Wnt信号转导通路与肝纤维化

Wnt信号通路包括经典通路和非经典通路,其参与调控细胞的分化、癌变、凋亡及机体免疫、应激等生理病理过程。最近有研究表明Wnt信号通路与肝星状细胞的活化及肝纤维化的发生相关,深入研究Wnt信号通路在肝纤维化发生中的作用,将有助于进一步揭示肝纤维化的发生机制,为肝纤维化的防治提供新的可能途径及干预靶点。     

Wnt信号通路与抗纤维化策略

Wnt信号通路包括经典通路和非经典通路,参与人体各种生理病理过程。Wnt途径的异常与多种纤维增生紊乱性疾病相关,Wnt拮抗剂可以拮抗该途径。Wnt拮抗剂根据作用方式分为sFRP（Secreted frizzled related protein）和DKK（Dickkopf）两类家族。另外,显性负性作用以及转化生长因子（TGF）-β等均能调控Wnt信号途径,因此深人研究Wnt信号通路及其调控方式,可为将来抗纤维化治疗提供可行性的途径。     

Wnt信号转导通路与肝纤维化关系的研究现况

阻断该通路可以 Wnt 信号转导通路是近年来分子生物学、细抑制癌细胞的增殖和诱导凋亡.胞生物学和肿瘤研究中的一大热点,其参与调 控细胞分化、癌变、凋亡及机体免疫、应激 等多种病理生理过程.目前许多关于癌症方面 的研究均已证实,阻断Wnt 信号通路可以诱导 癌症细胞的凋亡.肝纤维化的发生与多种信号 通路的激活相关,有研究...     

Wnt信号通路相关分子在肝纤维化中的表达水平变化及其意义

目的 观察Wnt信号通路相关分子在实验性肝纤维化组织中表达水平的变化.探讨其在肝纤维化发生中的作用.方法 建立大鼠肝纤维化动物模型.用Wnt信号通路PCR array功能基因芯片观察Wnt信号通路相关分子在肝纤维化模型中表达水平的变化.以模型组较正常组表达上调或下调2倍为差异表达基因;利用免疫组化及Western印迹观察平滑肌肌动蛋白、Wnt4、Frizzled2、β-钙粘蛋白在肝纤维化组织表达水平的变化.结果 芯片检测发现共有36条基因发生了显著改变,模型组较正常组上调2倍的基因有25个,上调基因主要包括Wnt5a类基因,如Wnt4、Wnt5a、Wnt11等,分别上调了13.9、16.5和2.17倍;较正常组下调2倍的基因有11个,主要为Wnt1、Wnt3等.分别下调了2.32、2.15倍.免疫组化及Western印迹检测发现模型组肝组织Wnt4、Frizzled2的表达水平较正常组显著上升,而磷酸化的β-钙粘蛋白的表达水平下降.结论 经典及非经典Wnt信号通路均可能参与了实验性肝纤维化的发生机制.     

Wnt4／Frizzled2在肝纤维化组织中的表达及其意义

目的观察Wnt4／Frizzled2在肝纤维化模型肝组织中的表达水平变化，探讨wnt信号通路在肝纤维化发生中的作用。方法建立四氯化碳诱导大鼠实验性肝纤维化模型，采用免疫组织化学及免疫印迹技术观察Wnt4／Frizzled2在肝组织中的表达水平变化。结果模型组Ⅰ型胶原表达明显增强，包绕并形成假小叶；免疫组织化学和免疫印迹技术检测发现，肝纤维化模型肝组织Wnt4／Frizzled2的表达水平较正常对照组显著升高。结论非经典Wnt信号通路可能参与实验性肝纤维化的发生。     

