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通讯作者:

王丹丹,E-mail:dandanwangffd@nju.edu.cn

中图分类号:R593.2

文献标识码:A

文章编号:1007-4368(2023)03-371-09

DOI:10.7655/NYDXBNS20230311

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参考文献 10
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参考文献 12
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参考文献 13
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参考文献 14
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参考文献 15
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参考文献 16
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参考文献 18
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参考文献 19
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参考文献 20
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参考文献 21
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目录contents

    摘要

    目的:研究系统性红斑狼疮(systemic lupus erythematosus,SLE)和类风湿关节炎(rheumatoid arthritis,RA)患者的血清代谢谱特征,解析两种疾病可能存在的代谢差异。方法:收集SLE、RA患者及健康志愿者的血清样本,通过亲水相互作用超高效液相色谱-四级杆飞行时间质谱联用技术(hydrophilic interaction and ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry,HILIC UHPLC-Q-TOF MS)对样本进行全谱分析,经正交偏最小二乘判别分析 (orthogonal partial least squares-discriminant analysis,OPLS-DA)模型结合单变量统计方法筛选组间差异代谢物,受试者工作特征(receiver operating characteristic,ROC)曲线分析候选代谢标志物的诊断效力。通过对差异代谢物进行KEGG通路富集分析观察主要差异代谢途径。结果:SLE、RA患者与健康人群的血清代谢谱有明显差异,筛选出5种可能作为疾病潜在诊断靶标的差异代谢物,分别是1-棕榈酰基-2-羟基-sn-甘油-3-磷酸乙醇胺、牛磺酸、十六烷二酸、(+-)12-羟基二十碳四烯酸(12-hydroxye- icosantetraenoic acid,12-HETE)以及次黄嘌呤。KEGG 通路富集分析发现了逆行内源性大麻素信号等 7 条显著差异代谢通路。结论:非靶向代谢组学研究方法可用于比较SLE、RA以及健康人群之间的血清代谢谱差异,分析、筛选出潜在代谢标志物及差异代谢通路,有望为上述疾病的诊疗提供新思路。

    Abstract

    Objective:The current study aims to explore the potential metabolic differences caused by systemic lupus erythematosus (SLE)and rheumatoid arthritis(RA),the characteristics of serum metabolic profiles of patients with SLE and RA were analyzed. Methods:Serum samples were respectively collected from SLE patients,RA patients,and healthy volunteers. Hydrophilic interaction and ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry(HILIC UHPLC-Q-TOF MS)was performed to analyze the full spectrum of these serum samples. The significantly altered metabolites were enriched by orthogonal partial least squares - discriminant analysis(OPLS -DA)models combined with univariate statistical analysis. The receiver operating characteristic(ROC)curve was used to evaluate the diagnostic efficacy of the candidate serum metabolite biomarkers. KEGG pathway enrichment analysis was conducted to uncover the significantly altered pathways in each disease group. Results:The serum profiles showed remarkable differences among the SLE group,RA group,and the control group. Five significantly altered metabolites, including 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphoethanolamine,taurine,hexadecanedioic acid,(+-)12-hydroxyeicosantetraenoic acid(12 - HETE)and hypoxanthine,were proposed as potential diagnostic biomarkers. Furthermore,7 KEGG pathways,such as retrograde endocannabinoid signaling pathway,significantly altered in the SLE group when compared with the control group or RA group. Conclusion:Untargeted metabolomics study could be used to reveal the discrepancy of serum metabolic profiles among SLE patients,RA patients,and healthy people. The screened metabolite biomarkers and significantly altered pathways are expected to provide novel insights into the diagnosis and treatment of aforementioned diseases.

