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1.
Proc Natl Acad Sci U S A ; 120(17): e2220565120, 2023 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-37071684

RESUMEN

DNA-based biomaterials have been proposed for tissue engineering approaches due to their predictable assembly into complex morphologies and ease of functionalization. For bone tissue regeneration, the ability to bind Ca2+ and promote hydroxyapatite (HAP) growth along the DNA backbone combined with their degradation and release of extracellular phosphate, a known promoter of osteogenic differentiation, make DNA-based biomaterials unlike other currently used materials. However, their use as biodegradable scaffolds for bone repair remains scarce. Here, we describe the design and synthesis of DNA hydrogels, gels composed of DNA that swell in water, their interactions in vitro with the osteogenic cell lines MC3T3-E1 and mouse calvarial osteoblast, and their promotion of new bone formation in rat calvarial wounds. We found that DNA hydrogels can be readily synthesized at room temperature, and they promote HAP growth in vitro, as characterized by Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, atomic force microscopy, and transmission electron microscopy. Osteogenic cells remain viable when seeded on DNA hydrogels in vitro, as characterized by fluorescence microscopy. In vivo, DNA hydrogels promote the formation of new bone in rat calvarial critical size defects, as characterized by micro-computed tomography and histology. This study uses DNA hydrogels as a potential therapeutic biomaterial for regenerating lost bone.


Asunto(s)
Hidrogeles , Osteogénesis , Ratones , Ratas , Animales , Hidrogeles/química , Microtomografía por Rayos X , Regeneración Ósea , Materiales Biocompatibles/farmacología , Materiales Biocompatibles/química , Durapatita/farmacología , Durapatita/química , Ingeniería de Tejidos , Andamios del Tejido/química
2.
Syst Biol ; 2024 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-38577768

RESUMEN

Increased sampling of genomes and populations across closely related species has revealed that levels of genetic exchange during and after speciation are higher than previously thought. One obvious manifestation of such exchange is strong cytonuclear discordance, where the divergence in mitochondrial DNA (mtDNA) differs from that for nuclear genes more (or less) than expected from differences between mtDNA and nuclear DNA (nDNA) in population size and mutation rate. Given genome-scale datasets and coalescent modelling, we can now confidently identify cases of strong discordance and test specifically for historical or recent introgression as the cause. Using population sampling, combining exon capture data from historical museum specimens and recently collected tissues we showcase how genomic tools can resolve complex evolutionary histories in the brachyotis group of rock-wallabies (Petrogale). In particular, applying population and phylogenomic approaches we can assess the role of demographic processes in driving complex evolutionary patterns and assess a role of ancient introgression and hybridisation. We find that described species are well supported as monophyletic taxa for nDNA genes, but not for mtDNA, with cytonuclear discordance involving at least four operational taxonomic units (OTUs) across four species which diverged 183-278 kya. ABC modelling of nDNA gene trees supports introgression during or after speciation for some taxon pairs with cytonuclear discordance. Given substantial differences in body size between the species involved, this evidence for gene flow is surprising. Heterogenous patterns of introgression were identified but do not appear to be associated with chromosome differences between species. These and previous results suggest that dynamic past climates across the monsoonal tropics could have promoted reticulation among related species.

3.
Brain ; 147(4): 1166-1189, 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38284949

RESUMEN

Polyglutamine disorders are a complex group of incurable neurodegenerative disorders caused by an abnormal expansion in the trinucleotide cytosine-adenine-guanine tract of the affected gene. To better understand these disorders, our dependence on animal models persists, primarily relying on transgenic models. In an effort to complement and deepen our knowledge, researchers have also developed animal models of polyglutamine disorders employing viral vectors. Viral vectors have been extensively used to deliver genes to the brain, not only for therapeutic purposes but also for the development of animal models, given their remarkable flexibility. In a time- and cost-effective manner, it is possible to use different transgenes, at varying doses, in diverse targeted tissues, at different ages, and in different species, to recreate polyglutamine pathology. This paper aims to showcase the utility of viral vectors in disease modelling, share essential considerations for developing animal models with viral vectors, and provide a comprehensive review of existing viral-based animal models for polyglutamine disorders.


