UBCS039
目录号 : GC34849
UBCS039 is the first synthetic SIRT6 activator with EC50 of 38 μM,induces a time-dependent activation of autophagy in several human tumor cell lines.
Cas No.:358721-70-7
Sample solution is provided at 25 µL, 10mM.
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UBCS039 is the first synthetic SIRT6 activator with EC50 of 38 μM,induces a time-dependent activation of autophagy in several human tumor cell lines.
UBCS039 induces deacetylation of SIRT6-targeted histone H3 sites in human cancer cells.UBCS039 leads to autophagosome accumulation and induces autophagic flux in human cancer cells.UBCS039 also induces autophagy-associated cell death.[1]
[1] You W,et al.Angew Chem Int Ed Engl. 2017 19;56(4):1007-1011.
| Cas No. | 358721-70-7 | SDF | |
| Canonical SMILES | N12C(C(C3=CC=CN=C3)NC4=C2C=CC=C4)=CC=C1 | ||
| 分子式 | C16H13N3 | 分子量 | 247.29 |
| 溶解度 | DMSO : 125 mg/mL (505.48 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 4.0438 mL | 20.2192 mL | 40.4384 mL |
| 5 mM | 0.8088 mL | 4.0438 mL | 8.0877 mL |
| 10 mM | 0.4044 mL | 2.0219 mL | 4.0438 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
SIRT6 Activator UBCS039 Inhibits Thioacetamide-Induced Hepatic Injury In Vitro and In Vivo
Front Pharmacol 2022 Apr 20;13:837544.PMID:35517808DOI:10.3389/fphar.2022.837544.
SIRT6 has been reported to have multiple functions in inflammation and metabolism. In the present study, we explored the regulatory effects and mechanisms of SIRT6 in thioacetamide (TAA)-induced mice acute liver failure (ALF) models. The SIRT6 activator UBCS039 was used in this animal and cell experiments. We observed that UBCS039 ameliorated liver damage, including inflammatory responses and oxidative stress. Further study of mechanisms showed that the upregulation of SIRT6 inhibited the inflammation reaction by suppressing the nuclear factor-κB (NF-κB) pathway in the TAA-induced ALF mice model and lipopolysaccharide-stimulated macrophages. In addition, the upregulation of SIRT6 alleviated oxidative stress damage in hepatocytes by regulating the Nrf2/HO-1 pathway. These findings demonstrate that pharmacologic activator of SIRT6 could be a promising target for ALF.
SIRT6 inhibition delays peripheral nerve recovery by suppressing migration, phagocytosis and M2-polarization of macrophages
Cell Biosci 2021 Dec 14;11(1):210.PMID:34906231DOI:10.1186/s13578-021-00725-y.
Background: Silent information regulator 6 (SIRT6) is a mammalian homolog of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin family. Prior evidences suggested that the anti-inflammatory function of SIRT6 after spinal cord and brain injury, and it plays a crucial role in macrophages polarization of adipose tissue and skin. However, the role of SIRT6 in macrophages involved peripheral nerve injury is still unknown. Given the prominent role of macrophages in peripheral nerve recovery, we aim to investigate the role of SIRT6 in the regulation of phenotypes shift and functions in macrophages after peripheral nerve injury. Results: In the present study, we first identified a significant increase of SIRT6 expression during nerve degeneration and macrophages phagocytosis. Next, we found nerve recovery was delayed after SIRT6 silencing by injected shRNA lentivirus into the crushed sciatic nerve, which exhibited a reduced expression of myelin-related proteins (e.g., MAG and MBP), severer myoatrophy of target muscles, and inferior nerve conduction compared to the shRNA control injected mice. In vitro, we found that SIRT6 inhibition by being treated with a selective inhibitor OSS_128167 or lentivirus transfection impairs migration and phagocytosis capacity of bone marrow-derived macrophages (BMDM). In addition, SIRT6 expression was discovered to be reduced after M1 polarization, but SIRT6 was enhanced after M2 polarization in the monocyte-macrophage cell line RAW264.7 and BMDM. Moreover, SIRT6 inhibition increased M1 macrophage polarization with a concomitant decrease in M2 polarization both in RAW264.7 and BMDM via activating NF-κB and TNF-α expression, and SIRT6 activation by UBCS039 treatment could shift the macrophages from M1 to M2 phenotype. Conclusion: Our findings indicate that SIRT6 inhibition impairs peripheral nerve repair through suppressing the migration, phagocytosis, and M2 polarization of macrophages. Therefore, SIRT6 may become a favorable therapeutic target for peripheral nerve injury.
Sirtuin 6 regulates macrophage polarization to alleviate sepsis-induced acute respiratory distress syndrome via dual mechanisms dependent on and independent of autophagy
Cytotherapy 2022 Feb;24(2):149-160.PMID:34920961DOI:10.1016/j.jcyt.2021.09.001.
