SIRT1 (EC50 = 0.10 μM); SIRT1 (EC1.5 = 0.16 μM5); SIRT2 (EC1.5 = 37 μM)

由于 SRT 1720 抑制组蛋白乙酰转移酶 p300，因此即使不存在 SIRT1，它也能有效降低细胞中的 p53 乙酰化 [3]。

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SRT1720 是 SIRT1 的选择性激活剂，EC50 为 0.16 μM，比 SIRT2 和 SIRT3 低 230 倍以上。
在这里，研究人员检测了一种新型口服药物SRT1720的抗多发性骨髓瘤（MM）活性，该药物靶向SIRT1。SRT1720可抑制MM细胞的生长，诱导对常规和硼替佐米治疗有抗性的MM细胞凋亡，但不显著影响正常细胞的活力。机制研究表明，SRT1720的抗mm活性与：1)激活caspase-8、caspase-9、caspase-3、聚（ADP）核糖聚合酶有关；2)活性氧增加；2)诱导磷酸化的共济失调毛细血管扩张突变/检查点激酶2信号传导；3)血管内皮生长因子诱导的MM细胞迁移和相关血管生成减少；4)抑制核因子-κB。阻断ATM可减弱srt1720诱导的MM细胞死亡。[2]

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为了确定SRT1460和SRT1720是否与白藜芦醇在相同的分子位点结合并激活酶，我们进行了等距图分析。研究了白藜芦醇对SRT1720和SRT1720对SRT1460两种化合物的浓度矩阵，以确定这两种化合物的组合是拮抗、相加还是协同作用。在这两种情况下，化合物组合产生的可加性与假设一致，即sirt1 -底物复合物上存在单一的变构位点，结构上不同的化合物可以与之结合（图2c）。［１］

用 SRT 1720（10、30、100 mg/kg，口服）治疗的 Lepob/ob 小鼠的空腹血糖水平显着降低至接近正常水平 [1]。 SRT 1720 与氧化和脂肪酸代谢的变化以及对大鼠饮食诱导肥胖的保护作用有关 [3]。 SRT 1720（50-100 mg/kg，口服）可降低 WT 小鼠的动脉氧饱和度，并减轻肺气肿发展过程中弹性蛋白酶引起的气隙扩大和肺功能退化[4]。

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在 DIO 小鼠中，SRT1720 模拟了热量限制后观察到的几种效果，包括改善胰岛素敏感性、标准化葡萄糖和胰岛素水平以及增加线粒体容量。此外，在饮食诱导的肥胖和遗传性肥胖小鼠中，SRT1720 可以改善胰岛素敏感性、降低血浆葡萄糖并增加线粒体容量。因此，SRT1720是一种有前途的新型治疗剂，用于治疗2型糖尿病等衰老疾病。与糖耐量改善一致，SRT1720治疗的fa/fa大鼠中维持血糖正常所需的葡萄糖输注率增加了约35%，总葡萄糖处理率增加了约20%。 SRT1720 还可以预防多发性骨髓瘤肿瘤的生长。 SRT1720 增加硼替佐米或地塞米松的细胞毒活性。

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通过基因过表达和选择性药理激活剂SRT1720激活SIRT1，可以减轻应激诱导的细胞过早衰老，并保护小鼠免受香烟烟雾和弹性蛋白酶诱导的肺气肿。气道上皮Sirt1消融，但髓细胞不消融，气道扩大加重，肺功能受损，运动耐受性降低。这些影响是由于SIRT1能够使FOXO3转录因子去乙酰化，因为FOXO3缺乏降低了SRT1720对细胞衰老和肺气肿变化的保护作用。[4]

