luteolin-7-glucoside and Sepsis

Reduning injection (RDN), a popular traditional Chinese medicine, formulated by three herbs (i.e., Artemisia carvifolia Buch.-Ham. ex Roxb., Lonicera japonica Thunb., and Gardenia jasminoides J. Ellis), has been widely used to treat upper respiratory infectious diseases in China.. To investigate the protective effect of RDN on both lipopolysaccharides (LPS)- and cecal ligation and puncture (CLP)-induced septic mice. To identify the potentially effective constituent, and to determine its protective effect and underlying mechanism in vivo and in vitro.. Male C57BL/6 mice were used to establish septic model by tail intravenous injection of 4 mg/kg LPS or CLP surgery. After modeling, mice were administered by tail intravenous injection of RDN in the dose of 16 or 8 mL/kg/day. The mortality, histopathology, plasma levels of inflammatory cytokines were evaluated respectively. In addition, we screened the potentially effective substances of RDN against sepsis by detecting the nitric oxide (NO) production in LPS-stimulated Raw 264.7 cells and verified the effect of luteoloside in CLP-induced septic mice subsequently. Finally, the underlying mechanisms of RDN and luteoloside were investigated in the inflammatory model in vitro.. Administration of RDN significantly reduced the mortality and increased the survival rate in both LPS- and CLP-induced septic mice. Meanwhile, RDN reduced the release of inflammatory cytokines accompanied by alleviating the organs damage of lung, liver, and kidney in CLP-induced septic mice. Moreover, several components from Gardenia jasminoides J. Ellis extract (ZZ) or Lonicera japonica Thunb and Artemisia carvifolia Buch.-Ham. ex Roxb extract (JQ) as well as the constituents of luteoloside, quercetin, and caffeic acid were screened out to have obvious anti-inflammatory activity, which may be the potentially effective substances of RDN against sepsis. We further verified the protective role of luteoloside in CLP-induced septic mice. In addition, RDN and luteoloside significantly inhibited both the secretion and translocation of mobility group box (HMGB)1, and HMGB1-mediated activation of TLR4/NF-κB/MAPKs signaling pathways.. RDN and its effective constituent luteoloside exhibited a significant protective effect against sepsis, which were potential candidate drugs for treatment of sepsis. The mechanism of antisepsis partly was related to inhibition of HMGB1/TLR4/NF-κB/MAPKs signaling pathways. The results provide an evidence base for the follow-up clinical application of RDN in treatment of sepsis.

Topics: Animals; Anti-Infective Agents, Local; Cecum; Disease Models, Animal; Drugs, Chinese Herbal; Glucosides; HMGB1 Protein; Injections; Lipopolysaccharides; Luteolin; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Myeloid Differentiation Factor 88; NF-kappa B p50 Subunit; Nitric Oxide; Protective Agents; RAW 264.7 Cells; Sepsis; Signal Transduction; Toll-Like Receptor 4

The treatment of sepsis is still challenging and the liver is an important target of sepsis-related injury. Macrophages are important innate immune cells in liver, and modulation of macrophages M1/M2 polarization may be a promising strategy for septic liver injury treatment. Macrophage polarization and inflammation of liver tissue has been shown regulated by pyruvate kinase M2 (PKM2)-mediated aerobic glycolysis and immune inflammatory pathways. Therefore, modulating PKM2-mediated immunometabolic reprogramming presents a novel strategy for inflammation-associated diseases. In this study, cynaroside, a flavonoid compound, promoted macrophage phenotypic transition from pro-inflammatory M1 to anti-inflammatory M2, and mitigated sepsis-associated liver inflammatory damage. We established that cynaroside reduced binding of PKM2 to hypoxia-inducible factor-1α (HIF-1α) by abolishing translocation of PKM2 to the nucleus and promoting PKM2 tetramer formation, as well as suppressing phosphorylation of PKM2 at Y105 in vivo and in vitro. Moreover, cynaroside restored pyruvate kinase activity, inhibited glycolysis-related proteins including PFKFB3, HK2 and HIF-1α, and inhibited glycolysis-related hyperacetylation of HMGB1 in septic liver. Therefore, this study reports a novel function of cynaroside in hepatic macrophage polarization, and cecum ligation and puncture-induced liver injury in septic mice. The findings provide crucial information with regard to therapeutic efficacy of cynaroside in the treatment of sepsis.

Topics: Animals; Glucosides; Hypoxia-Inducible Factor 1, alpha Subunit; Liver; Luteolin; Macrophage Activation; Macrophages; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Phosphorylation; Pyruvate Kinase; RAW 264.7 Cells; Sepsis