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 immuno-regulatory 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.

Biodegradable poly(l-lactide-co-ε-caprolactone) (PLCL) are used to prepare inflatable balloon implants in treating rotator-cuff injuries and tissue separation. These balloon implants act as a temporary spacer for tissues, while reducing pain and allowing rehabilitation after surgery. It is essential to ensure that each balloon fulfill two requirements after implantation: (1) display a well-defined degradation profile, and (2) remain unaffected by premature rapture or leakage. Storage also affects the stability of a polymer-based implant. Since the balloons are implanted into humans, it is essential to understand their in vitro and in vivo degradation along with their physicochemical properties. It is unpredictable if balloon storage on their performance. Therefore, the in vitro and in vivo degradation behavior of PLCL balloons was examined during one year, and the information obtained was used to correlate reliability under prolonged storage conditions. We investigated changes in weight, melting temperature (Tm), molecular weight distribution (Mw, Mn and PDI), crystallinity (Χ), optical activity [α], and inherent viscosity (η) of the balloons during the entire degradation time. We also examined the molecular properties of the balloons under annealing and extreme temperature conditions, such as the combined effect of temperature and humidity that simulate various storage conditions. We have concluded that degradation of the PLCL balloons is slow, and they remain stable during the test period. Results reveal that the balloons retain their molecular properties under long-term storage, annealing, and extreme temperature conditions. The balloons did not show any variation from reference samples, and they exhibited a constant stability profile even after shelf-storage of more than 3 years. These findings can serve as a case study for evaluating various other biodegradable materials. Copyright © 2019 Elsevier B.V. All rights reserved.

Liquid nanovehicles are gaining interest in drug delivery because of the high solubilization capacity of bioactives at their interface and enhanced permeation of compounds across physiological membranes. However, the dermal application of liquid nanovehicles is still limited. The goal of this research is to develop a dermal delivery system based on embedding of liquid nanovehicles into polymeric films, which will allow controlled release of the nanodroplets with the solubilized drug. In this study, we describe the incorporation of empty and curcumin-loaded nanodomains into polymeric film. The novel technology results in formation of homogeneous, transparent and elastic films with high (up to 85 wt%) loading capacity of nanodomains. The fundamental structural characterizations show that nanodomain structures embedded in the dry film are spontaneously reformed during the dermal application with similar droplets size of 10 nm. Ex-vivo release studies were performed on Franz diffusion cells and demonstrated a significant permeation of curcumin through the pig skin. This novel film technology can serve as a “solid platform reservoir” for liquid nanovehicles which enables controlled release of nanodroplets with solubilized bioactive. © 2020 Elsevier B.V.

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.

The cannabis plant has been widely researched for many therapeutic indications and found to be effective in many chronic conditions such as epilepsy, neuropathic or chronic pain and more. However, biased opinion against compounds of the plant, regulatory as well as compounding challenges have led to very few approved cannabinoid medicinal products. Those formulations which are approved are dosed several times a day, creating an unmet need for controlled release (CR) formulations of cannabinoids. Conventional CR formulations rely on prolonged absorption of the drug, including absorption from the colon. The purpose of this work is to investigate regional absorption of major cannabinoids THC and CBD from the colon and develop a suitable CR formulation. As hypothesized by researchers, THC and CBD have poor absorption from the colon compared to small intestine, suggesting that these compounds have a narrow absorption window. The suggested CR formulation examined in-vitro was a floating gastro retentive tablet based on egg albumin matrix, gas generating agents and surfactants. In-vivo investigation of CBD containing formulation in the freely moving rat model proved a prolonged absorption phase with a substantial increase in bioavailability compared to CBD solution. The findings of this paper answer a crucial question regarding potential application of CR dosage forms for cannabinoids and shed light on the regional intestinal absorption of these compounds. Ultimately, these results cement the way for future development of cannabinoid gastro retentive dosage forms.

