Article

The Bibenzyl Canniprene Inhibits the Production of Pro-Inflammatory Eicosanoids and Selectively Accumulates in Some Cannabis sativa Strains

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Abstract

Canniprene (1), an isoprenylated bibenzyl unique to Cannabis sativa, can be vaporized and therefore potentially inhaled from marijuana. Canniprene (1) potently inhibited the production of inflammatory eicosanoids via the 5-lipoxygenase pathway (IC50 0.4 μM) and also affected the generation of prostaglandins via the cyclooxygenase/microsomal prostaglandin E2 synthase pathway (IC50 10 μM), while the related spiranoid bibenzyls cannabispiranol (2) and cannabispirenone (3) were almost inactive in these bioassays. The concentration of canniprene (1) was investigated in the leaves of 160 strains of C. sativa, showing wide variations, from traces to >0.2%, but no correlation was found between its accumulation and a specific phytocannabinoid profile.

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... Canniprene is not unique to the strain of Thailand cannabis, with further research identifying it again in a Panamanian strain of high delta-9 THC content [9]. More recent research suggests that canniprene concentration in a plant shows no distinct relationship with the specific cannabinoid profile present or the age of the plant [10]. The relationship between canniprene concentration and the concentration of cannflavin A and B, similar polyphenol compounds found in cannabis, was also investigated by Allegrone et al. [10], with an inverse relationship being identified. ...
... More recent research suggests that canniprene concentration in a plant shows no distinct relationship with the specific cannabinoid profile present or the age of the plant [10]. The relationship between canniprene concentration and the concentration of cannflavin A and B, similar polyphenol compounds found in cannabis, was also investigated by Allegrone et al. [10], with an inverse relationship being identified. This suggests a competition between the biosynthesis pathways of these polyphenol compounds [10]. ...
... The relationship between canniprene concentration and the concentration of cannflavin A and B, similar polyphenol compounds found in cannabis, was also investigated by Allegrone et al. [10], with an inverse relationship being identified. This suggests a competition between the biosynthesis pathways of these polyphenol compounds [10]. no distinct relationship with the specific cannabinoid profile present or the ag [10]. ...
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Cannabis sativa is a plant used for recreational and therapeutic purposes; however, many of the secondary metabolites in the plant have not been thoroughly investigated. Stilbenes are a class of compounds with demonstrated anti-inflammatory and antioxidant properties and are present in cannabis. Many stilbenes present in cannabis have been investigated for their therapeutic effects. Fourteen stilbenes have been identified to be present in cannabis, all of which are structurally dihydrostilbenoids, with half possessing a prenylated moiety. The stilbenes summarized in this analysis show varying degrees of therapeutic benefits ranging from anti-inflammatory, antiviral, and anti-cancer to antioxidant effects. Many of the identified stilbenes have been researched to a limited extent for potential health benefits. In addition, predictive in silico modeling was performed on the fourteen identified cannabis-derived stilbenes. This modeling provides prospective activity, pharmacokinetic, metabolism, and permeability data, setting the groundwork for further investigation into these poorly characterized compounds.
... Cannabis stilbenoids can be divided into three main types based on their structure: phenanthrenes, dihydrostilbenes, and spiroindans ( Figure 2). These components have been isolated from the cannabis stem, leaves and flower heads [31][32][33][34][35]. Despite their association with disease resistance and human health [36,37], only a few cannabis stilbenoids have been described in the literature with properties that may be beneficial to human health. ...
... Cannabispirone and cannabispirenone A, the most recurrent spiroindans, have also been studied and anti-inflammatory and anti-cancer activities have been reported. Furthermore, a competition in the formation of stilbenoids and flavonoids is suggested in C. sativa metabolism [2,29,34,36]. The lignans isolated from C. sativa belong to two main groups: phenolic amides and lignanamides ( Figure 3) [7,39]. ...
... For instance, TPC of the Futura type increased about twice when grown in the Cavriana region. Similar variations within varieties and cultivation sites are observed with flavonoid contents, and appear with stilbenoids content as well [34,48]. Therefore, the results from different studies cannot be compared with each other and this is the case with the other extraction techniques. ...
