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

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.

Gene signature for the prediction of the trajectories of sepsis-induced acute kidney injury

“…This gene has been found to mediate activation of MAPK8 and MAP kinase p38 [27,28]. Consistent with our findings, p38 MAPK is involved in the development of sepsis-related multiple organ failure, including AKI [29][30][31]. It would be reasonable to hypothesize that inhibition of this pathway may protect against AKI.…”

Integrated Single Cell and Bulk RNA-Seq Analysis Revealed Immunomodulatory Effects of Ulinastatin in Sepsis: A Multicenter Cohort Study

“…These suppressed genes were significantly enriched in the Fc receptor signaling pathways, phagocytosis, neutrophil degranulation, and neutrophil mediated immunity ( Figure 2B ). Many genes involved in neutrophil mediated immunity were established to play important roles in the pathogenesis of sepsis, such as MAPK14 ( 3 , 34 ), TLR2 ( 35 , 36 ), FPR2 ( 37 ) and ITGAM ( 38 ). Interestingly, pathways involving neutrophil activation and degranulation were clustered together to form the largest cluster of top enriched pathways ( Figure 2D ).…”

“…Although sepsis is initially caused by infection, subsequent organ dysfunction is the result of uncontrolled inflammatory response. Thus, strenuous effects have been made to develop immunomodulatory drugs, such as corticosteroids, topoisomerase inhibitors, rhodomeroterpene and pterostilbene ( 3 – 7 ). However, few agents have been proven to be clinically effective in reducing sepsis outcomes.…”

Sulforaphane prevents LPS-induced inflammation by regulating the Nrf2-mediated autophagy pathway in goat mammary epithelial cells and a mouse model of mastitis

“…Gram-negative bacteria, especially Escherichia coli ( E. coli ), are common pathogens of mastitis in ruminants [ 40 – 42 ]. LPS released from the bacterial cell wall causes a series of cellular immune responses, activating of inflammatory signaling, and producing of cytokines, and ROS [ 43 ]. Excessive ROS can further exacerbate the inflammatory response, which further increases the intensity of oxidative stress, leading to a vicious cycle of oxidative stress and inflammatory response [ 44 ].…”