Multilevel Screening Strategy to Identify the Hydrophobic Organic Components of Ambient PM2.5 Associated with Hepatocellular Steatosis.

Hepatic steatosis is the first step in a series of events that drives hepatic disease and has been considerably associated with exposure to fine particulate matter (PM2.5). Although the chemical constituents of particles matter in the negative health effects, the specific components of PM2.5 that trigger hepatic steatosis remain unclear. New strategies prioritizing the identification of the key components with the highest potential to cause adverse effects among the numerous components of PM2.5 are needed. Herein, we established a high-resolution mass spectrometry (MS) data set comprising the hydrophobic organic components corresponding to 67 PM2.5 samples in total from Taiyuan and Guangzhou, two representative cities in North and South China, respectively. The lipid accumulation bioeffect profiles of the above samples were also obtained. Considerable hepatocyte lipid accumulation was observed in most PM2.5 extracts. Subsequently, 40 of 695 components were initially screened through machine learning-assisted data filtering based on an integrated bioassay with MS data. Next, nine compounds were further selected as candidates contributing to hepatocellular steatosis based on absorption, distribution, metabolism, and excretion evaluation and molecular dockingin silico. Finally, seven components were confirmed in vitro. This study provided a multilevel screening strategy for key active components in PM2.5 and provided insight into the hydrophobic PM2.5 components that induce hepatocellular steatosis.

Estrogen deficiency impedes fracture healing despite eliminating the excessive absorption of the posterior callus in a semi-fixed distal tibial fracture mouse model.

BACKGROUND: Treatment of distal tibial fractures is a challenge due to their specific anatomical location. However, there is no appropriate mouse model to simulate a clinical distal tibial fracture for basic research. The aim of this investigation was to evaluate the feasibility of simulating a clinical fracture of the distal tibia of mice and to investigate the effect of ovariectomy (OVX)-induced osteoporosis on fracture healing in this model. METHODS: Sixty female 8-week-old C57BL/6 mice were randomly divided into two groups, either sham or OVX. A semi-fixation distal tibia fracture was established in the right tibia after 8 weeks of OVX. The right tibias were collected at 7, 14, 21, and 28 days post fracture. RESULTS: In the semi-fixation distal tibia fracture model, the posterior callus in the sham group showed excessive bone resorption and lower bone mass phenotype compared with the anterior site; a similar trend was not found in the OVX group. At 28 days post fracture, the posterior callus was more mineralized than the anterior callus in the OVX group. Although the fracture healing of the sham group showed a special phenotype in this mode, the progress and quality of fracture healing were still better than those of the OVX group. CONCLUSION: A semi-fixed distal tibial closed fracture mouse model was successfully established. In this model, excess bone resorption of the posterior callus impaired normal fracture healing, but not in OVX-induced osteoporotic bone. Although the stress shielding effect was not observed in the OVX group, impaired bone healing caused by OVX was still present. Our results suggest that this fracture model may have potential for studies on distal tibial fractures and stress shielding.

Establishment of a prognostic model toward lung squamous cell carcinoma based on m7G-related genes in the cancer genome atlas.

