Biosynthesis of cannflavins A and B from Cannabis sativa L.

Phytochemistry

“In addition to the psychoactive constituents that are typically associated with Cannabis sativa L., there exist numerous other specialized metabolites in this plant that are believed to contribute to its medicinal versatility. This study focused on two such compounds, known as cannflavin A and cannflavin B. These prenylated flavonoids specifically accumulate in C. sativa and are known to exhibit potent anti-inflammatory activity in various animal cell models. However, almost nothing is known about their biosynthesis. Using a combination of phylogenomic and biochemical approaches, an aromatic prenyltransferase from C. sativa (CsPT3) was identified that catalyzes the regiospecific addition of either geranyl diphosphate (GPP) or dimethylallyl diphosphate (DMAPP) to the methylated flavone, chrysoeriol, to produce cannflavins A and B, respectively. Further evidence is presented for an O-methyltransferase (CsOMT21) encoded within the C. sativa genome that specifically converts the widespread plant flavone known as luteolin to chrysoeriol, both of which accumulate in C. sativa. These results therefore imply the following reaction sequence for cannflavins A and B biosynthesis: luteolin ► chrysoeriol ► cannflavin A and cannflavin B. Taken together, the identification of these two unique enzymes represent a branch point from the general flavonoid pathway in C. sativa and offer a tractable route towards metabolic engineering strategies that are designed to produce these two medicinally relevant Cannabis compounds.”

https://www.ncbi.nlm.nih.gov/pubmed/31151063

https://www.sciencedirect.com/science/article/pii/S0031942218303819?via%3Dihub

“U of G Researchers First to Unlock Access to Pain Relief Potential of Cannabis”  https://news.uoguelph.ca/2019/07/u-of-g%E2%80%AFresearchers-first-to-unlock-access-to-pain%E2%80%AFrelief%E2%80%AFpotential-of-cannabis%E2%80%AF/

“Scientists unlock the secrets of marijuana’s pain-relief potential, study says” HTTPS://WWW.NEWSOBSERVER.COM/NEWS/NATION-WORLD/NATIONAL/ARTICLE233045517.HTML

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[Medicinal cannabis].

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“The use of cannabis products for medical purposes is rapidly increasing in the Netherlands. Studies suggest that these products have positive effects in the treatment of chronic neuropathic pain, multiple-sclerosis-related spasticity, certain epilepsy syndromes and chemotherapy-related nausea and vomiting.”

https://www.ncbi.nlm.nih.gov/pubmed/31120212

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The use of cannabinoids for sleep: A critical review on clinical trials.

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“Cannabis and its pharmacologically active constituents, phytocannabinoids, have long been reported to have multiple medicinal benefits.

One association often reported by users is sedation and subjective improvements in sleep.

Many of the reviewed studies suggested that cannabinoids could improve sleep quality, decrease sleep disturbances, and decrease sleep onset latency.”

https://www.ncbi.nlm.nih.gov/pubmed/31120284

https://psycnet.apa.org/doiLanding?doi=10.1037/pha0000285

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Diverse TRPV1 responses to cannabinoids.

 Publication Cover“Cannabinoid compounds are potential analgesics. Users of medicinal Cannabis report efficacy for pain control, clinical studies show that cannabis can be effective and opioid sparing in chronic pain, and some constituent cannabinoids have been shown to target nociceptive ion channels. Here, we explore and compare a suite of cannabinoids for their impact upon the physiology of TRPV1. The cannabinoids tested evoke differential responses in terms of kinetics of activation and inactivation. Cannabinoid activation of TRPV1 displays significant dependence on internal and external calcium levels. Cannabinoid activation of TRPV1 does not appear to induce the highly permeant, pore-dilated channel state seen with Capsaicin, even at high current amplitudes. Finally, we analyzed cannabinoid responses at nocioceptive channels other than TRPV1 (TRPV2, TRPM8 and TRPA1), and report that cannabinoids differentially activate these channels. On the basis of response activation and kinetics, state-selectivity and receptor selectivity, it may be possible to rationally design approaches to pain using single or multiple cannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/31096838

https://www.tandfonline.com/doi/full/10.1080/19336950.2019.1619436

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Terpenes in Cannabis sativa – From plant genome to humans.

