MAPKs信号转导在类风湿性关节炎滑膜细胞中作用

丝裂原活化蛋白激酶(mitogen-actived protein kinase,MAPK)是真核生物信号传递网络中的重要途径之一,在基因表达调控和细胞质功能活动中发挥关键作用。在哺乳动物机体中,5种不同的MAPK信号转导通路中ERK1/2信号转导通路调控细胞生长和分化,JNK和p38MAPK信号转导通路在炎症与细胞凋亡等应激反应中发挥重要作用。信号转导途径的活化是类风湿性关节炎(rheumatoid arthritis,RA)慢性滑膜炎的典型特征,通过这一途径诱导滑膜细胞胞质蛋白磷酸化,使转录因子和核蛋白如c-Fos、c-Jun、AP-1和NF-κB等磷酸化,从而促进细胞增殖和活化。上述机制研究对于RA发病机制的深入了解以及研制开发治疗RA的新型药物具有重要的意义。     

细胞因子在类风湿关节炎发病机制中作用的研究进展

类风湿关节炎（rheumatoid arthritis,RA）是一种病因尚未明确的以滑膜慢性炎症为主的自身免疫性疾病,近年研究发现,细胞因子网络失衡在RA的发病和进展中发挥着重要作用,该病的加重或好转依赖于炎性细胞冈子和调节性细胞因子之间的动态变化。其中TNF-α、IL-1、IL-17、IL-33等在RA滑膜病变中起核心作用,而IL-4、IL-10、TGF-β等细胞因子却可以起到减轻关节损伤的作用。本文将从致炎细胞因子、抑炎细胞因子与RA之间的关系来阐述RA的发病机制。     

类风湿性关节炎临床治疗方案的研究进展

类风湿性关节炎(RA)是一种临床上常见的全身性自身免疫性疾病,患者临床表现主要为对称性、涉及多个关节、慢性的关节疾病和滑膜关节炎,其发病相关因素主要涉及遗传、滑膜中T细胞、B细胞及细胞因子等免疫细胞等,但具体机制现仍不完全明确。目前,RA的临床治疗效果尚不理想,主要的治疗方法为常规药物、中医中药、外科手术及新技术疗法等。     

MAPKs信号转导在类风湿关节炎滑膜细胞中作用及其药物的影响

MAPKs信号转导途径的活化是RA慢性滑膜炎的典型特征,通过这一途径诱导滑膜细胞胞浆蛋白磷酸化,进而使转录因子和核蛋白如cfos、cjun、AP1和NFκB等磷酸化,从而促进细胞增殖和活化。上述机制研究对于RA发病机制的深入了解以及研制开发治疗类风湿关节炎的新型药物具有重要的意义。     

类风湿关节炎滑膜细胞信号转导机制研究进展

滑膜细胞因子IL 1、TNF α、EGF、TGF β、PDGF、IGF 1在RA发病过程中可活化细胞内两条重要的信号通路 :受体蛋白酪氨酸蛋白激酶 Ras MAPK途径和非受体蛋白酪氨酸蛋白激酶 JAK STAT途径 ,其中受体蛋白酪氨酸蛋白激酶 Ras MAPKs信号转导路径异常是RA慢性滑膜炎的典型特征。研究G蛋白 AC cAMP信号转导通路及该通路与酶偶联受体 Ras MAPKs信号转导通路间的交互联系将具有十分重要的意义。     

细胞因子与类风湿关节炎

以细胞因子为作用靶点的治疗措施是当前的研究热点。类风湿关节炎(rheumatoid arthritis，RA)的临床表现为局部关节疼痛、功能障碍等，具体表现为慢性滑膜炎、滑膜增生和纤维化。在RA炎症局部细胞因子相互作用的网络中，白细胞介素-1(IL-1)和肿瘤坏死因子(TNF)处于中心位置，近期还发现IL-17也参与了滑膜细胞的增生和诱导基质金属蛋白酶的产生，从而加重关节软骨的破坏。本文就部分与RA相关的主要细胞因子的研究现状做一简单综述。     

类风湿关节炎分子靶向治疗新药的研究进展

类风湿关节炎(RA)是一种自身免疫性疾病,发病率和致残率高。随着对RA发病机制研究的深入,RA分子靶向治疗药物相继出现。本文综述近年来以细胞因子、免疫细胞以及信号转导过程中各种酶为靶点的分子药物研究。     

苯甲酰乌头原碱在类风湿关节炎中作用的进展

类风湿关节炎(RA)是一种进行性、反复发作的慢性自身免疫性疾病,病理特征主要为滑膜增生、血管翳形成及软骨破坏,具有较高的致残和致死率,但发病机制至今仍不明确。苯甲酰乌头原碱(BAC)为单酯型生物碱,主要存在于制川乌、草乌和附子等中药中,具有抗炎镇痛功效,并参与RA疾病的信号转导过程,BAC可以有效调节RA患者血清中的细胞因子IL-1β、TNF-α和VEGF,且对滑膜中Nrf2,HO-1和NQO1的表达有显著上调作用。本文从BAC的结构与功能、参与RA炎症信号调节研究进展方面对BAC与RA的调控及其治疗前景进行综述,以期为进一步促进其临床应用提供依据。     