Lung squamous cell carcinoma (LUSC) is a non-small cell lung cancer with a poor prognosis owing to late diagnosis. New molecular markers are urgently needed to improve the diagnosis and prognosis of LUSC. 7-Methylguanosine (m7G) modifications, a tRNA modification, are common in eubacteria, eukaryotes, and a few archaea. These modifications promote the turnover and stability of some mRNAs to prevent mRNA decay, improve translation efficiency, and reduce ribosomal pausing but are associated with poor survival in human cancer cells. However, expression of m7G-related genes in LUSC and their association with prognosis remain unclear. In the present study, we identified nine differentially expressed genes related to prognosis by comparing the expression profiles of tumor tissues (502 LUSC reports) with normal tissues (49 adjacent nontumor lung tissue reports). The genes included six upregulated genes (KLK7, LCE3E, AREG, KLK6, ZBED2, and MAPK4) and three downregulated genes (ADH1C, NTS, and ERLIN2). Based on these nine genes, patients with LUSC were classified into low- and high-risk groups to analyze the trends in prognosis. We found that the nine m7G-related genes play important roles in immune regulation, hormone regulation, and drug sensitivity through pathways including antigen processing and presentation, adherent plaques, extracellular matrix receptor interactions, drug metabolism of cytochrome P-450, and metabolism of cytochrome P-450 to xenobiotics; the functions of these genes are likely accomplished in part by m6A modifications. The effect of m7G-related genes on the diagnosis and prognosis of LUSC was further indicated by population analysis.NEW & NOTEWORTHY Based on the differential expression of 7-methylguanosine (m7G) modification-associated genes between normal and lung squamous cell carcinoma (LUSC) tissues, and considering the performance of our m7G-related gene risk profiles as independent risk factors in predicting overall survival, we conclude that m7G modification is closely linked to the development of LUSC. In addition, this study offers a new genetic marker for predicting the prognosis of patients with LUSC and presents a crucial theoretical foundation for future investigations on the relationship between m7G modification-related genes, immunity, and drug sensitivity in LUSC.

Evaluating Classification Model Against Bayes Error Rate.

For a classification task, we usually select an appropriate classifier via model selection. How to evaluate whether the chosen classifier is optimal? One can answer this question via Bayes error rate (BER). Unfortunately, estimating BER is a fundamental conundrum. Most existing BER estimators focus on giving the upper and lower bounds of the BER. However, evaluating whether the selected classifier is optimal based on these bounds is hard. In this article, we aim to learn the exact BER instead of bounds on BER. The core of our method is to transform the BER calculation problem into a noise recognition problem. Specifically, we define a type of noise called Bayes noise and prove that the proportion of Bayes noisy samples in a data set is statistically consistent with the BER of the data set. To recognize the Bayes noisy samples, we present a method consisting of two parts: selecting reliable samples based on percolation theory and then employing a label propagation algorithm to recognize the Bayes noisy samples based on the selected reliable samples. The superiority of the proposed method compared to the existing BER estimators is verified on extensive synthetic, benchmark, and image data sets.

The fabrication and evaluation of silver nanoparticle-based keratin scaffolds.

The biotoxicity caused by focus releasing of Ag, which associated with the Ag loading mode, is a problematic issue that need to be solved for practical utilization of the keratin based wound dressing. In this study, keratin/AgNPs blend scaffolds (Ker/Ag) and keratin scaffolds with AgNPs attached on the scaffold's wall surface (Ag@Ker) were prepared. Structure and physical properties of the scaffolds were tested and investigated. In comparison to the Ag@Ker scaffolds, the Ker/Ag scaffolds with uniform dispersion of AgNPs have larger tensile strength and slower degradation rate. Both kind of scaffolds present excellent antibacterial property with 10 µg mL-1 AgNPs addition, while the Ker/Ag displayed a linear Ag releasing ratio in the first 5-7 days, which is beneficial for obtaining a continuous antibacterial property and avoiding the biotoxicity caused by focus release of Ag. Correspondingly, cytotoxicity assay further reveals that the continuously slow release of Ag of the Ker/Ag scaffolds accelerated the proliferation of cell. Infectious animal models and histological studies showed that the Ker/Ag scaffolds can effectively inhibit the inflammatory response and accelerate epithelialization. Thus, it can be concluded that the Ker/Ag scaffolds with uniform dispersion of AgNPs are more attractive as wound repair materials.

Local Causal Discovery in Multiple Manipulated Datasets.

