Advanced Center for Chronic Diseases

Santiago, Chile

Advanced Center for Chronic Diseases

Santiago, Chile
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Vio V.,University of Chile | Marchant M.J.,University of Chile | Marchant M.J.,Pontifical Catholic University of Valparaíso | Marchant M.J.,Advanced Center for Chronic Diseases | And 4 more authors.
Current Pharmaceutical Design | Year: 2017

This review focuses on the application of metal nanoparticles in the diagnosis and treatment of Alzheimer’s and Parkinson’s diseases. Metal nanoparticles present interesting physicochemical properties that can be applied to increase biomarker detection sensitivities in vitro and in vivo. Furthermore, these nanoparticles could be used in different strategies for the treatment of central nervous system diseases, particularly in regards to drug delivery. Herein, specific potential applications of metal nanoparticles are separately discussed for the contexts of in vitro diagnoses and treatments. Briefly, research using surface plasmon resonance methodologies has mainly used these nanoparticles for the in vitro detection of Aβ and, to a lesser extent, of α-synuclein. Regarding treatment approaches, in vitro studies have focused on using metal nanoparticles to manipulate the Aβ aggregation, thus reducing toxicity. Furthermore, in vivo applications of metal nanoparticles are also discussed, with many of the existing studies focusing on a magnetic nanoparticle-detection of Aβ through magnetic resonance imaging and, to a lesser degree, extension fluorescence techniques. Finally, conclusions and perspectives are provided regarding the real potential for using metal nanoparticles in the treatment and diagnosis of central nervous system diseases. © 2017 Bentham Science Publishers.

Budini M.,University of Chile | Buratti E.,International Center for Genetic Engineering and Biotechnology | Morselli E.,University of Santiago de Chile | Criollo A.,University of Chile | Criollo A.,Advanced Center for Chronic Diseases
Frontiers in Molecular Neuroscience | Year: 2017

Autophagy is a catabolic mechanism where intracellular material is degraded by vesicular structures called autophagolysosomes. Autophagy is necessary to maintain the normal function of the central nervous system (CNS), avoiding the accumulation of misfolded and aggregated proteins. Consistently, impaired autophagy has been associated with the pathogenesis of various neurodegenerative diseases. The proteins TAR DNA-binding protein-43 (TDP-43), which regulates RNA processing at different levels, and chromosome 9 open reading frame 72 (C9orf72), probably involved in membrane trafficking, are crucial in the development of neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). Additionally, recent studies have identified a role for these proteins in the control of autophagy. In this manuscript, we review what is known regarding the autophagic mechanism and discuss the involvement of TDP-43 and C9orf72 in autophagy and their impact on neurodegenerative diseases. © 2017 Budini, Buratti, Morselli and Criollo.

Lorenzo Bermejo J.,University of Heidelberg | Boekstegers F.,University of Heidelberg | Gonzalez Silos R.,University of Heidelberg | Marcelain K.,University of Chile | And 20 more authors.
PLoS Genetics | Year: 2017

Latin Americans are highly heterogeneous regarding the type of Native American ancestry. Consideration of specific associations with common diseases may lead to substantial advances in unraveling of disease etiology and disease prevention. Here we investigate possible associations between the type of Native American ancestry and leading causes of death. After an aggregate-data study based on genome-wide genotype data from 1805 admixed Chileans and 639,789 deaths, we validate an identified association with gallbladder cancer relying on individual data from 64 gallbladder cancer patients, with and without a family history, and 170 healthy controls. Native American proportions were markedly underestimated when the two main types of Native American ancestry in Chile, originated from the Mapuche and Aymara indigenous peoples, were combined together. Consideration of the type of Native American ancestry was crucial to identify disease associations. Native American ancestry showed no association with gallbladder cancer mortality (P = 0.26). By contrast, each 1% increase in the Mapuche proportion represented a 3.7% increased mortality risk by gallbladder cancer (95%CI 3.1–4.3%, P = 6×10−27). Individual-data results and extensive sensitivity analyses confirmed the association between Mapuche ancestry and gallbladder cancer. Increasing Mapuche proportions were also associated with an increased mortality due to asthma and, interestingly, with a decreased mortality by diabetes. The mortality due to skin, bladder, larynx, bronchus and lung cancers increased with increasing Aymara proportions. Described methods should be considered in future studies on human population genetics and human health. Complementary individual-based studies are needed to apportion the genetic and non-genetic components of associations identified relying on aggregate-data. © 2017 Public Library of Science. All Rights Reserved.

Perez-Ortiz M.,University of Chile | Perez-Ortiz M.,University of Barcelona | Zapata-Urzua C.,University of Chile | Zapata-Urzua C.,University of Barcelona | And 8 more authors.
Colloids and Surfaces B: Biointerfaces | Year: 2017

In this work, the potential application of gold nanoparticles for GLP-1 analogues delivery was studied. For this purpose, the original sequence of the incretin GLP-1 was slightly modified in the C-terminal region by adding a cysteine residue to facilitate conjugation to the gold surface. The interaction between peptides and gold nanoparticles and also the colloid stability of the conjugates were studied by UV–vis spectrophotometry, TEM, IR and XPS spectroscopy. Moreover, the permeability of these conjugates was assayed using a Caco-2/goblet monolayer model. On the basis of the stability and permeability results, one of the conjugates was chosen to be administered intraperitoneally to normoglycemic rats. The intraperitoneal delivery of the GLP-1 analogue using gold nanoparticles led to decrease levels of blood glucose in the same way as native GLP-1, thereby demonstrating that the formulation of the analogue is stable in physiological conditions and maintains the activity of this incretin. © 2017 Elsevier B.V.

