Background
BVT 2733 is a novel, small-molecule, nonsteroidal, isoform-selective inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) with IC50 of 96 nM (mice)[1].
BVT 2733 attenuated the mRNA levels of MCP-1 and IL-6 in PA or LPS treated J774A.1 macrophages. The protein levels of MCP-1 and IL-6 in the medium were also attenuated[2]. After constructing the mouse 11β-HSD1 overexpression lentiviral vector, MC3T3-E1 preosteoblasts were infected with negative control lentivirus and overexpressing 11β-HSD1 lentivirus, respectively, and then added with the selective inhibitor of 11β-HSD1 BVT 2733 to reverse the inhibitory effect of 11β-HSD1 expression on osteogenesis[6]. A significant increase in the expression of BAT-specific genes, including UCP1, Cidea, Cox7a1 and Cox8b, was observed in BVT 2733 treated and 11β-HSD1-deficient mouse native brown adipocytes[7].
BVT 2733 administration normalized the expression profile of adiponkines by up-regulating the mRNA levels of adiponectin and vaspin and down-regulating the expression of resistin in adipose tissue. In line with these changes in adipose tissue serum levels of adiponectin and leptin were also improved by BVT 2733 treatment[2]. BVT 2733 treatment attenuated the arthritis severity and anti-CII level in CIA mice. BVT-2733 also decreased the levels of serum TNF-α, IL-1β, IL-6 and IL-17. BVT 2733 treatment also significantly reduced synovial inflammation and joint destruction[3]. In hyperglycemic, but not in normal mice, BVT 2733 lowered circulating glucose and insulin levels. In oral glucose tolerance tests in ob/ob and KKAy mice, glucose concentrations were 65-75% of vehicle values after BVT 2733 treatment, and in KKAy mice insulin concentrations were decreased[4]. BVT 2733 reduced food intake but prevented a concomitant reduction in lean body mass and energy expenditure. The latter effects may have contributed to improved glucose tolerance[5].
参考文献:
[1]: Alberts P, Engblom L, et,al. Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice. Diabetologia. 2002 Nov;45(11):1528-32. doi: 10.1007/s00125-002-0959-6. Epub 2002 Sep 18. PMID: 12436336.
[2]: Wang L, Liu J, et,al. BVT.2733, a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, attenuates obesity and inflammation in diet-induced obese mice. PLoS One. 2012;7(7):e40056. doi: 10.1371/journal.pone.0040056. Epub 2012 Jul 2. PMID: 22768329; PMCID: PMC3388048.
[3]: Zhang L, Dong Y, et,al. 11β-Hydroxysteroid dehydrogenase 1 inhibition attenuates collagen-induced arthritis. Int Immunopharmacol. 2013 Nov;17(3):489-94. doi: 10.1016/j.intimp.2013.07.015. Epub 2013 Aug 11. PMID: 23938253.
[4]: Alberts P, Nilsson C, et,al. Selective inhibition of 11 beta-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains. Endocrinology. 2003 Nov;144(11):4755-62. doi: 10.1210/en.2003-0344. Epub 2003 Jul 31. PMID: 12960099.
[5]: Wang SJ, Birtles S, et,al. Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 reduces food intake and weight gain but maintains energy expenditure in diet-induced obese mice. Diabetologia. 2006 Jun;49(6):1333-7. doi: 10.1007/s00125-006-0239-y. Epub 2006 Apr 13. PMID: 16612591.
[6]: Wu L, Qi H, et,al. 11β-Hydroxysteroid dehydrogenase type 1 selective inhibitor BVT.2733 protects osteoblasts against endogenous glucocorticoid induced dysfunction. Endocr J. 2013;60(9):1047-58. doi: 10.1507/endocrj.ej12-0376. Epub 2013 Jun 12. PMID: 23759754.
[7]: Liu J, Kong X, et,al. Essential roles of 11β-HSD1 in regulating brown adipocyte function. J Mol Endocrinol. 2013 Jan 11;50(1):103-13. doi: 10.1530/JME-12-0099. PMID: 23197361.