Asunto(s)
Péptidos , Expansión de Repetición de Trinucleótido , Animales , Péptidos/genética , Modelos Animales de Enfermedad , Transgenes
4.
Oral Dis ; 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38696474

RESUMEN

Functional salivary glands (SG) are essential for maintaining oral health, and salivary dysfunction is a persistent major clinical challenge. Several cancer therapies also have off-target effects leading to SG dysfunction. Recent advances highlight the role of SG immune populations in homeostasis, dysfunction and gland regeneration. Here, we review what is known about SG immune populations during development and postnatal homeostasis. We summarize recent findings of immune cell involvement in SG dysfunction following cancer treatments such as irradiation (IR) for head and neck cancers, immune transplant leading to graft-versus-host-disease (GVHD) and immune checkpoint inhibitor (ICI) treatment. The role of immune cells in SG in both homeostasis and disease, is an emerging field of research that may provide important clues to organ dysfunction and lead to novel therapeutic targets.

5.
Liver Transpl ; 29(4): 431-448, 2023 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-36735478

RESUMEN

NAFLD can occur after liver transplantation (LT), as recurrence or de novo hepatic steatosis (HS). We aimed to evaluate the literature on prevalence, risk factors, and prognosis of post-LT HS. Systematic review with meta-analysis through a search on: PUBMED, Scopus, and Web-of-Science, from inception until the September 30, 2021. Forty studies were included, representing 6979 patients. The post-LT HS prevalence was 39.76% (95% CI, 34.06-45.46), with a rising kinetics (11.06% increase per decade, p =0.04), and a geographical distribution (15.10% more prevalent in American continent compared with Europe and Asia). Recurrent HS was up to 5-fold more likely than de novo HS [OR: 5.38 (2.69-10.76)]. Metabolic disturbances were stronger risk factors in the post-LT recipient [obesity: OR: 4.62 (3.07-6.96); metabolic syndrome: OR: 3.26 (2.03-5.25)] as compared with pre-LT recipients, with the exception of diabetes mellitus, which doubled the risk at any set [pre-LT diabetes mellitus: OR: 2.06 (1.58-2.68); post-LT diabetes mellitus: OR: 2.12 (1.73-2.59)]. Donor factors were not the relevant risk factors for post-LT HS and the only immunosuppressive drug associated with increased risk was sirolimus [OR: 1.68 (1.07-2.64)]. The prevalence of post-LT steatohepatitis was 28.82% (19.62-38.03) and the strongest risk factor was pre-LT NAFLD. Limited outcomes data suggest that post-LT HS did not increase the risk for liver cirrhosis or mortality in these studies. Two out of 5 patients submitted to LT will develop post-LT HS, being recurrent HS more common than de novo HS. Diabetes mellitus and post-LT metabolic syndrome are the strongest risk factors for HS and baseline NAFLD for steatohepatitis. All transplanted patients should be enrolled in lifestyle interventions to prevent post-LT metabolic syndrome, and sirolimus should be avoided in high-risk patients.


Asunto(s)
Diabetes Mellitus , Trasplante de Hígado , Síndrome Metabólico , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/etiología , Trasplante de Hígado/efectos adversos , Síndrome Metabólico/etiología , Síndrome Metabólico/complicaciones , Factores de Riesgo , Sirolimus
6.
J Exp Biol ; 226(17)2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37610044

RESUMEN

South America is a vast continent endowed with extraordinary biodiversity that offers abundant opportunities for neuroethological research. Although neuroethology is still emerging in the region, the number of research groups studying South American species to unveil the neural organization of natural behaviors has grown considerably during the last decade. In this Perspective, we provide an account of the roots and strategies that led to the present state of neuroethology in the Southern Cone of America, with a forward-looking vision of its role in education and its international recognition. Hopefully, our Perspective will serve to further promote the study of natural behaviors across South America, as well as in other scarcely explored regions of the world.


