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1.
Rev. cub. inf. cienc. salud ; 31(1): e1454, ene.-mar. 2020. tab
Artigo em Espanhol | LILACS, CUMED | ID: biblio-1126344

RESUMO

Las revistas científicas son uno de los medios de difusión científica más importantes para la ciencia, y su papel en el avance de la medicina es crucial. El objetivo de este estudio fue determinar los factores asociados al conocimiento de revistas científicas en estudiantes de medicina de 40 escuelas en Latinoamérica. El diseño realizado fue transversal de análisis de datos secundarios. Se definió el conocimiento de revista científica si el estudiante respondía correctamente al nombre de cualquier revista científica. Se obtuvieron valores p mediante modelos lineales generalizados multinivel de efectos mixtos. De 11 587 participantes, la mediana de edad fue de 21 años y el 53,8 por ciento era del sexo femenino. Solo el 1,4 por ciento reportó conocimiento en revistas científicas. Se asociaron a una mayor frecuencia de conocimiento de revistas científicas la edad en años (RP= 1,06; IC: 95 por ciento : 1,04-1,07); estudiar en universidad privada (RP= 1,50; IC: 95 por ciento : 1,19-1,66); estar afiliado a una sociedad científica (RP= 1,31; IC: 95 por ciento : 1,09-1,56); el grupo de investigación (RP= 1,55; IC: 95 por ciento : 1,24-1,93) y más de 1 grupo extracurricular (RP= 2,02; IC: 95 por ciento : 1,39-2,93), así como reportar nivel de inglés intermedio (RP= 2,12; IC 95 por ciento : 1,68-2,67) y avanzado (RP= 2,12; IC 95 por ciento : 1,65-2,72); la capacitación en la búsqueda bibliográfica (RP= 1,40; IC: 95 por ciento : 1,19-1,66); la base de datos (RP= 1,40; IC 95 por ciento : 1,18-1,52); la lectura crítica (RP= 1,34; IC: 95 por ciento : 1,18-1,52) y los gestores de referencia (RP= 1,32; IC 95 por ciento : 1,16-1,51). Se concluye que el conocimiento de revistas científicas parece incrementarse en estudiantes entrenados en investigación y afiliados a grupos científicos. Se recomienda reforzar las habilidades científicas-académicas esenciales en la formación médica(AU)


Scientific journals are among the most important scientific dissemination means, and their role in the advancement of medicine is crucial. The purpose of the study was to determine the factors associated to knowledge about scientific journals among students from 40 Latin American medical schools. The study was based on a cross-sectional secondary data analysis design. Knowledge about scientific journals was defined when the student responded correctly to the name of any scientific journal. P-values were obtained using generalized linear mixed effect multilevel models. Of the total 11 587 participants, 53.8 percent were female; mean age was 21 years. Only 1.4 percent reported knowledge about scientific journals. The following variables were associated to greater knowledge about scientific journals: age in years (AR= 1.06; CI 95 percent : 1.04-1.07), studying in a private university (AR= 1.50; CI: 95 percent : 1.19-1.66); being affiliated to a scientific society (AR= 1.31; CI: 95 percent : 1.09-1.56); the research group (AR= 1.55; CI: 95 percent : 1.24-1.93) and more than 1 extracurricular group (AR= 2.02; CI: 95 percent : 1.39-2.93); as well as reporting an intermediate level in English (AR= 2.12; CI: 95 percent : 1.68-2.67); or an advanced level in English (AR= 2.12; CI: 95 percent : 1.65-2.72); training in bibliographic search (AR= 1.40; CI: 95 percent : 1.19-1.66); the database (AR= 1.40; CI: 95 percent : 1.18-1.52); critical reading (AR= 1.34; CI: 95 percent : 1.18-1.52) and reference managers (AR= 1.32; CI 95 percent : 1.16-1.51). It is concluded that knowledge about scientific journals seems to be greater among students trained in research and affiliated to scientific groups. It is recommended to reinforce the scientific-academic skills essential to medical training(AU)


