β-Caryophyllene Inhibits Endothelial Tube Formation by Modulating the Secretome of Hypoxic Lung Cancer Cells-Possible Role of VEGF Downregulation

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“β-Caryophyllene (BCP), a bicyclic sesquiterpene that is a component of the essential oils of various spice and food plants, has been described as a selective CB2 cannabinoid receptor agonist. In the present study, the effect of BCP on angiogenesis was investigated.

It was found that conditioned media (CM) from BCP-treated hypoxic A549 lung cancer cells exhibited a concentration-dependent inhibitory effect on human umbilical vein endothelial cell (HUVEC) tube formation induced by CM from vehicle-treated hypoxic A549 cells. There was an associated concentration-dependent decrease in the proangiogenic factor vascular endothelial growth factor (VEGF) in the CM, with both BCP inhibitory effects (tube formation, VEGF secretion) being CB2 receptor-dependent. A reduction of the transcription factor hypoxia-inducible factor 1α (HIF-1α) was furthermore detected.

The antiangiogenic and VEGF-lowering properties of BCP were confirmed when CM from another lung cancer cell line, H358, were tested. When directly exposed to HUVECs, BCP showed no significant effect on tube formation, but at 10 µM, impaired VEGF receptor 2 (VEGFR2) phosphorylation triggered by recombinant VEGF in a CB2 receptor-independent manner. In summary, BCP has a dual antiangiogenic effect on HUVECs, manifested in the inhibition of tube formation through modulation of the tumor cell secretome and additionally in the inhibition of VEGF-induced VEGFR2 activation. Because the CB2 agonist has no psychoactive properties, BCP should continue to be evaluated preclinically for further antitumor effects.”

https://pubmed.ncbi.nlm.nih.gov/38255884/

https://www.mdpi.com/1422-0067/25/2/810

“Beta-caryophyllene is a dietary cannabinoid.” https://www.ncbi.nlm.nih.gov/pubmed/18574142

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934


Cannabinerol (CBNR) Influences Synaptic Genes Associated with Cytoskeleton and Ion Channels in NSC-34 Cell Line: A Transcriptomic Study

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“Cannabinoids are receiving great attention as a novel approach in the treatment of cognitive and motor disabilities, which characterize neurological disorders. To date, over 100 phytocannabinoids have been extracted from Cannabis sativa, and some of them have shown neuroprotective properties and the capacity to influence synaptic transmission.

In this study, we investigated the effects of a less-known phytocannabinoid, cannabinerol (CBNR), on neuronal physiology.

Using the NSC-34 motor-neuron-like cell line and next-generation sequencing analysis, we discovered that CBNR influences synaptic genes associated with synapse organization and specialization, including genes related to the cytoskeleton and ion channels. Specifically, the calcium, sodium, and potassium channel subunits (Cacna1bCacna1cCacnb1Grin1Scn8aKcnc1Kcnj9) were upregulated, along with genes related to NMDAR (Agap3Syngap1) and calcium (Cabp1Camkv) signaling. Moreover, cytoskeletal and cytoskeleton-associated genes (Actn2InaTrioMarcksBsnRtn4DgkzHtt) were also regulated by CBNR.

These findings highlight the important role played by CBNR in the regulation of synaptogenesis and synaptic transmission, suggesting the need for further studies to evaluate the neuroprotective role of CBNR in the treatment of synaptic dysfunctions that characterize motor disabilities in many neurological disorders.”

https://pubmed.ncbi.nlm.nih.gov/38255294/

https://www.mdpi.com/2227-9059/12/1/189

Antimicrobial Effect of Cannabidiol on Intracellular Mycobacterium tuberculosis

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“Introduction: Mycobacterium tuberculosis, the etiologic agent of tuberculosis (TB), has killed nearly one billion people during the last two centuries. Nowadays, TB remains a major global health problem ranked among the top 10 causes of death worldwide. One of the main challenges in developing new strategies to fight TB is focused on reducing the duration and complexity of drug regimens. Cannabidiol (CBD) is the main nonpsychoactive ingredient extracted from the Cannabis sativa L. plant, which has been shown to be biologically active against bacteria. The purpose of this work was to investigate the antimicrobial effect of CBD on M. tuberculosis intracellular infection. 

