Cannabidiol Increases Proliferation, Migration, Tubulogenesis, and Integrity of Human Brain Endothelial Cells through TRPV2 Activation.

Molecular Pharmaceutics

“The effect of cannabidiol (CBD), a high-affinity agonist of the transient receptor potential vanilloid-2 (TRPV2) channel, has been poorly investigated in human brain microvessel endothelial cells (BMEC) forming the blood-brain barrier (BBB). TRPV2 expression and its role on Ca2+ cellular dynamics, trans-endothelial electrical resistance (TEER), cell viability and growth, migration, and tubulogenesis were evaluated in human primary cultures of BMEC (hPBMEC) or in the human cerebral microvessel endothelial hCMEC/D3 cell line. Abundant TRPV2 expression was measured in hCMEC/D3 and hPBMEC by qRT-PCR, Western blotting, nontargeted proteomics, and cellular immunofluorescence studies. Intracellular Ca2+ levels were increased by heat and CBD and blocked by the nonspecific TRP antagonist ruthenium red (RR) and the selective TRPV2 inhibitor tranilast (TNL) or by silencing cells with TRPV2 siRNA. CBD dose-dependently induced the hCMEC/D3 cell number (EC50 0.3 ± 0.1 μM), and this effect was fully abolished by TNL or TRPV2 siRNA. A wound healing assay showed that CBD induced cell migration, which was also inhibited by TNL or TRPV2 siRNA. Tubulogenesis of hCMEC/D3 cells in 3D matrigel cultures was significantly increased by 41 and 73% after a 7 or 24 h CBD treatment, respectively, and abolished by TNL. CBD also increased the TEER of hPBMEC monolayers cultured in transwell, and this was blocked by TNL. Our results show that CBD, at extracellular concentrations close to those observed in plasma of patients treated by CBD, induces proliferation, migration, tubulogenesis, and TEER increase in human brain endothelial cells, suggesting CBD might be a potent target for modulating the human BBB.”

https://www.ncbi.nlm.nih.gov/pubmed/30721081

https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.8b01252

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Marijuana smoking and markers of testicular function among men from a fertility centre

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“Men who had ever smoked marijuana had significantly higher sperm concentration than men who had never smoked marijuana after adjusting for potential confounders.

These findings are not consistent with a deleterious effect of marijuana on testicular function.”

https://www.ncbi.nlm.nih.gov/pubmed/30726923

https://academic.oup.com/humrep/advance-article-abstract/doi/10.1093/humrep/dez002/5307080?redirectedFrom=fulltext

“SMOKING MARIJUANA APPEARS TO UP MEN’S SPERM COUNT—TO THE SURPRISE OF SCIENTISTS” https://www.newsweek.com/smoking-marijuana-appears-men-sperm-count-surprise-scientists-1318138

“Cannabis Smoking Associated With Higher Sperm Count, Study Finds”  https://www.bloomberg.com/news/articles/2019-02-06/cannabis-smoking-associated-with-higher-sperm-count-study-finds

“Smoking cannabis has unexpectedly been linked to greater fertility in men.” https://www.independent.ie/world-news/north-america/smoking-cannabis-can-make-men-more-fertile-say-scientists-37787137.html

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Role of miRNA in the regulation of cannabidiol-mediated apoptosis in neuroblastoma cells.

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“Neuroblastoma (NBL) is one of the most common childhood cancers that originate from the immature nerve cells of the sympathetic system. Studies with NBL cancers have also shown that miRNAs are dysregulated and may play a critical role in pathogenesis.

Cannabidiol (CBD) is a non-psychoactive compound found in marijuana which has been previously shown by our laboratory and others to induce apoptosis in cancer cells. However, there are no studies reported to test if CBD mediates these effects through regulation of miRNA.

In the current study, therefore, we investigated if CBD induces apoptosis in human NBL cell lines, SH SY5Y and IMR-32, and if it is regulated by miRNA.

Our data demonstrated that CBD induces apoptosis in NBL cells through activation of serotonin and vanilloid receptors. We also found that caspase-2 and -3 played an important role in the induction of apoptosis. CBD also significantly reduced NBL cell migration and invasion in vitro.

