Immune-mediated parasite clearance in mice infected with Plasmodium berghei following treatment with manzamine A
ABSTRACT Manzamine A, a sponge-derived alkaloid, was recently shown to possess in vivo antimalarial activity against the blood stages of the rodent malaria parasite Plasmodium berghei. A single intraperitoneal dose of 100 micromol/kg of manzamine A suppressed parasite growth but was followed by parasite recrudescence. Forty percent of mice with recrudescing parasites were able to recover and clear the fulminating parasitaemia. Examination of sera from these mice revealed that infected mice treated with manzamine A had a suppressed IFN-gamma production but an increase in their IL-10 and IgG production. The prolonged survival of infected mice treated with manzamine A and the eventual clearance of recrudescing parasites in some of these mice involve a down-regulation of Thl responses and a switch to antibody dependent-Th2 responses.
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Article: Anti-malarials from marine sponges[Show abstract] [Hide abstract]
ABSTRACT: Malaria, which is caused by multiplication of the protozoan parasite Plasmodium falciparum in erythrocytes, is a major health problem in many southern countries. There is an urgent need to discover new antimalarials, due to the spread of chloroquinine resistance and the limited number of available drugs. Among marine invertebrates, Porifera (sponges) are potential source of novel bioactive compounds to provide future drugs against malaria, cancer and a range of viral diseases. A number of sponge-derived antimalarials have been discovered during the last decade. The compounds are mostly nitrogen containing ones (proteins, pyridines, tyrosine-based metabolites, alkaloids, indoles and amides) and also non-nitrogenous compounds (terpenes, polyketides and polysaccharides).
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ABSTRACT: Thromboxane B2 (TXB2) and superoxide anion (O2-) are neuroinflammatory mediators that appear to be involved in the pathogenesis of several neurodegenerative diseases. Because activated-microglia are the main source of TXB2 and O2- in these disorders, modulation of their synthesis has been hypothesized as a potential therapeutic approach for neuroinflammatory disorders. Marine natural products have become a source of novel agents that modulate eicosanoids and O2- generation from activated murine and human leukocytes. With the exception of manzamine C, all other manzamines tested are characterized by a complex pentacyclic diamine linked to C-1 of the beta-carboline moiety. These marine-derived alkaloids have been reported to possess a diverse range of bioactivities including anticancer, immunostimulatory, insecticidal, antibacterial, antimalarial and antituberculosis activities. The purpose of this investigation was to conduct a structure-activity relationship study with manzamines (MZ) A, B, C, D, E and F on agonist-stimulated release of TXB2 and O2- from E. coli LPS-activated rat neonatal microglia in vitro. The manzamines differentially attenuated PMA (phorbol 12-myristate 13-acetate)-stimulated TXB2 generation in the following order of decreasing potency: MZA (IC50 < 0.016 microM) > MZD (IC50 = 0.23 microM) > MZB (IC50 = 1.6 microM) > MZC (IC50 = 2.98 microM) > MZE and F (IC50 > 10 microM). In contrast, there was less effect on OPZ (opsonized zymosan)-stimulated TXB2 generation: MZB (IC50 = 1.44 microM) > MZA (IC50 = 3.16 microM) > MZC (IC50 = 3.34 microM) > MZD, MZE and MZF (IC50 > 10 microM). Similarly, PMA-stimulated O2- generation was affected differentially as follows: MZD (apparent IC50 < 0.1 microM) > MZA (IC50 = 0.1 microM) > MZB (IC50 = 3.16 microM) > MZC (IC50 = 3.43 microM) > MZE and MZF (IC50 > 10 microM). In contrast, OPZ-stimulated O2- generation was minimally affected: MZB (IC50 = 4.17 microM) > MZC (IC50 = 9.3 microM) > MZA, MZD, MZE and MZF (IC50 > 10 microM). From the structure-activity relationship perspective, contributing factors to the observed differential bioactivity on TXB2 and O2- generation are the solubility or ionic forms of MZA and D as well as changes such as saturation or oxidation of the beta carboline or 8-membered amine ring. In contrast, the fused 13-membered macrocyclic and isoquinoline ring system, and any substitutions in these rings would not appear to be factors contributing to bioactivity. To our knowledge, this is the first experimental study that demonstrates that MZA, at in vitro concentrations that are non toxic to E. coli LPS-activated rat neonatal microglia, potently modulates PMA-stimulated TXB2 and O2- generation. MZA may thus be a lead candidate for the development of novel therapeutic agents for the modulation of TXB2 and O2- release in neuroinflammatory diseases. Marine natural products provide a novel and rich source of chemical diversity that can contribute to the design and development of new and potentially useful anti-inflammatory agents to treat neurodegenerative diseases.BMC Pharmacology 03/2005; 5:6. DOI:10.1186/1471-2210-5-6
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ABSTRACT: Manzamine A, a member of the manzamine alkaloids, was originally isolated from marine sponges of the genus Haliclona. It was recently shown to have activity against pancreatic cancer cells, but the precise mechanism of action remained unclear. To further our understanding of the mechanism of action of manzamine A, chemogenomic profiling in the yeast S. cerevisiae was performed, suggesting that manzamine A is an uncoupler of vacuolar ATPases. Fluorescence microscopy confirmed this effect on yeast vacuoles, where manzamine A produced a phenotype very similar to that of the established v-ATPase inhibitor bafilomycin A1. In pancreatic cancer cells, 10 µM manzamine A affected vacuolar ATPase activity and significantly increased the level of autophagosome marker LC3-II and p62/SQSTM1 as observed by western blot analysis. Treatment with manzamine A in combination with bafilomycin A1 (inhibitor of autophagosome-lysosome fusion) did not change the levels of LC3-II when compared to cells treated with bafilomycin A1 alone, suggesting that manzamine A is a potential inhibitor of autophagy by preventing autophagosome turnover. As autophagy is essential for pancreatic tumor growth, blocking this pathway with manzamine A suggests a promising strategy for the treatment of pancreatic cancer.Marine Drugs 09/2013; 11(9):3500-16. DOI:10.3390/md11093500 · 3.51 Impact Factor