Cannabidiolic acid dampens the expression of cyclooxygenase-2 in MDA-MB-231 breast cancer cells: Possible implication of the peroxisome proliferator-activated receptor β/δ abrogation.

The Journal of Toxicological Sciences “A growing body of experimental evidence strongly suggests that cannabidiolic acid (CBDA), a major component of the fiber-type cannabis plant, exerts a variety of biological activities.

We have reported that CBDA can abrogate cyclooxygenase-2 (COX-2) expression and its enzymatic activity. It is established that aberrant expression of COX-2 correlates with the degree of malignancy in breast cancer.

Although the reduction of COX-2 expression by CBDA offers an attractive medicinal application, the molecular mechanisms underlying these effects have not fully been established.

It has been reported that COX-2 expression is positively controlled by peroxisome proliferator-activated receptor β/δ (PPARβ/δ) in some cancerous cells, although there is “no” modulatory element for PPARβ/δ on the COX-2 promoter. No previous studies have examined whether an interaction between PPARβ/δ-mediated signaling and COX-2 expression exists in MDA-MB-231 cells.

We confirmed, for the first time, that COX-2 expression is positively modulated by PPARβ/δ-mediated signaling in MDA-MB-231 cells. CBDA inhibits PPARβ/δ-mediated transcriptional activation stimulated by the PPARβ/δ-specific agonist, GW501516. Furthermore, the disappearance of cellular actin stress fibers, a hallmark of PPARβ/δ and COX-2 pathway activation, as evoked by the GW501516, was effectively reversed by CBDA. Activator protein-1 (AP-1)-driven transcriptional activity directly involved in the regulation of COX-2 was abrogated by the PPARβ/δ-specific inverse agonists (GSK0660/ST-247). Thus, it is implicated that there is positive interaction between PPARβ/δ and AP-1 in regulation of COX-2.

These data support the concept that CBDA is a functional down-regulator of COX-2 through the abrogation of PPARβ/δ-related signaling, at least in part, in MDA-MB-231 cells.”

https://www.ncbi.nlm.nih.gov/pubmed/32238697

https://www.jstage.jst.go.jp/article/jts/45/4/45_227/_article

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Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant.

molecules-logo “Medicinal use of Cannabis sativa L. has an extensive history and it was essential in the discovery of phytocannabinoids, including the Cannabis major psychoactive compound-Δ9-tetrahydrocannabinol (Δ9-THC)-as well as the G-protein-coupled cannabinoid receptors (CBR), named cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R), both part of the now known endocannabinoid system (ECS).

Cannabinoids is a vast term that defines several compounds that have been characterized in three categories: (i) endogenous, (ii) synthetic, and (iii) phytocannabinoids, and are able to modulate the CBR and ECS. Particularly, phytocannabinoids are natural terpenoids or phenolic compounds derived from Cannabis sativa.

However, these terpenoids and phenolic compounds can also be derived from other plants (non-cannabinoids) and still induce cannabinoid-like properties. Cannabimimetic ligands, beyond the Cannabis plant, can act as CBR agonists or antagonists, or ECS enzyme inhibitors, besides being able of playing a role in immune-mediated inflammatory and infectious diseases, neuroinflammatory, neurological, and neurodegenerative diseases, as well as in cancer, and autoimmunity by itself.

In this review, we summarize and critically highlight past, present, and future progress on the understanding of the role of cannabinoid-like molecules, mainly terpenes, as prospective therapeutics for different pathological conditions.”

https://www.ncbi.nlm.nih.gov/pubmed/32235333

https://www.mdpi.com/1420-3049/25/7/1567

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The effect of attitudes, subjective norms and stigma on health-care providers’ intention to recommend medicinal cannabis to patients.

International Journal of Nursing Practice“The aim of this study was to explore the effect of health-care providers’ attitudes towards the medical use of cannabis, subjective norms and perceived stigma towards medicinal cannabis users on health-care providers’ intention to recommend medicinal cannabis for patients with qualifying conditions.

RESULTS:

More positive attitudes towards the medical use of cannabis were associated with lower stigma towards medicinal cannabis users, which, in turn, was associated with a higher intention of recommending medicinal cannabis for patients with qualifying conditions. The relationship between attitudes towards the medical use of cannabis and the intention to recommend medicinal cannabis varies according to subjective norms.

CONCLUSIONS:

Among nurses and physicians, stigma towards medicinal cannabis users mediated the relationship between attitudes towards the medical use of cannabis and the intention to recommend medicinal cannabis for patients with qualifying conditions, whereas subjective norms moderated this relationship.

Effective treatment with medicinal cannabis might be compromised by health-care providers’ negative attitudes, stigma and subjective norms.”

https://www.ncbi.nlm.nih.gov/pubmed/32237017

https://onlinelibrary.wiley.com/doi/abs/10.1111/ijn.12836

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Dosage, Efficacy and Safety of Cannabidiol Administration in Adults: A Systematic Review of Human Trials.