Background aims: Sepsis-induced acute respiratory distress syndrome (ARDS) can be mediated by an imbalance in macrophage polarization; however, the underlying mechanisms remain poorly understood. This study aimed to investigate the modulatory role of sirtuin 6 (SIRT6) in macrophage polarization during sepsis-induced ARDS. Methods: A mouse ARDS model was established using cecal ligation and puncture. Isolated alveolar macrophages (AMs) and lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDMs) were adopted as in vitro models. Macrophage polarization was evaluated by measuring M1 and M2 macrophage percentages via flow cytometry and expression of specific markers. The expression of microtubule-associated light chain protein 3I/II and beclin-1 was detected for assessing macrophage autophagy. Binding between specificity protein 1 (SP1) and the target gene promoter was evaluated using a chromatin immunoprecipitation assay. RNA expression was analyzed by quantitative reverse transcription polymerase chain reaction and western blotting. Results: Treatment with the SIRT6 activator UBCS039 significantly alleviated lung injury in the mouse ARDS model and enhanced autophagy and M2 polarization in isolated AMs. M2 polarization and autophagy in LPS-challenged BMDMs were also effectively promoted by UBCS039 treatment or SIRT6 overexpression. An adenosine monophosphate-activated protein kinase inhibitor (Compound C) or autophagy inhibitor (3-methyladenine) partially abrogated M2 polarization mediated by SIRT6 overexpression upon LPS exposure. SIRT6 induced autophagy and M2 polarization of BMDMs partially via its deacetylase activity. SIRT6 inhibited mammalian target of rapamycin transcription by modulating SP1 to promote BMDM M2 polarization, which was independent of autophagy. Conclusions: SIRT6 promotes M2 polarization of macrophages to alleviate sepsis-induced ARDS in an autophagy-dependent and -independent manner.
Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells
Cell Death Dis 2018 Sep 24;9(10):996.PMID:30250025DOI:10.1038/s41419-018-1065-0.
Sirtuin 6 (SIRT6) is a member of the NAD+-dependent class III deacetylase sirtuin family, which plays a key role in cancer by controlling transcription, genome stability, telomere integrity, DNA repair, and autophagy. Here we analyzed the molecular and biological effects of UBCS039, the first synthetic SIRT6 activator. Our data demonstrated that UBCS039 induced a time-dependent activation of autophagy in several human tumor cell lines, as evaluated by increased content of the lipidated form of LC3B by western blot and of autophagosomal puncta by microscopy analysis of GFP-LC3. UBCS039-mediated activation of autophagy was strictly dependent on SIRT6 deacetylating activity since the catalytic mutant H133Y failed to activate autophagy. At the molecular level, SIRT6-mediated autophagy was triggered by an increase of ROS levels, which, in turn, resulted in the activation of the AMPK-ULK1-mTOR signaling pathway. Interestingly, antioxidants were able to completely counteract UBCS039-induced autophagy, suggesting that ROS burst had a key role in upstream events leading to autophagy commitment. Finally, sustained activation of SIRT6 resulted in autophagy-related cell death, a process that was markedly attenuated using either a pan caspases inhibitor (zVAD-fmk) or an autophagy inhibitor (CQ). Overall, our results identified UBCS039 as an efficient SIRT6 activator, thereby providing a proof of principle that modulation of the enzyme can influence therapeutic strategy by enhancing autophagy-dependent cell death.
Downregulation of Sirt6 by CD38 promotes cell senescence and aging
Aging (Albany NY) 2022 Dec 6;14(23):9730-9757.PMID:36490326DOI:10.18632/aging.204425.
Decreased nicotinamide adenine dinucleotide (NAD+) levels accompany aging. CD38 is the main cellular NADase. Cyanidin-3-O-glucoside (C3G), a natural inhibitor of CD38, is a well-known drug that extends the human lifespan. We investigated mechanisms of CD38 in cell senescence and C3G in antiaging. Myocardial H9c2 cells were induced to senescence with D-gal. CD38 siRNA, C3G and UBCS039 (a chemical activator of Sirt6) inhibited D-gal-induced senescence by reducing reactive oxygen species, hexokinase 2 and SA-β-galactosidase levels. These activators also stimulated cell proliferation and telomerase reverse transcriptase levels, while OSS-128167 (a chemical inhibitor of Sirt6) and Sirt6 siRNA exacerbated the senescent process. H9c2 cells that underwent D-gal-induced cell senescence increased CD38 expression and decreased Sirt6 expression; CD38 siRNA and C3G decreased CD38 expression and increased Sirt6 expression, respectively; and Sirt6 siRNA stimulated cell senescence in the presence of C3G and CD38 siRNA. In D-gal-induced acute aging mice, CD38 and Sirt6 exhibited increased and decreased expression, respectively, in myocardial tissues, and C3G treatment decreased CD38 expression and increased Sirt6 expression in the tissues. C3G also reduced IL-1β, IL-6, IL-17A, TNF-α levels and restored NAD+ and NK cell levels in the animals. We suggest that CD38 downregulates Sirt6 expression to promote cell senescence and C3G exerts an antiaging effect through CD38-Sirt6 signaling.