Air pollution has been associated with elevated blood pressure in adults. However, epidemiological evidence from children and adolescents is limited. We investigated the associations between ...long-term exposure to particulate matter (PM) air pollution and blood pressure in a large population of children and adolescents.
A cross-sectional analysis was performed in a nationally representative sample consisting of 43,745 children and adolescents aged 7 to 18 years in seven provinces in China. Exposure to ambient fine particles (PM2.5) and thoracic particles (PM10) was estimated using spatiotemporal models based on satellite remote sensing, meteorological data and land use information. Mixed-effects (two-level) linear and logistic regression models were used to investigate the associations between PM exposure and systolic blood pressure (SBP), diastolic blood pressure (DBP) and hypertension.
After adjustment for a wide range of covariates, every 10 μg/m3 increment in PM2.5 and PM10 concentration was associated with 1.46 95% confidence interval (CI): 0.05, 2.88 and 1.36 (95% CI: 0.34, 2.39) mmHg increases in SBP, respectively. PM10 was also associated with higher prevalence of hypertension odds ratio per 10 μg/m3 increment: 1.45 (95% CI: 1.07, 1.95).
Long-term exposure to ambient PM air pollution was associated with increased blood pressure and higher prevalence of hypertension in children and adolescents. Our findings support air pollution reduction strategies as a prevention measure of childhood hypertension, a well-recognized risk factor of future cardiovascular health.
•There is limited evidence on air pollution and childhood blood pressure.•Exposure to PM 2.5 and PM10 was associated with increased systolic blood pressure in children and adolescents.•Exposure to PM10 was also associated with higher prevalence of hypertension.•No significant effect modification by sex or obesity was observed.
microRNAs (miRNA) are small noncoding RNAs that participate in diverse biological processes by suppressing target gene expression. Altered expression of miR-21 has been reported in cancer. To gain ...insights into its potential role in tumorigenesis, we generated miR-21 knockout colon cancer cells through gene targeting. Unbiased microarray analysis combined with bioinformatics identified cell cycle regulator Cdc25A as a miR-21 target. miR-21 suppressed Cdc25A expression through a defined sequence in its 3'-untranslated region. We found that miR-21 is induced by serum starvation and DNA damage, negatively regulates G(1)-S transition, and participates in DNA damage-induced G(2)-M checkpoint through down-regulation of Cdc25A. In contrast, miR-21 deficiency did not affect apoptosis induced by a variety of commonly used anticancer agents or cell proliferation under normal cell culture conditions. Furthermore, miR-21 was found to be underexpressed in a subset of Cdc25A-overexpressing colon cancers. Our data show a role of miR-21 in modulating cell cycle progression following stress, providing a novel mechanism of Cdc25A regulation and a potential explanation of miR-21 in tumorigenesis.
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•Children in China were extensively exposed to phthalates.•The exposure to phthalates in children had higher risk of overweight and obesity.•A dose-response relationship of phthalates ...with overweight and obesity existed.
There was growing interest in endocrine disrupting chemicals that might have effect on the obesity epidemic, but few studies on the association of phthalates (PAEs) with childhood overweight and obesity in China based on longitudinal cohort study were available, which was the purpose of the present study.
A nested case-control study was conducted in a prospective cohort of 2298 children aged 7–13 years from October 2017 to October 2020 with five waves visits in Xiamen city, China. A total of 829 children remained in the first wave of follow up with collection of urine for measuring seven PAEs metabolites, including mono-methyl phthalate (MMP), mono-ethyl phthalate (MEP), mono-n-butyl phthalate (MBP), mono-iso-butyl phthalate (MiBP), mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP) and mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), utilizing ultra high performance liquid chromatography-triple quadrupole mass spectrometry. Overweight and obesity, defined by WHO classifications, were allocated to the cases group, and those of all normal weight and matched cases with normal weight in each wave of follow-up as two control groups. Logistic regression models after adjusting for confounders were utilized to analyze the effect of PAEs on overweight and obesity in children with divided four groups based on the quartile distribution of each and total PAEs concentration.
The detection rates of children for each PAEs metabolite were 99.4% for MMP, 99.4% for MEP, 99.8% for MBP, 54.5% for MEHP, 84.4% for MEOHP, 99.9% for MEHHP, and 97.2% for MiBP. The geometric mean of concentrations of PAEs, MMP, MEP, MBP, MEHP, MEHHP, and MiBP were 310.085, 34.658, 9.127, 166.347, 7.043, 3.400, 18.571, and 24.093 (ng/ml), respectively. The total PAEs and seven metabolites concentrations were positively associated with childhood BMI Z-Scores with statistically significant slope rates and correlation coefficients, and were higher in the cases group than those in two controls groups in each wave of follow-up. The PAEs concentrations in the cases group was 5.90 (95 %CI: 5.79, 6.01) ng/ml in the first wave of survey, which was higher than those normal controls group (5.68 (95 %CI: 5.61, 5.75) ng/ml, P < 0.001) and matched controls group (5.72 (95 %CI: 5.61, 5.84) ng/ml, P = 0.018). The prevalence and ORs of overweight and obesity increased with quartile group of each and total PAEs concentrations accompanying a dose-response relationship. Compared with the quartile1 reference group with lowest total PAEs concentrations, the ORs of overweight and obesity in quartile2, quartile3 and quartile4 group increased gradually and reached at 1.20 (0.74–1.95), 1.49 (0.93–2.38) and 2.22 (1.41–3.48), respectively (Ptrend < 0.001). The strength of the associations between PAEs and overweight and obesity was sex-specific in children.
