OSS_128167
目录号 : GC32745
OSS_128167是一种有效的选择性沉默调节蛋白6 (SIRT6)抑制剂，IC50为89 μM。
Cas No.:887686-02-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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Cell experiment [1]: |
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Cell lines |
BxPC-3 cell |
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Preparation method |
Cells was plated in six-well plates and allowed to adhere for 24 h before being stimulated for 24 h with OSS_128167. |
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Reaction Conditions |
0-200 μM;24h |
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Applications |
OSS_128167 can promote the increase of H3K9 acetylation, the decrease of TNF-α secretion, the up-regulation of GLUT-1, and the increase of glucose uptake in BxPC-3 cells. |
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Animal experiment [2]: |
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Animal models |
C57BL/6 male mice (6-8 weeks, weight 20-25 g) |
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Preparation method |
The mice were divided into four groups: the control group, OSS_128167 group, the LPS group, and LPS+OSS_128167 group. Mice were given an intraperitoneal injection of 1% sodium pentobarbital to induce anesthesia and then fixed to a 45-degree inclined board. LPS was dissolved in 0.9% normal saline and then instilled intratracheally at a dose of 5 mg/kg. To ensure that LPS was distributed evenly throughout the mouse lungs, the mice were placed in a prone position after 30 seconds of vertical rotation. Mice in the control group received the same volume of 0.9% saline and manipulations. To inhibit SIRT6, mice were intraperitoneally injected with 80 mg/kg OSS_128167 1 h before LPS administration. All mice were sacrificed 24 h after saline or drug administration, and the lungs and bronchoalveolar lavage fluid (BALF) were collected for further study. |
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Dosage form |
80 mg/kg; i.p;1h |
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Applications |
OSS_128167 significantly accelerated LPS-induced loss of tight junction proteins, lung inflammation, and apoptosis. |
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References: [1]. Parenti MD, Grozio A, et,al. Discovery of novel and selective SIRT6 inhibitors. J Med Chem. 2014 Jun 12;57(11):4796-804. doi: 10.1021/jm500487d. Epub 2014 May 19. PMID: 24785705. [2]. Liu H, Wang S, et,al. SIRT6 ameliorates LPS-induced apoptosis and tight junction injury in ARDS through the ERK1/2 pathway and autophagy. Int J Med Sci. 2023 Mar 5;20(5):581-594. doi: 10.7150/ijms.80920. PMID: 37082736; PMCID: PMC10110478. |
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OSS_128167 is a potent selective silencing regulatory protein 6 (SIRT6) inhibitor with an IC50 of 89 μM[1]. OSS_128167 can inhibit HBV transcription and replication, and has antiviral and anti-inflammatory effects[2-3].
OSS_128167(0-200 μM;24h) can promote the increase of H3K9 acetylation, the decrease of TNF-α secretion, the up-regulation of GLUT-1, and the increase of glucose uptake in BxPC-3 cells[1]. OSS_128167(10 μM-50 μM OSS_128167; 24 h) can reverse the protective effect of Oridonin (Ori) on Doxorubicin induced cardiotoxicity (DIC) [4]. OSS_128167 attenuated ROS generation and protective polarization caused by Caffeic acid phenethyl ester (CAPE) pretreatment[5].
OSS_128167(OSS-128167 in a final concentration of 12 mg/mL in a solution containing 2% DMSO, 40% PEG 300, and 2% Tween-80; 100 mg/kg; i.v) treatment caused increased toe swelling in collagen-induced arthritis (CIA) rats, and the proportion of CD38+ NK cells in peripheral blood of CIA rats increased[6]. OSS_128167(80 mg/kg;i.p;1h) significantly accelerated LPS-induced loss of tight junction proteins, lung inflammation, and apoptosis[7].
References:
[1]. Parenti MD, Grozio A, et,al. Discovery of novel and selective SIRT6 inhibitors. J Med Chem. 2014 Jun 12;57(11):4796-804. doi: 10.1021/jm500487d. Epub 2014 May 19. PMID: 24785705.