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然而，SIRT1是否是治疗胆汁淤积症的合适治疗靶点尚不清楚。在本研究中，检测了SRT1720 （SIRT1的特异性激活剂）对17α-炔雌醇（EE）诱导的小鼠胆汁淤积的保护作用。数据表明，SRT1720显著阻止ee诱导的血清总胆汁酸（TBA）、总胆红素（TBIL）、γ-谷氨酰转肽酶（γ-GGT）和碱性磷酸酶（ALP）水平的变化。血红素和伊红（H&E）染色显示，SRT1720还能减轻ee诱导的肝脏病理损伤。SRT1720通过HNF1α/FXR信号通路，上调肝外排转运蛋白（Bsep和Mrp2）和肝摄取转运蛋白（Ntcp和Oatp1b2）的表达，对ee诱导的肝损伤有保护作用。SRT1720显著抑制EE诱导的TNF-α和IL-6水平。这些结果表明，SRT1720对ee诱导的小鼠胆汁淤积性肝损伤具有剂量依赖性的保护作用，其机制可能与激活HNF1α/FXR信号通路和抗炎机制有关。[5]

SIRT1荧光偏振测定和HTS [1]
在SIRT1 FP检测中，使用从p53序列中提取的20个氨基酸肽(AcGlu-Glu-Lys（生物素）- gly - gln - ser - thr - ser - ser - his - ser -Lys（Ac)- nle - ser - thr - glu - gly -Lys(MR121或Tamra)- gluu - gluu - nh2）来监测SIRT1的活性。该肽n端与生物素连接，c端用荧光标记修饰。监测酶活性的反应是一个偶联酶试验，第一个反应是由SIRT1催化的去乙酰化反应，第二个反应是由胰蛋白酶在新暴露的赖氨酸残基上切割。停止反应，加入链霉亲和素，以强调底物和产物之间的质量差异。总共筛选了29万种化合物，确认了127种。FP检测的灵敏度允许鉴定出SIRT1低水平激活（20 μM下激活≥17%）的化合物，产生代表不同结构类别的多种激活剂。荧光极化反应条件为：0.5 μM肽底物，150 μM βNAD+, 0-10 nM SIRT1, 25 mM Tris-acetate pH 8, 137 mM Na-Ac, 2.7 mM K-Ac, 1 mM Mg-Ac, 0.05% Tween-20, 0.1% Pluronic F127, 10 mM CaCl2, 5 mM DTT, 0.025% BSA， 0.15 mM烟酰胺。37℃孵育，加入烟酰胺停止反应，加入胰蛋白酶裂解去乙酰化底物。在1 μM链亲和素存在下，37℃孵育反应。在激发（650 nm）和发射（680 nm）波长处测定荧光偏振。

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作用机制研究[1]
测试化合物对乙酰化肽底物SIRT1酶Km的影响采用上述SIRT1质谱法检测。采用无细胞质谱法测定了9种化合物浓度（100、33、11、3.7、1.2、0.41、0.14、0.046和0.015 μM）和DMSO载体单独存在下肽底物SIRT1酶的Km。为了确定Km，对每种化合物浓度和对照进行了12种乙酰化肽底物浓度（50、25、12.5、6.25、3.12、1.56、0.78、0.39、0.19、0.098、0.049和0.024 μM）下的线性去乙酰化速率测定。SIRT1酶、2 mM NAD+和0-50 μM乙酰化肽底物与0-100 μM化合物在25°C下孵育。在0、3、6、9、12、15、20和25分钟，用10%甲酸和50 mM烟酰胺停止反应，并通过质谱测定底物到产物的转化。

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等温滴定量热法（ITC） [1]
人SIRT1-E5c蛋白(41 μM；ITC使用质谱肽底物（1.0 mM）和SRT1460 （0.84 mM）原液。缓冲条件为50 mM Tris-HCl （pH 8.0）、137 mM NaCl、2.7 mM KCl、1 mM MgCl2、2 mM TCEP和5%甘油。滴定在26℃的VP-ITC上进行。选择SRT1460进行这些研究是因为它在缓冲液中可溶到实验所需的毫摩尔浓度。

