SIRT1 modulating compounds from high-throughput screening as anti-inflammatory and insulin-sensitizing agents
| Autor: | Walter Stünkel, Haishan Wang, Xukun Wang, Michael Entzeroth, Yong Cheng Tan, Tony Ng, Anders Poulsen, BinHui Ni, Vasantha M. Nayagam, Kee Chuan Goh, Hong Yan Song |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Anti-Inflammatory Agents Drug Evaluation Preclinical Down-Regulation Pharmacology Biology Nicotinamide adenine dinucleotide Biochemistry Analytical Chemistry Proinflammatory cytokine Cell Line 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Downregulation and upregulation Sirtuin 1 Quinoxalines medicine Animals Humans Insulin Sirtuins Binding Sites Dose-Response Relationship Drug Molecular Structure Tumor Necrosis Factor-alpha Lipogenesis Biological activity 030104 developmental biology chemistry biology.protein Molecular Medicine Protein deacetylase lipids (amino acids peptides and proteins) NAD+ kinase 030217 neurology & neurosurgery Biotechnology |
| Zdroj: | Journal of biomolecular screening. 11(8) |
| ISSN: | 1087-0571 |
| Popis: | The nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylase SIRT1 has been linked to fatty acid metabolism via suppression of peroxysome proliferator-activated receptor gamma (PPAR-gamma) and to inflammatory processes by deacetylating the transcription factor NF-kappaB. First, modulation of SIRT1 activity affects lipid accumulation in adipocytes, which has an impact on the etiology of a variety of human metabolic diseases such as obesity and insulin-resistant diabetes. Second, activation of SIRT1 suppresses inflammation via regulation of cytokine expression. Using high-throughput screening, the authors identified compounds with SIRT1 activating and inhibiting potential. The biological activity of these SIRT1-modulating compounds was confirmed in cell-based assays using mouse adipocytes, as well as human THP-1 monocytes. SIRT1 activators were found to be potent lipolytic agents, reducing the overall lipid content of fully differentiated NIH L1 adipocytes. In addition, the same compounds have anti-inflammatory properties, as became evident by the reduction of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). In contrast, a SIRT1 inhibitory compound showed a stimulatory activity on the differentiation of adipocytes, a feature often linked to insulin sensitization. |
| Databáze: | OpenAIRE |
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