[2]. Jiang H, Cheng ST, et,al. SIRT6 Inhibitor, OSS_128167 Restricts Hepatitis B Virus Transcription and Replication Through Targeting Transcription Factor Peroxisome Proliferator-Activated Receptors α. Front Pharmacol. 2019 Oct 25;10:1270. doi: 10.3389/fphar.2019.01270. PMID: 31708789; PMCID: PMC6823301.
[3]. Cea M, Cagnetta A, et,al. Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells. Blood. 2016 Mar 3;127(9):1138-50. doi: 10.1182/blood-2015-06-649970. Epub 2015 Dec 16. PMID: 26675349; PMCID: PMC4778164.
[4]. Yu D, Li J, et,al. Oridonin ameliorates doxorubicin induced-cardiotoxicity via the E2F1/Sirt6/PGC1α pathway in mice. Food Chem Toxicol. 2023 Nov;181:114050. doi: 10.1016/j.fct.2023.114050. Epub 2023 Sep 20. PMID: 37734463.
[5]. Wang Y, Cai Z, et,al. Caffeic Acid Phenethyl Ester Suppresses Oxidative Stress and Regulates M1/M2 Microglia Polarization via Sirt6/Nrf2 Pathway to Mitigate Cognitive Impairment in Aged Mice following Anesthesia and Surgery. Antioxidants (Basel). 2023 Mar 13;12(3):714. doi: 10.3390/antiox12030714. PMID: 36978961; PMCID: PMC10045012.
[6]. Wang H, Li S, et,al. Potential therapeutic effects of cyanidin-3-O-glucoside on rheumatoid arthritis by relieving inhibition of CD38+ NK cells on Treg cell differentiation. Arthritis Res Ther. 2019 Oct 28;21(1):220. doi: 10.1186/s13075-019-2001-0. PMID: 31661005; PMCID: PMC6819496.
[7]. Liu H, Wang S, et,al. SIRT6 ameliorates LPS-induced apoptosis and tight junction injury in ARDS through the ERK1/2 pathway and autophagy. Int J Med Sci. 2023 Mar 5;20(5):581-594. doi: 10.7150/ijms.80920. PMID: 37082736; PMCID: PMC10110478.
OSS_128167是一种有效的选择性沉默调节蛋白6 (SIRT6)抑制剂，IC50为89 μM[1]。OSS_128167能抑制HBV转录和复制，并具有抗病毒和抗炎作用[2-3]。
OSS_128167(0 ~ 200 μM;24h)能促进BxPC-3细胞H3K9乙酰化水平升高、TNF-α分泌减少、GLUT-1表达上调、葡萄糖摄取增加[1]。OSS_128167(10 μm -50 μm;24 h)可逆转Oriidonin (Ori)对阿霉素致心脏毒性(DIC)的保护作用[4]。OSS_128167可减弱咖啡酸苯乙酯(CAPE)预处理引起的ROS生成和保护性极化[5]。
OSS_128167(OSS-128167 in a final concentration of 12 mg/mL in a solution containing 2% DMSO, 40% PEG 300, and 2% Tween-80; 100 mg/kg; i.v)处理导致胶原诱导性关节炎CIA大鼠足趾肿胀加重，外周血CD38+ NK细胞比例升高[6]。OSS_128167(80 mg/kg;i.p;1h)在小鼠中显著加速LPS诱导的紧密连接蛋白丢失、肺部炎症和细胞凋亡[7]。
| Cas No. | 887686-02-4 | SDF | |
| Canonical SMILES | O=C(C1=CC(NC(C2=CC=CO2)=O)=CC=C1)NC3=CC(C(O)=O)=C(O)C=C3 | ||
| 分子式 | C19H14N2O6 | 分子量 | 366.32 |
| 溶解度 | DMSO : 103.3 mg/mL (281.99 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 | 2.7299 mL | 13.6493 mL | 27.2985 mL |
| 5 mM | 0.546 mL | 2.7299 mL | 5.4597 mL |
| 10 mM | 0.273 mL | 1.3649 mL | 2.7299 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 | ||||||||||
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计算结果:
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 promotes tumorigenesis and drug resistance of diffuse large B-cell lymphoma by mediating PI3K/Akt signaling
J Exp Clin Cancer Res 2020 Jul 25;39(1):142.PMID:32711549DOI:10.1186/s13046-020-01623-w.