  • 随着“后基因组时代”到来,代谢组学研究技术应运而生,它通过研究生物体液内低分子量代谢物的表达谱,揭示整个代谢系统受内、外因素影响的变化[1]。由于比基因组学和蛋白质组学更能反映细胞或生物体的表型,代谢组学更适用于研究疾病诊断、分类、预后以及挖掘潜在标志物[2-3]

  • 系统性红斑狼疮(systemic lupus erythematosus, SLE)是一种慢性自身免疫病,可引起多器官系统损伤,因其临床表现多样且某些症状、体征可与其他风湿免疫病相“重叠”,常给临床医生带来诊断上的困扰[4],较易与一种慢性炎症性免疫病类风湿关节炎(rheumatoid arthritis,RA)混淆。RA 除了典型的类风湿结节和关节损伤外,也可有肺部受累、血管炎及全身并发症等关节外表现[5]

  • 目前关注 SLE 和 RA 代谢特征差异的研究较少,本研究采用非靶向代谢组学方法,探索 SLE 和 RA 的血清代谢谱特征,筛选疾病相关的潜在代谢标志物,为寻找上游关键表达调控基因,探索差异代谢物或代谢途径与疾病之间的相关性奠定基础。

  • 1 对象和方法

  • 1.1 对象

  • 招募2020年1—6月在南京鼓楼医院风湿免疫科住院的SLE 及RA 患者各30例,分别符合美国风湿病学会(American College of Rheumatology,ACR) 1997年修订的SLE诊断标准[6] 及1987年制定的 RA 分类标准[7]。排除标准:患有药物性狼疮或合并其他自身免疫病、心血管疾病、糖尿病、终末期肾病、活动性恶性肿瘤、活动性全身感染的患者,酗酒、吸烟或有口服避孕药史的患者,妊娠期或哺乳期女性患者。同时招募了30例健康女性志愿者作为健康对照(healthy control,HC)组,入组标准:无慢性基础疾病,志愿者本人及其一级亲属均无自身免疫病病史,近期未服用任何药物。本研究所有实验方案均经南京大学医学院附属鼓楼医院伦理委员会批准(伦理审批号为2016⁃027、2020⁃093)。

  • 1.2 方法

  • 1.2.1 代谢组学分析

  • 样品采集与预处理:采集每位研究对象空腹静脉血3 mL,以4℃ 1 000 g离心10 min去除血细胞,获得血清样本分装后置于-80℃保存。进行色谱⁃ 质谱分析前,先对血清样本进行预处理,步骤如下:取-80℃保存的血清样本在 4℃下缓慢解冻,从每个样本中取100 μL加入400 μL预冷的甲醇/乙腈(1∶1,V/V),涡旋混匀,-20℃静置 60 min 去除蛋白质,将混合物离心20 min(14 000 g,4℃),取上清液真空干燥。进行亲水相互作用超高效液相色谱⁃四级杆飞行时间质谱联用技术(hydrophilic interaction and ultra ⁃ high performance liquid chromatography coupled with quadrupole⁃time⁃of⁃flight mass spectrom⁃ etry,HILIC UHPLC⁃Q⁃TOF MS)分析时,在干燥后的上清中加入 100 μL 乙腈/水(1∶1,V/V)溶剂使其重新溶解,涡旋混匀后离心 15 min(14 000 g, 4℃),取上清液进样分析。为了在进样前确定仪器状态并平衡色谱⁃质谱系统,同时监测整个实验过程中系统的稳定性,将每个样品等比例混合以制备质控样本。

  • HILIC UHPLC⁃Q⁃TOF MS 分析:所有血清样本均使用Agilent 1290 Infinity LC超高效液相色谱系统 (UHPLC)(Agilent Technologies公司,美国)HILIC色谱柱进行分离,在色谱柱(Waters,ACQUITY UPLC BEH Amide1.7 μm,2.1 mm×100.0 mm)上对主要极性代谢物进行分离后,通过Triple TOF5600+质谱仪 (AB SCIEX公司,美国)进行质谱分析。

