β-Caryophyllene Induces Apoptosis and Inhibits Angiogenesis in Colorectal Cancer Models

ijms-logo“Beta-Caryophyllene (BCP), a naturally occurring sesquiterpene abundantly found in cloves, hops, and cannabis, is the active candidate of a relatively new group of vascular-inhibiting compounds that aim to block existing tumor blood vessels.

Previously, we have reported the anti-cancer properties of BCP by utilizing a series of in-vitro anti-tumor-related assays using human colorectal carcinoma cells. The present study aimed to investigate the effects of BCP on in-vitro, ex-vivo, and in-vivo models of anti-angiogenic assays and evaluate its anti-cancer activity in xenograft tumor (both ectopic and orthotopic) mice models of human colorectal cancer.

BCP showed a remarkable reduction in tumor size and fluorescence molecular tomography signal intensity in all the mice treated with BCP, in a dose-dependent relationship, in ectopic and orthotopic tumor xenograft models, respectively. The histological analysis of the tumor from BCP-treated mice revealed a clear reduction of the density of vascularization. In addition, BCP induced apoptosis through downregulation of HSP60, HTRA, survivin, and XIAP, along with the upregulation of p21 expressions.

These results suggest that BCP acts at multiple stages of angiogenesis and could be used as a promising therapeutic candidate to halt the growth of colorectal tumor cells.”

https://pubmed.ncbi.nlm.nih.gov/34638895/

https://www.mdpi.com/1422-0067/22/19/10550

“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

Protective Effects of ( E)-β-Caryophyllene (BCP) in Chronic Inflammation

nutrients-logo“(E)-β-caryophyllene (BCP) is a bicyclic sesquiterpene widely distributed in the plant kingdom, where it contributes a unique aroma to essential oils and has a pivotal role in the survival and evolution of higher plants.

Recent studies provided evidence for protective roles of BCP in animal cells, highlighting its possible use as a novel therapeutic tool.

Experimental results show the ability of BCP to reduce pro-inflammatory mediators such as tumor necrosis factor-alfa (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), thus ameliorating chronic pathologies characterized by inflammation and oxidative stress, in particular metabolic and neurological diseases.

Through the binding to CB2 cannabinoid receptors and the interaction with members of the family of peroxisome proliferator-activated receptors (PPARs), BCP shows beneficial effects on obesity, non-alcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) liver diseases, diabetes, cardiovascular diseases, pain and other nervous system disorders.

This review describes the current knowledge on the biosynthesis and natural sources of BCP, and reviews its role and mechanisms of action in different inflammation-related metabolic and neurologic disorders.”

https://pubmed.ncbi.nlm.nih.gov/33114564/

https://www.mdpi.com/2072-6643/12/11/3273

“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

Cannabidiol (CBD).

Cover of StatPearls“Cannabis sativa or Indian hemp (subfamily Cannaboideae of family Moraceae) is an annual herbaceous plant, native to central and western Asia, cultivated for medicinal properties and for hemp, which is a natural textile fiber. The plant contains over 400 chemical compounds, of which approximately 80 biologically active chemical molecules. The most important cannabis compounds are cannabinoids formed by a terpene combined with resorcinol, or, according to a different nomenclature, by a benzopyranic ring system. There are about sixty cannabinoids, of which the most important psychoactive compound is tetrahydrocannabinol (TCH), in particular the isomer delta (Δ9-THC). Other identified compounds are cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), and olivetol. In addition to cannabinoids, the plant contains terpenoids such as beta-myrcene, beta-caryophyllene, d-limonene, linalool, piperidine, and p-cymene, as well as flavonoids such as quercetin.”

https://www.ncbi.nlm.nih.gov/pubmed/32310508

https://www.ncbi.nlm.nih.gov/books/NBK556048/

Insulinotropic and antidiabetic effects of β-caryophyllene with l-arginine in type 2 diabetic rats.

Journal of Food Biochemistry banner“Beta-caryophyllene (BCP) is a flavoring agent, whereas l-arginine (LA) is used as a food supplement.

They possess insulinotropic and β cell regeneration activities, respectively.

We assessed the antidiabetic potential of BCP, LA, and its combination in RIN-5F cell lines and diabetic rats.

The results indicated that the combination of BCP with LA showed a significant decrease in glucose absorption and an increase in its uptake in tissues and also an increase in insulin secretion in RIN-5F cells. The combination treatment of BCP with LA showed a significant reduction in glucose, lipid levels, and oxidative stress in pancreatic tissue when compared with the diabetic group. Furthermore, the combination of BCP with LA normalized glucose tolerance and pancreatic cell damage in diabetic rats.

