Xia Sun

Multifunctional near infrared-emitting long-persistence luminescent nanoprobes for drug delivery and targeted tumor imaging.

In this paper, near infrared-emitting long-persistence luminescent porous Zn1.1Ga1.8Ge0.1O4:Cr(3+), Eu(3+) @SiO2 nanoprobes have been prepared using mesoporous silica nanospheres both as morphology-controlling templates and as vessels. These nanoprobes possessed an excellent capacity for drug delivery and allowed for real-time monitoring of the delivery routes of the drug carriers in vivo. The nanoprobes demonstrated a typical mesoporous structure, a brighter NIR emission (696 nm) and a long afterglow luminescence that persisted for 15 d. Furthermore, after surface modification with folic acid (FA), a tumor-targeting group, these nanoprobes exhibited an excellent ability to target tumors with high sensitivity in vitro and in vivo. Importantly, these modified nanoprobes could accurately diagnose tumors and allow for long-term tumor monitoring via in situ and in vivo re-excitation by a red LED lamp. Furthermore, the drug release data demonstrated that the modified nanoprobes could be loaded with a large amount of doxorubicin hydrochloride (DOX) and showed sustained release behavior. Together, the results of this study indicate that these nanoprobes can accurately diagnose tumors, allow for long-term in vivo and in situ monitoring and release DOX in situ to cure tumors.

Endothelial cell injury and dysfunction induced by silver nanoparticles through oxidative stress via IKK/NF-κB pathways.

Epidemiological studies have indicated that particulate matter (PM) exposure is most likely relevant to atherosclerosis. Endothelial cell injury and dysfunction are considered the early events in the initiation of atherosclerosis. Silver nanoparticles (AgNPs), with a smaller size and higher reactive activity, may induce much higher toxicity to endothelial cells compared with PM. However, few studies have been performed to determine the effect of AgNPs on endothelial cells. In the present study, human umbilical vein endothelial cells (HUVECs) were chosen as model cells to systematically explore the toxicity of AgNPs to endothelial cells. The obtained results indicated that exposure to AgNPs could inhibit proliferation, damage the cell membrane and seriously induce apoptosis. Simultaneously, the inflammatory cytokines, adhesion molecules, and chemokines of HUVECs were clearly up-regulated, which resulted in the adhesion of many monocytes to endothelial cells. More importantly, we found that dysfunctions of endothelial cells could be ascribed to the activation of NF-κB pathways. Furthermore, an oxidation inhibitor, N-acetyl-l-cysteine (NAC), effectively antagonized all of the AgNPs-induced responses, which indicated the key role of ROS production during the exposure of AgNPs in the toxicity of endothelial cells. In summary, our results clearly demonstrated that AgNPs could induce the injury and dysfunction of HUVECs through the activation of IKK/NF-κB, which is associated with oxidative stress, suggesting that exposure to AgNPs may be a potential hazardous factor for early atherosclerosis.

Perinatal exposure to bisphenol A exacerbates nonalcoholic steatohepatitis-like phenotype in male rat offspring fed on a high-fat diet

Bisphenol A (BPA) is one of the environmental endocrine disrupting chemicals, which is present ubiquitously in daily life. Accumulating evidence indicates that exposure to BPA contributes to metabolic syndrome. In this study, we examined whether perinatal exposure to BPA predisposed offspring to fatty liver disease: the hepatic manifestation of metabolic syndrome. Wistar rats were exposed to 50 μg/kg per day BPA or corn oil throughout gestation and lactation by oral gavage. Offspring were fed a standard chow diet (SD) or a high-fat diet (HFD) after weaning. Effects of BPA were assessed by examination of hepatic morphology, biochemical analysis, and the hepatic expression of genes and/or proteins involved in lipogenesis, fatty acid oxidation, gluconeogenesis, insulin signaling, inflammation, and fibrosis. On a SD, the offspring of rats exposed to BPA exhibited moderate hepatic steatosis and altered expression of insulin signaling elements in the liver, but with normal liver function. On a HFD, the offspring of rats exposed to BPA showed a nonalcoholic steatohepatitis-like phenotype, characterized by extensive accumulation of lipids, large lipid droplets, profound ballooning degeneration, impaired liver function, increased inflammation, and even mild fibrosis in the liver. Perinatal exposure to BPA worsened the hepatic damage caused by the HFD in the rat offspring. The additive effects of BPA correlated with higher levels of hepatic oxidative stress. Collectively, exposure to BPA may be a new risk factor for the development of fatty liver disease and further studies should assess whether this finding is also relevant to the human population.