  • 1.2.2 代谢组学数据分析

  • 将HILIC UHPLC⁃Q⁃TOF MS生成的原始数据经 Proteo Wizard 转换为.mzXML 格式文件,采用 XCMS 程序进行峰对齐、保留时间校正和峰面积提取。检索和比对实验室自建数据库(上海中科新生命生物科技有限公司),采用精确质量数匹配(Δm/z <25 ppm)和二级谱图匹配的方式进行代谢物结构鉴定。首先过滤峰强度数据,从XCMS提取的数据中删除组别总和>2/3 的离子峰。应用 SIMCA⁃P 14.1 软件进行模式识别,将总峰面积归一化后的数据通过Pareto⁃ scaling进行预处理后,采用多维统计分析方法⁃正交偏最小二乘判别分析(orthogonal partial least squares⁃ discriminant analysis,OPLS⁃DA)模型处理有效数据,计算变量投影重要度(variable importance for the pro⁃jection,VIP)来衡量各代谢物的表达模式对各组样本分类判别的影响强度和解释能力。结合单变量统计分析方法(单因素方差分析或非参数检验)筛选组间差异代谢物,并使用 R 语言进行差异倍数 (fold change,FC)分析来比较各代谢物在不同组别之间的表达水平。应用GraphPad Prism 5软件进行受试者工作特征(receiver operating characteristic, ROC)曲线分析,计算 ROC 曲线下面积(area under the curve,AUC)来评估候选代谢物的诊断效力。参考KEGG(Kyoto Encyclopedia of Genes and Genomes, http://www.kegg.jp/)通路数据库信息,对各组间差异代谢物进行KEGG通路富集分析,观察组间主要差异代谢途径。

  • 1.3 统计学方法

  • 研究对象的人群临床特征中,连续变量依据其是否符合正态分布,分别表示为均值±标准差(x-±s) 或中位数(四分位数)[MP25P75)]。应用统计学软件SPSS 26.0对各组数据进行正态性检验,根据数据是否服从正态分布,分别采用Student t检验或Mann⁃ Whitney U检验对各项指标进行SLE组和RA组的组间比较。筛选组间差异代谢物时,首先根据OPLS⁃ DA模型得到VIP值,VIP>1的代谢物被认为对组间差异贡献明显。其次,对3个研究组间代谢物的表达水平进行比较,根据代谢物在各组样本中的血清相对表达量是否服从近似正态分布、是否具有方差齐性,分别采用单因素方差分析及后续的多重比较 (LSD⁃t检验)或非参数检验(Kruskal⁃Wallis检验)及采用 Bonferroni 法校正显著性水平的事后两两比较。通过Fisher精确检验进行KEGG通路富集分析,计算P值以显示各代谢通路上差异代谢物富集度的显著性水平。P <0.05为差异有统计学意义。

  • 2 结果

  • 2.1 人群特征

  • SLE组、RA组患者的人口统计学及临床特征见表1。HC 组年龄为(31.2±4.5)岁,实验室指标均在正常范围,自身抗体均为阴性。SLE组患者的血清甘油三酯、肌酐、尿素氮、尿酸水平显著高于RA 组患者,空腹血糖、补体 C3、补体 C4 水平以及血小板数目显著低于RA组患者(P <0.05)。

  • 2.2 SLE组、RA组与HC组的血清代谢谱差异

  • 质控样本的 UHPLC⁃Q⁃TOF MS 总离子流图中各色谱峰的响应强度和保留时间基本重叠,提示整个实验过程中因仪器误差引起的变异极小。XCMS软件检测到的代谢物离子峰数据经归一化后采用 OPLS⁃DA 分类模型分析,图1显示SLE组、RA组及 HC组的血清样本在OPLS⁃DA模型得分图上均区分良好,提示3个研究组的血清代谢谱之间存在明显差异。

  • 2.3 潜在代谢标志物的筛选

  • 将多维统计分析方法与单变量统计分析方法结合,以VIP >1且P <0.05为条件筛选出各组间的显著差异代谢物(表2),共筛选出18种SLE组和HC 组间显著差异代谢物,其中5种在SLE组中的血清相对表达强度显著高于HC组,另13种低于HC组; 有21种RA组和HC组间显著差异代谢物,其中7种在 RA组中显著高于HC组,另14种低于HC组;有16种 SLE组和RA组间显著差异代谢物,其中4种在SLE 组中显著高于RA组,另12种低于RA组。

