Antifungal and immunomodulatory activity of a novel cochleate for amphotericin B delivery against Sporothrix schenckii

Introduction: Sporotrichosis is an emergent subcutaneous mycoses caused by species of the Sporothrix schenckii complex. Amphotericin B (AmB) remains the main antifungal drug for the treatment of systemic infections, but its use is limited by toxicity reasons. AFCo3 is a novel cochleate containing detoxified LPS, which exhibits drug delivery and immunomodulating properties. Here, AFCo3 was used as the vehicle for AmB to evaluate the immunomodulatory and antifungal efficacy against S. schenckii in vitro and in vivo. Methods and results: The minimum inhibitory concentrations of AFCo3-AmB and AmB were 0.25 and 1 μg/mL respectively. The minimum fungicidal concentration was 0.5 μg/mL for AFCo3-AmB and 2 μg/mL for AmB. AFCo3-AmB was less cytotoxic than AmB for peritoneal macrophages, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method and reduced the AmB-induced hemolysis in murine erythrocytes. AFCo3-AmB improved the intracellular killing of phagocytized yeast and it enhanced the in vitro production of IL-1β, TNF-α and NO in peritoneal macrophages. Moreover, AFCo3-AmB was more effective than AmB in reducing spleen and liver fungal burden after repeated (five days) intraperitoneal administration of 5 mg/kg of AmB, in a Balb/c model of systemic infection, associated to a significant induction of Th1/Th17 response. Finally, blood chemistry revealed that AFCo3-AmB did not cause changes suggestive of nephrotoxicity, such as increases in total proteins, albumin, creatinine and blood urea nitrogen that were caused by free AmB. Conclusions: AFCo3-AmB exhibited asignificant immunomodulator action, reduced toxicity and improved antifungal action against S. schenckii, suggesting a potential use as AmB delivery for systemic sporotrichosis treatment(AU)

Antifungal and immunomodulatory activity of a novel cochleate for amphotericin B delivery against Sporothrix schenckii.

INTRODUCTION: Sporotrichosis is an emergent subcutaneous mycoses caused by species of the Sporothrix schenckii complex. Amphotericin B (AmB) remains the main antifungal drug for the treatment of systemic infections, but its use is limited by toxicity reasons. AFCo3 is a novel cochleate containing detoxified LPS, which exhibits drug delivery and immunomodulating properties. Here, AFCo3 was used as the vehicle for AmB to evaluate the immunomodulatory and antifungal efficacy against S. schenckii in vitro and in vivo. METHODS AND RESULTS: The minimum inhibitory concentrations of AFCo3-AmB and AmB were 0.25 and 1µg/mL respectively. The minimum fungicidal concentration was 0.5µg/mL for AFCo3-AmB and 2µg/mL for AmB. AFCo3-AmB was less cytotoxic than AmB for peritoneal macrophages, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method and reduced the AmB-induced hemolysis in murine erythrocytes. AFCo3-AmB improved the intracellular killing of phagocytized yeast and it enhanced the in vitro production of IL-1ß, TNF-α and NO in peritoneal macrophages. Moreover, AFCo3-AmB was more effective than AmB in reducing spleen and liver fungal burden after repeated (five days) intraperitoneal administration of 5mg/kg of AmB, in a Balb/c model of systemic infection, associated to a significant induction of Th1/Th17 response. Finally, blood chemistry revealed that AFCo3-AmB did not cause changes suggestive of nephrotoxicity, such as increases in total proteins, albumin, creatinine and blood urea nitrogen that were caused by free AmB. CONCLUSIONS: AFCo3-AmB exhibited a significant immunomodulator action, reduced toxicity and improved antifungal action against S. schenckii, suggesting a potential use as AmB delivery for systemic sporotrichosis treatment.

Biomarkers in Obesity: Serum Myeloperoxidase and Traditional Cardiac Risk Parameters.

