With the aim of controlling nanoscale magnetism, we demonstrate an approach encompassing concepts of surface and exchange anisotropy while reflecting size, shape, and structural hybridization of nanoparticles. We visualize that cube has higher magnetization value than sphere with highest coercivity at 60 nm. Its hybridization into core-shell (CS) structure brings about a 14-fold increase in the coercivity with an exceptional energy conversion of magnetic field into thermal energy of 10600 W/g, the largest reported to date. Such capability of the CS-cube is highly effective for drug resistant cancer cell treatment.
The regulation of cellular activities in a controlled manner is one of the most challenging issues in fields ranging from cell biology to biomedicine. Nanoparticles have the potential of becoming useful tools for controlling cell signalling pathways in a space and time selective fashion. Here, we have developed magnetic nanoparticles that turn on apoptosis cell signalling by using a magnetic field in a remote and non-invasive manner. The magnetic switch consists of zinc-doped iron oxide magnetic nanoparticles (Zn(0.4)Fe(2.6)O(4)), conjugated with a targeting antibody for death receptor 4 (DR4) of DLD-1 colon cancer cells. The magnetic switch, in its On mode when a magnetic field is applied to aggregate magnetic nanoparticle-bound DR4s, promotes apoptosis signalling pathways. We have also demonstrated that the magnetic switch is operable at the micrometre scale and that it can be applied in an in vivo system where apoptotic morphological changes of zebrafish are successfully induced.
The high mobility group box 1 (HMGB1) protein, a non-histone nuclear factor, is overexpressed and localizes to the cytoplasm in some cancer cells. However, the mechanism of cytoplasmic HMGB1 transport, extracellular secretion, and its role in cancer progression is not clear. To simulate the activated state of HMGB1, we mutated serine residues of nuclear localization signals (NLSs) to glutamic acid and performed transfection assays. We carried out a kinase inhibitor study and evaluated the cell migration by invasion assay. We showed that phosphorylated HMGB1 localizes in the cytoplasm of colon cancer cells and also showed the interaction of PKC and HMGB1 by immunoprecipitation analysis. Concurrent mutations at six serine residues (35, 39, 42, 46, 53, and 181) to glutamic acid induced the nuclear to cytoplasmic transport of HMGB1, which was detected in the culture medium. We also observed that the secretion of HMGB1 correlated with increased cancer cell invasiveness. Our results suggest that phosphorylated HMGB1 is transported to the cytoplasm, is subsequently secreted from the cell, and has a role in tumor progression through the activation of genes related to cell migration.
HMGB1 protein is a delayed mediator of sepsis that is secreted to the extracellular milieu in response to various stimulants, inducing a pro-inflammatory response. HMGB1 is devoid of an endoplasmic reticulum (ER)-targeting signal peptide; hence, the mechanism of extracellular secretion is not completely understood, although HMGB1 is secreted after being subjected to post-translational modifications. Here, we identified the role of N-glycosylation of HMGB1 in extracellular secretion. We found two consensus (N37 and N134) and one non-consensus (N135) residues that were Nglycosylated in HMGB1 by performing liquid chromatography tandem mass spectrometry (LC-MS/MS) and analyzing for Nglycan composition and structure. Inhibition of N-glycosylation with tunicamycin resulted in a molecular shift of HMGB1 as assessed by gel electrophoresis. Non-glycosylated double mutant (N→Q) HMGB1 proteins (HMGB1 N37Q/N134Q and HMGB1 N37Q/N135Q ) showed localization to the nuclei, strong binding to DNA, weak binding to the nuclear export protein CRM1 and rapid degradation by ubiquitylation. These mutant proteins had reduced secretion even after acetylation, phosphorylation, oxidation and exposure to pro-inflammatory stimuli. Taken together, we propose that HMGB1 is N-glycosylated, and that this is important for its DNA interaction and is a prerequisite for its nucleocytoplasmic transport and extracellular secretion.
Tumor necrosis factor (TNF)-alpha plays a major role in the pathogenesis of Kawasaki disease (KD), a systemic vasculitis primarily affecting young children. We performed this study to examine the serum levels of TNF-alpha and to investigate a possible relation to promoter polymorphism at positions -238 and -308 in KD patients in Korea. We obtained 48 paired serum samples from 24 patients in the acute and subacute stages of KD, and control sera from 12 age-matched children who were having routine blood samples taken before elective surgical procedures. Our studies showed a significant increase in serum levels of TNF-alpha measured in the acute stage of KD (24.1 +/- 9.4 pg/mL) compared to those in the subacute stage (11.8 +/- 5.8 pg/mL; p < 0.01) and normal controls (10.4 +/- 4.9 pg/mL; p < 0.01). Previous studies report that the presence of the A allele at positions -308 and -238 may be associated with higher TNF-alpha levels. However, our results showed that the frequency of the A allele at position -308 in the KD patients was the same as the controls (2 out of 24, 8.3% vs. 8.3%, odds ratio (OR)= 1.00), while the frequency of the A allele at position -238 in the KD patients was lower than the controls (0/24, 0% vs. 8.3%, OR=0.00); this difference though was not statistically significant. We concluded that although TNF-alpha levels were significantly elevated in the acute stage of KD, there was no significant difference in the frequency of the A allele at positions -238 and -308 between the KD and control groups in Korean patients.
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