Asunto(s)
Biodiversidad , Reconocimiento en Psicología , América del Sur , Células Fotorreceptoras Retinianas Conos
7.
Molecules ; 28(3)2023 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-36771168

RESUMEN

The present work demonstrates the use of Cd2+ as a reactivity probe of the fulvic acids (FAs), humic acids (HAs) and dissolved organic matter (DOM) compost extracts. Significant differences were observed between the extracts, with the HA extract showing the highest reactivity. Comparing the different composts, the largest reactivity variation was again observed for HA then FA and finally DOM extracts. The Cd2+ binding extent was used to calculate the quality of composts and compared with a reference of uncomposted organic fertiliser (FLW), leading to the definition of an operational scale of compost quality. The parameter equivalent mass of fertiliser (mEF) was used for this scale sorted the seven composts from 0.353 to 1.09 kg FLW, for compost of sewage sludge (CSS) and vermicompost of domestic waste (CVDW), respectively. The significance of this parameter was verified through a correlation analysis between binding extent and the effect of compost application on lettuce crop growth in a field trial. The results demonstrate the potentiality of FA and HA extracts as markers of compost bioactivity and the use of Cd2+ as a reactivity probe.


Asunto(s)
Compostaje , Suelo , Cadmio/análisis , Fertilizantes/análisis , Sustancias Húmicas/análisis , Aguas del Alcantarillado , Materia Orgánica Disuelta , Extractos Vegetales
8.
Ecol Lett ; 25(6): 1365-1375, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35343052

RESUMEN

Nests are essential constructions that determine fitness, yet their structure can vary substantially across bird species. While there is evidence supporting a link between nest architecture and the habitat a species occupies, we still ignore what ecological and evolutionary processes are linked to different nest types. Using information on 3175 species of songbirds, we show that-after controlling for latitude and body size-species that build domed nests (i.e. nests with a roof) have smaller ranges, are less likely to colonise urban environments and have potentially higher extinction rates compared to species with open and cavity nests. Domed nests could be a costly specialisation, and we show that these nests take more time to be built, which could restrict breeding opportunities. These diverse strands of evidence suggest that the transition from domed to open nests in passerines could represent an important evolutionary innovation behind the success of the largest bird radiation.


Asunto(s)
Pájaros Cantores , Animales , Evolución Biológica , Tamaño Corporal , Ecosistema , Comportamiento de Nidificación
9.
Mol Ecol ; 31(12): 3496-3512, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35451535

RESUMEN

Analysing diversification dynamics is key to understanding the past evolutionary history of clades that led to present-day biodiversity patterns. While such analyses are widespread in well-characterized groups of species, they are much more challenging in groups for which diversity is mostly known through molecular techniques. Here, we use the largest global database on the small subunit (SSU) rRNA gene of Glomeromycotina, a subphylum of microscopic arbuscular mycorrhizal fungi that provide mineral nutrients to most land plants by forming one of the oldest terrestrial symbioses, to analyse the diversification dynamics of this clade in the past 500 million years. We perform a range of sensitivity analyses and simulations to control for potential biases linked to the nature of the data. We find that Glomeromycotina tend to have low speciation rates compared to other eukaryotes. After a peak of speciations between 200 and 100 million years ago, they experienced an important decline in speciation rates toward the present. Such a decline could be at least partially related to a shrinking of their mycorrhizal niches and to their limited ability to colonize new niches. Our analyses identify patterns of diversification in a group of obligate symbionts of major ecological and evolutionary importance and illustrate that short molecular markers combined with intensive sensitivity analyses can be useful for studying diversification dynamics in microbial groups.


