEA, and AA decreased significantly. The percent reduction in bowel movements was negatively correlated with changes observed in the circulating AEA and OEA, whereas improvement in quality of life was positively correlated with the levels of 2-AG. In the biopsies from UC patients, FAAH levels increased over the study period. In Caco-2 cells, both cannabis extracts increased NAPE-PLD levels but reduced FAAH expression levels. CONCLUSION: Our study supports the notion that cannabis use affects eCB "tone" in UC patients and may have beneficial effects on disease symptoms in UC patients.
R. Mechoulam. 2021. “Foreword.” Advances in Experimental Medicine and Biology, 1264, Pp. ix-xi.
George Habib, Doron Steinberg, and Adel Jabbour. 2021. “The impact of medical cannabis consumption on the oral flora and saliva.” PloS one, 16, 2, Pp. e0247044. Abstract
OBJECTIVE: To evaluate the effect of medical cannabis consumption on oral flora and saliva. DESIGN: A clinical prospective study, at the rheumatology clinic of the Nazareth Hospital in Nazareth, recruiting consecutively patients approved for medical cannabis, evaluating their saliva flow, pH and microbial load of Streptococcus mutans and Lactobacillus, prior to and under medical cannabis treatment. METHODS: Patients recently licensed for medical cannabis treatment, were recruited just prior to starting medical cannabis consumption (week 0), 1 and 4 weeks later, patients provided 5-minute time saliva samples, which were measured for their volume and pH, and cultured on a special microbial kit, evaluating the growth of Streptococcus mutans and Lactobacillus. RESULTS: Out of 16 patients enrolled, 14 were female and had fibromyalgia. The mean age of the patients was 52.8±12.9 years. The mean saliva flow at week 0, week 1 and week 4 were 5.38±3.36 ml/5-minutes, 6 (p = 0.769) and 5.45 (p = 0.391), respectively, and for saliva pH were 6.28, 5.94 (p = 0.51) and 5.5 (p = 0.07) respectively also. The mean Streptococcus mutans growth score at weeks 0, 1 and 4 was1.8±0.75, 1.6±0.83 (p = 0.234), and 2.4±0.84 (p = 0.058), respectively. The mean Lactobacilli growth score at weeks 0, 1 and 4 was 2.59±0.88, 3.1±0.69 (p = 0.033) and 3.3±0.67 (p = 0.025), respectively. CONCLUSIONS: The results of this study show that medical cannabis consumption has no significant effect on saliva volume or pH, but it may be associated with changes in salivary levels of oral microbes such as Streptococcus mutans and Lactobacilli.
V. Shumeiko, E. Malach, Y. Helman, Y. Paltiel, G. Bisker, Z. Hayouka, and O. Shoseyov. 2021. “A nanoscale optical biosensor based on peptide encapsulated SWCNTs for detection of acetic acid in the gaseous phase.” Sensors and Actuators, B: Chemical, 327. Abstract
Biosensors play a key role in almost every field of human activity – ranging from biomedical diagnosis and point-of-care health monitoring to environmental monitoring and forensics. Single-walled carbon nanotubes (SWCNTs) are one of the most promising materials for near-infrared (NIR) fluorescence-based biosensing. Herein, we develop a reusable, drop-casted, real-time optical biosensor based on peptide-encapsulated SWCNTs for the detection of low concentrations of acetic acid in the air, at room temperature. While detection of NIR signal usually requires expensive and bulky equipment, here we use the (6,5) SWCNTs chirality whose peak fluorescence lies within the range of 970 nm – 1050 nm, enabling the usage of low cost and compact silicon-based detectors. We demonstrate the detection of wine spoilage based on excess gaseous acetic acid using peptide-wrapped SWCNT sensors down to 0.05% (v/v) acetic acid concentrations. Our results open new avenues for gas phase detection using NIR fluorescent SWCNT nanosensors. © 2020 Elsevier B.V.