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等温图研究/Isobologram studies[1]
白藜芦醇与SRT1720和SRT1720与SRT1460联合使用的效果使用上述SIRT1质谱法测定。建立了两种化合物的浓度基质，并对SIRT1酶进行了检测。在基质中存在的每种组合下，测定乙酰化肽底物转化为去乙酰化肽产物的百分比。所得的等线图用于评价组合的效果。在分析中，产生相同效应水平的剂量组合的笛卡尔坐标图是等线图的基础。如果两种化合物具有可变效价，则选择恒定的相对效价(R) -即达到相同倍活性所需的化合物量（例如白藜芦醇vs SRT1720 EC1.25和SRT1720 vs SRT1460 EC2.5） -用于X和Y截距进行等温图分析。对应于各自EC值的两种化合物的浓度用作X和Y轴上的截距。利用这两个截距，在两点之间画出一条叫做可加性线的理论线。将两种化合物作为剂量对混合在一个矩阵中，产生相同的效应水平（EC值），通过对数滴定得到的实验数据绘制在等温线图上。通过对两种药物剂量组合的可加性曲线和可加性曲线进行统计比较，可以看出一种效应是否具有可加性。落在可加性线以下和以上的点进行回归分析。高于可加性线的实验数据被解释为拮抗，低于可加性线的实验数据被解释为协同，落在可加性线上的实验数据被认为是可加性。

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p53去乙酰化试验[1]
将人骨肉瘤细胞（U-2 OS）以每孔1.5 X 104个细胞的比例在96孔板中进行镀膜。24小时后，将测试化合物和对照（均为100% DMSO）添加到细胞板中。为了证明该检测结果对sirt1的依赖性，重复板组与测试化合物和sirt1特异性小分子抑制剂（6-氯-2,3,4,9-四氢-1- h -咔唑-1-carboxamide）共同处理。化合物添加后，每孔中加入阿霉素（终浓度1 μg/ml）诱导p53表达和乙酰化。p53诱导后，将细胞固定，然后用PBS-0.1% Triton-X-100渗透。在PBS-0.1% TWEEN 20（阻断溶液）中加入5%牛血清白蛋白阻断非特异性蛋白结合。一抗抗p53-acetyl-lysine-382（兔多克隆）和抗β - tubulin（小鼠单克隆）分别在Block Solution中稀释1:400和1:1000，加入孔中在40℃孵育过夜，然后在PBS-0.1% TWEEN 20 （Wash Buffer）中洗涤。二抗IR800CW山羊抗兔IgG和Alexa-Fluor 680山羊抗小鼠IgG在Block Solution中稀释，加入孔中室温孵育1小时。在Wash Buffer中再次洗涤5次。然后用Li-Cor奥德赛红外扫描仪扫描底片。使用制造商的软件提取数据。Ac-Lys382-p53和β -微管蛋白的信号均使用仅含二抗孵育的孔进行背景校正。然后将每个孔的ac - lys382信号归一化为相应的β -微管蛋白信号，以校正细胞数量的差异。然后将这些值归一化到载体中，以生成每口井的乙酰化p53 %值。

免疫组织化学（IHC）原位检测细胞凋亡[2]
从小鼠（对照）和SRT1720 -处理小鼠中切除肿瘤并保存在10%福尔马林中。如前所述，肿瘤中的凋亡细胞通过免疫组化染色检测caspase-3激活（Chauhan等，2010）。

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体外迁移和毛细血管样管结构形成测定[2]
如前所述，Transwell插入测定法用于测量迁移（Podar等，2001）。通过Matrigel毛细管样管结构形成试验评估体外血管生成（Chauhan et al, 2010）。为了进行内皮管形成实验，从克隆公司获得人血管内皮细胞（HUVECs），并将其保存在含有5%胎牛血清的内皮细胞生长培养基2 （EGM2 MV singlequotes）中。3代后，用台盼蓝排斥法测定HUVEC细胞活力，SRT1720处理HUVEC细胞死亡率<5%。