Assuntos
Humanos , Pesquisa , Estudantes de Medicina , Conhecimento
2.
PLoS Genet ; 16(1): e1008538, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31917787

RESUMO

Genome-wide association studies have identified multiple novel genomic loci associated with vascular diseases. Many of these loci are common non-coding variants that affect the expression of disease-relevant genes within coronary vascular cells. To identify such genes on a genome-wide level, we performed deep transcriptomic analysis of genotyped primary human coronary artery smooth muscle cells (HCASMCs) and coronary endothelial cells (HCAECs) from the same subjects, including splicing Quantitative Trait Loci (sQTL), allele-specific expression (ASE), and colocalization analyses. We identified sQTLs for TARS2, YAP1, CFDP1, and STAT6 in HCASMCs and HCAECs, and 233 ASE genes, a subset of which are also GTEx eGenes in arterial tissues. Colocalization of GWAS association signals for coronary artery disease (CAD), migraine, stroke and abdominal aortic aneurysm with GTEx eGenes in aorta, coronary artery and tibial artery discovered novel candidate risk genes for these diseases. At the CAD and stroke locus tagged by rs2107595 we demonstrate colocalization with expression of the proximal gene TWIST1. We show that disrupting the rs2107595 locus alters TWIST1 expression and that the risk allele has increased binding of the NOTCH signaling protein RBPJ. Finally, we provide data that TWIST1 expression influences vascular SMC phenotypes, including proliferation and calcification, as a potential mechanism supporting a role for TWIST1 in CAD.


Assuntos
Vasos Coronários/metabolismo , Células Endoteliais/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteínas Nucleares/genética , Proteína 1 Relacionada a Twist/genética , Doenças Vasculares/genética , Células Cultivadas , Vasos Coronários/citologia , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Proteínas Nucleares/metabolismo , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Transcriptoma , Proteína 1 Relacionada a Twist/metabolismo
3.
Stem Cells Dev ; 28(2): 81-100, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30375284

RESUMO

The neural crest (NC) is a transient multipotent cell population present during embryonic development. The NC can give rise to multiple cell types and is involved in a number of different diseases. Therefore, the development of new strategies to model NC in vitro enables investigations into the mechanisms involved in NC development and disease. In this study, we report a simple and efficient protocol to differentiate human pluripotent stem cells (HPSC) into NC using a chemically defined media, with basic fibroblast growth factor 2 (FGF2) and the transforming growth factor-ß inhibitor SB-431542. The cell population generated expresses a range of NC markers, including P75, TWIST1, SOX10, and TFAP2A. NC purification was achieved in vitro through serial passaging of the population, recreating the developmental stages of NC differentiation. The generated NC cells are highly proliferative, capable of differentiating to their derivatives in vitro and engraft in vivo to NC specific locations. In addition, these cells could be frozen for storage and thawed with no loss of NC properties, nor the ability to generate cellular derivatives. We assessed the potential of the derived NC population to model the neurocristopathy, Treacher Collins Syndrome (TCS), using small interfering RNA (siRNA) knockdown of TCOF1 and by creating different TCOF1+/- HPSC lines through CRISPR/Cas9 technology. The NC cells derived from TCOF1+/- HPSC recapitulate the phenotype of the reported TCS murine model. We also report for the first time an impairment of migration in TCOF1+/- NC and mesenchymal stem cells. In conclusion, the developed protocol permits the generation of the large number of NC cells required for developmental studies, disease modeling, and for drug discovery platforms in vitro.


Assuntos
Diferenciação Celular , Técnicas de Reprogramação Celular/métodos , Disostose Mandibulofacial/genética , Crista Neural/citologia , Células-Tronco Pluripotentes/citologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Benzamidas/farmacologia , Morte Celular , Movimento Celular , Embrião de Galinha , Dioxóis/farmacologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Disostose Mandibulofacial/patologia , Crista Neural/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/genética , Células-Tronco Pluripotentes/efeitos dos fármacos , Células-Tronco Pluripotentes/metabolismo , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo , Fator de Transcrição AP-2/genética , Fator de Transcrição AP-2/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína 1 Relacionada a Twist/genética , Proteína 1 Relacionada a Twist/metabolismo
4.
Front Med (Lausanne) ; 5: 190, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29998109

