Cannabinoid Signaling in Cancer.

“The family of chemical structures that interact with a cannabinoid receptor are broadly termed cannabinoids. Traditionally known for their psychotropic effects and their use as palliative medicine in cancer, cannabinoids are very versatile and are known to interact with several orphan receptors besides cannabinoid receptors (CBR) in the body. Recent studies have shown that several key pathways involved in cell growth, differentiation and, even metabolism and apoptosis crosstalk with cannabinoid signaling. Several of these pathways including AKT, EGFR, and mTOR are known to contribute to tumor development and metastasis, and cannabinoids may reverse their effects, thereby by inducing apoptosis, autophagy and modulating the immune system. In this book chapter, we explore how cannabinoids regulate diverse signaling mechanisms in cancer and immune cells within the tumor microenvironment and whether they impart a therapeutic effect. We also provide some important insight into the role of cannabinoids in cellular and whole body metabolism in the context of tumor inhibition. Finally, we highlight recent and ongoing clinical trials that include cannabinoids as a therapeutic strategy and several combinational approaches towards novel therapeutic opportunities in several invasive cancer conditions.”

https://www.ncbi.nlm.nih.gov/pubmed/31332734

https://link.springer.com/chapter/10.1007%2F978-3-030-21737-2_4

Endocannabinoids and endocannabinoid-like compounds modulate hypoxia-induced permeability in CaCo-2 cells via CB1, TRPV1, and PPARα.

Biochemical Pharmacology“We have previously reported that endocannabinoids modulate permeability in Caco-2 cells under inflammatory conditions and hypothesised in the present study that endocannabinoids could also modulate permeability in ischemia/reperfusion.

CONCLUSIONS AND IMPLICATIONS:

A variety of endocannabinoids and endocannabinoid-like compounds modulate Caco-2 permeability in hypoxia/reoxygenation, which involves multiple targets, depending on whether the compounds are applied to the basolateral or apical membrane. CB1 antagonism and TRPV1 or PPARα agonism may represent novel therapeutic targets against several intestinal disorders associated with increased permeability.”

https://www.ncbi.nlm.nih.gov/pubmed/31325449

https://www.sciencedirect.com/science/article/abs/pii/S0006295219302722?via%3Dihub

Cannabidiol improves behavioural and neurochemical deficits in adult female offspring of the maternal immune activation (poly I:C) model of neurodevelopmental disorders.

Brain, Behavior, and Immunity“Cognitive impairment is a major source of disability in schizophrenia and current antipsychotic drugs (APDs) have minimal efficacy for this symptom domain.

Cannabidiol (CBD), the major non-intoxicating component of Cannabis sativa L., exhibits antipsychotic and neuroprotective properties.

We recently reported the effects of CBD on cognition in male offspring of a maternal immune activation (polyinosinic-polycytidilic acid (poly I:C)) model relevant to the aetiology of schizophrenia; however, the effects of CBD treatment in females are unknown. Sex differences are observed in the onset of schizophrenia symptoms and response to APD treatment.

Furthermore, the endogenous cannabinoid system, a direct target of CBD, is sexually dimorphic in humans and rodents. Therefore, the present work aimed to assess the therapeutic impact of CBD treatment on behaviour and neurochemical signalling markers in female poly I:C offspring.

Overall, the findings of this study support the therapeutic benefits of CBD on recognition memory and sociability in female poly I:C offspring, and provide insight into the neurochemical changes that may underlie the therapeutic benefits of CBD in the poly I:C model.”

https://www.ncbi.nlm.nih.gov/pubmed/31326506

“These findings suggest that CBD is an efficacious treatment for behavioural and neurochemical changes in a female rodent model relevant to schizophrenia.”

https://www.sciencedirect.com/science/article/pii/S0889159119302806?via%3Dihub

Acute and short-term administrations of delta-9-tetrahydrocannabinol modulate major gut metabolomic regulatory pathways in C57BL/6 mice.