Magnetic, long persistent luminescent and mesoporous nanoparticles as trackable transport drug carriers

In this paper, Gd2O3@mSiO2@CaTiO3:Pr nanoparticles with a novel core/shell structure featured by mesoporous, magnetic and long persistent luminescent properties have been synthesized via a facile template method. The as-prepared nanoparticles show ordered mesoporous characteristics, monodisperse spherical morphology and narrow size distribution, so they are expected to be suitable as a drug carrier. These nanoparticles exhibit bright red phosphorescence at 614 nm after UV irradiation and the persistent luminescence can persist for more than one hour. Moreover, they possess a prominent longitudinal relaxivity (r1) value of 6.43 mM-1 s-1, which suggests that these nanoparticles can be used as MR imaging agents. The combination of long persistent luminescent and magnetic properties reveals the high imaging sensitivity, which suggests that these nanoparticles can be used for imaging in vivo with a high signal to noise ratio. Drug release results indicate that the nanoparticles hold excellent drug sustained properties. The cumulative released amount of drugs can also be easily monitored by the change of luminescence intensity. After modification with polyethylene glycol, the resulting nanoparticles demonstrate good biocompatibility and low toxicity. Furthermore, we can realize in vivo imaging for over 20 min using these nanoparticles. These results indicate the promising use of these nanoparticles as multifunctional traceable drug carriers in vivo.

Di(2-ethylhexyl) phthalate-induced apoptosis in rat INS-1 cells is dependent on activation of endoplasmic reticulum stress and suppression of antioxidant protection

Di(2‐ethylhexyl) phthalate (DEHP) is used as plasticizer and is ubiquitously found in the environment. Exposure to DEHP has been linked to an increased incidence of type 2 diabetes. Pancreatic β‐cell dysfunction is a hallmark of type 2 diabetes; however, it is unknown whether DEHP exposure contributes to this risk. Here, we aimed to investigate the cytotoxic effects of DEHP on INS‐1 cells and to further explore the related underlying mechanisms. INS‐1 cells were exposed to 0, 5, 25, 125 or 625 μM DEHP for 24 hrs. Cell viability, glucose‐stimulated insulin secretion, reactive oxygen species (ROS) generation, cellular antioxidant response, Ca2+ homoeostasis and the levels of genes and proteins involved in endoplasmic reticulum (ER) stress were measured. The results showed that DEHP decreased insulin secretion and content and induced apoptosis in INS‐1 cells in a dose‐dependent manner. Furthermore, ROS generation was increased and Nrf2‐dependent antioxidant defence protection was dysregulated in INS‐1 cells after DEHP exposure. Most importantly, DEHP effectively depleted ER Ca2+ and triggered the ER stress response as demonstrated by the elevated transcription and translation of the ER chaperone GRP78 and GRP94, the increased phosphorylation of protein kinase R‐like endoplasmic reticulum kinase (PERK) and its downstream substrate eukaryotic translation initiation factor 2α (eIF2α), as well as the increased levels of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP). Taken together, DEHP exerted toxic effects on INS‐1 cells by inducing apoptosis, which is dependent on the activation of the PERK–ATF4–CHOP ER stress signalling pathway and the suppression of Nrf2‐dependent antioxidant protection.

Apigenin Inhibits the Expression of IL-6, IL-8, and ICAM-1 in DEHP-Stimulated Human Umbilical Vein Endothelial Cells and In Vivo

Di-(2-ethylhexyl) phthalate (DEHP) in house dust is associated with asthma and allergic inflammatory symptoms in children. This study aimed to examine an inhibitory effect of a flavonoid apigenin on DEHP-stimulated inflammatory responses in human umbilical vein endothelial cells (HUVECs). We found that apigenin significantly suppressed DEHP-stimulated expression of intercellular adhesion molecule-1 (ICAM-1) at the mRNA and protein levels and subsequently inhibited the adhesion of THP-1 monocytic cells to HUVECs. Treatment with apigenin also led to a dose-dependent inhibition of mRNA and protein expression of interleukin (IL)-6 and IL-8 in DEHP-stimulated HUVECs. Moreover, pretreatment with apigenin partially inhibited the DEHP-induced activation of c-Jun N-terminal kinase (JNK) but not the degradation of IκBα or the phosphorylation of extracellular-regulated kinase (ERK)1/2, indicating that the inhibitory effect of apigenin on the expression of IL-6, IL-8, and ICAM-1 may be mediated by JNK pathway but not IκBα/nuclear factor-κB or ERK/mitogen-activated protein kinase pathway. Furthermore, apigenin reduced the release of IL-6, IL-8, and ICAM-1 and inhibited compound 48/80-induced systemic anaphylaxis in vivo. These results suggest that apigenin can be used as a therapeutic means for the treatment of DEHP-associated allergic disorders.

