Discovery of Novel Pterostilbene Derivatives That Might Treat Sepsis by Attenuating Oxidative Stress and Inflammation through Modulation of MAPKs/NF-κB Signaling Pathways

Antioxidants

Ban-Feng Ruan¹  Mengyuan Fang²  Zhen Zhang²  Yajun Duan²  Tingfeng Zou²  Jihong Han²  Peichang Cao²  Xiaoxiao Yang²  Qing-Shan Li² 

[1] Key Lab of Biofabrication of Anhui Higher Education Institution Centre for Advanced Biofabrication, Hefei University, Hefei 230601, China;Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, China;

关键词: antioxidants;    anti-inflammatory agents;    indanone;    pterostilbene;    sepsis;   

DOI  :  10.3390/antiox10091333

来源: DOAJ

【 摘 要 】

Sepsis remains one of the most common life-threatening illnesses that is characterized by a systemic inflammatory response syndrome (SIRS) and usually arises following severe trauma and various septic infections. It is still in urgent need of new effective therapeutic agents, and chances are great that some candidates can be identified that can attenuate oxidative stress and inflammatory responses. Pterostilbene, which exerts attractive anti-oxidative and anti-inflammatory activities, is a homologue of natural polyphenolic derivative of resveratrol. Starting from it, we have made several rounds of rational optimizations. Firstly, based on the strategy of pharmacophore combination, indanone moiety was introduced onto the pterostilbene skeleton to generate a novel series of pterostilbene derivatives (PIF_1–PIF_16) which could possess both anti-oxidative and anti-inflammatory activities for sepsis treatment. Then, all target compounds were subjected to their structure–activity relationships (SAR) screening of anti-inflammatory activity in mouse mononuclear macrophage RAW264.7 cell line, and their cytotoxicities were determined after. Finally, an optimal compound, PIF_9, was identified. It decreased the mRNA levels of lipopolysaccharide (LPS)-induced interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX2). We also found that the anti-inflammatory effects might be contributed by its suppression on the nuclear factor-κB (NF-κB) and MAPKs signaling pathway. Moreover, PIF_9 also demonstrated potent anti-oxidative activity in RAW264.7 macrophages and the sepsis mouse model. Not surprisingly, with the benefits mentioned above, it ameliorated LPS-induced sepsis in C57BL/6J mice and reduced multi-organ toxicity. Taken together, PIF_9 was identified as a potential sepsis solution, targeting inflammation and oxidative stress through modulating MAPKs/NF-κB.

【 授权许可】

Unknown