Notch信号通路和神经内分泌肿瘤

Notch信号通路既简单又复杂,表达于多个物种且高度保守.在不同的细胞类型中,Notch信号通路可促进或抑制细胞增殖、分化和凋亡.Notch信号通路与肿瘤的关系比较复杂,既可以作为癌基因,也可以作为抑癌基因,它的作用与细胞类型有关.在神经内分泌肿瘤(NETs)如类癌、小细胞肺癌(SCLC)和甲状腺髓样癌(MTC)中Notch信号通路失活,若激活Notch信号通路可抑制肿瘤细胞生长、减少NETs标志物,证明Notch信号通路在NETs中发挥肿瘤抑制作用.因此,Notch信号通路激活剂可能会成为NETs患者的一个潜在治疗药物.     

结核分枝杆菌靶向Toll样受体4对免疫细胞功能影响的研究进展

结核分枝杆菌(Mycobacterium tuberculosis,Mtb)与宿主细胞相互作用往往决定结核病的发生及病程发展。结核分枝杆菌及其分泌蛋白与宿主免疫细胞如巨噬细胞、中性粒细胞和树突状细胞等表面广泛表达的Toll样受体4(Toll-like receptor 4, TLR4)结合，相应激活或抑制免疫细胞相关信号通路，影响细胞因子表达、细胞吞噬和抗原呈递等功能，引发炎症或死亡，表现为抗结核免疫或免疫逃逸。本文主要综述了TLR4信号通路在介导结核杆菌调控免疫细胞功能过程中可能发挥的作用，旨在为进一步揭示Mtb致病机制及结核病治疗药物研发提供新思路。     

毒蕈碱胆碱受体与肿瘤关系的研究进展

非神经元性胆碱能信号通路与肿瘤关系密切，许多肿瘤细胞表达胆碱能自分泌环。肿瘤细胞自分泌及旁分泌乙酰胆碱，作用于自身或邻近细胞的烟碱胆碱受体及毒蕈碱胆碱受体，调节肿瘤细胞的增殖、血管发生及凋亡。毒蕈碱胆碱受体是 G 蛋白耦联受体，主要有 M1R-M5R 共5个亚型。研究发现毒蕈碱胆碱受体在肺癌、结肠癌、黑色素瘤、乳腺癌、卵巢癌、前列腺癌、胃癌和脑星形细胞瘤等多种恶性肿瘤中均有表达，与肿瘤细胞的增殖、迁移、血管发生、凋亡有密切关系，其中尤以毒蕈碱胆碱受体3最为重要，这为肿瘤的治疗提供了一个新的研究方向。     

Hedgehog信号通路在肝细胞癌中的作用及其与肿瘤微环境的关系

Hedgehog(Hh)信号通路在肝细胞癌的发生发展和肿瘤微环境中发挥重要作用。Hh信号异常激活可加速肿瘤的生长。Hh信号通路和肿瘤微环境之间的相互串扰与肿瘤的生长和抑制性肿瘤微环境的形成密切相关。有证据表明,抑制Hh信号在抑制肝细胞癌生长中发挥重要作用。本文就Hh信号异常激活在肝细胞癌和肝癌肿瘤微环境中作用及机制的研究现状与潜在的治疗意义作一综述,为肝癌的治疗提供新的思路。     

Wnt/β-catenin通路与消化道肿瘤发生发展的关系

Wnt/β-catenin信号通路是调节胚胎发育及细胞增殖的重要途径之一,其异常激活会影响细胞正常的生长、增殖及迁移,在消化道肿瘤的发生发展中扮演着重要角色。本文对Wnt/β-catenin信号通路在食管癌、胃癌、结直肠癌等发病机制中的影响进行综述,探讨Wnt/β-catenin信号通路与消化道肿瘤发生发展的关系,为消化道肿瘤的靶向治疗提供新的研究思路。     

mTOR信号传导通路及其相关药物与非小细胞肺癌

哺乳动物雷帕霉素靶蛋白(mTOR)处于细胞生长繁殖、细胞周期调控、生物合成、细胞迁移等信号通路调控的中心位置,因此在肿瘤以及肺癌的发生、发展,特别是在治疗和预后中具有重要的作用.mTOR磷酸化激活后,通过调控4EBP和P70S6K两条不同的下游通路,分别控制特定亚组mRNA的翻译,进而影响生物合成.对非小细胞肺癌来讲,mTOR能够加快细胞周期G1-S期的转换,促进细胞增殖.雷帕霉素、西罗莫司、依维莫司等mTOR信号通路的阻断药物在肺癌的治疗中显示出了希望.     

