Introduction: Fatty acid amide hydrolase (FAAH) is a membrane-bound enzyme, that inactivates endogenous signaling lipids of the fatty acid amide family, including the endocannabinoid anandamide (N-arachidonoylethanolamine, AEA). The latter compound has been shown to regulate a number of important pathophysiological conditions in humans, like feeding, obesity, immune response, reproductive events, motor coordination, and neurological disorders. Hence, direct manipulation of the endocannabinoid tone is thought to have therapeutic potential. A new opportunity to develop effective drugs may arise from multi-target directed ligand (MTDL) strategies, which brings the concept that a single compound can recognize different targets involved in the cascade of pathophysiological events. Areas covered: This review reports the latest advances in the development of new single targeted and dual-targeted FAAH inhibitors over the past 5 years. Expert opinion: In recent years, several FAAH inhibitors have been synthesized and investigated, yet to date none of them has reached the market as a systemic drug. Due to the diligence of inherent redundancy and robustness in many biological networks and pathways, multitarget inhibitors present a new prospect in the pharmaceutical industry for treatment of complex diseases.

Amniotic epithelial cells (AEC) have been proposed as promising clinical candidates for regenerative medicine therapies due to their immunomodulatory capacity. In this context, the endocannabinoid system (ECS) has been identified as mediating the immune-stem cell dialogue, even if no information on AEC is available to date. Therefore, this study was designed to assess whether ECS is involved in tuning the constitutive and lipopolysaccharide (LPS)-induced ovine AEC anti-inflammatory and pro-inflammatory interleukin (IL-10, IL-4, and IL-12) profiles. Firstly, interleukins and ECS expressions were studied at different stages of gestation. Then, the role of cannabinoid receptors 1 and 2 (CB1 and CB2) on interleukin expression and release was investigated in middle stage AEC using selective agonists and antagonists. AEC displayed a degradative more than a synthetic endocannabinoid metabolism during the early and middle stages of gestation. At the middle stage, cannabinoid receptors mediated the balance between pro-inflammatory (IL-12) and anti-inflammatory (IL-4 and IL-10) interleukins. The activation of both receptors mediated an overall pro-inflammatory shift—CB1 reduced the anti-inflammatory and CB2 increased the pro-inflammatory interleukin release, particularly after LPS stimulation. Altogether, these data pave the way for the comprehension of AEC mechanisms tuning immune-modulation, crucial for the development of new AEC-based therapy protocols.

A correspondência entre Schopenhauer e seus discípulos – cuja edição italiana eu acabei de finalizar, realizando a tradução e a redação de um aparato crítico novo e completo – é a principal fonte para o conhecimento daquela que é entendida como a Escola de Schopenhauer em sentido estrito, e constitui-se de um modo especial como indispensável para o conhecimento da personalidade dos discípulos de Schopenhauer que não escreveram sobre ele e que o filósofo chamava de Apóstolos, para distingui-los dos Evangelistas, os discípulos que escreveram sobre ele. Entre os Apóstolos destaca-se a figura de Johann August Becker, com o qual em 1844 Schopenhauer manteve uma correspondência filosófica sobre o tema da afirmação e da negação da vontade, da liberdade do querer, da doutrina do caráter e do critério das ações morais, correspondência que chegou até nós sem lacunas. A sua importância é tal que no interior da escola circulavam três cópias dela, um sinal de como os discípulos de Schopenhauer consideravam-na como documento fundador de sua organização.