RESUMO

A cohort of 141 males (18-80 yo, 42.9 ± 12.9) strongly suspected of being Insulin Resistant (IR) was prospectively studied by determining their insulin sensitivity (Pancreatic Suppression Test, PST) and testicular function (total testosterone and SHBG). The subjects were labeled as IR when the Steady State Plasma Glucose (SSPG) was ≥150 mg/dL and Non-Insulin Resistant (NIR) when SSPG was <150 mg/dl; similarly, the subjects were labeled as Hypogonadal (HYPOG) when total testosterone was ≤3.0 ng/mL and Eugonadal (EUG) when total testosterone was >3.0 ng/mL. Two out of three subjects turned out to be IR, while around one in four subjects were HYPOG. Contingency analysis indicated a significant interdependence between insulin resistance and hypogonadism (chi-square was 4.69, p = 0.0303). Age (>43 yo) predicted hypogonadism (AUROC 0.606, p = 0.0308). Twice as many HYPOG subjects were IR as compared with EUG subjects. Also, HYPOG subjects exhibited higher SSPG values as compared with EUG subjects. Statistically, neither Weight nor BMI predicted hypogonadism, while Waist Circumference (>110 cm) was only a mediocre predictor (AUROC 0.640, p = 0.009). SSPG (>224 mg/dL) on the other hand, was the best predictor of hypogonadism (AUROC 0.709, p = 0.002), outperforming Waist Circumference (half of the subjects with an SSPG >224 mg/dL were HYPOG). Age did not predict insulin resistance, while Weight (>99 kg), BMI (>29), and especially, Waist Circumference (>99 cm, AUROC 0.812, p < 0.0001) were all predictors of insulin resistance. Almost 90% of the subjects with a waist circumference >99 cm was IR. As a logical consequence of the selection criteria (various clues suggesting insulin resistance), most subjects with normal weight in this cohort were IR (53.3%) while 20% were HYPOG. On the other hand, 13.6% of the obese subjects were NIR, and 2 out of 3 of them were both NIR and EUG. In conclusion, Waist Circumference predicted both insulin resistance (>99 cm) and hypogonadism (>110 cm), suggesting that the first hit of abdominal obesity is insulin resistance and the second hit is male hypogonadism. Normal weight did not protect from IR, while a relevant proportion of obese subjects were NIR (with 2/3 being also EUG).

5.
Front Public Health ; 6: 141, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29876339

RESUMO

Sex hormones significantly impact women's lives. Throughout the different stages of life, from menarche to menopause and all stages in between, women experience dramatic fluctuations in the levels of progesterone and estradiol, among other hormones. These fluctuations affect the body as a whole, including the central nervous system (CNS). In the CNS, sex hormones act via steroid receptors. They also have an effect on different neurotransmitters such as GABA, serotonin, dopamine, and glutamate. Additionally, studies show that sex hormones and their metabolites influence brain areas that regulate mood, behavior, and cognitive abilities. This review emphasizes the benefits a proper hormonal balance during the different stages of life has in the CNS. To achieve this goal, it is essential that hormone levels are evaluated considering a woman's age and ovulatory status, so that a correct diagnosis and treatment can be made. Knowledge of steroid hormone activity in the brain will give women and health providers an important tool for improving their health and well-being.

