Cell Senescence, Multiple Organelle Dysfunction and Atherosclerosis

Our research is supported by national funds through FCT- Fundação para a Ciência e Tecnologia and by PROGRAMAS DE ATIVIDADES CONJUNTAS (PAC) grant numbers PTDC/MED-PAT/29395/2017 and N◦3/SAICT/2015. ARAM is supported by the CEECIND/01006/2017, funded by FCT.Atherosclerosis is an age-related disorder associated with long-term exposure to cardiovascular risk factors. The asymptomatic progression of atherosclerotic plaques leads to major cardiovascular diseases (CVD), including acute myocardial infarctions or cerebral ischemic strokes in some cases. Senescence, a biological process associated with progressive structural and functional deterioration of cells, tissues and organs, is intricately linked to age-related diseases. Cell senescence involves coordinated modifications in cellular compartments and has been demonstrated to contribute to different stages of atheroma development. Senescence-based therapeutic strategies are currently being pursued to treat and prevent CVD in humans in the near-future. In addition, distinct experimental settings allowed researchers to unravel potential approaches to regulate anti-apoptotic pathways, facilitate excessive senescent cell clearance and eventually reverse atherogenesis to improve cardiovascular function. However, a deeper knowledge is required to fully understand cellular senescence, to clarify senescence and atherogenesis intertwining, allowing researchers to establish more effective treatments and to reduce the cardiovascular disorders' burden. Here, we present an objective review of the key senescence-related alterations of the major intracellular organelles and analyze the role of relevant cell types for senescence and atherogenesis. In this context, we provide an updated analysis of therapeutic approaches, including clinically relevant experiments using senolytic drugs to counteract atherosclerosis.publishersversionpublishe

Lysosome (Dys)function in Atherosclerosis—A Big Weight on the Shoulders of a Small Organelle

Funding: This research was supported by the research project PTDC/MEDPAT/29395/2017, financed by national funds through the Fundação para a Ciência e Tecnologia (FCT) and by PROGRAMAS DE ATIVIDADES CONJUNTAS (PAC), Reference: No. 03/SAICT/2015. AM was supported by the CEECIND/01006/2017, funded by FCT. This manuscript was supported by the LYSOCIL project, which has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement no. 811087.Atherosclerosis is a progressive insidious chronic disease that underlies most of the cardiovascular pathologies, including myocardial infarction and ischemic stroke. The malfunctioning of the lysosomal compartment has a central role in the etiology and pathogenesis of atherosclerosis. Lysosomes are the degradative organelles of mammalian cells and process endogenous and exogenous substrates in a very efficient manner. Dysfunction of these organelles and consequent inefficient degradation of modified low-density lipoproteins (LDL) and apoptotic cells in atherosclerotic lesions have, therefore, numerous deleterious consequences for cellular homeostasis and disease progression. Lysosome dysfunction has been mostly studied in the context of the inherited lysosomal storage disorders (LSDs). However, over the last years it has become increasingly evident that the consequences of this phenomenon are more far-reaching, also influencing the progression of multiple acquired human pathologies, such as neurodegenerative diseases, cancer, and cardiovascular diseases (CVDs). During the formation of atherosclerotic plaques, the lysosomal compartment of the various cells constituting the arterial wall is under severe stress, due to the tremendous amounts of lipoproteins being processed by these cells. The uncontrolled uptake of modified lipoproteins by arterial phagocytic cells, namely macrophages and vascular smooth muscle cells (VSMCs), is the initial step that triggers the pathogenic cascade culminating in the formation of atheroma. These cells become pathogenic “foam cells,” which are characterized by dysfunctional lipid-laden lysosomes. Here, we summarize the current knowledge regarding the origin and impact of the malfunctioning of the lysosomal compartment in plaque cells. We further analyze how the field of LSD research may contribute with some insights to the study of CVDs, particularly how therapeutic approaches that target the lysosomes in LSDs could be applied to hamper atherosclerosis progression and associated mortality.publishersversionpublishe

In Vitro Cytotoxicity Assays Of Solid Lipid Nanoparticles In Epithelial And Dermal Cells