  • 本研究观察到肌酐、1⁃棕榈酰基⁃2⁃羟基⁃sn⁃甘油⁃ 3⁃磷酸乙醇胺、牛磺酸的血清相对表达强度在SLE 组 vs. HC 组以及 SLE 组 vs. RA 组间均存在显著差异,但未见于RA组vs. HC组间;DL⁃乳酸、十六烷二酸、(+⁃)12⁃羟基二十碳四烯酸(12⁃hydroxyeicosantet⁃ raenoic acid,12⁃HETE)、16⁃羟基棕榈酸、Nname,外消旋反式⁃9,10⁃环氧硬脂酸、次黄嘌呤的血清相对表达强度在 RA 组 vs. HC 组以及 SLE 组 vs. RA 组间均有显著差异,而未见于SLE组vs. HC组间。进一步采用ROC曲线分析方法对这9种候选代谢标志物的疾病诊断效力进行评估(图2)。结果显示1⁃棕榈酰基⁃2⁃羟基⁃sn⁃甘油⁃3⁃磷酸乙醇胺和牛磺酸在SLE 组vs. HC组和SLE组vs. RA组中的AUC均超过0.7; 十六烷二酸、(+⁃)12⁃HETE、次黄嘌呤在 RA 组 vs. HC 组和 SLE 组 vs. RA 组中的 AUC 均超过 0.7,提示这5种代谢物对于SLE或RA具有较强的预测价值,可能是鉴别SLE和RA的潜在代谢靶标。

  • 2.4 KEGG通路富集分析

  • 将各组间筛选出的差异代谢物(VIP>1,P< 0.1)放入 KEGG 数据库,对鉴定出的 KEGG 通路进行差异代谢物富集分析。图3显示了各组间差异代谢物显著富集的 KEGG 通路,其中 7 条代谢通路在 SLE组vs. HC组及SLE组vs. RA组间均有差异代谢物显著富集(P<0.05),而未见于RA组vs. HC组,它们分别是:逆行内源性大麻素信号、精氨酸生物合成、甘油磷脂代谢、初级胆汁酸生物合成、胆汁分泌、嘧啶代谢、精氨酸和脯氨酸代谢通路,提示这些通路在SLE疾病状态下受到了显著影响,可能在其病理生理过程中发挥一定作用。

  • 表1 SLE组和RA组患者的人口统计学及临床特征

  • Table1 Demographic and clinical characteristics of patients in the SLE and RA groups

  • 3 讨论

  • 本研究基于 HILIC UHPLC⁃Q⁃TOF MS 技术对 SLE、RA患者及健康人群进行非靶向血清代谢谱鉴定,最终筛选出对 SLE 和 RA 的预测及鉴别有潜在临床意义的5种代谢物和7条代谢途径。本研究发现 1⁃棕榈酰⁃2⁃羟基⁃sn⁃甘油⁃3⁃磷酸乙醇胺可能是识别 SLE 的一个潜在代谢标志,它是参与细胞膜构成的一种脂质小分子,可以通过活细胞膜自由扩散[8-9]。免疫细胞执行信号转导等功能依赖于质膜和肌动蛋白细胞骨架之间的动态相互作用[10],因此,该代谢物血清表达的变化可能暗示SLE 患者体内细胞功能的改变。

  • 图1 SLE组、RA组和HC组血清代谢谱的OPLS⁃DA得分图

  • Figure1 OPLS⁃DA score plots of serum metabolic profiling of the SLE group,RA group and the HC group

