Direct Macromolecular Drug Delivery to Cerebral Ischemia Area using Neutrophil-Mediated Nanoparticles.

Delivery of macromolecular drugs to the brain is impeded by the blood brain barrier. The recruitment of leukocytes to lesions in the brain, a typical feature of neuroinflammation response which occurs in cerebral ischemia, offers a unique opportunity to deliver drugs to inflammation sites in the brain. In the present study, cross-linked dendrigraft poly-L-lysine (DGL) nanoparticles containing cis-aconitic anhydride-modified catalase and modified with PGP, an endogenous tripeptide that acts as a ligand with high affinity to neutrophils, were developed to form the cl PGP-PEG-DGL/CAT-Aco system. Significant binding efficiency to neutrophils, efficient protection of catalase enzymatic activity from degradation and effective transport to receiver cells were revealed in the delivery system. Delivery of catalase to ischemic subregions and cerebral neurocytes in MCAO mice was significantly enhanced, which obviously reducing infarct volume in MCAO mice. Thus, the therapeutic outcome of cerebral ischemia was greatly improved. The underlying mechanism was found to be related to the inhibition of ROS-mediated apoptosis. Considering that neuroinflammation occurs in many neurological disorders, the strategy developed here is not only promising for treatment of cerebral ischemia but also an effective approach for various CNS diseases related to inflammation.

The flavonoid TL-2-8 induces cell death and immature mitophagy in breast cancer cells via abrogating the function of the AHA1/Hsp90 complex.

The flavonoid quercetin exhibits significant anticancer activities with few side effects. In the current study, we characterized TL-2-8, a quercetin derivative, as a novel anticancer agent in vitro and in vivo. Cell proliferation and viability were assessed using Cell Counting Kit-8 and CellTiter-Blue assay, respectively. Cell death was examined using PI staining or a TUNEL assay. Mitophagy was determined by measuring autophagic flux and by confocal imaging. Protein expression was examined by Western blotting. We found that TL-2-8 selectively inhibited the proliferation and decreased the viability of various cancer cells (the anti-proliferation IC50 values in MDA-MB-231, MDA-MB-468 and MCF-7 breast cancer cells at 72 h were 8.28, 8.56, and 9.58 µmol/L, respectively), and it displayed only slight cytotoxicity against normal MCF-10A and HEK-293 cells. In MDA-MB-231 and MDA-MB-468 breast cancer cells, TL-2-8 treatment induced the degradation of multiple Hsp90 client proteins without inducing Hsp70. TL-2-8 (3, 6, 12 µmol/L) dose-dependently inhibited the expression of AHA1, an activator of Hsp90 ATPase, and decreased Hsp90-AHA1 complex formation, leading to decreased Hsp90 chaperone function and reduced polo-like kinase 1 (PLK1) signaling. Consequently, impaired mitophagy was induced via the downregulation of lysosomal-associated membrane protein 2 (LAMP2). The in vivo anticancer effects of TL-2-8 were evaluated in an MDA-MB-231 breast cancer xenograft model, which was treated with TL-2-8 (25, 50, 100 mg·kg-1·d-1, po). Administration of TL-2-8 resulted in tumor growth inhibition rates of 37.9%, 58.9% and 70.9%, respectively, whereas quercetin treatment (100 mg·kg-1·d-1, po) produced only a lower tumor growth inhibition rate (49.5%). Furthermore, TL-2-8 treatment significantly extended the lifespan of mice bearing MDA-MB-231 breast cancer cell xenografts. Our results demonstrate that TL-2-8 induces significant cell death and immature mitophagy in breast cancer cells in vitro and in vivo via AHA1 abrogation.

(Z)-ligustilide increases ferroportin1 expression and ferritin content in ischemic SH-SY5Y cells.

The mechanisms involved in the antioxidant and anti-apoptotic properties of (Z)-ligustilide (LIG) are not fully elucidated. Based on the accumulated data, we hypothesized that LIG might be able to reduce ischemia/reperfusion-induced increase in brain iron by regulating expression of iron transport proteins. We therefore investigated the effects of LIG on iron uptake protein transferrin receptor 1, iron exporter protein ferroportin 1, iron storage protein ferritin light chain and also hypoxia inducible factor-1 alpha (HIF-1 alpha) in oxygen-glucose deprivation/reoxygenation (OGD/R)-treated SH-SY5Y cells, using Western blot analysis. We demonstrated that LIG completely reversed the OGD/R-induced reduction of ferroportin 1, increased ferritin light chain content, and also suppressed the OGD-induced increase in HIF-1 alpha in SH-SY5Y cells. These findings imply that LIG might reduce the OGD/R-induced increase in brain iron by promoting cell iron release and iron corporation into ferritin, and also by inhibiting the HIF-1 alpha-induced increase in transferrin-bound iron uptake and iron accumulation in the brain, consequently attenuating iron-mediated free radical formation, oxidative stress and apoptosis.

[Clinical manifestations, laboratory test, treatment and outcome of neuropsychiatric involvement in pediatric systemic lupus erythematosus patients].

OBJECTIVE: To investigate the clinical manifestations, laboratory test, treatment and outcome of neuropsychiatric (NP) involvement in pediatric systemic lupus erythematosus (SLE) patients. METHODS: Seventy-seven patients with NP syndromes of SLE (NPSLE) seen from 1987 to 2007 were retrospectively reviewed. The relationship between the relative factors and the relapse of NPSLE was analyzed with logistic regression model. RESULTS: NPSLE was found in 17.3% of the SLE patients and 75% of the NPSLE patients the NP involvements occurred in the first 2 years of the onset of SLE. The most frequent NP manifestations were headache (31.8%) and seizure disorder (29.1%). In the active phases, the levels of Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores of the 92.2% patients were higher than 15 and belonged to severe lupus. The patients were accompanied frequently with fever (88.3%) and rash (84.4%). The most frequently involved organs were kidney (76.6%) and blood system (67.5%). In the active phases, the ANA was positive (98.7%), the level of ESR increased (86.3%), the level of complement profile decreased (72.7%). The cerebrospinal fluid (CSF) study, the CT, the MRI and the EEG were abnormal (90.1%, 60.7%, 54.8%, 73.9%, respectively). All the patients received glucocorticoids and immunodepressant treatment in which 79.2% received IV high-dose methylprednisolone (MP), 51.9% received intrathecal (IT) methotrexate (MTX) and dexamethasone (DXM), 26.0% received IVIG, 2 patients received autologous peripheral blood stem cell transplantation. The mortality was 9.0%. The rate of relapse was 22.0% and in 75.0% of relapsed patients the relapse occurred within 24 months from the onset of NPSLE. The SLEDAI scores related to the relapse of the NPSLE (chi(2) = 3.987, P = 0.0459, OR = 1.172, 95% CI 1.003 and 1.370). CONCLUSION: SLEDAI scores were significantly helpful in predicting recurrence of NPSLE.