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Psoriasis is a chronic, systemic immune-mediated skin disease. Although many new strategies for psoriasis treatment have been developed, there is great need in clinic for treating psoriasis. Gentiopicroside (GPS), derived from Gentiana manshurica Kitagawa, has multiple pharmacological activities including anti-inflammatory, anti-oxidative and antiviral activities. In this study, we investigated the potential effects of GPS in imiquimod (IMQ)-induced psoriasis mouse model and the underlying mechanisms. The mice were sensitized on their shaved back with IMQ cream for 7 days with or without topical application of 1% or 2% GPS cream. We showed that the application of GPS cream significantly ameliorated psoriasis-like skin lesions; GPS effect was better than that of calcipotriol. GPS rectified the immune cells infiltration and keratinocytes activation in the skin lesions, and significantly inhibited TNF-α/IFN-γ stimulated human keratinocyte (HaCaT) activation in vitro. Proteomic analysis from keratinocytes with and without GPS treatment prompted that GPS regulated the Keap1-Nrf2 pathway, which was the most important pathway in regulating oxidative stress and inflammation. We demonstrated that GPS regulated the protein expression of p62 and Keap1, induced Nrf2 nuclear translocation followed by transcription of Nrf2 downstream antioxidant genes in HaCaT cells. Furthermore, the antioxidant effects of GPS were abolished in Nrf2 -/- keratinocytes. Simultaneously, Nrf2 -/- mice showed increased psoriasiform symptoms with a diminished protective effect in response to GPS treatment. Collectively, the study discloses that GPS inhibits keratinocyte activation and ameliorates psoriasis-like skin lesions in an Nrf2-dependent manner., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Sepsis,a syndrome characterized by organ dysfunction caused by infection,exhibits high incidence and mortality.The pathogenesis of sepsis is complex and involves a cascade of immune reactions,with no specific drugs currently available.Sepsis is mainly treated with Western medical supportive therapies such as antibiotics,hemodynamic management,and mechanical ventilation.However,the occurrence of immune cascades significantly increases patients' vulnerability to secondary infections,leading to septic shock and unfavorable prognoses.International consensus indicates that initiating dynamic monitoring of patients' immune function within 48 h post-sepsis diagnosis can effectively decelerate sepsis progression.Extensive studies have indicated that macrophages,serving as the first line of defense in the innate immune system against pathogens,play a vital role in treating immune system disorders by regulating macrophage polarization and the ratio of cytokines activated.Mitophagy,a hot topic in recent years,has increasingly been shown to play a crucial role in regulating inflammatory signal transduction.Promoting mitophagy during the stage of cytokine storm can mitigate uncontrolled infection and excessive inflammation in sepsis,and inhibiting mitophagy during immunosuppression can enhance host immunity,facilitate bacterial clearance,and improve the survival rate of patients.The idea of treating disease before its onset in traditional Chinese medicine (TCM) coincides with the current consensus among sepsis experts on prevention and interception.The TCM therapies such as extracts of Chinese medicine decoction pieces,TCM compound prescriptions,and acupuncture and moxibustion have the effects of clearing heat and detoxifying,activating blood and resolving stasis,reinforcing healthy qi and consolidating root,and purging.These approaches dynamically regulate the levels of mitophagy-related proteins,such as phosphatase and tension homology-induced putative kinase 1,Parkin-E3 ubiquitin protein ligase,light chain 3,and p62,while maintaining a suitable ratio between M1 and M2 macrophages.Consequently,they effectively prevent,halt,or even reverse the progression of sepsis,offering a novel perspective on sepsis management by emphasizing prevention before disease onset and controlling development of existing disease.