Objective

Rheumatoid arthritis is a progressive inflammatory disease with multiple dysfunctional intracellular signaling pathways that necessitate new approaches for its management. Hence, the study aimed to inspect the ability of the combination therapy of metformin and omega-3 to modulate different signaling pathways and micro RNAs such as (miR-155, miR-146a and miR-34) as new targets in order to mitigate adjuvant-induced arthritis and compare their effect to that of methotrexate.

Methods

Fourteen days post adjuvant injection, Sprague-Dawley rats were treated orally with metformin (200 mg/kg/day) and/or omega-3 (300 mg/kg/day) or intraperitoneally with methotrexate (2 mg/kg/week) for 4 weeks.

Results and conclusion

All drug treatments amended the arthrogram score and hind paw swelling as well as decreased serum tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels. On the molecular level, all therapies activated phospho-5′adenosine monophosphate-activated protein kinase (p-AMPK) and protein phosphatase 2A (PP2A), while they inhibited phospho-mammalian target of rapamycin (p-mTOR), phospho-signal transducers and activators of transcription (p-STAT3), nuclear factor (NF)-κB p65 subunit, phosho38 mitogen-activated protein kinase (p38 MAPK) and phospho- c-Jun N-terminal kinase (p-JNK). In addition, they decreased the elevated expression level of miRNA-155, 146a and increased the expression level of miRNA-34 and they decreased the expression level of retinoic acid receptor related orphan receptor γT (RORγT) and increased that of fork head box P3 (FOXP3), correcting Th17/Treg cells balance. On most of the aforementioned parameters, the effect of the combination therapy was comparable to that of methotrexate, emphasizing that this combination possesses better additive anti-inflammatory effect than either drug when used alone. In addition, the combination was capable of normalizing the serum transaminases levels as compared to untreated group offering hepatoprotective effect and suggesting the possibility of its use as a replacement therapeutic strategy for MTX in rheumatoid arthritis.

中文翻译：

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二甲双胍和omega-3鱼油通过调节实验性关节炎中一些失调的微RNA表达和信号通路来引发抗炎作用

目的

类风湿关节炎是一种进行性炎性疾病，具有多种功能异常的细胞内信号传导途径，因此需要新的治疗方法。因此，该研究旨在检验二甲双胍和omega-3联合治疗调节不同信号通路和微小RNA（例如miR-155，miR-146a和miR-34）作为新靶点以减轻佐剂的能力。引起的关节炎，并将其作用与甲氨蝶呤进行比较。

方法

佐剂注射后第十四天，将Sprague-Dawley大鼠口服二甲双胍（200 mg / kg /天）和/或omega-3（300 mg / kg /天）口服或腹膜内用甲氨蝶呤（2 mg / kg /周）处理4个星期

结果与结论

所有药物治疗均改善了关节造影评分和后爪肿胀，并降低了血清肿瘤坏死因子（TNF）-α和白介素（IL）-1β的水平。在分子水平上，所有疗法均激活了磷酸5'腺苷单磷酸激活的蛋白激酶（p-AMPK）和蛋白磷酸酶2A（PP2A），而它们却抑制了雷帕霉素（p-mTOR）的磷酸化靶标，磷酸信号转导子以及转录激活因子（p-STAT3），核因子（NF）-κBp65亚基，phosho38丝裂原活化蛋白激酶（p38 MAPK）和磷酸化c-Jun N末端激酶（p-JNK）。此外，它们降低了miRNA-155、146a的升高的表达水平，并且增加了miRNA-34的表达，并且降低了视黄酸受体相关的孤儿受体γT（RORγT）的表达水平，并增加了叉头盒P3的表达水平（ FOXP3），纠正Th17 / Treg细胞平衡。在大多数上述参数上，联合治疗的效果与甲氨蝶呤相当，并强调与单独使用时相比，该组合具有更好的累加抗炎作用。另外，与提供肝保护作用的未治疗组相比，该组合能够使血清转氨酶水平正常化，并暗示了其可作为类风湿关节炎中MTX的替代治疗策略的可能性。