The cannabis plant has been widely researched for many therapeutic indications and found to be effective in many chronic conditions such as epilepsy, neuropathic or chronic pain and more. However, biased opinion against compounds of the plant, regulatory as well as compounding challenges have led to very few approved cannabinoid medicinal products. Those formulations which are approved are dosed several times a day, creating an unmet need for controlled release (CR) formulations of cannabinoids. Conventional CR formulations rely on prolonged absorption of the drug, including absorption from the colon. The purpose of this work is to investigate regional absorption of major cannabinoids THC and CBD from the colon and develop a suitable CR formulation. As hypothesized by researchers, THC and CBD have poor absorption from the colon compared to small intestine, suggesting that these compounds have a narrow absorption window. The suggested CR formulation examined in-vitro was a floating gastro retentive tablet based on egg albumin matrix, gas generating agents and surfactants. In-vivo investigation of CBD containing formulation in the freely moving rat model proved a prolonged absorption phase with a substantial increase in bioavailability compared to CBD solution. The findings of this paper answer a crucial question regarding potential application of CR dosage forms for cannabinoids and shed light on the regional intestinal absorption of these compounds. Ultimately, these results cement the way for future development of cannabinoid gastro retentive dosage forms. © 2020 Elsevier B.V.

We report here on ion-exchange polymeric nanoparticles from a linear copolymer of maleic anhydride methyl vinyl ether esterified with 30% octadecanol. The side chains for the polymer structure were optimized through metadynamics simulations, which revealed the use of octadecanol esters generates ideal free energy surfaces for drug encapsulation and release. Nanoparticles were synthesized using a solvent evaporation-precipitation method by mixing the polymer solution in acetone into water; upon acetone evaporation, a nanodispersion with an average particle size of ∼150 nm was obtained. Gentamicin sulfate, possessing five amino groups, was spontaneously entrapped in the nanocarrier by ionic interactions. Encapsulation efficiency increases significantly with the increase in pH and ionic strength. In vivo results demonstrate high gentamicin (GM) content in the enteric chamber (AUC 8207 ± 1334 (μg min)/mL) compared to 3% GM solution (AUC 2024 ± 438 (μg min)/mL). The formulation was also able to significantly extend the release of gentamicin when applied to rabbit cornea. These anionic nanoparticles can be used for extended-release of other cationic drugs. © 2020 American Chemical Society.}, funding_text 1=his work was supported by a grant from Teva Pharm. Industries, affiliated with the David Bloom Center for Pharmacy and The Alex Grass Center for Drug Design. A.B. would like to thank the planning and budget commission (PBC) of Israel for providing Postdoctoral Fellowships.

Stem cells, poised to revolutionize current medicine, stand as major workhorses for monitoring changes in cell fate. Characterizing metabolic phenotypes is key to monitor in differentiating cells transcriptional and epigenetic shifts at a functional level and provides a non-genetic means to control cell specification. Expanding the arsenal of analytical tools for metabolic profiling of cell differentiation is therefore of importance. Here, we describe the metabolome of whole pluripotent stem cells (PSCs) using high‐resolution magic angle spinning (HR-MAS), a non-destructive approach for Nuclear Magnetic Resonance (NMR) analysis. The integrated 1H NMR analysis results in detection of metabolites of various groups, including energy metabolites, amino acids, choline derivatives and short chain fatty acids. It unveils new metabolites that discriminate PSCs from differentiated counterparts and directly measures substrates and co-factors of histone modifying enzymes, suggesting that NMR stands as a strategic technique for deciphering metabolic regulations of histone post-translational modifications. HR-MAS NMR analysis of whole PSCs complements the much used solution NMR of cell extracts. Altogether, our multi-platform NMR investigation provides a consolidated picture of PSC metabolic signatures and of metabolic pathways involved in differentiation. © 2020, The Author(s).

