The structure design of biotransformed unsymmetrical nitro-contained 1,5-diaryl-3-oxo-1,4-pentadienyls for the anti-parasitic activities

AbstractTwo 1,5-diaryl-3-oxo-1,4-pentadienyls (1 and 2) having nitro group attached exhibited potent anti-parasitic activity when evaluated against Trypanosoma cruzi and Leishmania amazonensis. In the present work, metabolomic analysis revealed that enzymatic action of T. cruzi reduces the CC bonds and let the nitro groups intact. Further, these two reduced compounds along with six other congeners were produced by chemical or microbiological methods and evaluated against T. cruzi. All reduced compounds showed less potency than compounds 1 and 2, proving the importance of unsaturated moieties for activity. This investigation provides insight into the mechanism of action of nitro unsaturated diarylpentadienones reinforcing previous studies showing their interference in the redox metabolism of T. cruzi. In the result increase in reactive oxygen and nitrogen species occurs, altering mitochondrial function and depleting the whole antioxidant system, which ultimately causes parasite death. Docking studies using trypanothione oxy-reductase as target helped understanding the activities. The present investigation confirms that enzymes play a pivotal role in drug activation

Copper and manganese cations alter secondary metabolism in the fungus Penicillium brasilianum

FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESThe fungus Penicillium brasilianum LaBioMMi 136 was isolated as an endophyte from Melia azedarach and has shown to be a prominent producer of great diversity of secondary metabolites, although it does not express some biosynthetic routes to other natural27814441451FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPES2014/03510-22010/52312-8SEM INFORMAÇÃOSEM INFORMAÇÃOThe authors are grateful to the Brazilian institutions (Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Process No. 2014/03510-2 and 2010/52312-8), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfei

Eupomatenoid-5 Isolated from Leaves of Piper regnellii Induces Apoptosis in Leishmania amazonensis

Leishmania spp. are protozoa responsible for leishmaniasis, a neglected disease that kills up to 50,000 people every year. Current therapies mainly rely on antimonial drugs that are inadequate because of their poor efficacy and safety and increased drug resistance. An urgent need exists to find new and more affordable drugs. Our previous study demonstrated the antileishmanial activity of eupomatenoid-5, a neolignan obtained from leaves of Piper regnellii var. pallescens. The aim of the present study was to clarify the mode of action of eupomatenoid-5 against L. amazonensis. We used biochemical and morphological techniques and demonstrated that eupomatenoid-5 induced cell death in L. amazonensis promastigotes, sharing some phenotypic features observed in metazoan apoptosis, including increased reactive oxygen species production, hypopolarization of mitochondrial potential, phosphatidylserine exposure, decreased cell volume, and G0/G1 phase cell cycle arrest

Drug carrier systems made from self-assembled glyco-nanoparticles of maltoheptaose-b-polyisoprene enhanced the distribution and activity of curcumin against cancer cells

International audienc

Additional Evidence of the Trypanocidal Action of (−)-Elatol on Amastigote Forms through the Involvement of Reactive Oxygen Species

Chagas’ disease, a vector-transmitted infectious disease, is caused by the protozoa parasite Trypanosoma cruzi. Drugs that are currently available for the treatment of this disease are unsatisfactory, making the search for new chemotherapeutic agents a priority. We recently described the trypanocidal action of (−)-elatol, extracted from the macroalga Laurencia dendroidea. However, nothing has been described about the mechanism of action of this compound on amastigotes that are involved in the chronic phase of Chagas’ disease. The goal of the present study was to evaluate the effect of (−)-elatol on the formation of superoxide anions (O2•−), DNA fragmentation, and autophagy in amastigotes of T. cruzi to elucidate the possible mechanism of the trypanocidal action of (−)-elatol. Treatment of the amastigotes with (−)-elatol increased the formation of O2•− at all concentrations of (−)-elatol assayed compared with untreated parasites. Increased fluorescence was observed in parasites treated with (−)-elatol, indicating DNA fragmentation and the formation of autophagic compartments. The results suggest that the trypanocidal action of (−)-elatol might involve the induction of the autophagic and apoptotic death pathways triggered by an imbalance of the parasite’s redox metabolism

Effects of (1E,4E)-2-Methyl-1,5-bis(4-nitrophenyl)penta-1,4-dien-3-one on Trypanosoma cruzi and Its Combinational Effect with Benznidazole, Ketoconazole, or Fluconazole

This study reports the activity induced by (1E,4E)-2-methyl-1,5-bis(4-nitrophenyl)penta-1,4-dien-3-one (A3K2A3) against Trypanosoma cruzi. This compound showed trypanocidal activity against the multiplicative epimastigote and amastigote forms of this protozoan, with IC50 values of 1.99±0.17 and 1.20±0.16 μM, respectively, and EC50 value of 15.57±0.34 μM against trypomastigotes. The combination of A3K2A3 with benznidazole or ketoconazole demonstrated strong synergism, increasing effectiveness against trypomastigotes or epimastigotes of T. cruzi. In addition, the drug combination of A3K2A3 with benznidazole or ketoconazole on LLCMK2 cells demonstrated an antagonist effect, which resulted in greater protection of the cells from drug damage. The combination of the compound with fluconazole was not effective. Transmission and scanning electron micrographs showed changes on parasites, mainly in the cytoplasmatic membrane, nucleus, mitochondrion, and Golgi complex, and a large increase in the number of autophagosome-like structures and lipid-storage bodies, accompanied by volume reduction and rounding of the parasite. A3K2A3 might be a promising compound against T. cruzi