We consider the problem of distinguishing direct causes from direct effects of a target variable of interest from multiple manipulated datasets with unknown manipulated variables and nonidentical data distributions. Recent studies have shown that datasets attained from manipulated experiments (i.e., manipulated data) contain richer causal information than observational data for causal structure learning. Thus, in this article, we propose a new algorithm, which makes full use of the interventional properties of a causal model to discover the direct causes and direct effects of a target variable from multiple datasets with different manipulations. It is more suited to real-world cases and is also a challenge to be addressed in this article. First, we apply the backward framework to learn parents and children (PC) of a given target from multiple manipulated datasets. Second, we orient some edges connected to the target in advance through the assumption that the target variable is not manipulated and then orient the remaining undirected edges by finding invariant V-structures from multiple datasets. Third, we analyze the correctness of the proposed algorithm. To the best of our knowledge, the proposed algorithm is the first that can identify the local causal structure of a given target from multiple manipulated datasets with unknown manipulated variables. Experimental results on standard Bayesian networks validate the effectiveness of our algorithm.

Causal Feature Selection With Dual Correction.

Causal feature selection methods aim to identify a Markov boundary (MB) of a class variable, and almost all the existing causal feature selection algorithms use conditional independence (CI) tests to learn the MB. However, in real-world applications, due to data issues (e.g., noisy or small samples), CI tests can be unreliable; thus, causal feature selection algorithms relying on CI tests encounter two types of errors: false positives (i.e., selecting false MB features) and false negatives (i.e., discarding true MB features). Existing algorithms only tackle either false positives or false negatives, and they cannot deal with both types of errors at the same time, leading to unsatisfactory results. To address this issue, we propose a dual-correction-strategy-based MB learning (DCMB) algorithm to correct the two types of errors simultaneously. Specifically, DCMB selectively removes false positives from the MB features currently selected, while selectively retrieving false negatives from the features currently discarded. To automatically determine the optimal number of selected features for the selective removal and retrieval in the dual correction strategy, we design the simulated-annealing-based DCMB (SA-DCMB) algorithm. Using benchmark Bayesian network (BN) datasets, the experimental results demonstrate that DCMB achieves substantial improvements on the MB learning accuracy compared with the existing MB learning methods. Empirical studies in real-world datasets validate the effectiveness of SA-DCMB for classification against state-of-the-art causal and traditional feature selection algorithms.

Brain copper clearance by the blood-cerebrospinal fluid-barrier: Effects of lead exposure.

Lead (Pb) is a heavy metal commonly found in the environment and is known to have neurotoxic, hematological, and other toxic effects. It has been reported that Pb exposure can disturb metal regulation in the blood-cerebrospinal fluid-barrier (BCB). Copper (Cu) plays a key role in maintaining normal brain function and can accumulate in the brain after Pb exposure. However, the mechanism by which Pb affects Cu levels in the brain is still unknown. This study investigated Cu clearance by the BCB in the central nervous system (CNS) of Sprague-Dawley rats after Pb exposure by focusing on the Cu transporter protein CTR1/ATP7A. Inductively coupled plasma mass spectrometry (ICP-MS) was used to examine how heavy metal levels change in the hippocampus, cortex, and cerebrospinal fluid (CSF) after Pb exposure. Ventriculo-cisternal perfusion measurements suggested that the ability of the BCB to deliver Cu from the CSF to the blood decreased after Pb exposure. The presence of excess Cu in the choroid plexus led to CTR1/ATP7A shifting toward the apical microvilli facing the CSF after Pb exposure. We further evaluated microstructure of the choroid plexus by transmission electron microscopy, revealing altered mitochondrial morphology with decreased microvilli after Pb exposure. Conclusively, exposure to Pb alters the cellular structure of the BCB and its Cu clearance function, which can cause further brain damage.

Dual-Representation-Based Autoencoder for Domain Adaptation.