Children in China were extensively exposed to PAEs, and the exposure to PAEs during childhood could significantly increase the risk of overweight and obesity with a dose-response relationship, particularly in girls. While limiting the exposure of PAEs products, the determination of exposure limit of plasticizer should be further strengthened.
Cancer cells often require glutamine for growth, thereby distinguishing them from most normal cells. Here we show that PIK3CA mutations reprogram glutamine metabolism by upregulating glutamate ...pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, making them more dependent on glutamine. Compared with isogenic wild-type (WT) cells, PIK3CA mutant CRCs convert substantially more glutamine to α-ketoglutarate to replenish the tricarboxylic acid cycle and generate ATP. Mutant p110α upregulates GPT2 gene expression through an AKT-independent, PDK1-RSK2-ATF4 signalling axis. Moreover, aminooxyacetate, which inhibits the enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumour growth of CRCs with PIK3CA mutations, but not with WT PIK3CA. Together, these data establish oncogenic PIK3CA mutations as a cause of glutamine dependency in CRCs and suggest that targeting glutamine metabolism may be an effective approach to treat CRC patients harbouring PIK3CA mutations.
To explore the associations between the Chinese famine exposure in early life and the dyslipidemia in adulthood.
We selected 2752 participants from the baseline survey of China Health and Retirement ...Longitudinal Study (CHARLS) 2011-2012 to evaluate the associations of early life the Chinese famine exposure with risk of dyslipidemia in adulthood. Dyslipidemia was defined as TC (Total Cholesterol): HDL-C (High-Density Lipoprotein Cholesterol) ratio ≥ 5.0 or use cholesterol lowering drugs. Famine exposure cohorts were categorized by birthdates of participants. Binary logistics regression model was used to examine the associations of early-life famine exposure with the risk of dyslipidemia.
The dyslipidemia prevalence of the non-exposed cohort, fetal stage-, infant stage-, and preschool stage-exposed cohorts in adulthood was 15.7%, 23.1%, 22.0%, and 18.6%, respectively. Early-life exposure to the Chinese famine significantly increased LDL cholesterol concentrations in adulthood after adjusted for age. The risks of dyslipidemia in fetal (OR = 1.58; 95% CI: 1.23-2.03; P < 0.001) and infant (OR = 1.52; 95% CI: 1.15-2.00; P = 0.003) stage-exposed cohorts were significantly higher than the non-exposed cohort after adjusted for gender and current family economic status. Following gender stratification, we found that fetal (OR = 1.80; 95% CI: 1.26-2.57; P = 0.001), infant (OR = 1.75; 95% CI: 1.17-2.62; P = 0.006), and preschool (OR = 1.63; 95% CI: 1.10-2.42; P = 0.015) -stage exposure to severe famine aggravated the risk of dyslipidemia in female adults. However, the similar association was not observed for male adults.
Early-life exposure to severe Chinese famine could link with the higher dyslipidemia risk in female adulthood, but not in male adulthood. This gender-specific effect might be associated with the hypothesis that parents in China prefer boys to girls traditionally or survivors' bias.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Following its tyrosine phosphorylation, STAT3 is methylated on K140 by the histone methyl transferase SET9 and demethylated by LSD1 when it is bound to a subset of the promoters that it activates. ...Methylation of K140 is a negative regulatory event, because its blockade greatly increases the steady-state amount of activated STAT3 and the expression of many (i.e., SOCS3) but not all (i.e., CD14) STAT3 target genes. Biological relevance is shown by the observation that overexpression of SOCS3 when K140 cannot be methylated blocks the ability of cells to activate STAT3 in response to IL-6. K140 methylation does not occur with mutants of STAT3 that do not enter nuclei or bind to DNA. Following treatment with IL-6, events at the SOCS3 promoter occur in an ordered sequence, as shown by chromatin immunoprecipitations. Y705-phosphoryl-STAT3 binds first and S727 is then phosphorylated, followed by the coincident binding of SET9 and dimethylation of K140, and lastly by the binding of LSD1. We conclude that the lysine methylation of promoter-bound STAT3 leads to biologically important down-regulation of the dependent responses and that SET9, which is known to help provide an activating methylation mark to H3K4, is recruited to the newly activated SOCS3 promoter by STAT3.
Early-life developmental adaptations in response to severe malnutrition may play a crucial role in susceptibility to hypertension. This study aimed to explore the associations between exposure to the ...Chinese famine (1959-1961) at fetal, infant and preschool stages during fetal life or childhood and the risk of hypertension in adulthood.
