Rationale: Atherosclerosis is characterized by lipid accumulation, plaque formation, and artery stenosis. The pharmacological treatment is a promising therapy for atherosclerosis, but this approach faces major challenges such as targeted drug delivery, controlled release, and non-specific clearance. Methods: Based on the finding that the cathepsin k (CTSK) enzyme is enriched in atherosclerotic lesions, we constructed an integrin α v β 3 targeted and CTSK-responsive nanoparticle to control the release of rapamycin (RAP) locally. The targeted and responsive nanoparticles (T/R NPs) were engineered by the self-assembly of a targeting polymer PLGA-PEG-c(RGDfC) and a CTSK-sensitive polymer PLGA-Pep-PEG. PLGA-Pep-PEG was also modified with a pair of FRET probe to monitor the hydrolysis events. Results: Our results indicated that RAP@T/R NPs accelerated the release of RAP in response to CTSK stimulation in vitro , which significantly inhibited the phagocytosis of OxLDL and the release of cytokines by inflammatory macrophages. Additionally, T/R NPs had prolonged blood retention time and increased accumulation in the early and late stage of atherosclerosis lesions. RAP@T/R NPs significantly blocked the development of atherosclerosis and suppressed the systemic and local inflammation in ApoE -/- mice. Conclusions: RAP@T/R NPs hold a great promise as a drug delivery system for safer and more efficient therapy of atherosclerosis.

No abstract

BackgroundPrimary angiitis of the central nervous system (PACNS) is a severe inflammatory disease, and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) has been reported to be associated with inflammation of the CNS. However, the role of sTREM2 in PACNS remains unknown.MethodsWe obtained serum and cerebrospinal fluid (CSF) samples from 18 patients diagnosed with PACNS, as well as 14 patients diagnosed with other neurological disorders with no evidence of inflammation. sTREM2 concentrations in the samples were detected by enzyme-linked immunosorbent assay. And routine CSF measurements of PACNS patients were analysed, including number of White Blood Cells (WBC), protein, Immunoglobulin G (IgG) index and CSF/serum quotients. Levels of inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-6, IL-8, IL-1β, and complement C4, also were tested. The modified Rankin scale (mRS), National Institutes of Health Stroke Scale (NIHSS), and activities of daily living (ADL) scores were obtained as indicators of disease severity. In PACNS patients, cerebral lesion volume was evaluated by magnetic resonance imaging.ResultssTREM2 levels in serum and CSF were significantly elevated in PACNS patients and significantly associated with the mRS, NIHSS and ADL scores as well as inflammatory cytokine levels. Additionally, positive correlations were observed between the cerebral lesion volume and the sTREM2 levels in both blood and CSF. Higher sTREM2 levels in either the blood or CSF seemed to predict a good prognosis in PACNS patients.ConclusionOur results indicate an association between serum and CSF sTREM2 levels and the severity of neurological damage. Thus, sTREM2 represents a potential biomarker for monitoring disease and potentially predicting the prognosis of PACNS patients.

Background Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disease characterized by complex neuropsychiatric syndrome and cerebrospinal fluid (CSF) NMDAR antibodies. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to be associated with inflammation of the central nervous system (CNS). Matrix metalloproteinase-9 (MMP9) and cluster of differentiation (CD44) were measured to evaluate blood‒brain barrier (BBB) permeability in anti-NMDAR encephalitis. The roles of microglial activation and BBB disruption in anti-NMDAR encephalitis are not well known. Findings In this work, we detected increased expression levels of CSF sTREM2, CSF and serum CD44, and serum MMP9 in anti-NMDAR encephalitis patients compared with controls. CSF sTREM2 levels were positively related to both CSF CD44 levels (r = 0.702, p < 0.0001) and serum MMP9 levels (r = 0.428, p = 0.021). In addition, CSF sTREM2 levels were related to clinical parameters (modified Rankin Scale scores, r = 0.422, p = 0.023, and Glasgow Coma Scale scores, r = − 0.401, p = 0.031). Conclusion Increased sTREM2 levels in CSF as well as increased CD44 and MMP9 in serum and CSF reflected activation of microglia and disruption of the BBB in anti-NMDAR encephalitis, expanding the understanding of neuroinflammation in this disease. The factors mentioned above may have potential as novel targets for intervention or novel diagnostic biomarkers.

Background Anti-NMDA receptor encephalitis is an autoimmune disease characterized by complex neuropsychiatric syndrome and cerebrospinal fluid (CSF) NMDAR antibodies. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to be associated with inflammation of the CNS. Matrix metalloproteinase-9 (MMP9) and the cluster of differentiation (CD44) were measured to evaluate the blood-brain barrier (BBB) permeability of anti-NMDAR encephalitis. The roles of the microglia activation and disruption of BBB in anti-NMDAR encephalitis are not well known. Findings: In this work, we detected the increased expression level of CSF sTREM2, CSF and serum CD44, and serum MMP9 in anti-NMDAR encephalitis patients, compared with control groups. CSF sTREM2 levels were positively related to both the CSF CD44 levels (r = 0.702, p < 0.0001) and serum MMP9 levels (r = 0.428, p = 0.021). In addition, CSF sTREM2 levels were related to the clinical parameters (mRS scale, r = 0.422, p = 0.023, and GCS scores, r=-0.401, p = 0.031). Conclusion The increased CSF sTREM2 levels and CD44, and MMP9 in serum or CSF showed evidence of the activated microglia and the disruption of BBB in anti-NMDAR encephalitis, expanding the understanding of the neuroinflammation in this disease. These factors mentioned above may be considered novel targets for intervention or novel potential diagnostic biomarkers.