Materials and Methods: To assess the minimum inhibitory concentration (MIC) of CBD on mycobacterial strains, the MTT assay was performed on Mycobacterium smegmatis, and the Colony-Forming Unit (CFU) assay was conducted on MtbH37Rv. Additionally, the cytotoxic effect of CBD on THP-1 cells was assessed by MTT assay. Moreover, macrophages derived from the THP-1 cell were infected with MtbH37Rv (multiplicity of infection 1:10) to evaluate the intracellular activity of CBD by determining the CFU/mL. 

Results: Antimicrobial activity against M. smegmatis (MIC=100 μM) and MtbH37Rv (MIC=25 μM) cultures was exhibited by CBD. Furthermore, the effect of CBD was also evaluated on MtbH37Rv infected macrophage cells. Interestingly, a reduction in viable intracellular MtbH37Rv bacteria was observed after 24 h of treatment. Moreover, CBD exhibited a safe profile toward human THP-1 cells, since it showed no toxicity (CC50=1075 μM) at a concentration of antibacterial effect (selectivity index 43). 

Conclusion: These results extend the knowledge regarding the antimicrobial activity of CBD and demonstrate its ability to kill the human intracellular pathogen M. tuberculosis.”

https://pubmed.ncbi.nlm.nih.gov/38252548/

https://www.liebertpub.com/doi/10.1089/can.2023.0124

Cannabis Roots: Therapeutic, Biotechnological and Environmental Aspects

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“Since the legalization of recreational cannabis in Canada in 2018, the number of licenses for this crop has increased significantly, resulting in an increase in waste generated.

Nevertheless, cannabis roots were once used for their therapeutic properties, indicating that they could be valued today rather than dismissed.

This review will focus on both traditional therapeutic aspects and potential use of roots in modern medicine while detailing the main studies on active phytomolecules found in cannabis roots. The environmental impact of cannabis cultivation and current knowledge of the root-associated microbiome are also presented as well as their potential applications in biotechnology and phytoremediation. Thus, several high added-value applications of cannabis roots resulting from scientific advances in recent years can be considered to remove them from discarded residues.”

https://pubmed.ncbi.nlm.nih.gov/38252502/

https://www.liebertpub.com/doi/10.1089/can.2023.0168

Recreational and Medical Cannabis Legalization and Opioid Prescriptions and Mortality

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“Importance: While some have argued that cannabis legalization has helped to reduce opioid-related morbidity and mortality in the US, evidence has been mixed. Moreover, existing studies did not account for biases that could arise when policy effects vary over time or across states or when multiple policies are assessed at the same time, as in the case of recreational and medical cannabis legalization.

Objective: To quantify changes in opioid prescriptions and opioid overdose deaths associated with recreational and medical cannabis legalization in the US.

Design, setting, and participants: This quasiexperimental, generalized difference-in-differences analysis used annual state-level data between January 2006 and December 2020 to compare states that legalized recreational or medical cannabis vs those that did not.

Intervention: Recreational and medical cannabis law implementation (proxied by recreational and medical cannabis dispensary openings) between 2006 and 2020 across US states.

Main outcomes and measures: Opioid prescription rates per 100 persons and opioid overdose deaths per 100 000 population based on data from the US Centers for Disease Control and Prevention.

Results: Between 2006 and 2020, 13 states legalized recreational cannabis and 23 states legalized medical cannabis. There was no statistically significant association of recreational or medical cannabis laws with opioid prescriptions or overall opioid overdose mortality across the 15-year study period, although the results also suggested a potential reduction in synthetic opioid deaths associated with recreational cannabis laws (4.9 fewer deaths per 100 000 population; 95% CI, -9.49 to -0.30; P = .04). Sensitivity analyses excluding state economic indicators, accounting for additional opioid laws and using alternative ways to code treatment dates yielded substantively similar results, suggesting the absence of statistically significant associations between cannabis laws and the outcomes of interest during the full study period.

