Iron Oxide Nanoparticles Inhibit Tumor Progression and Suppress Lung Metastases in Mouse Models of Breast Cancer.

Systemic exposure to starch-coated iron oxide nanoparticles (IONPs) can stimulate antitumor T cell responses, even when little IONP is retained within the tumor. Here, we demonstrate in mouse models of metastatic breast cancer that IONPs can alter the host immune landscape, leading to systemic immune-mediated disease suppression. We report that a single intravenous injection of IONPs can inhibit primary tumor growth, suppress metastases, and extend survival. Gene expression analysis revealed the activation of Toll-like receptor (TLR) pathways involving signaling via Toll/Interleukin-1 receptor domain-containing adaptor-inducing IFN-ß (TRIF), a TLR pathway adaptor protein. Requisite participation of TRIF in suppressing tumor progression was demonstrated with histopathologic evidence of upregulated IFN-regulatory factor 3 (IRF3), a downstream protein, and confirmed in a TRIF knockout syngeneic mouse model of metastatic breast cancer. Neither starch-coated polystyrene nanoparticles lacking iron, nor iron-containing dextran-coated parenteral iron replacement agent, induced significant antitumor effects, suggesting a dependence on the type of IONP formulation. Analysis of multiple independent clinical databases supports a hypothesis that upregulation of TLR3 and IRF3 correlates with increased overall survival among breast cancer patients. Taken together, these data support a compelling rationale to re-examine IONP formulations as harboring anticancer immune (nano)adjuvant properties to generate a therapeutic benefit without requiring uptake by cancer cells.

Mechanisms involved in the HMGB1 modulation of tumor multidrug resistance (Review).

Tumor multidrug resistance (MDR) remains one of the most challenging barriers to successful cancer treatment. Several previous studies have suggested that high mobility group box 1 (HMGB1) may be a promising therapeutic target for overcoming cancer drug resistance. Emerging evidence has indicated that HMGB1 functions as a 'double­edged sword' that plays both pro­ and anti­tumor roles in the development and progression of multiple types of cancer. HMGB1 has also been found to be a key regulator of several cell death and signaling pathways, and is involved in MDR by mediating cell autophagy and apoptosis, ferroptosis, pyroptosis and multiple signaling pathways. Additionally, HMGB1 is regulated by a variety of non­coding RNAs (ncRNAs), such as microRNAs, long ncRNAs and circular RNAs that are involved in MDR. Thus far, studies have been conducted to identify strategies with which to overcome HMGB1­mediated MDR by the targeted silencing of HMGB1 and the targeted interference of HMGB1 expression using drugs and ncRNAs. Therefore, HMGB1 is closely associated with tumor MDR and is a promising therapeutic target.

Effects of Highly Oxygenated Water in a Hyperuricemia Rat Model.

Recent years have seen a rapidly rising number of oxygenated water brands that claim to impart health benefits and increase athletic performance by improving oxygen availability in the body. Drinks with higher dissolved oxygen concentrations have in recent times gained popularity as potential ergogenic aids, despite the lack of evidence regarding their efficacy. The aim of this study was to characterize oxygenated water and assess the improvement in uric acid metabolism while identifying performance enhancements in animals administered oxygenated water. Oxygenated water was characterized by hydrogen and oxygen nuclear magnetic resonance (NMR) spectroscopy. Hyperuricemia in rats was induced by treatment with oxonic acid potassium salt, and the animals were given oxygenated drinking water before, during, or after oxonic acid treatment. Serum uric acid was measured to confirm the effects on uric acid metabolism. Following oxygenation, the full width at half maximum (FWHM) was reduced to 11.56 Hz and 64.16 Hz in the hydrogen and oxygen NMR spectra, respectively. Oxygenated water molecule clusters were reduced in size due to the reduction in FWHM. Oxygen concentration did not vary significantly with increased temperature. However, standing time played a critical role in the amount of oxygen dissolved in the water. The rat studies indicated that oxygenated water reduced serum uric acid levels and their rate of increase and enhanced uric acid metabolism. A significant improvement in uric acid metabolism and rate of increase in serum uric acid concentration was observed in hyperuricemic rats administered oxygenated water compared to that in rats administered regular water. High oxygen concentrations enhanced the rate of oxygen absorption, leading to increased glycolysis and mitochondrial protein synthesis. Therefore, oxygenated water is a potential adjuvant therapy or health food for treatment of hyperuricemia.

Systemically delivered antibody-labeled magnetic iron oxide nanoparticles are less toxic than plain nanoparticles when activated by alternating magnetic fields.

