Therapeutic properties of green tea against environmental insults.

Pesticides, smoke, mycotoxins, polychlorinated biphenyls (PCBs), and arsenic are the most common environmental toxins and toxicants to humans. These toxins and toxicants may impact on human health at the molecular (DNA, RNA, or protein), organelle (mitochondria, lysosome, or membranes), cellular (growth inhibition or cell death), tissue, organ, and systemic levels. Formation of reactive radicals, lipid peroxidation, inflammation, genotoxicity, hepatotoxicity, embryotoxicity, neurological alterations, apoptosis, and carcinogenic events are some of the mechanisms mediating the toxic effects of the environmental toxins and toxicants. Green tea, the nonoxidized and nonfermented form of tea that contains several polyphenols, including green tea catechins, exhibits protective effects against these environmental toxins and toxicants in preclinical studies and to a much-limited extent, in clinical trials. The protective effects are collectively mediated by antioxidant, antiinflammatory, antimutagenic, hepatoprotective and neuroprotective, and anticarcinogenic activities. In addition, green tea modulates signaling pathway including NF-κB and ERK pathways, preserves mitochondrial membrane potential, inhibits caspase-3 activity, down-regulates proapoptotic proteins, and induces the phase II detoxifying pathway. The bioavailability and metabolism of green tea and its protective effects against environmental insults induced by pesticides, smoke, mycotoxins, PCBs, and arsenic are reviewed in this paper. Future studies with emphasis on clinical trials should identify biomarkers of green tea intake, examine the mechanisms of action of green tea polyphenols, and investigate potential interactions of green tea with other toxicant-modulating dietary factors.

Socioeconomic status and fertility intentions among Chinese women with one child.

There has been a lack of socioeconomic status (SES) disparity analysis on women in China with only one child, the family planning target population. In 2008, the National Research Institute for Family Planning of China conducted a study investigating the relationship between SES and fertility intentions among 17,093 women in China who already had one child. A questionnaire was used to collect information on SES and fertility intentions, and logistic regression models were used to estimate the odds ratios and 95% CIs of fertility intentions according to SES. Compared with female farmers, women in other occupations intended to have fewer children (p < 0.05). Additionally, compared with women with low educational level (illiterate/primary), women with secondary and postsecondary education intended to have fewer children (p < 0.05) (OR = 0.70; 95% CI: 0.61-0.81 and OR = 0.56; 95% CI 0.47-0.66). A mother's education level was significantly and negatively associated with fertility intentions after adjustment for potential confounders (p < 0.05). Among Chinese women who had one child, the women with higher SES (e.g. higher educational level) had lower fertility intentions. There is an SES disparity in the fertility intention among Chinese women who already have one child. China's policy-makers should consider increasing high SES women's fertility intention.

Nuclear Export as a Novel Therapeutic Target: The CRM1 Connection.

The integrity of eukaryotic cellular function depends on molecular and biochemical compartmentalization. The transport of macromolecules between compartments requires specific and energydriven mechanisms. It occurs through a class of transport proteins known as karyopherins, which are divided in three different groups (exportins, importins, and transportins). The ubiquitous exportin Chromosome Region Maintenance 1 (CRM1) is involved in the transport of many proteins and RNA molecules from nucleus to cytoplasm. We have reviewed the available evidence supporting the relevance of CRM1 in the biology of several human neoplasms, its potential role in drug resistance, and its promise as a therapeutic target. Here we discuss different cancer related proteins (tumor suppressor genes, oncogenes, and enzymatic therapeutic targets), their function, and their association with CRM1, as well as agents that specifically inhibit CRM1, their mechanism of action, and their clinical relevance in certain human neoplasms. The directionality of nuclear transport and the specific molecular cargo in question are of paramount importance when examining the effects that CRM1 inhibition may have on cellular pathophysiology. The available data point out the potential role of CRM1-dependent nuclear export of regulatory proteins in the biology of certain human malignancies. Further studies should expand and clarify the importance of this mechanism in the pathobiology of human neoplasia.

MicroRNAs May Serve as Emerging Molecular Biomarkers for Diagnosis and Prognostic Assessment or as Targets for Therapy in Gastric Cancer.