BACKGROUND: Chronic low-grade inflammation, combined with traditional cardiovascular risk factors, is common in obesity, providing systemic inflammation that is associated with increased cardiovascular risk. Studies have shown serum mieloperoxidase as a potential biomarker and its clinical applicability for evaluating cardiovascular risk. This study aimed to evaluate the MPO in obese individuals, with or without systemic inflammation and potential cardiovascular risk, as well as correlating MPO with some classic cardiovascular risk parameters. METHODS: Inflammatory and cardiovascular risk markers, as well as different biochemical and hematological laboratory parameters, were analyzed. The volunteers were divided into 3 groups according to the presence (hs-CRP>3 mg/L) or absence (hs-CRP<3 mg/L) of systemic inflammation and possible cardiovascular risk. RESULTS: MPO was significantly increased (p<0.05) in the obese individuals with systemic inflammation. A significant increase (p<0.05) in the following biochemical parameters: glucose, HbA1c, triglycerides, non-HDL, TG/HDL was observed, and a significant decrease (p<0.01) in HDL was observed. Significant increases in the counts of total leukocytes, neutrophils and monocytes (p<0.01), as well as elevated blood pressure (p<0.05), were observed in the group of obese individuals with systemic inflammation. Serum MPO levels were correlated with classic proinflammatory and cardiovascular risk parameters. CONCLUSIONS: High serum levels of MPO were observed in obese individuals with hs-CRP above 3 mg/L, which is a classic biomarker for inflammation and cardiovascular risk, suggesting the potential role of MPO in clinical applicability for cardiovascular disease in this population. However, considering that inflammation in obesity appears to manifest as a non-classical mechanism, further studies are necessary to elucidate the role of MPO in cardiovascular events in the population with obesity.

Avaliação das atividades antioxidante, anti e pró-hemolítica do extrato etanólico das folhas de Pterogyne nitens Tul. (Fabaceae-Caesalpinioideae) / Evaluation of antioxidant, anti- and pro-hemolytic activities of ethanol extract from the leaves of Pterogynenitens Tul. (Fabaceae-Caesalpinioideae)

A pesquisa de produtos naturais permite a descoberta de novos princípios ativos, ou ainda, a descoberta de novas atividades para extratos de plantas (amplamente utilizados pela população brasileira) e princípios ativos naturais já conhecidos. Pterogyne nitens é uma planta cuja descrição das atividades é relativamente recente e, portanto, tem no extrato bruto boa fonte para pesquisas na área de produtos naturais. Desta forma, o objetivo deste trabalho foi estudar o perfil antioxidante do extrato bruto etanólico das folhas de P. nitens e possível interferência sobre a hemólise provocada pelo radical AAPH•. No estudo da ação antioxidante das espécies estudadas, ABTS•+, DPPH•, H2O2 e HOCl, encontrou-se os valores de IC50 de 5,0 µg mL-1, 17 µg mL-1, sem ação e 3,9 µg mL-1, respectivamente, valores relativamente baixos e que indicam bom potencial antioxidante. Foram encontradas atividades pró-hemolítica e anti-hemolítica para o extrato de forma concentração-dependente. O extrato estudado mostro boa fonte de moléculas naturais com potencial de ação biológica.

The search for natural products as a widespread practice enables the discovery of new active principles, or the discovery of new activities for plant extracts (extensively used by the population) and natural active principles already known. Pterogynenitensis is a plant whose descriptions of activities are relatively recent and therefore has in its crude extract a good source for research in the field of natural products. Thus, the aim of this study was to evaluate the antioxidant profile of crude ethanol extract from P. nitens leaves and a possible influence on the hemolysis caused by AAPH• radical. For the studied oxidant species, ABTS•+, DPPH•, HOCl and H2O2, the IC50 values were found of 5.0 µg mL-1, 17 µg mL-1, no action at all, and 3.9 µg mL-1, respectively, relatively low values, indicating a good antioxidant potential. Pro- and anti-hemolytic activities were found for the extract in a concentration-dependent way. The studied extract showed to be a good source of natural molecules with potential biological action.