The Search for New Agonists to P2X7R for Clinical Use: Tuberculosis as a Possible Target

Submitted by sandra infurna ([email protected]) on 2016-05-19T13:38:40Z No. of bitstreams: 1 romulo2_bezerra_etal_IOC_2015.pdf: 1671006 bytes, checksum: a42f82af8922708ebe9470ae107a86bf (MD5)Approved for entry into archive by sandra infurna ([email protected]) on 2016-05-19T13:49:16Z (GMT) No. of bitstreams: 1 romulo2_bezerra_etal_IOC_2015.pdf: 1671006 bytes, checksum: a42f82af8922708ebe9470ae107a86bf (MD5)Made available in DSpace on 2016-05-19T13:49:16Z (GMT). No. of bitstreams: 1 romulo2_bezerra_etal_IOC_2015.pdf: 1671006 bytes, checksum: a42f82af8922708ebe9470ae107a86bf (MD5) Previous issue date: 2015Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Comunicação Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Clínica. Rio de Janeiro, RJ, Brasil.Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro (IFRJ). Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Clínica. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Comunicação Celular. Rio de Janeiro, RJ, Brasil.Treatment for tuberculosis is effective with the use of proper antibiotics, but the number of drug-resistant cases is increasing. Drug resistance occurred in 650,000 cases of the 20 million patients in treatment worldwide in 2011, which demonstrates the necessity of finding new therapeutic approaches. In this context, the search for new medicines and immunomodulators could help reduce the prevalence and incidence of multi-drug-resistant tuberculosis cases. Thus several preclinical studies demonstrate the involvement of the P2X7 receptor (P2X7R) in the control of Mycobacterium tuberculosis (MTB) infection. Adenosine triphosphate (ATP), a natural agonist for P2X7R, promotes MTB death and the induction of apoptosis in monocytes and macrophages infected with MTB via activation of P2X7R by extracellular ATP. In addition, P2X7R activation in the presence of ATP increases the expression of major histocompatibility complex (MHC) class II by macrophages infected with Mycobacterium bovis (BCG) or MTB, which contributes to the generation of the antimicrobial immune response via T cells. Nevertheless, one idea that seems overlooked by the “purinergic community” is the use of the high-conductance channel associated with P2X7R to increase the passage of hydrophilic drugs to the cytoplasm of cells that express the P2X7 pore, a potential method for a drug delivery system. In this work, we propose the use of P2X7 agonists in conjunction with low molecular weight anti-tuberculosis medicines for the treatment of multi-drug-resistant tuberculosis

Novel Scintillating Nanoparticles for Potential Application in Photodynamic Cancer Therapy

The development of X-ray-absorbing scintillating nanoparticles is of high interest for solving the short penetration depth problem of visible and infrared light in photodynamic therapy (PDT). Thus, these nanoparticles are considered a promising treatment for several types of cancer. Herein, gadolinium oxide nanoparticles doped with europium ions (Gd2O3:Eu3+) were obtained by using polyvinyl alcohol as a capping agent. Hybrid silica nanoparticles decorated with europium-doped gadolinium oxide (SiO2-Gd2O3:Eu3+) were also prepared through the impregnation method. The synthesized nanoparticles were structurally characterized and tested to analyze their biocompatibility. X-ray diffraction, scanning electron microscopy, and transmission electron microscopy confirmed the high crystallinity and purity of the Gd2O3:Eu3+ particles and the homogeneous distribution of nanostructured rare earth oxides throughout the fumed silica matrix for SiO2-Gd2O3:Eu3+. Both nanoparticles displayed stable negative ζ-potentials. The photoluminescence properties of the materials were obtained using a Xe lamp as an excitation source, and they exhibited characteristic Eu3+ bands, including at 610 nm, which is the most intense transition band of this ion. Cytotoxicity studies on mouse glioblastoma GL261 cells indicated that these materials appear to be nontoxic from 10 to 500 μg·mL−1 and show a small reduction in viability in non-tumor cell lines. All these findings demonstrate their possible use as alternative materials in PDT

Evidence for a perforin-mediated mechanism controlling cardiac inflammation in Trypanosoma cruzi infection

CD8+ T lymphocytes are considered an important cell population involved in the control of parasitaemia and mortality after Trypanosoma cruzi infection. However, despite recent developments in this field, the mechanism whereby this control is exerted is still not completely understood. Here we have used perforin knockout (−/−) mice infected with Y strain T. cruzi in order to evaluate specifically the participation of the perforin-based cytotoxic pathway in the destruction of cardiomyocytes, cellular inflammatory infiltration, and control of parasitaemia and mortality. We observed that although parasitaemia was equivalent in perforin (+/+) and (−/−) groups, survival rate and spontaneous physical performance were significantly lower in the perforin deficient mice. The cardiac inflammatory cell infiltration, mostly composed of CD8+ cells, was more evident in perforin (−/−) mice. Ultrastructural and immunofluorescence analysis, as well as plasma creatine kinase activity, revealed cardiomyocyte damage and necrosis, more evident in perforin (−/−) mice. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assays performed in heart samples revealed similar and modest levels of apoptosis in both perforin (+/+) and (−/−) mice. These results indicate that perforin does not play a pivotal role in the control of parasitaemia and direct lysis of cardiomyocytes, but seems to be an important molecule involved in the control of cardiac inflammation and pathology induced by a highly virulent strain of T. cruzi