噻唑烷二酮通过Wnt通路改善2型糖尿病大鼠海马阿尔茨海默病样病变

目的:2型糖尿病(T2DM)是阿尔茨海默病(AD)发病的重要风险因子。本研究运用噻唑烷二酮类药物(TZD)对T2DM大鼠进行干预,检测W nt途径在用药前后变化,探讨TZD降低T2DM大鼠AD发生风险的可能机制。方法:造T2DM大鼠模型,TZD分别灌胃2周(TZD2W)及4周(TZD4W)。葡萄糖氧化酶法检测血浆葡萄糖水平,放免法检测血浆胰岛素水平,免疫印迹技术检测大鼠海马tau蛋白、tau蛋白上部分磷酸化位点及β淀粉样蛋白(Aβ)前体APP水平,W nt途径中β-联蛋白(β-caten in)和糖原合成激酶3β(GSK-3β)水平,及TZD作用物PPARγ水平。免疫组化技术检测各组大鼠海马Aβ沉积程度。结果:T2DM组及TZD2W组血糖、胰岛素水平及胰岛素抵抗程度显著高于对照组,TZD4W组虽胰岛素水平仍显著高于对照组,但血糖及胰岛素抵抗程度已明显下降,与对照组比较无显著差别。T2DM组大鼠海马tau蛋白上位点Ser199/202、Ser422磷酸化程度及Aβ前体APP水平均显著高于对照组,经TZD干预后,tau蛋白上上述位点磷酸化程度逐渐下降,Aβ沉积逐渐减少;T2DM组大鼠大脑PPAR-γ水平与对照组比较无差异,但运用TZD后,PPAR-γ水平显著升高;T2DM组大鼠大脑W nt途径中β-caten in水平下降,GSK-3β活性升高,运用TZD干预2周和4周大鼠大脑β-caten in水平显著升高,GSK-3β活性显著下降。结论:TZD干预可降低T2DM时AD发病风险。TZD通过上调W nt通路改善2型糖尿病大鼠海马AD样病变。该作用先于胰岛素信号转导通路。     

Wnt/β-catenin通路与NF-κB通路互相调控在创面愈合中的作用

正Wnt/β-catenin信号通路和核因子κB(nuclear factor kappa B,NF-κB)信号通路都是相对保守的信号通路,贯穿哺乳类动物的一生并可以调节很多生物学进程。研究显示,Wnt/β-catenin通路与NF-κB通路之间存在交互作用,且共同参与多方面的调控。创面愈合是一个复杂而有序的过程,是涉及炎性细胞、细胞外基质和细胞因子等多种因素的级联反应。     

β-链蛋白在Wnt信号转导途径中的作用

Wnt/ β-链蛋白通路参与调控胚胎正常发育和细胞增殖与分化等重要生理过程。正常组织细胞中 ,该信号通路的上下游调节分子 Axin、APC、GSK3β等通过自稳调节方式 ,使胞浆内 β-链蛋白保持低浓度状态。多种肿瘤细胞有 β-链蛋白的异常活化 ,目前出现了几种针对异常活化的 Wnt信号通路的新型抗肿瘤基因治疗措施     

T细胞因子-4及其剪接异构体与肿瘤

T细胞因子(TCF-4)是W nt信号转导通路中的核内信号分子,胞质区的β-连接素入核与之结合,可激活W nt转导通路靶基因的转录,影响一系列基因的表达,在多种胚胎的发育及肿瘤演进的过程中,起重要的作用。TCF-4在转录过程中发生选择性剪接,形成多种mRNA剪接异构体,其剪接主要发生在羧基末端,形成长短不等的开放阅读框架,进而对下游基因产生多种转录调节机制,并对W nt信号在各系统肿瘤中的作用进行调控。TCF-4及其剪接异构体的过度表达和异常调控与肿瘤的发生发展密切相关。     

Wnt/β-catenin信号转导途径与宫颈癌

信号转导通路异常在肿瘤发生、发展过程中发挥着作用,其中Wnt/β-catenin信号转导通路在调控细胞的生长和分化、胚胎发育及肿瘤的发生发展起重要作用.Wnt/β-catenin信号转导通路异常与宫颈癌的发病机制密切相关.     

