Oral methylthioadenosine administration attenuates fibrosis and chronic liver disease progression in Mdr2-/- mice.
Oral methylthioadenosine administration attenuates fibrosis and chronic liver disease progression in Mdr2-/- mice.
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DOI：
10.1371/journal.pone.0015690
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发表时间：
2010-12-29
期刊：
影响因子：
3.7
通讯作者：
Avila MA
中科院分区：
文献类型：
--
作者：
Latasa MU;Gil-Puig C;Fernández-Barrena MG;Rodríguez-Ortigosa CM;Banales JM;Urtasun R;Goñi S;Méndez M;Arcelus S;Juanarena N;Recio JA;Lotersztajn S;Prieto J;Berasain C;Corrales FJ;Lecanda J;Avila MA
炎症和纤维化与慢性肝病的进展直接相关，包括肝细胞癌的发展。目前，几乎没有可用的治疗方案来抑制肝纤维化。我们评价了口服5‘-甲硫腺苷对MDR2−/−小鼠的保肝和抗纤维化作用。MDR2小鼠是一种临床上相关的硬化性胆管炎和自发性胆管纤维化的模型，随后发展为肝癌。野生型和mdr2−/−小鼠每日灌胃给予甲氨蝶呤3周。MTA的抗炎和抗纤维化作用及其可能的作用机制在持续纤维化的MDR2−/−小鼠的肝脏和培养的肝成纤维细胞(肌成纤维细胞)中进行了检测。MTA治疗可减少肝肿大和肝损伤。α-平滑肌肌动蛋白免疫反应和胶原沉积也明显减少。在体内，甲氨蝶呤可减少炎症细胞的浸润，减少细胞因子IL 6和单核细胞趋化蛋白1的表达，减少促纤维化因子β2和Tenascin C的表达，减少促纤维化的细胞内信号转导途径。MTA可抑制肌成纤维细胞的活化和增殖，并在转录水平下调细胞周期蛋白D1基因的表达。MTA还可降低活化的肌成纤维细胞中肝纤维化关键转录因子Jund的表达。口服MTA耐受性良好，证明了其在减轻肝脏炎症和纤维化方面的有效性。MTA可能有多个分子和细胞靶点。这些包括抑制炎症和促纤维化的细胞因子，以及抑制肌成纤维细胞的激活和增殖。下调肌成纤维细胞中Jund和Cyclin D1的表达可能是MTA作用机制中的重要环节。该化合物可能是治疗(胆汁性)肝纤维化的一个很好的候选药物。
Inflammation and fibrogenesis are directly related to chronic liver disease progression, including hepatocellular carcinoma (HCC) development. Currently there are few therapeutic options available to inhibit liver fibrosis. We have evaluated the hepatoprotective and anti-fibrotic potential of orally-administered 5′-methylthioadenosine (MTA) in Mdr2−/− mice, a clinically relevant model of sclerosing cholangitis and spontaneous biliary fibrosis, followed at later stages by HCC development. MTA was administered daily by gavage to wild type and Mdr2−/− mice for three weeks. MTA anti-inflammatory and anti-fibrotic effects and potential mechanisms of action were examined in the liver of Mdr2−/− mice with ongoing fibrogenesis and in cultured liver fibrogenic cells (myofibroblasts). MTA treatment reduced hepatomegaly and liver injury. α-Smooth muscle actin immunoreactivity and collagen deposition were also significantly decreased. Inflammatory infiltrate, the expression of the cytokines IL6 and Mcp-1, pro-fibrogenic factors like TGFβ2 and tenascin-C, as well as pro-fibrogenic intracellular signalling pathways were reduced by MTA in vivo. MTA inhibited the activation and proliferation of isolated myofibroblasts and down-regulated cyclin D1 gene expression at the transcriptional level. The expression of JunD, a key transcription factor in liver fibrogenesis, was also reduced by MTA in activated myofibroblasts. Oral MTA administration was well tolerated and proved its efficacy in reducing liver inflammation and fibrosis. MTA may have multiple molecular and cellular targets. These include the inhibition of inflammatory and pro-fibrogenic cytokines, as well as the attenuation of myofibroblast activation and proliferation. Downregulation of JunD and cyclin D1 expression in myofibroblasts may be important regarding the mechanism of action of MTA. This compound could be a good candidate to be tested for the treatment of (biliary) liver fibrosis.
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姜黄素通过抑制胆管细胞炎症反应和门户肌纤维细胞增殖来改善MDR2 - / - 小鼠中的硬化性胆管炎。
影响因子：
24.5
作者：
Baghdasaryan A;Claudel T;Kosters A;Gumhold J;Silbert D;Thüringer A;Leski K;Fickert P;Karpen SJ;Trauner M
通讯作者：
Trauner M
影响因子：
13.5
作者：
Dranoff, Jonathan A.;Wells, Rebecca G.
通讯作者：
Wells, Rebecca G.
影响因子：
8.5
作者：
Eto, I
通讯作者：
Eto, I
影响因子：
64.5
作者：
Guenther, Matthew G.;Levine, Stuart S.;Young, Richard A.
通讯作者：
Young, Richard A.
影响因子：
11.2
作者：
Katzenellenbogen, M;Pappo, O;Goldenberg, D
通讯作者：
Goldenberg, D