Background: Sirtuin 6 (Sirt6) is a highly conserved ADP-ribosylase and NAD+ dependent deacylase, involved in broad cellular processes. This molecule possesses contradictory roles in carcinogenesis, as it has been documented to both suppressing and augmenting tumor growth. This project aimed to explore the expression and functions of Sirt6 in diffuse large B-cell lymphoma (DLBCL), especially with regards to the regulatory role of OSS_128167, a novel small molecular inhibitor targeting Sirt6. Methods: Immunohistochemistry (IHC) was conducted to assess the expression of Sirt6 on paraffin-embedded tissues. Microarray dataset GSE32918 and GSE83632 were obtained from Gene Expression Omnibus and survival analysis was performed. Lentivirus vectors either encoding shSirt6, lvSirt6 or empty lentiviral vector were stably transfected into DLBCL cells. LY1 cell transfected with shSirt6 were performed RNA-sequencing (RNA-seq) analysis, functional enrichment analyses of gene ontology (GO) and gene set enrichment analysis (GSEA). DLBCL cells were subcutaneously injected to SCID beige mice to establish xenograft models. Results: Sirt6 is found to be overexpressed in DLBCL, and is related to poor prognosis. Sirt6-deprived DLBCL cells displayed augmented sensitivity towards chemotherapy, higher rates of apoptosis, dysfunctional cell proliferation, and arrested cell cycle progression between the G2 and M phases. Selective OSS_128167-mediated Sirt6 blockage resulted in similar anti-lymphoma effects when compared to Sirt6 knocked-down DLBCL cells. PI3K signaling along with phosphorylation of its downstream targets was reduced upon Sirt6 downregulation. Xenograft models subjected to either OSS_128167 treatment or Sirt6-knockdown showed suppressed tumor growth and lower Ki-67 level. Conclusions: These findings provide mechanistic insights into the oncogenic activity of Sirt6 in DLBCL for the first time and highlighted the potency of OSS_128167 for novel therapeutic strategies in DLBCL.
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.
SIRT6 Inhibitor, OSS_128167 Restricts Hepatitis B Virus Transcription and Replication Through Targeting Transcription Factor Peroxisome Proliferator-Activated Receptors α
Front Pharmacol 2019 Oct 25;10:1270.PMID:31708789DOI:10.3389/fphar.2019.01270.
Hepatitis B virus (HBV) is a major public health threat and anti-HBV drugs are limited to nucleos(t)ide analogs (NAs) and pegylated interferon alpha (Peg-IFNα). Toward identifying an effective compound for HBV treatment is important to suppress and eradicate HBV. In this study, we explored the anti-viral effect of Sirtuin 6 (SIRT6) inhibitor, OSS_128167, in HBV transcription and replication. Firstly, we found that OSS_128167 could decrease the level of HBV core deoxyribonucleic acid (DNA) and 3.5-Kb ribonucleic acid (RNA) in vitro. Furthermore, the level of HBV DNA and 3.5-Kb RNA were also markedly suppressed by OSS_128167 administration in HBV transgenic mice. In addition, we found that depletion of SIRT6 inhibited HBV transcription and replication in HepG2.2.15 and HBV-infected HepG2-sodium taurocholate cotransporting polypeptide cells, whereas overexpression of SIRT6 enhanced HBV transcription and replication. Importantly, the positive effect of SIRT6 overexpression on HBV transcription could be blocked by OSS_128167 treatment. Further mechanism studies showed that HBV core promoter was significantly activated by SIRT6 through upregulating peroxisome proliferator-activated receptors α (PPARα) expression. And ectopical expression of SIRT6 or PPARα relieved the restriction of HBV transcription mediated by OSS_128167. In summary, our results showed that OSS_128167 might serve as a potential antiviral agent for HBV therapy and SIRT6 played a pivotal role in HBV transcription and replication.