Wnt/β-catenin信号通路调控哮喘气道重塑的机制研究

目的:探讨Wnt/β-catenin信号通路调控哮喘气道平滑肌细胞(ASMC)的功能和参与哮喘气道重塑的机制。方法:建立大鼠哮喘模型,提取大鼠ASMC。Western blot法检测哮喘组和正常组大鼠ASMC中β-连环蛋白(β-catenin)、糖原合成酶激酶-3β(GSK-3β)、原癌基因c-Myc和细胞周期蛋白D1(cyclin D1)的蛋白表达。抑制哮喘组和对照组ASMC中β-catenin和转录辅助因子p300/CBP间的相互作用后,采用CCK-8法和流式细胞术检测ASMC的细胞活力和周期变化。抑制P38丝裂原活化蛋白激酶(MAPK)活性后,采用Western blot法检测c-Myc和cyclin D1的蛋白表达变化。结果:Western blot法显示哮喘组ASMC中β-catenin、c-Myc和cyclin D1的蛋白表达水平均明显高于对照组(P0.05),同时GSK-3β的蛋白表达水平则低于对照组(P0.05)。抑制β-catenin和p300/CBP间相互作用后,哮喘组ASMC的细胞活力下降幅度和细胞周期改变程度均较对照组更为明显(P0.05)。抑制P38 MAPK活性后,哮喘模型大鼠及对照大鼠ASMC中Wnt/β-catenin信号通路的靶蛋白c-Myc和cyclin D1的表达均下调,差异有统计学意义(P0.05)。结论:Wnt/β-catenin信号通路可能通过上调c-Myc和cyclin D1的表达、与P38 MAPK信号通路相互作用以及调控ASMC的生长和分化等途径,影响ASMC的功能,参与哮喘气道重塑。     

Wnt/β-catenin信号通路与肝脏的发育及异常分化

Wnt/β-catenin信号通路在人类生物学的各个方面都发挥着重要作用,该通路在肝脏生物学中的作用也备受关注。Wnt/β-catenin信号通路在肝脏的生长、发育、再生、代谢等方面发挥重要作用,该通路也参与各种肝脏疾病进程,提示Wnt/β-catenin信号通路的正常调控是控制和影响肝脏生命活动的关键,其异常激活与肝脏的病理及肿瘤发生密切相关。本文对该通路与肝脏发育分化及疾病的关系研究作一综述。     

Wnt信号通路与胸腺发育

胸腺是人体重要的中枢淋巴器官,是T淋巴细胞分化发育的场所。起源于骨髓的淋巴细胞祖细胞,在胸腺中历经阳性选择和阴性选择后发育为成熟的T细胞,然后通过血液循环参与外周细胞免疫。研究表明,Wnt信号通路广泛存在于胸腺上皮细胞和T细胞,它不但影响胸腺上皮细胞的形态、功能,而且对于维持T细胞前体细胞和后期T细胞的分化发育都很重要。最近研究发现,Wnt信号通路参与了胸腺增龄性萎缩过程的调节,Wnt信号通路的改变可引起上皮网络结构的改变,最终导致胸腺微环境的破坏。因此,研究Wnt信号通路在胸腺发育中的作用,对于探索胸腺增龄性萎缩的调控机制和改善老年人的健康状况有重要意义。     

经典Wnt信号通路对细胞成骨分化的调控作用

Wnt信号通路是参与体内多种器官发育和组织新陈代谢的保守性通路,可分为经典和非经典Wnt信号通路.其中,经典Wnt信号通路通过调节下游的成骨相关转录因子调控细胞成骨分化、骨基质形成和矿化,且在细胞分化的不同阶段发挥不同的调控作用.此外,经典Wnt信号通路还调控牙周组织干细胞成骨分化,该作用受外界微环境的影响.加深对经典Wnt信号通路的认识有助于治疗相关的骨疾病.     

长链非编码RNA及其在下咽鳞状细胞癌发生发展中的作用机制

目的 总结长链非编码RNA(LncRNA)在肿瘤发生、发展中的调控机制,以及LncRNA在下咽鳞状细胞癌(HSCC)发生、发展中的作用。方法 在中国知网、万方数据、PubMed、谷歌学术、EMBASE等数据库上,以“长链非编码RNA,下咽癌/下咽鳞状细胞癌” “β-连环蛋白,下咽癌/下咽鳞状细胞癌”“ LncRNA, tumor ” “ LncRNA, Hypopharyngeal carcinoma/ HSCC ”“Wnt/β-catenin ,EMT”“Wnt/β-catenin or/and EMT,Hypopharyngeal carcinoma/HSCC”等为关键词,检索2000年1月—2018年5月国内外针对LncRNA及其在HSCC发生发展中作用机制进行研究的有关文献资料,共检索到文献3 297篇,最终纳入44篇文献,其中中文文献2篇、英文文献42篇。总结LncRNA对肿瘤调控机制的研究进展,并对 LncRNA和Wnt通路在HSCC发生发展中的作用机制进行重点分析。结果 LncRNA广泛参与DNA损伤修复和细胞凋亡等生理或病理过程,在生物调节过程中扮演着重要角色;Wnt信号通路是重要的细胞信号转导通路,在细胞的增殖、分化中发挥重要的作用。LncRNAs与mRNA结合促进了HSCC的发生发展,LncRNA通过Wnt信号通路促进HSCC的转移及复发。结论 LncRNA与许多肿瘤等多种疾病的发生密切相关;HSCC的发生发展受LncRNA的调控,LncRNA通过Wnt信号通路在HSCC肿瘤细胞的生长、迁移、侵袭中发挥重要作用。     