Asunto(s)
Glomeromycota , Micorrizas , Biodiversidad , Evolución Biológica , Glomeromycota/genética , Micorrizas/genética , Simbiosis/genética
10.
FASEB J ; 35(9): e21799, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34339055

RESUMEN

Cardiac fibroblasts (CFBs) support heart function by secreting extracellular matrix (ECM) and paracrine factors, respond to stress associated with injury and disease, and therefore are an increasingly important therapeutic target. We describe how developmental lineage of human pluripotent stem cell-derived CFBs, epicardial (EpiC-FB), and second heart field (SHF-FB) impacts transcriptional and functional properties. Both EpiC-FBs and SHF-FBs exhibited CFB transcriptional programs and improved calcium handling in human pluripotent stem cell-derived cardiac tissues. We identified differences including in composition of ECM synthesized, secretion of growth and differentiation factors, and myofibroblast activation potential, with EpiC-FBs exhibiting higher stress-induced activation potential akin to myofibroblasts and SHF-FBs demonstrating higher calcification and mineralization potential. These phenotypic differences suggest that EpiC-FBs have utility in modeling fibrotic diseases while SHF-FBs are a promising source of cells for regenerative therapies. This work directly contrasts regional and developmental specificity of CFBs and informs CFB in vitro model selection.


Asunto(s)
Linaje de la Célula/fisiología , Miofibroblastos/fisiología , Células Madre Pluripotentes/fisiología , Diferenciación Celular/fisiología , Células Cultivadas , Matriz Extracelular/fisiología , Humanos , Miocardio/patología , Miocitos Cardíacos/fisiología , Fenotipo , Transcripción Genética/fisiología
12.
Bioorg Chem ; 120: 105600, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35078048

RESUMEN

Peroxisome proliferator-activated receptors are promising therapeutic targets for metabolic diseases, including obesity, diabetes, and dyslipidemia. This study describes the design, synthesis and pharmacological evaluation of stilbene-based compounds as dual PPARα/γ partial agonists with potency in the nanomolar range. In vitro and in vivo assays revealed that the lead compound (E)-4-styrylphenoxy-propanamide (5b) removed 14C-cholesterol from the foam cells through apolipoprotein A-I and High-Density Lipoprotein-2. In the high-fat diet-induced obesity mouse model, the oral administration of compound 5b increased HDL levels, paraoxonase-1 activity, and insulin sensitivity, and decreased glucose levels. Moreover, the adipogenesis pathway and triglyceride accumulation slightly changed in the adipocyte cells upon treatment with compound 5b, without affecting the body weight and adipose tissue in obese mice. Compound 5b did not affect the plasma levels of hepatic and renal injury biomarkers. Thus, stilbene-based compound 5b is a promising prototype for developing novel candidates to treat dyslipidemia and diabetes.


Asunto(s)
Diabetes Mellitus , Dislipidemias , Estilbenos , Adipogénesis , Animales , Colesterol , Dieta Alta en Grasa/efectos adversos , Dislipidemias/tratamiento farmacológico , Glucosa/metabolismo , Lipoproteínas HDL/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , PPAR alfa/agonistas , Estilbenos/uso terapéutico
13.
BMC Nephrol ; 23(1): 119, 2022 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-35331148

