BAFF/BAFF-R通过PI3K/Akt/mTOR信号转导通路调节B淋巴细胞功能在类风湿关节炎发病机制中的意义

B淋巴细胞活化和生存在类风湿关节炎(RA)病程中起关键作用。肿瘤坏死因子家族B细胞活化因子(BAFF)是维持B细胞功能的重要细胞因子。BAFF与其受体BAFF-R结合(BAFF/BAFF-R),能够激活PI3K/Akt/mTOR信号通路,调节B淋巴细胞的增殖、存活和活化。该文就B淋巴细胞、BAFF/BAFF-R以及PI3K/Akt/mTOR信号通路参与RA的发病机制加以综述。     

AS炎性信号通路与中医药干预

动脉粥样硬化(atherosclerosis,AS)是血管内皮损伤导致的慢性炎症反应性血管疾病,该文就AS炎性信号通路相关因子,如细胞间黏附分子-1(ICAM-1)、血管细胞黏附分子-1(VCAM-1)、核因子-κB(NF-κB)和过氧化物酶体增殖物激活受体γ(PPARγ),以及中医药在抗AS中调节这些炎性信号通路方面研究进展做一综述。     

基于网络药理学和分子对接探讨复方风湿宁片治疗类风湿关节炎的作用机制

目的 采用网络药理学联合分子对接技术探讨复方风湿宁片治疗类风湿性关节炎的作用机制。方法 通过TCMSP、BATMAN-TCM、Swiss TargetPrediction数据库及文献报道收集复方风湿宁片的活性化学成分靶点,并使用GeneCards数据库检索类风湿关节炎的疾病靶点,将两者取交集,并通过绘制“复方风湿宁片–活性成分–靶点–通路–类风湿关节炎”网络图。对复方风湿宁片中的活性成分与类风湿关节炎靶点进行分子对接。结果 通过网络药理学分析得到复方风湿宁片中有34种活性化学成分,对应1059个靶点,与类风湿关节炎靶点交集356个。通过KEGG富集分析发现复方风湿宁片主要可能在肿瘤坏死因子（TNF）信号通路、白细胞介素-17(IL-17)信号通路、Th17细胞分化、T细胞受体信号通路、Toll样受体（TLR）信号通路、核因子κB(NF-κB)信号通路、Th1和Th2细胞分化、Janus激酶（JAK）-信号传导和转录激活蛋白3(STAT3)信号通路、B细胞受体信号通路和类风湿性关节炎等通路上发挥治疗作用。蛋白激酶B(Akt1)、前列腺素内过氧化物酶2(PTGS2)、丝裂原活化蛋白激酶1(...     

弥漫性大B细胞淋巴瘤常见致病信号通路及其靶向药物的研究进展

弥漫性大B细胞淋巴瘤是亚洲人最常见的淋巴肿瘤亚型,经过R-CHOP方案治疗后仍有相当一部分患者表现为难治或复发。弥漫性大B细胞淋巴瘤的常见致病信号通路有B细胞受体、Toll样受体4/髓样分子因子88/核因子-κB、磷脂酰肌醇3-激酶/蛋白激酶B信号通路,靶向药物包括Bruton酪氨酸激酶抑制剂、来那度胺、硼替佐米、凋亡蛋白抑制剂抑制剂、磷脂酰肌醇3-激酶抑制剂、蛋白激酶B抑制剂、哺乳动物雷帕霉素靶蛋白抑制剂。阐述了弥漫性大B细胞淋巴瘤中常见致病信号通路及其遗传学改变,并总结了相关通路常见的靶向药物的研究进展。     