Furthermore, CBD blocked mitochondrial respiration and caused a shift in metabolism towards glycolysis. CBD altered the expression of miRNA specifically, down-regulating hsa-let-7a and upregulating hsa-mir-1972. Downregulation of let-7a increased expression of target caspase-3, and growth arrest specific-7 (GAS-7) genes. Upregulation of hsa-mir-1972 caused decreased expression of BCL2L1 and SIRT2 genes.

Together, our studies suggest that CBD-mediated apoptosis in NBL cells is regulated by miRNA.”

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Recreational marijuana legalization and prescription opioids received by Medicaid enrollees.

Drug and Alcohol Dependence

“Medical marijuana use may substitute prescription opioid use, whereas nonmedical marijuana use may be a risk factor of prescription opioid misuse. This study examined the associations between recreational marijuana legalization and prescription opioids received by Medicaid enrollees. In models comparing eight states and DC, legalization was not associated with Schedule II opioid outcomes; having recreational marijuana legalization effective in 2015 was associated with reductions in number of prescriptions, total doses, and spending of Schedule III opioids by 32%, and 31%, respectively. In models comparing eight states and DC to six states with medical marijuana legalization, recreational marijuana legalization was not associated with any opioid outcome. No evidence suggested that recreational marijuana legalization increased prescription opioids received by Medicaid enrollees. There was some evidence in some states for reduced Schedule III opioids following the legalization.” https://www.ncbi.nlm.nih.gov/pubmed/30390550

https://www.sciencedirect.com/science/article/pii/S0376871618307567?via%3Dihub

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Marijuana Consumption in Liver Transplant Recipients.

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“Marijuana is legalized for either medical or recreational use in over half of the United States and in Canada, but many transplant centers will not list patients who are using marijuana. However, the effect of marijuana on transplant outcomes remains unclear. Thus, we performed a retrospective analysis of all adult (≥18 years old) liver transplant patients treated at our center between 2007 and 2017. After adjustment, current tobacco users were over three times as likely to die within 5 years, compared to never users, but no difference was seen between current/former and never marijuana users. No significant differences in inpatient respiratory complications, reintubation, or >24 hours intubation was seen. Overall, pre-transplant marijuana use, past or current, does not appear to impact liver transplant outcomes; however, tobacco smoking remains detrimental.”

https://www.ncbi.nlm.nih.gov/pubmed/30693668

https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/lt.25417

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Cannabisin F from Hemp (Cannabis sativa) Seed Suppresses Lipopolysaccharide-Induced Inflammatory Responses in BV2 Microglia as SIRT1 Modulator.

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“Hemp seed (Fructus cannabis) is rich in lignanamides, and initial biological screening tests showed their potential anti-inflammatory and anti-oxidative capacity.

This study investigated the possible effects and underlying mechanism of cannabisin F, a hempseed lignanamide, against inflammatory response and oxidative stress in lipopolysaccharide (LPS)-stimulated BV2 microglia cells.

Cannabisin F suppressed the production and the mRNA levels of pro-inflammatory mediators such as interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) in a concentration-dependent manner in LPS-stimulated BV2 microglia cell. Furthermore, cannabisin F enhanced SIRT1 expression and blocked LPS-induced NF-κB (Nuclear factor kappa B) signaling pathway activation by inhibiting phosphorylation of IκBα (Inhibit proteins of nuclear factor kappaB) and NF-κB p65. And the SIRT1 inhibitor EX527 significantly inhibited the effect of cannabisin F on pro-inflammatory cytokines production, suggesting that the anti-inflammatory effects of cannabisin F are SIRT1-dependent. In addition, cannabisin F reduced the production of cellular reactive oxygen species (ROS) and promoted the expression of Nrf2 (Nuclear factor erythroid-2 related factor 2) and HO-1 (Heme Oxygenase-1), suggesting that the anti-oxidative effects of cannabisin F are related to Nrf2 signaling pathway.

