更新于：2024-11-21

sirtinol

更新于：2024-11-21

概要

研发状态

概要

基本信息

药物类型

小分子化药

别名-

靶点

SIRT1 x SIRT2

作用机制

SIRT1抑制剂(NAD依赖性脱乙酰酶sirtuin-1抑制剂)、SIRT2抑制剂(sirtuin 2 inhibitors)

治疗领域-

在研适应症-

非在研适应症-

原研机构

The Howard Hughes Medical Institute

在研机构

The Howard Hughes Medical Institute

非在研机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C26H22N2O2

InChIKeyUXJFDYIHRJGPFS-UHFFFAOYSA-N

CAS号410536-97-9

关联

100 项与 sirtinol 相关的临床结果

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100 项与 sirtinol 相关的转化医学

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100 项与 sirtinol 相关的专利（医药）

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项与 sirtinol 相关的文献（医药）

2023-02-01·NeuroReport

Silent information regulator 1 mediates H2S-inhibited chronic restraint stress-induced depressive-like behaviors by regulating hippocampal autophagy

Article

作者: Tang, Yi-Yun ; Zou, Wei ; Jiang, Jia-Mei ; Luo, Bang ; Chen, Yong-Jun ; Chen, Lei ; Du, Lv ; Zhang, Ping

ObjectivesOur previous study has demonstrated that hydrogen sulfide (H2S), a novel gasotransmitter, attenuates excessive autophagy and depressive-like behaviors in chronic restraint stress (CRS)-exposed rats, but the underlying molecular mechanism remains to be elucidated. Silent information regulator 1 (SIRT1), a deacetylase at the consumption of NAD+ plays an important regulatory role in depression. Hence, this study aimed to investigate whether SIRT1 mediates the protective effect of H2S on CRS-induced depressive-like behaviors by regulating hippocampal autophagy.MethodsAdult male Sprague-Dawley (SD) rats were subjected to CRS (6 h × 28 days) to induce depression-like behavior. Rats were injected with sodium hydrosulfate (NaHS, 100 μmol/kg/d, i.p.), as a donor of H2S, alone or in combination with Sirtinol (a SIRT1 inhibitor; 10 nmol, i.c.v.) during CRS process. The depression-like characteristics of rats were assessed by the novelty-suppressed feeding test (NSFT), tail suspension test (TST), forced swimming test (FST) and open field test (OFT). The number of hippocampal autophagosomes was detected by transmission electron microscopy. The expressions of hippocampal autophagy-related proteins were measured by western blotting analysis.ResultsSirtinol blocked the inhibitory effect of H2S on depressive-like behaviors in CRS-exposed rats according to NSFT, TST, FST and OFT. In addition, sirtinol reversed the protective response of H2S to CRS-induced excessive autophagy, as proved by the increases in the number of autophagosomes and the expression of Beclin-1 as well as a decrease in the expression of P62 in the hippocampus.ConclusionThese results indicated that SIRT1 contributes to the antidepressant-like function of H2S during CRS via reducing hippocampal autophagy.

2021-12-01·Hepatology

Histone Deacetylase Sirtuin 1 Promotes Loss of Primary Cilia in Cholangiocarcinoma

Article

作者: Biswas, Aalekhya ; Ha, Yeonjung ; Peixoto, Estanislao ; Salati, Massimiliano ; Richard, Seth ; Roberts, Lewis R ; Carotenuto, Pietro ; Gradilone, Sergio A ; Ren, Yanan ; Giama, Nasra ; Yang, Rendong ; Franco, Brunella ; Pant, Kishor ; O'Sullivan, M Gerard ; Yin, Jun