6.
J Alzheimers Dis ; 63(2): 705-723, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29660932

RESUMO

Soluble amyloid-ß (Aß) oligomers have been recognized as early neurotoxic intermediates with a key role in the synaptic dysfunction observed in Alzheimer's disease (AD). Aß oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Additionally, the presence of Aß oligomers is associated with imbalanced intracellular calcium levels and apoptosis in neurons. In this context, we evaluated the effects of three diterpenes (ferruginol, jatrophone, and junicedric acid) that are found in medicinal plants and have several forms of biological activity. The intracellular calcium levels in hippocampal neurons increased in the presence of ferruginol, jatrophone, and junicedric acid, a result that was consistent with the observed increase in CA1 synaptic transmission in mouse hippocampal slices. Additionally, assays using Aß peptide demonstrated that diterpenes, particularly ferruginol, restore LTP and reduce apoptosis. Recovery of the Aß oligomer-induced loss of the synaptic proteins PSD-95, synapsin, VGlut, and NMDA receptor subunit 2A was observed in mouse hippocampal slices treated with junicedric acid. This cascade of events may be associated with the regulation of kinases, e.g., protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII), in addition to the activation of the canonical Wnt signaling pathway and could thus provide protection against Aß oligomers, which trigger synaptic dysfunction. Our results suggest a potential neuroprotective role for diterpenes against the Aß oligomers-induced neurodegenerative alterations, which make them interesting molecules to be further studied in the context of AD.


Assuntos
Abietanos/farmacologia , Peptídeos beta-Amiloides/metabolismo , Alcaloides Diterpenos/farmacologia , Diterpenos/farmacologia , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/metabolismo , Abietanos/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Cálcio/metabolismo , Células Cultivadas , Alcaloides Diterpenos/química , Diterpenos/química , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/química , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/patologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Técnicas de Cultura de Tecidos
9.
Linacre Q ; 84(4): 343-355, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29255329

RESUMO

The concept of the ovarian continuum can be understood as a process that occurs during a woman's lifetime and begins during intrauterine life with fertilization. Women start their reproductive years with approximately five hundred thousand follicles containing oocytes, of which only around five hundred will be released during ovulation. Ovulation has been recognized as an event linked with reproduction; however, recent evidence supports the role of ovulation as a sign of health. The use of biomarkers that help women recognize ovulation enables them to identify their health status. This knowledge helps medical healthcare providers in the prevention, diagnosis, and treatment of different pathologies related with endocrine disorders, gynecological abnormalities, autoimmune, genetic, and neoplastic diseases, as well as pregnancy-related issues. The knowledge of the ovarian continuum and the use of biomarkers to recognize ovulation should be considered a powerful tool for women and medical professionals. Summary: The ovarian continuum is a process that occurs during a woman's lifetime. It begins during intrauterine life with fertilization and ends with menopause. This process can be greatly affected by different conditions such as changes in hormonal levels and illnesses. Therefore, understanding and promoting the knowledge and use of biomarkers of ovulation in women is a key aspect to consider when evaluating their health status. The knowledge and education about the ovarian continuum should be taken into account as a powerful tool for women and medical professionals.

11.
PLoS One ; 12(10): e0185673, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28982181

RESUMO

INTRODUCTION: Sci-Hub is a useful web portal for people working in science as it provides access to millions of free scientific articles. Satisfaction and usage should be explored in the Latino student population. The objective of this study was to evaluate the use, knowledge, and perception of the scientific contribution of Sci-Hub in medical students from Latin America. METHODOLOGY: A multicenter, observational, analytical study was conducted in 6632 medical students from 6 countries in Latin America. We surveyed from a previously validated instrument, delving into knowledge, monthly average usage, satisfaction level, and perception of the scientific contributions provided by Sci-Hub. Frequencies and percentages are described, and generalized linear models were used to establish statistical associations. RESULTS: Only 19.2% of study participants knew of Sci-Hub and its function, while the median use was twice a month. 29.9% of Sci-Hub-aware participants claimed they always find the desired scientific information in their Sci-Hub search; 62.5% of participants affirmed that Sci-Hub contributes to scientific investigation; only 2.2% reported that Sci-Hub does not contribute to science. CONCLUSION: The majority of Latino students are not aware of Sci-Hub.


