WWL229
目录号 : GC45164
A selective inhibitor of Ces3
Cas No.:1338575-28-2
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
Mouse carboxylesterase 3 (Ces3, also named Ces1d) mediates triglyceride hydrolysis in white adipose tissue, liberating free fatty acids into circulation. Although important for basal lipolysis, Ces3 expression can be induced by xenobiotics. Ces3 activity is significantly elevated during adipocyte differentiation. WWL229 is a selective inhibitor of Ces3 (IC50 = 1.94 µM) that has no significant effect on other, related enzymes. By inhibiting the triglyceride hydrolase activity of Ces3, WWL229 promotes lipid storage in cultured adipocytes and prevents basal lipolysis.
| Cas No. | 1338575-28-2 | SDF | |
| Canonical SMILES | O=C(OC1=CC=C([N+]([O-])=O)C=C1)N2CCCCC2CCCOC | ||
| 分子式 | C16H22N2O5 | 分子量 | 322.4 |
| 溶解度 | DMF: 30 mg/ml,DMSO: 25 mg/ml,Ethanol: 30 mg/ml,Ethanol:PBS(pH 7.2) (1:1): 0.5 mg/ml | 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 | 3.1017 mL | 15.5087 mL | 31.0174 mL |
| 5 mM | 0.6203 mL | 3.1017 mL | 6.2035 mL |
| 10 mM | 0.3102 mL | 1.5509 mL | 3.1017 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 | ||||||||||
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。
Carboxylesterase 1d Inactivation Augments Lung Inflammation in Mice
ACS Pharmacol Transl Sci 2022 Sep 12;5(10):919-931.PMID:PMC9578131DOI:10.1021/acsptsci.2c00098.
Carboxylesterases are members of the serine hydrolase superfamily and metabolize drugs, pesticides, and lipids. Previous research showed that inhibition of carboxylesterase 1 (CES1) in human macrophages altered the immunomodulatory effects of lipid mediators called prostaglandin glyceryl esters, which are produced by cyclooxygenase-catalyzed oxygenation of the endocannabinoid 2-arachidonoylglycerol (2-AG). Ces1d - the mouse ortholog of human CES1 - is the most abundant Ces isoform in murine lung tissues and alveolar macrophages and a major target of organophosphate poisons. Monoacylglycerol lipase (Magl) is also expressed in murine lung and is the main enzyme responsible for 2-AG catabolism. Several metabolic benefits are observed in Ces1d-/- mice fed a high-fat diet; thus, we wondered whether pharmacological and genetic inactivation of Ces1d in vivo might also ameliorate the acute inflammatory response to lipopolysaccharide (LPS). C57BL/6 mice were treated with WWL229 (Ces1d inhibitor) or JZL184 (Magl inhibitor), followed 30 min later by either LPS or saline. Wild-type (WT) and Ces1d-/- mice were also administered LPS to determine the effect of Ces1d knockout. Mice were sacrificed at 6 and 24 h, and cytokines were assessed in serum, lung, liver, and adipose tissues. Lipid mediators were quantified in lung tissues, while activity-based protein profiling and enzyme assays determined the extent of lung serine hydrolase inactivation by the inhibitors. WWL229 was shown to augment LPS-induced lung inflammation in a female-specific manner, as measured by enhanced neutrophil infiltration and Il1b mRNA. The marked Ces inhibition in female lung by 4 h after drug treatment might explain this sex difference, although the degree of Ces inhibition in female and male lungs was similar at 6 h. In addition, induction of lung Il6 mRNA and prostaglandin E2 by LPS was more pronounced in Ces1d-/- mice than in WT mice. Thus, WWL229 inhibited lung Ces1d activity and augmented the female lung innate immune response, an effect observed in part in Ces1d-/- mice and Ces1d/CES1-deficient murine and human macrophages. In contrast, JZL184 attenuated LPS-induced Il1b and Il6 mRNA levels in female lung, suggesting that Ces1d and Magl have opposing effects. Mapping the immunomodulatory molecules/pathways that are regulated by Ces1d in the context of lung inflammation will require further research.
A Unique Role of Carboxylesterase 3 (Ces3) in β-Adrenergic Signaling-Stimulated Thermogenesis
Diabetes 2019 Jun;68(6):1178-1196.PMID:30862682DOI:10.2337/db18-1210.