  • 表2 SLE组、RA组和HC组间的显著差异代谢物

  • Table2 Significantly altered metabolites among the SLE,RA and HC groups

  • 图2 候选代谢标志物的ROC曲线分析结果

  • Figure2 ROC curve analysis of candidate metabolite biomarkers

  • 牛磺酸是一种必需营养素,目前普遍认为其抗氧化特性在维持大脑功能和发育方面发挥重要作用,但关于牛磺酸对SLE疾病的影响,现有研究尚未达成一致结论。研究发现牛磺酸对高胆固醇饮食的 NZB/WF1小鼠肝细胞凋亡有保护作用,认为牛磺酸对 SLE 具有治疗潜力[11];而另一项研究结果显示,SLE患者血清中牛磺酸水平高于健康人群和RA 患者,并且牛磺酸可通过增强浆细胞样树突状细胞介导Ⅰ型干扰素产生,加剧SLE进展,因此提出靶向抑制牛磺酸或限制牛磺酸饮食摄入治疗SLE[12]。本研究筛选出的牛磺酸是辅助诊断SLE的良好潜在代谢标志物之一,SLE患者血清牛磺酸水平低于RA组和健康对照组,推测血清牛磺酸水平可能与患者所处的疾病阶段有关,其代谢异常对于SLE的影响可能是多方面的,有待进一步研究证实。

  • 本研究观察到RA组患者血清中十六烷二酸的水平显著低于SLE组和HC组,而(+⁃)12⁃HETE和次黄嘌呤的水平明显高于SLE组和HC组。十六烷二酸是一种长链二羧酸,在脂肪酸ω氧化过程中产生,在过氧化物酶体中经β氧化进行代谢。英国的一项研究显示十六烷二酸与血压呈显著关联,可能与血脂、肥胖、胰岛素抵抗的调控相关[13]。十六烷二酸代谢异常可能影响RA患者的糖脂代谢以及心血管系统,但目前尚缺乏相关研究。目前认为 RA 患者的无菌性关节炎本质上是一种免疫病理损伤,多种致炎因子参与该过程。12⁃HETE 是花生四烯酸代谢的脂质产物之一,被认为是许多炎症疾病的促炎介质[14]。12⁃HETE 还被发现参与调节真皮细胞外基质的组成,并且对成纤维细胞具有显著趋化性,在伤口愈合过程中发挥作用[15]。因此,12⁃HETE还可能参与纤维化疾病的发展,如硬皮病、肺纤维化、动脉粥样硬化等。多项研究结果显示,12⁃HETE兼具抗血栓和促血栓形成作用[16],其发挥作用的差异可能与机体所处的内环境状态有关,已有文献报道RA 可能增加肺栓塞和深静脉血栓的发生风险[17-18]。因此认为(+⁃)12⁃HETE可能在RA的关节及关节外损伤中发挥一定作用。

  • 图3 SLE组、RA组和HC组间差异代谢物的KEGG通路富集分析

  • Figure3 KEGG pathway enrichment analysis of differential metabolites among the SLE,RA and HC groups

  • 嘌呤代谢与 RA 等疾病的免疫紊乱有关,次黄嘌呤是嘌呤代谢的主要中间产物之一,已有多项研究发现,RA患者关节滑液中次黄嘌呤的浓度高于骨关节炎患者及健康人群,可能与RA患者关节压力增高引起的缺血缺氧和关节炎症性损伤相关[19-20],并且 RA患者血浆次黄嘌呤水平也高于健康人群,可能与关节组织中嘌呤代谢局部增强和组织缺氧相关[21]

  • 除了KEGG富集分析获得的7条可能在SLE病理生理过程中扮演重要角色的代谢通路外,mTOR 信号转导途径、蛋白质的消化吸收途径、不饱和脂肪酸的生物合成、卵巢类固醇生成等途径在两个疾病组中均存在差异代谢物的显著富集,暗示这些代谢途径的改变是 SLE 和 RA 疾病过程中共有的,甚至在其他自身免疫病中也可能存在。关于SLE代谢特征的现有研究结果表明,SLE患者体内的能量代谢受到显著影响,与氧化应激相关的代谢物增加[22]。本研究通过对各组间差异代谢物显著富集的KEGG通路归类,发现 SLE 组与 RA 组存在的代谢变化以脂质和氨基酸代谢为主。