炎症在肝纤维化中的作用

慢性肝损伤引起的炎症反应是肝纤维化发生发展的主要病理因素。在肝纤维化发展的过程中,大量炎症信号被激活,促使肝星状细胞向肌成纤维细胞转化,最终导致肝脏中细胞外基质的大量分泌和沉积,形成瘢痕组织。本文综述了肝星状细胞、Kupffer细胞、炎症小体、炎症信号通路等在肝纤维化过程中的作用,以对临床诊断和治疗提供参考。     

PI3K/Akt通路阻断在恶性肿瘤治疗中的研究进展

在肺癌的发生发展过程中,常伴有PI3K/Akt信号通路的异常活化,过度激活后,可导致一系列反应,包括肿瘤牛长、血管生成、增殖和转移.本文拟就PI3K/Akt信号通路的组成与功能、调节、抗肿瘤细胞凋亡以及治疗等方面的研究进展作一综述,并就其通路的阻断作用在肺癌治疗中的应用作介绍,期待以PI3K/Akt信号通路中关键分子为靶点对肺癌治疗研究提供参考.     

恶性胸腔积液的诊断研究进展

恶性胸腔积液(malignant pleural effusion,MPE)是指细胞病理学证实胸腔积液中有脱落的肿瘤细胞或胸膜组织活检证实存在肿瘤细胞。MPE是由肿瘤直接侵袭胸腔或诱发炎症导致,最常继发于肺癌(尤其是腺癌),其次是乳腺癌,二者所致的MPE占其总数一半以上[1]。第三位是霍奇金淋巴瘤和非霍奇金淋巴瘤,其他病因还包括恶性血液系统肿瘤、胃肠道肿瘤、妇科恶性肿瘤、间皮瘤等[2]。     

Wnt信号通路与消化道肿瘤关系的研究进展

Wnt信号通路对控制胚胎发育起着重要作用,其异常激活参与了人类多种肿瘤的发病过程,与消化道肿瘤有着密切关系.而Wnt信号通路的拮抗剂能阻滞信号转导,抑制Wnt2信号通路的异常激活,可望为将来抗肿瘤治疗提供一条新的途径.     

Platelet secretion in inflammatory and infectious diseases

Platelets are small, anucleate circulating cells that possess a dynamic repertoire of functions spanning the hemostatic, inflammatory, and immune continuum. Once thought to be merely cell fragments with responses limited primarily to acute hemostasis and vascular wall repair, platelets are now increasingly recognized as key sentinels and effector cells regulating host responses to many inflammatory and infectious cues. Platelet granules, including α-granules and dense-granules, store hundreds of factors and secrete these mediators in response to activating signals. The cargo packaged and stored within platelet granules orchestrates communication between platelets and other circulating cells, augments host defense mechanisms to invading pathogens and tumor cells, and – in some settings – drives dysregulated and injurious responses. This focused review will highlight several of the established and emerging mechanisms and roles of platelet secretion in inflammatory and infectious diseases.     

酪氨酸激酶信号级联与支气管哮喘发病的关系

支气管哮喘的发病机制涉及炎症细胞和气道结构细胞、细胞因子、趋化因子、生长因子和炎症介质的相互作用.酪氨酸激酶信号级联在变应性气道炎症中起重要作用,活化的酪氨酸激酶激活了多重下游信号转导途径如磷酯酰肌醇3激酶、丝裂原活化蛋白激酶和核因子κB,导致细胞的分化、存活、增殖、脱颗粒和趋化.     

Virus-mediated modulation of the host endocrine signaling systems: clinical implications.

Viruses, which are among the simplest infective pathogens, can produce characteristic endocrine manifestations in infected patients. In addition to the classic modification of the host endocrine system by either direct or indirect destruction of the endocrine organs and/or effects exerted by systemic production of inflammatory and/or stress mediators, recent progress in molecular virology and endocrinology has revealed that virus-encoded molecules might alter the host endocrine-signaling systems by affecting extracellular and/or intracellular signal transduction and hormone sensitivity of host target tissues. Here, we provide a brief overview of such viral-mediated modulation of host endocrine signaling systems. We propose that virus-encoded molecules and the signaling systems they influence are potential therapeutic targets for the treatment of disorders that are associated with some viral infections.     

