Monthly Archives: July 2022

Anti-Tumorigenic Effect of a Novel Derivative of 2-Hydroxyoleic Acid and the Endocannabinoid Anandamide on Neuroblastoma Cells

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“Modulation of the endogenous cannabinoid system has been suggested as a potential anticancer strategy.

In the search for novel and less toxic therapeutic options, structural modifications of the endocannabinoid anandamide and the synthetic derivative of oleic acid, Minerval (HU-600), were done to obtain 2-hydroxy oleic acid ethanolamide (HU-585), which is an HU-600 derivative with the anandamide side chain.

We showed that treatment of SK-N-SH neuroblastoma cells with HU-585 induced a better anti-tumorigenic effect in comparison to HU-600 as evidenced by 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide assay, colony-forming assay, and migration assay. Moreover, HU-585 demonstrated pro-apoptotic properties shown by increased levels of activated caspase-3 following treatment and a better senescence induction effect in comparison to HU-600, as demonstrated by increased activity of lysosomal β-galactosidase. Finally, we observed that combined treatment of HU-585 with the senolytic drugs ABT-263 in vitro, and ABT-737 in vivo resulted in enhanced anti-proliferative effects and reduced neuroblastoma xenograft growth in comparison to treatment with HU-585 alone.

Based on these results, we suggest that HU-585 is a pro-apoptotic and senescence-inducing compound, better than HU-600. Hence, it may be a beneficial option for the treatment of resistant neuroblastoma especially when combined with senolytic drugs that enhance its anti-tumorigenic effects.”

https://pubmed.ncbi.nlm.nih.gov/35884854/

“The cannabinoids are a group of more than 100 chemically related compounds found in the marijuana plant Cannabis sativa, that have been found to possess diverse pharmacological activities in cancer, including cytostatic, apoptotic, and antiangiogenic effects. Tetrahydrocannabinol (THC), the main psychoactive constituent in Cannabis sativa, acts mainly through the activation of specific cannabinoid receptors CB1 and CB2 and thus mimics the binding of the animal endogenous cannabinoids (named endocannabinoids).”

https://www.mdpi.com/2227-9059/10/7/1552/htm

Activation of Peripheral Cannabinoid Receptors Synergizes the Effect of Systemic Ibuprofen in a Pain Model in Rat

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“Pharmacological synergism is a current strategy for the treatment of pain. However, few studies have been explored to provide evidence of the possible synergism between a non-steroidal anti-inflammatory drug (NSAID) and a cannabinoid agonist, in order to establish which combinations might be effective to manage pain.

The aim of this study was to explore the synergism between ibuprofen (IBU) and the synthetic cannabinoid WIN 55,212-2 (WIN) to improve pain relief by analyzing the degree of participation of the CB1 and CB2 cannabinoid receptors in the possible antinociceptive synergism using an experimental model of pain in Wistar rats.

First, the effective dose thirty (ED30) of IBU (10, 40, 80, and 160 mg/kg, subcutaneous) and WIN (3, 10, and 30 µg/p, intraplantar) were evaluated in the formalin test. Then, the constant ratio method was used to calculate the doses of IBU and WIN to be administered in combination (COMB) to determine the possible synergism using the isobolographic method. The participation of the CB1 and CB2 receptors was explored in the presence of the antagonists AM281 and AM630, respectively.

The combination of these drugs produced a supra-additive response with an interaction index of 0.13. In addition, AM281 and AM630 antagonists reversed the synergistic effect in 45% and 76%, respectively, suggesting that both cannabinoid receptors are involved in this synergism, with peripheral receptors playing a relevant role.

In conclusion, the combination of IBU + WIN synergism is mainly mediated by the participation of the CB2 receptor, which can be a good option for the better management of pain relief.”

https://pubmed.ncbi.nlm.nih.gov/35893735/

https://www.mdpi.com/1424-8247/15/8/910

Differential Effects of D9 Tetrahydrocannabinol (THC)- and Cannabidiol (CBD)-Based Cannabinoid Treatments on Macrophage Immune Function In Vitro and on Gastrointestinal Inflammation in a Murine Model

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“Phytocannabinoids possess a wide range of immune regulatory properties, mediated by the endocannabinoid system.

Monocyte/macrophage innate immune cells express endocannabinoid receptors. Dysregulation of macrophage function is involved in the pathogenesis of different inflammatory diseases, including inflammatory bowel disease.

