Evaluation of 3-(3-chloro-phenyl)-5-(4-pyridyl)-4,5-dihydroisoxazole as a Novel Anti-Inflammatory Drug Candidate

BACKGROUND: 3-(3-chloro-phenyl)-5-(4-pyridyl)-4,5-dihydroisoxazole (DIC) is a five-membered heterocyclic compound containing a N-O bond. The anti-inflammatory effects of this compound were studied both in vitro and in vivo. PRINCIPAL FINDINGS: DIC effectively decreased TNF-α and IL-6 release from LPS-stimulated macrophages in a dose dependent manner. DIC diminished the levels of COX-2 with subsequent inhibition of PGE(2) production. DIC also compromised HMGB1 translocation from the nucleus to the cytoplasm. Moreover, DIC prevented the nuclear translocation of NF-κB and inhibited the MAPK pathway. In vivo, DIC inhibited migration of neutrophils to the peritoneal cavity of mice. CONCLUSIONS: This study presents the potential utilization of a synthetic compound, as a lead for the development of novel anti-inflammatory drugs

The Politics of (and Behind) the UNFCCC’s Loss and Damage Mechanism

Despite being one of the most controversial issues to be recently treated within climate negotiations, Loss and Damage (L&D) has attracted little attention among scholars of International Relations (IR). In this chapter we take the “structuralist paradox” in L&D negotiations as our starting point, considering how IR theories can help to explain the somewhat surprising capacity of weak parties to achieve results while negotiating with stronger parties. We adopt a multi-faceted notion of power, drawing from the neorealist, liberal and constructivist schools of thought, in order to explain how L&D milestones were reached. Our analysis shows that the IR discipline can greatly contribute to the debate, not only by enhancing understanding of the negotiation process and related outcomes but also by offering insights on how the issue could be fruitfully moved forward. In particular, we note the key importance that discursive power had in the attainment of L&D milestones: Framing L&D in ethical and legal terms appealed to standards relevant beyond the UNFCCC context, including basic moral norms linked to island states’ narratives of survival and the reference to international customary law. These broader standards are in principle recognised by both contending parties and this broader framing of L&D has helped to prove the need for action on L&D. However, we find that a change of narrative may be needed to avoid turning the issue into a win-lose negotiation game. Instead, a stronger emphasis on mutual gains through adaptation and action on L&D for both developed and developing countries is needed as well as clarity on the limits of these strategies. Examples of such mutual gains are more resilient global supply chains, reduction of climate-induced migration and enhanced security. As a result, acting on L&D would not feel as a unilateral concession developed countries make to vulnerable ones: it would rather be about elaborating patterns of collective action on an issue of common concern

Smoking p66Shc Knocked Out Mice Develop Respiratory Bronchiolitis with Fibrosis but Not Emphysema

The adaptor protein p66Shc regulates intracellular oxidant levels through the modulation of a forkhead-related transcription factor (FOXO3a). The genetic ablation of p66Shc (p66Shc-/-) renders mice resistant to oxidative stress and p53-dependent apoptosis. We investigated whether p66Shc ablation in mice modifies lung cellular and molecular responses to cigarette smoke (CS) exposure. No differences between wild type (WT) and p66Shc-/- mice were observed in terms of inflammation and oxidant burden after acute CS exposure; however, p66Shc ablation modifies specific features of chronic inflammation induced by repeated exposure to CS. Unlike WT mice, p66Shc-/- mice did not develop emphysema, showing protection toward oxidative damage to DNA and apoptosis as revealed by a trivial 8-hydroxyguanosine staining and faint TUNEL and caspase-3 positivity on alveolar epithelial cells. Unexpectedly, CS exposure in p66Shc-/- mice resulted in respiratory bronchiolitis with fibrosis in surrounded alveoli. Respiratory bronchiolitis was characterized by peribronchiolar infiltrates of lymphocytes and histiocytes, accumulation of ageing pigmented macrophages within and around bronchioles, and peribronchiolar fibrosis. The blockage of apoptosis interferes with the macrophage "clearance" from alveolar spaces, favouring the accumulation of aging macrophages into alveoli and the progressive accumulation of iron pigment in long-lived senescent cells. The presence of areas of interstitial and alveolar fibrosis in peripheral parenchyma often accompanied the bronchiolar changes. Macrophages from smoking p66Shc-/- mice elaborate M2 cytokines (i.e., IL-4 and IL-13) and enzymes (i.e., chitinase and arginase I), which can promote TGF-beta expression, collagen deposition, and fibrosis in the surrounding areas. We demonstrate here that resistance to oxidative stress and p53-dependent apoptosis can modify tissue responses to CS caused by chronic inflammation without influencing early inflammatory response to CS exposure