Persistent cellular stress induced perpetuation and uncontrolled amplification of inflammatory response results in a shift from tissue repair toward collateral damage, significant alterations of tissue functions, and derangements of homeostasis which in turn can lead to a large number of acute and chronic pathological conditions, such as chronic heart failure, atherosclerosis, myocardial infarction, neurodegenerative diseases, diabetes, rheumatoid arthritis, and cancer. Keeping the vital role of balanced inflammation in maintaining tissue integrity in mind, the way to combating inflammatory diseases may be through identification and characterization of mediators of inflammation that can be targeted without hampering normal body function. Pirin (PIR) is a non-heme iron containing protein having two different conformations depending on the oxidation state of the iron. Through exploration of the Pirin interactome and using molecular docking approaches, we identified that the Fe2+-bound Pirin directly interacts with BCL3, NFKBIA, NFIX and SMAD9 with more resemblance to the native binding pose and higher affinity than the Fe3+-bound form. In addition, Pirin appears to have a function in the regulation of inflammation, the transition between the canonical and non-canonical NF-κB pathways, and the remodeling of the actin cytoskeleton. Moreover, Pirin signaling appears to have a critical role in tumor invasion and metastasis, as well as metabolic and neuro-pathological complications. There are regulatory variants in PIR that can influence expression of not only PIR but also other genes, including VEGFD and ACE2. Disparity exists between South Asian and European populations in the frequencies of variant alleles at some of these regulatory loci that may lead to differential occurrence of Pirin-mediated pathogenic conditions.

中文翻译：

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Pirin 结合辅因子的氧化还原状态在与炎症和其他途径的主要调节因子相互作用中的作用。

持续的细胞应激诱导炎症反应的持续存在和不受控制的放大，导致从组织修复转向附带损伤、组织功能显着改变以及体内平衡紊乱，进而导致大量急性和慢性病理状况，例如慢性心力衰竭、动脉粥样硬化、心肌梗塞、神经退行性疾病、糖尿病、类风湿性关节炎和癌症。考虑到平衡炎症在维持组织完整性方面的重要作用，对抗炎症性疾病的方法可能是通过识别和表征炎症介质，这些介质可以在不妨碍正常身体功能的情况下进行靶向治疗。Pirin (PIR) 是一种非血红素含铁蛋白质，根据铁的氧化态具有两种不同的构象。通过探索 Pirin 相互作用组并使用分子对接方法，我们发现 Fe2+ 结合的 Pirin 直接与 BCL3、NFKBIA、NFIX 和 SMAD9 相互作用，比 Fe3+ 结合形式更类似于天然结合姿势，亲和力更高。此外，Pirin 似乎在炎症调节、经典和非经典 NF-κB 通路之间的转换以及肌动蛋白细胞骨架的重塑中具有功能。此外，Pirin 信号传导似乎在肿瘤侵袭和转移以及代谢和神经病理并发症中发挥着关键作用。PIR 中的调控变异不仅可以影响 PIR 的表达，还可以影响其他基因的表达，包括 VEGFD 和 ACE2。南亚和欧洲人群中某些调控位点的变异等位基因频率存在差异，这可能导致 Pirin 介导的致病条件的不同发生。