GW4869 是非竞争性的中性鞘磷脂酶 (N-SMase)抑制剂，IC50值为1 μM。GW4869 是外泌体合成/释放的抑制剂。
| 生物活性 | GW4869 is a noncompetitiveneutral sphingomyelinase (N-SMase)inhibitor with anIC50of 1 μM. GW4869 is an inhibitor ofexosomebiogenesis/release[1][2][3][4]. |
| IC50& Target | IC50: 1 μM (neutral sphingomyelinase)[1] |
体外研究
(In Vitro) | GW4869 (10 μM) partially inhibits TNF-induced sphingomyelin (SM) hydrolysis, and 20 μM of the compound is protected completely from the loss of SM. The addition of 10-20 μM GW4869 completely inhibits the initial accumulation of ceramide, whereas this effect is partially lost at later time points (24 h). The action of GW4869 occurs downstream of the drop in glutathione. GW4869 is able, in a dose-dependent manner, to significantly protect from cell death[1].
GW4869 (10 or 20 μM) inhibits both exosome release and pro-inflammatory cytokine production in macrophages. GW4869 inhibits the ceramide-mediated inward budding of multivesicular bodies (MVBs) and release of mature exosomes from MVBs[2].
GW4869 also could reverse the inhibition of CCN2 3’-UTR activity by miR-214-enriched exosomes in hepatic stellate cells[3].
Solution Attention: GW4869 is routinely stored at –80 ℃ as a stock suspension in DMSO.
Cell Viability Assay[1] | Cell Line: | MCF7 human breast cancer cells. | | Concentration: | 10-20 μM. | | Incubation Time: | 30 min (then treated with TNF (3 nM) followed). | | Result: | Significantly inhibited TNF-induced SM hydrolysis, whereas 20 μM of the compound protected completely from the loss of SM. |
Cell Viability Assay[2] | Cell Line: | Fresh RAW264.7 macrophages. | | Concentration: | 10 or 20 μM. | | Incubation Time: | 2 hours (then treated with 1 μg/mL LPS incubation). | | Result: | LPS-triggered exosome generation was remarkably attenuated in macrophages upon pre-treatment of macrophages with 10 μM GW4869, as evidenced by a 22% reduction in the activity of AChE. Such attenuation was further enhanced by treatment with the dose of 20 μM. |
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体内研究
(In Vivo) | GW4869 (2.5 μg/g, i.p.) causes inhibition of exosome release blocks LPS-stimulated pro-inflammatory cytokine production and cardiac inflammation in mice. GW4869 mitigates LPS-caused myocardial dysfunction and improves survival in mice[2].
GW4869 (2.5 μg/g, i.p.) blocks the production of pro-inflammatory cytokines and cardiac inflammation in CLP mice[2].
| Animal Model: | 10-12 weeks old Male wild-type C57BL/6 mice (Endotoxin-Challenged Mice)[2]. | | Dosage: | 2.5 μg/g. | | Administration: | I.P. once (1 h later, followed by an i.p. injection of LPS (2.5 μg/g, 100 μL)). | | Result: | Significantly decreased exosome levels by 37% in sera, compared to levels collected from control mice. At 12 h after LPS injection, the levels of circulating exosomes
were increased significantly compared to PBS-controls, as evidenced by a 1.7-fold elevation in the AChE activity. |
| Animal Model: | 10-12 weeks old Male wild-type C57BL/6 mice (CLP Polymicrobial Sepsis Model)[2]. | | Dosage: | 2.5 μg/g. | | Administration: | I.P. once (before sham or CLP surgery). | | Result: | Decreased exosome concentration by 33% compared to mice injected with PBS in sham-surgery controls.
CLP-stimulated exosome release was significantly inhibited by pre-treatment of CLP mice compared to CLP mice pre-treated with PBS. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | 4°C, sealed storage, away from moisture *In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture) |
| 溶解性数据 | In Vitro: DMSO : 0.1 mg/mL(0.17 mM;Need ultrasonic) 0.1 M HCL :< 1 mg/mL (ultrasonic;adjust pH to 2 with HCl)(insoluble) H2O :< 0.1 mg/mL (ultrasonic)(insoluble) *GW4869 is usually formulated as a suspension. |
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