Pharmacology and Toxicology Department, Faculty of Pharmacy, Nahda University, Kornish Al Nil, Bayad Al Arab, Beni Suef, Egypt.
Pharmacology and Toxicology Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, 3 Cairo-Belbeis Desert Rd, Second Al Salam, Cairo, Egypt.
Inflammopharmacology. 2020 Oct;28(5):1253-1267. doi: 10.1007/s10787-020-00693-8. Epub 2020 Mar 5.
Activated factor X (FXa) is strongly linked to various inflammatory events. This study aimed to investigate the effect of FXa on janus kinase2/signal transducers and activators of transcription3 (JAK2/STAT3) and mitogen-activated protein kinase (MAPK) phosphorylation in relation to rheumatoid arthritis (RA). It also extends its scope to explore the possible anti-arthritic effects of apixaban, a selective FXa inhibitor. Rats were allocated into normal control; complete Freund's adjuvant (CFA, 0.4 ml/4 days/12 days); FXa (120 µg/kg/day/3 days) and CFA + FXa groups as well as three treated groups including CFA + apixaban; FXa + apixaban and CFA + FXa + apixaban. Apixaban was administered at a dose of 10 mg/kg/12 h for15 days. By the end of the experimental period, tissue samples were collected for the assessment of phosphorylated (p)-JAK2, STAT3, MAPK, matrixmetalloprotein-1 (MMP-1) and protease-activated receptor 2. Furthermore, Serum interleukin-6 (IL-6), platelet-derived growth factor (PDGF), anti-citrullinated protein antibody (ACPA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), plasma level of FXa and prothrombin time were evaluated. In support, histopathological and macroscopical examinations were performed. FXa activated JAK2, STAT3 and MAPK phosphorylation through activation of PAR 2, PDGF and IL-6 and concomitantly led to a significant elevation in ACPA, MMP-1 and 8-OHdG. Apixaban markedly amended FXa-induced changes. Conclusively, the current study revealed that FXa may have a drastic role in RA progression and pathogenesis at least through stimulation of JAK2/STAT3 and MAPK phosphorylation. Furthermore, apixaban exerted robust arthro-protective effects. These beneficial outcomes could be attributed to its ability to impede JAK2/STAT3 and MAPK activation, as well as to its antioxidant property.
激活的因子 X（FXa）与各种炎症事件密切相关。本研究旨在探讨 FXa 对关节炎（RA）中 Janus 激酶 2/信号转导和转录激活因子 3（JAK2/STAT3）和丝裂原活化蛋白激酶（MAPK）磷酸化的影响，并扩展其范围以探索选择性 FXa 抑制剂阿哌沙班的可能抗关节炎作用。将大鼠分为正常对照组；完全弗氏佐剂（CFA，0.4ml/4 天/12 天）；FXa（120µg/kg/天/3 天）和 CFA+FXa 组以及包括 CFA+apixaban、FXa+apixaban 和 CFA+FXa+apixaban 在内的三个治疗组。阿哌沙班以 10mg/kg/12h 的剂量给药 15 天。在实验期末，收集组织样本以评估磷酸化（p）-JAK2、STAT3、MAPK、基质金属蛋白酶-1（MMP-1）和蛋白酶激活受体 2。此外，评估血清白细胞介素 6（IL-6）、血小板衍生生长因子（PDGF）、抗瓜氨酸蛋白抗体（ACPA）、8-羟基-2'-脱氧鸟苷（8-OHdG）、血浆 FXa 水平和凝血酶原时间。支持性地，进行了组织病理学和宏观检查。FXa 通过激活 PAR2、PDGF 和 IL-6 激活 JAK2、STAT3 和 MAPK 磷酸化，同时导致 ACPA、MMP-1 和 8-OHdG 显著升高。阿哌沙班显著修正了 FXa 诱导的变化。总之，本研究表明，FXa 至少通过刺激 JAK2/STAT3 和 MAPK 磷酸化，在 RA 进展和发病机制中可能具有重要作用。此外，阿哌沙班发挥了强大的关节保护作用。这些有益的结果可能归因于其抑制 JAK2/STAT3 和 MAPK 激活的能力以及其抗氧化特性。