中药单体成分及复方促进骨折愈合的作用机制研究进展

中药在治疗骨折愈合过程中具有多成分、多途径、多靶点的作用特点,对于具有复杂病理机制的骨折具有较好的治疗优势和潜力。笔者对中药单体成分及复方促进骨折愈合的作用机制进行了归纳,发现内脂素A、葛根素等可通过激活丝裂原活化蛋白激酶（MAPK）信号通路,续骨丹、固本增骨方等可通过激活骨形态发生蛋白（BMP）信号通路,黄芩苷、牛膝多糖等可通过激活Wnt/β-catenin信号通路,芹菜素、三七皂苷等可通过激活核因子κB(NF-κB)受体激活蛋白/NF-κB受体激活蛋白配体/护骨因子（RANK/RANKL/OPG）信号通路,活血接骨复方胶囊、健骨颗粒等可通过抑制磷脂酰肌醇3-激酶/蛋白激酶B(PI3K/AKT)信号通路,淫羊藿苷等可通过激活Notch信号通路,桃红四物汤、藏红花素等可通过激活Hippo信号通路,酸枣仁皂苷A、蛇床子素等可通过抑制NF-κB信号通路,发挥促进骨折愈合的作用。     

B淋巴细胞刺激因子参与类风湿性关节炎的发病机制及其靶向治疗药物研究进展

目的:为研究B淋巴细胞刺激因子(BLyS)参与类风湿性关节炎(RA)的发病机制及其靶向治疗药物提供文献支持。方法:综述了BLyS的生物学特性、参与RA的发病机制以及靶向于BLyS治疗RA的新药研究等方面的内容。结果:BLyS是一种Ⅱ型跨膜蛋白,由285个氨基酸组成,其作为肿瘤坏死因子家族的新成员,对B淋巴细胞的增殖活化起重要调节作用;BLyS的过表达与RA等自身免疫病的发病机制和疾病进程关系密切;以BLyS为靶点的治疗RA的药物(Belimumab、BR3-Fc、TACI-Ig)经临床试验证实取得了良好的治疗效果。结论:BLyS参与了RA等自身免疫病的发病机制,是具有高度特异性的新靶点,故研制BLyS拮抗药将成为RA等自身免疫病高效且安全的免疫治疗方法。     

穿心莲内酯促进骨折骨愈合作用机制的研究进展

骨折后的愈合状态直接影响患者的生活质量,如何提高骨折患者骨愈合效果是亟待解决的问题。穿心莲内酯是穿心莲中主要活性成分,可能通过促进成骨细胞增殖,抑制核因子κB（NF-κB）信号通路激活,激活Wnt/β-连环蛋白（Wnt/β-catenin）信号通路,调节护骨素/细胞核因子κB受体活化因子配基（OPG/RANKL）信号通路,调节成骨基因表达产物,改善软骨细胞功能,抑制雌激素相关受体α（ERRα）信号通路等多途径促使骨愈合。总结了穿心莲内酯促进骨折骨愈合作用及其作用机制,希望为穿心莲内酯的临床使用提供依据。     

青藤碱治疗痛风性关节炎的药理研究进展

青藤碱是从药材青风藤的根和茎分离出的生物碱类有效活性成分,青风藤和青藤碱均广泛用于痛风性关节炎等炎性关节炎的治疗。本文主要阐述近年来青藤碱发挥抗炎镇痛药理作用的机制,青藤碱通过调控环氧合酶2(COX-2)的表达抑制炎症因子的分泌、调控核苷酸结合寡聚结构域样受体蛋白3(NALP3)的表达抑制促炎因子的分泌、调控Toll样受体（TLR）/抑制核转录因子（NF-κB）信号通路抑制炎症反应以及调控丝裂原活化蛋白激酶（MAPK）信号通路抑制炎症因子的表达和抑制炎症反应等多种途径发挥抗炎药理作用,通过调控钙-钙调蛋白依赖性蛋白激酶2α(CaMK2α)-酸敏感离子通道3(ASIC3)-NLRP3信号通路、p38 MAPK信号通路及非受体酪氨酸激酶2(JAK2)/信号转导子和转录激活子3(STAT3)信号通路发挥镇痛药理作用。本文就近年青藤碱治疗痛风性关节炎的药理研究进行综述,以期为青藤碱治疗痛风性关节炎的作用机制研究和临床应用提供参考。     