  • 本研究尚存在一些不足,疾病组研究对象在接受糖皮质激素、免疫抑制剂等治疗过程中,药物可能会影响患者血清代谢物的水平,尽管分析时已通过OPLS⁃DA 模型尽可能减少与分类无关因素的干扰,但疾病组代谢谱中呈现出的部分差异仍不能排除与药物治疗有关。未来将对筛选出的潜在代谢靶标及代谢通路进行进一步研究论证,以期为探索 SLE和RA的发病机制以及开发新型诊疗工具提供新思路。

  • 参考文献

    • [1] ZHANG Y,GAN L,TANG J,et al.Metabolic profiling re⁃ veals new serum signatures to discriminate lupus nephri⁃ tis from systemic lupus erythematosus[J].Front Immu⁃ nol,2022,13:967371

    • [2] VASQUEZ ⁃ CANIZARES N,WAHEZI D,PUTTERMAN C.Diagnostic and prognostic tests in systemic lupus ery⁃ thematosus[J].Best Pract Res Clin Rheumatol,2017,31(3):351-363

    • [3] TERUEL M,CHAMBERLAIN C,ALARCÓN ⁃ RIQU ⁃ ELME M E.Omicsstudies:their use in diagnosis and reclassification of SLE and other systemic autoimmune diseases[J].Rheumatol Oxf Engl,2017,56(suppl1):i78-i87

    • [4] BENGTSSON A A,TRYGG J,WUTTGE D M,et al.Meta⁃ bolic profiling of systemic lupus erythematosus and com⁃ parison with primary sjögren’s syndrome and systemic sclerosis[J].PLoS One,2016,11(7):0159384

    • [5] SMOLEN J S,ALETAHA D,MCINNES I B.Rheumatoid arthritis[J].Lancet,2016,388(10055):2023-2038

    • [6] FELETAR M,IBAÑEZ D,UROWITZ M B,et al.The im⁃ pact of the 1997 update of the American College of Rheu⁃ matology revised criteria for the classification of systemic lupus erythematosus:what has been changed?[J].Arthri⁃ tis Rheum,2003,48(7):2067-2069

    • [7] ARNETT F C,EDWORTHY S M,BLOCH D A,et al.The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis[J].Arthritis Rheum,1988,31(3):315-324

    • [8] DIRIENZO C,GRATTON E,BELTRAM F,et al.From fast fluorescence imaging to molecular diffusion law on live cell membranes in a commercial microscope[J].J Vis Exp,2014(92):e51994

    • [9] WANG Y,WANG Y,WANG Y,et al.Untargeted global metabolomic analysis reveals the mechanism of tripropyla⁃ mine ⁃enhanced lycopene accumulation in Blakeslea tris⁃ pora[J].Front Bioeng Biotechnol,2021,9:673225

    • [10] SCHNEIDER F,COLIN⁃YORK H,FRITZSCHE M.Quan⁃ titative bio⁃imaging tools to dissect the interplay of mem⁃ brane and cytoskeletal actin dynamics in immune cells [J].Front Immunol,2020,11:612542

    • [11] HSU T C,CHIANG S Y,WU J H,et al.Treatment with taurine attenuates hepatic apoptosis in NZB/W F1 mice fed with a high ⁃cholesterol diet[J].J Agric Food Chem,2008,56(20):9685-9691

    • [12] LI J,DING H,MENG Y,et al.Taurine metabolism aggra⁃ vates the progression of lupus by promoting the function of plasmacytoid dendritic cells[J].Arthritis Rheumatol,2020,72(12):2106-2117

    • [13] MENNI C,GRAHAM D,KASTENMÜLLER G,et al.Me⁃ tabolomic identification of a novel pathway of blood pres⁃ sure regulation involving hexadecanedioate[J].Hyperten⁃ sion,2015,66(2):422-429

