β-Caryophyllene ameliorates cisplatin-induced nephrotoxicity in a cannabinoid 2 receptor-dependent manner

(E)-β-caryophyllene (BCP) is a natural sesquiterpene found in many essential oils of spice (best known for contributing to the spiciness of black pepper) and food plants with recognized anti-inflammatory properties. Recently it was shown that BCP is a natural agonist of endogenous cannabinoid 2 (CB(2)) receptors, which are expressed in immune cells and mediate anti-inflammatory effects. In this study we aimed to test the effects of BCP in a clinically relevant murine model of nephropathy (induced by the widely used antineoplastic drug cisplatin) in which the tubular injury is largely dependent on inflammation and oxidative/nitrative stress. β-caryophyllene dose-dependently ameliorated cisplatin-induced kidney dysfunction, morphological damage, and renal inflammatory response (chemokines MCP-1 and MIP-2, cytokines TNF-α and IL-1β, adhesion molecule ICAM-1, and neutrophil and macrophage infiltration). It also markedly mitigated oxidative/nitrative stress (NOX-2 and NOX-4 expression, 4-HNE and 3-NT content) and cell death. The protective effects of BCP against biochemical and histological markers of nephropathy were absent in CB(2) knockout mice. Thus, BCP may be an excellent therapeutic agent to prevent cisplatin-induced nephrotoxicity through a CB(2) receptor-dependent pathway. Given the excellent safety profile of BCP in humans it has tremendous therapeutic potential in a multitude of diseases associated with inflammation and oxidative stress.

Beta-caryophyllene is a dietary cannabinoid

The psychoactive cannabinoids from Cannabis sativa L. and the arachidonic acid-derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 (CB(1)) and CB(2) receptors. Although the CB(1) receptor is responsible for the psychomodulatory effects, activation of the CB(2) receptor is a potential therapeutic strategy for the treatment of inflammation, pain, atherosclerosis, and osteoporosis. Here, we report that the widespread plant volatile (E)-beta-caryophyllene [(E)-BCP] selectively binds to the CB(2) receptor (K(i) = 155 +/- 4 nM) and that it is a functional CB(2) agonist. Intriguingly, (E)-BCP is a common constituent of the essential oils of numerous spice and food plants and a major component in Cannabis. Molecular docking simulations have identified a putative binding site of (E)-BCP in the CB(2) receptor, showing ligand pi-pi stacking interactions with residues F117 and W258. Upon binding to the CB(2) receptor, (E)-BCP inhibits adenylate cylcase, leads to intracellular calcium transients and weakly activates the mitogen-activated kinases Erk1/2 and p38 in primary human monocytes. (E)-BCP (500 nM) inhibits lipopolysaccharide (LPS)-induced proinflammatory cytokine expression in peripheral blood and attenuates LPS-stimulated Erk1/2 and JNK1/2 phosphorylation in monocytes. Furthermore, peroral (E)-BCP at 5 mg/kg strongly reduces the carrageenan-induced inflammatory response in wild-type mice but not in mice lacking CB(2) receptors, providing evidence that this natural product exerts cannabimimetic effects in vivo. These results identify (E)-BCP as a functional nonpsychoactive CB(2) receptor ligand in foodstuff and as a macrocyclic antiinflammatory cannabinoid in Cannabis.

Synthetic versus natural curcumin: bioequivalence in an in vitro oral mucositis model

BACKGROUND Curcumin (CUR) is a dietary spice and food colorant (E100). Its potent anti-inflammatory activity by inhibiting the activation of Nuclear Factor-kappaB is well established. METHODS The aim of this study was to compare natural purified CUR (nCUR) with synthetically manufactured CUR (sCUR) with respect to their capacity to inhibit detrimental effects in an in vitro model of oral mucositis. The hypothesis was to demonstrate bioequivalence of nCUR and sCUR. RESULTS The purity of sCUR was HPLC-confirmed. Adherence and invasion assays for bacteria to human pharyngeal epithelial cells demonstrated equivalence of nCUR and sCUR. Standard assays also demonstrated an identical inhibitory effect on pro-inflammatory cytokine/chemokine secretion (e.g., interleukin-8, interleukin-6) by Detroit pharyngeal cells exposed to bacterial stimuli. There was bioequivalence of sCUR and nCUR with respect to their antibacterial effects against various pharyngeal species. CONCLUSION nCUR and sCUR are equipotent in in vitro assays mimicking aspects of oral mucositis. The advantages of sCUR include that it is odorless and tasteless, more easily soluble in DMSO, and that it is a single, highly purified molecule, lacking the batch-to-batch variation of CUR content in nCUR. sCUR is a promising agent for the development of an oral anti-mucositis agent.

