EXOSSOMOS: ESTRUTURAS PROMISSORAS PARA O DIAGNÓSTICO E TRATAMENTO DE DOENÇAS E REGULAÇÃO DOS PROCESSOS DE INTERAÇÃO PARASITO-HOSPEDEIRO

Introdução: Os exossomos são pequenas vesículas com diâmetro que varia entre 40 e 100 nm, produzidas pelo sistema endocítico de diversos tipos celulares. O interesse recente nos exosssomos é atribuído ao seu papel na disseminação de organismos patogênicos, bem como na sua função em promover e regular a resposta imune. Destaca-se ainda o promissor uso dos exossomos como biomarcadores de doenças e como ferramentas terapêuticas. Além de mediarem a comunicação intercelular, os exossomos também estão envolvidos em enfermidades como câncer e doenças degenerativas. Objetivo: Levantar novas abordagens relacionadas aos exosossomos, sua formação, função e sua relevância para o uso de novas técnicas diagnósticas e terapêuticas, e durante a interação parasito-hospedeiro. Metodologia: Este é um estudo de revisão bibliográfica desenvolvido através de levantamento na literatura sobre o tema abordado. Resultados e discussão: Os exossomos tem sido atribuído a diferentes funções biológicas, entre elas estão a influência no sistema imune, transferência de receptores de uma célula para outra, assim como a entrega de mRNAs, miRNAs e proteínas específicas da célula de origem para o citoplasma da célula recipiente. Os exossomos facilitam também o transporte e disseminação de patógenos. Sua análise tem sido descrita em abordagens diagnósticas e terapêuticas. Conclusão: Componentes específicos dos exossomos tem mostrado serem uma ferramenta não invasiva no diagnóstico de doenças como câncer, além disso desempenham importantes papéis durante a interação parasito-hospedeiro.Palavras chave: exossomos, biomarcadores, terapias, patógenos, comunicação celular

Lipid lowering effects of the CETP inhibitor obicetrapib in combination with high-intensity statins: a randomized phase 2 trial

Global guidelines for the management of high-cardiovascular-risk patients include aggressive goals for low-density lipoprotein cholesterol (LDL-C). Statin therapy alone is often insufficient to reach goals and nonstatin options have limitations. Here, we tested the lipid-lowering effects of the cholesteryl ester transfer protein (CETP) inhibitor drug obicetrapib in a randomized, double-blind, placebo-controlled trial in dyslipidaemic patients (n = 120, median LDL-C 88 mg dl−1) with background high-intensity statin treatment (NCT04753606). Over the course of 8 weeks, treatment with 5 mg or 10 mg obicetrapib resulted in a significant decrease as compared with placebo in median LDL-C concentration (by up to 51%; P < 0.0001), the primary trial outcome. As compared with placebo, obicetrapib treatment also significantly (P < 0.0001) decreased apolipoprotein B (by up to 30%) and non-high-density lipoprotein cholesterol (non-HDL-C) concentration (by up to 44%), and significantly (P < 0.0001) increased HDL-C concentration (by up to 165%; the secondary trial outcomes) and had an acceptable safety profile. These results support the potential of obicetrapib to address an unmet medical need for high-cardiovascular-risk patients

Quantitative autofluorescence and cell density maps of the human retinal pigment epithelium

Purpose.: Lipofuscin (LF) accumulation within RPE cells is considered pathogenic in AMD. To test whether LF contributes to RPE cell loss in aging and to provide a cellular basis for fundus autofluorescence (AF) we created maps of human RPE cell number and histologic AF. Methods.: Retinal pigment epithelium–Bruch's membrane flat mounts were prepared from 20 donor eyes (10 ≤ 51 and 10 > 80 years; postmortem: ≤4.2 hours; no retinal pathologies), preserving foveal position. Phalloidin-binding RPE cytoskeleton and LF-AF (488-nm excitation) were imaged at up to 90 predefined positions. Maps were assembled from 83,330 cells in 1470 locations. From Voronoi regions representing each cell, the number of neighbors, cell area, and total AF intensity normalized to an AF standard was determined. Results.: Highly variable between individuals, RPE-AF increases significantly with age. A perifoveal ring of high AF mirrors rod photoreceptor topography and fundus-AF. Retinal pigment epithelium cell density peaks at the fovea, independent of age, yet no net RPE cell loss is detectable. The RPE monolayer undergoes considerable lifelong re-modeling. The relationship of cell size and AF, a surrogate for LF concentration, is orderly and linear in both groups. Autofluorescence topography differs distinctly from the topography of age-related rod loss. Conclusions.: Digital maps of quantitative AF, cell density, and packing geometry provide metrics for cellular-resolution clinical imaging and model systems. The uncoupling of RPE LF content, cell number, and photoreceptor topography in aging challenges LF's role in AMD