Plant Science“Cannabis sativa (cannabis) produces a resin that is valued for its psychoactive and medicinal properties. Despite being the foundation of a multi-billion dollar global industry, scientific knowledge and research on cannabis is lagging behind compared to other high-value crops. This is largely due to legal restrictions that have prevented many researchers from studying cannabis, its products, and their effects in humans. Cannabis resin contains hundreds of different terpene and cannabinoid metabolites. Our understanding of the genomic and biosynthetic systems of these metabolites in cannabis, and the factors that affect their variability, is rudimentary. As a consequence, there is concern about lack of consistency with regard to the terpene and cannabinoid composition of different cannabis ‘strains’. Likewise, claims of some of the medicinal properties attributed to cannabis metabolites would benefit from thorough scientific validation.”
https://www.ncbi.nlm.nih.gov/pubmed/31084880 

https://www.sciencedirect.com/science/article/pii/S0168945219301190?via%3Dihub

“Medicinal properties of terpenes found in Cannabis sativa”   https://www.ncbi.nlm.nih.gov/pubmed/30096653

“Terpene synthases from Cannabis sativa”   https://www.ncbi.nlm.nih.gov/pubmed/28355238

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Marijuana for Parkinson’s Disease?

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“Marijuana is popular in the United States and is being widely legalized for recreational and medicinal purposes. It remains a Schedule 1 substance without fully proven risks and benefits; yet, it is increasingly available in many US states and territories.

Cannabis might have medicinal efficacy in Parkinson’s disease as a form of medical marijuana. Endocannabinoid receptors exist throughout the nervous system and are documented to influence receptors affecting a wide variety of areas. Neuroprotective aspects might be induced by cannabis exposure that might yield benefit against the nigrostriatal degeneration of patients with Parkinson’s disease.

Animal investigations support suggestions of improvement in bradykinesia and/or tremors, but this is unsubstantiated in human studies. However, some patient surveys and anecdotal or case reports indicate that marijuana attenuates some motor manifestations of parkinsonism and also of non-motor, mood and/or cognitive symptoms. Medical marijuana might benefit motor and nonmotor aspects of Parkinson’s disease patients. Currently, these assertions are not substantiated in human investigations and cannabis can also induce side effects. Until studies clarify the safety and efficacy of pharmacotherapy with cannabis products, medical marijuana remains largely without scientific endorsement. Research has yet to document the full benefits, risks, and clinical applications of marijuana as a treatment for patients with Parkinson’s disease.”

https://www.ncbi.nlm.nih.gov/pubmed/31037227

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The onus of cannabinoids in interrupting the molecular odyssey of breast cancer: A critical perspective on UPRER and beyond.

Saudi Pharmaceutical Journal

“Cannabinoids, commonly used for medicinal and recreational purposes, consist of various complex hydrophobic molecules obtained from Cannabis sativa L. Acting as an inhibitory molecule; they have been investigated for their antineoplastic effect in various breast tumor models. Lately, it was found that cannabinoid treatment not only stimulates autophagy-mediated apoptotic death of tumor cells through unfolded protein response (UPRER) activated downstream effectors, but also imposes cell cycle arrest. The exploitation of UPRER tumors as such is believed to be a major molecular event and is therefore employed in understanding the development and progression of breast tumor. Simultaneously, the data on clinical trials following administration of cannabinoid is currently being explored to find its role not only in palliation but also in the treatment of breast cancer. The present study summarizes new achievements in understanding the extent of therapeutic progress and highlights recent developments in cannabinoid biology towards achieving a better cure of breast cancer through the exploitation of different cannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/30976189

https://www.sciencedirect.com/science/article/pii/S1319016419300064?via%3Dihub

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Cannabimimetic plants: are they new cannabinoidergic modulators?

