Targeting Cancer Resistance via Multifunctional Gold Nanoparticles.

Resistance to chemotherapy is a major problem facing current cancer therapy, which is continuously aiming at the development of new compounds that are capable of tackling tumors that developed resistance toward common chemotherapeutic agents, such as doxorubicin (DOX). Alongside the development of new generations of compounds, nanotechnology-based delivery strategies can significantly improve the in vivo drug stability and target specificity for overcoming drug resistance. In this study, multifunctional gold nanoparticles (AuNP) have been used as a nanoplatform for the targeted delivery of an original anticancer agent, a Zn(II) coordination compound [Zn(DION)2]Cl2 (ZnD), toward better efficacy against DOX-resistant colorectal carcinoma cells (HCT116 DR). Selective delivery of the ZnD nanosystem to cancer cells was achieved by active targeting via cetuximab, NanoZnD, which significantly inhibited cell proliferation and triggered the death of resistant tumor cells, thus improving efficacy. In vivo studies in a colorectal DOX-resistant model corroborated the capability of NanoZnD for the selective targeting of cancer cells, leading to a reduction of tumor growth without systemic toxicity. This approach highlights the potential of gold nanoformulations for the targeting of drug-resistant cancer cells.

The characterization of Bordetella pertussis strains isolated in the Central-Western region of Brazil suggests the selection of a specific genetic profile during 2012-2014 outbreaks.

Pertussis is a worldwide acute respiratory disease caused by the bacterium Bordetella pertussis. Despite high vaccine coverage, the bacterium continues to circulate in populations and is still one of the most common vaccine-preventable diseases. In Brazil, pertussis incidence has presented a significant decrease since 1990 but since 2011 a sudden increase in incidence has been observed. Thus, the aim of this study was to perform a molecular epidemiological characterization of B. pertussis strains isolated in the Central-Western region (specifically in Distrito Federal) of Brazil from August 2012 to August 2014. During this period, 92 B. pertussis strains were isolated from the outbreaks. All strains were characterized by serotyping and XbaI pulsed-field gel electrophoresis profiles. From August to December 2012, the most prevalent serotype observed was 1,3 (13/17). During 2013 the prevalence of serotype 1,3 decreased (13/30) and from January 2014 to August 2014 the most prevalent serotype was 1,2 (33/45). Fourteen PFGE profiles were identified. Of these, BP-XbaI0039 prevalence increased from 3/17 in 2012 to 10/30 in 2013, and 35/45 in 2014. These results evidence the selection of a specific genetic profile during this period, suggesting the occurrence of a bacterial genomic profile with high circulation potential.

Indoor radon risk associated to post-tectonic biotite granites from Vila Pouca de Aguiar pluton, northern Portugal.

At Vila Pouca de Aguiar area, northern Portugal, crops out a post-tectonic Variscan granite pluton, related with the Régua-Vila Real-Verín fault zone, comprising three types of biotite granites. Among these granites, PSG granite yield the highest average contents of U, probably due to its enrichment in accessory U-bearing minerals such as zircon. In the proximity of faults and joints, these granites are often affected by different degrees of hydrothermal alteration, forming reddish altered rocks, commonly known as "episyenites". These altered rocks are probably associated to the occurrence of hydrothermal processes, which led to uranium enrichment in the most advanced stages of episyenitization. In these granites, both average gamma absorbed dose rates in outdoor and indoor air are higher than those of the world average. Furthermore, even in the worst usage scenario, all these granites can be used as a building material, since their annual effective doses are similar to the limit defined by the European Commission. The geometric mean of radon activity of 91 dwellings located at the Vila Pouca de Aguiar pluton is 568Bqm(-3), exceeding that of other northern Portuguese granites. Measurements carried out during a winter season, indicate that 62.6% of the analysed dwellings yield higher indoor radon average values than the Portuguese legislation limit (400Bqm(-3)), and annual effective doses due higher than the world's average value (1.2mSvy(-1)). The interaction of geogenic, architectural and anthropogenic features is crucial to explain the variance in the geometric mean of radon activity of dwellings from Vila Pouca de Aguiar pluton, but the role of geologic faults is probably the most important decisive factor to increase the indoor radon concentration in dwellings. Hence, the development of awareness campaigns in order to inform population about the incurred radiological risks to radon exposure are highly recommended for this specific area.

