微量元素在风湿关节病领域的研究

通过综述多年来的临床观察与实验研究，发现风湿关节病存在着某些酶活性的缺陷，同时伴有相应常量元素或微量元素代谢障碍，两者密切相关，在风湿关节炎的综合治疗中，适当调整相应元素的浓度可提高疗效和改善体质．文中还介绍如何调整微量元素治疗的体会。     

A study for quality evaluation of Taxilli Herba from different hosts based on fingerprint-activity relationship modeling and multivariate statistical analysis

In this study, a fingerprint-activity relationship modeling between chemical fingerprints and antirheumatic activity was established, and multivariate statistical analysis was used to evaluate the quality of Taxilli Herba (TH) from different hosts. Characteristic fingerprints of 20 batches of TH samples were generated by high-performance liquid chromatography coupled with triple quadrupole-time of flight tandem mass spectrometry (HPLC-Triple TOF-MS/MS), and the similarity analysis was calculated based on thirteen common characteristic peaks by hierarchical clustering analysis (HCA). Subsequently, nine efficacy markers were discovered by combining fingerprints and antirheumatic activity through grey correlation analysis (GCA) and bivariate correlation analysis (BCA). Meanwhile, the content of 5 constituents in 9 markers was determined by high-performance liquid chromatography coupled with triple quadrupole-linear ion trap tandem mass spectrometry (HPLC-QTRAP-MS/MS). The comprehensive quality of TH was assessed using multivariate statistical analysis, including principal components analysis (PCA) and technique for order preference by similarity to ideal solution (TOPSIS). The results showed that a high dose of TH extract could markedly ameliorate arthritis damage compared to other doses, with flavonoids playing an important role in the antirheumatic activity. The comprehensive quality of samples from Morus alba L. (SS) was superior to those from Liquidambar formosana Hance (FXS). The present study will demonstrate the markers associated with efficacy, and provide an applicable strategy for more comprehensive quality control and evaluation of TH.     

Traditional Chinese Medicine Rhodiola Sachalinensis Borissova from Baekdu Mountain (RsBBM) for Rheumatoid Arthritis: Therapeutic Effect and Underlying Molecular Mechanisms

The lack of effective rheumatoid arthritis (RA) therapies is a persistent challenge worldwide, prompting researchers to urgently evaluate traditional Chinese medicines (TCMs) as potential clinical RA treatments. The present investigation was conducted to evaluate the therapeutic effects and potential molecular mechanisms of the active components isolated from TCM Rhodiola sachalinensis Borissova from Baekdu Mountain (RsB^BM) using an experimental adjuvant arthritis model induced by injection of rats with Freund’s complete adjuvant. After induction of the adjuvant arthritis rat model, the extract-treated and untreated groups of arthritic rats were evaluated for RsB^BM therapeutic effects based on comparisons of ankle circumferences and ELISA-determined blood serum inflammatory factor levels (TNF-α, IL-1β, and PGE2). In addition, the joint health of rats was evaluated via microscopic examination of hematoxylin-eosin-stained synovial tissues. Furthermore, to explore whether NF-κB and RANK/RANKL/OPG signaling pathways participated in observed therapeutic effects from a molecular mechanistic viewpoint, mRNA and protein levels related to the expression of nuclear factor kappa-B (NF-κB), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-Β ligand (RANKL) were analyzed via quantitative RT-PCR and Western blot analysis, respectively. Treatment of arthritic rats with the extract of RsB^BM was shown to reduce ankle swelling, reduce blood serum levels of inflammatory factors, and alleviate arthritis-associated synovial inflammation and joint damage. Moreover, an RsB^BM 50% ethanol extract treatment inhibited bone destruction by up-regulating OPG-related mRNA and protein expression and down-regulating RANKL-related mRNA and protein expression, while also reducing inflammation by the down-regulating of the NF-κB pathway activity. The results clearly demonstrated that the extract of RsB^BM alleviated adjuvant arthritis-associated joint damage by altering activities of inflammation-associated NF-κB and the RANK/RANKL/OPG signaling pathways. Due to its beneficial effects for alleviating adjuvant arthritis, this RsB^BM 50% ethanol extract should be further evaluated as a promising new therapeutic TCM treatment for RA.     

