The cannabinoid receptor 2 agonist, β-caryophyllene, improves working memory and reduces circulating levels of specific proinflammatory cytokines in aged male mice.

Behavioural Brain Research“Age-related cognitive decline has been associated with proinflammatory cytokines, yet the precise relationship between cognitive decline and cytokine load remains to be elucidated. β-caryophyllene (BCP) is a cannabinoid receptor 2 (CB2) agonist with established anti-inflammatory effects that is known to improve memory and increase lifespan. It is of interest to explore the potential of BCP to reduce age-related cognitive decline and proinflammatory cytokine load. In this study, we assessed changes in circulating cytokines across the lifespan, memory performance in young and aged mice, and the effects of BCP on memory function and cytokine load. The plasma levels of 12 cytokines were assessed in male Swiss-Webster mice at 3, 12, and 18 months of age using multiplexed flow cytometry. Working memory was compared in 3 and 12 month-old mice using spontaneous alternations. A dose-response function (100-300 mg/kg, subchronic administration) for BCP-induced memory restoration was determined in 3 and 12 month-old mice. Finally, the effects on cytokine levels of the peak memory enhancing dose of BCP was assessed in 18 month-old mice. Circulating levels of several cytokines significantly increased with age. Multilinear regression analysis showed that IL-23 levels were most strongly associated with age. Aged mice showed deficits in working memory and higher levels of IL-23, both of which were reversed by BCP treatment. BCP appears to reverse age-associated impairments in memory and modulates cytokine production. IL-23 may play a significant role in the aging process, and future research should determine whether it has utility as a biomarker for novel anti-aging therapeutics.”

https://www.ncbi.nlm.nih.gov/pubmed/31173795

https://www.sciencedirect.com/science/article/pii/S0166432819304516?via%3Dihub

“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

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

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β-Caryophyllene, a Natural Sesquiterpene, Attenuates Neuropathic Pain and Depressive-Like Behavior in Experimental Diabetic Mice.

 View details for Journal of Medicinal Food cover image“Neuropathic pain (NP) is associated with chronic hyperglycemia and emotional disorders such as depression in diabetic patients, complicating the course of treatment. Drugs currently used to treat NP have undesirable side effects, so research on other natural sources has been required.

β-caryophyllene (BCP), a natural sesquiterpene found in some food condiments and considered an agonist to cannabinoid receptor type 2, could have potential therapeutic effects to treat conditions such as NP and emotional disorders. For this reason, we assessed whether BCP modulates nociception, anxiety, and depressive-like behavior in streptozotocin (STZ)-induced experimental diabetic BALB/c female mice.

BCP was orally chronic administrated (10 mg/kg/60 μL). Pain developed with STZ was evaluated with von Frey filament test, SMALGO®, and hot plate test. Anxiety and depression-like behavior were assessed by marbles test, forced swim test, and tail suspension test. BCP significantly reduced glycemia in experimental diabetic mice. The pain was also mitigated by BCP administration. Depression-like behavior assessed with tail suspension test was attenuated with orally chronic BCP administration. Substance P and cytokines such as interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6) were also attenuated with BCP administration. NP was positively correlated with substance P and IL-6 and IL-1β release.

Our data using an orally chronic BCP administration in the STZ challenged mice to suggest that glycemia, diabetes-related NP, and depressive-like behavior could be prevented/reduced by dietary BCP.”

https://www.ncbi.nlm.nih.gov/pubmed/30864870

https://www.liebertpub.com/doi/10.1089/jmf.2018.0157

“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

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

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The protective effects of β-caryophyllene on LPS-induced primary microglia M1/M2 imbalance: A mechanistic evaluation.

Life Sciences

“Neuroinflammation is observed as a routine characterization of neurodegenerative disorders such as dementia, multiple sclerosis (MS) and Alzheimer’s diseases (AD). Scientific evidence propounds both of the neuromodulatory and immunomodulatory effects of CB2 in the immune system. β-Caryophyllene (BCP) is a dietary selective CB2 agonist, which deserves the anti-inflammatory and antioxidant effects at both low and high doses through activation of the CB2 receptor.

METHODS:

In this study, we investigated the protective effects of a broad range concentration of BCP against LPS-induced primary microglia cells inflammation and M1/M2 imbalance and identifying the portion of the involvement of related signaling pathways on BCP effects using pharmacological antagonists of CB2, PPAR-γ, and sphingomyelinase (SMase).

KEY FINDINGS:

The protective effects of BCP on LPS-induced microglia imbalance is provided by the M2 healing phenotype of microglia, releasing the anti-inflammatory (IL-10, Arg-1, and urea) and anti-oxidant (GSH) parameters and reducing the inflammatory (IL-1β, TNF-α, PGE2, iNOS and NO) and oxidative (ROS) biomarkers. Moreover, we showed that BCP exerts its effects through CB2receptors which overproduction of ceramides by SMase at middle to higher concentrations of BCP reduce the protective activity of BCP and results in the activation of the PPAR-γ pathway.

