Luteoloside Inhibits Proliferation and Promotes Intrinsic and Extrinsic Pathway-Mediated Apoptosis Involving MAPK and mTOR Signaling Pathways in Human Cervical Cancer Cells.

Cervical cancer is a common gynecological malignancy with high incidence and mortality. Drugs commonly used in chemotherapy are often accompanied by strong side-effects. To find an anti-cervical cancer drug with high effects and low toxicity, luteoloside was used to treat the cervical cancer cell line Hela to investigate its effects on cell morphology, proliferation, apoptosis, and related proteins. The study demonstrated that luteoloside could inhibit proliferation remarkably; promote apoptosis and cytochrome C release; decrease the mitochondrial membrane potential and reactive oxygen species level; upregulate the expression of Fas, Bax, p53, phospho-p38, phospho-JNK, and cleaved PARP; downregulate the expression of Bcl-2 and phospho-mTOR; activate caspase-3 and caspase-8; change the nuclear morphology, and fragmentate DNA in Hela cells. These results strongly suggest that luteoloside can significantly inhibit the proliferation and trigger apoptosis in Hela cells. In contrast, luteoloside had less proliferation inhibiting effects on the normal cell lines HUVEC12 and LO2, and minor apoptosis promoting effects on HUVEC12 cells. Furthermore, the luteoloside-induced apoptosis in Hela cells is mediated by both intrinsic and extrinsic pathways and the effects of luteoloside may be regulated by the mitogen-activated protein kinases and mTOR signaling pathways via p53.

Polycyclic aromatic hydrocarbons exposure and lung function decline among coke-oven workers: A four-year follow-up study.

OBJECTIVES: This study aimed to investigate quantitative relationships of urinary PAH metabolites with lung function declines among coke-oven workers. METHODS: We performed a prospective investigation involving 1243 workers with follow-up periods from 2010 to 2014. Their lung function measurements, including forced vital capacity (FVC), forced expiratory volume in one second (FEV1), the percentage of predicted FVC (FVC%) and FEV1 (FEV1%), FEV1/FVC ratio, and forced expiratory flow between 25% and 75% of vital capacity (FEF25-75), were detected in both baseline (2010) and follow-up study (2014). We also detected the urinary concentrations of 12 PAH metabolites in the baseline study. The relationships between the baseline urinary PAH metabolites and 4-year lung function declines were analyzed by multivariate linear regressions, with adjustment for potential confounders. RESULTS: We found that the baseline concentrations of urinary 1-hydroxynaphthalene (1-OHNa), 2-OHNa, 2-hydroxyfluorene (2-OHFlu), 9-OHFlu, 1-hydroxyphenanthrene (1-OHPh), 2-OHPh, and ΣOH-PAHs were significantly associated with accelerated decline in FEV1/FVC [all ß>0 and false discovery rate (FDR) P<0.05]. Additionally, the baseline levels of urinary 1-OHNa, 1-OHPh, 2-OHPh, 9-OHPh, 1-hydroxypyrene (1-OHP), and ΣOH-PAHs were associated with significantly deeper decline in FEF25-75 (all ß>0 and FDR P<0.10). When using backward selection to adjustment for 10 urinary PAH metabolites, the most significant determiner for FEV1/FVC decline was 1-OHNa among nonsmokers and 9-OHFlu among smokers, and the significant determiner for FEF25-75 decline was 9-OHPh among nonsmokers and 1-OHP among smokers. CONCLUSIONS: This longitudinal study revealed that higher baseline exposure levels of PAHs could lead to greater decline in lung function over a 4-year follow-up.

Effect of thallium exposure and its interaction with smoking on lung function decline: A prospective cohort study.

BACKGROUND: Thallium (Tl) is a cumulative high toxicant in the environment, but few longitudinal studies have investigated the respiratory impairment of Tl exposure. OBJECTIVES: This study aimed to evaluate the effect of Tl and its interaction with smoking on lung function decline, and explore the potential mechanisms. METHODS: The baseline and follow-up lung functions were measured from a prospective cohort study of 1243 workers, who were followed from 2010 to 2014. Their baseline urinary levels of Tl were determined. We also measured the plasma C-reactive protein (CRP) and urinary 8-iso-prostaglandin-F2α (8-iso-PGF2α) in a randomly selected subcohort of 474 subjects. RESULTS: The results showed that a 2-fold increase in urinary Tl was associated with 29.81 mL (95%CI: 3.83-55.80) increased decline in forced expiratory volume in 1 s (FEV1). The effect was more pronounced among heavy-smokers (≥15 pack-years) [ß(95%CI) = 56.42 mL (9.66-103.19)]. In particular, compared to never-smokers with low Tl, heavy-smokers with high Tl had a separate 158.44 mL (95%CI: 54.88-262.00) and 4.58% (95%CI: 1.40-7.76) increased declines in FEV1 and percentage of predicted (ppFEV1), respectively. There was a significant interaction between Tl and smoking intensity on ppFEV1 decline (Pint = 0.034). More importantly, the increasing level of urinary Tl was correlated with elevated CRP and 8-iso-PGF2α. CONCLUSION: Our prospective cohort study identified that exposure to high Tl had a deleterious effect on lung function, and this effect may be enhanced by tobacco smoking. Increased inflammation may partly contribute to the joint effects of Tl and smoking on impaired lung function, but the biological mechanisms need further explorations.

Circulating essential metals and lung cancer: Risk assessment and potential molecular effects.

OBJECTIVE: Essential metals play important roles in the carcinogenic process. However, seldom longitudinal investigations have evaluated their roles in lung cancer development. We aimed to investigate the associations between multiple essential metals and lung cancer incidence and to explore the potential mechanisms. METHODS: A nested case-control study of 440 incident lung cancer cases and 1:3 frequency matched 1320 healthy controls from the Dongfeng-Tongji Cohort was conducted. The baseline plasma concentrations of 11 essential metals (cobalt, copper, iron, manganese, molybdenum, rubidium, selenium, strontium, stannum, vanadium, and zinc) were measured, and their associations with lung cancer incidence were estimated. Effect of positive metal (zinc) on 4-year telomere attrition was then evaluated among an occupational cohort of 724 workers. We also assessed the transcriptional regulation effects of plasma zinc on mRNA expression profiles, and the expressions of zinc-related genes were further compared in pair-wised lung tumor and normal tissues. RESULTS: Elevated plasma level of zinc was associated with lower incident risk of lung cancer [OR (95% CI) = 0.89 (0.79, 0.99)] and decreased 4-year telomere attrition [ß (95% CI) = -0.73 (-1.27, -0.19)]. These effects were pronounced among males. In particularly, zinc could regulate the expressions of 8 cancer-related genes, including SOD1, APE, TP53BP1, WDR33, LAPTM4B, TRIT1, HUWE1, and ZNF813, which were over-expressed in lung tumor tissues. CONCLUSIONS: We propose that high plasma zinc could prevent incident lung cancer, probably by slowing down telomere attrition and regulating the expressions of cancer-related genes. These results provided a new insight into lung cancer prevention.