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

Mengyuan Fang,Ban-Feng Ruan,Peichang Cao,Jihong Han,Xiaoxiao Yang,Zhen Zhang,Qing-Shan Li,Tingfeng Zou,Yajun Duan

doi:10.3390/antiox10091333

Mengyuan Fang, Ban-Feng Ruan + Show 7 more

Open Access

https://doi.org/10.3390/antiox10091333

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Journal: Antioxidants	Publication Date: Aug 24, 2021
Citations: 18	License type: CC BY 4.0

Affiliation: Hefei University of Technology, Hefei University

Abstract

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.

Highlights

Since tumor necrosis factor-α (TNF-α) and IL-1β are identified as keystone cytokines in the inflammatory process and oxidative stress, we further evaluated the expression of TNF-α and IL-1β expression at protein level
Nikhil et al [19] have shown that pterostilbene derivatives have an inhibitory effect on the release of Nitric oxide (NO) and inflammatory factors, as confirmed by our experimental results. These results further proved that compound PIF_9 was able to inhibit the expression of inflammatory mediators (TNF-α and IL-1β) in addition to NO
We introduced the indanone moiety into the skeleton of pterostilbene based on the strategy of pharmacophore combination and synthesized a series of pterostilbene indanone derivatives possessing anti-oxidative and anti-inflammatory activities for sepsis treatment

Summary

Introduction

Sepsis is caused by a series of inflammatory reactions due to the flow of pathogenic bacteria into various tissues through the bloodstream, which eventually leads to the failure of different organs [1,2]. Owing to the essence of SIRS in sepsis, evaluating the degree of inflammatory reaction of patients can contribute to an accurate assessment of the disease stage [6]. Inflammatory cytokines, such as TNF-α and IL-1β, are first responders which can dysregulate the immune response and cause damage to multiple tissues in sepsis [7,8], because they can be massively produced 4.0/).

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