Quantitative Autofluorescence and Cell Density Maps of the Human Retinal Pigment Epithelium

PURPOSE. Lipofuscin (LF) accumulation within RPE cells is considered pathogenic in AMD. To test whether LF contributes to RPE cell loss in aging and to provide a cellular basis for fundus autofluorescence (AF) we created maps of human RPE cell number and histologic AF. METHODS. Retinal pigment epithelium–Bruch's membrane flat mounts were prepared from 20 donor eyes (10 ≤ 51 and 10 > 80 years; postmortem: ≤4.2 hours; no retinal pathologies), preserving foveal position. Phalloidin-binding RPE cytoskeleton and LF-AF (488-nm excitation) were imaged at up to 90 predefined positions. Maps were assembled from 83,330 cells in 1470 locations. From Voronoi regions representing each cell, the number of neighbors, cell area, and total AF intensity normalized to an AF standard was determined. RESULTS. Highly variable between individuals, RPE-AF increases significantly with age. A perifoveal ring of high AF mirrors rod photoreceptor topography and fundus-AF. Retinal pigment epithelium cell density peaks at the fovea, independent of age, yet no net RPE cell loss is detectable. The RPE monolayer undergoes considerable lifelong re-modeling. The relationship of cell size and AF, a surrogate for LF concentration, is orderly and linear in both groups. Autofluorescence topography differs distinctly from the topography of age-related rod loss. CONCLUSIONS. Digital maps of quantitative AF, cell density, and packing geometry provide metrics for cellular-resolution clinical imaging and model systems. The uncoupling of RPE LF content, cell number, and photoreceptor topography in aging challenges LF's role in AMD

Mutation analysis of CHCHD10 in different neurodegenerative diseases

A recent study by Bannwarth et al. (2014) implicated CHCHD10 as a novel gene for amyotrophic lateral sclerosis/frontotemporal lobar degeneration (ALS/FTLD), reporting a p.S59L substitution (c.176C > T; NM_213720.2) in a large French kindred. Affected family members were presented with a complex phenotype that included symptoms of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), cerebellar ataxia, Parkinson's disease and a mitochondrial myopathy associated with multiple mitochondrial DNA deletions. So far, seven missense CHCHD10 mutations have been reported in patients with a broad phenotypic range, including ALS/FTLD (p.S59L and p.P34S) (Bannwarth et al., 2014; Chaussenot et al., 2014), ALS (p.R15L and p.G66V) (Johnson et al., 2014; Muller et al., 2014), myopathy (p.R15S and p.G58R) (Ajroud-Driss et al., 2015) and late-onset spinal motor neuronopathy (p.G66V) (Penttila et al., 2015). All of them affect exon 2 (a mutational hotspot of CHCHD10).Fil: Zhang, Ming. University of Toronto; CanadáFil: Xi, Zhengrui. University of Toronto; CanadáFil: Zinman, Lorne. Sunnybrook Health Sciences Centre; Estados UnidosFil: Bruni, Amalia C.. Lamezia Terme. Regional Neurogenetic Centre; ItaliaFil: Maletta, Raffaele G.. Lamezia Terme. Regional Neurogenetic Centre; ItaliaFil: Curcio, Sabrina A. M.. Lamezia Terme. Regional Neurogenetic Centre; ItaliaFil: Rainero, Innocenzo. Università di Torino; ItaliaFil: Rubino, Elisa. Università di Torino; ItaliaFil: Pinessi, Lorenzo. Università di Torino; ItaliaFil: Nacmias, Benedetta. Universita Degli Studi Di Firenze; ItaliaFil: Sorbi, Sandro. Universita Degli Studi Di Firenze; ItaliaFil: Galimberti, Daniela. Università degli Studi di Milano; ItaliaFil: Lang, Anthony E.. Toronto Western Hospital University Of Toronto; Canadá. University of Toronto; CanadáFil: Fox, Susan. Toronto Western Hospital University Of Toronto; Canadá. University of Toronto; CanadáFil: Surace, Ezequiel Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas "Raúl Carrea"; ArgentinaFil: Ghani, Mahdi. University of Toronto; CanadáFil: Guo, Jing. University of Toronto; CanadáFil: Sato, Christine. University of Toronto; CanadáFil: Moreno, Danielle. University of Toronto; CanadáFil: Liang, Yan. University of Toronto; CanadáFil: Keith, Julia. Sunnybrook Health Sciences Centre; CanadáFil: Traynor, Bryan J.. National Institute on Aging. Laboratory of Neurogenetics. Neuromuscular Diseases Research Section; Estados UnidosFil: George-Hyslop, Peter St.. University of Toronto; Canadá. University of Cambridge; Reino UnidoFil: Rogaeva, Ekaterina. University of Toronto; Canad