糖尿病肾病与炎症致病作用及治疗研究进展

糖尿病肾病（diabetic nephropathy,DN）是糖尿病的重要微血管病变之一,其发病虽与高血糖明确相关,但仍有研究显示严格控制血糖以及应用血管紧张素转换酶抑制剂或血管紧张素Ⅱ受体拮抗剂等药物仅能部分延缓DN进展,绝大部分患者最终缓慢进展至终末期肾衰竭,新的发病机制亟待探索。最近研究揭示炎症机制是DN发生发展的关键因素,本文就DN与炎症发病机制,致病作用及治疗的研究进展作相关阐述。     

鞘氨醇激酶信号通路

近年来,从信号传导通路水平对疾病发病机制进行阐述逐渐成为研究的热点,随着各条信号通路及其成员在疾病中的作用不断被阐明,从分子水平治疗疾病将会成为临床治疗的一个新方向。多项研究表明,鞘氨醇激酶(Sph K)信号通路是一条攸关细胞存亡的信号途径,在调节细胞增殖与凋亡、诱导迁移、调节炎症、血管形成以及肿瘤代谢等过程中起着重要作用。本文就Sph K信号通路与肾病、肿瘤及炎症性疾病发生发展之间的关系作一简单综述。     

miR-181在动脉粥样硬化相关血管炎症和免疫调节中的研究进展

动脉粥样硬化(atherosclerosis,As)是病变从内膜开始的一种慢性炎症性疾病,主要累及全身大中动脉,是危害人类健康的主要疾病之一。近年来,研究发现微小核糖核酸(microRNAs,miRNAs)参与As的发生、发展。其中,miR-181家族通过调控血管炎症和免疫相关的信号通路在As发生、发展中起着重要作用,如调控下游NF-κB信号通路、内皮细胞激活相关靶点的表达和免疫细胞稳态等。该文就近年来miR-181在As相关炎症和免疫反应的研究进展作一综述。     

叔丁基对苯二酚对早期糖尿病小鼠肾脏氧化应激损伤影响的实验研究

糖尿病肾病(DN)发病机制复杂,是多种因素综合作用的结果,氧化应激在DN发病中起重要作用.研究表明,抗氧化剂可以延缓DN的发生发展[1-2].近年发现,NF-E2相关因子-抗氧化反应元件(Nrf2-ARE)信号通路相互作用调节编码抗氧化蛋白,是细胞抗氧化反应的中枢调节者[3].而叔丁基对苯二酚(tBHQ)是Nrf2的激活剂,γ-谷氨酰半胱氨酸合成酶(γ-GCS)是受Nrf2-ARE信号通路转录调节的抗氧化蛋白之一.     

同一患者中甲状腺良性瘤与癌组织DNA甲基化差异基因的炎症相关信号通路分析

目的:研究同一患者体内甲状腺良性瘤与癌组织在DNA甲基化方面的差异,从而揭示DNA甲基化在肿瘤发生发展中的重要作用。方法:使用基因甲基化芯片技术对同一患者的并发甲状腺癌、甲状腺良性瘤组织样本的基因组甲基化水平进行检测,对筛选出的差异化显著的基因进行生物信息学分析得到功能基因的信号通路,并针对与甲状腺癌明显相关的信号通路进行分析讨论。结果:甲状腺的良性瘤与癌在DNA甲基化水平上存在显著差异;参与恶性肿瘤相关的信号通路包括T细胞受体的信号通路,Jak-STAT信号通路与细胞因子-细胞因子受体相互作用信号通路等炎症相关信号通路。结论:研究得出炎症的相关生物信息学通路与甲状腺肿瘤的发生发展密切相关,为甲状腺恶性肿瘤的发生发展机制的阐明与潜在药物靶点的选择提供新的思路与方向。     