In our research, we aimed to evaluate the effects of the phytocannabinoids D9 tetrahydrocannabinol (THC) and cannabidiol (CBD) on macrophage activation.

Macrophages from young and aged C57BL/6 mice were activated in vitro in the presence of pure cannabinoids or cannabis extracts. The phenotype of the cells, nitric oxide (NO•) secretion, and cytokine secretion were examined. In addition, these treatments were administered to murine colitis model. The clinical statuses of mice, levels of colon infiltrating macrophages, and inflammatory cytokines in the blood, were evaluated.

We demonstrated inhibition of macrophage NO• and cytokine secretion and significant effects on expression of cell surface molecules. In the murine model, clinical scores were improved and macrophage colon infiltration reduced following treatment. We identified higher activity of cannabis extracts as compared with pure cannabinoids. Each treatment had a unique effect on cytokine composition.

Overall, our results establish that the effects of cannabinoid treatments differ. A better understanding of the reciprocal relationship between cannabinoids and immunity is essential to design targeted treatment strategies.”

https://pubmed.ncbi.nlm.nih.gov/35892693/

“Overall, our results indicate both similarities and differences between the impact of CBD- and THC-based drugs. Although all the tested treatments had an anti-inflammatory effect, their specific effects (for example, on phenotype of the cells and on cytokine production) differed. These differences may influence the clinical outcome of the treatment. We were surprised to find very similar anti-inflammatory results for the two cannabis extracts, which had diverse content of THC and CBD. This could suggest that THC/CBD content may not be the best indicator for anti-inflammatory properties of a cannabis-based drug. These results highlight the need to expand the research on the interplay between cannabinoids and other phytochemicals in the cannabis extracts. A better understanding of the effects of each molecule and the synergism between these molecules on the immune response will assist physicians to provide the best possible individually targeted treatment for their patients and will allow the design of new treatments.”

https://www.mdpi.com/2227-9059/10/8/1793/htm

Improved Therapeutic Efficacy of CBD with Good Tolerance in the Treatment of Breast Cancer through Nanoencapsulation and in Combination with 20(S)-Protopanaxadiol (PPD)

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“Cannabidiol (CBD), a nonpsychoactive major component derived from Cannabis sativa, widely used in neurodegenerative diseases, has now been proven to have growth inhibitory effects on many tumor cell lines, including breast tumors. Meanwhile CBD can effectively alleviate cancer-associated pain, anxiety, and depression, especially tumor cachexia, thus it is very promising as an anti-tumor drug with unique advantages.

20(S)-Protopanaxadiol (PPD) derived from the best-known tonic Chinese herbal medicine Ginseng was designed to be co-loaded with CBD into liposomes to examine their synergistic tumor-inhibitory effect. The CBD-PPD co-loading liposomes (CP-liposomes) presented a mean particle size of 138.8 nm. Further glycosyl-modified CP-liposomes (GMCP-liposomes) were prepared by the incorporation of n-Dodecyl β-D-maltoside (Mal) into the liposomal bilayer with glucose residue anchored on the surface to act as a ligand targeting the GLUT1 receptor highly expressed on tumor cells.

In vivo studies on murine breast tumor (4T1 cells)-bearing BALB/c mice demonstrated good dose dependent anti-tumor efficacy of CP-liposomes. A high tumor inhibition rate (TIR) of 82.2% was achieved with good tolerance. However, glycosylation modification failed to significantly enhance TIR of CP-liposomes.

In summary, combined therapy with PPD proved to be a promising strategy for CBD to be developed into a novel antitumor drug, with characteristics of effectiveness, good tolerance, and the potential to overcome tumor cachexia.”

https://pubmed.ncbi.nlm.nih.gov/35893789/

https://www.mdpi.com/1999-4923/14/8/1533/htm

Cannabidiol Regulates PPARγ-Dependent Vesicle Formation as well as Cell Death in A549 Human Lung Cancer Cells

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“Extracts of phytocannabinoids from Cannabis sativa have been studied for therapeutic purposes. Although nonpsychoactive CBD has been studied as a promising anticancer drug because it induces apoptosis in many cancer cells, it is also known to induce several physiological changes.

In this study, we clarify the functional role it plays in the morphological characteristics of intracellular vesicle formation as well as apoptosis in A549 human lung cancer cells.

CBD treatment shows growth inhibition at concentrations above 20 μM, but FACS analysis shows low efficacy in terms of cell death. Microscopic observations suggest that multiple vesicles were detected in the cytoplasmic region of CBD-treated A549 cells.

