Project description:Potential risks associated with releases of human pharmaceuticals into the environment have become an increasingly important issue in environmental health. This concern has been driven by the widespread detection of pharmaceuticals in all aquatic compartments. Therefore, 22 pharmaceuticals, 6 metabolites and transformation products, belonging to 7 therapeutic groups, were selected to perform a review on their toxicity and environmental risk assessment (ERA) in different aquatic compartments, important issues to tackle the water framework directive (WFD). The toxicity data collected reported, with the exception of anxiolytics, at least one toxicity value for concentrations below 1 µg L-1. The results obtained for the ERA revealed risk quotients (RQs) higher than 1 in all the aquatic bodies and for the three trophic levels, algae, invertebrates and fish, posing ecotoxicological pressure in all of these compartments. The therapeutic groups with higher RQs were hormones, antiepileptics, anti-inflammatories and antibiotics. Unsurprisingly, RQs values were highest in wastewaters, however, less contaminated water bodies such as groundwaters still presented maximum values up to 91,150 regarding 17α-ethinylestradiol in fish. Overall, these results present an important input for setting prioritizing measures and sustainable strategies, minimizing their impact in the aquatic environment.
Project description:Hybridisation of reference strains to the VirEp Staphylococcus aureus microarray, and characterisation of different S. aureus isolates from different locations and associated with different diseases.
Project description:Autologous macrophage transfer is an emerging platform for cell therapy. It is anticipated that conventional macrophage reprogramming based on ex vivo polarization using cytokines and ligands of TLRs may enhance the therapeutic effect. We describe an alternative approach based on small interfering RNA (siRNA) knockdown of selected molecular cues of macrophage polarization, namely EGR2, IRF3, IRF5, and TLR4 in Raw264.7 monocyte/macrophage cell line and mouse-bone-marrow-derived macrophages (BMDMs). The impact of IRF5 knockdown was most pronounced, curtailing the expression of other inflammatory mediators such as IL-6 and NOS2, especially in M1-polarized macrophages. Contrary to IRF5, EGR2 knockdown potentiated M1-associated markers while altogether abolishing M2 marker expression, which is indicative of the principal role of EGR2 in the maintenance of alternative phenotypes. IRF3 knockdown suppressed M1 polarization but upregulated Arg 1, a canonical marker of alternative polarization in M1 macrophages. As anticipated, the knockdown of TLR4 also attenuated the M1 phenotype but, akin to IRF3, significantly induced Arginase 1 in M0 and M1, driving the phenotype towards M2. This study validates RNAi as a viable option for the alteration and maintenance of macrophage phenotypes.
Project description:Calcium/calmodulin-stimulated protein kinase II (CaMKII) is a family of broad substrate specificity serine (Ser)/threonine (Thr) protein kinases widely expressed in many tissues that is capable of mediating diverse functional responses depending on its cellular and molecular microenvironment. This review briefly summarises current knowledge on the structure and regulation of CaMKII and focuses on how the molecular environment, and interaction with binding partner proteins, can produce different populations of CaMKII in different cells, or in different subcellular locations within the same cell, and how these different populations of CaMKII can produce diverse functional responses to activation following an increase in intracellular calcium concentration. This review also explores the possibility that identifying and characterising the molecular interactions responsible for the molecular targeting of CaMKII in different cells in vivo, and identifying the sites on CaMKII and/or the binding proteins through which these interactions occur, could lead to the development of highly selective inhibitors of specific CaMKII-mediated functional responses in specific cells that would not affect CaMKII-mediated responses in other cells. This may result in the development of new pharmacological agents with therapeutic potential for many clinical conditions.