Background and AimsSirtuin 1 (SIRT1) is a complex NAD+‐dependent protein deacetylase known to act as a tumor promoter or suppressor in different cancers. Here, we describe a mechanism of SIRT1‐induced destabilization of primary cilia in cholangiocarcinoma (CCA).Approach and ResultsA significant overexpression of SIRT1 was detected in human CCA specimens and CCA cells including HuCCT1, KMCH, and WITT1 as compared with normal cholangiocytes (H69 and NHC). Small interfering RNA (siRNA)‐mediated knockdown of SIRT1 in HuCCT1 cells induced cilia formation, whereas overexpression of SIRT1 in normal cholangiocytes suppressed ciliary expression. Activity of SIRT1 was regulated by presence of NAD+ in CCA cells. Inhibition of NAD ‐producing enzyme nicotinamide phosphoribosyl transferase increased ciliary length and frequency in CCA cells and in SIRT1‐overexpressed H69 cells. Furthermore, we also noted that SIRT1 induces the proteasomal mediated degradation of ciliary proteins, including α‐tubulin, ARL13B, and KIF3A. Moreover, overexpression of SIRT1 in H69 and NHC cells significantly induced cell proliferation and, conversely, SIRT1 inhibition in HuCCT1 and KMCH cells using siRNA or sirtinol reduced cell proliferation. In an orthotopic transplantation rat CCA model, the SIRT1 inhibitor sirtinol reduced tumor size and tumorigenic proteins (glioma‐associated oncogene 1, phosphorylated extracellular signal‐regulated kinase, and IL‐6) expression.ConclusionsIn conclusion, these results reveal the tumorigenic role of SIRT1 through modulation of primary cilia formation and provide the rationale for developing therapeutic approaches for CCA using SIRT1 as a target.

2021-05-01·Journal of Neural Transmission4区 · 医学

SIRT1 and SIRT2 modulators reduce LPS-induced inflammation in HAPI microglial cells and protect SH-SY5Y neuronal cells in vitro

4区 · 医学

Article

作者: Zhang, Yuqing ; Davey, Andrew K ; Mallik, Sanchari Basu ; Anoopkumar-Dukie, Shailendra

Neuroinflammation is associated with the development of depression. Deacetylases SIRT1 and SIRT2 are reported to exert neuroprotective effects in aging, neurogenesis, neurodegeneration and neuroinflammation. Therefore, this study aimed to investigate the effects of SIRT1 and SIRT2 modulators on LPS-induced neuroinflammation and neurodegeneration in vitro. To achieve this, HAPI rat microglial cells were pre-treated with the SIRT1 activator resveratrol (0.1-20 µM), the selective SIRT1 inhibitor EX527 (0.1; 1 µM), the dual SIRT1/SIRT2 inhibitor sirtinol (0.1-20 µM) and the SIRT2 inhibitor AGK2 (0.1; 1 µM), prior to exposure with LPS (5 ng/mL) for 20 h. The reference antidepressant drug fluoxetine and the nonsteroidal anti-inflammatory drug ibuprofen were also evaluated in the same paradigm, both at 1 μM. Resveratrol and sirtinol inhibited TNF-α production to a greater degree than either fluoxetine or ibuprofen. Resveratrol, sirtinol, EX527 and AGK2 significantly reduced PGE₂ production by up to 100% in microglia. Then, the supernatant was transferred to treat SH-SY5Y cells for 24 h. In all cases, SIRT modulator pretreatment significantly protected undifferentiated SH-SY5Y human neuroblastoma cells from the insult of LPS-stimulated HAPI supernatant by up to 40%. Moreover, resveratrol and sirtinol also showed significantly better neuroprotection than fluoxetine or ibuprofen by up to 83 and 69%, respectively. In differentiated SH-SY5Y cells, only sirtinol (20, 10 µM) and AGK2 (0.1 µM) pretreatment protected the cells from LPS-stimulated HAPI supernatant. This study suggests that SIRT1 and SIRT2 modulators are effective in inhibiting LPS-stimulated production of TNF-α and PGE₂ in HAPI microglial cells and protecting SH-SY5Y cells from inflammation. Thus, we provide proof of concept for further investigation of the therapeutic effect of SIRT1 and SIRT2 modulators and combination with current antidepressant medication as a treatment option.

100 项与 sirtinol 相关的药物交易

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