Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Adv Sci (Weinh) ; 11(35): e2404326, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38952069

RESUMO

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents an impending global health challenge. Current management strategies often face setbacks, emphasizing the need for preclinical models that faithfully mimic the human disease and its comorbidities. The liver disease progression aggravation diet (LIDPAD), a diet-induced murine model, extensively characterized under thermoneutral conditions and refined diets is introduced to ensure reproducibility and minimize species differences. LIDPAD recapitulates key phenotypic, genetic, and metabolic hallmarks of human MASLD, including multiorgan communications, and disease progression within 4 to 16 weeks. These findings reveal gut-liver dysregulation as an early event and compensatory pancreatic islet hyperplasia, underscoring the gut-pancreas axis in MASLD pathogenesis. A robust computational pipeline is also detailed for transcriptomic-guided disease staging, validated against multiple harmonized human hepatic transcriptomic datasets, thereby enabling comparative studies between human and mouse models. This approach underscores the remarkable similarity of the LIDPAD model to human MASLD. The LIDPAD model fidelity to human MASLD is further confirmed by its responsiveness to dietary interventions, with improvements in metabolic profiles, liver histopathology, hepatic transcriptomes, and gut microbial diversity. These results, alongside the closely aligned changing disease-associated molecular signatures between the human MASLD and LIDPAD model, affirm the model's relevance and potential for driving therapeutic development.


Assuntos
Modelos Animais de Doenças , Animais , Camundongos , Fígado Gorduroso/metabolismo , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Progressão da Doença , Camundongos Endogâmicos C57BL , Humanos , Dieta/métodos , Fígado/metabolismo , Fígado/patologia
2.
Int J Cardiol ; 168(6): 5277-86, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-23998552

RESUMO

BACKGROUND: Type 3 long QT syndrome (LQT3) is the third most common form of LQT syndrome and is characterized by QT-interval prolongation resulting from a gain-of-function mutation in SCN5A. We aimed to establish a patient-specific human induced pluripotent stem cell (hiPSC) model of LQT3, which could be used for future drug testing and development of novel treatments for this inherited disorder. METHODS AND RESULTS: Dermal fibroblasts obtained from a patient with LQT3 harboring a SCN5A mutation (c.5287G>A; p.V1763M) were reprogrammed to hiPSCs via repeated transfection of mRNA encoding OCT-4, SOX-2, KLF-4, C-MYC and LIN-28. hiPSC-derived cardiomyocytes (hiPSC-CMs) were obtained via cardiac differentiation. hiPSC-CMs derived from the patient's healthy sister were used as a control. Compared to the control, patient hiPSC-CMs exhibited dominant mutant SCN5A allele gene expression, significantly prolonged action potential duration or APD (paced CMs of control vs. patient: 226.50 ± 17.89 ms vs. 536.59 ± 37.1 ms; mean ± SEM, p < 0.005), an increased tetrodotoxin (TTX)-sensitive late or persistent Na(+) current (control vs. patient: 0.65 ± 0.11 vs. 3.16 ± 0.27 pA/pF; n = 9, p < 0.01), a positive shift of steady state inactivation and a faster recovery from inactivation. Mexiletine, a NaV1.5 blocker, reversed the elevated late Na(+) current and prolonged APD in LQT3 hiPSC-CMs. CONCLUSIONS: We demonstrate that hiPSC-CMs derived from a LQT3 patient recapitulate the biophysical abnormalities that define LQT3. The clinical significance of such an in vitro model is in the development of novel therapeutic strategies and a more personalized approach in testing drugs on patients with LQT3.


Assuntos
Cromossomos Humanos Par 3 , Síndrome do QT Longo/fisiopatologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/fisiologia , Células-Tronco Pluripotentes/citologia , Potenciais de Ação/fisiologia , Criança , Pré-Escolar , Derme/citologia , Eletrocardiografia , Feminino , Fibroblastos/citologia , Fibroblastos/fisiologia , Genótipo , Parada Cardíaca/genética , Parada Cardíaca/fisiopatologia , Humanos , Síndrome do QT Longo/genética , Potenciais da Membrana/fisiologia , Mexiletina/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Técnicas de Patch-Clamp , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia
3.
In Vitro Cell Dev Biol Anim ; 46(3-4): 210-6, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20177998

RESUMO

The Singapore Stem Cell Bank has generated human embryonic stem cell banks from clinical-grade cell lines ESI-017, ESI-035, ESI-049, and ESI-053. All banks were prepared and characterized according to principles of Good Laboratory Practice for quality assurance. Importantly, each cell line has clearly documented and approved ethical provenance and meets recognized standards for performance and safety. The banks are intended to facilitate the translation of stem cell research to clinical medicine by enabling early phase research and development with high-quality, low-cost cells that are also available as clinical-grade stocks.


Assuntos
Técnicas de Cultura de Células/métodos , Pesquisas com Embriões , Células-Tronco Embrionárias/citologia , Bancos de Tecidos/normas , Biomarcadores/metabolismo , Diferenciação Celular/genética , Linhagem Celular , Citometria de Fluxo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Imuno-Histoquímica , Cariotipagem , Reação em Cadeia da Polimerase Via Transcriptase Reversa
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA