Monocyte-derived myeloid cells play vital roles in inflammation-related autoimmune/inflammatory diseases and cancers. Here, we report that exosomes can deliver anti-inflammatory agents, such as curcumin, to activated myeloid cells in vivo. This technology provides a means for anti-inflammatory drugs, such as curcumin, to target the inflammatory cells as well as to overcome unwanted off-target effects that limit their utility. Using exosomes as a delivery vehicle, we provide evidence that curcumin delivered by exosomes is more stable and more highly concentrated in the blood. We show that the target specificity is determined by exosomes, and the improvement of curcumin activity is achieved by directing curcumin to inflammatory cells associated with therapeutic, but not toxic, effects. Furthermore, we validate the therapeutic relevance of this technique in a lipopolysaccharide (LPS)-induced septic shock mouse model. We further show that exosomes, but not lipid alone, are required for the enhanced anti-inflammatory activity of curcumin. The specificity of using exosomes as a drug carrier creates opportunities for treatments of many inflammation-related diseases without significant side effects due to innocent bystander or off-target effects.
In this study, exosomes used to encapsulate curcumin (Exo-cur) or a signal transducer and activator of transcription 3 (Stat3) inhibitor, i.e., JSI124 (Exo-JSI124) were delivered noninvasively to microglia cells via an intranasal route. The results generated from three inflammation-mediated disease models, i.e., a lipopolysaccharide (LPS)-induced brain inflammation model, experimental autoimmune encephalitis and a GL26 brain tumor model, showed that mice treated intranasally with Exo-cur or Exo-JSI124 are protected from LPS-induced brain inflammation, the progression of myelin oligodendrocyte glycoprotein (MOG) peptide induced experimental autoimmune encephalomyelitis (EAE), and had significantly delayed brain tumor growth in the GL26 tumor model. Intranasal administration of Exo-cur or Exo-JSI124 led to rapid delivery of exosome encapsulated drug to the brain that was selectively taken up by microglial cells, and subsequently induced apoptosis of microglial cells. Our results demonstrate that this strategy may provide a noninvasive and novel therapeutic approach for treating brain inflammatory-related diseases.
OBJECTIVEWe sought to determine whether exosome-like vesicles (ELVs) released from adipose tissue play a role in activation of macrophages and subsequent development of insulin resistance in a mouse model.RESEARCH DESIGN AND METHODSELVs released from adipose tissue were purified by sucrose gradient centrifugation and labeled with green fluorescent dye and then intravenously injected into B6 ob/ob mice (obese model) or B6 mice fed a high-fat diet. The effects of injected ELVs on the activation of macrophages were determined through analysis of activation markers by fluorescence-activated cell sorter and induction of inflammatory cytokines using an ELISA. Glucose tolerance and insulin tolerance were also evaluated. Similarly, B6 mice with different gene knockouts including TLR2, TLR4, MyD88, and Toll-interleukin-1 receptor (TIR) domain–containing adaptor protein inducing interferon-β (TRIF) were also used for testing their responses to the injected ELVs.RESULTSELVs are taken up by peripheral blood monocytes, which then differentiate into activated macrophages with increased secretion of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Injection of obELVs into wild-type C57BL/6 mice results in the development of insulin resistance. When the obELVs were intravenously injected into TLR4 knockout B6 mice, the levels of glucose intolerance and insulin resistance were much lower. RBP4 is enriched in the obELVs. Bone marrow–derived macrophages preincubated with recombinant RBP4 led to attenuation of obELV-mediated induction of IL-6 and TNF-α.CONCLUSIONSELVs released by adipose tissue can act as a mode of communication between adipose tissues and macrophages. The obELV-mediated induction of TNF-α and IL-6 in macrophages and insulin resistance requires the TLR4/TRIF pathway.
We report here evidence in support of the role of 17beta-estradiol- (E2-) induced mitochondrial (mt) reactive oxygen species (ROS) as signal-transducing messengers. On the basis of monitoring the oxidation of 2',7'-dichlorofluorescin by spectrofluorometry, flow cytometry, and confocal microscopy, we have identified that exposure of E2 triggers the immediate rapid production of intracellular ROS ranging from a 1- to severalfold increase in a variety of cells. E2-stimulated ROS production does not correlate with the activity of the estrogen receptor (ER) in the cells. The ROS is most likely hydrogen peroxide based on its inhibition by antioxidants and catalase and lack of any effects of E2 on O(2)(*)(-) or NO(*) formation. Confocal microscopy showed that ROS is localized in the perinuclear mitochondria. E2 through anchorage- and integrin-dependent signaling to mitochondria increased ROS generation. Increased intracellular ROS formation identified here for the first time may explain the mechanism of previously reported oxidative damage and subsequent genetic alterations including mutations produced by elevated concentrations of estrogens. The functional consequences of E2-induced ROS formation included the enhanced cell motility as shown by the increase in cdc42 and activation of Pyk2 and the increased phosphorylation of signaling proteins c-jun and CREB. E2-induced ROS activated the binding of three oxidant-sensitive transcription factors: AP-1, CREB, and nuclear respiratory factor 1. In addition to ERs as signaling molecules, our findings further revealed that E2-induced mt ROS also act as signal transducing messengers and suggest new targets for the development of antioxidant-based drugs or antioxidant gene therapy for the prevention and treatment of estrogen-dependent cancer.
The neck circumference, as waist circumference, is also a valuable tool for identifying MetS and obesity, with established cut-off points for the prediction of MetS and obesity in Chinese elders.
Performing current shift work and performing shift work previously were significantly associated with poor sleep quality. An appropriate arrangement and intervention strategies are needed in Chinese hospitals in order to improve sleep quality among shift-working nurses.
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