BVT 2733 是一种新型、小分子、非甾体、异构体选择性 11β-羟基类固醇脱氢酶 1 型 (11β-HSD1) 抑制剂，IC50 为 96 nM（小鼠）[1]。
BVT 2733 减弱了 PA 或 LPS 处理的 J774A.1 巨噬细胞中 MCP-1 和 IL-6 的 mRNA 水平。培养基中 MCP-1 和 IL-6 的蛋白水平也降低了[2]。构建小鼠11β-HSD1过表达慢病毒载体后，MC3T3-E1前成骨细胞分别感染阴性对照慢病毒和过表达11β-HSD1慢病毒，然后加入11β-HSD1选择性抑制剂BVT 2733逆转11β的抑制作用-HSD1 在成骨过程中的表达[6]。在 BVT 2733 处理和 11β-HSD1 缺陷的小鼠天然棕色脂肪细胞中观察到 BAT 特异性基因（包括 UCP1、Cidea、Cox7a1 和 Cox8b）的表达显着增加[7]。\n
BVT 2733 给药通过上调脂联素和 vaspin 的 mRNA 水平以及下调脂肪组织中抵抗素的表达来使脂联素的表达谱正常化。与脂肪组织的这些变化一致，BVT 2733 治疗也改善了脂联素和瘦素的血清水平[2]。 BVT 2733 治疗减轻了 CIA 小鼠的关节炎严重程度和抗 CII 水平。 BVT-2733 还降低了血清 TNF-α、IL-1β、IL-6 和 IL-17 的水平。 BVT 2733 治疗还显着减少了滑膜炎症和关节破坏[3]。在高血糖症小鼠中，但在正常小鼠中，BVT 2733 降低了循环葡萄糖和胰岛素水平。在 ob/ob 和 KKAy 小鼠的口服葡萄糖耐量试验中，BVT 2733 处理后葡萄糖浓度为载体值的 65-75%，并且在 KKAy 小鼠中胰岛素浓度降低[4]。 BVT 2733 减少了食物摄入量，但阻止了随之而来的瘦体重和能量消耗的减少。后一种作用可能有助于改善葡萄糖耐量[5]。
Protocol
| Cell experiment [1]: |
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Cell lines
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Mouse reticulum cell sarcoma-derived cell, J774.1
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Preparation Method
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J774.1 macrophages were activated by PA or LPS and co-treated with 11β-HSD1 inhibitor BVT 2733 (25-100 μmol/L) for 24 h.
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Reaction Conditions
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25-100 μM BVT 2733 for 24h
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Applications
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BVT 2733 attenuated the mRNA levels of MCP-1 and IL-6 in PA or LPS treated J774A.1 macrophages. The protein levels of MCP-1 and IL-6 in the medium were also attenuated.
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| Animal experiment [2]: |
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Animal models
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Male C57BL/6J mice at age of 18 days
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Preparation Method
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From 3 weeks of age, all mice were fed with a normal chow diet containing 10% calory from fat (NC mice), or a high fat diet (HFD) containing 50% calorie from fat for 24 weeks. During the last four weeks the HFD-fed mice were dosed with BVT 2733 (100 mg/kg, orally) (HFD+BVT mice) or vehicle (HFD mice).
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Dosage form
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BVT 2733 (100 mg/kg, orally) for 4 weeks
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Applications
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BVT 2733 administration normalized the expression profile of adiponkines by up-regulating the mRNA levels of adiponectin and vaspin and down-regulating the expression of resistin in adipose tissue. In line with these changes in adipose tissue serum levels of adiponectin and leptin were also improved by BVT 2733 treatment.
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参考文献:
[1]. Wang L, Liu J, et,al. BVT.2733, a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, attenuates obesity and inflammation in diet-induced obese mice. PLoS One. 2012;7(7):e40056. doi: 10.1371/journal.pone.0040056. Epub 2012 Jul 2. PMID: 22768329; PMCID: PMC3388048.
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