CBD treatment upregulates apoptosis-related proteins, such as p53, PARP, RIP1, RIP3, Atg12, and Beclin, indicating that CBD regulates several types of cell death. CBD treatment also induced E-cadherin, PPARγ, clathrin, β-adaptin, and Tsg101, also known to be cellular-differentiation inducers or vesicle-formation components.

Treatment combining CBD with GW9662, a PPARγ inhibitor, reduced CBD-induced cytoplasmic vesicle formation. This indicates that PPARγ regulates the vesicle-formation mechanism. However, CBD-treated E-cad KO clones did not show this regulatory mechanism.

These results elucidate the pharmacological and molecular networks associated with CBD in PPARγ-dependent vesicle formation and the induction of apoptosis.”

https://pubmed.ncbi.nlm.nih.gov/35890134/

“Recently, the pharmacological efficacy of CBD has been focused on in many types of disease models. In this study, we have shown that CBD treatment upregulated cell death proteins, such as p53, PARP, RIP1, RIP3, Atg12, and Beclin. In addition, CBD treatment also induced E-cadherin, PPARγ, clathrin, β-adaptin, and Tsg101, also known to be cellular-differentiation inducers or vesicle-formation components.

We have also shown that PPARγ regulates the vesicle-formation mechanism. Therefore, not only have we confirmed cell death induction by CBD, we have also confirmed the regulation of vesicle formation by PPARγ in various cancer models.

Detailed molecuclar insights would enhance the therapeutic utilization of CBD without side effects. Cellular proliferation and death could be determined by a variety of molecular regulations in cellular networks composed of a variety of proteins. Moreover, the physiological changes in cells will be closely related to functional changes in intracellular organelles.

We suggest that an understanding of the complex intracellular network system is necessary to optimize the pharmacological efficacy of CBD. These steady research efforts will make significant progress in increasing the utilization of CBD, which has been restricted by legal regulations in some countries.”

https://www.mdpi.com/1424-8247/15/7/836/htm


The Origin and Biomedical Relevance of Cannabigerol

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“The constant search for new pharmacologically active compounds, especially those that do not exhibit toxic effects, intensifies the interest in plant-based ingredients and their potential use in pharmacotherapy.

One of the plants that has great therapeutic potential is Cannabis sativa L., a source of the psychoactive Δ9-tetrahydrocannabinol (Δ9-THC), namely cannabidiol (CBD), which exhibits antioxidant and anti-inflammatory properties, and cannabigerol (CBG)-a biologically active compound that is present in much smaller quantities.

CBG is generated during the non-enzymatic decarboxylation of cannabigerolic acid, a key compound in the process of biosynthesis of phytocannabinoids and consequently the precursor to various phytocannabinoids. By interacting with G-protein-coupled receptors, CBG exhibits a wide range of biological activities, inter alia, anti-inflammatory, antibacterial and antifungal activities, regulation of the redox balance, and neuromodulatory effects.

Due to the wide spectrum of biological activities, CBG seems to be a very promising compound to be used in the treatment of diseases that require multidirectional pharmacotherapy. Moreover, it is suggested that due to the relatively rapid metabolism of cannabigerol, determination of the concentration of the phytocannabinoid in blood or oral fluid can be used to determine cannabis use. Therefore, it seems obvious that new therapeutic approaches using CBG can be expected.”

https://pubmed.ncbi.nlm.nih.gov/35887277/

“Although plants and their components have been used in therapeutic activities for several thousand years, their conscious use as elements of drugs, dietary supplements, cosmetics, and other products exhibiting biomedical properties are the result of research carried out over the last 20 years. One of the plants whose ingredients are more and more often studied for use in biomedical and pharmaceutical activities is Cannabis sativa L. At the same time, it should be noted that compounds obtained from Cannabis sativa L. are usually considered more beneficial than synthetic ones, because the latter may cause unwanted side effects when used for longer periods of time.”