Polyneuropathy is a disease involving multiple peripheral nerves injuries. Axon regrowth remains the major prerequisite for plasticity, regeneration, circuit formation, and eventually functional recovery and therefore, regulation of neurite outgrowth might be a candidate for treating polyneuropathies. In a recent study, we synthesized and established the methylene-cycloalkylacetate (MCAs) pharmacophore as a lead for the development of a neurotropic drug (inducing neurite/axonal outgrowth) using the PC12 neuronal model. In the present study we extended the characterizations of the in vitro neurotropic effect of the derivative 3-(3-allyl-2-methylenecyclohexyl) propanoic acid (MCA-13) on dorsal root ganglia and spinal cord neuronal cultures and analyzed its safety properties using blood biochemistry and cell counting, acute toxicity evaluation in mice and different in vitro “off-target” pharmacological evaluations. This MCA derivative deserves further preclinical mechanistic pharmacological characterizations including therapeutic efficacy in in vivo animal models of polyneuropathies, toward development of a clinically relevant neurotropic drug. © 2020 American Chemical Society

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.

Recent advances in the research of medicinal cannabis has placed the non-intoxicating cannabinoid cannabidiol (CBD) at the front of scientific research. The reasons behind this popularity is the compound's therapeutic properties, alongside a safe profile of administration lacking addictive properties such as euphoric state of mind and a wide dosing range. Oral administration of CBD is challenging due to poor solubility in the gastro-intestinal system and susceptibility to extensive first pass metabolism. As a result, the practice in clinic and investigational trials is to administer cannabinoids in edible oils or oil-based solutions. Nonetheless, reported pharmacokinetics of cannabinoids and CBD in particular are not uniform among research groups and are affected by the vehicle of administration. The purpose of the work presented here is to investigate oral absorption processes of synthetic CBD when given in different oral formulations in healthy volunteers. The study design was a three way, blind, cross-over single administration study of 12 healthy male volunteers. CBD was administered in powder form, dissolved in sesame oil and in self-nano-emulsifying drug delivery system (SNEDDS). Administration of CBD in lipid-based vehicles resulted in a significant increase in Cmax and AUC of CBD, as compared to powder form. Overall plasma exposure of CBD did not differ between sesame oil vehicle and the SNEDDS formulation. However, administration of CBD in pure oil resulted in two absorption behaviors of early and delayed absorption among subjects, as opposed to SNEDDS platform that resulted in a uniform early absorption profile. Results of this trial demonstrate the importance of solubilization process of lipophilic drugs such as CBD and demonstrated the ability of the nano formulation to achieve a reliable, predictable PK profile of the drug. These findings offer a standardized oral formulation for the delivery of cannabinoids and contribute data for the growing field of cannabinoid pharmacokinetics. © 2020 Elsevier B.V.

Recent advances in the research of medicinal cannabis has placed the non-intoxicating cannabinoid cannabidiol (CBD) at the front of scientific research. The reasons behind this popularity is the compound's therapeutic properties, alongside a safe profile of administration lacking addictive properties such as euphoric state of mind and a wide dosing range. Oral administration of CBD is challenging due to poor solubility in the gastro-intestinal system and susceptibility to extensive first pass metabolism. As a result, the practice in clinic and investigational trials is to administer cannabinoids in edible oils or oil-based solutions. Nonetheless, reported pharmacokinetics of cannabinoids and CBD in particular are not uniform among research groups and are affected by the vehicle of administration. The purpose of the work presented here is to investigate oral absorption processes of synthetic CBD when given in different oral formulations in healthy volunteers. The study design was a three way, blind, cross-over single administration study of 12 healthy male volunteers. CBD was administered in powder form, dissolved in sesame oil and in self-nano-emulsifying drug delivery system (SNEDDS). Administration of CBD in lipid-based vehicles resulted in a significant increase in C(max) and AUC of CBD, as compared to powder form. Overall plasma exposure of CBD did not differ between sesame oil vehicle and the SNEDDS formulation. However, administration of CBD in pure oil resulted in two absorption behaviors of early and delayed absorption among subjects, as opposed to SNEDDS platform that resulted in a uniform early absorption profile. Results of this trial demonstrate the importance of solubilization process of lipophilic drugs such as CBD and demonstrated the ability of the nano formulation to achieve a reliable, predictable PK profile of the drug. These findings offer a standardized oral formulation for the delivery of cannabinoids and contribute data for the growing field of cannabinoid pharmacokinetics.

