Liensinine reduces acute lung injury brought on by lipopolysaccharide by inhibiting the activation of the NF-κB signaling pathway through modification of the Src/TRAF6/TAK1 axis.

ALI is characterized by macrophage-driven inflammation, causing severe lung damage. Currently, there are limited therapeutic options available for ALI. Liensinine (LIEN), with known anti-inflammatory properties, lacks extensive study in the ALI context. This study aimed to investigate the impact of LIEN on ALI and elucidate its molecular mechanisms. A total of thirty-six male BALB/c mice altogether were split into six groups: Control, LPS (10 mg/kg), Low (10 mg/kg LIEN + 10 mg/kg LPS), Middle (20 mg/kg LIEN + 10 mg/kg LPS), High (40 mg/kg LIEN + 10 mg/kg LPS), and DEX (2 mg/kg DEX + 10 mg/kg LPS). Lung tissue injury, pulmonary edema, and inflammatory factor levels were evaluated in lung tissues and LPS-stimulated bone marrow-derived macrophages (BMDM). TAK1 activation, TRAF6 ubiquitination, and their interactions were assessed to understand the involved molecular mechanisms. LIEN treatment ameliorated lung tissue injury and suppressed LPS-induced inflammatory factor levels in lung tissues and BMDM. Mechanistically, LIEN inhibited TAK1 activation by disrupting TRAF6-TAK1 interactions, limiting p65's nuclear translocation, and reducing the release of inflammatory factors. According to network pharmacology and molecular docking, LIEN most likely prevents inflammation by interfering directly with the Src. Overexpression of Src in BMDM abolished the regulation of TRAF6 by LIEN, supporting the involvement of the Src/TRAF6/TAK1 axis in its mechanism of action. Based on this study, LIEN treats ALI by modifying the Src/TRAF6/TAK1 axis and blocking the activation of the NF-κB pathway, regulating the release of inflammatory factors. These findings highlight the promise of LIEN as a prospective therapeutic option for the treatment of ALI.

Malvidin promotes PGC-1α/Nrf2 signaling to attenuate the inflammatory response and restore mitochondrial activity in septic acute kidney injury.

Acute kidney injury (AKI) in sepsis is a vital and dangerous organ failure caused by an infection-induced dysregulation of the host reaction. Malvidin possesses significant anti-inflammatory and antioxidant bioactivities. This study explored the critical roles of malvidin in sepsis AKI and the crosstalk among mitochondrial function, nucleotide-binding oligomerization-like receptor 3 (NLRP3) inflammasome and nuclear factor erythroid 2 (Nrf2) signaling pathway. First, C57BL/6 mice were administered lipopolysaccharide intraperitoneally for 6 h to create an AKI model of sepsis. Hematoxylin-eosin staining and serum biomarker assays showed that malvidin protected from AKI in sepsis. Real-time fluorescence quantitative polymerase chain reaction analysis revealed that malvidin was able to inhibit inflammatory cytokines and mediators. Western blot assays indicated that malvidin suppressed NLRP3 inflammasome activation and enhanced antioxidant properties. Additionally, human renal tubular epithelial cells were stimulated by lipopolysaccharide/adenosine triphosphate to establish an NLRP3 inflammasome activation model in vitro, and in line with findings in vivo, malvidin significantly inhibited NLRP3 inflammasome activation. Furthermore, our data indicate that malvidin restored mitochondrial quality and function, reduced reactive oxygen species production, increased mitochondrial membrane potential, enhanced mitochondrial DNA copy number, and promoted peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) nuclear translocation. Moreover, inhibitor blockade assays indicated that both PGC-1α and Nrf2 affected the inhibition of the NLRP3 inflammasome by malvidin. Finally, immunoprecipitation assays showed that malvidin promoted PGC-1α and Nrf2 interactions. Overall, malvidin alleviated lipopolysaccharide-induced sepsis AKI, improved mitochondrial function and mitochondrial biogenesis, and inhibited the NLRP3 inflammasome through the PGC-1α/Nrf2 signaling pathway, suggesting that malvidin might translate into clinical applications for sepsis AKI therapy.