Low vitamin D status is associated with progression in patients with renal cell carcinoma (RCC). The present study found that vimentin, a mesenchymal marker, was accordingly upregulated, and ...E‐cadherin, an epithelial marker, was downregulated in RCC patients with low vitamin D status. Thus, we investigated the effects of calcitriol or vitamin D3, an active form of vitamin D, on epithelial‐mesenchymal transition (EMT) in RCC cells. RCC cells were treated by two models. In model 1, three RCC cell lines, ACHN, 786‐O and CAKI‐2, were incubated with either LPS (2.0 μg/mL) or transforming growth factor (TGF)‐β1 (10 ng/mL) in the presence or absence of calcitriol (200 nmol/L). In model 2, two RCC cell lines, ACHN and CAKI‐2, were incubated with calcitriol (200 nmol/L) only. Calcitriol inhibited migration and invasion not only in TGF‐β1‐stimulated but also in TGF‐β1‐unstimulated RCC cells. Moreover, calcitriol suppressed E‐cadherin downregulation and vimentin upregulation not only in TGF‐β1‐stimulated but also in TGF‐β1‐unstimulated ACHN and CAKI‐2 cells. Calcitriol attenuated LPS‐induced upregulation of MMP‐2, MMP‐7, MMP‐9, MMP‐26 and urokinase‐type plasminogen activator (u‐PA) in ACHN cells. In addition, calcitriol blocked TGF‐β1‐induced nuclear translocation of ZEB1, Snail and Twist1 in ACHN and CAKI‐2 cells. Mechanistically, calcitriol suppressed EMT through different signaling pathways: (i) calcitriol suppressed Smad2/3 phosphorylation by reinforcing physical interaction between vitamin D receptor (VDR) and Smad3 in TGF‐β1‐stimulated RCC cells; (ii) calcitriol inhibited signal transducer and activator of transcription (STAT)3 activation in LPS‐stimulated RCC cells; (iii) calcitriol inhibited β‐catenin/TCF‐4 activation by promoting integration of VDR with β‐catenin in TGF‐β1‐unstimulated RCC cells. Taken together, calcitriol inhibits migration and invasion of RCC cells partially by suppressing Smad2/3‐, STAT3‐ and β‐catenin‐mediated EMT.
Calcitriol suppressed EMT through two different signaling pathways: (i) calcitriol suppressed Smad2/3 phosphorylation by reinforcing physical interaction between vitamin D receptor (VDR) and Smad3 in TGF‐β1‐stimulated RCC cells; (ii) calcitriol inhibited β‐catenin/TCF‐4 activation by promoting integration of VDR with β‐catenin in TGF‐β1‐unstimulated RCC cells. Taken together, calcitriol inhibits migration and invasion of RCC cells by suppressing Smad2/3‐ and β‐catenin‐mediated EMT.
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Humans are exposed to an ever-increasing number of environmental toxicants, some of which have gradually been elucidated to be important risk factors for metabolic diseases, such as ...diabetes and obesity. These metabolism-sensitive diseases typically occur when key metabolic and signaling pathways were disrupted, which can be influenced by the exposure to contaminants such as endocrine disrupting chemicals (EDCs), along with genetic and lifestyle factors. This promotes the concept and research on environmental metabolism disrupting chemicals (MDCs). In addition, identifying endogenous biochemical markers of effect linked to disease states is becoming an important tool to screen the biological targets following environmental contaminant exposure, as well as to provide an overview of toxicity risk assessment. As such, the current review aims to contribute to the further understanding of exposome and human health and disease by characterizing environmental exposure and effect metabolic biomarkers. We summarized MDC-associated metabolic biomarkers in laboratory animal and human cohort studies using high throughput targeted and nontargeted metabolomics techniques. Contaminants including heavy metals and organohalogen compounds, especially EDCs, have been repetitively associated with metabolic disorders, whereas emerging contaminants such as perfluoroalkyl substances and microplastics have also been found to disrupt metabolism. In addition, we found major limitations in the effective identification of metabolic biomarkers especially in human studies, toxicological research on the mixed effect of environmental exposure has also been insufficient compared to the research on single chemicals. Thus, it is timely to call for research efforts dedicated to the study of combined effect and metabolic alterations for the better assessment of exposomic toxicology and health risks. Moreover, advanced computational and prediction tools, further validation of metabolic biomarkers, as well as systematic and integrative investigations are also needed in order to reliably identify novel biomarkers and elucidate toxicity mechanisms, and to further utilize exposome and metabolome profiling in public health and safety management.