Carboxylesterase 3 (Ces3) is a hydrolase with a wide range of activities in liver and adipose tissue. In this study, we identified Ces3 as a major lipid droplet surface-targeting protein in adipose tissue upon cold exposure by liquid chromatography-tandem mass spectrometry. To investigate the function of Ces3 in the β-adrenergic signaling-activated adipocytes, we applied WWL229, a specific Ces3 inhibitor, or genetic inhibition by siRNA to Ces3 on isoproterenol (ISO)-treated 3T3-L1 and brown adipocyte cells. We found that blockage of Ces3 by WWL229 or siRNA dramatically attenuated the ISO-induced lipolytic effect in the cells. Furthermore, Ces3 inhibition led to impaired mitochondrial function measured by Seahorse. Interestingly, Ces3 inhibition attenuated an ISO-induced thermogenic program in adipocytes by downregulating Ucp1 and Pgc1α genes via peroxisome proliferator-activated receptor γ. We further confirmed the effects of Ces3 inhibition in vivo by showing that the thermogenesis in adipose tissues was significantly attenuated in WWL229-treated or adipose tissue-specific Ces3 heterozygous knockout (Adn-Cre-Ces3flx/wt) mice. As a result, the mice exhibited dramatically impaired ability to defend their body temperature in coldness. In conclusion, our study highlights a lipolytic signaling induced by Ces3 as a unique process to regulate thermogenesis in adipose tissue.
Inactivation of CES1 Blocks Prostaglandin D2 Glyceryl Ester Catabolism in Monocytes/Macrophages and Enhances Its Anti-inflammatory Effects, Whereas the Pro-inflammatory Effects of Prostaglandin E2 Glyceryl Ester Are Attenuated
ACS Omega 2020 Nov 3;5(45):29177-29188.PMID:33225149DOI:10.1021/acsomega.0c03961.
Human monocytic cells in blood have important roles in host defense and express the enzyme carboxylesterase 1 (CES1). This metabolic serine hydrolase plays a critical role in the metabolism of many molecules, including lipid mediators called prostaglandin glyceryl esters (PG-Gs), which are formed during cyclooxygenase-mediated oxygenation of the endocannabinoid 2-arachidonoylglycerol. Some PG-Gs have been shown to exhibit anti-inflammatory effects; however, they are unstable compounds, and their hydrolytic breakdown generates pro-inflammatory prostaglandins. We hypothesized that by blocking the ability of CES1 to hydrolyze PG-Gs in monocytes/macrophages, the beneficial effects of anti-inflammatory prostaglandin D2-glyceryl ester (PGD2-G) could be augmented. The goals of this study were to determine whether PGD2-G is catabolized by CES1, evaluate the degree to which this metabolism is blocked by small-molecule inhibitors, and assess the immunomodulatory effects of PGD2-G in macrophages. A human monocytic cell line (THP-1 cells) was pretreated with increasing concentrations of known small-molecule inhibitors that block CES1 activity [chlorpyrifos oxon (CPO), WWL229, or WWL113], followed by incubation with PGD2-G (10 μM). Organic solvent extracts of the treated cells were analyzed by liquid chromatography with tandem mass spectrometry to assess levels of the hydrolysis product PGD2. Further, THP-1 monocytes with normal CES1 expression (control cells) and "knocked-down" CES1 expression (CES1KD cells) were employed to confirm CES1's role in PGD2-G catabolism. We found that CES1 has a prominent role in PGD2-G hydrolysis in this cell line, accounting for about 50% of its hydrolytic metabolism, and that PGD2-G could be stabilized by the inclusion of CES1 inhibitors. The inhibitor potency followed the rank order: CPO > WWL113 > WWL229. THP-1 macrophages co-treated with WWL113 and PGD2-G prior to stimulation with lipopolysaccharide exhibited a more pronounced attenuation of pro-inflammatory cytokine levels (interleukin-6 and TNFα) than by PGD2-G treatment alone. In contrast, prostaglandin E2-glyceryl ester (PGE2-G) had opposite effects compared to those of PGD2-G, which appeared to be dependent on the hydrolysis of PGE2-G to PGE2. These results suggest that the anti-inflammatory effects induced by PGD2-G can be further augmented by inactivating CES1 activity with specific small-molecule inhibitors, while pro-inflammatory effects of PGE2-G are attenuated. Furthermore, PGD2-G (and/or its downstream metabolites) was shown to activate the lipid-sensing receptor PPARγ, resulting in altered "alternative macrophage activation" response to the Th2 cytokine interleukin-4. These findings suggest that inhibition of CES1 and other enzymes that regulate the levels of pro-resolving mediators such as PGD2-G in specific cellular niches might be a novel anti-inflammatory approach.