Wnt/β-连环蛋白信号转导途径与呼吸系统疾病

Wnt/β-连环蛋白信号转导途径是一条Wnt胞外信号和β-连环蛋白核内信号双重依赖的信号转导通路,在胚胎发育、肿瘤发生和器官纤维化等重要生理及病理过程中发挥重要作用。在呼吸系统,Wnt/β-连环蛋白信号转导途径除参与肺组织的发育外,其各组分的异常也与肿瘤、间质性肺疾病和囊性纤维化等疾病的发生发展有关。从细胞和分子水平理解Wnt/β-连环蛋白信号转导途径,将有助于阐明相关肺部疾病的发病机制,发展诊断和治疗策略。     

Wnt信号通路与肝纤维化发生发展的关系

肝纤维化的发生发展机制复杂,包含众多细胞内外信号转导通路,但其具体机制尚未明确。最近较多研究证实Wnt信号通路异常激活进而使肝星状细胞活化是导致肝纤维化的重要原因;靶向抑制Wnt信号通路能够阻止肝星状细胞的活化、增殖,从而达到抗纤维化的目的。对Wnt信号通路在肝纤维化发生和发展中的作用以及干扰Wnt信号通路抗肝纤维化的最新研究进展进行综述,期望为抗肝纤维化和延缓早期肝硬化提供新的思路。     

Wnt信号通路与肝纤维化的关系

在各种慢性肝损伤后,肝纤维化是生物体的一种自我修复性病理过程,并能引起肝硬化、肝癌等疾病。Wnt信号通路广泛存在于无脊椎动物和脊椎动物中,是一类在物种进化过程中高度保守的信号通路。许多研究已经证实Wnt信号通路与肝纤维化的发生发展有密切联系。主要从经典和非经典Wnt信号通路调控肝星状细胞、肝巨噬细胞、肝祖细胞的机制方面进行概述,为后续深入开展Wnt信号调控肝纤维化机制研究及探索可逆转肝纤维化的治疗靶点提供新思路。     

Wnt/β-catenin信号通路在肝癌发病机制中作用的研究

Wnt/β-catenin信号通路也称Wnt经典信号通路,参与调控细胞分化、癌变、凋亡及机体免疫、应激等多种病理生理过程。有研究表明Wnt信号通路与肝癌(hepatocellular carcinoma,HCC)的发生相关。深入研究Wnt/β-catenin信号通路在肝癌发病中的作用,将有助于进一步揭示肝癌的发病机制,为肝癌的防治提供新的可能途径及干预靶点。     

骨形态发生蛋白和Wnt信号通路在心脏发育及生物起搏中的研究进展

心脏胚胎发育过程由骨形态发生蛋白(BMP)、Wnt、Notch等信号通路共同调控,其中BMP和Wnt信号通路是心脏胚胎发育过程中两条重要的信号通路。BMP通过由转化生长因子-β超家族转导的Smad和TAK1两条信号途径诱导胚胎干细胞向心肌细胞分化。Wnt信号通路对胚胎发育、细胞极性决定、细胞特异性分化、心血管系统发育具有重要的调控作用,在心脏胚胎发育早期促进中胚层的形成,在后期抑制其向心肌细胞分化;但这两条信号通路共同诱导干细胞向心肌细胞分化的效率高于BMP或Wnt信号通路的诱导效率。BMP和Wnt信号通路共同诱导干细胞分化的心肌细胞,不仅为药物实验、心脏疾病研究提供体外模型,而且也为构建生物起搏器提供重要基础。     

Gene expression profile of quiescent and activated rat hepatic stellate cells implicates Wnt signaling pathway in activation

BACKGROUND/AIMS: Liver fibrosis is characterized by accumulation of extracellular matrix proteins synthesized by activated hepatic stellate cells (HSCs). To understand molecular mechanisms of HSCs activation a comprehensive comparison of gene expression between quiescent and activated HSCs is needed. METHODS: Using DNA microarrays we compared expression of 31,100 genes between quiescent rat HSCs and culture activated rat HSCs. Expression of the components of Wnt signaling was analyzed in HSCs and fibrotic livers by RT-PCR. Activation of beta-catenin was analyzed by Western blot. RESULTS: Nine hundred genes were upregulated more than 4.6-fold and 500 genes were downregulated more than 5.7-fold in activated HSCs. The upregulated genes included Wnt receptor frizzled 2, ligands Wnt4 and Wnt5, which was confirmed in fibrotic livers. Expression of the target genes of Wnt signaling was increased from 5- to 70-fold. Phosphorylation and nuclear translocation of beta-catenin were unchanged, indicating activation of the noncanonical Wnt pathway. CONCLUSIONS: Highly upregulated expression of Wnt5a and its receptor frizzled 2 implicates this pathway in differentiation of quiescent HSCs into myofibroblasts. Activation of Wnt signaling pathway in HSCs and in animal models of liver fibrosis has not been described previously, suggesting an important role of Wnt signaling in development of liver fibrosis.     

