Departments of Basic Medical Sciences, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA.
Lipids Health Dis. 2010 Dec 16;9:143. doi: 10.1186/1476-511X-9-143.
Inflammation has been implicated in cardiovascular disease, and the important role of proteasomes in the development of inflammation and other macrophage functions has been demonstrated. Tocotrienols are potent hypocholesterolemic agents that inhibit β-hydroxy-β-methylglutaryl coenzyme A reductase activity, which is degraded via the ubiquitin-proteasome pathway. Our objective was to evaluate the effect of tocotrienols in reducing inflammation. Lipopolysaccharide (LPS) was used as a prototype for inflammation in murine RAW 264.7 cells and BALB/c female mice.
The present results clearly demonstrate that α-, γ-, or δ-tocotrienol treatments inhibit the chymotrypsin-like activity of 20 S rabbit muscle proteasomes (> 50%; P < 0.05). Chymotrypsin, trypsin, and post-glutamase activities were decreased > 40% (P < 0.05) with low concentrations (< 80 μM), and then increased gradually with concentrations of (80--640 μM) in RAW 264.7 whole cells. Tocotrienols showed 9--33% (P < 0.05) inhibitions in TNF-α secretion in LPS-stimulated RAW 264.7 cells. Results of experiments carried out in BALB/c mice demonstrated that serum levels of TNF-α after LPS treatment were also reduced (20--48%; P < 0.05) by tocotrienols with doses of 1 and 10 μg/kg, and a corresponding rise in serum levels of corticosterone (19--41%; P < 0.05) and adrenocorticotropic hormone (81--145%; P < 0.02) was observed at higher concentrations (40 μM). Maximal inhibition of LPS-induced TNF-α was obtained with δ-tocotrienol (10 μg/kg). Low concentrations of δ-Tocotrienols (< 20 μM) blocked LPS-induced gene expression of TNF-α, IL-1β, IL-6 and iNOS (> 40%), while higher concentrations (40 μM) increased gene expression of the latter in peritoneal macrophages (prepared from BALB/c mice) as compared to control group.
These results represent a novel approach by using natural products, such as tocotrienols as proteasome modulators, which may lead to the development of new dietary supplements of tocotrienols for cardiovascular diseases, as well as others that are based on inflammation.
炎症与心血管疾病有关，蛋白酶体在炎症的发展和其他巨噬细胞功能中的重要作用已经得到证实。生育三烯酚是一种强效的降胆固醇剂，可抑制羟甲基戊二酰基辅酶 A 还原酶的活性，该酶通过泛素蛋白酶体途径降解。我们的目的是评估生育三烯酚在减少炎症中的作用。脂多糖（LPS）被用作小鼠 RAW 264.7 细胞和 BALB/c 雌性小鼠炎症的原型。
本研究结果清楚地表明，α-、γ-或δ-生育三烯酚处理抑制 20S 兔肌蛋白酶体的糜蛋白酶样活性（>50%；P<0.05）。在 RAW 264.7 全细胞中，低浓度（<80μM）下，糜蛋白酶、胰蛋白酶和后谷氨酰胺酶活性降低>40%（P<0.05），然后随着浓度（80-640μM）逐渐增加。生育三烯酚对 LPS 刺激的 RAW 264.7 细胞中 TNF-α分泌的抑制率为 9-33%（P<0.05）。在 BALB/c 小鼠中进行的实验结果表明，LPS 处理后血清 TNF-α水平也被生育三烯酚降低（20-48%；P<0.05），剂量为 1 和 10μg/kg，同时血清皮质酮（19-41%；P<0.05）和促肾上腺皮质激素（81-145%；P<0.02）水平相应升高在较高浓度（40μM）下。δ-生育三烯酚（10μg/kg）对 LPS 诱导的 TNF-α的抑制作用最大。低浓度的 δ-生育三烯酚（<20μM）阻断 LPS 诱导的 TNF-α、IL-1β、IL-6 和 iNOS 基因表达（>40%），而较高浓度（40μM）则增加了腹腔巨噬细胞（来自 BALB/c 小鼠）中后者的基因表达与对照组相比。
这些结果代表了一种使用天然产物（如生育三烯酚）作为蛋白酶体调节剂的新方法，这可能导致基于炎症的心血管疾病和其他疾病的生育三烯酚新膳食补充剂的开发。
