Host-defense peptides AC12, DK16 and RC11 with immunomodulatory activity isolated from Hypsiboas raniceps skin secretion

Inflammation is a natural defense mechanism of the immune system; however, when unregulated, it can lead to chronic illness. Glucocorticoids are the most commonly used agents to effectively treat inflammatory conditions, including autoimmune diseases, however these substances can trigger a number of side effects. Thus, viable alternatives to the use of these drugs would be advantageous. In this study, we have analyzed the anti-inflammatory profile of three synthetic peptides first identified in skin secretion of the tree frog Hypsiboas raniceps. Structural characterization was performed using NMR spectroscopy and Mass Spectrometry, and the peptides were tested in vitro in RAW 264.7 cells and in vivo in Balb/c mice for their functional properties. The samples did not show a significant antimicrobial profile. NMR spectroscopy indicated that AC12 (ACFLTRLGTYVC) has a disulfide bond between C2 and C11 and a β-sheet-turn-β-sheet conformation in aqueous solution. This peptide showed no cytotoxic effect in mammalian cells and it was the most effective in reducing anti-inflammatory markers, such as NO, TNF-α and IL-12. Peptide DK16 (DKERPICSNTFRGRKC) demonstrated anti-inflammatory properties in vitro, while RC11 (RCFRRRGKLTC) significantly altered the cell viability in RAW 264.7 but was shown to be safe in Balb/c erythrocytes. Our results indicate that, of the three peptides studied, AC12 is the most efficient in reducing anti-inflammatory markers, and it could be a potential agent for the treatment of inflammatory diseases.publishe

Cryptococcus neoformans Secretes Small Molecules That Inhibit IL-1β Inflammasome-Dependent Secretion

Cryptococcus neoformans is an encapsulated yeast that causes disease mainly in immunosuppressed hosts. It is considered a facultative intracellular pathogen because of its capacity to survive and replicate inside phagocytes, especially macrophages. This ability is heavily dependent on various virulence factors, particularly the glucuronoxylomannan (GXM) component of the polysaccharide capsule. Inflammasome activation in phagocytes is usually protective against fungal infections, including cryptococcosis. Nevertheless, recognition of C. neoformans by inflammasome receptors requires specific changes in morphology or the opsonization of the yeast, impairing proper inflammasome function. In this context, we analyzed the impact of molecules secreted by C. neoformans B3501 strain and its acapsular mutant Δcap67 in inflammasome activation in an in vitro model. Our results showed that conditioned media derived from B3501 was capable of inhibiting inflammasome-dependent events (i.e., IL-1β secretion and LDH release via pyroptosis) more strongly than conditioned media from Δcap67, regardless of GXM presence. We also demonstrated that macrophages treated with conditioned media were less responsive against infection with the virulent strain H99, exhibiting lower rates of phagocytosis, increased fungal burdens, and enhanced vomocytosis. Moreover, we showed that the aromatic metabolite DL-Indole-3-lactic acid (ILA) and DL-p-Hydroxyphenyllactic acid (HPLA) were present in B3501’s conditioned media and that ILA alone or with HPLA is involved in the regulation of inflammasome activation by C. neoformans. These results were confirmed by in vivo experiments, where exposure to conditioned media led to higher fungal burdens in Acanthamoeba castellanii culture as well as in higher fungal loads in the lungs of infected mice. Overall, the results presented show that conditioned media from a wild-type strain can inhibit a vital recognition pathway and subsequent fungicidal functions of macrophages, contributing to fungal survival in vitro and in vivo and suggesting that secretion of aromatic metabolites, such as ILA, during cryptococcal infections fundamentally impacts pathogenesis

Instituições e cooperação social em Douglass North e nos intérpretes weberianos do atraso brasileiro

O artigo tem por objetivo resgatar a aproximação teórica entre o arcabouço institucionalista de Douglass North e os argumentos utilizados por intérpretes do Brasil de reconhecida orientação weberiana, como Sérgio Buarque de Holanda, Vianna Moog e Raymundo Faoro. Para tanto, privilegia o entendimento da relação entre instituições e cooperação social presentes na obra desses autores como variável relevante para explicar o desempenho de longo prazo da economia brasileira, bem como de seu relativo atraso