Article
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Cannabis sativa L. is a controversial crop due to its high tetrahydrocannabinol content varieties; however, the hemp varieties get an increased interest. This paper describes (i) the main categories of phenolic compounds (flavonoids, stilbenoids and lignans) and terpenes (monoterpenes and sesquiterpenes) from C. sativa by-products and their biological activities and (ii) the main extraction techniques for their recovery. It includes not only common techniques such as conventional solvent extraction, and hydrodistillation, but also intensification and emerging techniques such as ultrasound-assisted extraction or supercritical CO2 extraction. The effect of the operating conditions on the yield and composition of these categories of phenolic compounds and terpenes was discussed. A thorough investigation of innovative extraction techniques is indeed crucial for the extraction of phenolic compounds and terpenes from cannabis toward a sustainable industrial valorization of the whole plant.
... The database search initially returned 308 abstracts and two further records were identified through the additional measures described. Forty-three full-text articles were assessed for eligibility, with 26 articles (9)(10)(11)(12)(15)(16)(17)(18)(19)22,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42) included for qualitative synthesis ( ...
... Six separate studies detailed the effects of cannflavins in anti-inflammatory models (Table 4) (11,12,27,32,33,36). CFL-A and CFL-B demonstrated potent inhibition of molecular targets microsomal prostaglandin E synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) (11,12,27,32,33,36). ...
... Six separate studies detailed the effects of cannflavins in anti-inflammatory models (Table 4) (11,12,27,32,33,36). CFL-A and CFL-B demonstrated potent inhibition of molecular targets microsomal prostaglandin E synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) (11,12,27,32,33,36). CFL-A did not demonstrate any significant inhibition of cyclooxygenase (COX) enzymes (27,33). ...
Article
Introduction Cannflavins are a group of prenylflavonoids derived from Cannabis sativa L.. Cannflavin A (CFL-A), B (CFL-B) and C (CFL-C) have been heralded for their anti-inflammatory properties in pre-clinical evaluations. This scoping review aims to synthesise the evidence base on cannflavins to provide an overview of the current research landscape to inform research strategies to aid clinical translation. Methods A scoping review was conducted of EMBASE, MEDLINE, Pubmed, CENTRAL and Google Scholar databases up to 26th February 2020. All studies describing original research on cannflavins and their isomers were included for review. Results 26 full text articles were included. CFL-A and CFL-B demonstrated potent anti-inflammatory activity via inhibition of 12-o-tetradecanoylphorbol 13-acetate induced PGE2 release (CFL-A half maximal inhibitory concentration (IC50): 0.7 μM; CFL-B IC50: 0.7 μM) and microsomal prostaglandin E synthase-1 (CFL-A IC50: 1.8 μM; CFL-B IC50: 3.7 μM). Outcomes were also described in preclinical models of anti-oxidation (CFL-A), anti-parasitic activity (CFL-A, CFL-C), neuroprotection (CFL-A) and cancer (Isocannflavin B, a CFL-B isomer). In-silico screening identified that CFL-A has binding affinity with viral proteins that warrant further investigation. Conclusions Cannflavins demonstrate a number of promising therapeutic properties, most notably as an anti-inflammatory agent. Low yields of extraction however have previously limited research to small pre-clinical investigations. Identification of cannflavin-rich chemovars, novel extraction techniques and recent identification of a biosynthetic pathway will hopefully allow research to be scaled appropriately. In order to fully evaluate the therapeutic properties of cannflavins focused research now needs to be embedded within institutions with a track-record of clinical translation.
... The pharmaceutical interest in this plant has been mainly addressed to drug-type Cannabis, thanks to its new therapeutic applications [7], while hemp is at the moment under-employed in this ambit. However, the number of studies focused on the characterisation of fibre-type hemp varieties and on the evaluation of the biological potential of non-psychoactive compounds has increased lately [2,3,[8][9][10][11][12][13][14][15][16]. ...