“At the moment, cannabigerol is one of the least-known phytocannabinoids found in Cannabis sativa L., which, however, shows promising potential in therapeutic actions. Considering that both CBG and its precursors and metabolites are lipophilic, it favors the penetration the penetration through biological membranes and indicates the possibility of biological activity in the lipid sphere mainly through interactions with the endocannabinoid system, including G-protein-coupled receptors. As a result of these interactions as well as direct actions, CBD exhibits antioxidant and anti-inflammatory properties, while both CBG and CBGA as well as its synthetic derivatives exhibit neuromodulatory effects. Moreover, CBG has been shown to reduce the survival of glioblastoma cells, similar to temozolomide used both in monotherapy and with CBG. So far, however, the data in this regard are inconclusive and, moreover, come from in vitro and animal studies that require validation on human tissues and cells used ex vivo, prior to possible clinical trials. No harmful effect of CBG on the human body has been found so far, and the proven biological activity indicates CBG and its derivatives as very promising natural compounds that should be thoroughly tested both in vitro and in vivo in order to unequivocally determine the therapeutic usefulness, especially with regard to inflammatory diseases. Therefore, it seems obvious that new therapeutic approaches using the non-psychoactive ingredients of Cannabis sativa L, including CBG, can be expected in the nearest future.”

https://www.mdpi.com/1422-0067/23/14/7929/htm

The chemical structure of Cannabigerol (CBG). | Download Scientific Diagram


Anti-Inflammatory and Analgesic Properties of the Cannabis Terpene Myrcene in Rat Adjuvant Monoarthritis

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“Cannabis-based terpenes are believed to modulate physiological responses to disease and alter the efficacy of cannabinoids in the so-called “entourage effect”. The monoterpene myrcene can reduce nociception produced by noxious thermal and mechanical stimuli as well as reducing acute inflammation.

The current study examined the role of myrcene and cannabidiol (CBD) in controlling chronic joint inflammation and pain.

Chronic arthritis was induced in male Wistar rats by intra-articular injection of Freund’s complete adjuvant into the right knee. On days 7 and 21 after arthritis induction, joint pain (von Frey hair algesiometry), inflammation (intravital microscopy, laser speckle contrast analysis) and joint histopathology were assessed.

Local application of myrcene (1 and 5 mg/kg s.c.) reduced joint pain and inflammation via a cannabinoid receptor mechanism. The combination of myrcene and CBD (200 μg) was not significantly different from myrcene alone. Repeated myrcene treatment had no effect on joint damage or inflammatory cytokine production.

These data suggest that topical myrcene has the potential to reduce chronic arthritis pain and inflammation; however, it has no synergistic effect with CBD.”

https://pubmed.ncbi.nlm.nih.gov/35887239/

“In summary, myrcene was found to have anti-inflammatory and analgesic effects in inflammatory joint disease by activating articular cannabinoid receptors. Together, these findings may explain why arthritis patients prefer Cannabis strains rich in myrcene to help manage their pain and inflammation.”

https://www.mdpi.com/1422-0067/23/14/7891/htm

The Endocannabinoid System and Physical Activity-A Robust Duo in the Novel Therapeutic Approach against Metabolic Disorders

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“Rapidly increasing worldwide prevalence of obesity and related pathologies encompassing coronary heart disease, hypertension, metabolic syndrome, or type 2 diabetes constitute serious threats to global health and are associated with a significantly elevated risk of premature death. Considering the enormous burden of these pathologies, novel therapeutic and preventive patterns are indispensable.

Dysregulation of one of the most complex biological systems in the human body namely, the endocannabinoid system (ECS) may result in metabolic imbalance and development of insulin resistance, type 2 diabetes, or non-alcoholic fatty liver disease. Furthermore, many studies showed that physical exercises, depending on their type, intensity, and frequency, exert various alterations within the ECS.

Emerging evidence suggests that targeting the ECS via physical activity may produce robust beneficial effects on the course of metabolic pathologies. However, the data showing a direct correlation between the ECS and physical activity in the aspect of metabolic health are very scarce. Therefore, the aim of this review was to provide the most up-to-date state of knowledge about the interplay between the ECS activity and physical exercises in the novel therapeutic and preventive approach toward metabolic pathologies.