Effect of 2% chlorhexidine digluconate on bond strength of a glass-fibre post to root dentine.

AIM: To assess the immediate influence of dentine bonding systems (DBS) associated with 2% chlorhexidine digluconate (CHX) on glass-fibre post-bond strength to root dentine, in terms of coronal, middle and apical thirds. METHODOLOGY: Sixty bovine roots were root filled and randomly assigned to 1 of 6 groups (n = 10): SBMP (3-step etch-and-rinse system, Scotchbond Multi-Purpose), SB (2-step etch-and-rinse system, Single Bond 2), SE (2-step self-etching system, Clearfil SE Bond) and SBMP-CHX, SB-CHX and SE-CHX, respectively, associated with CHX. For all groups, a glass-fibre post was luted with a dual-cure resin cement, RelyX ARC. After 7-day storage, specimens were subjected to the push-out test. Failure modes were analysed under optical microscopy (40x). Bond strength values were statistically analysed by two-way anova and Bonferroni tests (P < 0.05). RESULTS: The effect of DBS was significant (P < 0.05), and SE reached higher bond strength in comparison with the other DBS tested. CHX association did not show improvement with any DBS (P > 0.05); rather, it negatively affected SE, which was detected for all thirds. There was no difference between thirds (P > 0.05), except for the SE-CHX, which presented lower values for the apical third (P < 0.05). Adhesive cement/dentine adhesive failure was predominant for all groups. CHX did not influence the failure mode for any DBS (P > 0.05). CONCLUSIONS: The performance of the dentine bonding systems was material dependent. CHX did not improve immediate bond strength; however, CHX negatively affected the bond strength of the self-etching system, especially in the third apical.

GD1a modulates GM-CSF-induced cell proliferation.

Gangliosides have been extensively described to be involved in the proliferation and differentiation of various cell types, such including hematopoietic cells. Our previous studies on murine models of stroma-mediated myelopoiesis have shown that gangliosides are required for optimal capacity of stromal cells to support proliferation of myeloid precursor cells, being shed to the supernatant and selectively incorporated into myeloid cell membranes. Here we describe the effect of gangliosides on the specific granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced proliferation. For that, we used the monocytic FDC-P1 cell line, which is dependent upon GM-CSF for survival and proliferation. Cells were cultured in the presence of GM-CSF and exogenous gangliosides (GM3, GD1a or GM1) or in the absence of endogenous ganglioside synthesis by the use of a ceramide-synthase inhibitor, D-PDMP. We observed that exogenous addition of GD1a enhanced the GM-CSF-induced proliferation of the FDC-P1 cells. Also, we detected an increase in the expression of the α isoform of the GM-CSF receptor (GMRα) as well as of the transcription factor C/EBPα. On the contrary, inhibition of glucosylceramide synthesis was accompanied by a decrease in cell proliferation, which was restored upon the addition of exogenous GD1a. We also show a co-localization of GD1a and GMR by immunocytochemistry. Taken together, our results suggest for the first time that ganglioside GD1a play a role on the modulation of GM-CSF-mediated proliferative response, which might be of great interest not only in hematopoiesis, but also in other immunological processes, Alzheimer disease, alveolar proteinosis and wherever GM-CSF exerts its effects.

Comparison of the Effect of Agitation on Whitening and Tooth Sensitivity of In-Office Bleaching: A Randomized Clinical Trial.