... In addition to flavonoids, dihydrostilbenoids represent another class of polyphenolic substances isolated from hemp, of which canniprene is the main representative ( Figure 2) [25]. As to canniprene, it has been demonstrated to exert an anti-inflammatory activity as well, by inhibiting the production of pro-inflammatory eicosanoids [8]. Among non-psychoactive cannabinoids, CBD represents the most promising one from the pharmaceutical point of view, due to its high anti-oxidant and anti-inflammatory activity, in addition to its anticonvulsant, anxiolytic, neuroprotective, and antibiotic properties [2,4,[20][21][22][23]. ...
... In addition to flavonoids, dihydrostilbenoids represent another class of polyphenolic substances isolated from hemp, of which canniprene is the main representative ( Figure 2) [25]. As to canniprene, it has been demonstrated to exert an anti-inflammatory activity as well, by inhibiting the production of pro-inflammatory eicosanoids [8]. As regards the other compounds present in hemp, terpenes are responsible for the characteristic aroma of the plant. ...
Article
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Cannabis sativa L. is a dioecious plant belonging to the Cannabaceae family. The main phytochemicals that are found in this plant are represented by cannabinoids, flavones, and terpenes. Some biological activities of cannabinoids are known to be enhanced by the presence of terpenes and flavonoids in the extracts, due to a synergistic action. In the light of all the above, the present study was aimed at the multi-component analysis of the bioactive compounds present in fibre-type C. sativa (hemp) inflorescences of different varieties by means of innovative HPLC and GC methods. In particular, the profiling of non-psychoactive cannabinoids was carried out by means of HPLC-UV/DAD, ESI-MS, and MS2. The content of prenylated flavones in hemp extracts, including cannflavins A and B, was also evaluated by HPLC. The study on Cannabis volatile compounds was performed by developing a new method based on headspace solid-phase microextraction (HS-SPME) coupled with GC-MS and GC-FID. Cannabidiolic acid (CBDA) and cannabidiol (CBD) were found to be the most abundant cannabinoids in the hemp samples analysed, while β-myrcene and β-caryophyllene were the major terpenes. As regards flavonoids, cannflavin A was observed to be the main compound in almost all the samples. The methods developed in this work are suitable for the comprehensive chemical analysis of both hemp plant material and related pharmaceutical or nutraceutical products in order to ensure their quality, efficacy, and safety.
... Other unique compounds of cannabis are canniprene 6 and cannflavins 7a and 8, which open a new field for chemical and biological exploration [1,10]. In particular, canniprene 6 potently inhibits the production of inflammatory eicosanoids via the 5-lipoxygenase (5-LOX) pathway [11]. It outperforms the structural analogue resveratrol in suppressing pro-inflammatory readouts in diverse cell-free test systems and shows a remarkable potential for application in skin care [12]. ...
... Plants 2022,11, 2130 ...
Article
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The growing general interest surrounding Cannabis sativa L. has led to a renewal in breeding and resulted in an impressive variability of chemotypical characteristics that required the division of cannabis into different recognized chemotypes. The chemotype V has been overlooked in terms of phytochemical composition due to the almost total absence of cannabinoids, on which biomedical attention is focused. Systematic approaches addressing diverse chemotypes are, however, needed to discriminate and define phytochemical aspects beyond cannabinoids. Such thoroughly characterized chemotypes guarantee blinding in controlled studies by mimicking the sensory properties of hemp and may help to unravel the “entourage effect”. Capitalizing on the ability of cannabis to synthesize a large number of non-cannabinoid phenolic compounds, we here investigated, for the first time, the composition of the Ermo chemotype V and identified new compounds: two dihydrophenanthrenes and the methoxy-dihydrodenbinobin. All three compounds suppress pro-inflammatory leukotriene biosynthesis in activated macrophage subtypes by targeting 5-lipoxygenase, but substantially differ in their capacity to elevate the levels of specialized pro-resolving lipid mediators and their precursors in M2 macrophages. We conclude that the discovered compounds likely contribute to the anti-inflammatory properties of Cannabis sativa L. chemotype V and might promote inflammation resolution by promoting a lipid mediator class switch.