Nano-Based Co-Delivery System for Treatment of Rheumatoid Arthritis

A systemic autoimmune condition known as rheumatoid arthritis (RA) has a significant impact on patients’ quality of life. Given the complexity of RA’s biology, no single treatment can totally block the disease’s progression. The combined use of co-delivery regimens integrating various diverse mechanisms has been widely acknowledged as a way to make up for the drawbacks of single therapy. These days, co-delivery systems have been frequently utilized for co-treatment, getting over drug limitations, imaging of inflammatory areas, and inducing reactions. Various small molecules, nucleic acid drugs, and enzyme-like agents intended for co-delivery are frequently capable of producing the ability to require positive outcomes. In addition, the excellent response effect of phototherapeutic agents has led to their frequent use for delivery together with chemotherapeutics. In this review, we discuss different types of nano-based co-delivery systems and their advantages, limitations, and future directions. In addition, we review the prospects and predicted challenges for the combining of phototherapeutic agents with conventional drugs, hoping to provide some theoretical support for future in-depth studies of nano-based co-delivery systems and phototherapeutic agents.     

Combination Therapy of Carnosic Acid and Methotrexate Effectively Suppressed the Inflammatory Markers and Oxidative Stress in Experimental Arthritis

Background: Combination therapy with methotrexate (MTX) is the most common therapeutic strategy used for the treatment of patients with rheumatoid arthritis (RA). In this study, we combined the natural compound carnosic acid (CA) with MTX to reduce inflammation and oxidative stress in adjuvant arthritis (AA). Methods: AA was induced in 6–8 rats per group. MTX was administrated twice a week at a dose of 0.3 mg/kg b.w., while CA was administered daily at a dose of 100 mg/kg both in monotherapy and in combination with MTX. Plasma samples were collected on the 14th, 21st, and 28th day. Body weight and hind paw volume were measured once a week. Results: We found that, mainly, the CA + MTX combination significantly reduced the hind paw swelling, the levels of IL-17A, MMP-9, and MCP-1 in plasma, and GGT activity in joint homogenates. The mRNA expression of HO-1, catalase, and IL-1β in the liver were significantly improved by CA + MTX only. Our results indicate that adding CA to MTX treatment could be a good therapeutic option for patients suffering from RA. Conclusions: The addition of CA to methotrexate treatment significantly improved its efficacy in decreasing the development of AA by inhibiting the markers of inflammation and oxidative stress.     

Dimethyl Sulfoxide: A Bio-Friendly or Bio-Hazard Chemical? The Effect of DMSO in Human Fibroblast-like Synoviocytes

The effect of dimethyl sulfoxide (DMSO) in rheumatoid arthritis (RA) human fibroblast-like synoviocytes (FLSs) has been studied on five different samples harvested from the joints (fingers, hands and pelvis) of five women with RA. At high concentrations (>5%), the presence of DMSO induces the cleavage of caspase-3 and PARP-1, two phenomena associated with the cell death mechanism. Even at a 0.5% concentration of DMSO, MTT assays show a strong toxicity after 24 h exposure (≈25% cell death). Therefore, to ensure a minimum impact of DMSO on RA FLSs, our study shows that the concentration of DMSO has to be below 0.05% to be considered safe.     

大鼠胶原诱导性关节炎早期外周血TNF-α与性激素水平的动态观察及相关性研究

同步观察大鼠胶原诱导性关节炎早期血浆肿瘤坏死因子-α(TNF-α)与性激素水平的变化,探讨TNF-α和性激素在类风湿关节炎(RA)发病中的作用及其相关性。用Ⅱ型胶原与完全弗氏佐剂诱导SD大鼠胶原性关节炎(CIA),检测CIA大鼠不同时间点的血浆TNF-α、雌二醇和睾酮,同时观察其发病时间、滑膜新生血管形成、关节炎指数评分。随着CIA免疫时间的延长,滑膜轻度增厚,滑膜新生血管开始增多,关节炎指数评分渐增加,TNF-α含量也升高,睾酮水平下降,雌二醇水平无明显变化;TNF-α含量与睾酮水平呈负相关关系(r=-0.364,P<0.05),血浆TNF-α含量与雌二醇水平无明显相关关系(r=-0.209,P>0.05)。TNF-α在RA炎症反应的细胞因子网络中起重要作用,性激素与RA的发病也有密切关系,雄激素是天然的抗炎激素,雌激素的作用可能与其浓度有关。     

Pharmacokinetic comparison of five tanshinones in normal and arthritic rats after oral administration of Huo Luo Xiao Ling Dan or its single herb extract by UPLC‐MS/MS