TGR5受体介导的信号转导通路的研究进展

GPCBAR1也称作TGR5受体,是GPCRs家族成员之一。TGR5受体在人类和动物体内广泛的表达,是一种位于细胞膜的模式识别受体,在抗炎免疫调节、能量代谢、葡萄糖代谢、抗癌等方面都具有十分重要的作用。配体一旦激活TGR5受体,介导一系列信号通路,从而发挥不同的生物学效应。本文就AKT信号通路、NF-κB信号通路、ERK信号通路、STAT3信号通路、cAMP信号通路、TGR5受体介导信号通路的研究方法与研究成果,以及TGR5受体介导信号转导通路研究与新药开发展开综述。     

肿瘤坏死因子受体相关因子6在NF-κB炎症通路中的研究进展

肿瘤坏死因子受体相关因子6(tumor necrosis factor receptor-associated factor,TRAF6)既可与肿瘤坏死因子受体(TNFR)超家族结合,又可与白细胞介素-1受体/Toll样受体(IL-1R/TLR)超家族相互作用来传递胞外信号的一种胞内接头蛋白,在炎症反应、免疫应答、骨代谢中发挥着重要作用.文章就TRAF6的蛋白结构、核因子-κB炎症通路以及与炎症疾病和临床应用等方面进行综述.     

Co-Delivery of Autoantigen and B7 Pathway Modulators Suppresses Experimental Autoimmune Encephalomyelitis

Autoimmune diseases such as multiple sclerosis (MS) are characterized by the breakdown of immune tolerance to autoantigens. Targeting surface receptors on immune cells offers a unique strategy for reprogramming immune responses in autoimmune diseases. The B7 signaling pathway was targeted using adaptations of soluble antigen array (SAgA) technology achieved by covalently linking B7-binding peptides and disease causing autoantigen (proteolipid peptide (PLP)) to hyaluronic acid (HA). We hypothesized that co-delivery of a B7-binding peptide and autoantigen would suppress experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Three independent B7-targeted SAgAs were created containing peptides to either inhibit or potentially stimulate the B7 signaling pathway. Surprisingly, all SAgAs were found to suppress EAE disease symptoms. Altered cytokine expression was observed in primary splenocytes isolated from SAgA-treated mice, indicating that SAgAs with different B7-binding peptides may suppress EAE through different immunological mechanisms. This antigen-specific immunotherapy using SAgAs can successfully suppress EAE through co-delivery of autoantigen and peptides targeting with the B7 signaling pathway.     

CD160/HVEM/BTLA/LIGHT通路在自身免疫病中的研究进展

共信号分子是免疫细胞表面信号传递分子及其配体，对调控T细胞或B细胞的活化有重要作用。近年来，研究显示多种共信号分子对T细胞的激活与免疫平衡有重要调控作用，这些分子的异常表达可以引起T细胞的过度激活并引发自身免疫病。CD160/HVEM/BTLA/LIGHT通路是近年来共信号分子领域的研究热点，该信号通路在免疫调节中起重要的作用，其功能异常或异常表达与自身免疫病的发生密切相关。本文对该通路在自身免疫病中的研究进展做一简要综述。     

TLR9 as a key receptor for the recognition of DNA

Unmethylated DNA with CpG-motifs is recognized by Toll-like receptor 9 (TLR9) and pleiotropic immune responses are elicited. Macrophages and conventional dendritic cells (cDCs) produce proinflammatory cytokines to B/K-type CpG-DNA, whereas plasmacytoid DCs induce type I interferons to A/D-type CpG-DNA and DNA viruses. The TLR9 mediated signaling pathway is not only responsible for activation of innate immune cells, but also for mounting acquired responses. Thus, it has been attempted to exploit TLR9 ligands as a vaccine adjuvant for anti-cancer immunotherapy. Further, TLR9 mediated signaling is implicated in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus. Nevertheless, recent studies revealed that double-stranded DNA can be recognized by intracellular receptor(s) in a TLR9-independent manner. This review will focus on the roles of TLR9 in immune responses, and its signaling pathways.     

