The preferential accumulation of heavy metals in different tissues following frequent respiratory exposure to PM2.5 in rats.

This study aimed to explore the pattern of accumulation of some of main heavy metals in blood and various organs of rats after exposed to the atmospheric fine particulate matter (PM2.5). Rats were randomly divided into control and three treatment groups (tracheal perfusion with 10 mg/kg, 20 mg/kg and 40 mg/kg of PM2.5 suspension liquid, respectively). Whole blood and the lung, liver, kidney, and cerebral cortex were harvested after rats were treated and sacrificed. The used heavy metals were detected using inductively coupled plasma-mass spectrometry (ICP-MS) instrument. As results, Lead was increased in the liver, lung and cerebral cortex and the level of manganese was significantly elevated in the liver and cerebral cortex in PM2.5 treated rats. Besides, arsenic was prominently enriched both in cerebral cortex and in blood, and so did the aluminum in the cerebral cortex and the copper in the liver. However, cadmium, chromium and nickel have shown no difference between the control group and the three PM2.5 treated groups. Following the exposure of PM2.5, different heavy metals are preferentially accumulated in different body tissues.

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.

Neuropilin 1 expression in human aortas, coronaries and the main bypass grafts.

OBJECTIVES: Development of intimal hyperplasia (IH) is the main pathology underlying graft failure following coronary artery bypass graft surgeries for ischaemic heart diseases, especially for great saphenous vein grafts which have a lower patency rate than internal mammary arteries. Neuropilin 1 (NRP1), which is a co-receptor for vascular endothelial growth factor found in vascular endothelial and smooth muscle cells, affects the development of IH. We examined the difference in NRP1 expression and distribution in human coronaries, aortas, mammary arteries and saphenous veins to detect a possible relation to their susceptibility to IH. METHODS: Ninety-five human vascular segments obtained from 40 patients were used for the comparison of NRP1 expression between different groups of blood vessels by western blot and real-time PCR. Additionally, staining scores were generated by computerized analysis of the microscopic images obtained after immunofluorescence and immunohistochemical staining to compare NRP1 expression patterns in endothelium, smooth muscles and adventitia in each vessel type. RESULTS: NRP1 expression in the aorta (2.03 ± 1.44) was more than twice as high as mammary artery expression (0.85 ± 0.75; n = 16, P = 0.0004); NRP1 of the latter (0.99 ± 0.91) was more than 30% greater than that of the corresponding saphenous vein (0.73 ± 0.69; n = 20, P = 0.0085). In adventitia, NRP1 receptor staining of the saphenous vein was higher (22.96 ± 8.73) than in the mammary artery (15.83 ± 7.13; n = 7, P = 0.049). Variations in NRP1 protein levels were accompanied by parallel variations in its mRNA levels (n = 15, P = 0.34). CONCLUSIONS: Autologous saphenous vein grafts, unlike internal mammary artery grafts, have lower NRP1 expression and abundant adventitial distribution of NRP1 within their walls; this may correlate with higher susceptibility to IH development.

Targeting the prohibitin scaffold-CRAF kinase interaction in RAS-ERK-driven pancreatic ductal adenocarcinoma.

BACKGROUND: Robust ERK1/2 activity, which frequently results from KRAS mutation, invariably occurs in pancreatic ductal adenocarcinoma (PDAC). However, direct interference of KRAS signaling has not led to clinically successful drugs. Correct localization of RAF is regulated by the scaffold protein prohibitin (PHB) that ensures the spatial organization between RAS and RAF in plasma membranes, thus leading to activation of downstream effectors. METHODS: PHB expression was analyzed in human pancreatic cancer cell lines, normal pancreas, and PDAC tissue. Furthermore, genetic ablation or pharmacological inhibition of PHB was performed to determine its role in growth, migration, and signaling of pancreatic cancer cells in vitro and in vivo. RESULTS: The level of PHB expression was crucial for maintenance of oncogenic ERK-driven pancreatic tumorigenesis. Additionally, rocaglamide (RocA), a small molecular inhibitor, selectively bound to PHB with nanomolar affinity to disrupt the PHB-CRAF interaction by altering its localization to the plasma membrane. Consequently, there was an impairment of oncogenic RAS-ERK signaling, thereby blocking in vitro and in vivo growth and metastasis of pancreatic cancer cells that were addicted to RAS-ERK signaling. More importantly, RocA treatment resulted in a significant increase of the lifespan of tumor-bearing mice without any detectable toxicity. CONCLUSIONS: Blockade of the PHB scaffold-CRAF kinase interaction, which is distinct from direct kinase inhibition, may be a new therapeutic strategy to target oncogenic ERK-driven pancreatic cancer.