We believe that this paper, at least in part, will fulfill the existing gap in knowledge and encourage researchers to further explore this very complex yet interesting link between the ECS, its action in physical activity, and subsequent positive outcomes for metabolic health.”

https://pubmed.ncbi.nlm.nih.gov/35328503/

“To the best of our knowledge, this is the first review directly and comprehensively discussing the uncharted link between physical activity and its influence on the endocannabinoid signaling in the aspect of beneficial effects in the management of metabolic disorders. Considering the very alarming worldwide prevalence of these diseases as well as the unexplored potential of the topic, we believe that this paper, at least in part, will encourage researchers toward investigating this interesting, yet very complicated interplay. ECS and physical activity constitute robust and valuable therapeutic and preventive approaches that may significantly contribute to the decreased socioeconomic burden and the reduced annual number of patients suffering from obesity and other metabolic disorders. The future investigation should primarily encompass further discovery of the link between physical activity, alterations within endocannabinoid signaling and subsequently improved metabolic status of overweight, obese, and diabetic individuals.”

https://www.mdpi.com/1422-0067/23/6/3083/htm


“Exercise activates the endocannabinoid system”

https://pubmed.ncbi.nlm.nih.gov/14625449/

Cannabidiol improves thyroid function via modulating vitamin D 3 receptor in vitamin D 3 deficiency diet-induced rat model

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“The study was evaluated the impact of cannabidiol (CBD) on thyroid hormones by modulation cannabinoid receptor-2 (CB2) and vitamin D receptor (VDR) in rats fed with vitamin D3 deficiency diet (VDD).

CB2-receptors were analyzed by RT-PCR method and others biomarkers by ELISA. The relative expression of CB2 (thyroid ~ 4 folds), VDR protein (liver, 151.72%), and (kidney, 66%) was significantly increased in CBD-60 compared to VDD. Vitamin D3 metabolites were significantly increased serum (189.42%), kidney (73.84%), and liver (58.11%) in CBD-60 than VDD. Increased thyroxine (59.9%) and calcitonin (213.59%); while decreased thyroid-stimulating hormone (36.15%) and parathyroid hormone (38.64%) was observed CBD treatment in VDD rats.

In conclusion, CBD treatment improves CB2 and VDR expression and the level of vitamin D3 metabolites, along with improved thyroid hormones, including calcitonin. This is the first report with an improved CB2 and VDR expression after CBD treatment in VDD induced animals.

Thus, CBD can be considered to use in hypothyroidism conditions and to maintain bone health.”

https://pubmed.ncbi.nlm.nih.gov/35872737/

https://link.springer.com/article/10.1007/s13197-022-05492-3

Anti-cancer properties of cannflavin A and potential synergistic effects with gemcitabine, cisplatin, and cannabinoids in bladder cancer

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“Introduction: Several studies have shown anti-tumor effects of components present in cannabis in different models. Unfortunately, little is known about the potential anti-tumoral effects of most compounds present in cannabis in bladder cancer and how these compounds could potentially positively or negatively impact the actions of chemotherapeutic agents. Our study aims to evaluate the effects of a compound found in Cannabis sativa that has not been extensively studied to date, cannflavin A, in bladder cancer cell lines. We aimed to identify whether cannflavin A co-treatment with agents commonly used to treat bladder cancer, such as gemcitabine and cisplatin, is able to produce synergistic effects. We also evaluated whether co-treatment of cannflavin A with various cannabinoids could produce synergistic effects.

Results: Cell viability of bladder cancer cell lines was affected in a concentration-dependent fashion in response to cannflavin A, and its combination with gemcitabine or cisplatin induced differential responses-from antagonistic to additive-and synergism was also observed in some instances, depending on the concentrations and drugs used. Cannflavin A also activated apoptosis via caspase 3 cleavage and was able to reduce invasion by 50%. Interestingly, cannflavin A displayed synergistic properties with other cannabinoids like Δ9-tetrahydrocannabinol, cannabidiol, cannabichromene, and cannabivarin in the bladder cancer cell lines.

Discussion: Our results indicate that compounds from Cannabis sativa other than cannabinoids, like the flavonoid cannflavin A, can be cytotoxic to human bladder transitional carcinoma cells and that this compound can exert synergistic effects when combined with other agents. In vivo studies will be needed to confirm the activity of cannflavin A as a potential agent for bladder cancer treatment.”

https://pubmed.ncbi.nlm.nih.gov/35869542/

“A study recently demonstrated that the combination of Δ9-tetrahydrocannabinol and cannabichromene produced synergistic effects in a bladder cancer model, while another focused on the effects of cannabidiol and their potential formulation within nanoparticles to treat bladder cancer. Here, we show that other compounds from cannabis, like cannflavin A, may also induce beneficial cytotoxic and synergistic effects on bladder cancer cells. Our results also showed the ability of cannabinoids, other than Δ9-tetrahydrocannabinol, to produce synergistic effects when combined with the flavonoid cannflavin A.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-022-00151-y