Domain adaptation aims to facilitate the learning task in an unlabeled target domain by leveraging the auxiliary knowledge in a well-labeled source domain from a different distribution. Almost existing autoencoder-based domain adaptation approaches focus on learning domain-invariant representations to reduce the distribution discrepancy between source and target domains. However, there is still a weakness existing in these approaches: the class-discriminative information of the two domains may be damaged while aligning the distributions of the source and target domains, which makes the samples with different classes close to each other, leading to performance degradation. To tackle this issue, we propose a novel dual-representation autoencoder (DRAE) to learn dual-domain-invariant representations for domain adaptation. Specifically, DRAE consists of three learning phases. First, DRAE learns global representations of all source and target data to maximize the interclass distance in each domain and minimize the marginal distribution and conditional distribution of both domains simultaneously. Second, DRAE extracts local representations of instances sharing the same label in both domains to maintain class-discriminative information in each class. Finally, DRAE constructs dual representations by aligning the global and local representations with different weights. Using three text and two image datasets and 12 state-of-the-art domain adaptation methods, the extensive experiments have demonstrated the effectiveness of DRAE.

Semi-Supervised Clustering With Constraints of Different Types From Multiple Information Sources.

Semi-supervised clustering is one of important research topics in cluster analysis, which uses pre-given knowledge as constraints to improve the clustering performance. While clustering a data set, people often get prior constraints from different information sources, which may have different representations and contents, to guide clustering process. However, most of existing semi-supervised clustering algorithms are based on single-source constraints and rarely consider to integrate multi-source constraints to enhance the clustering quality. To solve the problem, we analyze the relations among different types of constraints and propose an uniform representation for them. Based it, we propose a new semi-supervised clustering algorithm to find out a clustering that has good cluster structure and high consensus of all the sources of constraints. In the algorithm, we construct an optimization objective model and its solution method to achieve the aim. This algorithm can integrate multi-source constraints well to reduce the effect of incorrect constraints from single sources and find out a high-quality clustering. By the experimental studies on several benchmark data sets, we illustrate the effectiveness of the proposed algorithm, compared to other semi-supervised clustering algorithms.

Estrogen Receptor α Agonist is Beneficial for Young Female Rats Against Chronic Unpredicted Mild Stress-Induced Depressive Behavior and Cognitive Deficits.

BACKGROUND: Women are reported more likely to develop depression and dementia. However, the involved mechanism is poorly understood. OBJECTIVE: Here, we clarified the role of estrogen receptor α (ERα) in depression and cognitive deficit in young female rats. METHODS: After being exposed to 7-weeks' chronic unpredicted mild stress (CUMS), the depression resilient rats (Res rats) and depressed rats (Dep rats) were selected according to their records in sucrose preference test, forced swimming test, and open field test. Their cognition abilities were tested by Morris water maze. Proteomic assay, immunoprecipitation, western blotting, immunohistochemical, and Nissl staining were also used to understand the involved mechanism. RESULTS: Compared with control rats and Res rats, Dep rats showed cognitive deficits and hippocampal impairments revealed by proteomic data, neuron losses, increased cleaved caspase-3, ß-catenin phosphorylation, and glycogen synthase kinase3ß (GSK3ß) activation. As ERα, but not ERß, was found declined in hippocampi of Dep rats, 4,4k,4a-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT, an ERα agonist, 1 mg/kg/day), was used to treat Dep rats (Dep + PPT). Twenty days later, the depressive behaviors, cognition deficits, and hippocampal neuron loss were rescued in Dep + PPT rats. Furthermore, Res and Dep + PPT rats had higher levels of ß-catenin combined with ERα and lower levels of ß-catenin combined with GSK3ß than Dep rats in hippocampi. CONCLUSION: These results demonstrated hippocampal ERα is an important pro-resilient factor in CUMS-induced depressive behaviors and cognitive deficits. It was also given that the neuroprotection afforded by hippocampal ERα/Wnt interactions have significant implications for cognition and emotion in young females.

Protection of melatonin against acidosis-induced neuronal injuries.

