Danielle Macêdo Gaspar

Synergistic Effect of the Flavonoid Catechin, Quercetin, or Epigallocatechin Gallate with Fluconazole Induces Apoptosis in Candida tropicalis Resistant to Fluconazole

ABSTRACT Flavonoids are a class of phenolic compounds commonly found in fruits, vegetables, grains, flowers, tea, and wine. They differ in their chemical structures and characteristics. Such compounds show various biological functions and have antioxidant, antimicrobial, anti-inflammatory, and antiapoptotic properties. The aim of this study was to evaluate the in vitro interactions of flavonoids with fluconazole against Candida tropicalis strains resistant to fluconazole, investigating the mechanism of synergism. Three combinations formed by the flavonoids (+)-catechin hydrated, hydrated quercetin, and (−)-epigallocatechin gallate at a fixed concentration with fluconazole were tested. Flavonoids alone had no antifungal activity within the concentration range tested, but when they were used as a cotreatment with fluconazole, there was significant synergistic activity. From this result, we set out to evaluate the possible mechanisms of cell death involved in this synergism. Isolated flavonoids did not induce morphological changes or changes in membrane integrity in the strains tested, but when they were used as a cotreatment with fluconazole, these changes were quite significant. When evaluating mitochondrial damage and the production of reactive oxygen species (ROS) only in the cotreatment, changes were observed. Flavonoids combined with fluconazole were shown to cause a significant increase in the rate of damage and the frequency of DNA damage in the tested strains. The cotreatment also induced an increase in the externalization of phosphatidylserine, an important marker of early apoptosis. It is concluded that flavonoids, when combined with fluconazole, show activity against strains of C. tropicalis resistant to fluconazole, promoting apoptosis by exposure of phosphatidylserine in the plasma membrane and morphological changes, mitochondrial depolarization, intracellular accumulation of ROS, condensation, and DNA fragmentation.

Antifungal Activity of Naphthoquinoidal Compounds In Vitro against Fluconazole-Resistant Strains of Different Candida Species: A Special Emphasis on Mechanisms of Action on Candida tropicalis

In recent decades, the incidence of candidemia in tertiary hospitals worldwide has substantially increased. These infections are a major cause of morbidity and mortality; in addition, they prolong hospital stays and raise the costs associated with treatment. Studies have reported a significant increase in infections by non-albicans Candida species, especially C. tropicalis. The number of antifungal drugs on the market is small in comparison to the number of antibacterial agents available. The limited number of treatment options, coupled with the increasing frequency of cross-resistance, makes it necessary to develop new therapeutic strategies. The objective of this study was to evaluate and compare the antifungal activities of three semisynthetic naphthofuranquinone molecules against fluconazole-resistant Candida spp. strains. These results allowed to us to evaluate the antifungal effects of three naphthofuranquinones on fluconazole-resistant C. tropicalis. The toxicity of these compounds was manifested as increased intracellular ROS, which resulted in membrane damage and changes in cell size/granularity, mitochondrial membrane depolarization, and DNA damage (including oxidation and strand breakage). In conclusion, the tested naphthofuranquinones (compounds 1–3) exhibited in vitro cytotoxicity against fluconazole-resistant Candida spp. strains.

Subchronic administration of riparin III induces antidepressive-like effects and increases BDNF levels in the mouse hippocampus