The use of gem-diborylalkenes as radical-reactive groups is explored for the first time. These reactions provide an efficient and general method for the photochemical conversion of gem-diborylalkenes to rapidly access 1,1-bisborylalkanes. This method exploits a novel photoredox decarboxylative radical addition to gem-diborylalkenes to afford α-gem-diboryl carbon-centered radicals, which benefit from additional stability by virtue of an interaction with the empty p-orbitals on borons. The reaction offers a highly modular and regioselective approach to γ-amino gem-diborylalkanes. Furthermore, EPR spectroscopy and DFT calculations have provided insight into the radical mechanism underlying the photochemistry reaction and the stability of the bis-metalated radicals, respectively. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

The central dogma in biology defines the flow of genetic information from DNA to RNA to protein. Accordingly, RNA molecules generally accurately follow the sequences of the genes from which they are transcribed. This rule is transgressed by RNA editing, which creates RNA products that differ from their DNA templates. Analyses of the RNA landscapes of terrestrial plants have indicated that RNA editing (in the form of C-U base transitions) is highly prevalent within organelles (that is, mitochondria and chloroplasts). Numerous C→U conversions (and in some plants also U→C) alter the coding sequences of many of the organellar transcripts and can also produce translatable mRNAs by creating AUG start sites or eliminating premature stop codons, or affect the RNA structure, influence splicing and alter the stability of RNAs. RNA-binding proteins are at the heart of post-transcriptional RNA expression. The C-to-U RNA editing process in plant mitochondria involves numerous nuclear-encoded factors, many of which have been identified as pentatricopeptide repeat (PPR) proteins that target editing sites in a sequence-specific manner. In this review we report on major discoveries on RNA editing in plant organelles, since it was first documented 30 years ago. © 2019 The Authors The Plant Journal © 2019 John Wiley & Sons Ltd

Infections caused by antibiotic-resistant strains of Staphylococcus aureus have reached epidemic proportions globally. Our previous study showed antimicrobial effects of anandamide (AEA) and arachidonoyl serine (AraS) against methicillin (MET)-resistant S. aureus (MRSA) strains, proposing the therapeutic potential of these endocannabinoid/endocannabinoid-like (EC/EC-like) agents for the treatment of MRSA. Here, we investigated the potential synergism of combinations of AEA and AraS with different types of antibiotics against MRSA grown under planktonic growth or biofilm formation. The most effective combinations under planktonic conditions were mixtures of AEA and ampicillin (AMP), and of AraS and gentamicin (GEN). The combination with the highest synergy in the biofilm formation against all tested bacterial strains was AEA and MET. Moreover, the combination of AraS and MET synergistically caused default of biofilm formation. Slime production of MRSA was also dramatically impaired by AEA or AraS combined with MET. Our data suggest the novel potential activity of combinations of EC/EC-like agents and antibiotics in the prevention of MRSA biofilm formation. Copyright: © 2020 Feldman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Infections caused by antibiotic-resistant strains of Staphylococcus aureus have reached epidemic proportions globally. Our previous study showed antimicrobial effects of anandamide (AEA) and arachidonoyl serine (AraS) against methicillin (MET)-resistant S. aureus (MRSA) strains, proposing the therapeutic potential of these endocannabinoid/endocannabinoid-like (EC/EC-like) agents for the treatment of MRSA. Here, we investigated the potential synergism of combinations of AEA and AraS with different types of antibiotics against MRSA grown under planktonic growth or biofilm formation. The most effective combinations under planktonic conditions were mixtures of AEA and ampicillin (AMP), and of AraS and gentamicin (GEN). The combination with the highest synergy in the biofilm formation against all tested bacterial strains was AEA and MET. Moreover, the combination of AraS and MET synergistically caused default of biofilm formation. Slime production of MRSA was also dramatically impaired by AEA or AraS combined with MET. Our data suggest the novel potential activity of combinations of EC/EC-like agents and antibiotics in the prevention of MRSA biofilm formation.