Assuntos
Estudantes de Medicina/psicologia , Adolescente , Adulto , Feminino , Humanos , América Latina , Masculino , Adulto Jovem
12.
Stem Cells Transl Med ; 6(8): 1673-1683, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28628273

RESUMO

Human induced pluripotent stem cells (iPSCs) can be differentiated into vascular endothelial (iEC) and smooth muscle (iSMC) cells. However, because iECs and iSMCs are not derived from an intact blood vessel, they represent an immature phenotype. Hemodynamics and heterotypic cell:cell communication play important roles in vascular cell phenotypic modulation. Here we tested the hypothesis that hemodynamic exposure of iECs in coculture with iSMCs induces an in vivo-like phenotype. iECs and iSMCs were cocultured under vascular region-specific blood flow hemodynamics, and compared to hemodynamic cocultures of blood vessel-derived endothelial (pEC) and smooth muscle (pSMC) cells. Hemodynamic flow-induced gene expression positively correlated between pECs and iECs as well as pSMCs and iSMCs. While endothelial nitric oxide synthase 3 protein was lower in iECs than pECs, iECs were functionally mature as seen by acetylated-low-density lipoprotein (LDL) uptake. SMC contractile protein markers were also positively correlated between pSMCs and iSMCs. Exposure of iECs and pECs to atheroprone hemodynamics with oxidized-LDL induced an inflammatory response in both. Dysfunction of the transforming growth factor ß (TGFß) pathway is seen in several vascular diseases, and iECs and iSMCs exhibited a transcriptomic prolife similar to pECs and pSMCs, respectively, in their responses to LY2109761-mediated transforming growth factor ß receptor I/II (TGFßRI/II) inhibition. Although there are differences between ECs and SMCs derived from iPSCs versus blood vessels, hemodynamic coculture restores a high degree of similarity in their responses to pathological stimuli associated with vascular diseases. Thus, iPSC-derived vascular cells exposed to hemodynamics may provide a viable system for modeling rare vascular diseases and testing new therapeutic approaches. Stem Cells Translational Medicine 2017;6:1673-1683.


Assuntos
Diferenciação Celular , Células Endoteliais/citologia , Hemodinâmica , Células-Tronco Pluripotentes Induzidas/citologia , Miócitos de Músculo Liso/citologia , Fenótipo , Transcriptoma , Células Cultivadas , Técnicas de Cocultura/métodos , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Miócitos de Músculo Liso/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
14.
Nat Genet ; 49(1): 97-109, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27893734

RESUMO

Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in FBN1, which encodes the extracellular matrix protein fibrillin-1. To investigate the pathogenesis of aortic aneurysms in MFS, we generated a vascular model derived from human induced pluripotent stem cells (MFS-hiPSCs). Our MFS-hiPSC-derived smooth muscle cells (SMCs) recapitulated the pathology seen in Marfan aortas, including defects in fibrillin-1 accumulation, extracellular matrix degradation, transforming growth factor-ß (TGF-ß) signaling, contraction and apoptosis; abnormalities were corrected by CRISPR-based editing of the FBN1 mutation. TGF-ß inhibition rescued abnormalities in fibrillin-1 accumulation and matrix metalloproteinase expression. However, only the noncanonical p38 pathway regulated SMC apoptosis, a pathological mechanism also governed by Krüppel-like factor 4 (KLF4). This model has enabled us to dissect the molecular mechanisms of MFS, identify novel targets for treatment (such as p38 and KLF4) and provided an innovative human platform for the testing of new drugs.


Assuntos
Aneurisma Aórtico/patologia , Apoptose , Células-Tronco Pluripotentes Induzidas/patologia , Síndrome de Marfan/patologia , Modelos Biológicos , Músculo Liso Vascular/patologia , Aneurisma Aórtico/metabolismo , Fibrilina-1/metabolismo , Regulação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Síndrome de Marfan/metabolismo , Músculo Liso Vascular/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Development ; 143(23): 4405-4418, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27899508

RESUMO

Inducible loss of gene function experiments are necessary to uncover mechanisms underlying development, physiology and disease. However, current methods are complex, lack robustness and do not work in multiple cell types. Here we address these limitations by developing single-step optimized inducible gene knockdown or knockout (sOPTiKD or sOPTiKO) platforms. These are based on genetic engineering of human genomic safe harbors combined with an improved tetracycline-inducible system and CRISPR/Cas9 technology. We exemplify the efficacy of these methods in human pluripotent stem cells (hPSCs), and show that generation of sOPTiKD/KO hPSCs is simple, rapid and allows tightly controlled individual or multiplexed gene knockdown or knockout in hPSCs and in a wide variety of differentiated cells. Finally, we illustrate the general applicability of this approach by investigating the function of transcription factors (OCT4 and T), cell cycle regulators (cyclin D family members) and epigenetic modifiers (DPY30). Overall, sOPTiKD and sOPTiKO provide a unique opportunity for functional analyses in multiple cell types relevant for the study of human development.