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细胞活力和凋亡测定[2]
采用先前描述的3-（4,5 -二甲基噻唑-2-基）- 2,5 -二苯基溴化四唑（MTT）比色法评估细胞活力（Hideshima等人，2000年）。凋亡测定采用Annexin V-FITC/碘化丙啶（PI）细胞凋亡检测试剂盒，按照制造商的说明进行定量，然后在FACS Calibur上进行分析。

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Western blotting和蛋白定量[2]
采用caspase-3、caspase-7、caspase-8、caspase-9、多聚（ADP）核糖聚合酶（PARP）、Ace-Lys 382 p53、磷酸化-失调性毛细血管扩张突变（pATM）、磷酸化-检查点激酶2 （pCHK2）、磷酸化- i - κ b ser32/36和GAPDH抗体进行免疫印迹分析。然后通过增强化学发光形成印迹。使用AlphaImager EC凝胶记录系统获取蛋白质条带的密度，并使用斑点密度分析工具对条带进行分析。

Pharmacokinetics of SRT1720 [1]
SRT1720 in vehicle (2% HPMC + 0.2% DOSS) was administered via oral gavage to C57BL/6 male mice (18-22 grams; 3 mice per dose group per time point) at the doses doi: 10.1038/nature06261 SUPPLEMENTARY INFORMATION www.nature.com/nature 4 indicated. For all in vivo studies SRT1720 was dosed as the hydrochloride salt. Mice were sacrificed by CO2 asphyxiation and blood was collected at 5, 30, 120 and 360 minutes after dosing. Blood was collected and plasma was sent to Charles River Labs (CRL) for drug level analysis. To determine oral bioavailability, SRT1720 in vehicle (10% ethanol/ 40% Polyethylene glycol / 50% H2O) was administered into the tail vein of C57BL/6 male mice (18-22 grams; 3 mice per dose group per time point) at the doses indicated. Blood was collected at 5, 30, 120, and 360 minutes and analyzed for drug levels as described above. SRT1720 was administered via oral gavage to Sprague-Dawley male rats (250 grams; 3 rats per dose group) at 100 mg/kg in vehicle (2% HPMC + 0.2% DOSS). Blood was collected at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post dose and analyzed for drug levels. To determine oral bioavailability, SRT1720 was administered into the tail vein at 10 mg/kg doses. SRT1720 was administered in 10% ethanol/ 40% Polyethylene glycol / 50% H2O for IV studies.

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Diet induced obesity model [1]
Nine week old C57BL/6 male mice were fed a high fat diet (60% calories from fat) until their mean body weight reached approximately 40 g. The mice were then divided into test groups (6-10 per group). SRT1460 (100 mg/kg), SRT1720 (100 mg/kg), SRT501 (500 mg/kg) and rosiglitazone (5 mg/kg) were administered once daily via oral gavage. The vehicle used was 2% HPMC + 0.2% DOSS. Individual mouse body weights were measured twice weekly. At 2, 4, 6, 8 and 10 weeks of dosing a fed blood glucose measure was taken and after 5 weeks of treatment an IPGTT was conducted on all mice from each of the groups. After 10 weeks of treatment, an ITT was conducted.

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Citrate synthase assay [1]
5 Citrate synthase (CS) activity in skeletal muscle (gastrocnemius) and white adipose tissue (epididymal) was determined after 11 weeks of treatment using the method described by Srere and Moyes29,30. The five mice best representing the mean fasting blood glucose level of each group (DIO Vehicle and DIO SRT1720) were selected for this analysis.

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. ob/ob model[1]
ob/ob mice and a heterozygous ob/+ mice were received at 6 week of age. Mice were placed on a high fat diet (60% calories from fat) for a minimum of one week prior to the start of a study and remained on the high fat diet for the duration of the study. After a one week acclimation, all mice were weighed and blood glucose measurements were taken. The average body weight of the ob/ob mice used in the study were ~ 40-45 grams. All mice were sorted by body weight and glucose levels and then were allocated into groups. Animals were dosed with either SRT1720 (100 mg/kg), SRT501 (1000 mg/kg), or vehicle (2% HPMC + 0.2% DOSS) once daily by oral gavage. Blood glucose and insulin were determined as described above.

