Cannabinoid Combination Induces Cytoplasmic Vacuolation in MCF-7 Breast Cancer Cells

molecules-logo“This study evaluated the synergistic anti-cancer potential of cannabinoid combinations across the MDA-MB-231 and MCF-7 human breast cancer cell lines. Cannabinoids were combined and their synergistic interactions were evaluated using median effect analysis.

The most promising cannabinoid combination (C6) consisted of tetrahydrocannabinol, cannabigerol (CBG), cannabinol (CBN), and cannabidiol (CBD), and displayed favorable dose reduction indices and limited cytotoxicity against the non-cancerous breast cell line, MCF-10A. C6 exerted its effects in the MCF-7 cell line by inducing cell cycle arrest in the G2 phase, followed by the induction of apoptosis.

Morphological observations indicated the induction of cytoplasmic vacuolation, with further investigation suggesting that the vacuole membrane was derived from the endoplasmic reticulum. In addition, lipid accumulation, increased lysosome size, and significant increases in the endoplasmic reticulum chaperone protein glucose-regulated protein 78 (GRP78) expression were also observed.

The selectivity and ability of cannabinoids to halt cancer cell proliferation via pathways resembling apoptosis, autophagy, and paraptosis shows promise for cannabinoid use in standardized breast cancer treatment.”

https://pubmed.ncbi.nlm.nih.gov/33066359/

https://www.mdpi.com/1420-3049/25/20/4682

Antioxidant and antimicrobial activity of two standardized extracts from a new Chinese accession of non-psychotropic Cannabis sativa L

Phytotherapy Research “The purpose of this study was to evaluate the antioxidant and antimicrobial properties of two extracts from a new Chinese accession (G-309) of Cannabis sativa L. (Δ9 -tetrahydrocannabinol <0.2%) with high content of propyl side chain phytocannabinoids.

Dried flowering tops, as such and after hydrodistillation of the essential oil, were extracted with acidic hexane to produce the Cannabis Chinese hexane extract 1 (CChHE1) and 2 (CChHE2), respectively. The phytochemical profile of CChHE1 and CChHE2 was investigated by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-diode array detector-electrospray ionization-tandem mass spectrometry (LC-DAD-ESI-MS/MS) analyses. The antioxidant properties were assessed by several in vitro cell-free assays. The antimicrobial activity was evaluated against Gram-positive and Gram-negative bacteria and the yeast Candida albicans.

Phytochemical analyses highlighted a high content of cannabidivarinic acid (CBDVA) and tetraydrocannabivarinic acid (THCVA) in CChHE1, and cannabidivarin (CBDV) and tetraydrocannabivarin (THCV) in CChHE2. Both extracts showed remarkable antioxidant activity and strong antimicrobial properties (MIC 39.06 and MBC 39.06-78.13 μg/ml) against both ATCC and methicillin-resistant clinical strains of Staphylococcus aureus.

In conclusion, standardized extracts of C. sativa Chinese accession could be promising for their possible use as novel antibacterial agents for the treatment of widespread S. aureus infections.”

https://pubmed.ncbi.nlm.nih.gov/33034400/

https://onlinelibrary.wiley.com/doi/10.1002/ptr.6891

Signaling Through the Type 2 Cannabinoid Receptor Regulates the Severity of Acute and Chronic Graft versus Host Disease

Blood“Graft versus host disease (GVHD) pathophysiology is a complex interplay between cells that comprise the adaptive and innate arms of the immune system. Effective prophylactic strategies are therefore contingent upon approaches that address contributions from both immune cell compartments.

In the current study, we examined the role of the type 2 cannabinoid receptor (CB2R) which is expressed on nearly all immune cells and demonstrated that absence of the CB2R on donor CD4+ or CD8+ T cells, or administration of a selective CB2R pharmacological antagonist, exacerbated acute GVHD lethality. This was accompanied primarily by the expansion of proinflammatory CD8+ T cells indicating that constitutive CB2R expression on T cells preferentially regulated CD8+ T cell alloreactivity. Using a novel CB2R-EGFP reporter mouse, we observed significant loss of CB2R expression on T cells, but not macrophages, during acute GVHD, indicative of differential alterations in receptor expression under inflammatory conditions.