OBJECTIVE: This single-blind, split-mouth, randomized trial was aimed at evaluating the bleaching efficacy (BE) and tooth sensitivity (TS) of a 20% hydrogen peroxide (HP) bleaching agent used under active or passive application. METHODS AND MATERIALS: Twenty-two patients with canines darker than C2 were selected. Teeth were bleached in two sessions, with a one-week interval between treatments. The bleaching agent was applied using active (HPactive) or passive (HPpassive) application. Each tooth in the HPactive-allocated hemiarch received bleaching gel with sonic activation after 10 and 30 minutes from the start of treatment, with rounded movements all over the buccal surface. The color changes were evaluated by subjective (Vita Classical and Vita Bleachedguide) and objective (VITA Easyshade Spectrophotometer) methods at baseline and 30 days after the second session. TS was recorded up to 48 hours after treatment using a 0-10 visual analog scale. Color change in shade guide units (SGUs) and ΔE was analyzed using a Wilcoxon test (α=0.05). The absolute risk and intensity of TS were evaluated using McNemar test and a Wilcoxon test, respectively (α=0.05). RESULTS: Significant whitening was observed in both groups after 30 days of clinical evaluation. The activation did not significantly influence BE (ΔSGU HPpassive=5.6 and HPActive=5.8; p=0.98; and ΔE HPpassive=10.6 and HPactive=10.3; p=0.83). Absolute risk of TS (HPactive=36.4% and HPpassive=31.8%; p=0.94) was similar for both groups (Fisher exact test). TS intensity (visual analogue scale) was higher during the bleaching sessions and up to 24 hours thereafter for both groups, with no differences between groups (two-way analysis of variance and Tukey). CONCLUSION: The active application of a 20% HP gel did not improve BE and TS.

Sonic Activation of a Desensitizing Gel Prior to In-Office Bleaching.

This double-blind, randomized, and controlled clinical trial evaluated the effect of sonic activation during the application of a desensitizing agent (DA) containing 5% potassium nitrate and 2% sodium fluoride on the occurrence of tooth sensitivity (TS) associated with in-office dental bleaching. Treatment with or without sonic activation of the DA was randomly assigned to one-half of the maxillary teeth of 34 patients in a split-mouth design. On the side without sonic activation (noSA), the DA was applied and maintained in contact with the teeth for 10 minutes. On the sonic activation side (SA), the DA was activated 30 seconds per tooth. The DA application was followed by application of 35% hydrogen peroxide in two bleaching sessions separated by a one-week interval. The primary outcome was the absolute risk of TS, recorded using a numeric rating scale and a visual analog scale. Color was evaluated with a digital spectrophotometer and a value-oriented shade guide. No significant difference between treatments was observed in the absolute risk of TS, which occurred in 93% (p=1.00) of both noSA and SA groups. The TS intensity was higher in the 24-hour interval after sessions, for both treatments, without differences between them. There was no difference in the color change for the treatments, with the average change in number of shade guide units of the Vita Classical scale of 6.35 for both (p=0.87). Sonic activation of DA containing 5% potassium nitrate and 2% sodium fluoride did not reduce the absolute risk and intensity of TS associated with in-office bleaching.

Comparison of the Effect of Agitation on Whitening and Tooth Sensitivity of In-Office Bleaching: A Randomized Clinical Trial.

OBJECTIVE: This single-blind, split-mouth, randomized trial was aimed at evaluating the bleaching efficacy (BE) and tooth sensitivity (TS) of a 20% hydrogen peroxide (HP) bleaching agent used under active or passive application. METHODS AND MATERIALS: Twenty-two patients with canines darker than C2 were selected. Teeth were bleached in two sessions, with a one-week interval between treatments. The bleaching agent was applied using active (HPactive) or passive (HPpassive) application. Each tooth in the HPactive-allocated hemiarch received bleaching gel with sonic activation after 10 and 30 minutes from the start of treatment, with rounded movements all over the buccal surface. The color changes were evaluated by subjective (Vita Classical and Vita Bleachedguide) and objective (VITA Easyshade Spectrophotometer) methods at baseline and 30 days after the second session. TS was recorded up to 48 hours after treatment using a 0-10 visual analog scale. Color change in shade guide units (SGUs) and ΔE was analyzed using a Wilcoxon test (α=0.05). The absolute risk and intensity of TS were evaluated using McNemar test and a Wilcoxon test, respectively (α=0.05). RESULTS: Significant whitening was observed in both groups after 30 days of clinical evaluation. The activation did not significantly influence BE (ΔSGU HPpassive=5.6 and HPActive=5.8; p=0.98; and ΔE HPpassive=10.6 and HPactive=10.3; p=0.83). Absolute risk of TS (HPactive=36.4% and HPpassive=31.8%; p=0.94) was similar for both groups (Fisher exact test). TS intensity (visual analogue scale) was higher during the bleaching sessions and up to 24 hours thereafter for both groups, with no differences between groups (two-way analysis of variance and Tukey). CONCLUSION: The active application of a 20% HP gel did not improve BE and TS.