Conclusions and relevance: The results of this study suggest that, after accounting for biases due to possible heterogeneous effects and simultaneous assessment of recreational and medical cannabis legalization, the implementation of recreational or medical cannabis laws was not associated with opioid prescriptions or opioid mortality, with the exception of a possible reduction in synthetic opioid deaths associated with recreational cannabis law implementation.”

https://pubmed.ncbi.nlm.nih.gov/38241056/

https://jamanetwork.com/journals/jama-health-forum/fullarticle/2813866

Hemp Seed Cake Flour as a Source of Proteins, Minerals and Polyphenols and Its Impact on the Nutritional, Sensorial and Technological Quality of Bread

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“Hemp (Cannabis sativa L.) seeds contain a high concentration of proteins and biologically active compounds. The protein content is even higher in case of lipid part removal in oil production. The remaining part is considered a leftover, usually being used in animal feed. The aim of this study was to investigate the physicochemical composition of hemp seed cake flour, its nutritional quality and its impact on bread quality parameters. The properties of hemp seed cake flour were assessed in terms of protein quality, mineral composition, polyphenols and antioxidant activity.

Hemp seed cake proved to be an important source of high-quality protein (31.62% d.m.) with the presence of eight essential amino acids.

The biologically active potential of hemp seed cake has been demonstrated by the high content of polyphenols, especially those from the Cannabisin group. Hemp seed cake flour was incorporated in wheat flour at levels from 5 to 40% (w/w) to investigate its influence on bread quality parameters.

The addition of hemp seed cake flour increased the total phenol content of bread, thus greatly enhancing the antioxidant activity. The protein content of bread was found to be enhanced from 11.11% d.m (control sample) to 18.18% d.m (for sample with 40% hemp seed cake flour). On the other hand, the addition of hemp seed cake flour led to decreased bread porosity, increased hardness and decreased resilience in the seed cake. Although, all bread samples recorded sensorial attributes ranging between “slightly like” and “like it very much”.”

https://pubmed.ncbi.nlm.nih.gov/38231840/

“Hemp (Cannabis sativa L.) is a low-cost, unconventional feed resource with a unique phytochemical composition and various uses (pharmaceutical industry, food industry, etc)”

https://www.mdpi.com/2304-8158/12/23/4327

Review: Nutritional aspects of hemp-based products and their effects on health and performance of monogastric animals

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“Sustainable agriculture aims to produce food and feed that ensure food security and play a key role in environmental protection. For this, producers, supported by scientific research, are investigating new protein alternatives for animals that guarantee high performance and preserve their health.

Among these, hemp (Cannabis sativa L.) is gaining great success, both for its active role in environmental conservation and for the high nutritional profile of the seeds (20-30% carbohydrates, 25-30% proteins easy to digest and rich in essential amino acids, and 25-35% lipids with a balanced fatty acid composition), also ensured by the co-products, particularly seed cakes (30-34% proteins and 10-12% lipids).

However, the last scientific report by the European Food Safety Authority for the use of hemp-based products in the feed sector now dates back to 2011. For this reason, the objective of this review, in addition to outlining the nutritional profile of hempseeds (HSs) and co-products, aims to investigate their use in the monogastric sector, particularly in the diets of pigs, broilers, and laying hens, by summarising the main works in the literature up to 2023, investigating the effects on animal health and performances.

The reported results showed that the addition of 50 g/kg of HSs and HS oil improved the nutritional profile of milk and colostrum in lactating sows, particularly the lipid profile, positively affecting the health of piglets. For broilers, the inclusion of HSs (20 g/kg) resulted in better values on growth performance. This was not matched by the addition of HS oil (up to 60 g/kg). In particular, although a better polyunsaturated fatty acid profile was observed, the results on growth performance were contradictory. The same trend was observed for HSs cakes with 50, 150, and 200 g/kg inclusion. For laying hens, the inclusion of HSs (up to 250 g/kg), HS oil (up to 300 g/kg), and HSs cake (up to 150 g/kg) increased the nutritional and functional profile of the eggs, safeguarding performance and animal welfare. However, despite the promising results, the function of hemp-based products in the diet of monogastric animals needs to be further investigated to identify the optimal level of inclusion and timing of administration, necessary to ensure high performance and health of the animals.”

https://pubmed.ncbi.nlm.nih.gov/38211413/

“Hempseeds and hemp-based products are characterised by a high nutritional aspect.”

https://www.sciencedirect.com/science/article/pii/S1751731123003750?via%3Dihub

The NLRP3 inflammasome: a vital player in inflammation and mediating the anti-inflammatory effect of CBD

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“Background: The NLRP3 inflammasome is a vital player in the emergence of inflammation. The priming and activation of the NLRP3 inflammasome is a major trigger for inflammation which is a defense response against adverse stimuli. However, the excessive activation of the NLRP3 inflammasome can lead to the development of various inflammatory diseases. Cannabidiol, as the second-most abundant component in cannabis, has a variety of pharmacological properties, particularly anti-inflammation. Unlike tetrahydrocannabinol, cannabidiol has a lower affinity for cannabinoid receptors, which may be the reason why it is not psychoactive. Notably, the mechanism by which cannabidiol exerts its anti-inflammatory effect is still unclear.