Therapeutic targeting of the CB2R with the agonists, tetrahydrocannabinol (THC) and JWH-133, revealed that only THC mitigated lethal T cell-mediated acute GVHD. Conversely, only JWH-133 was effective in a sclerodermatous chronic GVHD model where macrophages contribute to disease biology. In vitro, both THC and JWH-133 induced arrestin recruitment and ERK phosphorylation via CB2R, but THC had no effect on CB2R-mediated inhibition of adenylyl cyclase.

These studies demonstrate that the CB2R plays a critical role in the regulation of GVHD and suggest that effective therapeutic targeting is dependent upon agonist signaling characteristics and receptor selectivity in conjunction with the composition of pathogenic immune effector cells.”

https://pubmed.ncbi.nlm.nih.gov/33027805/

https://ashpublications.org/blood/article-abstract/doi/10.1182/blood.2020004871/464166/Signaling-Through-the-Type-2-Cannabinoid-Receptor?redirectedFrom=fulltext

An Agathokakological tale of ∆9 -THC: Exploration of Possible Biological Targets

“∆ 9 -Tetrahydrocannabinol (∆9 -THC), the active phytocannabinoid in cannabis, is virtually an adjunct to the endogenous endocannabinoid signaling system.

By interacting with G-protein-coupled receptors CB1 and CB2, ∆9 -THC affects peripheral and central circulation by lowering sympathetic activity, altering gene expression, cell proliferation, and differentiation, decreasing leukocyte migration, modulating neurotransmitter release thereby modulating cardiovascular functioning, tumorigenesis, immune responses, behavioral and locomotory activities respectively.

∆ 9 -THC is effective in suppressing chemotherapy-induced vomiting, retards malignant tumor growth, inhibits metastasis, and promotes apoptosis. Other mechanisms involved are targeting cell cycle at the G2-M phase in human breast cancer, downregulation of E2F transcription factor 1 (E2F1) in human glioblastoma multiforme, and stimulation of ER stress-induced autophagy.

∆ 9 -THC also plays a role in ameliorating neuroinflammation, excitotoxicity, neuroplasticity, trauma, and stroke and is associated with reliving childhood epilepsy, brain trauma, and neurodegenerative diseases.

∆9 -THC via CB1 receptors affects nociception, emotion, memory, and reduces neuronal excitability and excitotoxicity in epilepsy. It also increases renal blood flow, reduces intraocular pressure via a sympathetic pathway, and modulates hormonal release, thereby decreasing the reproductive function and increasing glucose metabolism.

Versatile medical marijuana has stimulated abundant research demonstrating substantial therapeutic promise, suggesting the possibilities of first-in-class drugs in diverse therapeutic segments. In this review, we represent the current pharmacological status of the phytocannabinoid, ∆ 9 -THC, and synthetic analogs in cancer, cardiovascular, and neurodegenerative disorders.”

https://pubmed.ncbi.nlm.nih.gov/33001012/

https://www.eurekaselect.com/186455/article

Investigating the cumulative effects of Δ9-tetrahydrocannabinol and repetitive mild traumatic brain injury on adolescent rats

 Issue Cover“The prevalence of mild traumatic brain injury is highest amongst the adolescent population and can lead to complications including neuroinflammation and excitotoxicity.

Δ9-Tetrahydrocannabinol, the main psychoactive component of cannabis, is known to have anti-inflammatory properties and serves as a neuroprotective agent against excitotoxicity.

Thus, we investigated the effects of Δ9-tetrahydrocannabinol on recovery when administered either prior to or following repeated mild brain injuries.

We hypothesized that, in both experiments, Δ9-tetrahydrocannabinol administration would provide neuroprotection against mild injury outcomes and confer therapeutic benefit.

