ABSTRACT
BACKGROUND: Neutrophil extracellular traps (NETs) is the key means for neutrophils to resist bacterial invasion. Sepsis is a systemic inflammatory response syndrome caused by infection. METHODS: In our study, qRT-PCR was used to detect the gene expression in neutrophils, Western blot was used to detect the protein expression in mouse tissues and neutrophils, flow cytometry was used to detect the purity of neutrophils in the whole blood and immunofluorescence was used to detect the NETs formation. RESULTS: In this study, we analyzed the NETs formation in the blood of patients with sepsis. The results showed that a large number of NETs appeared. And the expression of GPR109A in neutrophils of patients with sepsis was significantly up regulated. Then we collected neutrophils from WT mice and GPR109A-/- mice and found that GPR109A knockout could significantly inhibit the early NETs formation of neutrophils. The results also showed that knockout of GPR109A or inhibition of the NETs formation could increase the inflammatory response of liver, spleen, lung and kidney in mice, thus affecting the disease process of sepsis. Then we observed the death of mice in 16 days. The results showed that inhibiting the NETs formation could significantly affect the early mortality of mice, while knocking out GPR109A could directly affect the mortality of the whole period. CONCLUSIONS: This study confirmed the regulatory effect of GPR109A on early NETs formation for the first time, and provided a new target for the treatment of sepsis.
ABSTRACT
Our previous study showed that α-Cyperone inhibited the inflammatory response triggered by activated microglia and protected dopaminergic neuron in in vitro cell model of Parkinson's disease (PD). It is unclear the effect of α-Cyperone in animal models of PD. In this study, our results indicated that α-Cyperone ameliorated motor dysfunction, protected dopaminergic neurons, and inhibited the reduction of dopamine and its metabolites in lipopolysaccharide (LPS)-induced PD rat model. Moreover, α-Cyperone suppressed the activation of microglia and the expression of neuroinflammatory factor (TNF-α, IL-6, IL-1ß, iNOS, COX-2 and ROS). Furthermore, the molecular mechanism research revealed that α-Cyperone inhibited neuroinflammation and oxidative stress to exert protective effect in microglia by activating Nrf2/HO-1 and suppressing NF-κB signaling pathway. Moreover, α-Cyperone upregulated the expression of antioxidant enzymes (GCLC, GCLM and NQO1) in microglia. In conclusion, our study demonstrates α-Cyperone alleviates dopaminergic neurodegeneration by inhibiting neuroinflammation and oxidative stress in LPS-induced PD rat model via activating Nrf2/HO-1 and suppressing NF-κB signaling pathway.