SIGNIFICANCE:

In conclusion, the low concentration of BCP has higher selective anti-inflammatory effects rather than high levels. On this occasion, BCP by modulating the microglia is able to have potential therapeutic effects in neuro-inflammation conditions and microglia cells such as MS and AD.”

https://www.ncbi.nlm.nih.gov/pubmed/30620895

https://www.sciencedirect.com/science/article/abs/pii/S0024320518308610?via%3Dihub

“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

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

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Production, digestibility and allergenicity of hemp (Cannabis sativa L.) protein isolates.

Food Research International

“Hemp (Cannabis sativa L.), traditionally cultivated for industrial use and harvested for fibers and seeds, has raised much interest as a sustainable crop in the last years.

Recently, hemp seeds and derived oil have started to be used in a variety of food products. Hemp-based food products are considered less allergenic than those from other edible seeds, although this statement has never been experimentally verified.

In this study high purity grade hemp flour (HF) and hemp protein isolate (HPI) were obtained through a fast and cheap process starting from defatted hemp cakes, a residue of hempseed oil extraction.

HPI resulted enriched at nearly 86% protein, mainly constituted by the storage protein edestin (accounting for 70% total protein). In vitro protein digestibility was determined using a static model of gastrointestinal digestion (GID), which included a final step with purified brush border membrane (BBM) enzyme preparations. HF and HPI showed a high degree of digestibility. The survival of potential bioactive and/or allergenic peptide sequences in digests was investigated by peptidomic analysis. Only a limited number of sequences survived GID. Among them, fragments from 12 seed proteins. These fragments were precursors of sequences with potential bioactive peptides, which might justify the bioactivity of HPI hydrolysates, reported in previous studies.

More importantly, all known hemp allergens, including the major thaumatin-like protein and LTP, were entirely eliminated by the HPI production process, neither fragments of the proteins were present after GID.

These data support the use of HPI as an ingredient for hypoallergenic foods.”

https://www.ncbi.nlm.nih.gov/pubmed/30599980

https://www.sciencedirect.com/science/article/pii/S0963996918307427?via%3Dihub

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Nutraceutical potential of hemp (Cannabis sativa L.) seeds and sprouts.

 Food Chemistry

“In this study the antioxidant effect of Cannabis sativa L. seeds and sprouts (3 and 5 days of germination) was evaluated.

Total polyphenols, flavonoids and flavonols content, when expressed on dry weight basis, were highest in sprouts; ORAC and DPPH (in vitro assays), CAA-RBC (cellular antioxidant activity in red blood cells) and hemolysis test (ex vivo assays) evidenced a good antioxidant activity higher in sprouts than in seeds. Untargeted analysis by high resolution mass spectrometry in negative ion mode allowed the identification of main polyphenols (caffeoyltyramine, cannabisin A, B, C) in seeds and of ω-6 (linoleic acid) in sprouts. Antimutagenic effect of seeds and sprouts extracts evidenced a significant decrease of mutagenesis induced by hydrogen peroxide in Saccharomyces cerevisiae D7 strain.

In conclusion our results show that C. sativa seeds and sprouts exert beneficial effects on yeast and human cells and should be further investigated as a potential functional food.”

https://www.ncbi.nlm.nih.gov/pubmed/29751921

https://www.sciencedirect.com/science/article/pii/S0308814618307180?via%3Dihub

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β-Caryophyllene (BCP) ameliorates MPP+ induced cytotoxicity.

Biomedicine & Pharmacotherapy

“Parkinson’s disease (PD) is one of the most common neurodegenerative diseases resulting from the continuous death of dopaminergic neurons in substantia nigra. MPP+ (1-methyl-4-phenylpyridinium) has been reported to be a major neurotoxin causing neurotoxic insults on dopaminergic neurons in humans.

β-Caryophyllene (BCP), an important cannabinoid derived from the essential oils of different species, has displayed pharmacological properties in different kinds of tissues and cells. However, neuroprotective effects of BCP in PD haven’t been reported before.

Our results indicate that treatment with MPP+ in SH-SY5Y cells led to a significant decrease in cell viability, which was restored by BCP. Additionally, BCP suppressed MPP+-induced release of lactic dehydrogenase (LDH) and the generation of reactive oxygen species (ROS). In contrast, BCP treatment restored the reduction in mitochondrial membrane potential (MMP) induced by MPP+. BCP treatment increased intracellular GSH and GPx activity.

Also, we found that the antioxidant effects of BCP against MPP+- induced neurotoxicity are dependent on cannabinoid receptor type 2 (CB2R). Moreover, our results indicated that BCP prevented MPP+-induced apoptosis of SH-SY5Y through inhibiting the up-regulation of cleaved Caspase-3, Bax, and restoring the expression of Bcl-2. Besides, BCP markedly suppressed HO-1 activation and c-Jun N-terminal Kinase (JNK) phosphorylation.