Doxorubicin-Loaded Iron Oxide Nanoparticles Induce Oxidative Stress and Cell Cycle Arrest in Breast Cancer Cells

Cancer is one of the most common diseases nowadays and derives from the uncontrollable growth of a single cell. Magnetic nanoparticles (NpMag) offer various possibilities for use in the biomedical area, including drug delivery mediated by magnetic fields. In the current study, we evaluated the in vitro effects of iron-oxide magnetic nanoparticles conjugated with the antitumor drug doxorubicin (Dox) on human breast cancer cells. Our results revealed that magnetic nanoparticles with Dox (NpMag+Dox) induce cellular redox imbalance in MCF-7 cells. We also demonstrate that iron-oxide nanoparticles functionalized with Dox induce oxidative stress evidenced by DNA damage, lipid peroxidation, cell membrane disruption, and loss of mitochondria potential. As a result, NpMag+Dox drives MCF-7 cells to stop the cell cycle and decrease cell migration. The association of NpMg+Dox induced a better delivery of Dox to MCF cells, mainly in the presence of a magnetic field, increasing the death of MCF cells which might reduce the toxicity for healthy cells providing a better efficacy for the treatment. Thus, iron-oxide nanoparticles and doxorubicin conjugated may be candidate for anticancer therapy

Development of Environmentally Responsive Self-Emulsifying System Containing Copaiba Oil-Resin for Leishmaniasis Oral Treatment

Leishmaniasis is a disease caused by protozoa species of the Leishmania genus, and the current treatments face several difficulties and obstacles. Most anti-leishmanial drugs are administered intravenously, showing many side effects and drug resistance. The discovery of new anti-leishmanial compounds and the development of new pharmaceutical systems for more efficient and safer treatments are necessary. Copaiba oil-resin (CO) has been shown to be a promising natural compound against leishmaniasis. However, CO displays poor aqueous solubility and bioavailability. Self-emulsifying drug delivery systems (SEDDS) can provide platforms for release of hydrophobic compounds in the gastrointestinal tract, improving their aqueous solubilization, absorption and bioavailability. Therefore, the present work aimed to develop SEDDS containing CO and Soluplus® surfactant for the oral treatment of leishmaniasis. The design of the systems was accomplished using ternary phase diagrams. Emulsification and dispersion time tests were used to investigate the emulsification process in gastric and intestinal environments. The formulations were nanostructured and improved the CO solubilization. Their in vitro antiproliferative activity against promastigote forms of L. amazonensis and L. infantum, and low in vitro cytotoxicity against macrophages were also observed. More studies are necessary to determine effectiveness of SOL in these systems, which can be candidates for further pharmacokinetics and in vivo investigations

Copper and Manganese Cations Alter Secondary Metabolism in the Fungus Penicillium brasilianum

The fungus Penicillium brasilianum LaBioMMi 136 was isolated as an endophyte from Melia azedarach and has shown to be a prominent producer of great diversity of secondary metabolites, although it does not express some biosynthetic routes to other natural compounds found in Penicillium genera. The present study aimed at the diversification of P. brasilianum secondary metabolism by varying the chemical composition used for its growth. Medium composition supplemented with CuSO4 and MnSO4 locked verruculogen biosynthesis and addressed proline to the production of a series of cyclodepsipeptides identified as JBIR 113, JBIR 114 and JBIR 115, never described for this species so far. The induced cyclodepsipeptide JBIR 113 was isolated by the use of combined chromatographic procedures and identified by spectroscopic methods. The unique structure with three neighboring cyclic amino acids proline and twice pipecolinic acid is rare as natural products and has been described for the first time in terrestrial organism. Verruculogen and JBIR 113 exhibited weak antiparasitary activity against Leishmania amazonensis

The Combination of Vitamin K3 and Vitamin C Has Synergic Activity against Forms of Trypanosoma cruzi through a Redox Imbalance Process.

Chagas' disease is an infection that is caused by the protozoan Trypanosoma cruzi, affecting millions of people worldwide. Because of severe side effects and variable efficacy, the current treatments for Chagas' disease are unsatisfactory, making the search for new chemotherapeutic agents essential. Previous studies have reported various biological activities of naphthoquinones, such as the trypanocidal and antitumor activity of vitamin K3. The combination of this vitamin with vitamin C exerted better effects against various cancer cells than when used alone. These effects have been attributed to an increase in reactive oxygen species generation. In the present study, we evaluated the activity of vitamin K3 and vitamin C, alone and in combination, against T. cruzi. The vitamin K3 + vitamin C combination exerted synergistic effects against three forms of T. cruzi, leading to morphological, ultrastructural, and functional changes by producing reactive species, decreasing reduced thiol groups, altering the cell cycle, causing lipid peroxidation, and forming autophagic vacuoles. Our hypothesis is that the vitamin K3 + vitamin C combination induces oxidative imbalance in T. cruzi, probably started by a redox cycling process that leads to parasite cell death