Additional file 1: Figure S1. of A new formulation of cannabidiol in cream shows therapeutic effects in a mouse model of experimental autoimmune encephalomyelitis

LFB staining shows naive group (A:10x) and CTRL-CBD cream (B:10x). May-Grunwald Giemsa staining for naive mice (C:10x) and mice CTRL-CBD cream (D:10x). Immunohistochemical evaluation for Foxp3 in naive group (E:10x) and in CTRL-CBD cream (F:10x). Immunohistochemical evaluation for GFAP in naive mice (G:10x) and in mice CTRL-CBD cream (H:10x). (TIFF 18429 kb

Iodine-Promoted Aromatization of <i>p</i>‑Menthane-Type Phytocannabinoids

Treatment with iodine cleanly converts various <i>p</i>-menthane-type phytocannabinoids and their carboxylated precursors into cannabinol (CBN, <b>1a</b>). The reaction is superior to previously reported protocols in terms of simplicity and substrate range, which includes not only tricyclic tetrahydrocannabinols such as Δ⁹-THC (<b>2a</b>) but also bicyclic phytocannabinoids such as cannabidiol (CBD, <b>3a</b>). Lower homologues from the viridin series (<b>2c</b> and <b>3c</b>, respectively) afforded cannabivarin (CBV), a non-narcotic compound that, when investigated against a series of ionotropic (thermo-TRPs) biological end-points of phytocannabinoids, retained the submicromolar TRPA1-activating and TRPM8-inhibiting properties of CBN, while also potently activating TRPV2. Treatment with iodine provides an easy access to CBN (<b>1a</b>) from crude extracts and side-cuts of the purification of Δ⁹-THC and CBD from respectively narcotic <i>Cannabis sativa</i> (marijuana) and fiber hemp, substantially expanding the availability of this compound and, in the case of fiber hemp, dissecting it from narcotic phytocannabinoids

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

Canniprene (<b>1</b>), an isoprenylated bibenzyl unique to <i>Cannabis sativa</i>, can be vaporized and therefore potentially inhaled from marijuana. Canniprene (<b>1</b>) 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 (<b>2</b>) and cannabispirenone (<b>3</b>) were almost inactive in these bioassays. The concentration of canniprene (<b>1</b>) was investigated in the leaves of 160 strains of <i>C. sativa</i>, showing wide variations, from traces to >0.2%, but no correlation was found between its accumulation and a specific phytocannabinoid profile

Turmeric Sesquiterpenoids: Expeditious Resolution, Comparative Bioactivity, and a New Bicyclic Turmeronoid

An expeditious strategy to resolve turmerone, the lipophilic anti-inflammatory principle of turmeric (<i>Curcuma longa</i>), into its individual bisabolane constituents (<i>ar</i>-, α-, and β-turmerones, <b>2</b>–<b>4</b>, respectively) was developed. The comparative evaluation of these compounds against a series of anti-inflammatory targets (NF-κB, STAT3, Nrf2, HIF-1α) evidenced surprising differences, providing a possible explanation for the contrasting data on the activity of turmeric oil. Differences were also evidenced in the profile of more polar bisabolanes between the Indian and the Javanese samples used to obtain turmerone, and a novel hydroxylated bicyclobisabolane ketol (bicycloturmeronol, <b>8</b>) was obtained from a Javanese sample of turmeric. Taken together, these data support the view that bisabolane sesquiterpenes represent an important taxonomic marker for turmeric and an interesting class of anti-inflammatory agents, whose strict structure–activity relationships are worth a systematic evaluation

Antimicrobial Phenolics and Unusual Glycerides from <i>Helichrysum italicum</i> subsp. <i>microphyllum</i>

During a large-scale isolation campaign for the heterodimeric phloroglucinyl pyrone arzanol (<b>1a</b>) from <i>Helichrysum italicum</i> subsp. <i>microphyllum</i>, several new phenolics as well as an unusual class of lipids named santinols (<b>5a</b>–<b>c</b>, <b>6</b>–<b>8</b>) have been characterized. Santinols are angeloylated glycerides characterized by the presence of branched acyl- or keto-acyl chains and represent a hitherto unreported class of plant lipids. The antibacterial activity of arzanol and of a selection of <i>Helichrysum</i> phenolics that includes coumarates, benzofurans, pyrones, and heterodimeric phloroglucinols was evaluated, showing that only the heterodimers showed potent antibacterial action against multidrug-resistant <i>Staphylococcus aureus</i> isolates. These observations validate the topical use of <i>Helichrysum</i> extracts to prevent wound infections, a practice firmly established in the traditional medicine of the Mediterranean area

STAT-3 Inhibitory Bisabolanes from <i>Carthamus glaucus</i>

Apart from a large amount (ca. 2.0%) of α-bisabolol β-d-fucopyranoside (<b>2a</b>), the aerial parts of the Mediterranean weed <i>Carthamus glaucus</i> afforded an unusual triglyceride (<i>E</i>-2-crotonyl-1,3-distearolylglycerol, <b>7</b>), two lipophilic flavonoids (<b>6a</b>,<b>b</b>), and a series of bisabolane fucopyranosides variously acylated on the sugar moiety (<b>2b</b>–<b>e</b>) or oxidized on the terpenoid core (<b>3</b>, <b>4a</b>,<b>b</b>, <b>5a</b>,<b>b</b>). The fucopyranoside <b>2a</b> is more soluble in polar media and more versatile in terms of formulation than its aglycone [(−)-α-bisabolol, <b>1</b>], an anti-inflammatory cosmetic ingredient in current short supply in its natural form. A comparative investigation of the activity of α-bisabolol (<b>1a</b>), the fucopyranoside <b>2a</b>, and its senecioate <b>2b</b> on transcription factors involved in inflammation and cancer pathways (NF-κB and STAT-3) showed only marginal activity on NF-κB inhibition for all compounds, while STAT-3 was inhibited potently by the fucoside <b>2a</b> and, to a lesser extent, also by α-bisabolol. These observations qualify <b>2a</b> as an easily available compound, both as an apoptotic lead structure and as a potential alternative to natural α-bisabolol (<b>1</b>) for pharmaceutical and/or cosmetic development

Table1_Bitter taste receptor (TAS2R) 46 in human skeletal muscle: expression and activity.DOCX

Bitter taste receptors are involved not only in taste perception but in various physiological functions as their anatomical location is not restricted to the gustatory system. We previously demonstrated expression and activity of the subtype hTAS2R46 in human airway smooth muscle and broncho-epithelial cells, and here we show its expression and functionality in human skeletal muscle cells. Three different cellular models were used: micro-dissected human skeletal tissues, human myoblasts/myotubes and human skeletal muscle cells differentiated from urine stem cells of healthy donors. We used qPCR, immunohistochemistry and immunofluorescence analysis to evaluate gene and protein hTAS2R46 expression. In order to explore receptor activity, cells were incubated with the specific bitter ligands absinthin and 3ß-hydroxydihydrocostunolide, and calcium oscillation and relaxation were evaluated by calcium imaging and collagen assay, respectively, after a cholinergic stimulus. We show, for the first time, experimentally the presence and functionality of a type 2 bitter receptor in human skeletal muscle cells. Given the tendentially protective role of the bitter receptors starting from the oral cavity and following also in the other ectopic sites, and given its expression already at the myoblast level, we hypothesize that the bitter receptor can play an important role in the development, maintenance and in the protection of muscle tissue functions.</p