'La mucha destemplanza de la tierra' : Una aproximación al relato de Maximiliano de Transilvano sobre el descubrimiento del Estrecho de Magallanes

Una de las empresas más emblemáticas en la historia del descubrimiento, conquista y colonización del Nuevo Mundo es la que comanda Hernando de Magallanes y concluye Sebastián Elcano en procura de encontrar una nueva ruta hacia las islas Molucas, paraíso de la especiería. Este artículo propone una lectura de la carta escrita en latín por Maximiliano Transilvano, Secretario de Carlos V, firmada a los pocos días del retorno de los sobrevivientes (5 de octubre de 1522) de la travesía interoceánica. El análisis se detiene en el episodio del desembarco en Puerto San Julián, en las costas patagónicas argentinas, y en el modo en que ingresa en la escritura un espacio geográfico hostil e intimidante, generador de violencia y enfrentamientos

'La mucha destemplanza de la tierra' : Una aproximación al relato de Maximiliano de Transilvano sobre el descubrimiento del Estrecho de Magallanes

Una de las empresas más emblemáticas en la historia del descubrimiento, conquista y colonización del Nuevo Mundo es la que comanda Hernando de Magallanes y concluye Sebastián Elcano en procura de encontrar una nueva ruta hacia las islas Molucas, paraíso de la especiería. Este artículo propone una lectura de la carta escrita en latín por Maximiliano Transilvano, Secretario de Carlos V, firmada a los pocos días del retorno de los sobrevivientes (5 de octubre de 1522) de la travesía interoceánica. El análisis se detiene en el episodio del desembarco en Puerto San Julián, en las costas patagónicas argentinas, y en el modo en que ingresa en la escritura un espacio geográfico hostil e intimidante, generador de violencia y enfrentamientos

'La mucha destemplanza de la tierra' : Una aproximación al relato de Maximiliano de Transilvano sobre el descubrimiento del Estrecho de Magallanes

Una de las empresas más emblemáticas en la historia del descubrimiento, conquista y colonización del Nuevo Mundo es la que comanda Hernando de Magallanes y concluye Sebastián Elcano en procura de encontrar una nueva ruta hacia las islas Molucas, paraíso de la especiería. Este artículo propone una lectura de la carta escrita en latín por Maximiliano Transilvano, Secretario de Carlos V, firmada a los pocos días del retorno de los sobrevivientes (5 de octubre de 1522) de la travesía interoceánica. El análisis se detiene en el episodio del desembarco en Puerto San Julián, en las costas patagónicas argentinas, y en el modo en que ingresa en la escritura un espacio geográfico hostil e intimidante, generador de violencia y enfrentamientos

Building memristor applications: from device model to circuit design

Since the memristor was first built in 2008 at HP Labs, no end of devices and models have been presented. Also, new applications appear frequently. However, the integration of the device at the circuit level is not straightforward, because available models are still immature and/or suppose high computational loads, making their simulation long and cumbersome. This study assists circuit/systems designers in the integration of memristors in their applications, while aiding model developers in the validation of their proposals. We introduce the use of a memristor application framework to support the work of both the model developer and the circuit designer. First, the framework includes a library with the best-known memristor models, being easily extensible with upcoming models. Systematic modifications have been applied to these models to provide better convergence and significant simulations speedups. Second, a quick device simulator allows the study of the response of the models under different scenarios, helping the designer with the stimuli and operation time selection. Third, fine tuning of the device including parameters variations and threshold determination is also supported. Finally, SPICE/Spectre subcircuit generation is provided to ease the integration of the devices in application circuits. The framework provides the designer with total control overconvergence, computational load, and the evolution of system variables, overcoming usual problems in the integration of memristive devices.