“Considering data from in vitro and in vivo studies, cannabidiol (CBD) seems to be a promising candidate for the treatment of both somatic and psychiatric disorders.

The aim of this review was to collect dose(s), dosage schemes, efficacy and safety reports of CBD use in adults from clinical studies.

From the controlled trials, we identified anxiolytic effects with acute CBD administration, and therapeutic effects for social anxiety disorder, psychotic disorder and substance use disorders.

There was evidence to support single dose positive effect on social anxiety disorder, short medium-term effects on symptomatic improvement in schizophrenia and lack of effect in the short medium-term on cognitive functioning in psychotic disorders.

Overall, the administration was well tolerated with mild side effects.”

https://www.ncbi.nlm.nih.gov/pubmed/32231748

https://www.jocmr.org/index.php/JOCMR/article/view/4090

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Molecular Mechanism and Cannabinoid Pharmacology.

 “Since antiquity, Cannabis has provoked enormous intrigue for its potential medicinal properties as well as for its unique pharmacological effects.

The elucidation of its major cannabinoid constituents, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), led to the synthesis of new cannabinoids (termed synthetic cannabinoids) to understand the mechanisms underlying the pharmacology of Cannabis.

These pharmacological tools were instrumental in the ultimate discovery of the endogenous cannabinoid system, which consists of CB1 and CB2 cannabinoid receptors and endogenously produced ligands (endocannabinoids), which bind and activate both cannabinoid receptors.

CB1 receptors mediate the cannabimimetic effects of THC and are highly expressed on presynaptic neurons in the nervous system, where they modulate neurotransmitter release. In contrast, CB2 receptors are primarily expressed on immune cells.

The endocannabinoids are tightly regulated by biosynthetic and hydrolytic enzymes. Accordingly, the endocannabinoid system plays a modulatory role in many physiological processes, thereby generating many promising therapeutic targets.

An unintended consequence of this research was the emergence of synthetic cannabinoids sold for human consumption to circumvent federal laws banning Cannabis use. Here, we describe research that led to the discovery of the endogenous cannabinoid system and show how knowledge of this system benefitted as well as unintentionally harmed human health.”

https://www.ncbi.nlm.nih.gov/pubmed/32236882

https://link.springer.com/chapter/10.1007%2F164_2019_298

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n-3 Polyunsaturated Fatty Acid Amides: New Avenues in the Prevention and Treatment of Breast Cancer.

ijms-logo “Over the last decades a renewed interest in n-3 very long polyunsaturated fatty acids (PUFAs), derived mainly from fish oils in the human diet, has been observed because of their potential effects against cancer diseases, including breast carcinoma. These n-3 PUFAs mainly consist of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that, alone or in combination with anticancer agents, induce cell cycle arrest, autophagy, apoptosis, and tumor growth inhibition. A large number of molecular targets of n-3 PUFAs have been identified and multiple mechanisms appear to underlie their antineoplastic activities. Evidence exists that EPA and DHA also elicit anticancer effects by the conversion to their corresponding ethanolamide derivatives in cancer cells, by binding and activation of different receptors and distinct signaling pathways. Other conjugates with serotonin or dopamine have been found to exert anti-inflammatory activities in breast tumor microenvironment, indicating the importance of these compounds as modulators of tumor epithelial/stroma interplay. The objective of this review is to provide a general overview and an update of the current n-3 PUFA derivative research and to highlight intriguing aspects of the potential therapeutic benefits of these low-toxicity compounds in breast cancer treatment and care.”

https://www.ncbi.nlm.nih.gov/pubmed/32224850

https://www.mdpi.com/1422-0067/21/7/2279

“Anticancer effects of n-3 EPA and DHA and their endocannabinoid derivatives on breast cancer cell growth and invasion.”  https://www.ncbi.nlm.nih.gov/pubmed/31679810

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Adolescent treatment admissions for marijuana following recreational legalization in Colorado and Washington.

Drug and Alcohol Dependence“There is concern that recreational marijuana legalization (RML) may lead to increased cannabis use disorder (CUD) among youth due to increased marijuana use.

This study investigates whether adolescent substance use disorder treatment admissions for marijuana use increased in Colorado and Washington following RML.

RESULTS:

Over all states in the analysis, the rate of adolescent treatment admissions for marijuana use declined significantly over the study period (β=-3.375, 95 % CI=-4.842, -1.907), with the mean rate falling nearly in half. The decline in admissions rate was greater in Colorado and Washington compared to non-RML states following RML, though this difference was not significant (β=-7.671, 95 % CI=-38.798, 23.456).