We used the data of 1,966 adults born between 1956 and 1964 in selected families from the China Health and Retirement Longitudinal Study (CHARLS) national survey.
Prevalence of hypertension among adults in non-exposed, fetal-exposed, infant-exposed, and preschool-exposed cohorts was 18.9, 20.7, 28.7, and 23.4 %, respectively. In severely affected famine areas, only infant-exposed cohort had a significant increased risk of hypertension compared with non-exposed cohort (OR 2.12; 95 % CI 1.19, 3.79; P = 0.011), and the significance remained after adjusted gender, smoking, and drinking (OR 2.11; 95 % CI 1.18, 3.77; P = 0.012). After stratification by BMI and economic status, the risk of hypertension was higher for subjects with BMI ≥ 24 kg/m(2)(OR 2.09; 95 % CI 1.09, 4.01; P = 0.026) or high economic status(OR 2.26; 95 % CI 1.19, 4.31; P = 0.013) than those with BMI < 24 kg/m(2)(OR 1.65; 95 % CI 0.71, 3.83; P = 0.246) or low economic status (OR 2.18; 95 % CI 1.14, 4.18; P = 0.019) in infant-exposed cohort of severely affected famine areas. However, there was no consistent association observed in less severely affected area or other exposed cohorts in severely affected areas.
Infanthood exposed to famine might increase the risk of hypertension in adulthood, and a postnatal 'rich' nutrient environment further increased the risk.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tumor tissues are chronically exposed to hypoxia owing to aberrant vascularity. Lipid droplet (LD) accumulation is a hallmark of hypoxic cancer cells, yet how LDs form and function during hypoxia ...remains poorly understood. Herein, we report that in various cancer cells upon oxygen deprivation, HIF-1 activation down-modulates LD catabolism mediated by adipose triglyceride lipase (ATGL), the key enzyme for intracellular lipolysis. Proteomics and functional analyses identified hypoxia-inducible gene 2 (HIG2), a HIF-1 target, as a new inhibitor of ATGL. Knockout of HIG2 enhanced LD breakdown and fatty acid (FA) oxidation, leading to increased ROS production and apoptosis in hypoxic cancer cells as well as impaired growth of tumor xenografts. All of these effects were reversed by co-ablation of ATGL. Thus, by inhibiting ATGL, HIG2 acts downstream of HIF-1 to sequester FAs in LDs away from the mitochondrial pathways for oxidation and ROS generation, thereby sustaining cancer cell survival in hypoxia.
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Nε-Thiocarbamoyl-lysine was recently demonstrated by our laboratory to be a potent catalytic mechanism-based SIRT1/2/3 inhibitory warhead, in the current study, among the prepared ...analogs of Nε-thiocarbamoyl-lysine with its terminal NH2 mono-substituted with alkyl and aryl groups, we found that Nε-methyl-thiocarbamoyl-lysine and Nε-carboxyethyl-thiocarbamoyl-lysine, respectively, also behaved as strong inhibitory warheads against SIRT1/2/3 and SIRT5, typical deacetylases and deacylase in the human sirtuin family, respectively. Moreover, Nε-methyl-thiocarbamoyl-lysine was found in the study to be a ∼2.5–18.4-fold stronger SIRT1/2/3 inhibitory warhead than its lead warhead Nε-thiocarbamoyl-lysine.
encodes the p110α catalytic subunit of PI3K and is frequently mutated in human cancers, including ∼30% of colorectal cancer. Oncogenic mutations in
render colorectal cancers more dependent on ...glutamine. Here we report that the glutaminase inhibitor CB-839 preferentially inhibits xenograft growth of
-mutant, but not wild-type (WT), colorectal cancers. Moreover, the combination of CB-839 and 5-fluorouracil (5-FU) induces
-mutant tumor regression in xenograft models. CB-839 treatment increased reactive oxygen species and caused nuclear translocation of Nrf2, which in turn upregulated mRNA expression of uridine phosphorylase 1 (UPP1). UPP1 facilitated the conversion of 5-FU to its active compound, thereby enhancing the inhibition of thymidylate synthase. Consistently, knockout of UPP1 abrogated the tumor inhibitory effect of combined CB-839 and 5-FU administration. A phase I clinical trial showed that the combination of CB-839 and capecitabine, a prodrug of 5-FU, was well tolerated at biologically-active doses. Although not designed to test efficacy, an exploratory analysis of the phase I data showed a trend that
-mutant patients with colorectal cancer might derive greater benefit from this treatment strategy as compared with
WT patients with colorectal cancer. These results effectively demonstrate that targeting glutamine metabolism may be an effective approach for treating patients with
-mutant colorectal cancers and warrants further clinical evaluation. SIGNIFICANCE: Preclinical and clinical trial data suggest that the combination of CB-839 with capecitabine could serve as an effective treatment for
-mutant colorectal cancers.
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