Scientific Reports “Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive compound in Cannabis, which is studied extensively for its medicinal value. A central gap in the science is the underlying mechanisms surrounding THC’s therapeutic effects and the role of gut metabolite profiles. Using a mass-spectrometry based metabolomics, we show here that intraperitoneal injection of THC in C57BL/6 mice modulates metabolic profiles that have previously been identified as integral to health. Specifically, we investigated the effects of acute (single THC injection denoted here as ‘1X’) and short -term (five THC injections on alternate days denoted as ‘5X’) THC administration on fecal and intestinal tissue metabolite profiles. Results are consistent with the hypothesis that THC administration alters host metabolism by targeting two prominent lipid metabolism pathways: glycerophospholipid metabolism and fatty acid biosynthesis.”

https://www.ncbi.nlm.nih.gov/pubmed/31324830

https://www.nature.com/articles/s41598-019-46478-0

Potential Mechanisms Influencing the Inverse Relationship Between Cannabis and Nonalcoholic Fatty Liver Disease: A Commentary.

Image result for Nutrition and Metabolic Insights“Nonalcoholic fatty liver disease (NAFLD) develops when the liver is unable to oxidize or export excess free fatty acids generated by adipose tissue lipolysis, de novo lipogenesis, or dietary intake. Although treatment has generally been centered on reversing metabolic risk factors that increase the likelihood of NAFLD by influencing lifestyle modifications, therapeutic modalities are being studied at the cellular and molecular level.

The endocannabinoid system has been of recent focus. The agonism and antagonism of cannabinoid receptors play roles in biochemical mechanisms involved in the development or regression of NAFLD. Exocannabinoids and endocannabinoids, the ligands which bind cannabinoid receptors, have been studied in this regard.

Exocannabinoids found in cannabis (marijuana) may have a therapeutic benefit. Our recent study demonstrated an inverse association between marijuana use and NAFLD among adults in the United States.

This commentary combines knowledge on the role of the endocannabinoid system in the setting of NAFLD with the findings in our article to hypothesize different potential mechanisms that may influence the inverse relationship between cannabis and NAFLD.” https://www.ncbi.nlm.nih.gov/pubmed/31308686

https://journals.sagepub.com/doi/10.1177/1178638819847480

Biological bases for a possible effect of cannabidiol in Parkinson’s disease.

 SciELO - Scientific Electronic Library Online“Current pharmacotherapy of Parkinson’s disease (PD) is palliative and unable to modify the progression of neurodegeneration. Treatments that can improve patients’ quality of life with fewer side effects are needed, but not yet available.

Cannabidiol (CBD), the major non-psychotomimetic constituent of cannabis, has received considerable research attention in the last decade. In this context, we aimed to critically review the literature on potential therapeutic effects of CBD in PD and discuss clinical and preclinical evidence supporting the putative neuroprotective mechanisms of CBD.

RESULTS:

Few studies addressed the biological bases for the purported effects of CBD on PD. Six preclinical studies showed neuroprotective effects, while three targeted the antidyskinetic effects of CBD. Three human studies have tested CBD in patients with PD: an open-label study, a case series, and a randomized controlled trial. These studies reported therapeutic effects of CBD on non-motor symptoms.

CONCLUSIONS:

Additional research is needed to elucidate the potential effectiveness of CBD in PD and the underlying mechanisms involved.”

https://www.ncbi.nlm.nih.gov/pubmed/31314869

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-44462019005012104&tlng=en

Cannabinoid receptors in osteoporosis and osteoporotic pain: a narrative update of review.

Journal of Pharmacy and Pharmacology banner“Osteoporosis is a skeletal disease with decreased bone mass and alteration in microarchitecture of bone tissue, and these changes put patients in risk of bone fracture. As a common symptom of osteoporosis and complication of osteoporotic fracture, chronic pain is a headache for clinicians. Nonsteroidal anti-inflammatory drugs (NSAIDs), selective COX-2 inhibitors and opioid drugs can temporarily reduce osteoporotic pain but have relevant side effects, such as addiction, tolerability and safety. The review summarized the recent advancements in the study of CB receptors in osteoporosis and osteoporotic pain and related mechanisms.