A fast, sensitive and reliable ultra performance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS) method has been developed and validated for simultaneous quantitation and pharmacokinetic study of five tanshinones (tanshinone I, tanshinone IIA, tanshinone IIB, dihydrotanshinone I, cryptotanshinone), the bio‐active ingredients of Huo Luo Xiao Ling Dan (HLXLD) in rat plasma. After liquid–liquid extraction, chromatographic separation was accomplished on a Shim‐pack XR‐ODS column (75 × 3.0 mm, 2.2 µm particles) and eluted with a mobile phase consisting of acetonitrile–0.05% formic acid aqueous solution (80:20, v/v) at a flow rate of 0.4 mL/min, and the total run time was 7.0 min. The detection was performed on a triple quadrupole tandem mass spectrometry equipped with an electrospray ionization source in positive ionization and multiple reaction monitoring mode. The lower limits of quantification were 0.050–0.400 ng/mL for all the analytes. Linearity, precision and accuracy, the mean extraction recoveries and matrix effects all satisfied criteria for acceptance. This validated method was successfully applied to a comparative pharmacokinetic study of five bio‐active components in rat plasma after oral administration of HLXLD or Salvia miltiorrhiza extract in normal and arthritic rats. The results showed that there were different pharmacokinetic characteristics among different groups. Copyright © 2016 John Wiley & Sons, Ltd.     

Exploration of the mechanism of Zisheng Shenqi decoction against gout arthritis using network pharmacology

BackgroundIn this study, the network pharmacological methods were used to predict the target of effective components of compounds in Zisheng Shenqi Decoction (ZSD, or Nourishing Kidney Qi Decoction) in the treatment of gouty arthritis (GA).MethodThe main effective components and corresponding key targets of herbs in the ZSD were discerned through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis (TCMSP), Bioinformatics Analysis Tool for Molecular mechanism of Traditional Chinese Medicine (BATMAN-TCM) database. UniProt database and Swiss Target Prediction (STP) database was used to rectify and unify the target names and supply the target information. The targets related to GA were obtained by using GeneCards database. After we discovered the potential common targets between ZSD and GA, the interaction network diagram of “ZSD-component-GA-target” was constructed by Cytoscape software (Version 3.7.1). Subsequently, the Protein-protein interaction (PPI) network of ZSD effective components-targets and GA-related targets was constructed by Search Tool for the Retrieval of Interacting Genes Database (STRING). Bioconductor package “org.Hs.eg.db” and “cluster profiler” package were installed in R software (Version 3.6.0) which used for Gene Ontology analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis.Results146 components and 613 targets of 11 herbal medicines in the ZSD were got from TCMSP database and BATMAN-TCM database. 987 targets of GA were obtained from GeneCards database. After intersected and removed duplications, 132 common targets between ZSD and GA were screened out by Cytoscape software (Version 3.7.1). These common targets derived from 81 effective components of 146 components, such as quercetin, stigmasterol and kaempferol. They were closely related to anti-inflammatory, analgesic and anti oxidative stress and the principal targets comprised of Purinergic receptor P2X, ligand-gated ion channel 7 (P2x7R), Nod-like receptor protein 3 (NLRP3) and IL-1β. GO enrichment analysis and KEGG pathway enrichment analysis by R software (Version 3.6.0) showed that the key target genes had close relationship with oxidative stress, reactive oxygen species (ROS) metabolic process and leukocyte migration in aspects of biological process, cell components and molecular function. It also indicated that ZSD could decrease inflammatory reaction, alleviate ROS accumulation and attenuate pain by regulating P2 × 7R and NOD like receptor signaling pathway of inflammatory reaction.ConclusionA total of 81 effective components and 132 common target genes between ZSD and GA were screened by network pharmacology. The PPI network, GO enrichment analysis and KEGG pathway enrichment analysis suggested that ZSD can exerte anti-inflammatory and analgesic effects on the treatment of GA by reducing decreasing inflammatory reaction, alleviating ROS accumulation, and attenuating pain. The possible molecular mechanism of it mainly involved multiple components, multiple targets and multiple signaling pathways, which provided a comprehensive understanding for further study. In general, the network pharmacological method applied in this study provides an alternative strategy for the mechanism of ZSD in the treatment of GA.     

灵芝多糖对佐剂性关节炎大鼠血清IL-12影响的研究

目的探讨灵芝多糖对佐剂性关节炎大鼠血清IL-12的影响.方法用弗氏完全佐剂诱导大鼠佐剂性关节炎模型,以IL-12 EIA检测试剂盒检测大鼠血清IL-12水平.结果与对照组相比,灵芝多糖组对佐剂性关节炎大鼠血清IL-12的分泌具有明显的抑制作用(P<0.01).结论灵芝多糖可明显抑制佐剂性关节炎大鼠血清IL-12的分泌.