原发性胆汁性肝硬化的治疗进展

原发性胆汁性肝硬化(PBC)是一种慢性胆汁淤积性疾病。临床上主要表现为乏力、黄疸、皮肤瘙痒、门脉高压、骨质疏松和脂溶性维生素缺乏。多见于中年女性。由于PBC的病因尚未探明,所以还没有统一确切的治疗方案。此文对PBC的治疗进展做一总结。     

The research progress of Wnt/β-catenin signaling pathway in colorectal cancer

The Wnt/β-catenin signaling pathway is highly conservative. β-catenin is the key molecule in this pathway. The β-catenin target genes regulate cell proliferation and apoptosis. Since Wnt pathway proteins are distributed on the cell membrane, cytoplasm, and nucleus, inhibiting or activating these pathway proteins presents a novel target for cancer treatment via the Wnt signaling pathway. Studies have found that this pathway plays a significant role in the formation and progression of cancers, particularly colorectal cancer. We summarised the activation and inhibition of the Wnt signaling pathway in tumors, its relationship with the microenvironment and crosstalk with other pathways, and the effect of targeting abnormal Wnt signaling in the treatment of colorectal cancer. Here is to review future targeted therapeutics in colorectal cancer research and implementation.     

Canonical Wnt signaling negatively regulates platelet function

Wnts regulate important intracellular signaling events, and dysregulation of the Wnt pathway has been linked to human disease. Here, we uncover numerous Wnt canonical effectors in human platelets where Wnts, their receptors, and downstream signaling components have not been previously described. We demonstrate that the Wnt3a ligand inhibits platelet adhesion, activation, dense granule secretion, and aggregation. Wnt3a also altered platelet shape change and inhibited the activation of the small GTPase RhoA. In addition, we found the Wnt-β-catenin signaling pathway to be functional in platelets. Finally, disruption of the Wnt Frizzled 6 receptor in the mouse resulted in a hyperactivatory platelet phenotype and a reduced sensitivity to Wnt3a. Taken together our studies reveal a novel functional role for Wnt signaling in regulating anucleate platelet function and may provide a tractable target for future antiplatelet therapy.     

Uterine Wnt/beta-catenin signaling is required for implantation

Successful implantation relies on precisely orchestrated and reciprocal signaling between the implanting blastocyst and the receptive uterus. We have examined the role of the Wnt/beta-catenin signaling pathway during the process of implantation and demonstrate that this pathway is activated during two distinct stages. Wnt/beta-catenin signaling is first transiently activated in circular smooth muscle forming a banding pattern of activity within the uterus on early day 4. Subsequently, activation is restricted to the luminal epithelium at the prospective site of implantation. Activation at both sites requires the presence of the blastocyst. Furthermore, inhibition of Wnt/beta-catenin signaling interferes with the process of implantation. Our results demonstrate that the Wnt/beta-catenin signaling pathway plays a central role in coordinating uterus-embryo interactions required for implantation.     