Delivery of drugs through oral mucosa enables bypass of the gastrointestinal tract and "first pass" metabolism in the liver and the gut. Thus, a higher and less variable bioavailability can be obtained. Mechanisms of this administration route for cannabidiol were investigated in the current research in pigs. Results show that cannabidiol has substantially low permeability rate over 8 h through oral mucosa and accumulates significantly within it. Furthermore, following the removal of the delivery device, residual prolongation of release from the oral mucosa into systemic blood circulation continues for several hours. This method of delivery enabled acquisition of clinically relevant plasma levels of cannabidiol. The absorption profile indicates that cannabidiol, as well as other lipophilic molecules, should be delivered through oral mucosa for systemic absorption from a device that conceals the drug and prevents its washout by the saliva flow and subsequent ingestion into gastrointestinal tract.

Delivery of drugs through oral mucosa enables bypass of the gastrointestinal tract and “first pass“ metabolism in the liver and the gut. Thus, a higher and less variable bioavailability can be obtained. Mechanisms of this administration route for cannabidiol were investigated in the current research in pigs. Results show that cannabidiol has substantially low permeability rate over 8 h through oral mucosa and accumulates significantly within it. Furthermore, following the removal of the delivery device, residual prolongation of release from the oral mucosa into systemic blood circulation continues for several hours. This method of delivery enabled acquisition of clinically relevant plasma levels of cannabidiol. The absorption profile indicates that cannabidiol, as well as other lipophilic molecules, should be delivered through oral mucosa for systemic absorption from a device that conceals the drug and prevents its washout by the saliva flow and subsequent ingestion into gastrointestinal tract. © 2020 Elsevier B.V.

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.

Objective: The endocannabinoid (eCB) system is increasingly recognized as being crucially important in obesity-related hepatic steatosis. By activating the hepatic cannabinoid-1 receptor (CB1R), eCBs modulate lipogenesis and fatty acid oxidation. However, the underlying molecular mechanisms are largely unknown. Methods: We combined unbiased bioinformatics techniques, mouse genetic manipulations, multiple pharmacological, molecular, and cellular biology approaches, and genomic sequencing to systematically decipher the role of the hepatic CB1R in modulating fat utilization in the liver and explored the downstream molecular mechanisms. Results: Using an unbiased normalized phylogenetic profiling analysis, we found that the CB1R evolutionarily coevolves with peroxisome proliferator-activated receptor-alpha (PPAR$\alpha$), a key regulator of hepatic lipid metabolism. In diet-induced obese (DIO) mice, peripheral CB1R blockade (using AM6545) induced the reversal of hepatic steatosis and improved liver injury in WT, but not in PPAR$\alpha$−/− mice. The antisteatotic effect mediated by AM6545 in WT DIO mice was accompanied by increased hepatic expression and activity of PPAR$\alpha$ as well as elevated hepatic levels of the PPAR$\alpha$-activating eCB-like molecules oleoylethanolamide and palmitoylethanolamide. Moreover, AM6545 was unable to rescue hepatic steatosis in DIO mice lacking liver sirtuin 1 (SIRT1), an upstream regulator of PPAR$\alpha$. Both of these signaling molecules were modulated by the CB1R as measured in hepatocytes exposed to lipotoxic conditions or treated with CB1R agonists in the absence/presence of AM6545. Furthermore, using microRNA transcriptomic profiling, we found that the CB1R regulated the hepatic expression, acetylation, and transcriptional activity of p53, resulting in the enhanced expression of miR-22, which was found to specifically target SIRT1 and PPAR$\alpha$. Conclusions: We provide strong evidence for a functional role of the p53/miR-22/SIRT1/PPAR$\alpha$ signaling pathway in potentially mediating the antisteatotic effect of peripherally restricted CB1R blockade.