OBJECTIVE: Toxicity from off-target heating with magnetic hyperthermia (MHT) is generally assumed to be understood. MHT research focuses on development of more potent heating magnetic iron oxide nanoparticles (MIONs), yet our understanding of factors that define biodistribution following systemic delivery remains limited. Preclinical development relies on mouse models, thus understanding off-target heating with MHT in mice provides critical knowledge for clinical development. METHODS: Eight-week old female nude mice received a single tail vein injection of bionized nanoferrite (BNF) MIONs or a counterpart labeled with a polyclonal human antibody (BNF-IgG) at 1 mg, 3 mg or 5 mg Fe/mouse on day 1. On day 3, mice were exposed to an alternating magnetic field (AMF) having amplitude of 32, 48 or 64 kA/m at ∼145 kHz for 20 min. Twenty-four hours later, blood, livers and spleens were harvested and analyzed. RESULTS: Damage to livers was apparent by histology and serum liver enzymes following MHT with BNF or BNF-IgG at doses ≥3 mg Fe and AMF amplitudes ≥48 kA/m. Differences between effects with BNF vs. BNF-IgG at a dose of 3 mg Fe were noted in all measures, with less damage and increased survival occurring in mice injected with BNF-IgG. Necropsies revealed severe damage to duodenum and upper small intestines, likely the immediate cause of death at the highest MHT doses. CONCLUSION: Results demonstrate that the MION coating affects biodistribution, which in turn determines off-target effects. Developments to improve heating capabilities of MIONs may be clinically irrelevant without better control of biodistribution.

[Screening genotypes and identifying indicators of different Fagopyrum tataricum varieties with low phosphorus tolerance.] / è‹¦èžè€ä½Žç£·åŸºå› åž‹ç­›é€‰åŠè¯„ä»·æŒ‡æ ‡çš„é‰´å®š.

Soil phosphorus (P) deficiency is one of the main factors that diminish the yield of crops on the Loess Plateau. Fagopyrum tataricum is a dominant cereal plant on the Loess Plateau, whose responses to low-P stress are significantly different and dependent on its genotypes. Therefore, screening genotypes with efficient P utilization is an important approach to increase the yield of F. tataricum and promote the sustainable development of local agriculture. With fourteen F. tataricum genotypes, the agronomic traits, physiology and biochemical characters of F. tataricum at seedling stage under normal (2 mmol·L-1) and low-P treatment (0.2 mmol·L-1) were studied by using sand culture. By examining the characters of selected F. tataricum at seedling stage, the varieties of F. tataricum with low-P tolerance were screened out and their evaluation indices were assessed to provide theoretical basis for the breeding of F. tataricum with high P-efficiency and the infertile soil cultivation on the Loess Plateau. The results showed that under low-P stress, the shoots of all genotypes were more affected than roots, with the decline of shoot aboveground index, average root diameter, root surface area and root volume, whereas the length of main root was elongated. Root activity and soluble protein content were decreased. In contrast, other physiological and biochemical indicators were increased. Moreover, plant total phosphorus content and plant phosphorus accumulation reduced, but phosphorus use efficiency increased. The principal component analysis divided the 22 individual indicators into four mutually independent comprehensive indicators (cumulative contribution rate of 90.1%). Cluster analysis divided 14 kinds of F. tataricum into three categories: Low phosphorus tolerant, intermediate and phosphorus sensitive. In order to investigate the index of low-P tolerance of F. tataricum at seedling stage, the optimal regression equation was established with the comprehensive evaluation value of low-P tolerance (D value) as the dependent variable and the low-P tolerance index of each indicator as the independent variables. Seven indicators of root surface area, root length, plant height, aboveground dry mass, acid phosphatase, phosphorus accumulation and POD activity were examined, which could be used for the rapid identification of low-P tolerance of F. tataricum at seedling stage.

ROS-induced HepG2 cell death from hyperthermia using magnetic hydroxyapatite nanoparticles.

HepG2 cell death with magnetic hyperthermia (MHT) using hydroxyapatite nanoparticles (mHAPs) and alternating magnetic fields (AMF) was investigated in vitro. The mHAPs were synthesized as thermo-seeds by co-precipitation with the addition of Fe2+. The grain size of the HAPs and iron oxide magnetic were 39.1 and 19.5 nm and were calculated by the Scherrer formula. The HepG2 cells were cultured with mHAPs and exposed to an AMF for 30 min yielding maximum temperatures of 43 ± 0.5 °C. After heating, the cell viability was reduced by 50% relative to controls, lactate dehydrogenase (LDH) concentrations measured in media were three-fold greater than those measured in all control groups. Readouts of toxicity by live/dead staining were consistent with cell viability and LDH assay results. Measured reactive oxygen species (ROS) in cells exposed to MHT were two-fold greater than in control groups. Results of cDNA microarray and Western blotting revealed tantalizing evidence of ATM and GADD45 downregulation with possible MKK3/MKK6 and ATF-2 of p38 MAPK inhibition upon exposure to mHAPs and AMF combinations. These results suggest that the combination of mHAPs and AMF can increase intracellular concentrations of ROS to cause DNA damage, which leads to cell death that complement heat stress related biological effects.