RESUMEN
Lipoic acid is an essential enzyme cofactor in central metabolic pathways. Due to its claimed antioxidant properties, racemic (R/S)-lipoic acid is used as a food supplement but is also investigated as a pharmaceutical in over 180 clinical trials covering a broad range of diseases. Moreover, (R/S)-lipoic acid is an approved drug for the treatment of diabetic neuropathy. However, its mechanism of action remains elusive. Here, we performed chemoproteomics-aided target deconvolution of lipoic acid and its active close analog lipoamide. We find that histone deacetylases HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, and HDAC10 are molecular targets of the reduced form of lipoic acid and lipoamide. Importantly, only the naturally occurring (R)-enantiomer inhibits HDACs at physiologically relevant concentrations and leads to hyperacetylation of HDAC substrates. The inhibition of HDACs by (R)-lipoic acid and lipoamide explain why both compounds prevent stress granule formation in cells and may also provide a molecular rationale for many other phenotypic effects elicited by lipoic acid.
Asunto(s)
Inhibidores de Histona Desacetilasas , Ácido Tióctico , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Ácido Tióctico/farmacología , Histona Desacetilasas/metabolismo , Antioxidantes/farmacologíaAsunto(s)
Oro , Nanotubos , Neoplasias/terapia , Fototerapia , Nanomedicina Teranóstica , Antineoplásicos , Línea Celular Tumoral , Humanos , Tamaño de la Partícula , Fototerapia/instrumentación , Fototerapia/métodos , Polietilenglicoles/química , Compuestos de Sulfhidrilo/química , Propiedades de SuperficieRESUMEN
The interaction of astringent substances with salivary proteins, which results in protein precipitation, is considered a key event in the molecular mechanism underlying the oral sensation of puckering astringency. As the chemical nature of orally active astringents is diverse and the knowledge of their interactions with salivary proteins rather fragmentary, human whole saliva samples were incubated with suprathreshold and isointensity solutions of the astringent polyphenol (-)-epigallocatechin gallate, the multivalent metal salt iron(III) sulfate, the amino-functionalized polysaccharide chitosan, and the basic protein lysozyme. After separation of the precipitated proteins, the proteins affected by the astringents were identified and relatively quantified for the first time by complementary bottom-up and top-down mass spectrometry-based proteomics approaches. Major salivary target proteins, which may be involved in astringency perception, are reported here for each astringent stimulus.