Δ9-Tetrahydrocannabinol administration following repeated mild traumatic brain injury was beneficial to three of the six behavioural outcomes affected by injury (reducing anxiety and depressive-like behaviours while also mitigating injury-induced deficits in short-term working memory). Δ9-Tetrahydrocannabinol administration following injury also showed beneficial effects on the expression of Cnr1Comt and Vegf-2R in the hippocampus, nucleus accumbens and prefrontal cortex.

There were no notable benefits of Δ9-tetrahydrocannabinol when administered prior to injury, suggesting that Δ9-tetrahydrocannabinol may have potential therapeutic benefit on post-concussive symptomology when administered post-injury, but not pre-injury.”

https://pubmed.ncbi.nlm.nih.gov/32954298/

 “Overall, this study suggests that THC has potential therapeutic efficacy for the treatment of RmTBI-induced symptomology but requires additional examination.”

https://academic.oup.com/braincomms/article/2/1/fcaa042/5819138

Cannabis Extracts Affected Metabolic Syndrome Parameters in Mice Fed High-Fat/Cholesterol Diet

View details for Cannabis and Cannabinoid Research cover image“Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic syndrome, which often includes obesity, diabetes, and dyslipidemia. Several studies in mice and humans have implicated the involvement of the gut microbiome in NAFLD.

While cannabis may potentially be beneficial for treating metabolic disorders such as NAFLD, the effects of cannabis on liver diseases and gut microbiota profile are yet to be addressed. In this study, we evaluated the therapeutic effects of cannabis strains with different cannabinoid profiles on NAFLD progression.

Conclusions: The results of this study indicate that the administration of cannabis containing elevated levels of THC may help ameliorate symptoms of NAFLD, whereas administration of CBD-rich cannabis extracts may cause a proinflammatory effect in the liver, linked with an unfavorable change in the microbiota profile. Our preliminary data suggest that these effects are mediated by mechanisms other than increased expression of the endocannabinoid receptors cannabinoid receptor 1 (CB1) and CB2.”

https://pubmed.ncbi.nlm.nih.gov/32923658/

“The results of this study provide an indication that administration of certain strains of cannabis, preferably with a higher THC level, may be helpful in treating certain symptoms of metabolic syndrome, which include preventing the development and/or ameliorating the symptoms of NAFLD.”

https://www.liebertpub.com/doi/10.1089/can.2020.0013

Δ 9 -Tetrahydrocannabinol promotes oligodendrocyte development and CNS myelination in vivo

“Δ9 -Tetrahydrocannabinol (THC), the main bioactive compound found in the plant Cannabis sativa, exerts its effects by activating cannabinoid receptors present in many neural cells.

Cannabinoid receptors are also physiologically engaged by endogenous cannabinoid compounds, the so-called endocannabinoids. Specifically, the endocannabinoid 2-arachidonoylglycerol has been highlighted as an important modulator of oligodendrocyte (OL) development at embryonic stages and in animal models of demyelination. However, the potential impact of THC exposure on OL lineage progression during the critical periods of postnatal myelination has never been explored.

Here, we show that acute THC administration at early postnatal ages in mice enhanced OL development and CNS myelination in the subcortical white matter by promoting oligodendrocyte precursor cell cycle exit and differentiation. Mechanistically, THC-induced-myelination was mediated by CB1 and CB2 cannabinoid receptors, as demonstrated by the blockade of THC actions by selective receptor antagonists. Moreover, the THC-mediated modulation of oligodendroglial differentiation relied on the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, as mTORC1 pharmacological inhibition prevented the THC effects.