RESUMEN

BACKGROUND: Hemodialysis (HD) treatment affects functioning, physical activity level, clinical biomarkers, and body composition. However, the association between these variables with functioning, considering International Classification of Functioning, Disability and Health (ICF) domains remains unclear. Thus, the aim of this study was to investigate the possible association between physical activity, biomarkers, and body composition with functioning in HD patients in reference to the ICF. METHODS: Eighty HD patients performed different tests grouped according to ICF domain: Body structure and function - handgrip strength (HS), 5-repetition sit-to-stand test, and 60-s sit-to-stand test (5-STS, 60-STS, respectively); Activity - short physical performance battery (SPPB); and Participation - participation scale questionnaire. Physical activity [Human Activity Profile questionnaire (HAP)], body composition (Dual-energy X-ray absorptiometry), Parathormone (PTH), and alkaline phosphatase were analyzed as possible variables associated with ICF domains. Data analyses were performed using simple and multiple regression models adjusted for age, duration of HD, and diuresis volume. RESULTS: In the body structure and function domain, appendicular lean mass, PTH level, and age were associated with HS (R2 = 0.558); HAP and PTH were associated with 5-STS (R2 = 0.263); and HAP, PTH, duration of HD, and age were associated with 60-STS (R2 = 0.337). In the activity domain, HAP, PTH, alkaline phosphatase, duration of HD, age, and body fat were associated with SPPB (R2 = 0.689). Finally, only HAP was associated with the participation scale (R2 = 0.067). CONCLUSION: Physical activity and PTH levels are determinant protagonists of functioning in all ICF domains in hemodialysis patients.


Asunto(s)
Fuerza de la Mano , Clasificación Internacional del Funcionamiento, de la Discapacidad y de la Salud , Absorciometría de Fotón , Fosfatasa Alcalina , Humanos , Hormona Paratiroidea , Diálisis Renal
14.
Acta Neurochir (Wien) ; 164(4): 973-984, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35239013

RESUMEN

PURPOSE: Currently, there is an increasing tendency to refer only complex aneurysms for microsurgery. The formation of new neurosurgeons dedicated to open vascular neurosurgery becomes challenging in a situation in which complex aneurysms must be dealt with early in the career, raising questions about the safety of the learning curve. METHODS: We analyzed the characteristics and surgical results of the first 300 consecutively treated patients after subarachnoid hemorrhage by a single neurosurgeon. The incidence of surgical complications and clinical outcomes during the learning curve were analyzed, looking for critical periods regarding patient safety. Microsurgical operative times were also studied. RESULTS: A high frequency of wide-necked aneurysms was observed (70.3%), and, as a result, large (> 10 mm), MCA and paraclinoid aneurysms were overrepresented. A statistically significant correlation between surgical experience and clinical outcomes was observed, with progressive surgical experience resulting in a lower incidence of unfavorable outcomes. We also observed a higher frequency of major surgical complications, unfavorable clinical outcomes, and lower complete occlusion rates among the first 40 patients. Microsurgical operative times progressively and significantly decreased during the learning curve. CONCLUSIONS: We observed a high prevalence of wide-necked aneurysms. Young neurosurgeons must be trained and prepared to deal with these aneurysms early in their careers. Although we observed a decrease in unfavorable results with cumulative surgical experience, the first 40 cases were associated with higher rates of major surgical complications, worse clinical outcomes, and lower complete occlusion rates, indicating that this period may be more critical to patient safety.


Asunto(s)
Aneurisma Roto , Procedimientos Endovasculares , Aneurisma Intracraneal , Hemorragia Subaracnoidea , Aneurisma Roto/etiología , Procedimientos Endovasculares/efectos adversos , Humanos , Aneurisma Intracraneal/complicaciones , Curva de Aprendizaje , Microcirugia/efectos adversos , Microcirugia/métodos , Estudios Retrospectivos , Hemorragia Subaracnoidea/complicaciones , Resultado del Tratamiento
15.
J Nutr ; 151(10): 3197-3204, 2021 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-34293140