Diosgenin protects against podocyte injury in early phase of diabetic nephropathy through regulating SIRT6
Phytomedicine 2022 Sep;104:154276.PMID:35728388DOI:10.1016/j.phymed.2022.154276.
Background: Diabetic nephropathy (DN) is a serious complication of diabetes mellitus. DN is the main cause of end-stage renal disease (ESRD). SIRT6 becomes the important target of DN. Diosgenin (a monomer from Chinese herbs) is probable to bind to SIRT6. Purpose: Based on studies presented in the literature on kidney injuries plus screening for the binding effects of the drug to Sirt6, we aimed to carry out the study to assess the effects of diosgenin involved in improving podocyte damage in the early phase of DN.. Methods: DN model was established in spontaneous diabetic db/db mice. Animal experiment was in two parts. The first part includes four groups consisting of control (Con) group, model (Mod) group, low dose of diosgenin (DL) group and high dose of diosgenin (DH) group. The second part includes four groups consisting of control group, model group, DH+OSS_128167 (OSS, inhibitor of SIRT6) group, MDL800 (agonist of SIRT6) group. MPC5 cell line was selected in cell experiment, which was mainly composed of six groups including Con group, palmitic acid (PA) group, PA+DL group, PA+DH group, PA+DH+OSS group, PA+MDL800 group. Some procedures such as transcriptomics, RT-qPCR and so on were used in the study to explore and verify the mechanism. Results: The abnormal changes of mesangial matrix expansion, glomerular basement membrane (GBM) thickness, foot process (FP) width, urine albumin/creatinine (UACR), DESMIN, ADRP, NEPHRIN, PODOCIN, SIRT6 in Mod group were alleviated in DH group rather than DL group in the first part of animal experiment. The effect in DH group could be reversed in DH+OSS group and the same effect was observed in MDL800 group in the second part of animal experiment. The same results were also found in cell experiment. Protein level and mRNA expression of pyruvate dehydrogenase kinase 4 (PDK4) and Angiopoietin-like-4 (ANGPTL4) were increased in PA group, which could be alleviated in DH group, MDL800 group rather than DH+OSS group. Conclusions: Diosgenin could protect against podocyte injury in early phase of diabetic nephropathy by regulating SIRT6.
Caffeic Acid Phenethyl Ester Suppresses Oxidative Stress and Regulates M1/M2 Microglia Polarization via Sirt6/Nrf2 Pathway to Mitigate Cognitive Impairment in Aged Mice following Anesthesia and Surgery
Antioxidants (Basel) 2023 Mar 13;12(3):714.PMID:36978961DOI:10.3390/antiox12030714.
Postoperative cognitive dysfunction (POCD) is a severe neurological complication after anesthesia and surgery. However, there is still a lack of effective clinical pharmacotherapy due to its unclear pathogenesis. Caffeic acid phenethyl ester (CAPE), which is obtained from honeybee propolis and medicinal plants, shows powerful antioxidant, anti-inflammatory, and immunomodulating properties. In this study, we aimed to evaluate whether CAPE mitigated cognitive impairment following anesthesia and surgery and its potential underlying mechanisms in aged mice. Here, isoflurane anesthesia and tibial fracture surgery were used as the POCD model, and H2O2-induced BV2 cells were established as the microglial oxidative stress model. We revealed that CAPE pretreatment suppressed oxidative stress and promoted the switch of microglia from the M1 to the M2 type in the hippocampus, thereby ameliorating cognitive impairment caused by anesthesia and surgery. Further investigation indicated that CAPE pretreatment upregulated hippocampal Sirt6/Nrf2 expression after anesthesia and surgery. Moreover, mechanistic studies in BV2 cells demonstrated that the potent effects of CAPE pretreatment on reducing ROS generation and promoting protective polarization were attenuated by a specific Sirt6 inhibitor, OSS_128167. In summary, our findings opened a promising avenue for POCD prevention through CAPE pretreatment that enhanced the Sirt6/Nrf2 pathway to suppress oxidative stress as well as favor microglia protective polarization.