Acidosis, a common feature of cerebral ischaemia and hypoxia, plays a key role in these pathological processes by aggravating the ischaemic and hypoxic injuries. To explore the mechanisms, in this research, we cultured primary neurons in an acidic environment (potential of hydrogen [pH]6.2, 24 hours) to mimic the acidosis. By proteomic analysis, 69 differentially expressed proteins in the acidic neurons were found, mainly related to stress and cell death, synaptic plasticity and gene transcription. And, the acidotic neurons developed obvious alterations including increased neuronal death, reduced dendritic length and complexity, reduced synaptic proteins, tau hyperphosphorylation, endoplasmic reticulum (ER) stress activation, abnormal lysosome-related signals, imbalanced oxidative stress/anti-oxidative stress and decreased Golgi matrix proteins. Then, melatonin (1 × 10-4  mol/L) was used to pre-treat the cultured primary neurons before acidic treatment (pH6.2). The results showed that melatonin partially reversed the acidosis-induced neuronal death, abnormal dendritic complexity, reductions of synaptic proteins, tau hyperphosphorylation and imbalance of kinase/phosphatase. In addition, acidosis related the activations of glycogen synthase kinase-3ß and nuclear factor-κB signals, ER stress and Golgi stress, and the abnormal autophagy-lysosome signals were completely reversed by melatonin. These data indicate that melatonin is beneficial for neurons against acidosis-induced injuries.

Regulatory effect of immunosuppressive agents in mice with renal ischemia reperfusion injury.

This study was designed to investigate the regulatory effect of rapamycin in mice with renal ischemia-reperfusion injury. A total of 100 mice were randomly divided into normal control, sham operation, model and experimental groups with 25 rats in each group. Mice in the experimental group were subjected to rapamycin gavage. Mice in each group were sacrificed 24 h after operation. Then, blood, spleen and left kidney were collected. PAS staining was used for semi-quantitative analysis of renal pathological injury. Serum creatinine (SCr) and blood urea nitrogen (BUN) levels were measured. TUNEL method was used to detect cell apoptosis. Flow cytometry was used to detect the percentage of NKT cells. The expression of CXC chemokine ligand 10 (CXCL10), hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) mRNA were detected by RT-qPCR. Semi-quantitative scoring of renal pathological injury showed that pathological injury score of the experimental group was significantly lower than that of the model group (p<0.05). Serum levels of SCr and BUN in the experimental group was compared to those in the model group (p<0.05). The number of apoptotic cells in the experimental group was compared to that of the model group (p<0.05). The percentage of NKT cells in the experimental group was compared to that of the model group (p<0.05). The percentage of NKT cells was significantly higher in the kidney and peripheral blood of the experimental group than that in the model group (p<0.05). The expression levels of HIF-1α and VEGF mRNA in the model and experimental groups were significantly lower in the experimental group than those in the model group (p<0.05). The expression levels of CXCL10 mRNA in the model and experimental groups were significantly higher in the experimental group than those in the model group (p<0.05). The results indicated that rapamycin can significantly upregulate the expression level of CXCL9 and promote the accumulation of NKT cells in kidney from spleen through peripheral blood. Rapamycin can also inhibit the HIF-1α expression level and protect renal ischemia-reperfusion injury.

In Vivo Biocompatibility and Improved Compression Strength of Reinforced Keratin/Hydroxyapatite Scaffold.

A rapid freezing/lyophilizing/reinforcing process is suggested to fabricate reinforced keratin/hydroxyapatite (HA) scaffold with improved mechanical property and biocompatibility for tissue engineering. The keratin, extracted from human hair, and HA mixture were rapidly frozen with liquid nitrogen and then lyophilized to prepare keratin/HA laminar scaffold. The scaffold was then immersed in PBS for reinforcement treatment, and followed by a second lyophilization to prepare the reinforced keratin/HA scaffold. The morphology, mechanical, chemical, crystal and thermal property of the keratin/HA scaffold were investigated by SEM, FTIR, XRD, DSC, respectively. The results showed that the keratin/HA scaffold had a high porosity of 76.17 ± 3%. The maximum compressive strength and compressive modulus of the reinforced scaffold is 0.778 and 3.3 MPa respectively. Subcutaneous implantation studies in mice showed that in vivo the scaffold was biocompatible since the foreign body reaction seen around the implanted scaffold samples was moderate and became minimal upon increasing implantation time. These results demonstrate that the keratin/HA reinforced scaffold prepared here is promising for biomedical utilization.

