Functionalization of Ruthenium(II) terpyridine complexes with cyclic RGD peptides to target integrin receptors in cancer cells

The lack of selectivity for cancer cells and the resulting negative impact on healthy tissue is a severe drawback of actual cancer chemotherapy. Tethering of cytotoxic drugs to targeting vectors such as peptides, which recognize receptors overexpressed on the surface of tumor cells, is one possible strategy to overcome such a problem. The pentapeptide cyc(RGDfK) targets the integrin receptor αvβ3, important for tumor growth and metastasis formation. In this work, two terpyridine based Ru(II) complexes were prepared and for the first time conjugated to cyc(RGDfK) via amide bond formation resulting in a monomeric and a dimeric bioconjugate. Both Ru(II) complexes bind strongly and selectively to integrin αvβ3, with the dimeric molecule displaying a 20-fold higher affinity to the receptor than the monomeric one. However, the cytotoxicity of the complexes and related bioconjugates against human A549 and SKOV-3 cell lines is still not sufficient for application as anticancer agents. Nevertheless, considering the high selectivity for integrin receptor αvβ3, the synthesis of Ru-based bioconjugates with cyc(RGDfK) paves a promising way towards the design of effective targeted anticancer agents

URBSOIL-LISBON-Geoquímica dos solos urbanos de Lisboa: caracterização e cartografia, suporte para futuros estudos de saúde humana: resultados preliminares

A Geologia, e em especial a Geoquímica em ambiente urbano, têm-se revelado ferramentas essenciais não só no estudo dos materiais naturais neste ambiente, como na ligação entre a Geologia e a acção antrópica. Este estudo, com uma metodologia que usa vários meios de amostragem, pretende avaliar quais os elementos químicos que podem intervir num contexto de interacção em que as crianças são tomadas como alvo principal. Os primeiros resultados sobre concentrações de elementos químicos para os solos urbanos de Lisboa apontam para uma exposição esparsa na cidade de alguns dos elementos químicos inorgânicos, mas havendo por vezes um zonamento por tipologia de local ou de elemento químico. Foram definidos quatro grupos de pontos de amostragem consoante o tipo de uso, e escolhidos para uma análise mais próxima alguns elementos considerados tendencialmente de input antrópico e que se relacionam com a saúde humana.

Cactus Cladodes Opuntia or Nopalea and By-Product of Low Nutritional Value as Solutions to Forage Shortages in Semiarid Areas

Simple Summary In the different livestock production systems, forage is the main feed resource. However, the availability and quality of the forage fluctuate throughout the year due to variable environmental conditions, such as temperature, humidity, location, or lack of rainfall. In semiarid regions, this fact is even more critical. The option for forage plants adapted to the semiarid climate, such as cactus cladodes, becomes indispensable for the sustainability of the systems. Nonetheless, it is necessary to combine the cactus with high-fiber-content feeds (silage, hay, and agroindustry residues, among others) to increase fiber contents in the diet to promote ideal rumen conditions. Based on the knowledge that cactus cladodes (Opuntia spp. and Nopalea spp.) are one of the most viable crops in semiarid regions, the association with a by-product rich in NDF proves to be a more feasible alternative in terms of price and availability, with the producer making the final decision. We aimed to evaluate the effect of the cactus cladodes Nopalea cochenillifera (L). Salm-Dyck. (NUB) and cactus cladodes Opuntia stricta (Haw.) Haw. (OUB), both combined with sugarcane bagasse (SB) plus urea, Tifton hay (TH), corn silage (CS), and sorghum silage (SS) plus urea on nutrient intake and digestibility, ruminal dynamics, and parameters. Five male sheep, fistulated in the rumen, were assigned in a 5 x 5 Latin square design. The NUB provided a higher intake of dry matter (DM) and any nutrients than SS. TH provided larger pools of DM and iNDF. The OUB and CS provided a higher DM degradation. CS provided a higher NDF degradation rate. OUB provided a lower ruminal pH. Depending on the collection time, the lowest pH value was estimated at 3.79 h after the morning feeding. There was an interaction between treatments and collection time on VFA concentrations. Due to the high degradation rate, greater energy intake, less change in rumen pH, greater volatile fatty acid production, and feasibility, we recommend using cactus associated with sugarcane bagasse plus urea in sheep diets

Antiproliferative activity of flavonoids from croton Sphaerogynus baill. (euphorbiaceae)

Croton sphaerogynus is a shrub from the Atlantic Rain Forest in southeastern Brazil. A lyophilized crude EtOH extract from leaves of C. sphaerogynus, obtained by maceration at room temperature (seven days), was suspended in methanol and partitioned with hexane. The purified MeOH phase was fractionated over Sephadex LH-20 yielding five fractions (F1-F5) containing flavonoids, as characterized by HPLC-DAD and HPLC-MS analyses. The antiproliferative activity of the crude EtOH extract, MeOH and hexane phases, and fractions F1-F5 was evaluated on in vitro cell lines NCI-H460 (nonsmall cell lung), MCF-7 (breast cancer), and U251 (glioma). The MeOH phase showed activity (mean log GI(50) 0.54) higher than the hexane phase and EtOH extract (mean log GI(50) 1.13 and 1.19, resp.). F1 exhibited activity against NCI-H460 (nonsmall cell lung) (GI(50) 1.2 mu g/mL), which could be accounted for the presence of flavonoids and/or diterpenes. F4 showed moderate activity (mean log GI(50) 1.05), while F5 showed weak activity (mean log GI(50) 1.36). It is suggested that the antiproliferative activity of the crude EtOH extract and MeOH phase is accounted for a synergistic combination of flavonoids and diterpenes2015COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPsem informação2012/10079-

