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.
Psoriasis is a chronic autoimmune disease featured by patches on the skin. It is caused by malfunction of immune cells and keratinocytes with inflammation as one of its key features. Apigenin (API) is a natural flavonoid with anti-inflammatory and immunoregulatory properties. Therefore, we speculated that API can ameliorate psoriasis, and determined its effect on the development of psoriasis by using imiquimod (IMQ)-induced psoriasis mouse model. Our results showed that API attenuated IMQ-induced phenotypic changes, such as erythema, scaling and epidermal thickening, and improved splenic hyperplasia. Abnormal differentiation of immune cells was restored in API-treated mice. Mechanistically, we revealed that API is a key regulator of signal transducer activator of transcription 3 (STAT3). API regulated immune responses by reducing interleukin-23 (IL-23)/STAT3/IL-17A axis. Moreover, it suppressed IMQ-caused cell hyperproliferation by inactivating STAT3 through regulation of extracellular signal-regulated kinase 1/2 and nuclear factor-κB (NF-κB) pathway. Furthermore, API reduced expression of inflammatory cytokines through inactivation of NF-κB. Taken together, our study demonstrates that API can ameliorate psoriasis and may be considered as a strategy for psoriasis treatment.
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