KEY FINDINGS:

Recent studies indicated the two nociceptive receptors, cannabinoid receptor (CB) and transient receptor potential vanilloid type 1 (TRPV1) channel, are co-expressed in bone cells and play important role in the metabolism of bone cells, suggesting that dualtargeting these 2 receptors/channel may provide a novel approach for osteoporotic pain. In addition, both CB receptor and TRPV1 channel are found to be expressed in the glial cells which play vital role in mediating inflammation, chronic pain and metabolism of bone cells, suggesting a role of glial cells inosteoporotic pain.

SUMMARY:

Multiple-targeting against glial cells, CB receptors and TRPV1 channel may be one effective therapeutic strategy for osteoporotic pain in the future, following the elucidation of the complicated mechanism.”

https://www.ncbi.nlm.nih.gov/pubmed/31294469

https://onlinelibrary.wiley.com/doi/full/10.1111/jphp.13135

Overcoming the psychiatric side effects of the cannabinoid CB1 receptor antagonists: Current approaches for therapeutics development.

“The cannabinoid receptor 1 (CBR1) is involved in a variety of physiological pathways and has long been considered a golden target for therapeutic manipulation. A large body of evidence in both animal and human studies suggests that CB1R antagonism is highly effective for the treatment of obesity, metabolic disorders and drug addiction. However, the first-in-class CB1R antagonist/inverse agonist, rimonabant, though demonstrating effectiveness for obesity treatment and smoking cessation, displays serious psychiatric side effects, including anxiety, depression and even suicidal ideation, resulting in its eventual withdrawal from the European market. Several strategies are currently being pursued to circumvent the mechanisms leading to these side effects by developing neutral antagonists, peripherally restricted ligands, and allosteric modulators. In this review, we describe the progress in the development of therapeutics targeting the cannabinoid receptor 1 in the last two decades.”

https://www.ncbi.nlm.nih.gov/pubmed/31284863

http://www.eurekaselect.com/173316/article

[Topical cannabinoid agonists. An effective new possibility for treating chronic pruritus].

“Chronic, therapy-resistant pruritus often fails to respond to standard measures so new therapeutic approaches are needed.

Recently, the expression of cannabinoid receptors on cutaneous sensory nerve fibers was described, so cannabinoid agonists seem a rational therapeutic option for pruritus.

RESULTS:

In 14/22 patients a good antipruritic effect could be documented. The average reduction in itch was 86.4%. The therapy was well-tolerated by all patients; neither burning burn nor contact dermatitis was observed.

CONCLUSIONS:

Topical cannabinoid agonists represent an new effective and well-tolerated therapy for refractory itching of various origins. Creams with a higher concentration may be even more effective with broader indications.”

https://www.ncbi.nlm.nih.gov/pubmed/16874533

https://link.springer.com/article/10.1007%2Fs00105-006-1180-1

“Cannabinoids for the treatment of chronic refractory pruritus.”  https://www.ncbi.nlm.nih.gov/pubmed/31264498

Cannabis sativa L. extract and cannabidiol inhibit in vitro mediators of skin inflammation and wound injury.

Publication cover image“The present study investigates the potential effect of a Cannabis sativa L. ethanolic extract standardized in cannabidiol as antiinflammatory agent in the skin. The extract inhibited the release of mediators of inflammation involved in wound healing and inflammatory processes occurring in the skin. Cannabis extract and cannabidiol showed different effects on the release of interleukin-8 and vascular endothelial growth factor, which are both mediators whose genes are dependent on NF-κB. Our findings provide new insights into the potential effect of Cannabis extracts against inflammation-based skin diseases.” https://www.ncbi.nlm.nih.gov/pubmed/31250491

https://onlinelibrary.wiley.com/doi/abs/10.1002/ptr.6400

“The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757311/

“The endocannabinoid system of the skin. A potential approach for the treatment of skin disorders” https://www.sciencedirect.com/science/article/abs/pii/S0006295218303484

Cannabinoid system in the skin – a possible target for future therapies in dermatology.”   https://www.ncbi.nlm.nih.gov/pubmed/19664006

“Extracts of the hemp plant cannabis are traditionally used as a popular remedy against inflammation.” https://medicalxpress.com/news/2007-06-cannabinoids-human-body-anti-inflammatory-effect.html