Lrp4: A novel modulator of extracellular signaling in craniofacial organogenesis

The low-density lipoprotein (LDL) receptor family is a large evolutionarily conserved group of transmembrane proteins. It has been shown that LDL receptor family members can also function as direct signal transducers or modulators for a broad range of cellular signaling pathways. We have identified a novel mode of signaling pathway integration/coordination that occurs outside cells during development that involves an LDL receptor family member. Physical interaction between an extracellular protein (Wise) that binds BMP ligands and an Lrp receptor (Lrp4) that modulates Wnt signaling, acts to link these two pathways. Mutations in either Wise or Lrp4 in mice produce multiple, but identical abnormalities in tooth development that are linked to alterations in BMP and Wnt signaling. Teeth, in common with many other organs, develop by a series of epithelial-mesenchymal interactions, orchestrated by multiple cell signaling pathways. In tooth development, Lrp4 is expressed exclusively in epithelial cells and Wise mainly in mesenchymal cells. Our hypothesis, based on the mutant phenotypes, cell signaling activity changes and biochemical interactions between Wise and Lrp4 proteins, is that Wise and Lrp4 together act as an extracellular mechanism of coordinating BMP and Wnt signaling activities in epithelial-mesenchymal cell communication during development.     

Non-canonical Wnt signaling pathways in hematopoiesis

Hematopoietic stem cells (HSCs) are a rare population of cells that are responsible for life-long generation of blood cells of all lineages. In order to maintain their numbers, HSCs must establish a balance between the opposing cell fates of self-renewal and initiation of hematopoietic differentiation. Multiple signaling pathways have been implicated in the regulation of HSC cell fate. One such set of pathways are those activated by the Wnt family of ligands. The function of the canonical Wnt signaling pathway, which utilizes β-catenin to regulate gene expression, has been extensively studied in hematopoiesis. However, there is a growing body of evidence that the other Wnt signaling pathways, termed non-canonical, also play an important role. In this review, we will discuss the regulation of hematopoiesis by the Wnt signaling pathways, focusing on the potential functions of non-canonical Wnt signaling pathways.     

Wnt signaling and human diseases: what are the therapeutic implications?

Wnt signaling plays an important role in regulating cell proliferation and differentiation. De-regulation of these signaling pathways has been implicated in many human diseases, ranging from cancers to skeletal disorders. Wnt proteins are a large family of secreted factors that bind to the Frizzled receptors and LRP5/6 co-receptors and initiate complex signaling cascades. Over the past two decades, our understanding of Wnt signaling has been significantly improved due to the identification of many key regulators and mediators of these pathways. Given that Wnt signaling is tightly regulated at multiple cellular levels, these pathways themselves offer ample nodal points for targeted therapeutics. Here, we focus on our current understanding of these pathways, the associations of Wnt signaling with human disorders, and the opportunities to target key components of Wnt signaling for rational drug discovery.     

Blocking Dishevelled signaling in the noncanonical Wnt pathway in sea urchins disrupts endoderm formation and spiculogenesis,but not secondary mesoderm formation

Dishevelled (Dsh) is a phosphoprotein key to beta‐catenin dependent (canonical) and beta‐catenin independent (noncanonical) Wnt signaling. Whereas canonical Wnt signaling has been intensively studied in sea urchin development, little is known about other Wnt pathways. To examine roles of these beta‐catenin independent pathways in embryogenesis, we used Dsh‐DEP, a deletion construct blocking planar cell polarity (PCP) and Wnt/Ca²⁺ signaling. Embryos overexpressing Dsh‐DEP failed to gastrulate or undergo skeletogenesis, but produced pigment cells. Although early mesodermal gene expression was largely unperturbed, embryos exhibited reduced expression of genes regulating endoderm specification and differentiation. Overexpressing activated beta‐catenin failed to rescue Dsh‐DEP embryos, indicating that Dsh‐DEP blocks endoderm formation downstream of initial canonical Wnt signaling. Because Dsh‐DEP‐like constructs block PCP signaling in other metazoans, and disrupting RhoA or Fz 5/8 in echinoids blocks subsets of the Dsh‐DEP phenotypes, our data suggest that noncanonical Wnt signaling is crucial for sea urchin endoderm formation and skeletogenesis. Developmental Dynamics 238:1649–1665, 2009. © 2009 Wiley‐Liss, Inc.     