PI3K/AKT/mTOR信号通路参与自身免疫性

自身免疫性疾病（autoimmune disease，AD）是机体因自身抗原免疫耐受障碍而对自身抗原产生免疫反应，从而引起机体组织损伤的一类疾病。近年研究发现，磷脂酰肌醇-3-激酶/蛋白激酶B/雷帕霉素靶蛋白（phosphatidylin ositol 3-kinase/protein kinase B/mechanistic target of rapamycin kinase，PI3K/AKT/mTOR）信号通路与AD发病密切相关，其主要参与免疫细胞增殖分化、炎性细胞因子分泌、自噬及氧化应激等过程。本文重点概述PI3K/AKT/mTOR信号通路参与AD发病机理的研究进展。     

Protein kinase A (PKA)--a potential target for therapeutic intervention of dysfunctional immune cells

In several cases of immunodeficiency and autoimmunity, the dysfunctional immune system is associated with either hypo- or hyperactive T and B cells. In autoimmune conditions such as systemic lupus erythematosus (SLE) and immunodeficiencies such as acquired immunodeficiency syndrome (AIDS), it has been demonstrated that the regulatory effect of the signaling pathway of cyclic 3', 5' adenosine monophosphate (cAMP) and cAMP-dependent protein kinase (PKA) is abrogated. PKA is well-known as a key regulator of immune responses in that it inhibits both early and late phases of antigen induced T and B cell activation. Here we will discuss a potential useful strategy for therapeutic interventions of dysfunctional T cells associated with SLE and HIV by modulation of the cAMP-PKA pathway. Therefore, we will describe the components and architecture of the cAMP-PKA signaling pathway in T cells in order to point out one or several steps which potentially may serve as targets for therapeutic intervention.     

Low expression of RGL4 is associated with a poor prognosis and immune infiltration in lung adenocarcinoma patients

Lung adenocarcinoma (LUAD) is a frequently diagnosed histologic subtype with increasing morbidity and mortality. RalGDS-Like 4 (RGL4) has not been reported to be associated with cancer risk, prognosis, immunotherapy or any other treatments. We perform a bioinformatics analysis on data downloaded from the Cancer Genome Atlas (TCGA)-LUAD, and we find that low expression of RGL4 is accompanied by worse outcomes and prognosis in LUAD patients. As a promising predictor, the potential influence and mechanisms of RGL4 on overall survival are worth exploring. Moreover, RGL4 expression is significantly associated with a variety of tumor-infiltrating immune cells (TIICs), particularly memory B cells, CD8⁺T cells and neutrophils. Subsequently, we evaluated the most notable KEGG pathways, including glycolysis gluconeogenesis, the P53 signaling pathway, RNA degradation, and the B cell receptor signaling pathway, among others. Our findings provide evidence that the decreased expression of RGL4 is significantly associated with poor prognosis and immune cell infiltration in patients with LUAD and highlight the use of RGL4 as a novel predictive biomarker for the prognosis of LUAD and other cancers. RGL4 may also be used in combination with immune checkpoints to identify the benefits of immunotherapy.Subjects: Bioinformatics, Genomics, Oncology, Thoracic surgery.     

Alpha-lipoic acid inhibits TNF-alpha induced NF-kappa B activation through blocking of MEKK1-MKK4-IKK signaling cascades