A sigmoidal fit for pressure-volume curves of idiopathic pulmonary fibrosis patients on mechanical ventilation: clinical implications

OBJECTIVE: Respiratory pressure-volume curves fitted to exponential equations have been used to assess disease severity and prognosis in spontaneously breathing patients with idiopathic pulmonary fibrosis. Sigmoidal equations have been used to fit pressure-volume curves for mechanically ventilated patients but not for idiopathic pulmonary fibrosis patients. We compared a sigmoidal model and an exponential model to fit pressure-volume curves from mechanically ventilated patients with idiopathic pulmonary fibrosis. METHODS: Six idiopathic pulmonary fibrosis patients and five controls underwent inflation pressure-volume curves using the constant-flow technique during general anesthesia prior to open lung biopsy or thymectomy. We identified the lower and upper inflection points and fit the curves with an exponential equation, V = A-B.e-k.P, and a sigmoid equation, V = a+b/(1+e-(P-c)/d). RESULTS: The mean lower inflection point for idiopathic pulmonary fibrosis patients was significantly higher (10.5 ± 5.7 cm H2O) than that of controls (3.6 ± 2.4 cm H2O). The sigmoidal equation fit the pressure-volume curves of the fibrotic and control patients well, but the exponential equation fit the data well only when points below 50% of the inspiratory capacity were excluded. CONCLUSION: The elevated lower inflection point and the sigmoidal shape of the pressure-volume curves suggest that respiratory system compliance is decreased close to end-expiratory lung volume in idiopathic pulmonary fibrosis patients under general anesthesia and mechanical ventilation. The sigmoidal fit was superior to the exponential fit for inflation pressure-volume curves of anesthetized patients with idiopathic pulmonary fibrosis and could be useful for guiding mechanical ventilation during general anesthesia in this condition

Broadened T-cell Repertoire Diversity in ivIg-treated SLE Patients is Also Related to the Individual Status of Regulatory T-cells

Intravenous IgG (ivIg) is a therapeutic alternative for lupus erythematosus, the mechanism of which remains to be fully understood. Here we investigated whether ivIg affects two established sub-phenotypes of SLE, namely relative oligoclonality of circulating T-cells and reduced activity of CD4 + Foxp3+ regulatory T-cells (Tregs) reflected by lower CD25 surface density.Octapharma research funding; Fundação para a Ciência e a Tecnologia postdoctoral fellowships: (SFRH/BPD/20806/2004, SFRH/BPD/34648/2007); FCT Programa Pessoa travel grant

Sequence-independent characterization of viruses based on the pattern of viral small RNAs produced by the host. [Corrigendum]

published erratum2016 Apr 202016 01 21importedErratum for : Sequence-independent characterization of viruses based on the pattern of viral small RNAs produced by the host. [Nucleic Acids Res. 2015

Novel HIV-1 Knockdown Targets Identified by an Enriched Kinases/Phosphatases shRNA Library Using a Long-Term Iterative Screen in Jurkat T-Cells

HIV-1 is a complex retrovirus that uses host machinery to promote its replication. Understanding cellular proteins involved in the multistep process of HIV-1 infection may result in the discovery of more adapted and effective therapeutic targets. Kinases and phosphatases are a druggable class of proteins critically involved in regulation of signal pathways of eukaryotic cells. Here, we focused on the discovery of kinases and phosphatases that are essential for HIV-1 replication but dispensable for cell viability. We performed an iterative screen in Jurkat T-cells with a short-hairpin-RNA (shRNA) library highly enriched for human kinases and phosphatases. We identified 14 new proteins essential for HIV-1 replication that do not affect cell viability. These proteins are described to be involved in MAPK, JNK and ERK pathways, vesicular traffic and DNA repair. Moreover, we show that the proteins under study are important in an early step of HIV-1 infection before viral integration, whereas some of them affect viral transcription/translation. This study brings new insights for the complex interplay of HIV-1/host cell and opens new possibilities for antiviral strategies

Cell-Free Antigens from Paracoccidioides brasiliensis Drive IL-4 Production and Increase the Severity of Paracoccidioidomycosis

The thermally dimorphic fungus Paracoccidioides brasiliensis (Pb) is the causative agent of paracoccidioidomycosis (PCM), one of the most frequent systemic mycosis that affects the rural population in Latin America. PCM is characterized by a chronic inflammatory granulomatous reaction, which is consequence of a Th1-mediated adaptive immune response. In the present study we investigated the mechanisms involved in the immunoregulation triggered after a prior contact with cell-free antigens (CFA) during a murine model of PCM. The results showed that the inoculation of CFA prior to the infection resulted in disorganized granulomatous lesions and increased fungal replication in the lungs, liver and spleen, that paralleled with the higher levels of IL-4 when compared with the control group. The role of IL-4 in facilitating the fungal growth was demonstrated in IL-4-deficient- and neutralizing anti-IL-4 mAb-treated mice. The injection of CFA did not affect the fungal growth in these mice, which, in fact, exhibited a significant diminished amount of fungus in the tissues and smaller granulomas. Considering that in vivo anti-IL-4-application started one week after the CFA-inoculum, it implicates that IL-4-CFA-induced is responsible by the mediation of the observed unresponsiveness. Further, the characterization of CFA indicated that a proteic fraction is required for triggering the immunosuppressive mechanisms, while glycosylation or glycosphingolipids moieties are not. Taken together, our data suggest that the prior contact with soluble Pb antigens leads to severe PCM in an IL-4 dependent manner