ABSTRACT
In the progression of acute inflammation, the activation and recruitment of macrophages and neutrophils are mutually reinforcing, leading to amplified inflammatory response and severe tissue damage. Therefore, to regulate the axis of neutrophils and macrophages is essential to avoid tissue damage induced from acute inflammatory. Apoptotic neutrophils can regulate the anti-inflammatory activity of macrophages through the efferocytosis. The strategy of in situ targeting and inducing neutrophil apoptosis has the potential to modulate macrophage activity and transfer anti-inflammatory drugs. Herein, a natural glycyrrhiza protein nanoparticle loaded with dexamethasone (Dex@GNPs) was constructed, which could simultaneously regulate neutrophil and macrophage function during acute inflammation treatment by combining in situ neutrophil apoptosis and macrophage efferocytosis. Dex@GNPs can be rapidly and selectively internalized by neutrophils and subsequently induce neutrophils apoptosis through a ROS-dependent mechanism. The efferocytosis of apoptotic neutrophils not only promoted the polarization of macrophages into anti-inflammatory state, but also facilitated the transfer of Dex@GNPs to macrophages. This enabled dexamethasone to further modulate macrophage function. In mouse models of acute respiratory distress syndrome and sepsis, Dex@GNPs significantly ameliorated the disordered immune microenvironment and alleviated tissue injury. This study presents a novel strategy for drug delivery and inflammation regulation to effectively treat acute inflammatory diseases.
Subject(s)
Anti-Inflammatory Agents , Apoptosis , Dexamethasone , Glycyrrhiza , Inflammation , Macrophages , Nanoparticles , Neutrophils , Animals , Dexamethasone/administration & dosage , Dexamethasone/pharmacology , Apoptosis/drug effects , Neutrophils/drug effects , Neutrophils/immunology , Nanoparticles/chemistry , Macrophages/drug effects , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Inflammation/drug therapy , Glycyrrhiza/chemistry , Mice, Inbred C57BL , Male , Mice , Phagocytosis/drug effects , Humans , Sepsis/drug therapy , Sepsis/immunology , Respiratory Distress Syndrome/drug therapy , RAW 264.7 Cells , EfferocytosisABSTRACT
Dampened peripheral clocks have been linked to osteoarthritis (OA), yet it is unclear whether drugging the clock can ameliorate OA. Given that RORs and REV-ERBs mediate respectively, positive and negative transcriptional feedback of the master clock gene BMAL1, we investigate whether RORs agonist Nobiletin (NOB) and SR1078, and REV-ERBs antagonist SR8278 can enhance BMAL1 expression and attenuate cartilage degeneration. NOB and SR8278 promoted BMAL1 expression and elicited mitigating effects against IL-1ß-induced degeneration of cartilage explants, as evidenced by increased cellular density and collagen synthesis along with alleviated catabolism and collagen denaturation. Despite promoted BMAL1 expression, SR1078 concomitantly suppressed chondrocyte anabolism and catabolism. Consistent with these findings, NOB and SR8278 treatment, but not SR1078, effectively attenuated structural destruction of articular cartilage in surgery-induced OA mouse models. Notably, the beneficial effects of NOB and SR8278 were evidently observed in IL-1ß-induced degeneration of human cartilage explants and immortalized human chondrocytes. Moreover, BMAL1 knockdown assays indicated that NOB and SR8278 enhanced clock function and concordantly rendered protection against altered anabolism and catabolism in a BMAL1-dependent regime. Collectively, our study suggests that targeting RORs and REV-ERBs to promote the dampened peripheral clocks could be a route taken to apply chronotherapy within the context of OA.
Subject(s)
Cartilage, Articular , Circadian Clocks , Osteoarthritis , Mice , Animals , Humans , Circadian Clocks/genetics , ARNTL Transcription Factors/genetics , ARNTL Transcription Factors/metabolism , Feedback , Chondrocytes/metabolism , Osteoarthritis/drug therapy , Osteoarthritis/genetics , Osteoarthritis/metabolism , Cartilage/metabolism , Cartilage, Articular/metabolismABSTRACT
A continuous-flow Anaerobic/Anoxic/Oxic (A2/O) system was operated at different organic concentrations to systematically investigate the effect on the nutrient removal, secretion characteristics of extracellular polymer, phosphorus forms transformation and changes in functional flora in this system. The results showed that high organic loading was more conducive to promote the secretion of extracellular polymeric substance (EPS), the increase of polysaccharide content was more obvious compared with protein, the impact of organic loading on the components of loosely bound EPS (LB-EPS) was higher than that of tight-bound EPS (TB-EPS). Phosphorus in sludge floc mainly existed in the form of inorganic phosphorus (IP), and IP mainly existed in the form of apatite inorganic phosphorus (AP). High organic load showed higher phosphorus storage in EPS, and the phosphorus content in EPS was positively correlated with the content of EPS. Non-apatite phosphorus (NAIP) content played an important role in the extracellular dephosphorization. The abundance of Nitrosomonas and Nitrospira responsible for nitrification decreased with the increase in organic loading. The group of denitrifiers was large, and Azospira was the most abundant genus among them. Dechloromonas, Acinetobacter, Povalibacter, Chryseolinea and Pirellula were the functional genera closely associated with phosphorus removal.