In conclusion, the combinational treatment showed significant potentials in the treatment of type 2 diabetes mellitus.

PRACTICAL APPLICATIONS:

Type 2 diabetes mellitus is the most prevalent chronic metabolic disorder affecting a large population.

Beta-caryophyllene is a CB2 receptor agonist shown to have insulinotropic activity.

l-Arginine is a food supplement that possesses beta-cell regeneration property.

The combination of BCP with LA could work as a potential therapeutic intervention, considering the individual pharmacological activities of each.

We evaluated the antidiabetic activity of the combination of BCP with LA in diabetic rats using ex vivo and in vitro experimentations.

Results from the study revealed that the combination of BCP with LA showed a significant (p < .001) reduction in glucose and lipid levels as compared to individual treatment. In vitro study also supports the diabetic potential of the combination of BCP with LA in the glucose-induced insulin secretion in RIN-5F cell lines.

The study indicates a therapeutic approach to treat T2DM by BCP and LA combination as food and dietary supplement.”

https://www.ncbi.nlm.nih.gov/pubmed/31997410

https://onlinelibrary.wiley.com/doi/abs/10.1111/jfbc.13156

“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

β-Caryophyllene, a CB2-Receptor-Selective Phytocannabinoid, Suppresses Mechanical Allodynia in a Mouse Model of Antiretroviral-Induced Neuropathic Pain.

molecules-logo “Neuropathic pain associated with nucleoside reverse transcriptase inhibitors (NRTIs), therapeutic agents for human immunodeficiency virus (HIV), responds poorly to available drugs.

Smoked cannabis was reported to relieve HIV-associated neuropathic pain in clinical trials. Some constituents of cannabis (Cannabis sativa) activate cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors. However, activation of the CB1 receptor is associated with side effects such as psychosis and physical dependence.

Therefore, we investigated the effect of β-caryophyllene (BCP), a CB2-selective phytocannabinoid, in a model of NRTI-induced neuropathic pain.

BCP prevents NRTI-induced mechanical allodynia, possibly via reducing the inflammatory response, and attenuates mechanical allodynia through CB2 receptor activation. Therefore, BCP could be useful for prevention and treatment of antiretroviral-induced neuropathic pain.”

https://www.ncbi.nlm.nih.gov/pubmed/31892132

https://www.mdpi.com/1420-3049/25/1/106

“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

Beta-caryophyllene enhances wound healing through multiple routes.

 Image result for plos one“Beta-caryophyllene is an odoriferous bicyclic sesquiterpene found in various herbs and spices.

Recently, it was found that beta-caryophyllene is a ligand of the cannabinoid receptor 2 (CB2). Activation of CB2 will decrease pain, a major signal for inflammatory responses.

We hypothesized that beta-caryophyllene can affect wound healing by decreasing inflammation. Here we show that cutaneous wounds of mice treated with beta-caryophyllene had enhanced re-epithelialization.

The treated tissue showed increased cell proliferation and cells treated with beta-caryophyllene showed enhanced cell migration, suggesting that the higher re-epithelialization is due to enhanced cell proliferation and cell migration. The treated tissues also had up-regulated gene expression for hair follicle bulge stem cells. Olfactory receptors were not involved in the enhanced wound healing. Transient Receptor Potential channel genes were up-regulated in the injured skin exposed to beta-caryophyllene. Interestingly, there were sex differences in the impact of beta- caryophyllene as only the injured skin of female mice had enhanced re-epithelialization after exposure to beta-caryophyllene.

Our study suggests that chemical compounds included in essential oils have the capability to improve wound healing, an effect generated by synergetic impacts of multiple pathways.”

https://www.ncbi.nlm.nih.gov/pubmed/31841509

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216104

“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

Beta-caryophyllene alleviates diet-induced neurobehavioral changes in rats: The role of CB2 and PPAR-γ receptors.

Biomedicine & Pharmacotherapy

“Insulin resistance (IR) and obesity predispose diseases such as diabetes, cardiovascular and neurodegenerative disorders.

Beta-caryophyllene (BCP), a natural sesquiterpene, exerts neuroprotective, anxiolytic and antidepressant effects via its selective agonism to cannabinoid receptor 2 (CB2R). BCP was shown to have an anti-diabetic effect, however, the implication of CB2R is yet to be elucidated. A link between CB2R agonism and PPAR-γ activation has been discussed, but the exact mechanism is not well-defined.

