ABSTRACT
Sepsis is a lethal systemic inflammatory disease against infection that lacks effective therapeutic approaches. Liver resident macrophage Kupffer cell (KC)-initiated bacterial clearance is crucial for the host to defend against infection. However, it remains unclear whether this process also governs the antibacterial therapy of sepsis that would be used to improve therapeutic outcomes. Here, we found that copper-doped carbon dots (Cu-CDs) exhibited superior antibacterial capabilities in vitro but displayed limited therapeutic effects in septic mice due to their limited ability to target the liver and restore KC antimicrobial capacity. Thus, we developed a composite nanodrug of copper-doped carbon dot-loaded apoVs (CC-apoVs) that combined the antibacterial ability of Cu-CDs and liver KC targeting features of apoV. Moreover, intravenous injection of CC-apoVs markedly alleviated the systemic infection and decreased the mortality of septic mice compared to Cu-CD and apoV infusion alone. Mechanistically, CC-apoV injection rescued impaired liver KCs during sepsis and enhanced their ability to capture and kill bloodborne bacteria. In addition, apoV-promoted macrophage killing of bacteria could be blocked by the inhibition of small GTPase Rab5. This study reveals a liver KC-targeted therapeutic strategy for sepsis and provides a nanodrug CC-apoV to improve the host antibacterial defense and amplify the therapeutic effect of the nanodrug.
Subject(s)
Anti-Bacterial Agents , Carbon , Kupffer Cells , Sepsis , Animals , Mice , Kupffer Cells/drug effects , Kupffer Cells/metabolism , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Sepsis/drug therapy , Sepsis/microbiology , Sepsis/pathology , Carbon/chemistry , Carbon/pharmacology , Apoptosis/drug effects , Liver/pathology , Liver/drug effects , Mice, Inbred C57BL , Male , Quantum Dots/chemistry , Copper/chemistry , Copper/pharmacology , Microbial Sensitivity TestsABSTRACT
In this paper a new electrochemical DNA biosensor was prepared by using graphene (GR) and nickel oxide (NiO) nanocomposite modified carbon ionic liquid electrode (CILE) as the substrate electrode. GR and NiO nanoparticles were electrodeposited on the CILE surface step-by-step to get the nanocomposite. Due to the strong affinity of NiO with phosphate groups of ssDNA, oligonucleotide probe with a terminal 5'-phosphate group could be attached on the surface of NiO/GR/CILE, which could further hybridize with the target ssDNA sequence. Methylene blue (MB) was used as the electrochemical indicator for monitoring the hybridization reaction. Under the optimal conditions the reduction peak current of MB was proportional to the concentration of salmonella enteritidis gene sequence in the range from 1.0×10(-13) to 1.0×10(-6)molL(-1) with a detection limit as 3.12×10(-14)molL(-1). This electrochemical DNA sensor exhibited good discrimination ability to one-base and three-base mismatched ssDNA sequences, and the polymerase chain reaction amplification product of salmonella enteritidis gene sequences were further detected with satisfactory results.
