NF-κB与持久炎症及肿瘤发生关系

NF-κB是一种序列特异性转录因子.早先的研究证明其主要功能是参与炎症反应和天然免疫应答.最近的研究发现,某一部位的持久炎症反应将导致NF-κB信号通路组成性持续激活,导致NF-κB靶基因的异常表达,这些基因的异常表达往往与肿瘤的发生、转移、组织浸润以及肿瘤细胞的抗凋亡作用相关.因此,将NF-κB作为靶向分子,抑制其活性已成为肿瘤防治的研究热点和新的思路.     

大气可吸入颗粒物造成肺损伤的NF-κB研究进展

NF-κB信号通路在大气可吸入颗粒物（PM10）对肺的损伤过程中起到重要的作用,但NF-κB信号通路参与的损伤机理尚不清楚。本文对NF-κB的结构与组成、颗粒物中NF-κB的激活因素、激活过程和抑制剂的相关研究等内容做简要综述。     

NF-κB信号转导途径与肿瘤抗凋亡关系的研究进展

细胞核因子κB(NF—κB)家族及其介导的细胞信号转导通路广泛调控着人类免疫和炎症反应中一系列基因的表达,同时也发现它对肿瘤的发生发展有着重要作用,特别是它可以调控一些细胞凋亡相关基因如TRAF家族、IAPs家族、Bcl-2家族及FLIP基因、p53基因、COX-2基因的转录表达,从而大大提高肿瘤细胞的抗凋亡能力。本文就近年来对NF—κB通路与肿瘤抗凋亡关系的研究进展作一综述。     

痘病毒介导的NF-κB信号通路的调控

痘病毒是人和多种动物痘病的病原体,作为嗜上皮型的DNA病毒,在进化过程中,痘病毒特定的基因产物作用于机体免疫调控系统,调节免疫反应的进程和作用方式,进而完成其感染细胞、复制和繁殖的生物学过程。NF-κB信号通路是机体免疫系统重要的信号转导调节系统,各种痘病毒采用自身特殊的策略作用于这一免疫调节的重要靶系统,应对机体对其免疫清除和免疫反应。对痘病毒介导的宿主免疫调节的深入研究有助于研发新型疫苗和治疗性制剂。本文对近十年来各种痘病毒编码的多种目标蛋白参与宿主NF-κB信号通路调控的分子机制进行综述。     

NF-κB的生物学功能

NF—κB因其广泛参与机体的免疫及其它应激反应而受到人们的关注,其常见的形式是由p50和p65组成的异源二聚体。细胞受到外部因素刺激后,NF-κB由细胞质转移到细胞核中,并发生磷酸化和乙酰化,启动相关基因的表达。目前研究表明受NF-κB调节的基因有200多种,其激活因子不少于150种,所以对NF-κB在各种条件下的激活过程及信号传导网络的研究具有重要的意义。本文综合了当前关于NF—κB研究的最新进展,着重阐述了由TNF-α、IL-Ⅰ及LPS刺激而引起NF—κB激活的信号传导通路,并进一步阐述了其在人类某些疾病当中的生物学功能。     

核因子-κB与炎症

NF-κB是近年来研究较多的一类重要的转录因子,它参与许多与免疫炎症有关的细胞因子、粘附分子的转录调控,在免疫反应、炎症的形成过程中起重要作用.抑制NF-κB的活性,可能有助于炎症的治疗.     

遍在蛋白调节NF-κB信号转导通路的研究进展

NF-κB信号通路参与了多种基因的转录调控和很多重要的生理和病理过程.遍在蛋白在其中的不同的阶段发挥了不同的作用.一方面通过遍在蛋白化IκB,促使其被26S蛋白酶体识别而降解,从而释放出NF-κB进入核内,调控相应基因的表达;另一方面通过遍在蛋白化TRAF6来激活TAK1,然后进一步活化IKK.后一种途径为了解NF-κB信号通路的调控提供了新的线索,并为遍在蛋白功能的研究开辟了新的方向.     

Rel/NF-κB与神经系统疾病

自从 1 986年真核细胞核转录因子Ｒｅｌ/ＮＦ κＢ被发现以来 ,对它的研究就一直方兴未艾。Ｒｅｌ/ＮＦ κＢ参与一系列病理和生理过程反应 ,如免疫反应、炎症反应等 ,在细胞的生长、分化、粘附、凋亡等过程中也具有十分重要的作用。1 .Ｒｅｌ/ＮＦ κＢ信号转导通路在静息状态时 ,Ｒｅｌ/ＮＦ κＢ与抑制蛋白ＩκＢ结合 ,抑制其核转位信号 ,使之以无活性形式存在于胞浆中 ;胞外刺激信号如活性氧介质 (ＲＯＩ)、细胞因子、神经递质、病毒、ＵＶ、内质网超载等通过转导激活ＩＫＫ上游激酶ＭＥＫＫ 1或ＮＩＫ而使ＩＫＫ复合物活化 ,在酪蛋白激…     