IL-17在类风湿关节炎中的研究进展

类风湿关节炎(RA)是一种自身免疫性疾病,主要表现为关节滑膜的慢性炎症,软骨和骨的破坏。白细胞介素-17(IL-17)是新近发现的白介素成员,是Th17细胞分泌的主要细胞因子,研究发现其在RA中有异常升高,可能参与了RA的滑膜炎症、软骨和骨的破坏,在RA的发病和病情进展中有重要作用。干预IL-17成为治疗RA新的研究方向,近年来IL-17靶向治疗药物、传统抗风湿药、中医中药对IL-17的相关研究也取得了一定成果。该文主要就IL-17在RA发病及针对IL-17治疗RA的相关研究进展简单综述如下。     

成纤维样滑膜细胞原代培养及其在类风湿关节炎治疗机制研究中的应用进展

目的:综述成纤维样滑膜细胞(FLS)及其在类风湿关节炎(RA)药效作用机制研究中的应用进展。方法:以"成纤维样滑膜细胞""类风湿关节炎""中药单体""滑膜细胞""Arthritis""Fibroblast-like synoviocytes"为关键词,组合检索2006年1月-2015年10月在Pub Med、中国知网、维普等数据库中对FLS原代培养及其在RA治疗机制研究中的应用文献进行总结和归纳。结果:共查阅到相关文献68篇,其中有效文献32篇。FLS原代培养成功率较高,培养方法多样且日趋完善,在RA的治疗机制研究中得到了广泛的应用;同时,中药及化学合成药、激酶抑制剂等可通过NF-κB、Akt等信号通路抑制炎症因子或相关蛋白基因从而达到治疗RA的目的。结论:FLS体外试验在RA相关研究中得到广泛的应用,治疗药物如中药及化学合成药、激酶抑制剂通过细胞分子水平研究在信号通路的介导下都对RA有治疗作用。     

Emerging drugs for rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic, autoimmune disease characterized by symmetric arthritis of diarhthrodial joints leading to progressive erosion of cartilage and bone. The individual and social impacts of RA are of great importance. Objective: To investigate the development of new therapies for RA treatment. Methods: Various databases have been searched for new drugs in clinical trials (Phase I – III) and experimental future therapeutic agents for RA. Results/conclusion: The current management of the disease includes the use of disease modifying anti-rheumatic drugs and the biologic therapies. Progress in our understanding of RA pathophysiology led to the identification of new therapeutic targets. These include pro-inflammatory cytokines, T and B cells, adhesion molecules, chemokines and intra- and extracellular signaling pathways. Therapeutic modulation of the above targets can provide new treatment strategies. This article reviews a few of the new treatment strategies currently being evaluated.     

G protein coupled receptors signaling pathways implicate in inflammatory and immune response of rheumatoid arthritis

G protein coupled receptors(GPCRs)are transmembrane receptor proteins,which allow signals to transfer across membrane.GPCRs include a large number of receptors,different receptors mediated different signaling pathways of GPCRs-adenylyl cyclase(AC)-cyclic adenosine 3',5'-monophosphate(c AMP),including β2 adrenergic receptors(β2-ARs)-AC-c AMP signaling pathways,E-prostanoid2/4(EP2/4)-AC-cA MP signaling pathways.Regulatory proteins,such as G protein coupled receptor kinases(GRKs)andβ-arrestins,play important modulatory roles in GPCRs signaling pathway.GPCRs signaling pathway and regulatory proteins implicate the pathogenesis process of inflammatory and immune response.Rheumatoid arthritis(RA)is an autoimmune disease characterized by synovitis and accompanied with inflammatory and abnormal immune response.This article review the advances on GPCRs signaling pathway implicating in the inflammatory and immune response of RA.     

生物制剂对类风湿性关节炎患者血脂水平影响的研究进展

加速的动脉粥样硬化在类风湿性关节炎(Rheumatoid arthritis,RA)患者的心血管疾病中起关键作用,导致RA患者比一般人群死亡率更高。血脂的异常和炎性细胞因子的增加可能是这些患者在动脉粥样硬化过程早期出现内皮功能障碍的主要原因,生物制剂已问世多年,是治疗RA的关键性药物,但其对RA患者血脂的影响还存在争议,本文归纳了常见生物制剂对RA患者脂质谱的影响,提示临床医生应更加关注RA患者的血脂管理。     

Cytokines as therapeutic targets to reduce cardiovascular risk in chronic inflammation

Patients with chronic inflammatory diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus, psoriasis and Crohn's disease have an increased atherosclerotic risk which cannot be explained by traditional cardiovascular risk factors alone. Inflammatory pathways are implicated in this increased vascular risk. The involvement of cytokine-related signaling pathways in inflammatory diseases has prompted the development of many therapeutic strategies aimed at their modulation to limit disease severity and progression. Whether modulation of these pathways would similarly alter the inflammatory processes related to accelerated atherosclerosis remains unknown. In this review we will focus on the role of pro-inflammatory cytokines and their inhibitors in RA, and whether they may be causal in the accelerated atherosclerosis seen in these patients.     

