Ranjit Arina, Khajeh Pour Sana, Aghazadeh-Habashi Ali
College of Pharmacy, Idaho State University, Pocatello, ID 83209, USA.
Pharmaceutics. 2022 Aug 12;14(8):1681. doi: 10.3390/pharmaceutics14081681.
Rheumatoid arthritis (RA) is an autoimmune inflammatory bone destructive disorder that is orchestrated by multiple systems in the body, including Renin-Angiotensin System (RAS) and arachidonic acid (ArA) pathway. Current therapeutic options are not highly effective and are associated with severe side effects, including cardiovascular complications. Therefore, new safe and effective disease modulators are seriously needed. In this study, we investigate the anti-inflammatory effects of a synthetic peptide, novokinin, through Angiotensin Type (II) receptor (AT2R). Peptide drugs like novokinin suffer from plasma instability and short half-life. Thus, we developed a novel bone targeting novokinin conjugate (Novo Conj). It uses the bone as a reservoir for sustained release and protection from systemic degradation, improving stability and enhancing pharmacological efficacy. We tested Novo Conj's anti-inflammatory effects in adjuvant-induced arthritis (AIA) rat model to prove our hypothesis by measuring various RAS and ArA pathway components. We observed that inflammation causes a significant imbalance in cardioprotective RAS components like ACE2, AT2R, and Ang 1-7 and increases the ArA inflammatory metabolites like hydroxyeicosatetraenoic acids (HETEs). Treatment with novokinin or Novo Conj restores balance in the RAS and favors the production of different epoxyeicosatrienoic acids (EETs), which are anti-inflammatory mediators. This study demonstrated that the bone-targeted delivery improved the stability and enhanced the anti-inflammatory effects of the parent peptide novokinin in AIA. These observations offer an efficacious alternative therapy for managing RA.
类风湿性关节炎（RA）是一种自身免疫性炎症性骨破坏疾病，由体内多个系统共同作用引发，包括肾素-血管紧张素系统（RAS）和花生四烯酸（ArA）途径。目前的治疗方法效果并不显著，且伴有严重的副作用，包括心血管并发症。因此，迫切需要新的安全有效的疾病调节剂。在本研究中，我们通过血管紧张素II型受体（AT2R）研究了合成肽novokinin的抗炎作用。像novokinin这样的肽类药物存在血浆稳定性差和半衰期短的问题。因此，我们开发了一种新型的骨靶向novokinin偶联物（Novo Conj）。它利用骨骼作为储存库，实现持续释放并防止全身降解，从而提高稳定性并增强药理疗效。我们在佐剂诱导的关节炎（AIA）大鼠模型中测试了Novo Conj的抗炎作用，通过测量各种RAS和ArA途径成分来验证我们的假设。我们观察到炎症会导致心脏保护RAS成分如ACE2、AT2R和Ang 1-7出现显著失衡，并增加ArA炎症代谢产物如羟基二十碳四烯酸（HETEs）。用novokinin或Novo Conj治疗可恢复RAS的平衡，并有利于产生不同的环氧二十碳三烯酸（EETs），这些都是抗炎介质。本研究表明，骨靶向递送提高了母体肽novokinin在AIA中的稳定性并增强了其抗炎作用。这些观察结果为治疗RA提供了一种有效的替代疗法。
