Rheumatoid arthritis (RA) is a chronic, systemic, progressive autoimmune disease. The vascular permeability of inflamed joints in RA makes it a natural candidate for passive targeting, similar to the enhanced permeability and retention (EPR) effect in solid tumors. Thus, various therapeutic drugs have been encapsulated in nanocarriers to achieve longer in vivo circulation times and improve RA targeting. Although liposomes are the most widely used nanocarriers for RA treatment, the effects of physical and chemical characteristics of liposomes, such as particle sizes, surface charge, polyethylene glycol (PEG) chain length, and PEG concentration, on their passive RA targeting effect have not been fully elucidated. Here, we systematically investigated the effects of physical and chemical properties of liposomes on circulation time and conducted preliminary studies on their passive targeting mechanisms. A series of liposomes with different particle sizes (70, 100, 200, and 350 nm), surface charges (positive, negative, slight positive, and slight negative), PEG chain lengths (1, 2, and 5 kDa), and concentrations (5, 10, and 20% w/w of total lipid) were prepared by lipid film dispersion and extrusion. The pharmacokinetics of liposomes with different formulas were evaluated with a fluorescence microplate reader. A collagen-induced arthritis (CIA) mouse model was utilized to mimic RA pathological conditions and to evaluate the targeting and efficacy of liposomes with different properties using a near-infrared fluorescence imaging system. Uptake of fluorescent liposomes by various synovial cells was measured by flow cytometry. The results indicated that liposomes with 100 nm diameter, a slight negative charge, and 10% incorporation of 5 kDa PEG had better in vivo circulation time and inflamed joint targeting than did other liposomes. Dexamethasone (Dex) was encapsulated into optimized liposomes as an active ingredient for RA treatment. Pharmacodynamic studies demonstrated that Dex liposomes could significantly improve the antiarthritic efficacy of Dex in a CIA mouse model of RA. This study also found that the retention mechanism of RA was mainly increased because of the uptake of liposomes by fibroblasts and macrophages in inflamed joints. This study provides a persuasive explanation for passive RA targeting by liposomes and advances our ability to treat RA with nanomedicine.

Ginseng has been used worldwide as traditional medicine for thousands of years, and ginsenosides have been proved to be the main active components for their various pharmacological activities. Based on their structures, ginsenosides can be divided into ginseng diol-type A and ginseng triol-type B with different pharmacological effects. In this study, six ginsenosides, namely ginsenoside Rb1, Rh2, Rg3, Rg5 as diol-type ginseng saponins, and Rg1 and Re as triol-type ginseng saponins, which were reported to be effective for ischemia-reperfusion (I/R) treatment, were chosen to compare their protective effects on cerebral I/R injury, and their mechanisms were studied by in vitro and in vivo experiments. It was found that all ginsenosides could reduce reactive oxygen species (ROS), inhibit apoptosis and increase mitochondrial membrane potential in cobalt chloride-induced (CoCl2-induced) PC12 cells injury model, and they could reduce cerebral infarction volume, brain neurological dysfunction of I/R rats in vivo. The results of immunohistochemistry and western blot showed that the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), silencing information regulator (SIRT1) and nuclear transcription factor P65 (NF-κB) in hippocampal CA1 region of some ginsenoside groups were also reduced. In general, the effect on cerebral ischemia of Rb1 and Rg3 was significantly improved compared with the control group, and was the strongest among all the ginsenosides. The effect on SIRT1 activation of ginsenoside Rb1 and the inhibition effect of TLR4/MyD88 protein expression of ginsenoside Rb1 and Rg3 were significantly stronger than that of other groups. The results indicated that ginsenoside Rg1, Rb1, Rh2, Rg3, Rg5 and Re were effective in protecting the brain against ischemic injury, and ginsenoside Rb1 and Rg3 have the strongest therapeutic activities in all the tested ginsenosides. Their neuroprotective mechanism is associated with TLR4/MyD88 and SIRT1 activation signaling pathways, and they can reduce cerebral ischemic injury by inhibiting NF-κB transcriptional activity and the expression of proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).

Epithelial-mesenchymal transition (EMT) is associated with tumor invasion and metastasis, and offers insight into novel strategies for cancer treatment. Sotetsuflavone was isolated from Cycas revolute, which has excellent anticancer activity in the early stages. The present study aims to evaluate the anti-metastatic potential of sotetsuflavone in vitro. Our data demonstrated that sotetsuflavone inhibits metastasis of A549 cells, and EMT. This inhibition was reflected in the upregulation of E-cadherin, and downregulation of N-cadherin, vimentin, and Snail. Mechanistically, our study demonstrated that HIF-1α played an important role in the anti-metastatic effect of sotetsuflavone in non-small-cell lung cancer A549 cells. Sotetsuflavone not only mediated VEGF expression but also downregulated VEGF and upregulated angiostatin, and simultaneously affected the expression of MMPs and decreased MMP-9 and MMP-13 expression. More importantly, HIF-1α expression may be regulated by the inhibition of PI3K/AKT and TNF-α/NF-κB pathways. These results suggest that sotetsuflavone can reverse EMT, thereby inhibiting the migration and invasion of A549 cells. This process may be associated with both PI3K/AKT and TNF-α/NF-κB pathways, and sotetsuflavone may be efficacious in the treatment of non-small-cell lung cancer.

Cerebral ischemia (CI) results from inadequate blood flow to the brain. The difficulty of delivering therapeutic molecules to lesions resulting from CI hinders the effective treatment of this disease. The inflammatory response following CI offers a unique opportunity for drug delivery to the ischemic brain and targeted cells because of the recruitment of leukocytes to the stroke core and penumbra. In the present study, neutrophils and monocytes were explored as cell carriers after selectively carrying cRGD liposomes, which effectively transmigrated the blood-brain barrier, infiltrated the cerebral parenchyma, and delivered therapeutic molecules to the injured sites and target cells. Our results showed the successful comigration of liposomes with neutrophils/monocytes and that both monocytes and neutrophils were important for successful delivery. Enhanced protection against ischemic injury was achieved in the CI/reperfusion model. The strategy presented here shows potential in the treatment of CI and other diseases related to inflammation.