... Cannflavin A has shown a good antileishmanial activity and a moderate antioxidant action [17]. In the ambit of Cannabis phenolics, canniprene, which is a dyhydrostilbene unique to C. sativa, represents an interesting compound [19]. If compared with cannflavin A, which is the most potent cannflavin, canniprene has been found to be superior at inhibiting 5-LO, but it is less effective for mPGES-1 inhibition [19]. ...
... In the ambit of Cannabis phenolics, canniprene, which is a dyhydrostilbene unique to C. sativa, represents an interesting compound [19]. If compared with cannflavin A, which is the most potent cannflavin, canniprene has been found to be superior at inhibiting 5-LO, but it is less effective for mPGES-1 inhibition [19]. ...
Article
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In the last decades, a lot of attention has been paid to the compounds present in medicinal Cannabis sativa L., such as Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC) and cannabidiol (CBD), and their effects on inflammation and cancer-related pain. The National Cancer Institute (NCI) currently recognizes medicinal C. sativa as an effective treatment for providing relief in a number of symptoms associated with cancer, including pain, loss of appetite, nausea and vomiting, and anxiety. Several studies have described CBD as a multitarget molecule, acting as an adaptogen, and as a modulator, in different ways, depending on the type and location of disequilibrium both in the brain and in the body, mainly interacting with specific receptor proteins CB 1 and CB 2 . CBD is present in both medicinal and fibre-type C. sativa plants, but, unlike Δ ⁹ -THC, it is completely nonpsychoactive. Fibre-type C. sativa (hemp) differs from medicinal C. sativa , since it contains only few levels of Δ ⁹ -THC and high levels of CBD and related nonpsychoactive compounds. In recent years, a number of preclinical researches have been focused on the role of CBD as an anticancer molecule, suggesting CBD (and CBD-like molecules present in the hemp extract) as a possible candidate for future clinical trials. CBD has been found to possess antioxidant activity in many studies, thus suggesting a possible role in the prevention of both neurodegenerative and cardiovascular diseases. In animal models, CBD has been shown to inhibit the progression of several cancer types. Moreover, it has been found that coadministration of CBD and Δ ⁹ -THC, followed by radiation therapy, causes an increase of autophagy and apoptosis in cancer cells. In addition, CBD is able to inhibit cell proliferation and to increase apoptosis in different types of cancer models. These activities seem to involve also alternative pathways, such as the interactions with TRPV and GRP55 receptor complexes. Moreover, the finding that the acidic precursor of CBD (cannabidiolic acid, CBDA) is able to inhibit the migration of breast cancer cells and to downregulate the proto-oncogene c-fos and the cyclooxygenase-2 (COX-2) highlights the possibility that CBDA might act on a common pathway of inflammation and cancer mechanisms, which might be responsible for its anticancer activity. In the light of all these findings, in this review we explore the effects and the molecular mechanisms of CBD on inflammation and cancer processes, highlighting also the role of minor cannabinoids and noncannabinoids constituents of Δ ⁹ -THC deprived hemp.
... luteolin, canniprene, cannflavin A, cannflavin B, catechin, naringenin, isorhamnetin, resveratrol, rutintrihydrate, apigenin, and apigenin7-glucoside in C. Sativa extracts (Allegrone et al., 2017). ...
Article
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Cannabis sativa L. is used to treat drug-resistant epilepsy. Cannabinoids and phenolic compounds were identified in its composition. It is known that decarboxylation transforms acid cannabinoids into their neutral, usually more active, forms. Our aim was to determine the effect of the decarboxylation on C. sativa´s resin (CSR) antioxidant effect and its relationship with cannabinoids and polyphenolic compounds. The DPPH scavenger activity, the inhibition of lipid peroxidation and the metal chelating activities were determined for the raw CSR and decarboxylated C. sativa´s resin (CSRD). The phytochemical composition was studied by HPLC. The decarboxylation process modified the HPLC flavonoids profile and increased the resin’s antioxidant activities. The EC50 of CSRD for DPPH activity was 2.5 times lower than CSR EC50 (p<0.001); for the inhibition of lipid peroxidation, CSRD presented an EC50 2.7 times lower than CSR (p<0.001). CSR did not exert metal chelating activity. In view of these results, it could be promising to decarboxylate CSR to improve its antiepileptic and antioxidant effects.
