Pharmacologic Targeting of Bacterial -Glucuronidase Alleviates Nonsteroidal Anti-Inflammatory Drug-Induced Enteropathy in Mice

Small intestinal mucosal injury is a frequent adverse effect caused by nonsteroidal anti-inflammatory drugs (NSAIDs). The underlying mechanisms are not completely understood, but topical (luminal) effects have been implicated. Many carboxylic acid-containing NSAIDs, including diclofenac (DCF), are metabolized to acyl glucuronides (AGs), and/or ether glucuronides after ring hydroxylation, and exported into the biliary tree. In the gut, these conjugates are cleaved by bacterial β-glucuronidase, releasing the potentially harmful aglycone. We first confirmed that DCF-AG was an excellent substrate for purified Escherichia coli β-d-glucuronidase. Using a previously characterized novel bacteria-specific β-glucuronidase inhibitor (Inhibitor-1), we then found that the enzymatic hydrolysis of DCF-AG in vitro was inhibited concentration dependently (IC50 ∼164 nM). We next hypothesized that pharmacologic inhibition of bacterial β-glucuronidase would reduce exposure of enterocytes to the aglycone and, as a result, alleviate enteropathy. C57BL/6J mice were administered an ulcerogenic dose of DCF (60 mg/kg i.p.) with or without oral pretreatment with Inhibitor-1 (10 μg per mouse, b.i.d.). Whereas DCF alone caused the formation of numerous large ulcers in the distal parts of the small intestine and increased (2-fold) the intestinal permeability to fluorescein isothiocyanate-dextran, Inhibitor-1 cotreatment significantly alleviated mucosal injury and reduced all parameters of enteropathy. Pharmacokinetic profiling of DCF plasma levels in mice revealed that Inhibitor-1 coadministration did not significantly alter the Cmax, half-life, or area under the plasma concentration versus time curve of DCF. Thus, highly selective pharmacologic targeting of luminal bacterial β-d-glucuronidase by a novel class of small-molecule inhibitors protects against DCF-induced enteropathy without altering systemic drug exposure

Arqueología cultural de los videojuegos. Entre discursos nostálgicos, experiencia del gamer e innovación tecnológica

In this paper, it is presented a videogames history as an innovation beyond a form of entertainment, offering reasons why it is important to know and investigate its history in relation to their social and cultural contexts. Marking the importance that users have when creating video games through their experience, questioning masculinity constructed in the first era of videogames and no or less participation of the female gender in the early decades. The social and cultural context in which those games were born is basic to understanding the spread and gained popularity in the ‘80s and especially in the ‘90s. The objective of this study is to identify communication strategies and information about the videogame before the arrival of the Internet and how information was shared in the Spanish context. In the first part we introduce the theoretical and methodological framework in which this research is based through the concept of cultural archeology. In the second part we present stories built by users to analyze the experiences of the game and how to share it, using the concepts of playformance and playworld. To finish questioning the identity of the gamer as a male subject, young white and upper middle class.En este trabajo, se presentara una historia de los videojuegos como una innovación más allá de una forma de entretenimiento, ofreciendo razones acerca de por qué es importante conocer e investigar su historia en relación a sus contextos sociales y culturales. Haciendo énfasis en la importancia que los usuarios tienen a la hora de crear videojuegos a través de su experiencia, cuestionando la masculinidad construida en los primeros videojuegos y la ausencia, o menor participación, del género femenino en las primeras décadas. El contexto social y cultural en que nacieron aquellos videojuegos es básico para entender la difusión y la popularidad que obtuvieron en los años ‘80 y sobre todo, en los ‘90. El objetivo de este trabajo es identificar las estrategias de comunicación y de información respecto a los videojuegos antes de la llegada de Internet, en especial la forma y el cómo se compartía esta información en el contexto español. En la primera parte introducimos el marco teórico y metodológico en que se basa esta investigación a través del concepto de arqueología cultural. En la segunda parte presentamos los relatos construidos por los usuarios para analizar las experiencias del juego y la forma de compartirlo, utilizando los conceptos de playformance y playworld. Para finalizar cuestionando la identidad del gamer como sujeto masculino, blanco y joven de clase media-alta