Involvement of Free Radicals in the Development and Progression of Alzheimer’s Disease

Alzheimer’s disease (AD) is a major dementia related to an overproduction of free radicals (FRs), which leads to the generation of oxidative stress in brain tissue. Amyloid beta-peptide of 42 amino acid residues (Aβ1–42) is the main source of FRs in patients with AD. βA1–42 results from hydrolysis of the amyloid precursor protein by β-secretase in a process known as the amyloidogenic pathway. During βA1–42 aggregation, the peptide interacts with various transition metals to produce hydrogen peroxide (H2O2) by the Fenton reaction, generating the hydroxyl radical (•OH), which damages lipids, proteins, and nucleic acids, thereby contributing to neurodegeneration. In addition, βA1–42 is recognized by microglial receptors; it activates these cells, causing overproduction of superoxide anion (O2•−) by NADPH oxidase; O2•− is also converted into H2O2 and finally to •OH in the Fenton reaction. Other factors that contribute to oxidative stress during microglial activation are the overproduction of nitric oxide and interleukins and the overexpression of some enzymes, including cyclooxygenase and inducible nitric oxide synthase, all of which contribute to FR production. Currently, various models in vitro and in vivo exist that permit quantification of O2•− and H2O2 and determination of the effects of these reactive oxygen species

Biomechanical behavior of customized scaffolds: A three-dimensional finite element analysis

Teeth loss due to periodontal diseases, trauma, or infections often causes dimensional loss in the affected maxillary. In patients with reduced maxillary size, restoration of chewing function and esthetics with endosseous dental implants may fail. The aim of this work was to simulate the biomechanical behavior, using the finite element method, of customized scaffolds fixed by a dental implant on a partially edentulous jaw. Porous scaffolds were designed from medical images of a partially edentulous jaw with type IV bone quality. The influence of the diameter of the hole and the porosity of the scaffold on the maximum levels of stress and strain in the peri-implant bone was evaluated. The highest stress values in the scaffolds, dental implant, and crown were lower than the yield strength of their respective materials. The customized scaffolds allow to recover the dimensions of the evaluated jaw. A significant decrease in stress and strain values was observed in the peri-implant cortical bone. Furthermore, it was found that the evaluated parameters did not have a significant influence on the maximum von Mises equivalent stress and maximum strain values in the peri-implant bone.MCIN/ AEI/10.13039/501100011033 PID2019-109371 GB-I0

Post-translationally modified muscle-specific ubiquitin ligases as circulating biomarkers in experimental cancer cachexia

Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation. Up to 80% of cancer patients experience cachexia, with 20-30% of cancer-related deaths directly linked to cachexia. Despite efforts to identify early cachexia and cancer relapse, clinically useful markers are lacking. Recently, we identified the role of muscle-specific ubiquitin ligases Atrogin-1 (MAFbx, FBXO32) and Muscle Ring Finger-1 in the pathogenesis of cardiac atrophy and hypertrophy. We hypothesized that during cachexia, the Atrogin-1 and MuRF1 ubiquitin ligases are released from muscle and migrate to the circulation where they could be detected and serve as a cachexia biomarker. To test this, we induced cachexia in mice using the C26 adenocarcinoma cells or vehicle (control). Body weight, tumor volume, and food consumption were measured from inoculation until ~day 14 to document cachexia. Western blot analysis of serum identified the presence of Atrogin-1 and MuRF1 with unique post-translational modifications consistent with mono- and poly- ubiquitination of Atrogin-1 and MuRF1 found only in cachectic serum. These findings suggest that both increased Atrogin-1 and the presence of unique post-translational modifications may serve as a surrogate marker specific for cachexia

Fractal diagnosis of severe cardiac dysfunction Fractal dynamic of the left coronary branching

