Strategies for understanding the role of cellular heterogeneity in the pathogenesis of lung cancer: a cell model for chronic exposure to cigarette smoke extract.

BACKGROUND: Human tumors are highly heterogeneous at the cellular, molecular, genetic and functional levels. Tumor heterogeneity has tremendous impact on cancer progression and treatment responses. However, the mechanisms for tumor heterogeneity have been poorly understood due to the lack of experimental models. METHODS: This study provides a novel exploration and analysis of the impacts of cellular and molecular heterogeneity of human lung epithelial cells on their malignant transformation following chronic exposure to cigarette smoke extracts. RESULTS: The ability of cigarette smoke extract (CSE) to cause malignant transformation of the human bronchial epithelial cells (16HBE) is dependent on the sizes of the cells. Epithelial-mesenchymal transition (EMT) plays an important role in this process. Mechanistically, CSE-induced malignant transformation of 16HBE cells was closely linked to the reduced relative telomere length of the larger 16HBE cells, thereby up-regulation of the expression of stemness genes. CONCLUSIONS: These findings provide novel insights for understanding the impact of cellular heterogeneity in lung cancer development. The in vitro transformation model described in this study could be extrapolated to studying the pathogenesis of other malignancies, as well as for mechanistic studies that are not feasible in vivo.

Enhancing the dewaterability of waste activated sludge by the combined ascorbic acid and zero-valent iron/persulfate system.

In this work, a reducing/chelating agent, ascorbic acid (H2A) was introduced to the traditional zero-valent iron (Fe0)/persulfate (PS) process for waste activated sludge dewatering. The experimental data indicated that H2A-Fe0/PS process significantly enhanced the dewatering performance of sludge and enhanced the oxidation efficiency of Fe0-PS treatment. Under optimal conditions, the capillary suction time ratio before and after treatment (CST0/CST) of H2A-Fe0/PS treated sludge increased by 118% and 31.3% compared with untreated sludge and Fe0-PS treated sludge, respectively. The mechanism investigations revealed that the H2A-Fe0/PS induced excellent enhancement for sludge dewaterability could be credited to the reduction and chelating capacity of ascorbic acid. Free radicals including SO4•-, O2•- and •OH produced in the H2A-Fe0/PS process destroyed proteinaceous components and humic substances in sludge extracellular polymeric substances (EPS), thus reducing the negative charge and water holding capacity of sludge, improving the sludge rheological properties. As a result, the dewatering performance of sludge has been significantly improved.

Association between Single Nucleotide Polymorphisms in Cardiovascular Developmental Critical Genes and Hypertension: A Propensity Score Matching Analysis.

Cardiovascular development critical genes are key determinants in cardiovascular diseases. We hypothesize that SNPs in these genes may play critical roles in the development of hypertension. Therefore, we enrolled 516 paired hypertension patients and controls in a total of 2,742 subjects in a cross-sectional population study by the propensity score matching (PSM) method. Twenty-one SNPs from 5 cardiovascular developmental related genes were detected by the improved multiplex ligase detection reaction (iMLDR) method. Conditioned logistic regression under three different genetic models, namely, additive model, dominant model, and recessive model, was performed. The odds ratio (ORs) and 95% confidence intervals (95% CIs) were used to estimate the associations of SNPs with hypertension. We found that the distribution of genotypes at rs833061, rs3025010, and rs699947 within the VEGFA gene and the distribution of alleles at rs3025010 in hypertension subjects were different from those in controls. Both rs833061 and rs3025010 were associated with hypertension in crude models, but only rs3025010 remains associated with hypertension after adjusting with confounding factors in the additive model and the dominant model. We also found that hypertension subjects with C/T and C/C genotypes at rs3025010 had lower SBP and DBP levels. In addition, rs3025010 could interact with rs6784267 within the CCM3 gene in the association. In conclusion, our findings suggest that rs3025010 may play a role in the pathogenesis of hypertension, which may be a potential target for individualized prevention and treatment of hypertension.

Environmental lead exposure aggravates the progression of Alzheimer's disease in mice by targeting on blood brain barrier.

Alzheimer's disease (AD) is a neurodegenerative disease that can be induced by heavy metals such as lead. However, there is limited information on the role of blood-brain barrier (BBB) in lead induced AD-like pathology. This study investigates the potential mechanism of lead exposure aggravating the progression of Alzheimer's disease in mice through the BBB. 200 mg/L and 500 mg/L lead acetate were given to C57BL/6J and APP/PS1 mice through drinking water from a week before mating, until the offspring were 7-months-old. 8 female juvenile mice in each group were selected for this investigation. Lead exposure increased blood lead concentration which revealed the internal exposure level, accelerated Aß1-42 deposition in APP/PS1 mouse cortexes and abnormal change in Zonula Occludin-1 (ZO-1) and Claudin-5 protein. It also increased the expression of p-tau in both the C57BL/6J and APP/PS1 mice, and decreased mRNA and protein expression in low-density lipoprotein receptor (LRP-1). Additionally, it increased the mRNA and protein expression of amyloid beta precursor protein (APP) and beta secretase 1 (BACE-1). The activated astrocytes increased in the brains of APP/PS1 mice, and coalesced around the Aß1-42 deposition after lead exposure. The main vessels in deutocerebrum were attached with Aß1-42 deposition. These results offer insight into the mechanism of preventing lead induced AD through cerebrovascular pathways.