RESUMEN

BACKGROUND: Vitamin A deficiency (VAD) and anemia are the most prevalent nutritional deficiency in children globally. The dried blood spot (DBS) method has been used in prevalence studies of VAD and anemia in different age groups. However, it has not yet been validated for children. OBJECTIVES: This study aimed to assess the reproducibility and validity of DBS in the diagnosis of VAD and anemia in preschoolers. METHODS: Venous and capillary blood samples were collected from a representative sample of children <5 y old who attended the public health system in Rio de Janeiro. Serum retinol and hemoglobin were measured in 235 and 182 children, respectively. Serum retinol was measured with HPLC and hemoglobin was measured with spectrophotometry in samples of venous (gold standard) and capillary blood (test method, DBS). DBS reproducibility was assessed with the intraclass correlation coefficient (ICC), κ, and prevalence-adjusted and bias-adjusted κ (PABAK). DBS validity was assessed with sensitivity, specificity, accuracy index (AI), positive predictive value (PPV), and negative predictive value (NPV). RESULTS: DBS showed very good reproducibility for serum retinol (ICC = 0.94, κ = 0.83, PABAK = 0.76) and very good/good reproducibility for hemoglobin (ICC = 0.86, κ = 0.69, PABAK = 0.69). Prevalence rates for VAD by the reference and test methods were 11.5% and 11.9%, respectively, whereas the anemia rates were 19.2% and 46.2%. The test method showed low sensitivity (33%) and PPV (32%) and high specificity (91%) and NPV (92%) for serum retinol. For hemoglobin, the test method showed fair sensitivity (71%), low PPV (30%), fair specificity (60%), and high NPV (90%). AI was 83% for VAD and 62% for anemia. CONCLUSIONS: The results suggest that DBS is adequate for the diagnosis of VAD in preschool children, but not for anemia.


Asunto(s)
Anemia , Deficiencia de Vitamina A , Anemia/diagnóstico , Brasil , Preescolar , Hemoglobinas/análisis , Humanos , Prevalencia , Reproducibilidad de los Resultados , Vitamina A , Deficiencia de Vitamina A/diagnóstico , Deficiencia de Vitamina A/epidemiología
16.
Biotechnol Bioeng ; 118(6): 2202-2219, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33624859

RESUMEN

Serological assays are valuable tools to study SARS-CoV-2 spread and, importantly, to identify individuals that were already infected and would be potentially immune to a virus reinfection. SARS-CoV-2 Spike protein and its receptor binding domain (RBD) are the antigens with higher potential to develop SARS-CoV-2 serological assays. Moreover, structural studies of these antigens are key to understand the molecular basis for Spike interaction with angiotensin converting enzyme 2 receptor, hopefully enabling the development of COVID-19 therapeutics. Thus, it is urgent that significant amounts of this protein became available at the highest quality. In this study, we produced Spike and RBD in two human derived cell hosts: HEK293-E6 and Expi293F™. We evaluated the impact of different and scalable bioprocessing approaches on Spike and RBD production yields and, more importantly, on these antigens' quality attributes. Using negative and positive sera collected from human donors, we show an excellent performance of the produced antigens, assessed in serologic enzyme-linked immunosorbent assay (ELISA) tests, as denoted by the high specificity and sensitivity of the test. We show robust Spike productions with final yields of approx. 2 mg/L of culture that were maintained independently of the production scale or cell culture strategy. To the best of our knowledge, the final yield of 90 mg/L of culture obtained for RBD production, was the highest reported to date. An in-depth characterization of SARS-CoV-2 Spike and RBD proteins was performed, namely the antigen's oligomeric state, glycosylation profiles, and thermal stability during storage. The correlation of these quality attributes with ELISA performance show equivalent reactivity to SARS-CoV-2 positive serum, for all Spike and RBD produced, and for all storage conditions tested. Overall, we provide straightforward protocols to produce high-quality SARS-CoV-2 Spike and RBD antigens, that can be easily adapted to both academic and industrial settings; and integrate, for the first time, studies on the impact of bioprocess with an in-depth characterization of these proteins, correlating antigen's glycosylation and biophysical attributes to performance of COVID-19 serologic tests.