Assuntos
Sistemas CRISPR-Cas/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Ciclina D/genética , Proteínas Fetais/genética , Engenharia Genética/métodos , Proteínas Nucleares/genética , Fator 3 de Transcrição de Octâmero/genética , Proteínas com Domínio T/genética , Diferenciação Celular/genética , Células Cultivadas , Células-Tronco Embrionárias/citologia , Técnicas de Inativação de Genes , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Fatores de Transcrição
16.
Stem Cell Res Ther ; 7(1): 96, 2016 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-27460218

RESUMO

BACKGROUND: Several studies have reported the direct conversion of mouse fibroblasts to hepatocyte-like cells with different degrees of maturation by expression of hepatic fate-conversion factors. METHODS: We have used a combination of lentiviral vectors expressing hepatic fate-conversion factors with Oct4, Sox2, Klf4, and Myc to convert mouse embryonic fibroblasts into hepatic cells. RESULTS: We have generated hepatic cells with progenitor-like features (iHepL cells). iHepL cells displayed basic hepatocyte functions but failed to perform functions characteristic of mature hepatocytes such as significant Cyp450 or urea cycle activities. iHepL cells expressed multiple hepatic-specific transcription factors and functional genes characteristic of immature hepatocytes and cholangiocytes, as well as high levels of Foxl1, Cd24a, and Lgr5, specific markers of hepatic progenitor cells. When transplanted into partial hepatectomized and hepatic irradiated mice, they differentiated into hepatocytes and cholangiocytes. However, iHepL cells formed malignant non-teratoma cell aggregations in one out of five engrafted livers and five out of five xenografts assays. All the cells in these tumors had silenced key hepatic fate-conversion factors, and lost hepatic features. CONCLUSIONS: This study highlights the dangers of using pluripotency factors in reprogramming strategies when fate-conversion factors are silenced in vivo, and urges us to perform extensive tumorigenic tests in reprogrammed cells.


Assuntos
Carcinogênese/genética , Reprogramação Celular , Fibroblastos/metabolismo , Inativação Gênica , Teratoma/genética , Animais , Biomarcadores/metabolismo , Antígeno CD24/genética , Antígeno CD24/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Diferenciação Celular , Embrião de Mamíferos , Fibroblastos/citologia , Fibroblastos/transplante , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Hepatectomia , Hepatócitos/metabolismo , Hepatócitos/patologia , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Lentivirus/genética , Lentivirus/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Células-Tronco/metabolismo , Células-Tronco/patologia , Teratoma/metabolismo , Teratoma/patologia , Transgenes
18.
Cell Rep ; 14(6): 1382-1394, 2016 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-26854229

RESUMO

Contextual memory formation relies on the induction of new genes in the hippocampus. A polymorphism in the promoter of the transcription factor XBP1 was identified as a risk factor for Alzheimer's disease and bipolar disorders. XBP1 is a major regulator of the unfolded protein response (UPR), mediating adaptation to endoplasmic reticulum (ER) stress. Using a phenotypic screen, we uncovered an unexpected function of XBP1 in cognition and behavior. Mice lacking XBP1 in the nervous system showed specific impairment of contextual memory formation and long-term potentiation (LTP), whereas neuronal XBP1s overexpression improved performance in memory tasks. Gene expression analysis revealed that XBP1 regulates a group of memory-related genes, highlighting brain-derived neurotrophic factor (BDNF), a key component in memory consolidation. Overexpression of BDNF in the hippocampus reversed the XBP1-deficient phenotype. Our study revealed an unanticipated function of XBP1 in cognitive processes that is apparently unrelated to its role in ER stress.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Hipocampo/metabolismo , Memória/fisiologia , Neurônios/metabolismo , Proteína 1 de Ligação a X-Box/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Retículo Endoplasmático/genética , Estresse do Retículo Endoplasmático/genética , Potenciais Evocados/fisiologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Hipocampo/citologia , Potenciação de Longa Duração/fisiologia , Masculino , Camundongos , Camundongos Knockout , Anotação de Sequência Molecular , Neurônios/citologia , Regiões Promotoras Genéticas , Transdução de Sinais , Resposta a Proteínas não Dobradas/genética , Proteína 1 de Ligação a X-Box/deficiência
19.
Curr Alzheimer Res ; 13(9): 1017-29, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26502813