NF-κB信号转导通路对细胞周期的调控

核转录因子NF-κB是哺乳动物Rel蛋白家族成员,属DNA结合蛋白,具有结合某些基因启动子κB序列并启动靶基因转录的功能。静息状态下,NF-κB二聚体在胞浆肉没有活性,当细胞受刺激后,它在NF-κB信号转导通路的上游激酶级联作用下被激活,并易位到细胞核内,增强靶基因表达。NF-κB是细胞分裂和生存的关键调节因子,参与调控细胞周期、细胞增殖和细胞分化。现就NF-κB对细胞周期的影响作一综述,着重阐述NF-κB通过细胞周期蛋白和CDK／CKI作用G1/S期检测点、G2/M期检测点,调控细胞周期进程。     

核呼吸因子1调控NF-κB介导LPS诱导的小鼠急性肺损伤

本文旨在研究核呼吸因子1 (nuclear respiratory factor 1, NRF1)对脂多糖(lipopolysaccharide, LPS)诱导的肺上皮细胞炎症应答中关键分子核因子-κB (nuclear factor kappa B, NF-κB)的影响,以阐明NRF1对肺上皮细胞炎性应答的调控作用及机制。在体内水平上,雄性BALB/c小鼠经呼吸道转染NRF1小干扰RNA,LPS (4 mg/kg)或生理盐水经呼吸道雾化给药,48 h后取肺组织。采用免疫印迹(Western blot, WB)及real-time PCR法检测肺组织NRF1、NF-κB p65及其靶基因表达变化,免疫荧光染色法检测NRF1及NF-κB p65核转位情况。体外培养L132肺上皮细胞,转染NRF1小干扰RNA,或给予BAY 11-7082 (5μmol/L)处理24 h后,给予1 mg/L LPS刺激6 h,用real-time PCR法检测NRF1、NF-κB p65及其靶基因表达变化。采用染色质免疫沉淀技术(chromatin immunoprecipitation assay, Ch...     

调控肺部炎症消退的内源性介质

炎症反应是宿主重要防御机制之一。慢性炎症或过度炎症反应可导致严重的肺部疾病,如哮喘、急性呼吸窘迫综合征等。新近研究表明炎症消退是一个主动过程,炎症的及时消退是防止炎症过强及走向慢性化的关键环节。因此,调控炎症消退的内源性介质成为新的研究热点。促进炎症消退内源性介质的发现不仅为肺部疾病研究提供新视野,也为全新的促炎症消退治疗策略防治肺部疾病提供理论依据。     

The role of inflammation and its related microRNAs in breast cancer: A narrative review

Breast cancer is recognized as the most common type of cancer among women with a high rate of mortality all over the world. Over the past years, growing attention has been regarded to realize more about the mechanisms underlying the disease process. It is revealed that the progression of breast cancer may be strongly linked to chronic inflammation owing to the role of inflammatory factors in genetic instability and subsequent cancer predisposition. Although the association between breast cancer and inflammatory pathways has been well-defined now, only recent evidence pointed towards the inflammation-related microRNAs (miRNAs) as potential biomarkers and therapeutic targets involved in the crosstalk of multiple pathways during breast cancer development. Moreover, the practical interactions between these miRNAs and inflammatory factors are also a little characterized. In this review, we intended to describe the effects of predominant inflammatory pathways such as cytokines, phosphoinositide 3-kinase/protein kinase B, and nuclear factor kappa B in association with tumor promoting and tumor suppressing miRNAs on breast cancer progression. Providing new studies in the field of combining biomarkers for early diagnosis, prognosis, and monitoring breast cancer are very important. Notably, understanding the underlying mechanisms of miRNAs as a possible link between inflammation and tumorigenesis may offer a novel insight for combating this epidemic.     

Tumour necrosis factor-alpha- vs. growth factor deprivation-promoted cell death: distinct converging pathways

Perturbations of neuronal physiological homeostasis are likely to underscore neuronal demise/impairments that are reportedly associated with aging of the central nervous system and age-related neurodegenerative diseases such as Alzheimer's disease (AD). A number of age- and/or disease-associated neurotoxic events has been described. These include abnormally modified proteins such as beta amyloid and hyper-phosphorylated Tau, cytokines such as tumour necrosis factor-alpha (TNFalpha), high levels of free radicals conducive to oxidative stress, and impaired/decreased neuronal trophic support by neurotrophic factors. Overall, it could be argued that toxic events in the aged brain are either active, such as those due to a direct action of cytokines, or passive, such as those due to lack of growth factor support. It is therefore conceivable that cellular responses to such diverse toxic stimuli are different, suggesting that interventions should be targeted accordingly. In order to begin answering this question, we determined in PC12 cells the time course of activity, in response to TNFalpha (active) or growth factor withdrawal (passive), of protein kinase c-zeta (PKCzeta), nuclear factor kappa B (NFkappaB), caspases 3 and 8, and poly (ADP-ribose) polymerase (PARP), key signal transduction elements associated with modulation of cell death/survival in PC12 cells. We found that the overall activity of PKCzeta, NFkappaB and caspase 8 was significantly different depending on the apoptotic initiator. The pattern of caspase 3 and PARP activity, however, was not statistically different between serum-free- and TNFalpha-induced cell death conditions. This suggests that two distinct cell responses are elicited that converge at caspase 3, which then induces downstream events involved in the execution of a common apoptotic programme. These results contribute to the aim of differentially targeting neuronal death in the aged brain (characterized by neurotrophic factor impairments) or in the diseased brain (e.g. AD, characterized by elevated levels of pro-inflammatory cytokines).     

