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Biochim Biophys Acta ; 1790(6): 566-74, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19264107

RESUMO

BACKGROUND: Amyloid fibrils created by misfolding and aggregation of proteins are a major pathological feature in a variety of degenerative diseases. Therapeutic approaches including amyloid vaccines and anti-aggregation compounds in models of amyloidosis point to an important role for amyloid in disease pathogenesis. Amyloid deposits derived from the beta-cell peptide islet amyloid polypeptide (IAPP or amylin) are a characteristic of type 2 diabetes and may contribute to loss of beta-cells in this disease. METHODS: We developed a cellular model of rapid amyloid deposition using cultured human islets and observed a correlation between fibril accumulation and beta-cell death. A series of overlapping peptides derived from IAPP was generated. RESULTS: A potent inhibitor (ANFLVH) of human IAPP aggregation was identified. This inhibitory peptide prevented IAPP fibril formation in vitro and in human islet cultures leading to a striking increase in islet cell viability. CONCLUSIONS: These findings indicate an important contribution of IAPP aggregation to beta-cell death in situ and point to therapeutic applications for inhibitors of IAPP aggregation in enhancing beta-cell survival. GENERAL SIGNIFICANCE: Anti-amyloid compounds could potentially reduce the loss of beta-cell mass in type 2 diabetes and maintain healthy human islet cultures for beta-cell replacement therapies.


Assuntos
Amiloide/antagonistas & inibidores , Sobrevivência Celular/fisiologia , Ilhotas Pancreáticas , Sequência de Aminoácidos , Amiloide/metabolismo , Animais , Apoptose/fisiologia , Células Cultivadas , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Ilhotas Pancreáticas/fisiologia , Ilhotas Pancreáticas/ultraestrutura , Dados de Sequência Molecular
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