A cyclopalladated complex interacts with mitochondrial membrane thiol-groups and induces the apoptotic intrinsic pathway in murine and cisplatin-resistant human tumor cells

<p>Abstract</p> <p>Background</p> <p>Systemic therapy for cancer metastatic lesions is difficult and generally renders a poor clinical response. Structural analogs of cisplatin, the most widely used synthetic metal complexes, show toxic side-effects and tumor cell resistance. Recently, palladium complexes with increased stability are being investigated to circumvent these limitations, and a biphosphinic cyclopalladated complex {Pd₂[<it>S_(-)</it>C², N-dmpa]₂(μ-dppe)Cl₂} named C7a efficiently controls the subcutaneous development of B16F10-Nex2 murine melanoma in syngeneic mice. Presently, we investigated the melanoma cell killing mechanism induced by C7a, and extended preclinical studies.</p> <p>Methods</p> <p>B16F10-Nex2 cells were treated <it>in vitro </it>with C7a in the presence/absence of DTT, and several parameters related to apoptosis induction were evaluated. Preclinical studies were performed, and mice were endovenously inoculated with B16F10-Nex2 cells, intraperitoneally treated with C7a, and lung metastatic nodules were counted. The cytotoxic effects and the respiratory metabolism were also determined in human tumor cell lines treated <it>in vitro </it>with C7a.</p> <p>Results</p> <p>Cyclopalladated complex interacts with thiol groups on the mitochondrial membrane proteins, causes dissipation of the mitochondrial membrane potential, and induces Bax translocation from the cytosol to mitochondria, colocalizing with a mitochondrial tracker. C7a also induced an increase in cytosolic calcium concentration, mainly from intracellular compartments, and a significant decrease in the ATP levels. Activation of effector caspases, chromatin condensation and DNA degradation, suggested that C7a activates the apoptotic intrinsic pathway in murine melanoma cells. In the preclinical studies, the C7a complex protected against murine metastatic melanoma and induced death in several human tumor cell lineages <it>in vitro</it>, including cisplatin-resistant ones. The mitochondria-dependent cell death was also induced by C7a in human tumor cells.</p> <p>Conclusions</p> <p>The cyclopalladated C7a complex is an effective chemotherapeutic anticancer compound against primary and metastatic murine and human tumors, including cisplatin-resistant cells, inducing apoptotic cell death via the intrinsic pathway.</p

Unexpected high diversity of galling insects in the Amazonian upper canopy: The savanna out there

A relatively large number of studies reassert the strong relationship between galling insect diversity and extreme hydric and thermal status in some habitats, and an overall pattern of a greater number of galling species in the understory of scleromorphic vegetation. We compared galling insect diversity in the forest canopy and its relationship with tree richness among upland terra firme, várzea, and igapó floodplains in Amazonia, Brazil. The soils of these forest types have highly different hydric and nutritional status. Overall, we examined the upper layer of 1,091 tree crowns. Galling species richness and abundance were higher in terra firme forests compared to várzea and igapó forests. GLM-ANCOVA models revealed that the number of tree species sampled in each forest type was determinant in the gall-forming insect diversity. The ratio between galling insect richness and number of tree species sampled (GIR/TSS ratio) was higher in the terra firme forest and in seasonally flooded igapó, while the várzea presented the lowest GIR/TSS ratio. In this study, we recorded unprecedented values of galling species diversity and abundance per sampling point. The GIR/TSS ratio from várzea was approximately 2.5 times higher than the highest value of this ratio ever reported in the literature. Based on this fact, we ascertained that várzea and igapó floodplain forests (with lower GIA and GIR), together with the speciose terra firme galling community emerge as the gall diversity apex landscape among all biogeographic regions already investigated. Contrary to expectation, our results also support the "harsh environment hypothesis", and unveil the Amazonian upper canopy as similar to vegetation habitats, hygrothermically stressed environments with temperature at lethal limits and high levels of leaf sclerophylly. © 2014 Julião et al

Diagnosis of iron deficiency anemia in children of Northeast Brazil

OBJECTIVE: To diagnose iron deficiency anemia in children. METHODS: The study was conducted with a sample of 301 children aged six to 30 months attending public daycare centers in the city of Recife, Northeast Brazil, in 2004. The diagnoses of anemia were based on a combination of different hematological and biochemical parameters: hemoglobin, mean corpuscular volume, ferritin, C-reactive protein, transferrin saturation and transferrin receptor. The chi-square test and ANOVA were used in the statistical analysis. RESULTS: Of all children studied, 92.4% had anemia (Hb OBJETIVO: Diagnosticar anemia por deficiencia de hierro en niños. MÉTODOS: El estudio fue desarrollado con una muestra de 301 niños con edades entre seis y 30 meses, usuarios de guarderías públicas de Recife, Noreste de Brasil, en 2004. Para el diagnóstico de la anemia se utilizó la combinación de diferentes parámetros hematológicos y bioquímicos: hemoglobina, volumen corpuscular promedio, ferritina, proteína C-reactiva, saturación de la transferrina y receptor de la transferrina. Para el análisis estadístico se empleó la prueba de chi-cuadrado y ANOVA. RESULTADOS: Del total de niños, 92,4% tenían anemia (HbOBJETIVO: Diagnosticar anemia por deficiência de ferro em crianças. MÉTODOS: O estudo foi desenvolvido com uma amostra de 301 crianças com idade entre seis e 30 meses, usuárias de creches públicas de Recife, PE, em 2004. Para o diagnóstico da anemia utilizou-se a combinação de diferentes parâmetros hematológicos e bioquímicos: hemoglobina, volume corpuscular médio, ferritina, proteína C-reativa, saturação da transferrina e receptor da transferrina. Para a análise estatística empregou-se o teste do qui-quadrado e ANOVA. RESULTADOS: Do total de crianças, 92,4% tinha anemia (Hb < 110g/L) e 28,9% apresentou anemia moderada/grave (Hb<90g/L). Níveis mais baixos de hemoglobina foram observados em crianças de seis a 17 meses. Encontrou-se deficiência de ferro em 51,5% das crianças, utilizando-se a ferritina (< 12µg/L) como parâmetro. Considerando a combinação da concentração de hemoglobina, ferritina e do receptor de transferrina, 58,1% tinha anemia com deficiência de ferro, 34,2% anemia sem déficit de ferro e 2,3% deficiência de ferro sem anemia. A concentração média de ferritina foi significativamente maior em crianças com proteína C-reativa aumentada quando comparada com aqueles com níveis normais (22,1 versus 14,8 µg/L). CONCLUSÕES: A utilização de diversos parâmetros bioquímicos e hematológicos possibilitou diagnosticar anemia por deficiência de ferro em dois terços das crianças, revelando a necessidade de identificar outros determinantes de anemia sem deficiência de ferro

EPIDEMIOLOGY OF PARACOCCIDIOIDOMYCOSIS

SUMMARYThe epidemiological characteristics of paracoccidioidomycosis were reviewed and updated. The new endemic areas in Brazil were discussed in the section regarding the geographic distribution of the mycosis. Subclinical infection with Paracoccidioides brasiliensis was discussed on the basis of skin test surveys with antigens of the fungus, seroepidemiological studies, and disease cases outside Latin America. Large case series permitted a comparison of the prevalence of the mycosis in different regions, its estimated incidence and risk factors for the development of the disease. Aspects modulating the expression of the clinical forms of paracoccidioidomycosis are also presented. This review also deals with diseases associated with the mycosis, opportunistic paracoccidioidomycosis, lethality, mortality and infection and disease in animals