... Both bibenzyls and flavonoids are derived from the phenylpropanoids pathway and share several similar upstream steps [6]. Flavonoids and bibenzyls not only play significant physiological roles in plants, but also have important medicinal properties, such as antioxidant, antibacterial and anti-inflammatory activity [7][8][9]. Various modifications of these compounds, including glycosylation, acylation and methylation, make the structure of natural products more diversified. Glycosylation can significantly affect the solubility, stability and toxicity of the compounds [10] and is usually essential for the storage, transportation and maintaining metabolic homeostasis of polyphenols [11]. ...
Article
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Liverworts are rich in bibenzyls and related O-glycosides, which show antioxidant activity. However, glycosyltransferases that catalyze the glycosylation of bibenzyls have not yet been characterized. Here, we identified two bibenzyl UDP-glucosyltransferases named MpUGT737B1 and MpUGT741A1 from the model liverwort Marchantia polymorpha. The in vitro enzymatic assay revealed that MpUGT741A1 specifically accepted the bibenzyl lunularin as substrate. MpUGT737B1 could accept bibenzyls, dihydrochalcone and phenylpropanoids as substrates, and could convert phloretin to phloretin-4-O-glucoside and phloridzin, which showed inhibitory activity against tyrosinase and antioxidant activity. The results of sugar donor selectivity showed that MpUGT737B1 and MpUGT741A1 could only accept UDP-glucose as a substrate. The expression levels of these MpUGTs were considerably increased after UV irradiation, which generally caused oxidative damage. This result indicates that MpUGT737B1 and MpUGT741A1 may play a role in plant stress adaption. Subcellular localization indicates that MpUGT737B1 and MpUGT741A1 were expressed in the cytoplasm and nucleus. These enzymes should provide candidate genes for the synthesis of bioactive bibenzyl O-glucosides and the improvement of plant antioxidant capacity.
... Prenylated bibenzyls from Cannabis sativa, Amorpha fruticosa and Glycyrrhiza foetida have the potential to reduce inflammation. Canniprene isolated from Cannabis sativa shows remarkable anti-inflammatory activity by inhibiting the production of inflammatory eicosanoids via the 5-lipoxygenase pathway and affecting the generation of prostaglandins via the cyclooxygenase/microsomal prostaglandin E2 synthase pathway (Allegrone et al. 2017). The ligands amorfrutins isolated from Amorpha fruticosa and Glycyrrhiza foetida selectively activates PPARγ (peroxisome proliferator-activated receptor gamma) receptors by inhibiting the gene expression and secretion of inflammatory mediators in colon cells. ...
Article
Prenylated stilbenoids are a unique class of natural phenolic compounds consisting of C6-C2-C6 skeleton with prenyl substitution. They are potential nutraceuticals and dietary supplements presented in some edible plants. Prenylated stilbenoids demonstrate promising health benefits, including antioxidant, anti-cancer, anti-inflammatory, anti-microbial activities. This review reports the structure, bioactivity and potential application of prenylated stilbeniods in food industry. Edible sources of these compounds are compiled and summarized. Structure-activity relationship of prenylated stilbenoids are also highlighted. The biosynthesis strategies of prenylated stilbenoids are reviewed. The findings of these compounds as food preservative, nutraceuticals and food additive are discussed. This paper combines the up-to-date information and gives a full image of prenylated stilbenoids.