    • [14] HARTLING I,CREMONESI A,OSUNA E,et al.Quanti⁃ tative profiling of inflammatory and pro⁃resolving lipid me⁃ diators in human adolescents and mouse plasma using UHPLC⁃MS/MS[J].Clin Chem Lab Med,2021,59(11):1811-1823

    • [15] SIMARD M,GRENIER A,RIOUX G,et al.Remodeling of the dermal extracellular matrix in a tissue ⁃ engineered psoriatic skin model by n ⁃ 3 polyunsaturated fatty acids [J].Biomedicines,2022,10(5):1078

    • [16] PORRO B,SONGIA P,SQUELLERIO I,et al.Analysis,physiological and clinical significance of 12 ⁃ HETE:a neglected platelet⁃derived 12⁃lipoxygenase product[J].J Chromatogr B Anal Technol Biomed Life Sci,2014,964:26-40

    • [17] CHUNG W S,PENG C L,LIN C L,et al.Rheumatoid arthritis increases the risk of deep vein thrombosis and pulmonary thromboembolism:a nationwide cohort study [J].Ann Rheum Dis,2014,73(10):1774-1780

    • [18] LI L,LU N,AVINA ⁃GALINDO A M,et al.The risk and trend of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis:a general population ⁃ based study [J].Rheumatology(Oxford),2021,60(1):188-195

    • [19] HERBERT K E,SCOTT D L,PERRET T D.Nucleosides and bases in synovial fluid from patients with rheumatoid arthritis and osteoarthritis[J].Clin Sci(Lond),1988,74(1):97-99

    • [20] SOOAH K,JIWON H,JUNGYEON K,et al.Metabolic discrimination of synovial fluid between rheumatoid ar⁃ thritis and osteoarthritis using gas chromatography/time⁃of ⁃ flight mass spectrometry[J].Metabolomics,2022,18(7):48

    • [21] GUDBJÖRNSSON B,ZAK A,NIKLASSON F,et al.Hy⁃ poxanthine,xanthine,and urate in synovial fluid from pa⁃ tients with inflammatory arthritides[J].Ann Rheum Dis,1991,50(10):669-672

    • [22] DUARTE⁃DELGADO N P,CALA M P,BARRETO A,et al.Metabolites and metabolic pathways associated with rheumatoid arthritis and systemic lupus erythematosus [J].J Transl Autoimmun,2022,5:100150

  • 参考文献

    • [1] ZHANG Y,GAN L,TANG J,et al.Metabolic profiling re⁃ veals new serum signatures to discriminate lupus nephri⁃ tis from systemic lupus erythematosus[J].Front Immu⁃ nol,2022,13:967371

    • [2] VASQUEZ ⁃ CANIZARES N,WAHEZI D,PUTTERMAN C.Diagnostic and prognostic tests in systemic lupus ery⁃ thematosus[J].Best Pract Res Clin Rheumatol,2017,31(3):351-363

    • [3] TERUEL M,CHAMBERLAIN C,ALARCÓN ⁃ RIQU ⁃ ELME M E.Omicsstudies:their use in diagnosis and reclassification of SLE and other systemic autoimmune diseases[J].Rheumatol Oxf Engl,2017,56(suppl1):i78-i87

    • [4] BENGTSSON A A,TRYGG J,WUTTGE D M,et al.Meta⁃ bolic profiling of systemic lupus erythematosus and com⁃ parison with primary sjögren’s syndrome and systemic sclerosis[J].PLoS One,2016,11(7):0159384

    • [5] SMOLEN J S,ALETAHA D,MCINNES I B.Rheumatoid arthritis[J].Lancet,2016,388(10055):2023-2038

    • [6] FELETAR M,IBAÑEZ D,UROWITZ M B,et al.The im⁃ pact of the 1997 update of the American College of Rheu⁃ matology revised criteria for the classification of systemic lupus erythematosus:what has been changed?[J].Arthri⁃ tis Rheum,2003,48(7):2067-2069

    • [7] ARNETT F C,EDWORTHY S M,BLOCH D A,et al.The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis[J].Arthritis Rheum,1988,31(3):315-324