KLF5 promotes cervical cancer proliferation, migration and invasion in a manner partly dependent on TNFRSF11a expression.

Although the transcription factor Krüppel-like factor 5 (KLF5) plays important roles in both inflammation and cancer, the mechanism by which this factor promotes cervical carcinogenesis remains unclear. In this study, we demonstrated a potential role for tumour necrosis factor receptor superfamily member 11a (TNFRSF11a), the corresponding gene of which is a direct binding target of KLF5, in tumour cell proliferation and invasiveness. Coexpression of KLF5 and TNFRSF11a correlated significantly with tumorigenesis in cervical tissues (P < 0.05) and manipulation of KLF5 expression positively affected TNFRSF11a mRNA and protein expression. Functionally, KLF5 promoted cancer cell proliferation, migration and invasiveness in a manner dependent partly on TNFRSF11a expression. Moreover, in vivo functional TNFRSF11a-knockdown mouse studies revealed suppression of tumorigenicity and liver metastatic potential. Notably, tumour necrosis factor (TNF)-α induced KLF5 expression by activating the p38 signalling pathway and high KLF5 and TNFRSF11a expression increased the risk of death in patients with cervical squamous cell carcinoma. Our results demonstrate that KLF5 and TNFRSF11a promote cervical cancer cell proliferation, migration and invasiveness.

Protective effects of oleanolic acid on oxidative stress and the expression of cytokines and collagen by the AKT/NF­κB pathway in silicotic rats.

Oleanolic acid (OA), a natural pentacyclic triterpenoid, has been reported to have several benefits and medicinal properties. However, its protective effects against silica­induced lung injury and fibrosis remain to be elucidated. The aim of the present study was to investigate the effects of OA on oxidative stress, and the expression of cytokines and collagen in silicotic rats. Male rats were induced by intratracheal instillation of silicosis (250 mg/kg), with the exception of the control group (NS). The rats in the OA group were intragastrically administered with OA (60 mg/kg/d). The rats in the solvent control group were gavaged daily with 0.6% sodium carboxymethyl cellulose (10 ml/kg) solution for 56 consecutive days. The data showed that OA significantly attenuated the extent of silicosis fibrosis by histopathologic analysis of the lung tissues. In addition, oxidative stress activated by silica exposure, as evidenced by increasing of malondialdehyde content, and activities of superoxide dismutase and glutathione peroxidase in the lung, was regulated by treatment with OA. Furthermore, enzyme­linked immunosorbent assay analysis showed that OA significantly decreased the levels of tumor necrosis factor­α and transforming growth factor­ß1. Immunohistochemistry analysis showed that OA significantly decreased collagen types I and III. In investigating the mechanisms underlying the action of OA, it was found that OA decreased the level of phosphorylated AKT1, which in turn inactivated the transcriptional of nuclear factor (NF)­κB in the development and progress of silicosis. In conclusion, these results suggested that the protective effects of OA were due, at least in part, to its anti­oxidant activity and its ability to decrease the expression of cytokines and collagen by modulating the AKT/NF­κB pathway.

Fluoride and arsenic exposure affects spatial memory and activates the ERK/CREB signaling pathway in offspring rats.