INTRODUCCIÓN Y OBJETIVOS: la geometría fractal evalúa la irregularidad de los objetos naturales, permitiendo caracterizar de forma imparcial la totalidad de la ramifi cación coronaria izquierda a diferencia de la metodología actual que evalúa únicamente partes de ésta. Con base en esta medida se generalizó una nueva metodología diagnóstica para detectar cualquier tipo de disfunción cardiaca severa. MÉTODOS: estudio de concordancia diagnóstica en el que se utilizó el método de box counting para medir dimensiones fractales de imágenes consecutivas entre sístole y diástole de la ramifi cación coronaria izquierda en proyección oblicua derecha anterior de angiografías de ocho pacientes con enfermedad arterial oclusiva leve. Así mismo, se evaluaron sus cambios por medio de los conceptos de variabilidad y diferencia neta y se compararon estos resultados con pacientes sin enfermedad arterial oclusiva, con enfermedad arterial oclusiva moderada y severa evaluados previamente de igual forma, para obtener una metodología matemática que evalúa el impacto de cualquier patología en la dinámica cardiaca. RESULTADOS: los casos que presentan diferencias netas de cero corresponden a pacientes con disfunciones cardiacas severas, independientemente del grado o ausencia de enfermedad arterial oclusiva diagnosticada. CONCLUSIONES: se generalizó una nueva metodología diagnóstica de aplicación clínica que detecta disfunciones cardiacas severas sub-diagnosticadas con las metodologías actuales, mediante la caracterización de la dinámica total de la ramifi cación coronaria izquierda.INTRODUCTION AND OBJECTIVES: fractal geometry evaluates the irregularity of natural objects, allowing impartially characterize the entire left coronary branching unlike the current methodology which evaluates only parts of it. Based on this measure, a new diagnostic method was generalized to detect any type of severe cardiac dysfunction. METHODS: Concordance study using the box counting method to measure fractal dimensions of consecutive images between systole and diastole of the left coronary branch in right anterior oblique projection in angiograms of eight patients with mild arterial occlusive disease. Likewise, we evaluated its changes through the concepts of variability and net difference and compared these results with patients without occlusive arterial disease, with moderate to severe arterial occlusive disease previously and similarly evaluated, to obtain a mathematical methodology to assess the impact of any pathology in cardiac dynamics.RESULTS: The cases with zero net differences occur in patients with severe cardiac dysfunction, regardless of the degree or absence of diagnosed occlusive arterial disease. CONCLUSIONS: a new diagnostic methodology of clinical application to detect sub-diagnosed severe heart dysfunction was generalized with current methodologies, through the characterization of the total dynamics of the left coronary branch

Cardiac Muscle Ring Finger-1 Increases Susceptibility to Heart Failure In Vivo

Muscle ring finger-1 (MuRF1) is a muscle-specific protein implicated in the regulation of cardiac myocyte size and contractility. MuRF2, a closely related family member, redundantly interacts with protein substrates, and hetero-dimerizes with MuRF1. Mice lacking either MuRF1 or MuRF2 are phenotypically normal whereas mice lacking both proteins develop a spontaneous cardiac and skeletal muscle hypertrophy indicating cooperative control of muscle mass by MuRF1 and MuRF2. In order to identify the unique role that MuRF1 plays in regulating cardiac hypertrophy in vivo, we created transgenic mice expressing increased amounts of cardiac MuRF1. Adult MuRF1 transgenic (Tg+) hearts exhibited a non-progressive thinning of the left ventricular wall and a concomitant decrease in cardiac function. Experimental induction of cardiac hypertrophy by trans-aortic constriction (TAC) induced rapid failure of MuRF1 Tg+ hearts. Microarray analysis identified that the levels of genes associated with metabolism (and in particular mitochondrial processes) were significantly altered in MuRF1 Tg+ hearts, both at baseline and during the development of cardiac hypertrophy. Surprisingly, ATP levels in MuRF1 Tg+ mice did not differ from wild type mice despite the depressed contractility following TAC. In comparing the level and activity of creatine kinase (CK) between wild type and MuRF1 Tg+ hearts we found that mCK and CK-M/B protein levels were unaffected in MuRF1 Tg+ hearts, however total CK activity was significantly inhibited. We conclude that increased expression of cardiac MuRF1 results in a broad disruption of primary metabolic functions, including alterations in CK activity that leads to increased susceptibility to heart failure following TAC. This study demonstrates for the first time a role for MuRF1 in the regulation of cardiac energetics in vivo