    • [8] DIRIENZO C,GRATTON E,BELTRAM F,et al.From fast fluorescence imaging to molecular diffusion law on live cell membranes in a commercial microscope[J].J Vis Exp,2014(92):e51994

    • [9] WANG Y,WANG Y,WANG Y,et al.Untargeted global metabolomic analysis reveals the mechanism of tripropyla⁃ mine ⁃enhanced lycopene accumulation in Blakeslea tris⁃ pora[J].Front Bioeng Biotechnol,2021,9:673225

    • [10] SCHNEIDER F,COLIN⁃YORK H,FRITZSCHE M.Quan⁃ titative bio⁃imaging tools to dissect the interplay of mem⁃ brane and cytoskeletal actin dynamics in immune cells [J].Front Immunol,2020,11:612542

    • [11] HSU T C,CHIANG S Y,WU J H,et al.Treatment with taurine attenuates hepatic apoptosis in NZB/W F1 mice fed with a high ⁃cholesterol diet[J].J Agric Food Chem,2008,56(20):9685-9691

    • [12] LI J,DING H,MENG Y,et al.Taurine metabolism aggra⁃ vates the progression of lupus by promoting the function of plasmacytoid dendritic cells[J].Arthritis Rheumatol,2020,72(12):2106-2117

    • [13] MENNI C,GRAHAM D,KASTENMÜLLER G,et al.Me⁃ tabolomic identification of a novel pathway of blood pres⁃ sure regulation involving hexadecanedioate[J].Hyperten⁃ sion,2015,66(2):422-429

    • [14] HARTLING I,CREMONESI A,OSUNA E,et al.Quanti⁃ tative profiling of inflammatory and pro⁃resolving lipid me⁃ diators in human adolescents and mouse plasma using UHPLC⁃MS/MS[J].Clin Chem Lab Med,2021,59(11):1811-1823

    • [15] SIMARD M,GRENIER A,RIOUX G,et al.Remodeling of the dermal extracellular matrix in a tissue ⁃ engineered psoriatic skin model by n ⁃ 3 polyunsaturated fatty acids [J].Biomedicines,2022,10(5):1078

    • [16] PORRO B,SONGIA P,SQUELLERIO I,et al.Analysis,physiological and clinical significance of 12 ⁃ HETE:a neglected platelet⁃derived 12⁃lipoxygenase product[J].J Chromatogr B Anal Technol Biomed Life Sci,2014,964:26-40

    • [17] CHUNG W S,PENG C L,LIN C L,et al.Rheumatoid arthritis increases the risk of deep vein thrombosis and pulmonary thromboembolism:a nationwide cohort study [J].Ann Rheum Dis,2014,73(10):1774-1780

    • [18] LI L,LU N,AVINA ⁃GALINDO A M,et al.The risk and trend of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis:a general population ⁃ based study [J].Rheumatology(Oxford),2021,60(1):188-195

    • [19] HERBERT K E,SCOTT D L,PERRET T D.Nucleosides and bases in synovial fluid from patients with rheumatoid arthritis and osteoarthritis[J].Clin Sci(Lond),1988,74(1):97-99

    • [20] SOOAH K,JIWON H,JUNGYEON K,et al.Metabolic discrimination of synovial fluid between rheumatoid ar⁃ thritis and osteoarthritis using gas chromatography/time⁃of ⁃ flight mass spectrometry[J].Metabolomics,2022,18(7):48

    • [21] GUDBJÖRNSSON B,ZAK A,NIKLASSON F,et al.Hy⁃ poxanthine,xanthine,and urate in synovial fluid from pa⁃ tients with inflammatory arthritides[J].Ann Rheum Dis,1991,50(10):669-672

    • [22] DUARTE⁃DELGADO N P,CALA M P,BARRETO A,et al.Metabolites and metabolic pathways associated with rheumatoid arthritis and systemic lupus erythematosus [J].J Transl Autoimmun,2022,5:100150