Riparin III (Rip III) is an alcamide isolated from Aniba riparia that has presented effects of antidepressant and anxiolytic activities in acute stress behavioral models. The trials goal was to investigate the activity of Rip III in mice exposed to corticosterone‐induced chronic depression model. Swiss female mice, 22–25 g, were distributed in following experimental groups: control group (vehicle1: saline containing 0.1% dimethyl sulfoxide and 0.1% Tween‐80, SC+ vehicle 2: distilled water emulsified with 2% Tween‐80, PO); stressed group (corticosterone, 20 mg/kg, SC, + vehicle 2, orally); Rip III group (50 mg/kg, orally); and fluvoxamine (Flu) group (50 mg/kg, orally). The mice were exposed to the behavioral tests, and posteriorly, Brain‐derived neurotrophic factor protein levels were assessed in hippocampal samples. Statistical analysis of the data was performed by one‐way anova, followed by Newman–Keuls test. Both administrations of Rip III and Flu significantly reduced the immobility time in tail suspension and forced swimming tests after 21 days without affecting locomotor function. There was also an increase in BDNF protein levels in the mice hippocampus. These findings further support the hypothesis that Rip III could be a new pharmacological target for the treatment of mood disorders.

Uso de Benzodiazepínicos como automedicação: consequências do uso abusivo, dependência, farmacovigilância e farmacoepidemiologia

O uso indiscriminado de medicamentos e motivo de preocupacao para as autoridades de varios paises. De acordo com dados da Organizacao Mundial da Saude (OMS), o percentual de internacoes hospitalares provocadas por reacoes adversas a medicamentos ultrapassa 10%. Este estudo objetiva realizar uma revisao sistematica da literatura, abrangendo a epidemiologia, a caracterizacao comportamental dos usuarios continuos de medicamentos controlados e o tratamento dos pacientes portadores de disturbios psiquicos. A pesquisa foi realizada a partir das bases de dados on-line, como SCIELO e PUBMED, no periodo de 2008 a 2012, buscando abranger consequencias negativas do uso abusivo, da dependencia, da farmacovigilância e da farmacoepidemiologia da automedicacao de benzodiazepinicos. Os benzodiazepinicos estao entre as drogas mais prescritas no mundo. Sao utilizados como ansioliticos e hipnoticos, alem de possuir acao miorrelaxante e anticonvulsivante. Sabe-se que esses medicamentos promovem altas taxas de dependencia, o que leva, respectivamente, ao aumento da dose necessaria para o mesmo efeito terapeutico e tem sido um grande problema de cunho social, abrangendo pessoas de diversas classes sociais e faixas etarias. Conclui-se queaautomedicacao apresenta-se como uma doenca que so pode ser superada com parcimonia. Alem de encorajamento dos dependentes de benzodiazepinicos a buscarem um tratamento. Descritores: Automedicacao. Contra-Indicacoes. Efeitos adversos

Antinociceptive activity of Riparin II from Aniba riparia : Further elucidation of the possible mechanisms

Riparin II (RipII) has an anti-inflammatory activity potentially due its ability to decrease TNF-α and IL-1β production and its histamine antagonism. The objective of this study was to evaluate the role of RipII in the pain process and the possible antinociceptive mechanisms involved, using classic models of nociception. Male Swiss mice were used in the assays. Determinate the acute toxicity according to the OECD 425 test guideline. The models used were the acetic acid-, formalin-, hot plate and glutamate-induced nociception. For evaluation of antinociceptive effect, the involvement of TRPV1, TRPA1, TRPM8, ASICS, Bradykinin, PKC and PKA were performed using the paw licking using agonists. The acute toxicity study did not detect any clinical signs or changes in behavior or mortality. RipII, administered orally (25 and 50 mg/kg) caused a reduction of nociception induced by acetic acid, formalin (on the second phase) and glutamate. In the investigation of antinociceptive mechanism, we used capsaicin (2.2 μg/paw), cinnamaldehyde (10 nmol/paw), menthol (1.2 μmol/paw), ASICS (2% acetic acid, pH 1.98) and bradykinin (10 μg/paw). The results showed that TRPV1, TRPA1, TRPM8, ASICS and bradykinin play a role in the antinociceptive effect of RipII. The results also showed that PKA is involved too. These data demonstrate that RipII has a low or not toxicity and produced an important antinociceptive effect through mechanisms that probably involve an interaction, at least in part, TRPV1, TRPA1, TRPM8, ASICS, bradykinin and PKA participate in the RipIIs antinociceptive effect.