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Zucker fa/fa model [1]
Six week old, male fatty (fa/fa) Zucker (ZF) rats were housed individually under controlled light (12:12 light:dark) and temperature conditions. At 7 weeks of age animals were randomly assigned to receive either the SIRT1 activator (SRT1720) or vehicle (i.e. 2% HPMC + 0.2% DOSS). The drug was administered by oral gavage on a daily basis (between 3-5pm) for 4 weeks and animals had ad libitum access to food and water. The night before beginning the drug treatment animals were overnight fasted (12 h), the following morning (Day 1) blood glucose concentration was measured, and a blood sample was taken in a heparinized capillary tube from the tail vein. This sample was centrifuged at 13,000 rpm for 5 min and the plasma was stored at -80o C for analysis. This procedure was subsequently repeated during the first 3 weeks of drug treatment (i.e.; Days 8, 15 and 22). Also, in the afternoon of Day 22, a fed blood glucose measurement was taken from the tail vein.

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Human plasmacytoma xenograft model [2]
The xenograft tumour model was performed as previously described (LeBlanc et al, 2002). This animal model has been immensely useful in extensively validating the novel anti-MM therapies, bortezomib and lenalidomide, leading to their translation to clinical trials and US Food and Drug Administration approval for the treatment of MM. Fox Chase-SCID mice (6 mice each group) were subcutaneously inoculated with 6.0 × 106 MM.1S cells in 100 μl of serum-free RPMI-1640 medium. When tumours were measurable (~100 mm3) approximately three weeks after MM cell injection, mice were treated orally with vehicle alone (20% PEG400/0.5% Tween80/79.5% deionized water) or SRT1720 (200 mg/kg) for four weeks on a five consecutive days/week schedule. In situ detection of apoptosis using immunohisto-chemistry (IHC)[2]
Tumours from vehicle (control)- and SRT1720-treated mice were excised and preserved in 10% formalin. Apoptotic cells in tumours were identified by IHC staining for caspase-3 activation, as previously described (Chauhan et al, 2010).

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Dissolved in 20% PEG400/0.5% Tween80/79.5% deionized water; 200 mg/kg/day; Oral administration

Chase-SCID mice with MM.1S cells

SRT1720 exhibited a pharmacokinetic profile (Fig. 3a) suitable for in vivo evaluation in both mouse (bioavailability = 50%, terminal t1/2 = ~5 h, Area Under the Curve (AUC) = 7,892 ng h−1 ml−1) and rat (bioavailability = 25%, terminal t1/2 = ~8.4 h, AUC = 3,714 ng h−1 ml−1). SRT501, a reformulated version of resveratrol with improved bioavailability (11% bioavailability, terminal t1/2 of ~ 1 h and an AUC of 10,524 ng h−1 ml−1), was also examined in genetically obese mice (Lepob/ob) and diet-induced obesity (DIO) mice. [1]

[1]. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007 Nov 29;450(7170):712-6.
[2]. Preclinical evaluation of a novel SIRT1 modulator SRT1720 in multiple myeloma cells. Br J Haematol. 2011 Dec;155(5):588-98.

[3]. Are sirtuins viable targets for improving healthspan and lifespan?,Nat Rev Drug Discov. 2012 Jun 1;11(6):443-61.

[4]. SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice.,J Clin Invest. 2012 Jun 1;122(6):2032-45.

[5]. Activation of SIRT1 Attenuates Klotho Deficiency-Induced Arterial Stiffness and Hypertension by Enhancing AMP-Activated Protein Kinase Activity. Hypertension. 2016 Nov;68(5):1191-1199.