Aspergillus section Flavi and aflatoxins in Brazilian cassava (Manihot esculenta Crantz) and products.

Aflatoxins are carcinogenic compounds produced by some species of Aspergillus, especially those belonging to Aspergillus section Flavi. Their occurrence in food may start in the field, in the post-harvest, or during storage due to inadequate handling and storage. Because cassava is a staple food for a high percentage of the Brazilian population, we evaluated the presence of aflatoxin-producing species in cassava tubers, cassava products (cassava flour, cassava starch, sour starch, and tapioca flour), and in soil samples collected from cassava fields. In addition, the levels of aflatoxin contamination in cassava products were quantified. A total of 101 samples were analyzed, and 45 strains of Aspergillus section Flavi were isolated. Among the identified species, Aspergillus flavus, Aspergillus arachidicola, Aspergillus novoparasiticus, and Aspergillus parasiticus were found. The majority of strains (73.3%) tested for their aflatoxin-producing ability in synthetic media was positive. Despite that, cassava and cassava products were essentially free of aflatoxins, and only one sample of cassava flour contained traces of AFB1 (0.35 µg/kg).

A new radon prediction approach for an assessment of radiological potential in drinking water.

Inhaled radon from groundwater used for domestic purposes is one of the sources of natural radioactivity into indoor air. Due to uranium-bearing minerals occurrences, hydrogeochemical conditions, tectonic structures, and hydraulic circuits, the radon pathway from rocks to groundwater is quite unpredictable. High radon potential from bedrocks is not always associated with high radon levels in groundwater. Besides, inhaled radon from domestic use may also increase the exposure toindoor radon levels. This innovative methodology using hydrogeochemical conditions and groundwater flow transport was used for radon predictions in the underground to ensure safe drinking water ingestion and inhalation. This innovative radon prediction methodology is based on classic hydrogeochemical analyses (Eh-pH, Piper, Schöeller and Gibb's diagrams) and multivariate statistical analyses (Principal Component Analysis and Pearson's correlation). High dissolution of major ions does not imply high radon mobilization from rocks to groundwater. The travel time was estimated to developed a flow transport of contaminated groundwater. Radiological results show that of the 25 sampled springs, five of them contained radon concentrations above the Portuguese imposed limit (222Rn = 500 Bq·L-1), and 16 of them with values above the WHO recommended limit (222Rn = 100 Bq·L-1). Overall, this new approach of radon prediction showed that uranium enrichment in rocks at ideal hydrochemical conditions and emanation coefficient, and shallow circuits, are responsible for radon increasing in drinking water. The proposed approach allow to predict the areas with high radon potential groundwaters, being a tool to be used by water planners and policy makers for corrective and preventive measures in shallow groundwater flows. To safeguard clean water within the predefined deadline of Sustainable Development Goals (2030) and to ensure human health in compliance with WHO guidelines for safe drinking water, should be established priority water protection policies to reduced radon in this contaminated springs (n = 16).

Clinical Effects of Desensitizing Prefilled Disposable Trays in In-office Bleaching: A Randomized Single-blind Clinical Trial.

OBJECTIVES: This study aimed to evaluate the desensitizing effect of a prefilled disposable tray containing potassium nitrate and fluoride on the self-reported tooth sensitivity (TS) and the bleaching efficacy of 40% hydrogen peroxide bleaching agent used for in-office bleaching in comparison with potassium nitrate and fluoride gel applied in a conventional-delivered tray system in an equivalence clinical trial. METHODS AND MATERIALS: Seventy-eight patients, with a right maxillary canine darker than A3, were selected for this single-blind (evaluators), randomized clinical trial. Teeth were bleached in two sessions with a one-week interval in between. Before in-office bleaching, the prefilled disposable tray or conventional tray containing potassium nitrate and fluoride was used for 15 minutes. Subsequently, the bleaching agent was applied in two 20-minute applications (per the manufacturer's directions) in each session. The color change was evaluated by subjective (Vita Classical and Vita Bleachedguide) and objective (Easyshade Advance Spectrophotometer) methods at baseline and 30 days after the first bleaching session. TS was recorded for up to 48 hours using a 0-10 visual analog scale. The absolute risk was evaluated by chi-square test, while the intensity of TS was evaluated by McNemar test (α=0.05). Color change in shade guide units and ΔE was analyzed by Student t-test for independent samples (α=0.05). RESULTS: Significant whitening was observed in both groups after 30 days of clinical evaluation. The use of different methods of desensitizer in a tray did not influence the absolute risk and intensity of TS (p>0.05), although a tendency of lower risk of TS with the prefilled disposable tray containing potassium nitrate and fluoride was observed. CONCLUSION: The use of a prefilled disposable tray containing potassium nitrate and fluoride before the application of the in-office bleaching product did not affect the whitening degree and decreased self-reported TS when compared with a conventional-delivered tray system.

