Evaluation of naphthoquinones identified the acetylated isolapachol as a potent and selective antiplasmodium agent.

This study reports on the design, synthesis and antiparasitic activity of three new semi-synthetic naphthoquinones structurally related to the naturally-occurring lapachol and lapachone. Of the compounds tested, 3-(3-methylbut-1-en-1-yl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl acetate (1) was the most active against Plasmodium falciparum among both natural and semi-synthetic naphthoquinones, showing potent and selective activity. Compound 1 was able to reduce the in vitro parasite burden, in vitro parasite cell cycle, as well as the blood parasitemia in Plasmodium berghei-infected mice. More importantly, infection reduction under compound 1-treatment was achieved without exhibiting mouse genotoxicity. Regarding the molecular mechanism of action, this compound inhibited the hemozoin crystal formation in P. falciparum treated cells, and this was further confirmed by observing that it inhibits the ß-hematin polymerization process similarly to chloroquine. Interestingly, this compound did not affect either mitochondria structure or cause DNA fragmentation in parasite treated cells. In conclusion, we identified a semi-synthetic antimalarial naphthoquinone closely related to isolapachol, which had stronger antimalarial activity than lapachol.

Bone marrow cells migrate to the heart and skeletal muscle and participate in tissue repair after Trypanosoma cruzi infection in mice.

Infection by Trypanosoma cruzi, the aetiological agent of Chagas disease, causes an intense inflammatory reaction in several tissues, including the myocardium. We have previously shown that transplantation of bone marrow cells (BMC) ameliorates the myocarditis in a mouse model of chronic Chagas disease. We investigated the participation of BMC in lesion repair in the heart and skeletal muscle, caused by T. cruzi infection in mice. Infection with a myotropic T. cruzi strain induced an increase in the percentage of stem cells and monocytes in the peripheral blood, as well as in gene expression of chemokines SDF-1, MCP1, 2, and 3 in the heart and skeletal muscle. To investigate the fate of BMC within the damaged tissue, chimeric mice were generated by syngeneic transplantation of green fluorescent protein (GFP(+) ) BMC into lethally irradiated mice and infected with Trypanosoma cruzi. Migration of GFP(+) BMC to the heart and skeletal muscle was observed during and after the acute phase of infection. GFP(+) cardiomyocytes and endothelial cells were present in heart sections of chimeric chagasic mice. GFP(+) myofibres were observed in the skeletal muscle of chimeric mice at different time points following infection. In conclusion, BMC migrate and contribute to the formation of new resident cells in the heart and skeletal muscle, which can be detected both during the acute and the chronic phase of infection. These findings reinforce the role of BMC in tissue regeneration.

Physalins B and F, seco-steroids isolated from Physalis angulata L., strongly inhibit proliferation, ultrastructure and infectivity of Trypanosoma cruzi.

We previously observed that physalins have immunomodulatory properties, as well as antileishmanial and antiplasmodial activities. Here, we investigated the anti-Trypanosoma cruzi activity of physalins B, D, F and G. We found that physalins B and F were the most potent compounds against trypomastigote and epimastigote forms of T. cruzi. Electron microscopy of trypomastigotes incubated with physalin B showed disruption of kinetoplast, alterations in Golgi apparatus and endoplasmic reticulum, followed by the formation of myelin-like figures, which were stained with MDC to confirm their autophagic vacuole identity. Physalin B-mediated alteration in Golgi apparatus was likely due to T. cruzi protease perturbation; however physalins did not inhibit activity of the trypanosomal protease cruzain. Flow cytometry examination showed that cell death is mainly caused by necrosis. Treatment with physalins reduced the invasion process, as well as intracellular parasite development in macrophage cell culture, with a potency similar to benznidazole. We observed that a combination of physalins and benznidazole has a greater anti-T. cruzi activity than when compounds were used alone. These results indicate that physalins, specifically B and F, are potent and selective trypanocidal agents. They cause structural alterations and induce autophagy, which ultimately lead to parasite cell death by a necrotic process.

Antinociceptive and anti-inflammatory properties of 7-hydroxycoumarin in experimental animal models: potential therapeutic for the control of inflammatory chronic pain.

OBJECTIVES: In the present study we investigated the antinociceptive, anti-inflammatory and antipyretic effects of 7-hydroxycoumarin (7-HC) in animal models. METHODS: The effects of oral 7-HC were tested against acetic acid-induced writhing, formalin test, tail flick test, complete Freund's adjuvant (CFA)-induced hypernociception, carrageenan-induced paw oedema, lipopolysaccharide-induced fever and the rota rod test. KEY FINDINGS: 7-HC (3-60 mg/kg) produced a dose-related antinociception against acetic acid-induced writhing in mice and in the formalin test. In contrast, treatment with 7-HC did not prevent thermal nociception in the tail flick test. A single treatment with 7-HC, 60 mg/kg, produced a long-lasting antinociceptive effect against CFA-induced hypernociception, a chronic inflammatory pain stimulus. Notably, at 60 mg/kg per day over 4 days the administration of 7-HC produced a continuous antinociceptive effect against CFA-induced hypernociception. 7-HC (30-120 mg/kg) produced anti-inflammatory and antipyretic effects against carrageenan-induced inflammation and lipopolysaccharide-induced fever, respectively. Moreover, 7-HC was found to be safe with respect to ulcer induction. In the rota rod test, 7-HC-treated mice did not show any motor performance alterations. CONCLUSIONS: The prolonged antinociceptive and anti-inflammatory effects of 7-HC, in association with its low ulcerogenic activity, indicate that this molecule might be a good candidate for development of new drugs for the control of chronic inflammatory pain and fever.