Fluoride and arsenic are inorganic contaminants that occur in the natural environment. Chronic fluoride and/or arsenic exposure can induce developmental neurotoxicity and negatively influence intelligence in children, although the underlying molecular mechanisms are poorly understood. This study explored the effects of fluoride and arsenic exposure in drinking water on spatial learning, memory and key protein expression in the ERK/CREB signaling pathway in hippocampal and cerebral cortex tissue in rat offspring. Pregnant rats were divided into four groups. Control rats drank tap water, while rats in the three exposure groups drank water with sodium fluoride (100mg/L), sodium arsenite (75mg/L), and a sodium fluoride (100mg/L) and sodium arsenite (75mg/L) combination during gestation and lactation. After weaning, rat pups drank the same solution as their mothers. Spatial learning and memory ability of pups at postnatal day 21 (PND21) and postnatal day 42 (PND42) were measured using a Morris water maze. ERK, phospho-ERK (p-ERK), CREB and phospho-CREB (p-CREB) protein expression in the hippocampus and cerebral cortex was detected using Western blot. Compared with the control pups, escape latencies increased in PND42 pups exposed to arsenic and co-exposed to fluoride and arsenic, and the short-term and long-term spatial memory ability declined in pups exposed to fluoride and arsenic, both alone and in combination. Compared with controls, ERK and p-ERK levels decreased in the hippocampus and cerebral cortex in pups exposed to combined fluoride and arsenic. CREB protein expression in the cerebral cortex decreased in pups exposed to fluoride, arsenic, and the fluoride and arsenic combination. p-CREB protein expression in both the hippocampus and cerebral cortex was decreased in pups exposed to fluoride and arsenic in combination compared to the control group. There were negative correlation between the proteins expression and escape latency periods in pups. These data indicate that exposure to fluoride and arsenic in early life stage changes ERK, p-ERK, CREB and p-CREB protein expression in the hippocampus and cerebral cortex of rat offspring at PND21 and PND 42, which may contribute to impaired neurodevelopment following exposure.

Extrasynaptic NMDA receptor-induced tau overexpression mediates neuronal death through suppressing survival signaling ERK phosphorylation.

Intracellular accumulation of the hyperphosphorylated tau is a pathological hallmark in the brain of Alzheimer disease. Activation of extrasynaptic NMDA receptors (E-NMDARs) induces excitatory toxicity that is involved in Alzheimer's neurodegeneration. However, the intrinsic link between E-NMDARs and the tau-induced neuronal damage remains elusive. In the present study, we showed in cultured primary cortical neurons that activation of E-NMDA receptors but not synaptic NMDA receptors dramatically increased tau mRNA and protein levels, with a simultaneous neuronal degeneration and decreased neuronal survival. Memantine, a selective antagonist of E-NMDARs, reversed E-NMDARs-induced tau overexpression. Activation of E-NMDARs in wild-type mouse brains resulted in neuron loss in hippocampus, whereas tau deletion in neuronal cultures and in the mouse brains rescued the E-NMDARs-induced neuronal death and degeneration. The E-NMDARs-induced tau overexpression was correlated with a reduced ERK phosphorylation, whereas the increased MEK activity, decreased binding and activity of ERK phosphatase to ERK, and increased ERK phosphorylation were observed in tau knockout mice. On the contrary, addition of tau proteins promoted ERK dephosphorylation in vitro. Taking together, these results indicate that tau overexpression mediates the excitatory toxicity induced by E-NMDAR activation through inhibiting ERK phosphorylation.

[Effects of nano-lead exposure on learning and memory as well as iron homeostasis in brain of offspring rats].

