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IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2024-12-26 DOI:10.1016/j.taap.2024.117217

Bo Cai, Zelin He, Dandan Liu, Yuping Zhang, Zikang Yin, Weijia Bao, Qiaoyi Le, Ju Shao, Hongyan Du, Ligang Jie

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引用次数: 0

摘要

与炎症性风湿病相关的心血管疾病（CVD）风险升高早已得到公认。由于血小板活化异常，已确诊的类风湿性关节炎（RA）患者的死亡率高于普通人群。胸腺嘧啶磷酸化酶（TYMP）在血小板活化和血栓形成过程中起着至关重要的作用，是类风湿性关节炎与心血管疾病之间联系的桥梁。基因表达总库（GEO）的数据显示，TYMP水平在RA患者尤其是高炎症水平患者的滑膜组织、免疫细胞和全血中高度表达。血小板计数（PLT）和血小板比容（PCT）与类风湿性关节炎的炎症严重程度呈正相关，而血小板分布宽度（PDW）和平均血小板体积（MPV）则呈负相关。与非活动期患者相比，活动期类风湿关节炎患者血小板中的 CD62P 和 TYMP 水平明显升高。体内实验表明，降低血小板中 TYMP 的表达水平可缓解佐剂诱发的关节炎（AIA）小鼠的炎症。AIA 模型小鼠的血小板活化明显升高，同时细胞内钙（Ca2+）、活性氧（ROS）水平升高，线粒体膜电位（ΔΨm）降低。然而，用盐酸替吡西尔（TPI）治疗或利用 Tymp-/- 小鼠可逆转这些影响。用肿瘤坏死因子-α（TNF-α）体外刺激野生型（WT）小鼠血小板可促进血小板活化、细胞内 Ca2+ 和 ROS 水平升高，同时降低ΔΨm。用 TPI 处理的 WT 小鼠血小板或 Tymp-/- 小鼠血小板均表现出不良结果。我们的研究说明了TYMP在促进RA炎症和血小板活化中的重要作用，提示TYMP可能是RA的潜在治疗靶点。

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Thymidine phosphorylase participates in platelet activation and promotes inflammation in rheumatoid arthritis.

The elevated risk of cardiovascular disease (CVD) associated with inflammatory rheumatic diseases has long been recognized. Patients with established rheumatoid arthritis (RA) have a higher mortality rate compared to the general population due to abnormal platelet activation. Thymidine phosphorylase (TYMP) plays a crucial role in platelet activation and thrombosis, following bridging the link between RA and CVD. Data from Gene Expression Omnibus (GEO) database exhibited that TYMP levels were highly expressed in synovial tissues, immune cells, and whole blood of RA patients especially those with high levels of inflammation. Platelet count (PLT) and plateletcrit (PCT) were positively correlated with the severity of inflammation in rheumatoid arthritis while platelet distribution width (PDW) and mean platelet volume (MPV) were adverse. Levels of CD62P and TYMP in platelets of patients with active RA were significantly elevated compared to patients in the inactive phase. In vivo experiments showed that reducing TYMP expression levels of platelets could relieve inflammation in Adjuvant-Induced Arthritis (AIA) mice. Platelet activation was significantly elevated in AIA model mice, along with increased levels of intracellular calcium (Ca²⁺), reactive oxygen species (ROS), and decreased Mitochondrial Membrane Potential (ΔΨm). However, treatment with Tipiracil hydrochloride (TPI) or the utilization of Tymp^-/- mice reversed these effects. In vitro stimulation of wild type (WT) mouse platelets with tumor necrosis factor-alpha (TNF-α) promoted platelet activation, elevated levels of intracellular Ca²⁺as well as ROS while decreased ΔΨm. Platelets of WT mice treated with TPI or platelets of Tymp^-/- mice exhibited the adverse results. Our study illustrates the vital role of TYMP in promoting RA inflammation and platelet activation, suggesting that TYMP may be a potential therapeutic target for RA.

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.