Wnt signaling: Role in LTP,neural networks and memory

Wnt components are key regulators of a variety of developmental processes, including embryonic patterning, cell specification, and cell polarity. The Wnt signaling pathway participates in the development of the central nervous system and growing evidence indicates that Wnts also regulates the function of the adult nervous system. In fact, most of the key components including Wnts and Frizzled receptors are expressed in the adult brain. Wnt ligands have been implicated in the regulation of synaptic assembly as well as in neurotransmission and synaptic plasticity. Deregulation of Wnt signaling has been associated with several pathologies, and more recently has been related to neurodegenerative diseases and to mental and mood disorders. In this review, we focus our attention on the Wnt signaling cascade in postnatal life and we review in detail the presence of Wnt signaling components in pre- and postsynaptic regions. Due to the important role of Wnt proteins in wiring neural circuits, we discuss recent findings about the role of Wnt pathways both in basal spontaneous activities as well as in activity-dependent processes that underlie synaptic plasticity. Finally, we review the role of Wnt in vivo and we finish with the most recent data in literature that involves the effect of components of the Wnt signaling pathway in neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling, as well as the data that support a neuroprotective role of Wnt proteins in relation to the pathogenesis of Alzheimer's disease.     

Wnt signaling pathway and lung disease

The Wnt pathway plays an important role in development and in regulating adult stem cell systems. A variety of cellular processes is mediated by Wnt signaling, which includes cellular proliferation, differentiation, survival, apoptosis, and cell motility. Loss of regulation of these pathways can lead to tumorigenesis, and the Wnt pathway has been implicated in the development of several types of cancers, including colon, lung, leukemia, breast, thyroid, and prostate. The Wnt pathway has also been associated with other lung diseases such as interstitial lung disease (ILD) and asthma. Our increasing understanding of the Wnt pathway offers great hope that new molecular-based screening tests and pharmaceutical agents that selectively target this pathway will be developed to diagnose and treat these diseases in the future.     

Regulation of dendritic cell differentiation and function by Notch and Wnt pathways

Summary: The process of dendritic cell differentiation is governed by a tightly controlled signaling network regulated by cytokines and direct interaction between progenitor cells and bone marrow stroma. Notch signaling represents one of the major pathways activated during direct interaction between hematopoietic progenitor cells and bone marrow stroma. Wnt pathway is activated by soluble proteins produced by bone marrow stroma. Until recently, the role of Notch and Wnt signaling in the development of myeloid cells and dendritic cells in particular remained unclear. In this review, we discuss recent exciting findings that shed light on the critical role of Notch and Wnt pathways, their interaction in differentiation and function of dendritic cells, and their impact on immune responses.     

Wnt Signaling and the Control of Human Stem Cell Fate

Wnt signaling determines major developmental processes in the embryonic state and regulates maintenance, self-renewal and differentiation of adult mammalian tissue stem cells. Both β-catenin dependent and independent Wnt pathways exist, and both affect stem cell fate in developing and adult tissues. In this review, we debate the response to Wnt signal activation in embryonic stem cells and human, adult stem cells of mesenchymal, hematopoetic, intestinal, gastric, epidermal, mammary and neural lineages, and discuss the need for Wnt signaling in these cell types. Due to the vital actions of Wnt signaling in developmental and maintenance processes, deregulation of the pathway can culminate into a broad spectrum of developmental and genetic diseases, including cancer. The way in which Wnt signals can feed tumors and maintain cancer stem stells is discussed as well. Manipulation of Wnt signals both in vivo and in vitro thus carries potential for therapeutic approaches such as tissue engineering for regenerative medicine and anti-cancer treatment. Although many questions remain regarding the complete Wnt signal cell-type specific response and interplay of Wnt signaling with pathways such as BMP, Hedgehog and Notch, we hereby provide an overview of current knowledge on Wnt signaling and its control over human stem cell fate.