Our study identifies THC as an effective pharmacological strategy to enhance oligodendrogenesis and CNS myelination in vivo.”

https://pubmed.ncbi.nlm.nih.gov/32956517/

“In summary, our findings identify THC as a novel pharmacological candidate to enhance OL development and CNS myelination in vivo.”

https://onlinelibrary.wiley.com/doi/10.1002/glia.23911

Activation of Cannabinoid Receptor 2 Prevents Colitis-Associated Colon Cancer through Myeloid Cell De-activation Upstream of IL-22 Production

iScience journal (@iScience_CP) | Twitter
” Here we show that delta-9-tetrahydrocannabinol (THC) attenuates colitis-associated colon cancer and colitis induced by anti-CD40.
 THC can prevent the development of colitis-associated colon cancer in mice.”

“Study reveals how cannabinoids may be useful to prevent colon cancer”   https://medicalxpress.com/news/2020-09-reveals-cannabinoids-colon-cancer.html

“Key cannabis chemical may help prevent colon cancer, researchers say”   https://www.heraldmailmedia.com/news/nation/key-cannabis-chemical-may-help-prevent-colon-cancer-researchers-say/article_7afd0a72-eead-57f0-a1d3-006be62b7469.html

“Treatment with a cannabinoid prevented the development of colon cancers in mice” https://www.news-medical.net/news/20200915/Treatment-with-a-cannabinoid-prevented-the-development-of-colon-cancers-in-mice.aspx

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Druggable Targets in Endocannabinoid Signaling

 “Cannabis and cannabinoid-based extracts have long been utilized for their perceived therapeutic value, and support for the legalization of cannabis for medicinal purposes continues to increase worldwide.

Since the discovery of Δ9-tetrahydrocannabinol (THC) as the primary psychoactive component of cannabis over 50 years ago, substantial effort has been directed toward detection of endogenous mediators of cannabinoid activity. The discovery of anandamide and 2-arachidonoylglycerol as two endogenous lipid mediators of cannabinoid-like effects (endocannabinoids) has inspired exponential growth in our understanding of this essential pathway, as well as the pathological conditions that result from dysregulated endocannabinoid signaling.

This review examines current knowledge of the endocannabinoid system including metabolic enzymes involved in biosynthesis and degradation and their receptors, and evaluates potential druggable targets for therapeutic intervention.”

https://pubmed.ncbi.nlm.nih.gov/32894511/

https://link.springer.com/chapter/10.1007%2F978-3-030-50621-6_8

Δ9 Tetrahydrocannabinol attenuates Staphylococcal enterotoxin B-induced inflammatory lung injury and prevents mortality in mice by modulation of miR-17-92 cluster and induction of T-regulatory cells

Logo of brjpharm“Staphylococcal enterotoxin B (SEB) is a potent activator of Vβ8+T-cells resulting in the clonal expansion of ∼30% of the T-cell pool. Consequently, this leads to the release of inflammatory cytokines, toxic shock, and eventually death.

In the current study, we investigated if Δ9tetrahydrocannabinol (THC), a cannabinoid known for its anti-inflammatory properties, could prevent SEB-induced mortality and alleviate symptoms of toxic shock.

Key Results

Exposure to SEB resulted in acute mortality, while THC treatment led to 100% survival of mice. SEB induced the miRNA-17-92 cluster, specifically miRNA-18a, which targeted Pten (phosphatase and tensin homologue), an inhibitor of the PI3K/Akt signalling pathway, thereby suppressing T-regulatory cells. In contrast, THC treatment inhibited the individual miRNAs in the cluster, reversing the effects of SEB.

Conclusions and Implications

We report, for the first time a role for the miRNA 17–92 cluster in SEB-mediated inflammation. Furthermore, our results suggest that THC is a potent anti-inflammatory compound that may serve as a novel therapeutic to suppress SEB-induced pulmonary inflammation by modulating critical miRNA involved in SEB-induced toxicity and death.

Δ9-Tetrahydrocannabinol (THC) is a marijuana plant-derived cannabinoid known for its robust anti-inflammatory and immunosuppressive properties. The anti-inflammatory and immunosuppressive effects of THC are diverse and function effectively to abrogate a number of inflammatory processes.

Taken together, our data demonstrate that THC is a strong anti-inflammatory agent capable of rescuing mice from SEB-mediated toxicity and death.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376457/