Collectively, these results suggest that the neuro-protection effect of cannabisin F against LPS-induced inflammatory response and oxidative stress in BV2 microglia cells involves the SIRT1/NF-κB and Nrf2 pathway.”

https://www.ncbi.nlm.nih.gov/pubmed/30691004

https://www.mdpi.com/1422-0067/20/3/507

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Dark Classics in Chemical Neuroscience: Δ9-Tetrahydrocannabinol.

 ACS Chemical Neuroscience

“Cannabis (Cannabis sativa) is the most widely used illicit drug in the world, with an estimated 192 million users globally.

The main psychoactive component of cannabis is (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), a molecule with a diverse range of pharmacological actions. The unique and distinctive intoxication caused by Δ9-THC primarily reflects partial agonist action at central cannabinoid type 1 (CB1) receptors.

Δ9-THC is an approved therapeutic treatment for a range of conditions, including chronic pain, chemotherapy-induced nausea and vomiting, and is being investigated in indications such as anorexia nervosa, agitation in dementia, and Tourette’s syndrome.

It is available as a regulated pharmaceutical in products such as Marinol®, Sativex®, and Namisol®, as well as in an ever-increasing range of unregistered medicinal and recreational cannabis products.

While cannabis is an ancient medicament, contemporary use is embroiled in legal, scientific, and social controversy, much of which relates to the potential hazards and benefits of Δ9-THC itself.

Robust contemporary debate surrounds the therapeutic value of Δ9-THC in different diseases, its capacity to produce psychosis and cognitive impairment, and the addictive and “gateway” potential of the drug.

This review will provide a profile of the chemistry, pharmacology, toxicology, and recreational and therapeutic uses of Δ9-THC, as well as the historical and societal importance of this unique, distinctive, and ubiquitous psychoactive substance.”

https://www.ncbi.nlm.nih.gov/pubmed/30689342

https://pubs.acs.org/doi/10.1021/acschemneuro.8b00651

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US Veterinarians’ Knowledge, Experience, and Perception Regarding the Use of Cannabidiol for Canine Medical Conditions.

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“Due to the myriad of laws concerning cannabis, there is little empirical research regarding the veterinary use of cannabidiol (CBD).

This study used the Veterinary Information Network (VIN) to gauge US veterinarians’ knowledge level, views and experiences related to the use of cannabinoids in the medical treatment of dogs.

 

Most participants agreed that both marijuana and CBD products offer benefits for humans and expressed support for use of CBD products for animals.”

https://www.ncbi.nlm.nih.gov/pubmed/30687726

https://www.frontiersin.org/articles/10.3389/fvets.2018.00338/full

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Cannabidiol modulates phosphorylated rpS6 signalling in a zebrafish model of Tuberous Sclerosis Complex.

Behavioural Brain Research

“Tuberous sclerosis complex (TSC) is a rare disease caused by mutations in the TSC1 or TSC2 genes and is characterized by widespread tumour growth, intractable epilepsy, cognitive deficits and autistic behaviour.

CBD has been reported to decrease seizures and inhibit tumour cell progression, therefore we sought to determine the influence of CBD on TSC pathology in zebrafish carrying a nonsense mutation in the tsc2 gene.

CBD treatment from 6 to 7 days post-fertilization (dpf) induced significant anxiolytic actions without causing sedation. Furthermore, CBD treatment from 3 dpf had no impact on tsc2-/- larvae motility nor their survival. CBD treatment did, however, reduce the number of phosphorylated rpS6 positive cells, and their cross-sectional cell size. This suggests a CBD mediated suppression of mechanistic target of rapamycin (mTOR) activity in the tsc2-/- larval brain.

Taken together, these data suggest that CBD selectively modulates levels of phosphorylated rpS6 in the brain and additionally provides an anxiolytic effect. This is pertinent given the alterations in mTOR signalling in experimental models of TSC. Additional work is necessary to identify upstream signal modulation and to further justify the use of CBD as a possible therapeutic strategy to manage TSC.”

https://www.ncbi.nlm.nih.gov/pubmed/30684511

https://www.sciencedirect.com/science/article/pii/S0166432818311215?via%3Dihub

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Cannabinoids (Marijuana) A Stem Cell Stimulator!!