“Phytochemicals and secondary metabolites able to interact with the endocannabinoid system (Cannabimimetics) have been recently described in a broad range of plants and fruits. These findings can open new alternative avenues to explore for the development of novel therapeutic compounds. The cannabinoids regulate many physiological and pathological functions in both animals and plants. Cannabis sativa is the main plant that produces phytocannabinoids inside resins capable to defend the plant from the aggression of parasites and herbivores. Animals produce anandamide and 2-arachidonoyl glycerol, which thanks to binding with main receptors such as type-1 cannabinoid receptor (CB1R) and the type-2 cannabinoid receptor (CB2R) are involved in inflammation processes and several brain functions. Endogenous cannabinoids, enzymes for synthesis and degradation of cannabinoids, and CB1R and CB2R constitute the endocannabinoid system (ECS). Other plants can produce cannabinoid-like molecules such as perrottetinene extracted from Radula perrottetii, or anandamide and 2-arachidonoyl glycerol extracted from some bryophytes. Moreover, several other secondary metabolites can also interact with the ECS of animals and take the name of cannabimimetics. These phytoextracts not derived from Cannabis sativa can act as receptor agonists or antagonist, or enzyme inhibitors of ECS and can be involved in the inflammation, oxidative stress, cancer, and neuroprotection. Finally, given the evolutionary heterogeneity of the cannabimimetic plants, some authors speculated on the fascinating thesis of the evolutionary convergence between plants and animals regarding biological functions of ECS. The review aims to provide a critical and complete assessment of the botanical, chemical and therapeutic aspects of cannabimimetic plants to evaluate their spread in the world and medicinal potentiality.”

https://www.ncbi.nlm.nih.gov/pubmed/30877436

https://link.springer.com/article/10.1007%2Fs00425-019-03138-x

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Second Cannabinoid Receptor Has the Yin to the First Receptor’s Yang

“Understanding the diverse effects that cannabis has on the human body is imperative if we hope to take advantage of its medicinal properties to treat various disorders. As such, elucidating the molecular structure of the receptors that bind endocannabinoids is a critical step toward developing selective drugs that can differentiate between the two known receptors—CB1 and CB2—for these molecules. Since the structure of the CB1 receptor was resolved a few years ago, an international team of researchers led by scientists at the iHuman Institute within ShanghaiTech University has just published the crystal structure of the human type 2 cannabinoid receptor, CB2.

Findings from the new study—published recently in Cell through an article titled “Crystal Structure of the Human Cannabinoid Receptor CB2”—should be helpful in the development of drugs against inflammatory, neurodegenerative, and other diseases. The study authors compared the newly discovered structure to that of the CB1 receptor, deeming the two receptors to be the “yin and yang” of the human endocannabinoid system.”

“Crystal Structure of the Human Cannabinoid Receptor CB1” https://www.cell.com/fulltext/S0092-8674(16)31385-X
“Crystal Structure of the Human Cannabinoid Receptor CB2” https://www.cell.com/cell/pdf/S0092-8674(18)31625-8.pdf
“This study compares newly discovered structures to those of the CB1 receptor, and deems the two receptors to be the Yin and Yang of the human endocannabinoid system, which is a signalling system that regulates biological processes such as pain, immune function, metabolism, and neuronal activities among others.” https://www.worldhealth.net/news/ying-yang-second-cannabinoid-receptor/
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Plant-Based Modulators of Endocannabinoid Signaling.

Journal of Natural Products

“Extracts from Cannabis species have aided the discovery of the endocannabinoid signaling system (ECSS) and phytocannabinoids that possess broad therapeutic potential. Whereas the reinforcing effects of C. sativa are largely attributed to CB1 receptor agonism by Δ9-tetrahydrocannabinol (Δ9-THC), the observed medicinal effects of Cannabis arise from the combined actions of various compounds. In addition to compounds bearing a classical cannabinoid structure, naturally occurring fatty acid amides and esters resembling anandamide and 2-arachidonoyl glycerol isolated from non- Cannabis species are also valuable tools for studying ECSS function. This review highlights the potential of plant-based secondary metabolites from Cannabis and unrelated species as ECSS modulators.”

https://www.ncbi.nlm.nih.gov/pubmed/30816712

https://pubs.acs.org/doi/10.1021/acs.jnatprod.8b00874

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