Transition from caspase-dependent to caspase-independent mechanisms at the onset of apoptotic execution.

We have compared cytoplasmic extracts from chicken DU249 cells at various stages along the apoptotic pathway. Extracts from morphologically normal "committed stage" cells induce apoptotic morphology and DNA cleavage in substrate nuclei but require ongoing caspase activity to do so. In contrast, extracts from frankly apoptotic cells induce apoptotic events in added nuclei in a caspase-independent manner. Biochemical fractionation of these extracts reveals that a column fraction enriched in endogenous active caspases is unable to induce DNA fragmentation or chromatin condensation in substrate nuclei, whereas a caspase-depleted fraction induces both changes. Further characterization of the "execution phase" extracts revealed the presence of an ICAD/DFF45 (inhibitor of caspase-activated DNase/DNA fragmentation factor)- inhibitable nuclease resembling CAD, plus another activity that was required for the apoptotic chromatin condensation. Despite the presence of active caspases, committed stage extracts lacked these downstream activities, suggesting that the caspases and downstream factors are segregated from one another in vivo during the latent phase. These observations not only indicate that caspases act in an executive fashion, serving to activate downstream factors that disassemble the nucleus rather than disassembling it themselves, but they also suggest that activation of the downstream factors (rather than the caspases) is the critical event that occurs at the transition from the latent to active phase of apoptosis.

Diversity of Anopheles mosquitoes from four landscapes in the highest endemic region of malaria transmission in Brazil.

Malaria transmission in South America is overwhelmingly located in the Amazon region with limited cases outside that biome. A key factor in the mitigation of malaria transmission is the determination of vector diversity and bionomics in endemic areas. Anopheles mosquitoes were collected in four different landscapes of Cruzeiro do Sul-Acre, the current area with highest malaria transmission in Brazil. We performed adult mosquito collections every three months over two years and associated vector occurrence with local abiotic factors. A total of 1,754 Anopheles belonging to nine species were collected, but only four of them (An. albitarsis s.l. Lynch-Arribalzaga, An. braziliensis Chagas, An. peryassui Dyar and Knab, and An. triannulatus Neiva and Pinto) represented 77.1% of the total. Vector density and diversity was uneven across field sites and collection periods. Higher Anopheles abundance (54.8%) and richness were observed in a deforested palm tree area (IFC), with An. braziliensis the most frequent mosquito (40.5%). Only 7.3% of mosquitoes were collected in the SAB village, but 66.4% of them were An. darlingi and An. oswaldoi, species often regarded as primary and secondary vectors of malaria in the Amazon region. A distinct biting preference was observed between 18:00-19:40. The distance from the nearest breeding site and minimum temperature explained 41.6% of the Anopheles community composition. Our data show that the Anopheles species composition may present great variation on a microgeographic scale.

An approach to validate groundwater contamination risk in rural mountainous catchments: the role of lateral groundwater flows.

Computer models dedicated to the validation of groundwater contamination risk in the rural environment, namely the risk of contamination by nitrate leachates from agriculture fertilizers, are frequently based on direct comparison of risky areas (e.g., cropland, pastures used for livestock production) and spatial distributions of contaminant (nitrate) plumes. These methods are fated to fail where lateral flows dominate in the landscape (mountainous catchments) displacing the nitrate plumes downhill and from the risky spots. In these cases, there is no connection between the spatial location of risky areas and nitrate plumes, unless the two locations can be linked by a contaminant transport model. The main purpose of this paper is therefore to introduce a method whereby spatio-temporal links can be demonstrated between risky areas (contaminant sources), actual nitrate plumes (contaminant sinks) and modeled nitrate distributions at specific groundwater travel times, thereby validating the risk assessment. The method assembles a couple of well known algorithms, namely the DRASTIC model [1,2] and the Processing Modflow software (https://www.simcore.com), but their combination as risk validation method is original and proved efficient in its initial application, the companion paper of Pacheco et al. [3].