基于生物信息学分析早期糖尿病肾病发病机制

目的 利用生物信息学筛选分析早期糖尿病肾病的差异基因表达,探讨糖尿病肾病发病机制并为其提供新的分子治疗靶点。方法 通过GEO数据库获取数据集GSE142025行生物信息学分析,筛选早期糖尿病肾病组（e DN组）相对对照组（NC组）差异表达基因。GSEA分析差异表达基因的富集通路,通过蛋白质相互网络（PPI）分析鉴定HUB基因。采用免疫组化和RT-qPCR检测目标基因在肾组织中的相对表达水平。结果 以P <0.05和|log2FC|> 1为标准,筛选得到eDN组有1 859个差异表达基因,其中有1 063个上调,有796个下调。GSEA行差异基因的KEGG通路富集显示eDN组在“JAK-STAT通路”、“细胞因子受体通路”、“趋化因子信号通路”、“细胞黏附分子通路”、“细胞外基质受体相互作用通路”等显著上调。CCR2作为HUB基因在eDN组中表达显著上调;免疫组化及RT-qPCR结果显示一致,e DN组中CCR2相对表达水平明显高于NC组（均P <0.05）。结论 KEGG分析功能富集主要显示炎症通路激活,而CCR2在早期糖尿病肾病的肾组织中表达显著上调,提示其可能在早...     

老年糖尿病肾病患者肠道菌群失调的研究进展

近年来,随着生活习惯的改变及人口老龄化进程的加快,我国老年糖尿病患者数量逐渐增多.在老年糖尿病患者中,糖尿病肾病(diabetic nephropathy,DN)的发病率极高,已经成为严重影响老年患者生活质量的主要问题之一.然而,DN的发病机制尚不清楚,有研究发现慢性炎症反应在DN的发生、发展中发挥着重要作用,而肠道菌...     

JAK/STAT通路在肾脏疾病发病中的作用

JAK/STAT信号通路是一类重要的细胞因子信号传导通路,广泛参与细胞的增生、分化、凋亡及炎症反应,在多种肾脏疾病中具有调控作用。该通路可通过调节JAK、STAT家族因子的表达,参与梗阻性肾病、糖尿病肾病、急性肾损伤等疾病的发生发展,抑制该信号通路有助于延缓疾病的进展。本文主要就JAK/STAT信号通路在肾脏疾病发病中的研究进展进行综述。     

TLR4与糖尿病肾病的研究进展

糖尿病肾病(diabetic nephropathy,DN)的发病机制尚不明确,近年来大量研究表明,Toll样受体4(Toll-like receptor4,TLR4)与DN密切相关。TLR4通过髓样分化因子88(myeloid differentiation factor88,MyD88)依赖性和非依赖性等途径激活下游信号分子,引发一系列的炎症反应,最终导致DN的发生与发展。     

载脂蛋白M-1-磷酸鞘氨醇轴与炎症相关疾病

载脂蛋白M-1-磷酸鞘氨醇轴(apo M-S1P轴)是一条由apo M、S1P和S1P受体信号通路构成的信号轴。apo M不仅是血浆S1P的主要载体,而且可通过调节血浆S1P水平而影响S1P受体相关信号通路。S1P受体信号通路对炎症反应的调节作用已较明确,近期研究表明,apo M与炎症相关疾病也密切相关。因此,apo M-S1P轴被认为对炎症相关疾病具有潜在的重要影响。     

GLP-1类似物利拉鲁肽对糖尿病肾病的影响进展

糖尿病肾病（DN）是糖尿病患者严重的微血管并发症,是引发终末期肾脏病的常见病因。DN的发病机制复杂,目前对DN的治疗尚无突破性进展。近年来出现的胰高血糖素样肽-1（GLP-1）作为一种新型降糖药不仅在降糖方面有优势,而且能影响DN的发生发展。GLP-1类似物利拉鲁肽通过抑制内质网应激、调节内皮细胞生长因子、延缓足细胞损伤、抑制炎症及氧化应激、调节自噬对肾脏起到保护作用,该文就相关研究进行综述,以期为DN治疗方案的选择提供新的思路。     

IRF4通过JAK/STAT信号通路调控糖尿病肾病炎症进展

目的 筛选分析糖尿病肾病（DN）的差异表达基因（DEG）,探讨IFN调节因子4(IRF4)在DN中的作用机制,为DN治疗寻找潜在的分子靶点。方法 经基因表达综合（GEO）数据库下载GSE142025数据集[包含对照组9例与进展期DN(aDN)组21例],进行DEG筛选,行基因集富集分析（GSEA）示DEG参与的分子生物学过程。使用String及Cytoscape软件可视化DEG蛋白质相互作用网络,定量逆转录PCR(RT-qPCR)和过碘酸-希夫（PAS）染色及链霉菌抗生物素蛋白-过氧化物酶（SP）染色并进一步验证主要DEG在6例DN肾组织（DN组）和6例肿瘤切除术后癌旁正常肾组织（NC组）中的表达。结果 GEO数据库筛选出1213个差异表达mRNA,其中684个上调、529个下调。GSEA及京都基因和基因组百科全书分析显示aDN组DEG在酪氨酸激酶/信号转导及转录激活因子信号通路、趋化因子信号通路、Fcγ受体介导巨噬细胞的吞噬作用信号通路、白细胞跨内皮迁移、T细胞受体信号通路明显富集。DN组肾组织中IRF4、信号淋巴细胞活化分子6和IL-2受体α亚基mRNA相对表达量均高于NC组肾组织...     