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•Environmental Cd exposure inhibits placental P4 synthesis and causes FGR.•Cd inhibits placental P4 synthesis by Parkin-dependent mitophagy.•PERK signaling mediates Cd-activated ...mitophagy in placental trophoblasts.•Placental mitophagy contributes to Cd-impaired fetal growth in mice.•FGR is associated with activated mitophagy and reduced P4 synthesis in human placenta.
Cadmium (Cd), an environmental toxicant, is positively associated with fetal growth restriction (FGR). However, the mechanism by which gestational exposure to Cd induces FGR remains unclear. This study designed in vitro and in vivo experiments to explore the role of placental mitophagy in Cd-impaired fetal growth. Based on our case-control study, we also investigated the association of placental mitophagy with reduced progesterone (P4) level and all-cause FGR. We firstly found environmental Cd exposure lowered the P4 content in maternal sera, placentae and amnioticfluids of mice. The level of three mitochondrial P4 synthases, including StAR, CYP11A1 and 3β-HSD, was also reduced in Cd-treated placentae. Furthermore, Cd triggered mitophagy, as determined by the degradation of two mitochondrial proteins HSP60 and COX IV, and the accumulation of co-localizations of TOM20 with LC3B or Parkin in placental trophoblasts. Correspondingly, Cd elevated mitochondrial Parkin level in placental trophoblasts. Mdivi-1, a mitophagy inhibitor, obviously attenuated Cd-induced reduction of placental P4 and FGR in mice. Moreover, mdivi-1 and Parkin siRNA (siR) markedly reversed Cd-caused P4 synthesis inhibition in human placental trophoblasts. Interestedly, the PERK/ATF4 signaling was activated in Cd-stimulated placental trophoblasts. PERK siR inhibited mitochondrial proteins degradation in Cd-stimulated placental trophoblasts. In particularly, mitophagy activation and P4 synthesis suppression occurred in small-for-gestational-age placentae based on our case-control study. Environmental Cd exposure induced FGR via activating PERK-regulated mitophagy and inhibiting P4 synthesis in placentaltrophoblasts. Furthermore, placental mitophagy was related to the reduced progesterone level and all-cause fetal growth restriction based on our case-control study. As above, placental mitophagy maybe the common mechanism of environmental toxicants-impaired fetal growth.
To assess the effects of cetuximab plus chemotherapy as first-line treatment for unresectable colorectal liver metastases (CLMs).
After resection of their primary tumors, patients with KRAS wild-type ...synchronous nonresectable liver-limited metastases from colorectal cancer were randomly assigned to receive chemotherapy (FOLFIRI fluorouracil, leucovorin, and irinotecan or mFOLFOX6 modified fluorouracil, leucovorin, and oxaliplatin) plus cetuximab (arm A) or chemotherapy alone (arm B). The primary end point was the rate of patients converted to resection for liver metastases. Secondary end points included tumor response and survival.
The intent-to-treat population comprised 138 patients; 70 patients were randomly assigned to arm A and 68 to arm B. After a median of 25.0 months of follow-up, the 3-year overall survival (OS) rate and median survival time (MST) for all patients were 30% and 24.4 months, respectively. The R0 resection rates for liver metastases were 25.7% (18 of 70 patients) in arm A and 7.4% (five of 68 patients) in arm B, which were significantly different (P < .01). Patients in arm A had improved objective response rates (57.1% v 29.4%; P < .01), increased 3-year OS rate (41% v 18%; P = .013) and prolonged MST (30.9 v 21.0 months; P = .013) compared with those in arm B. In addition, in arm A, patients who had resection of liver metastases had a significantly improved MST (46.4 v 25.7 months; P < .01) compared with those who did not undergo surgery.
For patients with initially unresectable KRAS wild-type CLMs, cetuximab combined with chemotherapy improved the resectability of liver metastases and improved response rates and survival compared with chemotherapy alone.