miRNA expression profiles associated with diagnosis and prognosis in lung cancer.

miRNAs, which are small single-stranded RNA molecules composed of 18-23 nts, act as oncogenes or tumor suppressor genes playing important roles in the processes of tumor formation, infiltration and metastasis. Lung cancer currently has the highest morbidity and mortality among all malignant tumors; yet, lack of early specific diagnostic markers and effective treatments hinders its proper management. In lung cancer, about 40-45 abnormal expression patterns of miRNAs have been discovered and are involved in lung cancer development. miRNAs have functions together with oncogenes and tumor suppressor genes of lung cancer. miRNAs-based tests can be used for early clinical diagnosis and prediction of clinical outcomes of lung cancer. Studying the role of miRNAs in lung cancer development and its relationship with diagnostic and prognostic parameters might help to improve the sensitivity of diagnosis and the efficacy of lung cancer treatment.

Neuropilin-1 expression in squamous cell carcinoma of the oesophagus.

OBJECTIVES: The development of new therapeutic targets is needed to change the current low survival rates of cancer of the oesophagus. In some clinical trials, angiogenic inhibitors, including those targeting the vascular endothelial growth factor (VEGF) and its receptors, have proven efficacious. In concert with this, neuropilin-1 (NRP1), a coreceptor for VEGF, is expressed by many tumours and may be related to their progression. This study aimed to assess the expression and prognostic value of fNRP1 in primary squamous cell carcinoma (SCC) of the oesophagus. METHODS: The expression of NRP1 receptors was assessed in 60 samples of resected oesophageal SCC and adjacent normal mucosa by western blotting, immunostaining and real-time quantitative PCR (qPCR). Furthermore, the relationship between NRP1 and the clinicopathological parameters was investigated. RESULTS: NRP1 staining was limited within normal tissues of the oesophagus, while it was prominent in tumour cells and vasculature. Overexpression of NRP1 receptors (3.6 ± 0.48-folds) was apparent in 81.7% specimens (n = 60, P = 0.0001). qPCR consistently revealed parallel NRP1-mRNA overexpression (3.7 ± 3.7-folds) (n = 16, P = 0.02). A higher molecular weight-modified NRP1 (mNRP1) species was identified in a large proportion of the tumour specimens (85%), accounting for 71.51 ± 20.6% of their total NRP1. Overexpression of tumour NRP1 was positively correlated with deeper invasion into the oesophageal wall (P = 0.05) though mNRP1-positive tumour populations were significantly associated with less lymph node metastasis (P = 0.036) and better prognostic tumour-node-metastasis stage (P = 0.037) than mNRP1 negative tumours. CONCLUSIONS: NRP1 overexpression in oesophageal SCC may contribute to local tumour invasiveness but the presence of the mNRP1 subtype correlates with less lymph node metastasis and better prognostic stage, suggesting that the balance between modified and unmodified NRP1 might be important for determining invasion potential.

The oxidative damage and inflammatory response induced by lead sulfide nanoparticles in rat lung.

Lead sulfide nanoparticles (PbS NPs) are one important nanoparticle materials which is widely used in photoelectric production, but its potential health hazard to respiratory system is not clear. This study aimed to explore the possible mechanism of lung injury induced by PbS NPs. Male SD rats were treated with nanoparticles of 60 nm and 30 nm lead sulfide. The main methods were detecting the vigor of superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) and the content of malondialdehyde (MDA) in both blood and lung tissues and observing the pathological changes in lung tissue. PbS NPs suppressed the activity of SOD and T-AOC, and increased serum MDA content (P<0.05); both effects were observed together in lung tissues of 30-nm group (P<0.05) accompanied by an obviously inflammatory response. PbS NPs induced oxidative damage and inflammatory response in lung tissue, which may be an underlying mechanism for its pulmonary toxicity. Additionally, the toxicity of PbS NPs was closely related with the size of nanoparticles.