Uric acid is a damage-associated molecular pattern (DAMP), released from ischemic tissues and dying cells which, when crystalized, is able to activate the NLRP3 inflammasome. Soluble uric acid (sUA) is found in high concentrations in the serum of great apes, and even higher in some diseases, before the appearance of crystals. In the present study, we sought to investigate whether uric acid, in the soluble form, could also activate the NLRP3 inflammasome and induce the production of IL-1β. We monitored ROS, mitochondrial area and respiratory parameters from macrophages following sUA stimulus. We observed that sUA is released in a hypoxic environment and is able to induce IL-1β release. This process is followed by production of mitochondrial ROS, ASC speck formation and caspase-1 activation. Nlrp3−/− macrophages presented a protected redox state, increased maximum and reserve oxygen consumption ratio (OCR) and higher VDAC protein levels when compared to WT and Myd88−/− cells. Using a disease model characterized by increased sUA levels, we observed a correlation between sUA, inflammasome activation and fibrosis. These findings suggest sUA activates the NLRP3 inflammasome. We propose that future therapeutic strategies for renal fibrosis should include strategies that block sUA or inhibit its recognition by phagocytes.

Marine natural products have proven, over the last half-century, to be effective biological modulators. These molecules have revealed new targets for cancer therapy as well as dissimilar modes of action within typical classes of drugs. In this scenario, innovation from marine-based pharmaceuticals has helped advance cancer chemotherapy in many aspects, as most of these are designated as first-in-class drugs. Here, by examining the path from discovery to development of clinically approved drugs of marine origin for cancer treatment-cytarabine (Cytosar-U®), trabectedin (Yondelis®), eribulin (Halaven®), brentuximab vedotin (Adcetris®), and plitidepsin (Aplidin®)-together with those in late clinical trial phases-lurbinectedin, plinabulin, marizomib, and plocabulin-the present review offers a critical analysis of the contributions given by these new compounds to cancer pharmacotherapy. 1 | INTRODUCTION Natural products have long been used in the treatment of human maladies and set a strong foundation upon which modern pharmacology has been erected. Particularly for cancer treatment, chemotherapeutic agents of natural origin have remarkably impacted the field, not only for their clinical importance but also for allowing the expansion of knowledge in cancer pharmacology. Natural agents like doxorubicin, paclitaxel, vincristine, and vinblastine are commonly used as first-line treatments for several cancers. The compounds of marine origin have a more recent history. Nevertheless, studies have shown their unique

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The actinomycete strain BRA 177 was recovered from sediment samples collected at the St. Peter and St. Paul Archipelago, Brazil. This work accessed the ability of this strain, identified as Actinomadura sp., to produce bioactive metabolites by exploring the genome and characterizing chemistry and cytotoxicity of isolated compounds. From the crude ethyl acetate extract, the pigments nonylprodigiosin, cyclononylprodigiosin and methylcyclooctilprodigiosin were isolated and displayed cytotoxicity against human tumor and non-tumor cell lines. Sequencing, assembling and prospection of BRA 177 draft genome led to identification of two contigs encoding enzymes with high homology to those from prodiginine biosynthetic gene clusters (BGC) in actinomycetes. Further, Actinomadura sp. BGC presented unique putatives RedJ thioesterase and RedL-like type I PKS, involved on selection of prodiginine biosynthetic fatty acyl precursor, and RedG-like Rieske oxygenase, key for cyclization of the prodiginines, suggesting that cyclononilprodigiosin and methylcyclooctylprodigiosin could actually be considered chemical signatures of Actinomadura spp.Keywords: cytotoxicity, genome mining, marine microorganisms, marine natural products, prodiginine derivatives IntroductionThe St. Peter and St. Paul Archipelago (SPSPA) is a remote group of islets located off the Brazilian coast. It is a rare case of geological formation, as this is the single portion of the Atlantic Ocean where the mantle has surfaced, permeating an area just about 17,000 m 2 above sea level.1 Peripheral habitats such as SPSPA and surroundings are a potential source of marine biodiversity with high degree of endemism. [1][2][3][4] Microbial diversity studies, however, are still very scarce, 5 while the biotechnological potential of microorganisms has only recently been described by our group in a preliminary assessment of the chemical diversity and prospection of anticancer compounds in extracts derived from culturable actinobacteria recovered from sediments collected therein. 6 Essentially, this work showed a high incidence of bioactive extracts among those obtained from the 268 isolates, and dereplication studies demonstrated the Bioprospecting Anticancer Compounds from the Marine-Derived Actinobacteria Actinomadura sp.J. Braz. Chem. Soc. 466 presence of notorious bioactive compounds, such as, but not restricted to, staurosporines, piericidins, saliniketals and rifamycins. Such preliminary results merely hinted on the biological and metabolic diversity that is predicted for the SPSPA. In this scenario, the strain, thereby coded as BRA 177, showed remarkable cytotoxicity against a human tumor cell line, 6 and was, thus, bidden for broader investigations. In fact, traditional bioprospective efforts have long merged chemical studies and biological assays in search for functional natural products. While these well-used equipment and methodologies have been ever evolving into more sensitive and high-throughput analytical tools, for the past decade or so, another perspectiv...