Gastric cancer (GC) is one of the most common cancers, with high incidences in East Asia countries. Most GC patients have been reported with low early diagnosis rate and show extremely poor prognosis. Therefore, it is necessary to develop novel and more sensitive biomarkers to improve early diagnosis and therapy in order to provide longer survival and better quality of life for gastric cancer patients. MicroRNAs (miRNAs) play crucial roles in GC development and progression. miRNAs have emerged as a novel molecular biomarker for cancer diagnosis, prognosis and therapy with surprising stability in tissues, serum or other body fluids. This review summarizes major advances in our current knowledge about potential miRNA biomarkers for GC that have been reported in the past two years.

Season of birth, sex and sleep timing preferences.

OBJECTIVE: To evaluate whether the season of birth and sex are associated with preferences for bedtime among Chinese adults. METHODS: A national population-based study on sleep preferences was conducted among Chinese in 2008. A questionnaire was used to collect information on the sleep time of Chinese adults. Analysis of covariance was used to examine the relationship between season of birth and preferences for bedtime. Two sets of potential confounders were used in the adjusted models. Model 1 adjusted for age. Model 2 additionally adjusted for area, occupation, education level, smoking, and drinking. PARTICIPANTS AND MEASUREMENTS: The questionnaire was administered to a sample of 3959 Chinese adults. RESULTS: Men had a higher delayed mean sleep onset and offset time (22:38 and 6:32) than women (22:18 and 6:25). Men also slept for a shorter duration compared to women (7 h 54 min vs. 8 h 7 min). Women born in fall had the latest sleep onset time sleep offset time (22:23/6:30), compared to their counterparts born in winter. These associations were attenuated by additional adjustments of more confounders. CONCLUSIONS: There were significant differences in sleep timing preferences between men and women. Season of birth was not associated with sleep timing in Chinese adults.

Overexpression of CRM1: A Characteristic Feature in a Transformed Phenotype of Lung Carcinogenesis and a Molecular Target for Lung Cancer Adjuvant Therapy.

Our previous study showed that chromosome region maintenance 1 (CRM1), a nuclear export receptor for various cancer-associated "cargo" proteins, was important in regulating lung carcinogenesis in response to a tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The objectives of this study are to comprehensively evaluate the significance of CRM1 in lung cancer development and investigate the therapeutic potential of targeting CRM1 for lung cancer treatment using both in vitro and in vivo models. We showed that CRM1 was overexpressed not only in lung tumor tissues from both lung cancer patients and mice treated with NNK but also in NNK-transformed BEAS-2B human bronchial epithelial cells. Furthermore, stable overexpression of CRM1 in BEAS-2B cells by plasmid vector transfection led to malignant cellular transformation. Moreover, a decreased CRM1 expression level in A549 cells by short hairpin siRNA transfection led to a decreased tumorigenic activity both in vitro and in nude mice, suggesting the potential to target CRM1 for lung cancer treatment. Indeed, we showed that the cytotoxic effects of cisplatin on A549 cells with CRM1 down-regulated by short hairpin siRNA were significantly increased, compared with A549 cells, and the cytotoxic effects of cisplatin became further enhanced when the drug was used in combination with leptomycin B, a CRM1 inhibitor, in both in vitro and in vivo models. Cancer target genes were significantly involved in these processes. These data suggest that CRM1 plays an important role in lung carcinogenesis and provides a novel target for lung cancer adjuvant therapy.

Serum amyloid A is increased in children with abusive head trauma: a gel-based proteomic analysis.

BACKGROUND: Abusive head trauma (AHT) is the leading cause of death from traumatic brain injury in infants and young children. Identification of mild AHT (Glasgow Coma Scale score: 13-15) is difficult because children can present with nonspecific symptoms and with no history of trauma. METHODS: Two-dimensional difference gel electrophoresis combined with mass spectrometry was used to compare the serum protein profile of children with mild AHT and age-matched controls. Protein changes were confirmed by western blots. Western blots were performed using serum from children with mild, moderate, and severe AHT to assess the effect of injury severity on protein intensity. The protein identified--serum amyloid A (SAA)--was then measured by enzyme-linked immunosorbent assay. RESULTS: Using serum from 18 mild AHT cases and 20 controls, there were ~1,000 protein spots; 2 were significantly different between groups. Both spots were identified as SAA. There was no relationship between protein levels and injury severity. SAA concentrations measured by enzyme-linked immunosorbent assay were increased in cases vs. controls. CONCLUSION: SAA may be a potential biomarker to identify children with mild AHT who present for medical care without a history of trauma and who might otherwise not be recognized as needing a head computed tomography.