V. Shumeiko, Y. Paltiel, G. Bisker, Z. Hayouka, and O. Shoseyov. 2021. “A nanoscale paper-based near-infrared optical nose (NIRON).” Biosensors and Bioelectronics, 172. Abstract
Electronic noses (e-nose) and optical noses (o-nose) are two emerging approaches for the development of artificial olfactory systems for flavor and smell evaluation. The current work leverages the unique optical properties of semiconducting single-wall carbon nanotubes (SWCNTs) to develop a prototype of a novel paper-based near-infrared optical nose (NIRON). We have drop-dried an array of SWCNTs encapsulated with a wide variety of peptides on a paper substrate and continuously imaged the emitted SWCNTs fluorescence using a CMOS camera. Odors and different volatile molecules were passed above the array in a flow chamber, resulting in unique modulation patterns of the SWCNT photoluminescence (PL). Quartz crystal microbalance (QCM) measurements performed in parallel confirmed the direct binding between the vapor molecules and the peptide-SWCNTs. PL levels measured before and during exposure demonstrate distinct responses to the four tested alcoholic vapors (ethanol, methanol, propanol, and isopropanol). In addition, machine learning tools directly applied to the fluorescence images allow us to distinguish between the aromas of red wine, beer, and vodka. Further, we show that the developed sensor can detect limonene, undecanal, and geraniol vapors, and differentiate between their smells utilizing the PL response pattern. This novel paper-based optical biosensor provides data in real-time, and is recoverable and suitable for working at room temperature and in a wide range of humidity levels. This platform opens new avenues for real-time sensing of volatile chemical compounds, odors, and flavors. © 2020 Elsevier B.V.
Erin M Rock, Cheryl L Limebeer, Megan T Sullivan, Marieka V DeVuono, Aron H Lichtman, Vincenzo Di Marzo, Raphael Mechoulam, and Linda A Parker. 2021. “N-Oleoylglycine and N-Oleoylalanine Do Not Modify Tolerance to Nociception, Hyperthermia, and Suppression of Activity Produced by Morphine.” Frontiers in synaptic neuroscience, 13, Pp. 620145. Abstract
The endogenous amide N-Oleoylglycine (OlGly) and its analog N-Oleoylalanine (OlAla), have been shown to interfere with the affective and somatic responses to acute naloxone-precipitated MWD in male rats. Here we evaluated the potential of a single dose (5 mg/kg, ip) which alleviates withdrawal of these endogenous fatty acid amides to modify tolerance to anti-nociception, hyperthermia, and suppression of locomotion produced by morphine in male Sprague-Dawley rats. Although rats did develop tolerance to the hypolocomotor and analgesic effects of morphine, they did not develop tolerance to the hyperthermic effects of this substance. Administration of neither OlGly nor OlAla interfered with the establishment of morphine tolerance, nor did they modify behavioral responses elicited by morphine on any trial. These results suggest that the effects of OlGly and OlAla on opiate dependence may be limited to naloxone-precipitated withdrawal effects.
Natalya M Kogan, Yarden Lavi, Louise M Topping, Richard O Williams, Fiona E McCann, Zhanna Yekhtin, Marc Feldmann, Ruth Gallily, and Raphael Mechoulam. 2021. “Novel CBG Derivatives Can Reduce Inflammation, Pain and Obesity.” Molecules (Basel, Switzerland), 26, 18. Abstract
Interest in CBG (cannabigerol) has been growing in the past few years, due to its anti-inflammatory properties and other therapeutic benefits. Here we report the synthesis of three new CBG derivatives (HUM-223, HUM-233 and HUM-234) and show them to possess anti-inflammatory and analgesic properties. In addition, unlike CBG, HUM-234 also prevents obesity in mice fed a high-fat diet (HFD). The metabolic state of the treated mice on HFD is significantly better than that of vehicle-treated mice, and their liver slices show significantly less steatosis than untreated HFD or CBG-treated ones from HFD mice. We believe that HUM-223, HUM-233 and HUM-234 have the potential for development as novel drug candidates for the treatment of inflammatory conditions, and in the case of HUM-234, potentially for obesity where there is a huge unmet need.
Madison N Myers, Maya Zachut, Joseph Tam, and Andres G Contreras. 2021. “A proposed modulatory role of the endocannabinoid system on adipose tissue metabolism and appetite in periparturient dairy cows.” Journal of animal science and biotechnology, 12, 1, Pp. 21. Abstract
To sustain the nutrient demands of rapid fetal growth, parturition, and milk synthesis, periparturient dairy cows mobilize adipose tissue fatty acid stores through lipolysis. This process induces an inflammatory response within AT that is resolved as lactation progresses; however, excessive and protracted lipolysis compounds the risk for metabolic and inflammatory diseases. The suppression of lipolytic action and inflammation, along with amplification of adipogenesis and lipogenesis, serve as prospective therapeutic targets for improving the health of periparturient dairy cows. Generally, the activation of cannabinoid receptors by endocannabinoids enhances adipogenesis and lipogenesis, suppresses lipolysis, and increases appetite in mammals. These biological effects of activating the endocannabinoid system open the possibility of harnessing the endocannabinoid system through nutritional intervention in dairy herds as a potential tool to improve dairy cows' health, although much is still to be revealed in this context. This review summarizes the current knowledge surrounding the components of the endocannabinoid system, elaborates on the metabolic effects of its activation, and explores the potential to modulate its activity in periparturient dairy cows.

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