Nanoparticle-and liposome-carried drugs: New strategies for active targeting and drug delivery across blood-brain barrier

The blood-brain barrier (BBB), the unusual microvascular endothelial interface between the central nervous system (CNS) and the circulatory system, is a major hindrance to drug delivery in the brain parenchyma. Besides the absence of fenestrations and the abundance of tight junctions, ATP-binding cassette (ABC) transporters critically reduce drug entry within the CNS, as they carry many drugs back into the bloodstream. Nanoparticle-and liposome-carried drugs, because of their increased cellular uptake and reduced efflux through ABC transporters, have been developed in recent times to circumvent the low drug permeability of the BBB. This review discusses the role of ABC transporters in controlling drug penetration into the brain parenchyma, the rationale for using nanoparticle-and liposome-based strategies to increase drug delivery across the BBB and new therapeutic strategies for using nanoparticle-and liposome-carried drugs in different conditions, ranging from CNS tumors and neurodegenerative diseases to viral infections and epilepsy. © 2013 Bentham Science Publishers

Accelerating progress in the Replacement, Reduction and Refinement of animal testing through better knowledge sharing

In the context of the European Commission's Communication published in response to the European Citizens' Initiative "Stop Vivisection", Action 1 aimed to conduct an assessment of current technologies, information sources and networks from all relevant sectors with potential impact on the advancement of the refinement, reduction and replacement of animals used for scientific purposes (the "Three Rs"). The main objective of this study is to map knowledge sources relevant to the Three Rs, to examine how knowledge is being shared, and to identify possible gaps and opportunities to enhance knowledge sharing. An inventory of knowledge sources (KS) potentially relevant to the Three Rs used in the area of life sciences has been compiled which should be viewed as a snapshot of the current status of knowledge sources available (the supply), and as a starting point for further analysis of knowledge sharing strategies. A public survey was also conducted to complement this study (supply versus demand), and to inform on how to proceed effectively with any knowledge management strategy. The survey has revealed that many involved in this area consider that whilst access to relevant knowledge sources is adequate, there is a need for better coordination of the sources, as well as for the communication of information. Opportunities for face-to-face exchanges are highly valued and there is a firm call for more developments in education and training at professional, university and secondary school levels.JRC.F.3-Chemicals Safety and Alternative Method

Nitric oxide and P-glycoprotein modulate the phagocytosis of colon cancer cells

The anticancer drug doxorubicin induces the synthesis of nitric oxide, a small molecule that enhances the drug cytotoxicity and reduces the drug efflux through the membrane pump P-glycoprotein (Pgp). Doxorubicin also induces the translocation on the plasma membrane of the protein calreticulin (CRT), which allows tumour cells to be phagocytized by dendritic cells. We have shown that doxorubicin elicits nitric oxide synthesis and CRT exposure only in drug-sensitive cells, not in drug-resistant ones, which are indeed chemo-immunoresistant. In this work, we investigate the mechanisms by which nitric oxide induces the translocation of CRT and the molecular basis of this chemo-immunoresistance. In the drug-sensitive colon cancer HT29 cells doxorubicin increased nitric oxide synthesis, CRT exposure and cells phagocytosis. Nitric oxide promoted the translocation of CRT in a guanosine monophosphate (cGMP) and actin cytoskeleton-dependent way. CRT translocation did not occur in drug-resistant HT29-dx cells, where the doxorubicin-induced nitric oxide synthesis was absent. By increasing nitric oxide with stimuli other than doxorubicin, the CRT exposure was obtained also in HT29-dx cells. Although in sensitive cells the CRT translocation was followed by the phagocytosis, in drug-resistant cells the phagocytosis did not occur despite the CRT exposure. In HT29-dx cells CRT was bound to Pgp and only by silencing the latter the CRT-operated phagocytosis was restored, suggesting that Pgp impairs the functional activity of CRT and the tumour cells phagocytosis. Our work suggests that the levels of nitric oxide and Pgp critically modulate the recognition of the tumour cells by dendritic cells, and proposes a new potential therapeutic approach against chemo-immunoresistant tumours

Characterization of Botrytis cinerea populations associated with treated and untreated cv. Moscato vineyards

Three Botrytis cinerea populations, isolated from three vineyards, one untreated and two treated twice a year, respectively, with fenhexamid or cyprodinil+fludioxonil, were investigated to evaluate the effect of repeated fungicide treatments on the presence and distribution of the transposons Boty and Flipper, and on the phenotypic traits of each pathogen community. The vacuma individuals lacking the two transposons represented the majority of the 390 B. cinerea isolates followed by transposa strains containing Boty and Flipper, while the remaining 67 isolates harboured respectively only Boty (60) or Flipper (7). This research has demonstrated that fungicide application did not influence the transposon distribution patterns, the sensitivity towards various botryticides, or the growth rate of the isolates belonging to the three different populations, but did induced overall reduction of the population size and selected isolates characterized by an enhanced pathogenicity, especially on Vitis vinifera leaves

Characterization of Botrytis cinerea populations associated with treated and untreated cv. Moscato vineyards

Three Botrytis cinerea populations, isolated from three vineyards, one untreated and two treated twice a year, respectively, with fenhexamid or cyprodinil+fludioxonil, were investigated to evaluate the effect of repeated fungicide treatments on the presence and distribution of the transposons Boty and Flipper, and on the phenotypic traits of each pathogen community. The vacuma individuals lacking the two transposons represented the majority of the 390 B. cinerea isolates followed by transposa strains containing Boty and Flipper, while the remaining 67 isolates harboured respectively only Boty (60) or Flipper (7). This research has demonstrated that fungicide application did not influence the transposon distribution patterns, the sensitivity towards various botryticides, or the growth rate of the isolates belonging to the three different populations, but did induced overall reduction of the population size and selected isolates characterized by an enhanced pathogenicity, especially on Vitis vinifera leaves