The therapeutic effects of alpha-lipoic acid (alpha-LA) via NF-kappa B down regulation were demonstrated on joint inflammation and erosion in an animal model. In this study, we investigated how alpha-LA inhibits the pathway of NF-kappa B activation by TNF-alpha via the mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis (RA) fibroblast-like synovial cells (FLS). FLS were stimulated with TNF-alpha following pre-treatment with or without alpha-LA. Electrophoretic mobility shift assays (EMSA) revealed that TNF-alpha activates NF-kappa B in FLS. This was inhibited by alpha-LA at concentrations of 1 mM. TNF-alpha induced IKK mediated phosphorylation of GST-I kappa B and pre-treatment with alpha-LA inhibited this pathway. FLS constitutively express MEKK1, MEKK2, MEKK3, and TAK1 and that their levels are unaffected by TNF-alpha or alpha-LA. Immunoprecipitation using anti-MEKK1 antibody phosphorylated GST-I kappa B and pre-treating the cells with alpha-LA could abolish the reaction. FLS were immunoprecipitated using an antibody to MEKK1, and MKK4 was coprecipitated with MEKK1. In addition, immune complexes precipitated with anti-MKK4 antibody phosphorylated GST-I kappa B, and pre-treatment with alpha-LA inhibited the phosphorylation. Immunoprecipitation assay showed that MEKK1, MKK4, IKK-alpha, IKK-beta, I kappa B, and NF-kappa B comprised immunocomplex. It can be concluded that TNF-alpha activates NF-kappa B in FLS through MEKK1-MKK4-IKK signaling complex, and alpha-LA inhibits this signaling at the level of or upstream of IKK-alpha and IKK-beta.     

The regulation of CD4+ T cell immune responses toward Th2 cell development by prostaglandin E2

As an important immune mediator, PGE2 plays an important role in the immune tolerance, autoimmune diseases, immune regulation and tumor immunotolerance. PGE2 is considered to be a promising candidate for the control of the immune diseases. To further understand the immuno-modulating effects of PGE2 on CD4+ T cells, in vitro investigation was conducted in the present study. The results showed that PGE2 inhibited the proliferation of T cells in vitro in a dose-dependent manner. Gene expression profiling showed that 1716 genes were down regulated and 73 genes were up regulated with a change of 1.5 fold. Several signal transduction pathways were involved, such as TNF-α and NF-kB signaling pathway, T cell receptor signaling pathway, IL-2 signaling pathway, and MAPK pathway. The results showed that PGE2 inhibited IFN-γ, TNF-α and IL-4 production by CD4+ T cells 24 h after cell culture. A comparison between IFN-γ and IL-4 production showed that PGE2 enhanced the relative ratio of IL-4 to IFN-γ in CD4+ T cells culture, and regulated CD4+ T cells toward Th2 cell development. The results of the present study indicated that PGE2 has the potential to treat Th1-mediated inflammatory diseases by regulating CD4+ T cells toward Th2 cell immune response.     

靶向程序性死亡分子1信号通路的单克隆抗体的研究进展

程序性死亡分子1 (programmed death-1,PD-1),1种T细胞表面的免疫抑制分子,可与程序性死亡配体1 (programmed death ligand-1,PD-L1)组成信号通路.PD-1/PD-L1信号通路可抑制T细胞活化,并对肿瘤免疫逃逸起关键作用.靶向PD-1信号通路的单克隆抗体包括抗PD-1和PD-L1抗体,它们通过阻断PD-1与PD-L1的相互作用来增强机体内源性抗肿瘤免疫效应,在临床试验中,该类单克隆抗体在各类肿瘤患者中表现出令人惊喜的疗效,成为一类有希望的肿瘤免疫治疗药物.此文就靶向PD-1信号通路的单克隆抗体的生物学功能及其临床应用等方面的研究进展做一综述.     

Notch信号通路调控Treg/Th17细胞机制的研究进展

摘要： Notch家族是多细胞生物发育过程中一类高度保守的、 十分重要的跨膜信号蛋白, 通过与相邻细胞之间的相互作用, 在细胞增殖、 分化、 凋亡中发挥着关键作用。调节性T细胞 （Treg） 及辅助性T细胞17 （Th17） 是目前发现的一类新型CD4+ T细胞亚群, 在生理状态下, 两者可通过分泌多种细胞因子来调节机体免疫的平衡。近年来, 越来越多的研究发现Notch信号通路通过调控Treg、 Th17细胞参与机体多种疾病的发生。本文就Notch信号通路在血液系统疾病、 自身免疫系统疾病等疾病中对Treg/Th17细胞调控机制的研究进展作一简要综述。