Silver nanoparticles interact with the cell membrane and increase endothelial permeability by promoting VE-cadherin internalization

The toxicological risks of silver nanoparticles (AgNPs) have attracted widespread attention, and many studies have been published that have contributed to understanding AgNPs-induced toxicity. However, little attention has been paid to the low-dose effects of AgNPs and the related toxicological mechanism is still unclear. Here, we show that short-term exposure to AgNPs at low doses induces a substantial increase in human umbilical vein endothelial cells (HUVECs) monolayer permeability, whereas Ag ions at low doses do not induce an observable increase in monolayer permeability. This effect is independent of oxidative stress and apoptosis. Scanning electron microscopy confirms that AgNPs adhere to the cell membrane after 1h exposure. Furthermore, adhesion of AgNPs to the cell membrane can trigger vascular endothelial (VE)-cadherin phosphorylation at Y658 followed by VE-cadherin internalization, which lead to the increase in endothelial monolayer permeability. Our data show that surface interactions of AgNPs with the cell membrane, in other words, the particle effect, is a major factor leading to endothelial dysfunction following low-dose and short-term exposure. Our findings will contribute to understanding the health effects and the toxicological mechanisms of AgNPs.

The inflammation and estrogen metabolism impacts of polychlorinated biphenyls on endometrial cancer cells

Polychlorinated biphenyls (PCBs) are persistent and bio-accumulative chemicals that provoke a wide range of toxic effects. Their adverse impacts on the reproductive system are of great concern, however, the effects of PCBs on endometrium are still unclear. In the study, the endometrial adenocarcinoma Ishikawa cells were exposed to both dioxin-like CB126 and non-dioxin-like CB153 at the nominal concentrations of 0.3, 3, and 30μM. The inflammatory and endocrine effects were detected after treatment by PCBs. Results showed that CB126 stimulated the proliferation of Ishikawa cells at lower concentrations of 0.3 and 3μM. By contrast, CB153 did not affect the viability of the cells. Both congeners exerted the stimulatory effects on the enzymatic activity of SOD1. CB126 decreased the abundance of Interleukin-8 both at the mRNA and protein levels. Blocking of estrogen receptor or aryl hydrocarbon receptor by the antagonist abolished the effects of CB126 on the expressions of inflammatory factors. The levels of testosterone and 17beta-estradiol were not changed after exposure to lower doses of PCBs. In accordance, PCBs did not affect the mRNA expressions of estrogen metabolism-related genes. In all, our study revealed that PCBs affected the expression of inflammatory factors through ER and AHR receptors, however, no toxic effects were observed on estrogen metabolism.

Near-infrared persistent luminescence hollow mesoporous nanospheres for drug delivery and in vivo renewable imaging

The design and fabrication of trackable drug carriers is of great importance for tracking the route of drug delivery in vivo. Here, we report novel stick-shell structure, near-infrared (NIR) persistent luminescence hollow mesoporous (ZnGa2O4:Cr3+@HMS) nanospheres. Due to the hollow mesoporous SiO2 skeleton structure, the prepared nanospheres possess a high Brunauer-Emmett-Teller (BET) surface area of 514 m2 g-1 and a pore volume of 1.16 cm3 g-1, which make these nanospheres ideal drug carriers for drug loading and sustained release. In addition, these nanospheres exhibit strong NIR emission at 696 nm, and their NIR persistent luminescence can persist for more than three hours after excitation. Thus, we can realize autofluorescence-free and long-term tracking of the transport routes of drug carriers by using the exceptional properties of NIR persistent luminescence of nanospheres. More importantly, we found that the NIR persistent luminescence of ZnGa2O4:Cr3+@HMS nanospheres can be repeatedly excited by a 655 nm LED lamp. Thus, the drug transport route can be tracked for an extended time with high sensitivity in deep tissue via the method of in situ repeatable excitation. Our results indicate that the ZnGa2O4:Cr3+@HMS nanospheres combine the advantages of high drug storage capacity and excellent NIR persistent luminescence, and they show potential for application as trackable drug carriers.

NOX4‐ and Nrf2‐mediated oxidative stress induced by silver nanoparticles in vascular endothelial cells

It has been widely reported that silver nanoparticles (AgNPs) induce oxidative stress in various cell lines. However, the mechanism for this effect and its consequences for cellular signaling are poorly understood. In this study, human umbilical vein endothelial cells (HUVECs) were used to assess the toxicity and investigate the associated molecular mechanisms caused by exposure to AgNPs. We demonstrated that AgNP exposure significantly and dose‐dependently decreased the cell viability, induced reactive oxygen species (ROS) generation and led to early apoptosis in HUVECs. Our findings showed that AgNPs induced excess ROS production that affected the signaling pathways by a mechanism that depended on activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity through upregulation of NADPH oxidase 4 (NOX4) protein expressions. Moreover, AgNPs could disrupt the inactivation of the nuclear factor erythroid 2‐related factor 2 (Nrf2)‐mediated antioxidant response, which is considered another important element for oxidative stress caused by AgNPs in HUVECs. The redox imbalance between NOX4 and Nrf2 was an important cause for the ROS overproduction that led to cell injury in HUVECs. The results provided insight into the mechanisms of oxidative stress induced by AgNPs in vascular endothelial cells.