Increased expression of basic fibroblast growth factor in hyperoxic-injured mouse lung

Basic fibroblast growth factor (bFGF) is a mitogenic polypeptide for a wide variety of cell types and has been immunolocalized in the rodent and human lung. We investigated the mRNA and protein expression of bFGF in hyperoxic-injured adult mouse lungs using northern blot analysis and immunohistochemistry. Mece (6–8weeks) were continuously exposed to 80% osygen up to 4 days. Levels of bFGF mRNA were increased from room air control on days 3 and 4 of hyperoxia. mRNA levels of acidic fibroblast growth factor (aFGF), fibronectin, and transin/stromelysin were also examined in this injury model. Similar to bFGF, the fibronectin and transin/stromelysin mRNA levels were increased after 3 days of hyperoxia. In contrast, the aFGF mRNA levels were gradually reduced on each day of hyperoxia. A rabbit polyclonal anti-bFGF antibody was used to determine the distribution and levels of expression in the hyperoxic-injured lungs. The room air control and day 1 hyperoxic-exposed lungs exhibited staining for bFGF in the basement membranes of the blood vessels, airways, and alveoli. Patchy but intense alveolar staining was prominent on day 4 of hyperoxia. The bFGF immunoreactivity of blood vessels and airways unaffected by the hyperoxia exposure. These results suggest that bFGF may play a role in the alveolar response to hyperoxic-induced injury by virtye of the altered mRNA levels and protein distribution in this injury model.     

Distinct roles for IκB kinases alpha and beta in regulating pulmonary endothelial angiogenic function during late lung development

Pulmonary angiogenesis is essential for alveolarization, the final stage of lung development that markedly increases gas exchange surface area. We recently demonstrated that activation of the nuclear factor kappa‐B (NFκB) pathway promotes pulmonary angiogenesis during alveolarization. However, the mechanisms activating NFκB in the pulmonary endothelium, and its downstream targets are not known. In this study, we sought to delineate the specific roles for the NFκB activating kinases, IKKα and IKKβ, in promoting developmental pulmonary angiogenesis. Microarray analysis of primary pulmonary endothelial cells (PECs) after silencing IKKα or IKKβ demonstrated that the 2 kinases regulate unique panels of genes, with few shared targets. Although silencing IKKα induced mild impairments in angiogenic function, silencing IKKβ induced more severe angiogenic defects and decreased vascular cell adhesion molecule expression, an IKKβ regulated target essential for both PEC adhesion and migration. Taken together, these data show that IKKα and IKKβ regulate unique genes in PEC, resulting in differential effects on angiogenesis upon inhibition, and identify IKKβ as the predominant regulator of pulmonary angiogenesis during alveolarization. These data suggest that therapeutic strategies to specifically enhance IKKβ activity in the pulmonary endothelium may hold promise to enhance lung growth in diseases marked by altered alveolarization.     

Identification of a wound-induced inhibitor of a nuclear factor that binds the carrot extensin gene

Following wounding of carrot (Daucus carota L.) roots, the activity of a nuclear factor (EGBF-1) that binds a 5′-region of the carrot extensin gene declines to undetectable levels within 48 h. Mixing of nuclear extracts from wounded roots with nuclear extracts from unwounded roots has demonstrated the existence of a wound-induced inhibitor of EGBF-1. Inhibition of EGBF-1 DNA-binding activity by nuclear extracts from wounded roots is shown to be specific for EGBF-1, and to be destroyed by heat treatment. In addition, inhibition is saturable and occurs rapidly. Active EGBF-1 can be reconstituted from its inhibited state by renaturation of proteins from mixed extracts following denaturation by boiling in sodium dodecyl sulfate and 2-mercaptoethanol, and electrophoretic separation, indicating that inhibition is dependent upon the reversible interaction of EGBF-1 with a titratable factor. However, EGBF-1 activity could not be detected in nuclear extracts from wounded roots following denaturation and electrophoretic separation. Inhibitory activity was not detectable in nuclear extracts from roots that had been trated with ethylene. The action of the inhibitor indicates one possible mechanism for the control of EGBF-1 activity in carrot roots following wounding.