[6]. SRT1720 induces lysosomal-dependent cell death of breast cancer cells. Mol Cancer Ther. 2015 Jan;14(1):183-92.

[7]. Protective effects of SRT1720 via the HNF1α/FXR signalling pathway and anti-inflammatory mechanisms in mice with estrogen-induced cholestatic liver injury. Toxicol Lett. 2016 Dec 15;264:1-11.

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.[1]

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SIRT1 belongs to the silent information regulator 2 (Sir2) protein family of enzymes and functions as a NAD(+) -dependent class III histone deacetylase. Here, we examined the anti-multiple myeloma (MM) activity of a novel oral agent, SRT1720, which targets SIRT1. Treatment of MM cells with SRT1720 inhibited growth and induced apoptosis in MM cells resistant to conventional and bortezomib therapies without significantly affecting the viability of normal cells. Mechanistic studies showed that anti-MM activity of SRT1720 is associated with: (i) activation of caspase-8, caspase-9, caspase-3, poly(ADP) ribose polymerase; (ii) increase in reactive oxygen species; (iii) induction of phosphorylated ataxia telangiectasia mutated/checkpoint kinase 2 signalling; (iv) decrease in vascular endothelial growth factor-induced migration of MM cells and associated angiogenesis; and (v) inhibition of nuclear factor-κB. Blockade of ATM attenuated SRT1720-induced MM cell death. In animal tumour model studies, SRT1720 inhibited MM tumour growth. Finally, SRT1720 enhanced the cytotoxic activity of bortezomib or dexamethasone. Our preclinical studies provide the rationale for novel therapeutics targeting SIRT1 in MM.[2]

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Although the increased lifespan of our populations illustrates the success of modern medicine, the risk of developing many diseases increases exponentially with old age. Caloric restriction is known to retard ageing and delay functional decline as well as the onset of disease in most organisms. Studies have implicated the sirtuins (SIRT1-SIRT7) as mediators of key effects of caloric restriction during ageing. Two unrelated molecules that have been shown to increase SIRT1 activity in some settings, resveratrol and SRT1720, are excellent protectors against metabolic stress in mammals, making SIRT1 a potentially appealing target for therapeutic interventions. This Review covers the current status and controversies surrounding the potential of sirtuins as novel pharmacological targets, with a focus on SIRT1. [3]

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Chronic obstructive pulmonary disease/emphysema (COPD/emphysema) is characterized by chronic inflammation and premature lung aging. Anti-aging sirtuin 1 (SIRT1), a NAD+-dependent protein/histone deacetylase, is reduced in lungs of patients with COPD. However, the molecular signals underlying the premature aging in lungs, and whether SIRT1 protects against cellular senescence and various pathophysiological alterations in emphysema, remain unknown. Here, we showed increased cellular senescence in lungs of COPD patients. SIRT1 activation by both genetic overexpression and a selective pharmacological activator, SRT1720, attenuated stress-induced premature cellular senescence and protected against emphysema induced by cigarette smoke and elastase in mice. Ablation of Sirt1 in airway epithelium, but not in myeloid cells, aggravated airspace enlargement, impaired lung function, and reduced exercise tolerance. These effects were due to the ability of SIRT1 to deacetylate the FOXO3 transcription factor, since Foxo3 deficiency diminished the protective effect of SRT1720 on cellular senescence and emphysematous changes. Inhibition of lung inflammation by an NF-κB/IKK2 inhibitor did not have any beneficial effect on emphysema. Thus, SIRT1 protects against emphysema through FOXO3-mediated reduction of cellular senescence, independently of inflammation. Activation of SIRT1 may be an attractive therapeutic strategy in COPD/emphysema. [4]