Institute of Regenerative Medicine®“Some time ago a wrote a blog about the use of certain components of the marijuana plant. It was a fairly short blog which I will include here. More and more states are proposing the legalization of marijuana. There are numerous health claims about hemp oil which is a derivative of Cannabis. There may be merit to these claims possibly by the action of the Cannabis on stem cells. Below is the blog and I will expand more on it:

“We use to think that marijuana was bad for one’s health. Now we are not so sure about it. We need to clarify things a bit.
Cannabinoids, the active components of cannabis (Cannabis sativa) extracts, have attracted the attention of human civilizations for centuries for a variety of uses. The use of Cannabis or Marijuana (scientific name is Cannabis sativa) came before we were able to discover the active portion or substrate. This substrate is called endocannabinoid system. The endocannabbinoid system has a number of components. The system consists of lipids, the receptors for the lipids and certain metabolic enzymes. The Cannabinoid signaling regulates cell proliferation, differentiation and it reduces cell aptosis or death. These receptors are found in the very early stages of life. The results of the Cannabinoid receptors depend upon molecular targets and cellular context involved. There are two main receptors which are called CB1 and CB2 receptors. These receptors seem to be involved in neural degeneration. They seem to be involved in all three germ layer formations. . CB1 and CB2 show opposite patterns of expression, the former increasing and the latter decreasing along neuronal differentiation. It is thought that the CB2 receptors may be most important. Recently, endocannabinoid (eCB) signaling has also been shown to regulate proliferation and differentiation of hematopoietic and mesenchymal stem cells, with a key role in determining the formation of several cell types in peripheral tissues, including blood cells, adipocytes, osteoblasts/osteoclasts and epithelial cells. The developmental regulation of cannabinoid receptor expression and cellular/sub-cellular localization, together with their role in progenitor/stem cell biology, may have important implications in human health and disease. Bone marrow and stem cells make endocannabinoids, these endocannabinoids interact with the cannabinoid receptors (Cannabinoid receptors have been found in nearly every cell in the human body). If cannabinoids can enhance stem cell migration and proliferation, this could be a powerful therapy. For instance, if you can increase the numbers and movement of stem cells to an injured tissue, you could vastly enhance the healing process. Lastly, the synthetic cannabinoid HU-210 is about 100-1000x times more potent than THC from Cannabis and this synthetic agent has been found to be neurogenic. Meaning that HU-210 can cause new neurons (brain cells) in the brain to form. However this study was done in rats…and humans are different from rats. Will I prescribe medical marijuana for my stem cell patients? At present I do not think I have enough information to make an intelligent decision about this. I suspect if some day I do prescribe this it will be some derivative of Cannabis. There are certainly some intriguing aspects of Cannabis but I feel the jury is still out. I suspect we will certainly hear more about this. Thanks Dr. P”

That was the blog I wrote some time ago. At this juncture I am getting closer to utilizing some component of Cannabis. I have further looked at the literature and there seems to be some very good science on the effect of Cannabis on stem cell workings. One of the intriguing aspects of the CB2 receptor is that it is found mostly in the immune system. At the University of South Carolina, a team discovered that THC could reduce the inflammation associated with autoimmune diseases by suppressing the activity of certain genes involved in the immune response. Its presence there interests scientists because the immune system triggers inflammation, and studies show marijuana can have an anti-inflammatory effect. When we start talking about the immune system we have a host of implications. We are aware that many diseases of aging may have some basis as an auto-immune disease. One of these that interests me is Osteoporosis. There may be both receptors at work. CB-2 works on the immune system while CB-1 is induced during osteogenic differentiation. As I have written in another blog, Very Small Embryonic Like Stem Cells may have a profound effect on the course of Osteoporosis. The next question is can we prime these cells additionally with Cannabis and take things to the next level. More to come I am sure. Dr. P.”

https://stemcellorthopedic.com/cannabinoids-marijuana-stem-cell-stimulator/?fbclid=IwAR1DDMIk0X8rJiWFPkNXWouQfdPNfG5iHEklW6oSxFqP5ELLt4lz3IM_O-k

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