Riveros A.L.,University of Chile | Riveros A.L.,Advanced Center for Chronic Diseases | Astudillo J.,University of Santiago de Chile | Vasquez C.C.,University of Santiago de Chile | And 7 more authors.
Journal of Nanoparticle Research | Year: 2016

Highly fluorescent nanoparticles, or quantum dots, have multiple applications in biology and biomedicine; however, in most cases, it is necessary to functionalize them to enhance their biocompatibility and selectivity. Generally, functionalization is performed after nanoparticle synthesis and involves the use of molecules or macromolecules having two important traits: specific biological activity and functional groups that facilitate nanoparticle capping (i.e. atom–atom interaction). For this reason, we carried out a simple protocol for the chemical synthesis of cadmium telluride quantum dots capped with glutathione, and we then functionalized these nanoparticles with the amphipathic peptide CLPFFD. This peptide attaches selectively to β-Amyloid fibres, which are involved in Alzheimer’s disease. Our results show that the optical properties of the quantum dots are not affected by functionalization with this peptide. Infrared spectra showed that cadmium telluride quantum dots were functionalized with the peptide CLPFFD. In addition, no significant differences were observed between the surface charge of the quantum dots with or without CLPFFD and the nanocrystal size calculated for HR-TEM was 4.2 nm. Finally, our results show that quantum dots with CLPFFD are stable and that they resulted in a significantly reduced cytotoxicity with respect to that induced by quantum dots not conjugated with the peptide. Moreover, the results show that the CLPFFD-functionalized nanoparticles bind to β-Amyloid fibres. © 2016, Springer Science+Business Media Dordrecht.

Pedrozo Z.,Southwestern Medical Center | Pedrozo Z.,Advanced Center for Chronic Diseases | Pedrozo Z.,University of Chile | Criollo A.,Southwestern Medical Center | And 15 more authors.
Circulation | Year: 2015

Background: L-type calcium channel activity is critical to afterload-induced hypertrophic growth of the heart. However, the mechanisms governing mechanical stress-induced activation of L-type calcium channel activity are obscure. Polycystin-1 (PC-1) is a G protein-coupled receptor-like protein that functions as a mechanosensor in a variety of cell types and is present in cardiomyocytes. Methods and Results-We subjected neonatal rat ventricular myocytes to mechanical stretch by exposing them to hypoosmotic medium or cyclic mechanical stretch, triggering cell growth in a manner dependent on L-type calcium channel activity. RNAi-dependent knockdown of PC-1 blocked this hypertrophy. Overexpression of a C-terminal fragment of PC-1 was sufficient to trigger neonatal rat ventricular myocyte hypertrophy. Exposing neonatal rat ventricular myocytes to hypo-osmotic medium resulted in an increase in α1C protein levels, a response that was prevented by PC-1 knockdown. MG132, a proteasomal inhibitor, rescued PC-1 knockdown-dependent declines in α1C protein. To test this in vivo, we engineered mice harboring conditional silencing of PC-1 selectively in cardiomyocytes (PC-1 knockout) and subjected them to mechanical stress in vivo (transverse aortic constriction). At baseline, PC-1 knockout mice manifested decreased cardiac function relative to littermate controls, and α1C L-type calcium channel protein levels were significantly lower in PC-1 knockout hearts. Whereas control mice manifested robust transverse aortic constriction-induced increases in cardiac mass, PC-1 knockout mice showed no significant growth. Likewise, transverse aortic constriction-elicited increases in hypertrophic markers and interstitial fibrosis were blunted in the knockout animals Conclusion-PC-1 is a cardiomyocyte mechanosensor that is required for cardiac hypertrophy through a mechanism that involves stabilization of α1C protein. © 2015 American Heart Association, Inc.

Smith A.H.,University of California at Berkeley | Marshall G.,University of Santiago de Chile | Yuan Y.,University of California at Berkeley | Steinmaus C.,University of California at Berkeley | And 8 more authors.
EBioMedicine | Year: 2014

Background: Arsenic trioxide is effective in treating promyelocytic leukemia, and laboratory studies demonstratethat arsenic trioxide causes apoptosis of human breast cancer cells. Region II in northern Chile experienced veryhigh concentrations of inorganic arsenic in drinking water, especially in the main city Antofagasta from 1958until an arsenic removal plant was installed in 1970.Methods:Weinvestigated breast cancermortality from1950 to 2010 amongwomen in Region II compared to RegionV, which had lowarsenicwater concentrations. Weconducted studies on human breast cancer cell lines andcompared arsenic exposure in Antofagasta with concentrations inducing apoptosis in laboratory studies. Findings: Before 1958, breast cancer mortality rates were similar, but in 1958-1970 the rates in Region II werehalf those in Region V (rate ratio RR= 0.51, 95% CI 0.40-0.66;p < 0.0001). Women under the age of 60 experienceda 70% reduction in breast cancer mortality during 1965-1970 (RR = 0.30, 0.17-0.54; p < 0.0001). Breastcancer cell culture studies showed apoptosis at arsenic concentrations close to those estimated to have occurredin people in Region II. Interpretation: We found biologically plausible major reductions in breast cancermortality during high exposureto inorganic arsenic in drinking waterwhich could not be attributed to bias or confounding. Werecommend clinicaltrial assessment of inorganic arsenic in the treatment of advanced breast cancer. © 2014 The Authors.

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