This study was designed to examine the role of BCP in improving diet-induced metabolic (insulin resistance), neurobehavioral (anxiety, depression and memory deficit), and neurochemical (oxidative, inflammatory and neurotrophic factor) alterations in the prefrontal cortex of obese rats’ brain. The involvement of CB2R and/or PPAR-γ dependent activity was also investigated.

KEY RESULTS:

Beta-caryophyllene alleviated HFFD-induced IR, oxidative-stress, neuroinflammation and behavioral changes. The anxiolytic, anti-oxidant and anti-inflammatory effects of BCP were mediated by both PPAR-γ and CB2R. The effects of BCP on glycemic parameters seem to be CB2R-dependent with the non-significant role of PPAR-γ. Furthermore, BCP-evoked antidepressant and memory improvement are likely mediated only via CB2R, mainly by upregulation of PGC-1α and BDNF.

CONCLUSION:

This study suggests the potential effect of BCP in treating HFFD-induced metabolic and neurobehavioral alterations. BCP seems to activate PPAR-γ in a ligand-independent manner, via upregulation and activation of PGC-1α. The BCP activation of PPAR–γ seems to be CB2R-dependent.”

https://www.ncbi.nlm.nih.gov/pubmed/30469079

https://www.sciencedirect.com/science/article/pii/S0753332218370033?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

Acute administration of beta-caryophyllene prevents endocannabinoid system activation during transient common carotid artery occlusion and reperfusion.

Image result for lipids in health and disease

“The transient global cerebral hypoperfusion/reperfusion achieved by induction of Bilateral Common Carotid Artery Occlusion followed by Reperfusion (BCCAO/R) has been shown to stimulate early molecular changes that can be easily traced in brain tissue and plasma, and that are indicative of the tissue physiological response to the reperfusion-induced oxidative stress and inflammation.

The aim of the present study is to probe the possibility to prevent the molecular changes induced by the BCCAO/R with dietary natural compounds known to possess anti-inflammatory activity, such as the phytocannabinoid beta-caryophyllene (BCP).

CONCLUSIONS:

Collectively, the pre-treatment with BCP, likely acting as agonist for CB2 and PPAR-alpha receptors, modulates in a beneficial way the ECS activation and the lipoperoxidation, taken as indicative of oxidative stress. Furthermore, our results support the evidence that BCP may be used as a dietary supplement to control the physiological response to the hypoperfusion/reperfusion-induced oxidative stress.”

“beta-caryophyllene (BCP), a sesquiterpene found as a common constituent of the essential oils of numerous food plants and primary component in Cannabis sativa L., is a dietary phytocannabinoid acting as selective agonist for CB2 receptor and peroxisome-proliferator activating receptor alpha (PPAR-alpha)”
“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 protects diet-induced dyslipidemia and vascular inflammation in rats: Involvement of CB2 and PPAR-γ receptors.

Chemico-Biological Interactions

“Beta-caryophyllene (BCP) is a phytocannabinoid possessing selective agonistic activity to cannabinoid type-2 receptors (CB2R) and peroxisome proliferator-activated receptors-α (PPAR-α). However, few studies reported the contribution of PPAR-γ receptors in BCP effects.

The aim of this study was to investigate the BCP effects on diet-induced dyslipidemia and vascular inflammation as well as the involvement of CB2R and PPAR-γ receptors.

BCP treatment was superior to pioglitazone in anti-inflammatory and anti-atherosclerotic measures. BCP may represent a more potent alternate to pioglitazone avoiding its side effects in the treatment of insulin resistance and vascular inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/30343038

https://www.sciencedirect.com/science/article/pii/S0009279718309347?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

Antiallodynic effect of β-caryophyllene on paclitaxel-induced peripheral neuropathy in mice.

Cover image

“Painful peripheral neuropathy is a common side effect of paclitaxel (PTX). The use of analgesics is an important component for management of PTX-induced peripheral neuropathy (PINP). However, currently employed analgesics have several side effects and are poorly effective.

β-caryophyllene (BCP), a dietary selective CB2 agonist, has shown analgesic effect in neuropathic pain models, but its role in chemotherapy-induced neuropathic pain has not yet been investigated. Herein, we used the mouse model of PINP to show the therapeutic effects of BCP in this neuropathy.

Our findings show that BCP effectively attenuated PINP, possibly through CB2-activation in the CNS and posterior inhibition of p38 MAPK/NF-κB activation and cytokine release. Taken together, our results suggest that BCP could be used to attenuate the establishment and/or treat PINP.”  https://www.ncbi.nlm.nih.gov/pubmed/28729222

http://www.sciencedirect.com/science/article/pii/S0028390817303465

“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