CONCLUSION:

Adolescent treatment admissions for marijuana use did not increase in Colorado and Washington following RML. This may be because youth marijuana use did not increase, CUD did not increase (even if use did increase), or treatment seeking behaviors changed due to shifts in attitudes and perceptions of risk towards marijuana use.”

https://www.ncbi.nlm.nih.gov/pubmed/32222560

“Youth treatment admissions in Colorado and Washington did not increase after RML. Admissions for 2008–2017 declined in both Colorado/Washington and non-RML states.”

https://www.sciencedirect.com/science/article/abs/pii/S0376871620301253?via%3Dihub

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Editorial: The Canonical and Non-Canonical Endocannabinoid System as a Target in Cancer and Acute and Chronic Pain

frontiers in pharmacology – Retraction Watch“The endocannabinoid system (ECS) comprises the canonical receptor subtypes CB1R and CB2R and endocannabinoids (anandamide, AEA and 2-arachidonoylglycerol, 2-AG), and a “non-canonical” extended signaling network consisting of: (i) other fatty acid derivatives; (ii) the defined “ionotropic cannabinoid receptors” (TRP channels); other GPCRs (GPR55, PPARα); (iii) enzymes involved in the biosynthesis and degradation of endocannabinoids (FAAH and MAGL); and (iv) protein transporters (FABP family).The ECS is currently a hot topic due to its involvement in cancer and pain.

The current Research Topic highlights various ways the endocannabinoid system (ECS) can impact cancer and pain. Ramer et al. review the anticancer potential of the canonical and noncanonical endocannabinoid system. Morales and Jagerovic provide a much needed summary of cannabinoid ligands as promising antitumor agents in a wide variety of tumors, in contrast to their palliative applications. In their article, the authors classify cannabinoids with anticancer potential in endocannabinoids, phytocannabinoids, and synthetic cannabinoids. Moreno et al. in their review explored the value of cannabinoid receptor heteromers as potential new targets for anti-cancer therapies and as prognostic biomarkers, showing the potential of the endocannabinoid network in the anti-cancer setting as well as the clinical and ethical pitfalls behind it.

As an ensemble, these studies provide further fuel to the discussion and underline the potential for targeting the ECS at multiple levels to treat certain cancers and for pain relief. Importantly, they also help to move the focal point of the discussion beyond THC, CBD, and the cannonical receptors. Several of these reports either review or provide data to support the use of/targeting of other members of the ECS system as well as alternative natural products beyond THC and CBD.”

https://www.frontiersin.org/articles/10.3389/fphar.2020.00312/full

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Δ9-Tetrahydrocannabinol (THC) Impairs CD8+ T Cell-Mediated Activation of Astrocytes.

“CD8+ T cells can contribute to neuroinflammation by secretion of inflammatory cytokines like interferon γ (IFNγ) and tumor necrosis factor α (TNFα). Astrocytes, a glial cell in the brain, can be stimulated by IFNγ and TNFα to secrete the inflammatory cytokines, monocyte chemotactic protein 1 (MCP-1), interleukin 6 (IL-6), and interferon-γ inducible protein 10 (IP-10).

Δ9-Tetrahydrocannabinol (THC), the primary psychoactive cannabinoid in Cannabis sativa, possesses potent anti-inflammatory activity.

The objective of this investigation was to assess the effects of THC treatment on CD8+ T cell-mediated activation of astrocytes.

The results suggest that cannabinoid treatment can selectively reduce certain CD8+ T cell responses that contribute to stimulation of astrocytes. Treatment with THC can abate CD8+ T cell-dependent neuroinflammatory processes by inhibiting CD8+ cell differentiation into effector cells, suppressing CD8+ effector cell function, and reducing activation of astrocytes by CD8+ T cell-derived inflammatory cytokines.”

https://www.ncbi.nlm.nih.gov/pubmed/32215844

https://link.springer.com/article/10.1007%2Fs11481-020-09912-z

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Cannabinoids Rescue Cocaine-Induced Seizures by Restoring Brain Glycine Receptor Dysfunction.

Cover image volume 30, Issue 12“Cannabinoids are reported to rescue cocaine-induced seizures (CISs), a severe complication in cocaine users. However, the molecular targets for cannabinoid therapy of CISs remain unclear.

Here, we report that the systemic administration of cannabinoids alleviates CISs in a CB1/CB2-receptor-independent manner.

These findings suggest that using GlyR-hypersensitive cannabinoids may represent a potential therapeutic strategy for treating CISs.”

https://www.ncbi.nlm.nih.gov/pubmed/32209479

“Cannabinoids alleviate cocaine-induced seizures (CISs) by glycine receptors (GlyRs).”

https://www.cell.com/cell-reports/fulltext/S2211-1247(20)30287-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124720302874%3Fshowall%3Dtrue

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