Developmental stage-specific biphasic roles of Wnt/beta-catenin signaling in cardiomyogenesis and hematopoiesis

Although Wingless (Wg)/Wnt signaling has been implicated in heart development of multiple organisms, conflicting results have been reported regarding the role of Wnt/beta-catenin pathway in cardiac myogenesis: Wg/armadillo signaling promotes heart development in Drosophila, whereas activation of Wnt/beta-catenin signaling inhibits heart formation in avians and amphibians. Using an in vitro system of mouse ES cell differentiation into cardiomyocytes, we show here that Wnt/beta-catenin signaling exhibits developmental stage-specific, biphasic, and antagonistic effects on cardiomyogenesis and hematopoiesis/vasculogenesis. Activation of the Wnt/beta-catenin pathway in the early phase during embryoid body (EB) formation enhances ES cell differentiation into cardiomyocytes while suppressing the differentiation into hematopoietic and vascular cell lineages. In contrast, activation of Wnt/beta-catenin signaling in the late phase after EB formation inhibits cardiomyocyte differentiation and enhances the expression of hematopoietic/vascular marker genes through suppression of bone morphogenetic protein signaling. Thus, Wnt/beta-catenin signaling exhibits biphasic and antagonistic effects on cardiomyogenesis and hematopoiesis/vasculogenesis, depending on the stage of development.     

The transformation of atrial fibroblasts into myofibroblasts is promoted by trimethylamine N-oxide via the Wnt3a/β-catenin signaling pathway

BackgroundAtrial fibrosis is an important pathophysiological mechanism in the development and maintenance of atrial fibrillation. Trimethylamine N-oxide (TMAO) is one of the most widely studied microbial metabolites involved in the promotion of cardiac fibrosis. TMAO promotes phenotypic transformation, proliferation, and migration and increases collagen secretion in cardiac fibroblasts. The Wnt/β-catenin pathway also plays a key role in the promotion of cardiac fibroblasts into myofibroblasts.MethodsThe expression of Alpha-smooth muscle actin (α-SMA) was determined to identify the formation of myofibroblasts. The effects of TMAO on the proliferation and migration of atrial fibroblasts were detected by cell counting kit 8, and transwell assays, respectively. Western blot and immunofluorescence were used to detect the activation of the β-catenin pathway by TMAO and the phenotypic transformation and collagen secretion of the atrial fibroblasts. Western blot and immunofluorescence assays were performed to detect the effects of exogenous Wnt3a and TMAO on the activation of β-catenin pathway and the phenotypic transformation of atrial fibroblasts.ResultsTMAO promoted the proliferation and migration of atrial fibroblasts. TMAO also promoted the phenotypic transformation, migration, and collagen secretion of the atrial fibroblasts by activating the β-catenin pathway. Exogenous Wnt3a and TMAO synergistically promoted the activation and phenotypic transformation of the β-catenin pathway in atrial fibroblasts.ConclusionsTMAO promotes the transformation of atrial fibroblasts into myofibroblasts by activating Wnt3a/β-catenin signaling pathway.     

Regulation of Avian Leukosis Virus Subgroup J Replication by Wnt/β-Catenin Signaling Pathway

Wnt/β-catenin signaling is a highly conserved pathway related to a variety of biological processes in different cells. The regulation of replication of various viruses by Wnt/β-catenin signaling pathway has been reported. However, the interaction between the Wnt/β-catenin pathway and avian leukosis virus is unknown. In the present study, we investigated the effect of modulating the Wnt/β-catenin pathway during avian leukosis virus subgroup J (ALV-J) infection. The activation of the Wnt/β-catenin pathway by GSK-3 inhibitor increased ALV-J mRNA, viral protein expression, and virus production in CEF cells. This increase was suppressed by iCRT14, one of the specific inhibitors of the Wnt/β-catenin signaling pathway. Moreover, treatment with iCRT14 reduced virus titer and viral gene expression significantly in CEF and LMH cells in a dose-dependent manner. Inhibition Wnt/β-catenin signaling pathway by knockdown of β-catenin reduced virus proliferation in CEF cells also. Collectively, these results suggested that the status of Wnt/β-catenin signaling pathway modulated ALV-J replication. These studies extend our understanding of the role of Wnt/β-catenin signaling pathway in ALV-J replication and make a new contribution to understanding the virus–host interactions of avian leukosis virus.