Adiponectin as an anti-inflammatory factor

Obesity is characterized by low-grade systemic inflammation. Adiponectin is an adipose tissue-derived hormone, which is downregulated in obesity. Adiponectin displays protective actions on the development of various obesity-linked diseases. Several clinical studies demonstrate the inverse relationship between plasma adiponectin levels and several inflammatory markers including C-reactive protein. Adiponectin attenuates inflammatory responses to multiple stimuli by modulating signaling pathways in a variety of cell types. The anti-inflammatory properties of adiponectin may be a major component of its beneficial effects on cardiovascular and metabolic disorders including atherosclerosis and insulin resistance. In this review, we focus on the role of adiponectin in regulation of inflammatory response and discuss its potential as an anti-inflammatory marker.     

Prophylactic and therapeutic implications of toll-like receptor ligands

The evolutionary conserved Toll-like receptors (TLRs) are the first identified and best characterized pattern recognition receptors (PRRs) which discriminate self from nonself, providing an early and effective immune response against invading pathogens. The ever expanding knowledge of TLR signaling network make it one of the most promising therapeutic strategies to modulate the immune response in various human diseases. Immune modulating strategies based on TLR-specific agonists elicit a potent immune response to adjuvant vaccine immunotherapy, cancers, allergic diseases, and chronic viral infections while minimizing the risk of uncontrolled provocation of systemic inflammatory response. Moreover, the contribution of TLR signaling in the pathogenesis of chronic noninfectious inflammatory and autoimmune diseases provides the rationale for the development and clinical implementation of TLR-specific antagonists. At present, a few TLR-specific agonists have been approved for both prophylactic and therapeutic applications, while the ongoing preclinical and clinical studies show promising results on various novel therapeutic molecules as an adjunctive to conventional pharmacotherapy or stand-alone therapeutic strategy.     

Protein kinase C beta inhibitors: a new therapeutic target for diabetic nephropathy and vascular complications

Diabetic nephropathy (DN) has emerged as the major causative pathology in patients entering end-stage renal disease (ESRD) worldwide and it is responsible for 30–40% of all ESRD cases. Treatments for DN are centered on control of hyperglycemia and blood pressure control. However, current therapeutic regimens have not yet provided satisfactory prevention from the onset of DN. Protein kinase C (PKC) is an intracellular signaling molecule and activation of it plays an important role in the development of diabetic complications. In numerous experimental and clinical studies, inhibition of PKC (LY333531) has been shown to delay/halt the progression of diabetic complications. Presently, the drug is submitted in USA-FDA for new drug application in moderate to severe diabetic retinopathy. This review selectively discusses the role of PKC in DN and therapeutic effects produced by PKC inhibitors in DN. The role of PKC inhibitor in other diabetic complications is also discussed.     

Modulation of experimental autoimmune encephalomyelitis through TRAF3-mediated suppression of interleukin 17 receptor signaling

Interleukin 17 (IL-17) plays critical roles in the pathogenesis of various autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE). How the signals triggered by this powerful inflammatory cytokine are controlled to avoid abnormal inflammatory responses is not well understood. In this study, we report that TRAF3 is a receptor proximal negative regulator of IL-17 receptor (IL-17R) signaling. TRAF3 greatly suppressed IL-17-induced NF-κB and mitogen-activated protein kinase activation and subsequent production of inflammatory cytokines and chemokines. Mechanistically, the binding of TRAF3 to IL-17R interfered with the formation of the receptor signaling activation complex IL-17R-Act1-TRAF6, resulting in suppression of downstream signaling. TRAF3 markedly inhibited IL-17-induced expression of inflammatory cytokine and chemokine genes in vivo and consequently delayed the onset and greatly reduced the incidence and severity of EAE. Thus, TRAF3 is a negative regulator of IL-17R proximal signaling.     

