Background Effects of different nanoparticles (NPs) exposure at acutely non-cytotoxic concentrations are particularly worthy to figure out, compare, and elucidate. Objective To investigate and compare the effect of a small library of NPs at non-cytotoxic concentration on the adherens junction of human umbilical vein endothelial cells (HUVECs), obtaining new insights of NPs safety evaluation. Materials and methods The HUVECs layer was exposed to NPs including gold (Au), platinum (Pt), silica (SiO 2 ), titanium dioxide (TiO 2 ), ferric oxide (Fe 2 O 3 ), oxidized multi-walled carbon nanotubes, with different surface chemistry and size distribution. Cellular uptake of NPs was observed by transmission electron microscopy. and the cytotoxicity was determined by Cell Counting Kit-8 assay. The NP-induced variation of intracellular reactive oxygen species (ROS) and catalase (CAT) activity was measured using the probe of 2ʹ7’-dichlorodihydr fluorescein diacetate and a CAT analysis kit, respectively. The level of VE-cadherin of HUVECs was analyzed by Western blot, and the loss of adherens junction was observed with laser confocal microscopy. Results The acutely non-cytotoxic concentrations of different NPs were determined and applied to HUVECs. The NPs increased the level of intracellular ROS and the activity of CAT to different degrees, depending on the characteristics. At the same time, the HUVECs lost their adherens junction protein VE-cadherin and gaps were formed between the cells. The NP-induced oxidative stress and gap formation could be rescued by the supplementary N-acetylcysteine in the incubation. Conclusion The increase of intracellular ROS and CAT activity was one common effect of NPs, even at the non-cytotoxic concentration, and the degree was dependent on the composition, surface chemistry, and size distribution of the NP. The effect led to the gap formation between the cells, while could be rescued by the antioxidant. Therefore, the variation of adherens junction between endothelial cells was suggested to evaluate for NPs when used as therapeutics and diagnostics.
Background Iron oxide nanoparticles (IONPs) have been extensively studied in different biomedical fields. Recently, the non-cytotoxic concentration of IONPs induced cell-specific response raised concern of their safety. Endothelial cell exposure was unavoidable in their applications, while whether IONPs affect the phenotype of vascular endothelial cells is largely unknown. In this work, the effect of IONPs on endothelial-to-mesenchymal transition (EndMT) was investigated in vitro and in vivo. Results The incubation with γ-Fe 2 O 3 nanoparticles modified with polyglucose sorbitol carboxymethyether (PSC-Fe 2 O 3 ) at non-cytotoxic concentration induced morphological changes of human umbilical vein endothelial cells (HUVECs) from cobblestone-like to spindle mesenchymal-like morphology, while PSC-Fe 2 O 3 mostly stay in the culture medium and intercellular space. At the same time, the endothelial marker CD31 and VE-cadherin was decreased along with the inhibitory of angiogenesis properties of HUVEC. Meanwhile, the mesenchymal marker α-smooth muscle actin (α-SMA) and fibroblast specific protein (FSP) was up regulated significantly, and the migration ability of the cells was enhanced. When ROS scavenger mannitol or AA was supplemented, the EndMT was rescued. Results from the in vivo study showed that, expression of CD31 was decreased and α-SMA increased in the liver, spleen and kidney of mice given PSC-Fe 2 O 3 , and the density of collagen fibers in the liver sinusoid of mice was increased. The supplementary mannitol or AA could reverse the degree of EndMT in the tissues. Mechanistic study in vitro indicated that the level of extracellular hydroxyl radicals (·OH) was up regulated significantly by PSC-Fe 2 O 3 , which induced the response of intracellular ROS and resulted in the EndMT effect on HUVECs. Conclusion The PSC-Fe 2 O 3 was capable of inducing EndMT in the endothelial cells at acutely non-cytotoxic dose due to its intrinsic peroxidase-like activity, though they were few taken up by endothelial cell. The EndMT effect on HUVEC can be rescued by ROS scavenger in vitro and in vivo. Electronic supplementary material The online version of this article (10.1186/s12989-019-0314-4) contains supplementary material, which is available to authorized users.
Chronic myeloid leukemia (CML) is one kind of hematological malignancy featured with retarded differentiation that is highly linked to the level of intracellular reactive oxygen species (ROS). In this work,...
Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic progenitor cells, and the AML cells are differentiation retarded which results in the hyperproliferation of those malignant tumor cells. To stop the uncontrollable proliferation, inducing the AML cell differentiation is one highly expected therapy because it can bring relatively low systematic side effects compared to conventional chemotherapies; however, there are few options of inductive therapeutics in the clinical applications so far. This study aims to investigate the differentiation-induction effects of lab-developed hydrophilic nanocrystals of As 4 S 4 (ee-As 4 S 4 ). Methods: In this work, ee-As 4 S 4 was applied upon a refractory mouse model co-expressing AML1-ETO and HyC-KIT D816V as well as a related human AML cell line, Kasumi-1, to investigate whether the nanocrystals can break the retardation of differentiation and drive the cells undergo apoptosis. Results: It was shown that ee-As 4 S 4 induced the upregulation of surface markers CD11b, CD235a, and CD41a, which indicate granulocytic, erythroid, and megakaryocytic differentiation respectively, leading to the multiple-lineage differentiation and postdifferentiation apoptosis, and the inhibition of histone deacetylase activity was largely involved with the differentiation-induction effects. In the AML mice, orally administered ee-As 4 S 4 increased the level of Ter119, CD11b, and CD41 in bone marrow-derived leukemia cells while reducing the percentage of leukemic cells in the bone marrow. Also, ee-As 4 S 4 improved the hemogram and relieved the hepatomegaly and splenomegaly of the AML mice. As a result, the survival of the AML mice was significantly prolonged. Importantly, ee-As 4 S 4 did not cause acute or chronic toxicity in healthy mice. Conclusion:In conclusion, ee-As 4 S 4 induced effective and multiple-lineage differentiation and apoptosis of AML cells in the refractory AML mouse model and cell line, suggesting that it holds promising potential as a novel inductive agent in differentiation therapy of AML.
Background Contrast-enhanced magnetic resonance imaging (MRI) is a powerful diagnostic tool for many diseases. In many situations, the contrasts are repeatedly administrated in order to monitor and assess the disease progression. Objective To investigate and compare the biological effects of γ-Fe 2 O 3 nanoparticle (NP) and gadolinium dimeglumine (Gd-DTPA) with high and multiple doses on the kidney of healthy mice. Methods Polydextrose sorbitol carboxymethyl ether coated γ-Fe 2 O 3 NP with hydrodynamic size of 68.2 nm and clinically applied Gd-DTPA were employed on healthy mice with the repeatedly intravenous administration of high doses. The cell viability of human umbilical vein endothelial cells (HUVEC) in high doses of these two contrast agents were measured using the xCELLigence Real-Time Cell Analysis (RTCA) S16 Instrument. The biological effects of γ-Fe 2 O 3 NP and Gd-DTPA on the kidney were obtained using a biochemical automatic analyzer and multiple proinflammatory factor kit on the serum. Histopathological and immunohistochemistry analysis were taken on kidney tissues. Results It showed that the proinflammatory responses elicited by the γ-Fe 2 O 3 NPs were weaker than that by Gd-DTPA, evidenced by the relatively much lower level of IL-1β, IL-6, IL-18, TNF-α, C-reactive protein (CRP) and Ferritin. At the same time, the γ-Fe 2 O 3 NPs did not have the biochemical index elevated, while the Gd-DTPA did. Conclusion The γ-Fe 2 O 3 NPs induced weaker proinflammatory effects in reference to the Gd-DTPA, indicating better renal safety. Therefore, it is suggested that γ-Fe 2 O 3 NPs should be safer and optional choice when repeated contrast-enhanced MRI is necessary.
Purpose Pt-based nanostructures are one of the promising nanomaterials for being used in catalysts, sensors, and therapeutics. However, their impacts on the health and biological systems are not adequately understood yet. Methods In this work, nanorods composed of ultrasmall platinum (Pt) nanoparticles deposited on the surface and gold nanorod as the core (Au@Pt NRs) were synthesized, and the distribution and toxic effects of Au@Pt NRs were investigated in C57BL/6 mice with intravenous injection by using atomic absorption spectroscopy (AAS), transmission electron microscope (TEM), hematoxylin-eosin (HE) staining and blood cell analyzer. Results At the time point of Day 1, Day 8 and Day 16 post injection of Au@Pt NRs (6 mg/kg of Pt atom), Au@Pt NRs were mainly accumulated in the liver and spleen. The energy dispersive spectrometer mapping images showed Au@Pt NRs experienced quick corrosion and Au released faster than Pt in the physiological environments. The catalase (CAT) activity in tissues increased slightly in the early stage of the Au@Pt NRs exposure and went down to the normal level. With HE staining, inflammatory cells infiltration could be seen in the tissues, while no significant influences were detected on the blood biochemistry and the function of liver and kidney. Conclusion In conclusion, intravenously injected Au@Pt NRs mainly distributed in the liver and spleen with comparable levels, and did not exert any significant toxic effects on the organs’ function within two weeks; meanwhile, Au@Pt NRs were able to degrade, which indicated acceptable safety to the mice and potentials of biomedical application.
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