Phytocannabinoids promote viability and functional adipogenesis of bone marrow-derived mesenchymal stem cells through different molecular targets.

Abstract The cellular microenvironment plays a critical role in the maintenance of bone marrow-derived mesenchymal stem cells (BM-MSCs) and their subsequent cell lineage differentiation. Recent studies suggested that individuals with adipocyte-related metabolic disorders have altered function and adipogenic potential of adipose stem cell subpopulations, primarily BM-MSCs, increasing the risk of heart attack, stroke or diabetes. In this study, we explored the potential therapeutic effect of some of the most abundant non-euphoric compounds derived from the Cannabis sativa plant (or phytocannabinoids) including tetrahydrocannabivarin (THCV), cannabidiol (CBD), cannabigerol (CBG), cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA), by analysing their pharmacological activity on viability of endogenous BM-MSCs as well as their ability to alter BM-MSC proliferation and differentiation into mature adipocytes. We provide evidence that CBD, CBDA, CBGA and THCV (5 µM) increase the number of viable BM-MSCs; whereas only CBG (5 µM) and CBD (5 µM) alone or in combination promote BM-MSCs maturation into adipocytes via distinct molecular mechanisms. These effects were revealed both in vitro and in vivo. In addition, phytocannabinoids prevented the insulin signalling impairment induced by palmitate in adipocytes differentiated from BM-MSCs. Our study highlights phytocannabinoids as a potential novel pharmacological tool to regain control of functional adipose tissue in unregulated energy homeostasis often occurring in metabolic disorders including type 2 diabetes mellitus (T2DM), aging and lipodystrophy

Topographic Maps of Mount Etna’s Summit Craters, updated to December 2015

New maps of the summit of Mount Etna volcano (1:5000–1:4000), derived from helicopter photogrammetry, thermal images and terrestrial laser scanner survey, are here presented. These maps indicate the main morpho-structural changes occurring during the powerful explosive and effusive eruptions involving the summit craters of Etna over the first two weeks of December 2015. The survey enabled identifying the proximal erupted volume (7.2 ± 0.14 × 106 m3) and the size and location of the vent causing the powerful explosive activity inside the Central Crater. Our survey also outlines the growth of a recent (2011–2015) summit cone on top of a former pit crater, named New SE-Crater. This new cone is by now comparable in size to the former SE-Crater. The shape and size of two small cinder cones that formed on the upper eastern flank of the summit zone in May–July 2014 are also shown. This approach can be used in fast and frequent monitoring of very active volcanoes

Identification and Characterization of Cannabimovone, a Cannabinoid from Cannabis sativa, as a Novel PPARγ Agonist via a Combined Computational and Functional Study

Phytocannabinoids (pCBs) are a large family of meroterpenoids isolated from the plant Cannabis sativa. Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best investigated phytocannabinoids due to their relative abundance and interesting bioactivity profiles. In addition to various targets, THC and CBD are also well-known agonists of peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor involved in energy homeostasis and lipid metabolism. In the search of new pCBs potentially acting as PPARγ agonists, we identified cannabimovone (CBM), a structurally unique abeo-menthane pCB, as a novel PPARγ modulator via a combined computational and experimental approach. The ability of CBM to act as dual PPARγ/α agonist was also evaluated. Computational studies suggested a different binding mode toward the two isoforms, with the compound able to recapitulate the pattern of H-bonds of a canonical agonist only in the case of PPARγ. Luciferase assays confirmed the computational results, showing a selective activation of PPARγ by CBM in the low micromolar range. CBM promoted the expression of PPARγ target genes regulating the adipocyte differentiation and prevented palmitate-induced insulin signaling impairment. Altogether, these results candidate CBM as a novel bioactive compound potentially useful for the treatment of insulin resistance-related disorders

Topographic Maps of Mount Etna’s Summit Craters, updated to December 2015

<p>New maps of the summit of Mount Etna volcano (1:5000–1:4000), derived from helicopter photogrammetry, thermal images and terrestrial laser scanner survey, are here presented. These maps indicate the main morpho-structural changes occurring during the powerful explosive and effusive eruptions involving the summit craters of Etna over the first two weeks of December 2015. The survey enabled identifying the proximal erupted volume (7.2 ± 0.14 × 10⁶ m³) and the size and location of the vent causing the powerful explosive activity inside the Central Crater. Our survey also outlines the growth of a recent (2011–2015) summit cone on top of a former pit crater, named New SE-Crater. This new cone is by now comparable in size to the former SE-Crater. The shape and size of two small cinder cones that formed on the upper eastern flank of the summit zone in May–July 2014 are also shown. This approach can be used in fast and frequent monitoring of very active volcanoes.</p

In Silico Identification and Experimental Validation of (−)-Muqubilin A, a Marine Norterpene Peroxide, as PPARα/γ-RXRα Agonist and RARα Positive Allosteric Modulator

The nuclear receptors (NRs) RAR&#945;, RXR&#945;, PPAR&#945;, and PPAR&#947; represent promising pharmacological targets for the treatment of neurodegenerative diseases. In the search for molecules able to simultaneously target all the above-mentioned NRs, we screened an in-house developed molecular database using a ligand-based approach, identifying (&#8722;)-Muqubilin (Muq), a cyclic peroxide norterpene from a marine sponge, as a potential hit. The ability of this compound to stably and effectively bind these NRs was assessed by molecular docking and molecular dynamics simulations. Muq recapitulated all the main interactions of a canonical full agonist for RXR&#945; and both PPAR&#945; and PPAR&#947;, whereas the binding mode toward RAR&#945; showed peculiar features potentially impairing its activity as full agonist. Luciferase assays confirmed that Muq acts as a full agonist for RXR&#945;, PPAR&#945;, and PPAR&#947; with an activity in the low- to sub-micromolar range. On the other hand, in the case of RAR, a very weak agonist activity was observed in the micromolar range. Quite surprisingly, we found that Muq is a positive allosteric modulator for RAR&#945;, as both luciferase assays and in vivo analysis using a zebrafish transgenic retinoic acid (RA) reporter line showed that co-administration of Muq with RA produced a potent synergistic enhancement of RAR&#945; activation and RA signaling