Effectiveness of In-office Hydrogen Peroxide With Two Different Protocols: A Two-center Randomized Clinical Trial.

OBJECTIVES: The aim of this study was to compare the bleaching efficacy and tooth sensitivity (TS) of a 38% hydrogen peroxide bleaching agent used for in-office bleaching, applied under different time protocols: a 40-minute application or two 20-minute applications. METHODS AND MATERIALS: Forty-four patients from Brazil and Colombia, with right superior canines darker than C2, were selected for this multicenter, single-blind, randomized trial. The teeth were bleached in two sessions, with a one-week interval between them, in a split-mouth design. The bleaching agent was applied in two 20-minute (2×20) applications or one 40-minute (1×40) application in each session according to the manufacturer's instructions. The color changes were evaluated by using subjective (Vita Classical and Vita Bleachedguide) and objective (Easyshade Spectrophotometer) methods at baseline and 30 days after the second session. Tooth sensitivity was recorded up to 48 hours with a 0-10 visual analog scale. Also, the pH values during the application of bleaching were recorded. Color change in shade guide units and ΔE were analyzed by using the Student t-test (α=0.05). The absolute risk and intensity of TS were evaluated with the McNemar test, the Wilcoxon signed-rank test, and the Friedman test, respectively (α= 0.05). RESULTS: Significant whitening was observed in both groups after 30 days of clinical evaluation. The use of a 40-minute application did not significantly influence the absolute risk of TS (68%, 95% confidence interval [CI] = 53-80) as well as the intensity of TS compared with the acid bleaching gel (absolute risk of 82%, 95% CI = 68-91). The pH values did not differ significantly between groups and at the different assessment periods ( p=0.42). CONCLUSION: The use of a 40-minute in-office bleaching agent gel application produced the same whitening degree and TS that the two 20-minute bleaching agent applications did. The former preferably should be applied because one 40-minute application does not require gel refreshing.

Involvement of FADD and caspase-8 signalling in detachment-induced apoptosis.

Detachment of most untransformed adherent cells from the extracellular matrix promotes apoptosis, in a process termed anoikis [1] [2]. The death signalling mechanisms involved in this process are not known, although adhesion or transformation by ras oncogenes have been shown to protect epithelial cells from apoptosis through activation of phosphatidylinositol 3-kinase and protein kinase B (PKB/Akt) [3]. Here we show that detachment-induced apoptosis (anoikis) is blocked by the expression of a dominant-negative form of FAS-associated death domain protein (FADD) in a number of untransformed epithelial cell lines. Because the soluble extracellular domains of the death receptors CD95, DR4 and DR5 failed to block anoikis, we conclude that ligand-dependent activation of these death receptors is not involved in this process. Detachment induced strong activation of caspase 8 and caspase 3. Detachment-induced caspase-8 activation did not require the function of downstream caspases but was blocked by overexpression of the anti-apoptotic proteins Bcl-2 or Bcl-X(L). We propose that caspase-8 activation is the initiating event in anoikis, which is subsequently subject to a positive-feedback loop involving mitochondrial events.

Enzymatic and immunochemical characterization of Bothrops insularis venom and its neutralization by polyspecific Bothrops antivenom.

