Identification of Pharmacological Modulators of HMGB1-Induced Inflammatory Response by Cell-Based Screening

High mobility group box 1 (HMGB1), a highly conserved, ubiquitous protein, is released into the circulation during sterile inflammation (e.g. arthritis, trauma) and circulatory shock. It participates in the pathogenesis of delayed inflammatory responses and organ dysfunction. While several molecules have been identified that modulate the release of HMGB1, less attention has been paid to identify pharmacological inhibitors of the downstream inflammatory processes elicited by HMGB1 (C23-C45 disulfide C106 thiol form). In the current study, a cell-based medium-throughput screening of a 5000+ compound focused library of clinical drugs and drug-like compounds was performed in murine RAW264.7 macrophages, in order to identify modulators of HMGB1-induced tumor-necrosis factor alpha (TNFα) production. Clinically used drugs that suppressed HMGB1-induced TNFα production included glucocorticoids, beta agonists, and the anti-HIV compound indinavir. A re-screen of the NIH clinical compound library identified beta-agonists and various intracellular cAMP enhancers as compounds that potentiate the inhibitory effect of glucocorticoids on HMGB1-induced TNFα production. The molecular pathways involved in this synergistic anti-inflammatory effect are related, at least in part, to inhibition of TNFα mRNA synthesis via a synergistic suppression of ERK/IκB activation. Inhibition of TNFα production by prednisolone+salbutamol pretreatment was also confirmed in vivo in mice subjected to HMGB1 injection; this effect was more pronounced than the effect of either of the agents administered separately. The current study unveils several drug-like modulators of HMGB1-mediated inflammatory responses and offers pharmacological directions for the therapeutic suppression of inflammatory responses in HMGB1-dependent diseases. © 2013 Gerö et al

Democratization of mathematics through Cremona's correspondence with foreign colleagues (1860-1901)

Between the 19th and 20th centuries many common traits were shared by national mathematical communities far apart geographically (from the Czech lands to Japan), culturally (from north to south Europe) or as to the dynamism of original research (from Germany to the United States). Societies and journals in the national language were launched, thanks to the widening of the social platform of mathematics and the emergence of a national leadership; the deployment of the state school systems increased mathematical information; and mathematics played a role and received encouragement from the processes of social and economical modernization and development of state institutions. Intellectual competition among nations, much in the spirit of the 19th century, seem to prevail on the early Modern European universalism. A panorama of almost planetary diffusion of Western mathematics resulted from this evolution, and eventually a reinforcement of international circulation of knowledge, which survived two world wars. The collection of letters written to Luigi Cremona conserved at the Sapienza University of Rome throws light on several aspects of this evolution. Letters offer a point of view on the "backstage", in contrast with official proclamations; they show the interplay between national leaders and the circles in the capitals and mathematicians working in isolation; they show a variety of connected activities – research, institutional commitments, and cultural fostering, including translations and textbooks. International dialog grew out of this nebula of initiatives driven by national passion, by philosophical and political convictions; in contrast with the present European trend to entrust the circulations of ideas – and the production of knowledge – to initiatives governed from the top, and standardized (design, funding and assessment), far beyond what would be needed. The edition (in the Académie Internationale d'Histoire des Sciences series "De diversis artibus") has been carried out by a European team directed by Giorgio Israel