铁蛋白与糖尿病肾病早期微炎症状态的关系

【目的】探讨铁蛋白与糖尿病肾病（Diabetic nephropathy ,DN）早期微炎症状态的关系。【方法】本院门诊及住院的2型糖尿病（Type 2 Diabetes Mellitus ,T2DM）患者120例,分为正常白蛋白尿组、早期DN组、临床DN组,各40例,以同期健康体检正常40例为对照组。检测4组对象的血清铁蛋白（SF）及炎症因子高敏反应蛋白（hs-CRP）、肿瘤坏死因子（TNF-α）、白介素-6（IL-6）水平。【结果】与健康对照组比较,SF水平、炎症因子指标明显升高（P＜0．01）;随着DN 的进展,SF及炎症因子的水平相应升高,DN 各组间差异有统计学意义（P＜0．05）;DN患者SF升高与炎症因子的水平呈正相关（r＞0．1,P＜0．01）。【结论】体内铁负荷过重即过高的SF参与了早期DN患者机体的微炎症状态,诱导机体炎症因子水平的升高,从而参与了DN的发生和发展过程。     

Differential synergy of Notch and T cell receptor signaling determines alphabeta versus gammadelta lineage fate

Thymic precursors expressing the pre-T cell receptor (TCR), the gammadeltaTCR, or the alphabetaTCR can all enter the CD4+ 8+ alphabeta lineage, albeit with different efficacy. Here it is shown that proliferation and differentiation of precursors with the different TCRs into alphabeta lineage cells require Notch signaling at the DN3 stage of thymic development. At the DN4 stage, Notch signaling still significantly contributes to the generation of alphabeta T cells. In particular, in alphabeta lineage commitment, the pre-TCR synergizes more efficiently with Notch signals than the other two TCRs, whereas gammadeltaTCR-expressing cells can survive and expand in the absence of Notch signals, even though Notch signaling enhances their proliferation. These observations suggest a new model of alphabeta versus gammadelta lineage choice in which lineage fate is determined by the extent of synergy between TCR and Notch signaling and in which the evolutionarily recent advent of the cell-autonomously signaling pre-TCR increased the efficacy of alphabeta T cell generation.     

Defined alphabeta T cell receptors with distinct ligand specificities do not require those ligands to signal double negative thymocyte differentiation

During T cell development in the thymus, pre-T cell receptor (TCR) complexes signal CD4(-) CD8(-) (double negative [DN]) thymocytes to differentiate into CD4(+) CD8(+) (double positive [DP]) thymocytes, and they generate such signals without apparent ligand engagements. Although ligand-independent signaling is unusual and might be unique to the pre-TCR, it is possible that other TCR complexes such as alphabeta TCR or alphagamma TCR might also be able to signal the DN to DP transition in the absence of ligand engagement if they were expressed on DN thymocytes. Although alphagamma TCR complexes efficiently signal DN thymocyte differentiation, it is not yet certain if alphabeta TCR complexes are also capable of signaling DN thymocyte differentiation, nor is it certain if such signaling is dependent upon ligand engagement. This study has addressed these questions by expressing defined alphabeta TCR transgenes in recombination activating gene 2(-/-) pre-Talpha(-/-) double deficient mice. In such double deficient mice, the only antigen receptors that can be expressed are those encoded by the alphabeta TCR transgenes. In this way, this study definitively demonstrates that alphabeta TCR can in fact signal the DN to DP transition. In addition, this study demonstrates that transgenic alphabeta TCRs signal the DN to DP transition even in the absence of their specific MHC-peptide ligands.     

Coagulation and inflammation. Molecular insights and diagnostic implications

Overwhelming evidence has linked inflammatory disorders to a hypercoagulable state. In fact, thromboembolic complications are among the leading causes of disability and death in many acute and chronic inflammatory diseases. Despite this clinical knowledge, coagulation and immunity were long regarded as separate entities. Recent studies have unveiled molecular underpinnings of the intimate interconnection between both systems. The studies have clearly shown that distinct pro-inflammatory stimuli also activate the clotting cascade and that coagulation in turn modulates inflammatory signaling pathways. In this review, we use evidence from sepsis and inflammatory bowel diseases as a paradigm for acute and chronic inflammatory states in general and rise hypotheses how a systematic molecular understanding of the "inflammation-coagulation" crosstalk may result in novel diagnostic and therapeutic strategies that target the inflammation-induced hypercoagulable state.