... Most of these studies quantified the phenolic compounds of the hemp extracts by the overall determination of the total phenolic content and total flavonoid content. In addition, several studies have quantified individual phenolic compounds, such as caffeic acid, gallic acid, rosmarinic acid, p-OH-benzoic acid, ferulic acid, 3,4-dihydroxybenzoic acid, p-coumaric acid, syringic acid, quercetin, luteolin, canniprene, cannflavin A, cannflavin B, catechin, naringenin, isorhamnetin, resveratrol, rutin trihydrate, apigenin, and apigenin 7-glucoside in the extracts [95][96][97][98]. Of note, most conventional extraction was conducted at room temperature and not under optimal conditions [99][100][101][102][103]. ...
Article
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Cannabis is well-known for its numerous therapeutic activities, as demonstrated in pre-clinical and clinical studies primarily due to its bioactive compounds. The Cannabis industry is rapidly growing; therefore, product development and extraction methods have become crucial aspects of Cannabis research. The evaluation of the current extraction methods implemented in the Cannabis industry and scientific literature to produce consistent, reliable, and potent medicinal Cannabis extracts is prudent. Furthermore, these processes must be subjected to higher levels of scientific stringency, as Cannabis has been increasingly used for various ailments, and the Cannabis industry is receiving acceptance in different countries. We comprehensively analysed the current literature and drew a critical summary of the extraction methods implemented thus far to recover bioactive compounds from medicinal Cannabis. Moreover, this review outlines the major bioactive compounds in Cannabis, discusses critical factors affecting extraction yields, and proposes future considerations for the effective extraction of bioactive compounds from Cannabis. Overall, research on medicinal marijuana is limited, with most reports on the industrial hemp variety of Cannabis or pure isolates. We also propose the development of sustainable Cannabis extraction methods through the implementation of mathematical prediction models in future studies.
... Moreover, it was found to decrease the synthesis of prostaglandin through the cyclooxygenase/microsomal prostaglandin E 2 synthase pathway. Other spiranoid bibenzyls harvested from C. sativa are cannabispiranol and cannabispirenone which showed no significant result in these bioassays [131]. ...
Article
Background The amphibian, non-vascular, gametophyte-dominant, bio-indicator class, bryophytes; with their wide ranges of habitat have attained importance due to their promising medicinal attributions and therapeutic role; mostly aided by presence of aromatic bibenzyl and bisbybenzyl class of compounds. Bibenzyls are steroidal ethane derivatives, resembling the structural moiety of bioactive dihydro-stilbenoids or iso-quinoline alkaloids. These stress triggered secondary metabolites are the by-products of the flavonoid biosynthetic pathway. Different classes of bryophytes (Bryophyta, Marchantiophyta and Anthocerotophyta) possess different subtypes of bibenzyls and dimeric bisbibenzyls. Among the liverwort, hornwort and mosses, former one is mostly enriched with bibenzyl type constituents as per the extensive study conducted for phytochemical deposit. Considering macrocyclic and acyclic group of bibenzyls and bisbybenzyls, generally marchantin type compounds are reported vividly for significant biological activity that includes neuro-nephro-cardio-protection besides anti-allergic, anti-microbial, anti-apoptotic and cytotoxic activities studied on in-vitro and in-vivo models or on cell lines.ResultThe critical analysis of reported chemical and pharmaceutical attributions of bibenzyls and bis-bibenzyls yielded detailed report on this compound class along with their application, mode of action, natural source, techniques of synthesis, extraction procedure, isolation and characterization. Further, the structure activity relationship studies and bioactivity of bibenzyls derived from non-bryophytic origin were also summarized.Conclusion This review encompasses prospective biological application of botanical reservoir of this primarily ignored, primeval land plant group where recent technical advances has paved the way for qualitative and quantitative isolation and estimation of novel compounds as well as marker components to study their impact on environment, as bio-control agents and as key leads in future drug designing. Graphical abstract
... In particular, studies show that flavonoids, canflavins A and B have an anti-inflammatory action and their molecular targets have been identified as prostaglandin E2 synthesis found in the microsomal fraction (mPGES-1) and 5-lipoxygenase (5-LO) (Wertz et al., 2014) and finally, flavonoids can also modulate pharmacokinetics of some cannabinoids by inhibiting liver enzymes P450 (Andre et al., 2016). Dihydrostilbenoids represent another class of polyphenolic substances isolated from Cannabis sp., of which canniprene is the main representative and exerts anti-inflammatory activity by inhibiting the production of eicosanoid proinflammatory drugs (Alledrone et al., 2017;Pollastro et al., 2018). Cunetti et al. (2018) evaluated the use of CBD in patients with chronic pain and as a result, cannabidiol showed good tolerance and no adverse effects were observed. ...