Thrombin generation and the pathogenesis of cancer

Advanced cancer is associated with a hypercoagulable state that is triggered by tissue factor (TF). TF-initiated thrombin generation is crucial for metastasis through fibrin and platelet deposition, as well as thrombin-dependent protease-activated receptor (PAR) 1 signaling. Surprisingly, PAR2, which is not cleaved by thrombin, appears to cosignal with PAR1 to elicit thrombin effects in metastatic tumor cells. In contrast to TF-driven thrombin pathways in metastasis, direct TF signaling plays a role in angiogenesis-dependent tumor growth. In TF cytoplasmic-domain-deleted mice, PAR2-dependent angiogenesis and tumor growth is enhanced, demonstrating a role for host cell TF signaling. In tumor cells, TF-factor VIIa (FVIIa) activates PAR2 and thereby regulates proangiogenic growth factor expression as well as integrins involving crosstalk with the TF cytoplasmic domain. In addition to thrombin-PAR signaling in metastasis and TF-FVIIa-PAR2 signaling in tumor growth, it is likely that additional protease pathways will prove to be crucial activators of PARs in cancer. Transmembrane serine proteases as well as matrix metalloproteinase are prime candidates for accessory pathways to regulate metastasis, tumor expansion, and angiogenesis dependent on specific features of the local tumor microenvironment.     

Inflammatory pathways and insulin action

Obesity and type 2 diabetes are associated with a state of abnormal inflammatory response. While this correlation has also been recognized in the clinical setting, its molecular basis and physiological significance are not yet fully understood. Studies in recent years have provided important insights into this curious phenomenon. The state of chronic inflammation typical of obesity and type 2 diabetes occurs at metabolically relevant sites, such as the liver, muscle, and most interestingly, adipose tissues. The biological relevance of the activation of inflammatory pathways became evident upon the demonstration that interference with these pathways improve or alleviate insulin resistance. The abnormal production of tumor necrosis factor alpha (TNF-alpha) in obesity is a paradigm for the metabolic significance of this inflammatory response. When TNF-alpha activity is blocked in obesity, either biochemically or genetically, the result is improved insulin sensitivity. Studies have since focused on the identification of additional inflammatory mediators critical in metabolic control and on understanding the molecular mechanisms by which inflammatory pathways are coupled to metabolic control. Recent years have seen a critical progress in this respect by the identification of several downstream mediators and signaling pathways, which provide the crosstalk between inflammatory and metabolic signaling. These include the discovery of c-Jun N-terminal kinase (JNK) and I kappa beta kinase (I kappa K) as critical regulators of insulin action activated by TNF-alpha and other inflammatory and stress signals, and the identification of potential targets. Here, the role of the JNK pathway in insulin receptor signaling, the impact of blocking this pathway in obesity and the mechanisms underlying JNK-induced insulin resistance will be discussed.     

Bacterial lipopolysaccharide directly induces angiogenesis through TRAF6-mediated activation of NF-kappaB and c-Jun N-terminal kinase

The intracellular pathways by which inflammatory mediators transmit their angiogenic signals is not well studied. The effects of a potent inflammatory mediator, bacterial lipopolysaccharide (LPS), are transmitted through Toll-like receptors (TLRs). A major, although not exclusive, LPS/TLR intracellular signaling pathway is routed through TNF (tumor necrosis factor) receptor associated factor 6 (TRAF6). In this report we demonstrate that LPS directly stimulates endothelial sprouting in vitro. By blocking TRAF6 activity using retroviral expression of a dominant-negative TRAF6 in endothelial cells, we show that TRAF6 is absolutely required for the LPS-initiated angiogenic response in vitro and in vivo. Inhibition of either c-Jun N-terminal kinase (JNK) activity or nuclear factor kappaB (NF-kappaB) activity, downstream of TRAF6, is sufficient to inhibit LPS-induced endothelial sprouting. In contrast, only inhibition of NF-kappaB, but not JNK, activity blocks basic fibroblast growth factor (bFGF)-induced angiogenesis. Our findings thus demonstrate a direct endothelial-stimulatory role of LPS in initiating angiogenesis through activation of TRAF6-dependent signaling pathways.