Asunto(s)
Antígenos Virales/biosíntesis , Glicosilación , Glicoproteína de la Espiga del Coronavirus/biosíntesis , Frío , Ensayo de Inmunoadsorción Enzimática/normas , Congelación , Células HEK293 , Humanos , Conformación Proteica , Estabilidad Proteica , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/normas , SARS-CoV-2 , Pruebas Serológicas/normas , Glicoproteína de la Espiga del Coronavirus/normas
17.
Brain ; 143(2): 407-429, 2020 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-31738395

RESUMEN

Polyglutamine (polyQ) disorders are a group of nine neurodegenerative diseases that share a common genetic cause, which is an expansion of CAG repeats in the coding region of the causative genes that are otherwise unrelated. The trinucleotide expansion encodes for an expanded polyQ tract in the respective proteins, resulting in toxic gain-of-function and eventually in neurodegeneration. Currently, no disease-modifying therapies are available for this group of disorders. Nevertheless, given their monogenic nature, polyQ disorders are ideal candidates for therapies that target specifically the gene transcripts. Antisense oligonucleotides (ASOs) have been under intense investigation over recent years as gene silencing tools. ASOs are small synthetic single-stranded chains of nucleic acids that target specific RNA transcripts through several mechanisms. ASOs can reduce the levels of mutant proteins by breaking down the targeted transcript, inhibit mRNA translation or alter the maturation of the pre-mRNA via splicing correction. Over the years, chemical optimization of ASO molecules has allowed significant improvement of their pharmacological properties, which has in turn made this class of therapeutics a very promising strategy to treat a variety of neurodegenerative diseases. Indeed, preclinical and clinical strategies have been developed in recent years for some polyQ disorders using ASO therapeutics. The success of ASOs in several animal models, as well as encouraging results in the clinic for Huntington's disease, points towards a promising future regarding the application of ASO-based therapies for polyQ disorders in humans, offering new opportunities to address unmet medical needs for this class of disorders. This review aims to present a brief overview of key chemical modifications, mechanisms of action and routes of administration that have been described for ASO-based therapies. Moreover, it presents a review of the most recent and relevant preclinical and clinical trials that have tested ASO therapeutics in polyQ disorders.


Asunto(s)
Proteína Huntingtina/efectos de los fármacos , Enfermedad de Huntington/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Oligonucleótidos Antisentido/farmacología , Péptidos/genética , Animales , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Enfermedades Neurodegenerativas/genética , Expansión de Repetición de Trinucleótido/genética
18.
Molecules ; 27(1)2021 Dec 24.
Artículo en Inglés | MEDLINE | ID: mdl-35011326

RESUMEN

Natural polymers have emerged as promising candidates for the sustainable development of materials in areas ranging from food packaging and biomedicine to energy storage and electronics. In tandem, there is a growing interest in the design of advanced materials devised from naturally abundant and renewable feedstocks, in alignment with the principles of Green Chemistry and the 2030 Agenda for Sustainable Development. This review aims to highlight some examples of the research efforts conducted at the Research Team BioPol4fun, Innovation in BioPolymer-based Functional Materials and Bioactive Compounds, from the Portuguese Associate Laboratory CICECO-Aveiro Institute of Materials at the University of Aveiro, regarding the exploitation of natural polymers (and derivatives thereof) for the development of distinct sustainable biobased materials. In particular, focus will be given to the use of polysaccharides (cellulose, chitosan, pullulan, hyaluronic acid, fucoidan, alginate, and agar) and proteins (lysozyme and gelatin) for the assembly of composites, coatings, films, membranes, patches, nanosystems, and microneedles using environmentally friendly strategies, and to address their main domains of application.