... Thus, cannflavin A exerts its inhibitory effects on mPGES-1 and 5-LO in a reversible and substrate concentration-independent manner (IC 50 = 1.8 and 0.9 μM), exhibited no marked radical sca- venger activity, and failed to substantially inhibit the related COX-1 and COX-2 enzymes as well as cPLA 2 (Werz et al., 2014). Furthermore, the isoprenylated bibenzyl canniprene from C. sativa efficiently inhibited 5- LO (IC 50 = 0.4 μM) and to a minor degree also mPGES-1 (IC 50 = 10 μM) ( Allegrone et al., 2017). Together, dual inhibition of 5- LO and mPGES-1 by ingredients of C. sativa may contribute to the well- recognized anti-inflammatory properties of this remedy, although more complex C. sativa preparations used as phytomedicine remain to be assessed for mPGES-1/5-LO inhibition. ...
Article
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostanoid formation and represent prevalent therapeutics for treatment of inflammatory disorders. However, NSAIDs are afflicted with severe side effects, which might be circumvented by more selective suppression of pro-inflammatory eicosanoid biosynthesis. This concept led to dual inhibitors of microsomal prostaglandin E2synthase (mPGES)-1 and 5-lipoxygenase that are crucial enzymes in the biosynthesis of pro-inflammatory prostaglandin E2and leukotrienes. The potential of their dual inhibition in light of superior efficacy and safety is discussed. Focus is placed on natural products, for which direct inhibition of mPGES-1 and leukotriene biosynthesis has been confirmed.
... Canniprene is an isoprenylated bibenzyl unique to cannabis (Allegrone et al., 2017), that can be vaporized and is potentially present in smoke. Potential antiinflammatory activity was demonstrated via inhibition of 5-LO (IC 50 0.4 μM) and COX/mPGES pathway (IC 50 10.1 μM). ...
Chapter
The golden age of cannabis pharmacology began in the 1960s as Raphael Mechoulam and his colleagues in Israel isolated and synthesized cannabidiol, tetrahydrocannabinol, and other phytocannabinoids. Initially, THC garnered most research interest with sporadic attention to cannabidiol, which has only rekindled in the last 15 years through a demonstration of its remarkably versatile pharmacology and synergy with THC. Gradually a cognizance of the potential of other phytocannabinoids has developed. Contemporaneous assessment of cannabis pharmacology must be even far more inclusive. Medical and recreational consumers alike have long believed in unique attributes of certain cannabis chemovars despite their similarity in cannabinoid profiles. This has focused additional research on the pharmacological contributions of mono- and sesquiterpenoids to the effects of cannabis flower preparations. Investigation reveals these aromatic compounds to contribute modulatory and therapeutic roles in the cannabis entourage far beyond expectations considering their modest concentrations in the plant. Synergistic relationships of the terpenoids to cannabinoids will be highlighted and include many complementary roles to boost therapeutic efficacy in treatment of pain, psychiatric disorders, cancer, and numerous other areas. Additional parts of the cannabis plant provide a wide and distinct variety of other compounds of pharmacological interest, including the triterpenoid friedelin from the roots, canniprene from the fan leaves, cannabisin from seed coats, and cannflavin A from seed sprouts. This chapter will explore the unique attributes of these agents and demonstrate how cannabis may yet fulfil its potential as Mechoulam's professed “pharmacological treasure trove.”