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Sirtuin 1 (SIRT1) is the most conserved mammalian NAD+-dependent protein deacetylase and is a member of the silent information regulator 2 (Sir2) families of proteins (also known as Sirtuins). In the liver, hepatic SIRT1 modulates bile acid metabolism through the regulation of farnesoid X receptor (FXR) expression. FXR is one of the most important nuclear receptors involved in the regulation of bile acid metabolism. SIRT1 modulates the FXR expression at multiple levels, including direct deacetylation of this transcription factor and transcriptional regulation through hepatocyte nuclear factor 1α (HNF1α). Therefore, hepatic SIRT1 is a vital regulator of the HNF1α/FXR signalling pathway and hepatic bile acid metabolism. However, whether SIRT1 is a suitable therapeutic target for the treatment of cholestasis is unknown. In the present study, we examined the protective effect of SRT1720, which is a specific activator of SIRT1, against 17α-ethinylestradiol (EE)-induced cholestasis in mice. Our data demonstrated that SRT1720 significantly prevented EE-induced changes in the serum levels of total bile acids (TBA), total bilirubin (TBIL), γ-glutamyltranspeptidase (γ-GGT) and alkaline phosphatase (ALP). SRT1720 also relieved EE-induced liver pathological injuries as indicated by haematoxylin and eosin (H&E) staining. SRT1720 treatment protected against EE-induced liver injury through the HNF1α/FXR signalling pathway, which up-regulated the expression of hepatic efflux transporter (Bsep and Mrp2) and hepatic uptake transporters (Ntcp and Oatp1b2). Moreover, SRT1720 significantly inhibited the TNF-α and IL-6 levels induced by EE. These findings indicate that SRT1720 exerts a dose-dependent protective effect on EE-induced cholestatic liver injury in mice and that the mechanism underlying this activity is related to the activation of the HNF1α/FXR signalling pathway and anti-inflammatory mechanisms.[5]

C25H24CLN7OS

506.0224

505.145

2060259-60-9

SRT 1720;925434-55-5;SRT 1720 dihydrochloride;2468639-77-0; 925434-55-5; 2060259-60-9 (HCl); 1001645-58-4 (x HCl)

25232708

Brown to reddish brown solid powder

116

3

7

5

35

707

0

Cl[H].S1C([H])=C(C([H])([H])N2C([H])([H])C([H])([H])N([H])C([H])([H])C2([H])[H])N2C([H])=C(C3=C([H])C([H])=C([H])C([H])=C3N([H])C(C3C([H])=NC4=C([H])C([H])=C([H])C([H])=C4N=3)=O)N=C12

DTGRRMPPXCRRIM-UHFFFAOYSA-N

InChI=1S/C25H23N7OS.ClH/c33-24(22-13-27-20-7-3-4-8-21(20)28-22)29-19-6-2-1-5-18(19)23-15-32-17(16-34-25(32)30-23)14-31-11-9-26-10-12-31;/h1-8,13,15-16,26H,9-12,14H2,(H,29,33);1H

N-[2-[3-(piperazin-1-ylmethyl)imidazo[2,1-b][1,3]thiazol-6-yl]phenyl]quinoxaline-2-carboxamide;hydrochloride

1001645-58-4; SRT 1720 Hydrochloride; SRT1720 HCl; SRT1720 Hydrochloride; SRT 1720 (Hydrochloride); N-(2-(3-(piperazin-1-ylmethyl)imidazo[2,1-b]thiazol-6-yl)phenyl)quinoxaline-2-carboxamide hydrochloride; SRT1720 xHydrochloride; ...; 2060259-60-9;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~62.5 mg/mL (~123.51 mM)
H2O : ~15.7 mg/mL (~31.03 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (4.11 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (4.11 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 1 mg/mL (1.98 mM) (饱和度未知) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 4 中的溶解度: ≥ 1 mg/mL (1.98 mM) (饱和度未知) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 5 中的溶解度: 10 mg/mL (19.76 mM) in 0.5% HPMC 0.2%Tween80 (这些助溶剂从左到右依次添加，逐一添加), 悬浮液； 超声助溶。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。