Evaluation of the antioxidant activity of cis/trans-N-phenyl-1,4,4a,5,8,8a-hexahydro-3, 1-benzoxazin-2-imines

The growing interest in the chemistry of unsaturated ring-fused 1,3-heterocycles, in this particular case 1,3-oxazines, arise in part from their versatile pharmacological applications. In the present article, the evaluation of the in vitro and ex vivo antioxidant activity of two cyclohexene-fused oxazines is discussed. The in vitro antioxidant activity was evaluated by trapping the ABTS and hydroxyl radicals as well as the inhibition of the enzyme acetyl-cholinesterase and hemolysis of erythrocytes by 2,2’-Azobis(2-amidinopropane) dihydrochloride (AAPH). The results suggest that both unsaturated 1,3-oxazines are auspicious sources of biologically active compounds with good antioxidant properties. In addition, a comprehensive analysis of the interaction between these heterocycles with 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radicals, as well as the measurements of redox potential, provided evidence for a mechanism of antioxidant activity that takes place through electron transfer (ET) processes.Fil: Firpo, Guadalupe. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Ramirez, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Faillace, Martín Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: de Brito, Maria Dos R. Mendes. Universidade Federal Do Piaui.; BrasilFil: Silva, Ana P. S. Correia Lima E.. Universidade Federal Do Piaui.; BrasilFil: Costa, Jessica Pereira. Universidade Federal Do Piaui.; BrasilFil: Rodríguez, Marcela C.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Argüello, Gustavo Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Szakonyi, Zsolt. Institute Of Pharmaceutical Chemistry Albert Szent-györ; HungríaFil: Fülöp, Ferenc. Institute Of Pharmaceutical Chemistry Albert Szent-györ; HungríaFil: Peláez, Walter José. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentin

Effect of graphene oxide on bacteria and peripheral blood mononuclear cells

"Background Driven by the potential biological applications of graphene, many groups have studied the response of cells exposed to graphene oxide (GO). In particular, investigations of bacteria indicate that there are 2 crucial parameters, which so far have only been investigated separately: GO size and exposure methodology. Our study took into account both parameters. We carefully characterized the samples to catalog sizes and structural properties, and tested different exposure methodologies: exposure in saline solution and in the presence of growth media. Furthermore, we performed experiments with peripheral blood mononuclear cells exposed to our GO materials. Methods Atomic force microscopy, scanning electron microscopy, Raman spectroscopy, X-ray photoelectron spectroscopy and transmission electron microscopy were used to characterize the morphology and composition of different samples of GO: GO-H2O, GO-PBS and GO-MG. Our samples had 2D sizes of ?100 nm (GO-H2O and GO-PBS) and >2 µm (GO-MG). We tested antibacterial activity and cytotoxicity toward peripheral blood mononuclear cells of 3 different GO samples. Results A size-dependent growth inhibition of Escherichia coli (DH5 ?) in suspension was found, which proved that this effect depends strongly on the protocol followed for exposure. Hemocompatibility was confirmed by exposing peripheral blood mononuclear cells to materials for 24 hours; viability and apoptosis tests were also carried out. Conclusions Our experiments provide vital information for future applications of GO in suspension. If its antibacterial properties are to be potentiated, care should be taken to select 2D sizes in the micrometer range, and exposure should not be carried out in the presence of grow media.

Regulation of the calpain and ubiquitin-proteasome systems in a canine model of muscular dystrophy

Previous studies have tested the hypothesis that calpain and/or proteasome inhibition is beneficial in Duchenne Muscular Dystrophy, based largely on evidence that calpain and proteasome activities are enhanced in the mdx mouse

Muscle Ring Finger 1 (MuRF1) and MuRF2 are Necessary but Functionally Redundant During Developmental Cardiac Growth and Regulate E2F1-Mediated Gene Expression In Vivo

Muscle ring finger (MuRF) proteins have been implicated in the transmission of mechanical forces to nuclear cell signaling pathways through their association with the sarcomere. We recently reported that MuRF1, but not MurF2, regulates pathologic cardiac hypertrophy in vivo. This was surprising given that MuRF1 and MuRF2 interact with each other and many of the same sarcomeric proteins experimentally