OBJECTIVE: To investigate the effects of nano-lead exposure on learning and memory and iron homeostasis in the brain of the offspring rats on postnatal day 21 (PND21) and postnatal day 42 (PND42). METHODS: Twenty adult pregnant female Sprague-Dawley rats were randomly divided into control group and nano-lead group. Rats in the nano-lead group were orally administrated 10 mg/kg nano-lead, while rats in the control group were administrated an equal volume of normal saline until PND21. On PND21, the offspring rats were weaned and given the same treatment as the pregnant rats until 42 days after birth. The learning and memory ability of offspring rats on PND21 and PND42 was evaluated by Morris water maze test. The hippocampus and cortex s amples of offspring rats on PND21 and PND42 were collected to determine iron and lead levels in the hippocampus and cortex by inductively coupled plasma-mass spectrometry. The distributions of iron in the hippocampus and cortex were observed by Perl's iron staining. The expression levels of ferritin, ferroportin 1 (FPN1), hephaestin (HP), and ceruloplasmin (CP) were measured by enzyme-linked immunosorbent assay. RESULTS: After nano-lead exposure, the iron content in the cortex of offspring rats on PND21 and PND42 in the nano-lead group was significantly higher than those in the control group (32.63 ± 6.03 µg/g vs 27.04 ± 5.82 µg/g, P<0.05; 46.20 ±10.60 µg/g vs 36.61 ± 10.2µg/g, P<0.05). The iron content in the hippocampus of offspring rats on PND42 in the nano-lead group was significantly higher than that in the control group (56.9 ± 4.37µg/g vs 37.71 ± 6.92µg/g, P<0.05). The Perl's staining showed massive iron deposition in the cortex and hippocampus in the nano-lead group. FPNl level in the cotfex of offspring rats on PND21 in the nano-lead group was significantly lower than that in the control group (3.64 ± 0.23 ng/g vs 4.99 ± 0.95 ng/g, P<0.05). FPN1 level in the hippocampus of offspring rats on PND42 in the nano-lead group was significantly lower than that in the control group (2.28 ± 0.51 ng/g vs 3.69 ± 0.69 ng/g, P<0.05). The escape latencies of offspring rats on PND21 and PND42 in the nano-lead group were longer than those in the control group (15.54 ± 2.89 s vs 9.01 ± 4.66 s; 6.16 ± 1.42 s vs 4.26 ± 1.51 s). The numbers of platform crossings of offspring rats on PND21 and PND42 in the nano- lead group were significantly lower than those in the control group (7.77 ± 2.16 times vs 11.2 ± 1.61 times, P<0.05; 8.12 ± 1.51 times vs 13.0 ± 2.21 times, P<0.05). ONCLUSION: n Nano-lead exposure can result in iron homeostasis disorders in the hippocampus and cortex of offspring rats and affect their learning and memory ability.

Oxidative injury induced by cadmium sulfide nanoparticles in A549 cells and rat lungs.

BACKGROUND: Rod-shaped cadmium sulfide nanoparticles (CdS NPs) are becoming increasingly important in many industrial fields, but their potential hazards remain unknown. OBJECTIVES: This study aimed to explore the patterns and mechanisms of lung injury induced by CdS NPs. METHODS: A549 cells and rats were exposed to two types of CdS NPs with a same diameter of 20-30 nm but different lengths, CdS1 (80-100 nm) and CdS2 (110-130 nm). The using doses were included 10 µg/ml and 20 µg/ml two types of CdS NPs for cellular experiments and five times dose of 20 mg/kg body weight for rats' exposure. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) and trypan blue staining were used to detect the A549 cell mortality percentage. The levels of reactive oxygen species (ROS) were determined in A549 cell. The vigor of superoxide dismutase (SOD) and the contents of catalase (CAT) and malondialdehyde (MDA) were detected both in A549 cells and in rats' serum and lung tissues. The cellular morphological changes were observed under transmission electron microscopy (TEM) and the pathological changes were observed in rats' lung tissue. RESULTS: CdS NPs significantly increased A549 cell mortality percentage. The CdS NPs also increased the levels of ROS and MDA content, whereas they decreased SOD and CAT activities. In parallel, similar changes of the contents of MDA, SOD and CAT were also observed in the sera and lung tissues of CdS NP-treated rats. The cellular TEM detection revealed that two types of CdS nanorods appeared as orderly arranged rounded fat droplets separately and leading to nucleus condensation (CdS1). These cellular and rats' tissues changes in the group treated with CdS1 were more significant than the CdS2 groups. Furthermore, CdS NPs induced many pathological changes, including emphysematous changes in rat lung tissue. Especially visible lung consolidation can be observed in the CdS1 group. CONCLUSIONS: CdS NPs induce oxidative injury in the respiratory system, and their toxic effects may be related to grain length.