We conclude that BCP might act as a promising therapeutic agent against MPP+ toxicity in neuronal cells.”

“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
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Detection of delta-9-tetrahydrocannabinol (THC) in oral fluid, blood and urine following oral consumption of low-content THC hemp oil.

 Forensic Science International

“Hemp-derivative (Cannabis sativa L.) food products containing trace levels of Δ-9-tetrahydrocannabinol (THC) are proposed for consumption in Australia and New Zealand; however, it is unclear whether use of these products will negatively affect existing drug screening protocols.

Consumption of low-content THC oil does not result in positive biological assessments.

It is therefore highly unlikely that ingestion of products containing these levels of THC will negatively impact existing region-specific drug driving enforcement protocols.”

https://www.ncbi.nlm.nih.gov/pubmed/29408718

https://www.sciencedirect.com/science/article/pii/S0379073817305492?via%3Dihub

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Phytochemical Aspects and Therapeutic Perspective of Cannabinoids in Cancer Treatment

Cannabis sativa L. – dried pistillate inflorescences and trichomes on their surface. (a) dried pistillate inflorescences (50% of the size); (b) non‐cystolithic trichome; (c) cystolithic trichome; (d) capitate‐sessile trichome; (e) simple bulbous trichome; (f) capitate‐stalked trichome (400×).

“Cannabis sativa L. (Cannabaceae) is one of the first plants cultivated by man and one of the oldest plant sources of fibre, food and remedies.

Cannabinoids comprise the plant‐derived compounds and their synthetic derivatives as well as endogenously produced lipophilic mediators. Phytocannabinoids are terpenophenolic secondary metabolites predominantly produced in CannabissativaL.

The principal active constituent is delta‐9‐tetrahydrocannabinol (THC), which binds to endocannabinoid receptors to exert its pharmacological activity, including psychoactive effect. The other important molecule of current interest is non‐psychotropic cannabidiol (CBD).

Since 1970s, phytocannabinoids have been known for their palliative effects on some cancer‐associated symptoms such as nausea and vomiting reduction, appetite stimulation and pain relief. More recently, these molecules have gained special attention for their role in cancer cell proliferation and death.

A large body of evidence suggests that cannabinoids affect multiple signalling pathways involved in the development of cancer, displaying an anti‐proliferative, proapoptotic, anti‐angiogenic and anti‐metastatic activity on a wide range of cell lines and animal models of cancer.”

https://www.intechopen.com/books/natural-products-and-cancer-drug-discovery/phytochemical-aspects-and-therapeutic-perspective-of-cannabinoids-in-cancer-treatment

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Oral administration of cannabis with lipids leads to high levels of cannabinoids in the intestinal lymphatic system and prominent immunomodulation.

 

 

“Cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC) have well documented immunomodulatory effects in vitro, but not following oral administration in humans. Here we show that oral co-administration of cannabinoids with lipids can substantially increase their intestinal lymphatic transport in rats. Moreover, immune cells from MS patients were more susceptible to the immunosuppressive effects of cannabinoids than those from healthy volunteers or cancer patients. Therefore, administering cannabinoids with a high-fat meal or in lipid-based formulations has the potential to be a therapeutic approach to improve the treatment of MS, or indeed other autoimmune disorders.”  https://www.ncbi.nlm.nih.gov/pubmed/29109461

“Cannabis sativa has a very long history of medical use. In summary, it has been demonstrated in this work that oral co-administration of cannabis or cannabis-based medicines with lipids results in extremely high levels of lipophilic cannabinoids in the intestinal lymphatic system and prominent immunomodulatory effects. Therefore, administering cannabinoids with a high-fat meal, as cannabis-containing food, or in lipid-based formulations has the potential to be a therapeutic approach to improve the treatment of MS, or indeed other autoimmune disorders.”  https://www.nature.com/articles/s41598-017-15026-z

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Challenges towards Revitalizing Hemp: A Multifaceted Crop.

Image result for cell journal

“Hemp has been an important crop throughout human history for food, fiber, and medicine. Despite significant progress made by the international research community, the basic biology of hemp plants remains insufficiently understood. Clear objectives are needed to guide future research. As a semi-domesticated plant, hemp has many desirable traits that require improvement, including eliminating seed shattering, enhancing the quantity and quality of stem fiber, and increasing the accumulation of phytocannabinoids. Methods to manipulate the sex of hemp plants will also be important for optimizing yields of seed, fiber, and cannabinoids. Currently, research into trait improvement is hindered by the lack of molecular techniques adapted to hemp. Here we review how addressing these limitations will help advance our knowledge of plant biology and enable us to fully domesticate and maximize the agronomic potential of this promising crop.”

https://www.ncbi.nlm.nih.gov/pubmed/28886910

http://www.cell.com/trends/plant-science/fulltext/S1360-1385(17)30177-2?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1360138517301772%3Fshowall%3Dtrue

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