Methods: We have performed a literature review based on published original and review articles encompassing the NLRP3 inflammasome and cannabidiol in inflammation from central databases, including PubMed and Web of Science.

Results and conclusions: In this review, we first summarize the composition and activation process of the NLRP3 inflammasome. Then, we list possible molecular mechanisms of action of cannabidiol. Next, we explain the role of the NLRP3 inflammasome and the anti-inflammatory effect of cannabidiol in inflammatory disorders. Finally, we emphasize the capacity of cannabidiol to suppress inflammation by blocking the NLRP3 signaling pathway, which indicates that cannabidiol is a quite promising anti-inflammatory compound.”

https://pubmed.ncbi.nlm.nih.gov/38191853/

https://link.springer.com/article/10.1007/s00011-023-01831-y

Sila-CBD Derivatives as Inhibitors of Heme-Induced NLRP3 Inflammasome: Application in Hemolytic Diseases

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“Synthesis and biological evaluation of silicon-incorporated phytocannabinoids with improved pharmacological properties toward inflammatory diseases are described. The synthesized sila-analogues 15a15b, and 15c displayed potent inhibition of pro-inflammatory cytokines, including IL-1β, TNF-α, and IL-6 at 10 μM. Further, the release of heme during the lysis of red blood cells in hemolytic diseases is one of the major reasons for inflammation associated with the pathophysiology of these diseases. Due to scanty literature related to inhibitors of heme-mediated induction of the NLRP3 inflammasome, we decided to test these compounds against it. Compounds 15a and 15c significantly inhibited the heme-mediated induction of the NLRP3 inflammasome at a concentration of 0.1 μM. Interestingly, the sila-CBD derivatives also showed higher metabolic stability in contrast to their carbon analogues. Anti-NLRP3 inflammasome activity of compounds 15a and 15c were further validated in vivo against heme-mediated peritoneal inflammation. The anti-inflammatory activity of these compounds could be useful in treating diseases such as sickle cell anemia and thalassemia involving the hemolysis-mediated activation of the NLRP3 inflammasome.”

https://pubmed.ncbi.nlm.nih.gov/38116428/

https://pubs.acs.org/doi/10.1021/acsmedchemlett.3c00352

Cannabinoids improve mitochondrial function in skeletal muscle of exhaustive exercise training rats by inhibiting mitophagy through the Pink1/Parkin and Bnip3 pathways

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“Cannabidiol (CBD) is a pure natural phytocannabinoid derived from cannabis that has anti-inflammatory, antiapoptotic and antioxidative stress abilities. In recent years, an increasing number of studies have reported the regulatory effect of CBD on skeletal muscle injury induced by exercise, but its mechanism is still unclear. Mitochondria are the main organelles responsible for the energy supply within eukaryotic cells, and their function has been closely linked to cellular health. Moderate exercise improves mitochondrial function, but the excessive exercise has a negative impact on mitochondria. Therefore, we speculate that CBD may promote exercise induced skeletal muscle cell damage by improving mitochondrial function. In this study, by establishing an animal model of exhaustive exercise training in rats, the effects of CBD on the protective effect of CBD on skeletal muscle mitochondrial structure and function was elaborated, and the possible molecular mechanism was discussed based on transcriptomics. Our results indicate that skeletal muscle mitochondrial structure and function were improved after CBD intervention. GO and KEGG pathway enrichment analysis showed that exhaustive exercise training induced mitochondrial dysfunction in skeletal muscle is associated with excessive autophagy/mitophagy, the signaling pathways involved in FOXO3 and GABARAPL1 may play important roles. After CBD intervention, the protein expression of Pink1, Parkin and Bnip3 was down-regulated, indicating that CBD may improve the mitochondrial function by inhibiting mitophagy through the Pink1/Parkin and Bnip3 pathway.”

https://pubmed.ncbi.nlm.nih.gov/38182033/

https://www.sciencedirect.com/science/article/abs/pii/S0009279724000012?via%3Dihub