Berberine derivatives reduce atherosclerotic plaque size and vulnerability in apoE(-/-) mice.
Berberine derivatives reduce atherosclerotic plaque size and vulnerability in apoE(-/-) mice.
复制标题
DOI：
10.1186/s12967-014-0326-7
复制
发表时间：
2014-11-26
影响因子：
7.4
通讯作者：
Meng S
中科院分区：
文献类型：
--
作者：
Chen J;Cao J;Fang L;Liu B;Zhou Q;Sun Y;Wang Y;Li Y;Meng S
我们前期的体外和临床研究已经证实了小檗碱（BBR）的抗炎作用，但其生物利用度低限制了其临床应用。已经表明BBR的衍生物与BBR相比具有增强的生物利用度。在这项研究中，我们测试了与BBR相比，BBR衍生物是否对apoE−/−小鼠的动脉粥样硬化斑块具有上级有益作用，并确定了这种作用的可能分子机制。在与oxLDL孵育之前，用BBR及其衍生物二氢小檗碱（dhBBR）和8，8-二甲基二氢小檗碱（Di-MeBBR）预处理大环内酯。用流式细胞术和Western blotting检测细胞表面EMMPRIN的表达，用Western blotting检测磷酸化p38、p-JNK、核NFκB p65和磷酸化p65。ApoE−/−小鼠用西方饮食喂养16周，用BBR、dhBBR和Di-MeBBR处理16周。采用油红O染色、Masson三色染色、免疫组化染色和实时荧光PCR检测主动脉粥样硬化病变大小、斑块基质蛋白、EMMPRIN和其他炎症因子。与BBR相比，dhBBR和Di-MeBBR均能显著降低巨噬细胞EMMPRIN的表达，并能显著抑制oxLDL诱导的p-p38、p-JNK、核NFκB p65和磷酸化p65的表达。dhBBR和Di-MeBBR（而非BBR）可减少动脉粥样硬化斑块大小并改善斑块稳定性，表现为α-平滑肌肌动蛋白和胶原含量增加以及纤维帽增厚。dhBBR和Di-MeBBR降低主动脉斑块中EMMPRIN、CD 68和NFκB p65的表达，Di-MeBBR还降低基质金属蛋白酶9、细胞间粘附分子1和血管细胞粘附分子1的表达。这些结果表明，BBR衍生物，dhBBR和Di-MeBBR，在抑制炎症和减少斑块大小和脆弱性方面上级BBR。
Our previous in vitro and clinical work has demonstrated anti-inflammatory effects of berberine (BBR), but the clinical application of BBR is limited by its poor bioavailability. Derivatives of BBR have been suggested to have enhanced bioavailability compared to BBR. In this study, we tested whether BBR derivatives, compared with BBR, had superior beneficial effects on atherosclerotic plaques in apoE−/− mice, and defined possible molecular mechanisms underlying such effects. Macrophages were pretreated with BBR and its derivatives, dihydroberberine (dhBBR) and 8,8-dimethyldihydroberberine (Di-MeBBR), before incubation with oxLDL. Cell surface EMMPRIN expression was measured by flow cytometry and Western blotting, and phospho-(p)-p38, p-JNK, nuclear NFκB p65, and phospho-p65 were measured by Western blotting. ApoE−/− mice fed with the Western diet for 16 weeks were treated with BBR, dhBBR and Di-MeBBR 16 weeks. Aortic atherosclerotic lesion size, plaque matrix proteins, and EMMPRIN and other inflammatory factors were measured using Oil Red O Staining, Masson’s trichromestaining and immunohistochemical staining and real-time PCR. Compared with BBR, dhBBR and Di-MeBBR significantly reduced EMMPRIN expression, which was associated with a greater inhibition of p-p38, p-JNK, nuclear NFκB p65 and phospho-p65 induced by oxLDL in macrophages. dhBBR and Di-MeBBR, but not BBR, reduced atherosclerotic plaque size and improved plaque stability indicated by increased α-smooth muscle actin and collagen content, and thicker fibrous caps. dhBBR and Di-MeBBR reduced expression of EMMPRIN, CD68, and NFκB p65, and Di-MeBBR also reduced expression of matrix metalloproteinase-9, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in aortic plaques. These results have demonstrated that BBR derivatives, dhBBR and Di-MeBBR, are superior to BBR in inhibiting inflammation and reducing plaque size and vulnerability.
登录
查看更多内容
影响因子：
64.5
作者：
Moore KJ;Tabas I
通讯作者：
Tabas I
DOI：
10.1161/01.atv.0000021411.53577.1c
发表时间：
2002-07-01
影响因子：
8.7
作者：
Major, TC;Liang, L;Bocan, TMA
通讯作者：
Bocan, TMA
DOI：
10.1161/01.atv.0000218496.60097.e0
发表时间：
2006-05-01
影响因子：
8.7
作者：
Kuzuya, M;Nakamura, K;Iguchi, A
通讯作者：
Iguchi, A
DOI：
10.1073/pnas.94.9.4642
发表时间：
1997-04-29
影响因子：
11.1
作者：
Dansky, HM;Charlton, SA;Smith, JD
通讯作者：
Smith, JD
影响因子：
4.3
作者：
Carr, S;Farb, A;Yao, JST
通讯作者：
Yao, JST