Green tea polyphenols benefits body composition and improves bone quality in long-term high-fat diet-induced obese rats.

This study investigates the effects of green tea polyphenols (GTPs) on body composition and bone properties along with mechanisms in obese female rats. Thirty-six 3-month-old Sprague Dawley female rats were fed either a low-fat (LF) or a high-fat (HF) diet for 4 months. Animals in the LF diet group continued on an LF diet for additional 4 months, whereas those in the HF diet group were divided into 2 groups: with GTP (0.5%) or without in drinking water, in addition to an HF diet for another 4 months. Body composition, femur bone mass and strength, serum endocrine and proinflammatory cytokines, and liver glutathione peroxidase (GPX) protein expression were determined. We hypothesized that supplementation of GTP in drinking water would benefit body composition, enhance bone quality, and suppress obesity-related endocrines in HF diet-induced obese female rats and that such changes are related to an elevation of antioxidant capacity and a reduction of proinflammatory cytokine production. After 8 months, compared with the LF diet, the HF diet increased percentage of fat mass and serum insulin-like growth factor I and leptin levels; reduced percentage of fat-free mass, bone strength, and GPX protein expression; but had no effect on bone mineral density and serum adiponectin levels in the rats. Green tea polyphenol supplementation increased percentage of fat-free mass, bone mineral density and strength, and GPX protein expression and decreased percentage of fat mass, serum insulin-like growth factor I, leptin, adiponectin, and proinflammatory cytokines in the obese rats. This study shows that GTP supplementation benefited body composition and bone properties in obese rats possibly through enhancing antioxidant capacity and suppressing inflammation.

Green tea polyphenols reduce body weight in rats by modulating obesity-related genes.

Beneficial effects of green tea polyphenols (GTP) against obesity have been reported, however, the mechanism of this protection is not clear. Therefore, the objective of this study was to identify GTP-targeted genes in obesity using the high-fat-diet-induced obese rat model. A total of three groups (n = 12/group) of Sprague Dawley (SD) female rats were tested, including the control group (rats fed with low-fat diet), the HF group (rats fed with high-fat diet), and the HF+GTP group (rats fed with high-fat diet and GTP in drinking water). The HF group increased body weight as compared to the control group. Supplementation of GTP in the drinking water in the HF+GTP group reduced body weight as compared to the HF group. RNA from liver samples was extracted for gene expression analysis. A total of eighty-four genes related to obesity were analyzed using PCR array. Compared to the rats in the control group, the rats in the HF group had the expression levels of 12 genes with significant changes, including 3 orexigenic genes (Agrp, Ghrl, and Nr3c1); 7 anorectic genes (Apoa4, Cntf, Ghr, IL-1ß, Ins1, Lepr, and Sort); and 2 genes that relate to energy expenditure (Adcyap1r1 and Adrb1). Intriguingly, the HF+GTP group restored the expression levels of these genes in the high-fat-induced obese rats. The protein expression levels of IL-1ß and IL-6 in the serum samples from the control, HF, and HF+GTP groups confirmed the results of gene expression. Furthermore, the protein expression levels of superoxide dismutase-1 (SOD1) and catechol-O-methyltransferase (COMT) also showed GTP-regulated protective changes in this obese rat model. Collectively, this study revealed the beneficial effects of GTP on body weight via regulating obesity-related genes, anti-inflammation, anti-oxidant capacity, and estrogen-related actions in high-fat-induced obese rats.

Chemotherapeutic sensitization of leptomycin B resistant lung cancer cells by pretreatment with doxorubicin.