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder in which the amyloid-ß (Aß) peptide plays a key role in synaptic impairment and memory decline associated with neuronal dysfunction and intra-neuronal accumulation of hyperphosphorylated tau protein. Two novel enantiopure rhein-huprine hybrids ((+)-1 and (-)-1) exhibit potent inhibitory effects against human acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), BACE-1 and both Aß and tau antiaggregation activity in vitro and reduction on the amyloid precursor protein (APP) processing in vivo. Interestingly, in this work, we observed beneficial effects with both (+)- and (-)-1 in the reversion of the neuropathology presented in the AßPPswe/PS-1 Alzheimer´s model, including a reduction in the Aß levels, tau phosphorylation and memory impairment with both treatments. Also, in young transgenic mice that present early symptoms of synaptic failure and memory loss, we found a protection of cognitive functions, including long-term potentiation (LTP) and a reduction of the neuro-inflammation by both (+)- and (-)-1. Furthermore, animals with an advanced disease (11month-old) present an exacerbate neurodegeneration that is reversed only with the dextrorotatory enantiomer. These studies indicated that rhein-huprine derivatives with multiple properties might have interesting therapeutic potential for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminoquinolinas/farmacologia , Antraquinonas/farmacologia , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Camundongos Transgênicos , Fragmentos de Peptídeos/metabolismo , Fosforilação/efeitos dos fármacos , Placa Amiloide/tratamento farmacológico , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Presenilina-1/genética , Presenilina-1/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/patologia , Proteínas tau/metabolismo
20.
Dis Markers ; 2015: 653537, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26494938

RESUMO

OBJECTIVE: To determine the association between oxidative stress parameters with periodontal disease, bleeding, and the presence of different periodontal bacteria. METHODS: A cross-sectional study in a sample of eighty-six patients, divided into three groups depending on their periodontal status. Thirty-three with chronic periodontitis, sixteen with gingivitis, and thirty-seven with periodontal healthy as control. Oxidative stress biomarkers (8-OHdG and MDA), total antioxidant capacity (TAOC), and the activity of two antioxidant enzymes (GPx and SOD) were determined in saliva. Subgingival plaque samples were obtained from the deepest periodontal pocket and PCR was used to determine the presence of the 6 fimA genotypes of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia, and Treponema denticola. RESULTS: Periodontal disease was found to be associated with increased oxidative stress parameter levels. These levels rose according to the number and type of different periodontal bacteria found in the periodontal pockets. The presence of different types of periodontal bacteria is predictive independent variables in linear regresion models of oxidative stress parameters as dependent variable, above all 8-OHdG. CONCLUSIONS: Oxidative stress parameter levels are correlated with the presence of different types of bacteria. Determination of these levels and periodontal bacteria could be a potent tool for controlling periodontal disease development.


Assuntos
Microbiota , Estresse Oxidativo , Periodontite/metabolismo , Saliva/metabolismo , 8-Hidroxi-2'-Desoxiguanosina , Adulto , Biomarcadores/metabolismo , Estudos de Casos e Controles , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Feminino , Glutationa Peroxidase/metabolismo , Humanos , Masculino , Malondialdeído/metabolismo , Periodontite/microbiologia , Periodontite/patologia , Superóxido Dismutase/metabolismo
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