Asunto(s)
Productos Biológicos/química , Polímeros/química , Materiales Biocompatibles/química , Fuentes de Energía Bioeléctrica , Biotecnología , Celulosa/química , Sistemas de Liberación de Medicamentos , Embalaje de Alimentos , Investigación , Desarrollo Sostenible
19.
Mod Rheumatol ; 31(1): 119-126, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32149558

RESUMEN

OBJECTIVES: To compare serum levels of RAS components in women with RA versus healthy females and to investigate the association between these molecules and subclinical atherosclerosis. METHODS: A cross-sectional study involving female RA patients without ischemic CVD. Disease activity was assessed using the DAS28 and the CDAI. IMT of the common carotid artery was evaluated by ultrasonography. Serum levels of Ang II, Ang-(1-7), ACE and ACE2 were determined by enzyme immunoassay. RESULTS: Fifty women with RA, mean 48.2 (7.3) years, were compared to 30 healthy women, paired by age. RA patients had higher plasma levels of Ang II (p < .01), Ang-(1-7) (p < .01), and ACE (p < .01) than controls. The ratios of ACE to ACE2 were higher in RA patients, whereas Ang II/Ang-(1-7) ratios were lower in RA patients. The presence of hypertension and the treatment with ACE inhibitors did not significantly modify serum levels of Ang II, Ang-(1-7), ACE and ACE2 in patients with RA. Seven RA patients had altered IMT, and eight patients exhibited atherosclerotic plaque. There was a negative correlation between ACE2 levels and IMT (p = .041). IMT positively correlated with age (p = .022), disease duration (p = .012) and overall Framingham risk score (p = .008). Ang II concentrations positively correlated with DAS28 (p = .034) and CDAI (p = .040). CONCLUSION: Patients with RA had an activation of the RAS, suggesting an association with disease activity and cardiovascular risk. Rheumatological key messages Imbalance of both RAS axes may be associated with cardiovascular risk and disease activity in rheumatoid arthritis. Ultrasonography of the carotid arteries can identify early, subclinical atherosclerotic disease in rheumatoid arthritis patients. Angiotensin-converting enzyme inhibition or angiotensin 1 receptor blockade may be beneficial for rheumatoid arthritis patients.


Asunto(s)
Enzima Convertidora de Angiotensina 2/sangre , Artritis Reumatoide , Aterosclerosis , Grosor Intima-Media Carotídeo , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/epidemiología , Artritis Reumatoide/metabolismo , Enfermedades Asintomáticas/epidemiología , Aterosclerosis/sangre , Aterosclerosis/diagnóstico , Aterosclerosis/epidemiología , Biomarcadores/sangre , Brasil/epidemiología , Estudios Transversales , Diagnóstico Precoz , Femenino , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Persona de Mediana Edad , Gravedad del Paciente , Sistema Renina-Angiotensina
20.
An Acad Bras Cienc ; 92 Suppl 1: e20180675, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32638859

RESUMEN

The objective of this study was to evaluate the weight and body yield of two families of selectively bred tambaqui farmed in different environments. Two families (FA and FB) were reared in the municipalities (environments) of Santo Antônio de Leverger (MT) and Campo Grande (MS) for 431 days. Pre-bleeding weight, body yield, and the interaction effect between families and environments on these traits were investigated. No interaction effect between the evaluated families and environments was detected on the evaluated traits. Pre-bleeding weight did not differ significantly between the families in MT (FA: 2,421.7g; FB: 2,478.0g) or in MS (FA: 1,138.7g; FB: 1,389.8g), but the fish from MT had a higher (P<0.05) pre-bleeding weight than those farmed in MS. The visceral fat yield (considering the two environments) was higher (P<0.05) in FB family (3.8%) than in FA family (3.3%).Fish from MS showed higher (P<0.05) offal yield (10.6%) and visceral fat yield (3.9%) but a lower clean-trunk yield (70.6%) than the tambaqui farmed in MT (offal: 7.7%; visceral fat: 3.1%; and clean trunk: 72.6%). In conclusion, the MT environment provides higher pre-bleeding weight and clean-trunk yield and lower offal and visceral-fat yields than the MS environment.


Asunto(s)
Characiformes , Animales , Peso Corporal , Cruzamiento
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