Herein we compared the biological activities of Bothrops insularis and Bothrops jararaca venoms as well as their neutralization by polyspecific Bothrops antivenom (PBA). On account of that, we investigated their antigenic cross-reactivity and the neutralization of lethal, myotoxic and defibrinating activities by polyspecific and species-specific antivenoms. Silver-stained SDS-PAGE gels evidenced many common bands particularly above 47 kDa between B. jararaca and B. insularis venoms. However, some protein bands between 46 and 28 kDa were observed exclusively in B. jararaca venom. Both venoms presented gelatinolytic, caseinolytic, fibrinogenolytic and phospholipase A(2) activities. No hyaluronidase activity was detected in both venoms by zymography. Polyspecific and species-specific antivenoms showed similar titers to B. jararaca and B. insularis venoms by ELISA, and recognized similar components by immunoblotting. The PBA was effective in neutralizing the lethal, myotoxic and defibrinating activities of both venoms as well as to abrogate microcirculatory disturbances induced by B. insularis venom. No statistically significant difference was observed for minimal hemorrhagic doses between both venoms. Antigenic cross-reactivity was evident between both venoms. Since toxic and enzymatic activities were similar, we speculate that B. insularis venoms can induce a local damage in humans comparable to that observed in other Bothrops venoms. Besides, the PBA was effective in neutralizing the toxic activities of B. insularis venom.

Targeting canine mammary tumours via gold nanoparticles functionalized with promising Co(II) and Zn(II) compounds.

BACKGROUND: Despite continuous efforts, the treatment of canine cancer has still to deliver effective strategies. For example, traditional chemotherapy with doxorubicin and/or docetaxel does not significantly increase survival in dogs with canine mammary tumors (CMTs). AIMS: Evaluate the efficiency of two metal compounds [Zn(DION)2 ]Cl (TS262, DION = 1,10-phenanthroline-5,6-dione) and [CoCl(H2 O)(DION)2 ][BF4 ] (TS265) and novel nanovectorizations designed to improve the anti-cancer efficacy of these compounds in a new CMT derived cell line (FR37-CMT). MATERIALS AND METHODS: FR37-CMT cells were exposed to different concentrations of TS262 and TS265 and two new nanoparticle systems and cellular viability was determined. These nanosystems are composed of polyethylene-glycol, bovine-serum-albumin and TS262 or TS265 (NanoTS262 or NanoTS265, respectively). RESULTS: In FR37-CMT, TS262 and TS265 displayed IC50 values well below those displayed by doxorubicin and cisplatin. The nanovectorizations further decreased the IC50 values. DISCUSSION: TS262 and TS265 proved to be effective against FR37-CMT cells and more effective than of doxorubicin and cisplatin. The Nanosystems efficiently delivered the cytotoxic cargo inducing a significant reduction of cell viability in FR37-CMT cell line when compared to the free compounds. CONCLUSIONS: TS262 and TS265 are compounds with potential in the treatment of CMTs. NanoTS262 and NanoTS265 demonstrate that such simple nanovectorization via gold nanoparticles shows tremendous potential as anti-cancer formulations, which may easily be expanded to suit other cargo.

Chemosensitization effects of XIAP downregulation in K562 leukemia cells.

The effect of downregulation of the expression of the antiapoptotic protein XIAP with antisense oligonucleotides was evaluated in the K562 chronic myeloid leukemia (CML) cell line. This was carried out by studying the effects of downregulation of XIAP expression on cellular viability, cellular apoptosis and on the response to two chemotherapeutical drugs, etoposide and doxorubicin. We document that downregulation of XIAP expression decreased cellular viability, increased cellular apoptosis and enhanced the effects of doxorubicin.

Parp mutations protect against mitochondrial dysfunction and neurodegeneration in a PARKIN model of Parkinson's disease.

The co-enzyme nicotinamide adenine dinucleotide (NAD(+)) is an essential co-factor for cellular energy generation in mitochondria as well as for DNA repair mechanisms in the cell nucleus involving NAD(+)-consuming poly (ADP-ribose) polymerases (PARPs). Mitochondrial function is compromised in animal models of Parkinson's disease (PD) associated with PARKIN mutations. Here, we uncovered alterations in NAD(+) salvage metabolism in Drosophila parkin mutants. We show that a dietary supplementation with the NAD(+) precursor nicotinamide rescues mitochondrial function and is neuroprotective. Further, by mutating Parp in parkin mutants, we show that this increases levels of NAD(+) and its salvage metabolites. This also rescues mitochondrial function and suppresses dopaminergic neurodegeneration. We conclude that strategies to enhance NAD(+) levels by administration of dietary precursors or the inhibition of NAD(+)-dependent enzymes, such as PARP, that compete with mitochondria for NAD(+) could be used to delay neuronal death associated with mitochondrial dysfunction.