In recent years, the interest in nanostructured systems to drug delivery has increased because they offer several advantages over conventional dosage forms. Solid Lipid Nanoparticles (SLN) have been highlighted among these systems because they have advantages such as high physical stability, protection against drug degradation and ease of scale-up and manufacturing, without using organic solvent. The aim of this work was to evaluate the potential of SLN, by in vitro cytotoxicity assays, for dermal drug delivery. SLN of three different lipids were prepared by hot high pressure homogenization and the cytotoxicity was assessed by 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test in mouse 3T3 fibroblasts and human HaCaT keratinocytes. SLN showed no cytotoxic potential suggesting a great potential for dermal application.3041Mishra, B., Patel, B.B., Tiwari, S., (2010) Nanomed.-Nanotechnol. Biol. Med., 6, p. 9Mehnert, W., Mäder, K., (2001) Adv. Drug Deliv. Rev., 47, p. 165Pardeike, J., Hommoss, A., Müller, R.H., (2009) Int. J. Pharm., 366, p. 170Lewinski, N., Colvin, V., Drezek, R., (2008) Small, 4, p. 26Schöler, N., Hahn, H., Müller, R.H., Liesenfeld, O., (2002) Int. J. Pharm., 231, p. 167Müller, R.H., Maassen, S., Schwarz, C., Mehnert, W., (1997) J. Control. Release, 47, p. 261Shöler, N., Hahn, H., Müller, R.H., Liesenfeld, O., (2002) Int. J. Pharm., 231, p. 167Weyenberg, W., Filev, P., Plas, D.V., Vandervoort, J., Smet, K.D., Sollie, P., Ludwig, A., (2007) Int. J. Pharm., 337, p. 291Kristl, J., Teskac, K., Milek, M., Rascan, I.M., (2008) Toxicol. Appl.Pharmacol., 232, p. 218Mosmann, T., (1983) J. Immunol. Methods, 65, p. 55Marcato, P.D., Caverzan, J., Rossi-Bergmann, B., Pinto, E.F., MacHado, D., Silva, R.A., Justos, G.Z., Durán, N., (2011) J. Nanosci. Nanotechnol

Encapsulation efficiency of Lactobacillus plantarum microencapsulado in Acrycoat S100

Several studies have attributed health benefits to probiotics, as the contribution to intestinal microflora activity (Khan et al. 2013). However, adverse conditions in gastrointestinal transit can reduce the viability of probiotics as Lactobacillus plantarum. Acrycoat S100 is a co-polymer from methacrylic acid and methyl methacrylate, water insoluble and soluble in pH ≥ 7. Therefore, microencapsulation of probiotic in Acrycoat S100 could allow microorganism protection until it reach the intestine. The objective of this study was to determine the encapsulation efficiency of L. plantarum microencapsulated in Acrycoat S100.info:eu-repo/semantics/publishedVersio

Diversity Of Medium-sized And Large Mammals From Atlantic Forest Remnants In Southern Minas Gerais State, Brazil

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Studies on mammal diversity provide the essential groundwork for the development of conservation methods and practices. The region of the Poços de Caldas Plateau is lacks such studies, which may be a problem for future conservation actions. Here, we analyze the richness of medium-sized and large mammals from Atlantic Forest remnants on the Poços de Caldas Plateau, Minas Gerais state. Diurnal censuses of direct observations and mammal signs were conducted, and we documented 20 species of mammals belonging to eight orders. Three species of primates, one carnivore, one cingulate, one lagomorpha, three rodents, one artiodactyla, and two marsupials were found. The largest forest remnant that presented the greatest richness is currently a conservation unit. Forest remnants are important for the consolidation of management strategies and have fundamental role for the conservation of mammal diversity in the south of Minas Gerais state. © 2016 Check List and Authors.125CNPq, Conselho Nacional de Desenvolvimento Científico e TecnológicoConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Generation and characterization of a recombinant chimeric protein (rCpLi) consisting of B-cell epitopes of a dermonecrotic protein from Loxosceles intermedia spider venom

AbstractA chimeric protein was constructed expressing three epitopes of LiD1, a dermonecrotic toxin from the venom of Loxosceles intermedia spider. This species is responsible for a large number of accidents involving spiders in Brazil. We demonstrated that the chimeric protein (rCpLi) generated is atoxic and that antibodies previously developed in rabbits against synthetic epitopes reactive with rCpLi in ELISA and immunoblot assays. The antibody response in rabbits against the rCpLi was evaluated by ELISA and we have detected an antibody response in all immunized animals. Overlapping peptides covering the amino acid sequence of the rCpLi were synthesized on a cellulose membrane, and their recognition by rabbit anti-rCpLi serum assessed. Three different antigenic regions were identified. The percentage of inhibition of the dermonecrotic, hemorrhagic and edematogenic activities caused by the recombinant protein LiD1r in naïve rabbits was assessed by pre-incubation with anti-rCpLi antibodies. Anti-rCpLi induced good dermonecrotic and hemorrhagic protection. The levels of protection were similar to the antiboides anti-LiD1r. In summary, we have developed a polyepitope recombinant chimeric protein capable of inducing multiple responses of neutralizing antibodies in a rabbit model. This engineered protein may be a promising candidate for therapeutic serum development or vaccination

Clinical outcomes of patients with acute myeloid leukemia: evaluation of genetic and molecular findings in a real-life setting

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