Rheumatoid arthritis: developing pharmacological therapies

Rheumatoid arthritis (RA) is a chronic inflammatory disease that, despite recent advances in therapy, still results in significant morbidity, mortality and disability. The aetiology remains unknown and past therapies, although helpful for the majority of patients, have been suboptimal. The recent introduction of newer agents has changed the treatment paradigm of RA. COX-2 inhibitors, anti-TNF agents and interleukin-1 antagonists have allowed us to treat RA more effectively with relatively low risk of side effects. Investigations of other possible treatment pathways, such as inhibition of angiogenesis, may produce still better treatment and rapid unraveling of the immune system and how it relates to RA greatly enhances the opportunities for improved therapeutics in RA.     

Rheumatoid arthritis: developing pharmacological therapies

Rheumatoid arthritis (RA) is a chronic inflammatory disease that, despite recent advances in therapy, still results in significant morbidity, mortality and disability. The aetiology remains unknown and past therapies, although helpful for the majority of patients, have been suboptimal. The recent introduction of newer agents has changed the treatment paradigm of RA. COX-2 inhibitors, anti-TNF agents and interleukin-1 antagonists have allowed us to treat RA more effectively with relatively low risk of side effects. Investigations of other possible treatment pathways, such as inhibition of angiogenesis, may produce still better treatment and rapid unraveling of the immune system and how it relates to RA greatly enhances the opportunities for improved therapeutics in RA.     

TNF inhibitors in the treatment of arthritis

Rheumatoid arthritis (RA) is a chronic destructive arthritis leading to joint destruction as a consequence of chronic inflammatory processes. Established therapy with slow-acting disease-modifying anti-rheumatic drugs (DMARDs), as with low-dose methotrexate (MTX), leads to a significant improvement of disease symptoms, but are unable to stop joint destruction. Novel therapeutic agents like monoclonal antibodies (mAb), cytokine receptor-human immunoglobulin constructs or recombinant human proteins have been tested in RA and in other chronic arthritides like ankylosing spondylitis or psoriatic arthritis with convincing success. In particular, clinical trials testing anti-TNF alpha agents either alone or in combination with MTX have proven the feasibility and efficacy of these novel approaches.     

Pharmacogenetics of therapies in rheumatoid arthritis

Rheumatoid arthritis (RA) is an inflammatory, aggressive arthritis causing irreversible joint destruction and damage when left untreated. Disease-modifying antirheumatic drugs (DMARDs) are the mainstay of treatment for RA and ameliorate not only the clinical signs and symptoms but also joint damage associated with the disease. In recent years, biological therapies have been introduced for the treatment of RA, and the effectiveness of these agents in slowing the clinical and radiographic progression in RA has been established beyond question. However, there is significant variability in the response of patients with RA to these therapies. Moreover, the biological therapies are expensive, totaling several thousand dollars in yearly patient costs. Pharmacogenomics, the study of genetic variations in drug-metabolizing enzymes and their translation to differential responses to drugs, is a nascent but rapidly evolving field. The application of pharmacogenomics to therapies used in RA, particularly the new expensive biological agents, holds great promise for tailoring therapy with these agents based on a patient's genetics. Published literature on the pharmacogenetics of commonly used DMARDs and the emerging body of literature on the pharmacogenetics of the new biological therapies in RA are the focus of this review. As evident from the contents of this review, pharmacogenomics is an exciting field which is progressing productively and rapidly. Pharmacogenomic approaches offer powerful tools to optimize drug therapy in individual patients.     

Proximal signaling molecules as potential targets for anti-inflammatory therapy

As a consequence of the limited efficacy and significant toxicity of current anti-inflammatory therapies, there is widespread interest in the development of novel drugs for this application. Progress in our understanding of inflammatory signaling pathways has identified novel targets, notably in pathways involving mitogen-activated protein kinases and T-cell receptor signaling. Recent observations have provided molecular insight into the mechanism of action of well-established anti-inflammatory and immunosuppressive drugs, such as glucocorticoids and azathioprine, and the anti-inflammatory small molecule semapimod (Cytokine PharmaSciences Inc). Data from these studies indicate that therapeutic agents which specifically target proximal signaling molecules might represent a powerful strategy for combating inflammatory diseases.