The development of novel targeted therapies has become an important research focus for lung cancer treatment. Our previous study has shown leptomycin B (LMB) significantly inhibited proliferation of lung cancer cells; however, p53 wild type lung cancer cells were resistant to LMB. Therefore, the objective of this study was to develop and evaluate a novel therapeutic strategy to sensitize LMB-resistant lung cancer cells by combining LMB and doxorubicin (DOX). Among the different treatment regimens, pretreatment with DOX (pre-DOX) and subsequent treatment with LMB to A549 cells significantly decreased the 50% inhibitory concentration (IC50) as compared to that of LMB alone (4.4 nM vs. 10.6 nM, P<0.05). Analysis of cell cycle and apoptosis by flow cytometry further confirmed the cytotoxic data. To investigate molecular mechanisms for this drug combination effects, p53 pathways were analyzed by Western blot, and nuclear proteome was evaluated by two dimensional-difference gel electrophoresis (2D-DIGE) and mass spectrometry. In comparison with control groups, the levels of p53, phospho-p53 (ser15), and p21 proteins were significantly increased while phospho-p53 (Thr55) and survivin were significantly decreased after treatments of pre-DOX and LMB (P<0.05). The 2D-DIGE/MS analysis identified that sequestosome 1 (SQSTM1/p62) had a significant increase in pre-DOX and LMB-treated cells (P<0.05). In conclusion, our results suggest that drug-resistant lung cancer cells with p53 wild type could be sensitized to cell death by scheduled combination treatment of DOX and LMB through activating and restoring p53 as well as potentially other signaling pathway(s) involving sequestosome 1.

p53-Dependent anticancer effects of leptomycin B on lung adenocarcinoma.

PURPOSE: Leptomycin B (LMB) and/or its derivatives are considered a novel class of cancer therapeutics through blocking chromosome maintenance region 1, which mediates p53 nuclear export. The objectives of the present study were to first evaluate the cytotoxic effects of LMB on a normal human lung epithelial cell line (BEAS-2B) and three human lung adenocarcinoma cell lines with various p53 status (wild type: A549, mutant: NCI-H522, and null: NCI-H358) and then to identify LMB-induced gene expression alterations in human p53 signaling pathway. METHODS: Cells were treated with 0.01-100 nM LMB or 0.1% ethanol (vehicle control) for 4-72 h. Gene expression analyses using gene array for 84 genes involved in p53-mediated signaling pathways were performed in A549 and NCI-H358 after treatment with 20 nM LMB or vehicle control for 24 h. RESULTS: Cytotoxic results from MTS assays revealed a significant dose- and time-dependent effect of LMB on all cell lines. However, this effect was more pronounced in cancer cells than in normal cells, and cancer cells with p53 wild type tended to be less sensitive than those with p53 mutant or null. A total of 23 genes, predominantly involved in apoptosis and cell cycle/proliferation, were significantly altered in A549 after LMB treatment, while no strong modulating effects were observed in NCI-H358. The protein expression of two selected genes, p21 and survivin, was further confirmed by Western blots. CONCLUSION: Our results suggest that LMB has anti-cancer potential and provides a new regimen of individualized therapy for lung cancer treatment.

A gel-based proteomic analysis of the effects of green tea polyphenols on ovariectomized rats.

OBJECTIVE: Our recent study demonstrated the protective action of green tea polyphenols (GTPs) against bone loss in ovariectomized (OVX) rats through their antioxidant capacities to scavenge reactive oxygen species. The objective of the present study was to evaluate the alterations of liver protein profiles in estrogen-deficient middle-aged rats after GTP treatment by a gel-based proteomic approach. This may lead to understanding the mechanisms of GTPs in promoting bone health. METHODS: Liver samples were obtained from 14-mo-old female OVX rats treated with no GTPs (OVX) or 0.5% (w/v) GTPs (OVX + GTP) in drinking water for 16 wk (n = 10/group). Two-dimensional difference gel electrophoresis combined with mass spectrometry was used to compare the liver protein profiles of pooled samples from the OVX and OVX + GTP groups. Liver proteins were labeled in duplicate by reversing the fluorescent dyes. RESULTS: Approximately 800 protein spots were detected. The expression levels of superoxide dismutase-1 and adenosine triphosphate synthase were 2.0-fold and 1.5-fold higher in the OVX + GTP group versus the OVX group, respectively, whereas the expression level of catechol-O-methyltransferase was 1.5-fold lower in the OVX + GTP group versus the OVX group. The changes of superoxide dismutase-1 and catechol-O-methyltransferase in individual liver samples were confirmed by western blots. CONCLUSION: Our data provide further evidence for the antioxidant role of GTPs by increasing superoxide dismutase-1 and adenosine triphosphate synthase and the estrogen-associated effect of GTPs by decreasing catechol-O-methyltransferase.