Article
Cannabinoids are phytochemicals from cannabis with anti-inflammatory actions in immune cells. Lipid mediators (LM), produced from polyunsaturated fatty acids (PUFA), are potent regulators of the immune response and impact all stages of inflammation. How cannabinoids influence LM biosynthetic networks is unknown. Here, we reveal cannabidiol (CBD) as a potent LM class-switching agent that stimulates the production of specialized pro-resolving mediators (SPMs) but suppresses pro-inflammatory eicosanoid biosynthesis. Detailed metabololipidomics analysis in human monocyte-derived macrophages showed that CBD (i) upregulates exotoxin-stimulated generation of SPMs, (ii) suppresses 5-lipoxygenase (LOX)-mediated leukotriene production, and (iii) strongly induces SPM and 12/15-LOX product formation in resting cells by stimulation of phospholipase A2-dependent PUFA release and through Ca2+-independent, allosteric 15-LOX-1 activation. Finally, in zymosan-induced murine peritonitis, CBD increased SPM and 12/15-LOX products and suppressed pro-inflammatory eicosanoid levels in vivo. Switching eicosanoid to SPM production is a plausible mode of action of CBD and a promising inflammation-resolving strategy.
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Bibenzyls, a kind of important plant polyphenols, have attracted growing attention for their broad and remarkable pharmacological activities. However, due to the low abundance in nature, uncontrollable and environmentally unfriendly chemical synthesis processes, these compounds are not readily accessible. Herein, one high-yield bibenzyl backbone-producing Escherichia coli strain was constructed by using a highly active and substrate-promiscuous bibenzyl synthase identified from Dendrobium officinale in combination with starter and extender biosynthetic enzymes. Three types of efficiently post-modifying modular strains were engineered by employing methyltransferases, prenyltransferase, and glycosyltransferase with high activity and substrate tolerance together with their corresponding donor biosynthetic modules. Structurally different bibenzyl derivatives were tandemly and/or divergently synthesized by co-culture engineering in various combination modes. Especially, a prenylated bibenzyl derivative (12) was found to be an antioxidant that exhibited potent neuroprotective activity in the cellular and rat models of ischemia stroke. RNA-seq, quantitative RT-PCR, and Western-blot analysis demonstrated that 12 could up-regulate the expression level of an apoptosis-inducing factor, mitochondria associated 3 (Aifm3), suggesting that Aifm3 might be a new target in ischemic stroke therapy. This study provides a flexible plug-and-play strategy for the easy-to-implement synthesis of structurally diverse bibenzyls through a modular co-culture engineering pipeline for drug discovery.
Article
The liverwort Radula perrottetii contains various bibenzyl derivatives which are known to possess various biological activities, such as anti-inflammatory effects. Mast cells (MC) play crucial roles in allergic and inflammatory diseases; thus, inhibition of MC activation is pivotal for the treatment of allergic and inflammatory disorders. We investigated the effects of perrottetin D (perD), isolated from Radula perrottetii, and perD diacetate (Ac-perD) on antigen-induced activation of MCs. Bone marrow-derived MCs (BMMCs) were generated from C57BL/6 mice. The degranulation ratio, histamine release, and the interleukin (IL)-4 and leukotriene B4 productions on antigen-triggered BMMC were investigated. Additionally, the effects of the bibenzyls on binding of IgE to FcεRI were observed by flow cytometry, and signal transduction proteins was examined by Western blot. Furthermore, binding of the bibenzyls to the Fyn kinase domain was calculated. At 10 μM, perD decreased the degranulation ratio (p<0.01), whereas 10 μM Ac-perD down-regulated IL-4 production (p<0.05) in addition to decreasing the degranulation ratio (p<0.01). Both compounds tended to decrease histamine release at a concentration of 10 μM. Although 10 μM perD reduced only Syk phosphorylation, 10 μM Ac-perD diminished phosphorylation of Syk, Gab2, PLC-γ, and p38. PerD appeared to selectively bind Fyn, whereas Ac-perD appeared to act as a weak but broad-spectrum inhibitor of kinases, including Fyn. In conclusion, perD and Ac-perD suppressed the phosphorylation of signal transduction molecules downstream of the FcεRI and consequently inhibited degranulation, and/or IL-4 production. These may be beneficial potential lead compounds for the development of novel anti-allergic and anti-inflammatory drugs.
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