1-Nitropyrene (1-NP) is one component of atmospheric fine particles. Previous report revealed that acute 1-NP exposure induced respiratory inflammation. This study aimed to investigate whether ...chronic 1-NP exposure induces pulmonary fibrosis. Male C57BL6/J mice were intratracheally instilled to 1-NP (20 μg/mouse/week) for 6 weeks. Diffuse interstitial inflammation, a-smooth muscle actin (a-SMA)-positive cells, a marker of epithelial-mesenchymal transition (EMT), and an extensive collagen deposition, measured by Masson staining, were observed in 1-NP-exposed mouse lungs. Pulmonary function showed that lung dynamic compliance (Cydn-min) was reduced in 1-NP-exposed mice. Conversely, inspiratory resistance (Ri) and expiratory resistance (Re) were elevated in 1-NP-exposed mice. Mechanistically, cell migration and invasion were accelerated in 1-NP-exposed pulmonary epithelial cells. In addition, E-cadherin, an epithelial marker, was downregulated, and vimentin, a-SMA and N-cadherin, three mesenchymal markers, were upregulated in 1-NP-exposed pulmonary epithelial cells. Although TGF-β wasn’t altered, phosphorylated Smad2/3 were enhanced in 1-NP-exposed pulmonary epithelial cells. Moreover, reactive oxygen species (ROS) were increased and endoplasmic reticulum (ER) stress was activated in 1-NP-exposed pulmonary epithelial cells. N-Acetylcysteine (NAC), an antioxidant, attenuated 1-NP-evoked excess ROS, ER stress and EMT in pulmonary epithelial cells. Similarly, pretreatment with NAC alleviated 1-NP-caused pulmonary EMT and lung fibrosis in mice. These results demonstrate that ROS-evoked ER stress contributes, at least partially, to 1-NP-induced EMT and pulmonary fibrosis.
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•Chronic 1-NP exposure induced EMT and lung fibrosis.•1-NP exposure promoted Smad2/3 phosphorylation and EMT independent of TGF-β.•ROS-evoked ER stress involved in 1-NP-induced Smad2/3 activation and EMT.•Pretreatment with NAC protected against 1-NP-evoked EMT and lung fibrosis.
Gestational exposure to environmental stress induces fetal growth restriction (FGR), and thereby increasing the risk of infant death and chronic noncommunicable diseases in adults. However, the ...mechanism by which environmental stress induces FGR remains unclear. Based on case-control study, we found that the reduced level of melatonin (MT), a major secretory product from the pineal gland, was observed in placentae of FGR. This work was to investigate the protective effect of MT on environmental stress-caused FGR and its mechanisms. We used cadmium (Cd) as an environmental stressor to stimulate pregnant mice and thereby establishing a FGR model. The data showed that maternal Cd exposure lowered the P4 concentration in maternal sera, placentae and amniotic fluid, and caused FGR. Correspondingly, the expression of CYP11A1, a critical P4 synthase, was markedly downregulated in Cd-treated placentae. Simultaneously, Cd triggered BNIP3-dependent mitophagy in placental trophoblasts, as determined by the degradation of mitochondrial proteins, including HSP60 and COX IV, and the accumulation of puncta representing co-localization of TOM20 with LC3B or BNIP3 with LC3B. Based on our case-control study, we also found that activated BNIP3-dependent mitophagy and P4 synthesis inhibition occurred in SGA placentae. Most importantly, BNIP3 siRNA reversed Cd-induced P4 synthesis suppression in human placental trophoblasts. It is noteworthy that MT alleviated Cd-caused P4 synthesis suppression and FGR via antagonizing BNIP3-dependent mitophagy in placental trophoblasts. Further results confirmed that MT attenuated Cd-triggered BNIP3-dependent mitophagy via blocking GCN2/ATF4 signaling. Amusingly, Cd triggered oxidative stress and then activating GCN2/ATF4 signaling in placental trophoblasts. As expected, MT obviously suppressed Cd-caused reactive oxygen species (ROS) release. In the present study, we propose a neoteric mechanism by which MT protects against environmental stress-impaired P4 synthesis and fetal growth via suppressing ROS-mediated GCN2/ATF4/BNIP3-dependent mitophagy in placental trophoblasts. As above, MT is a potential therapeutic agent antagonizing environmental stress-induced developmental toxicity.
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•Melatonin protects against Cd-induced fetal growth restriction.•Melatonin attenuates Cd-induced placental P4 synthesis inhibition by mitophagy.•Melatonin suppresses Cd-triggered placental mitophagy via blocking GCN2/ATF4.•Melatonin blocks Cd-activated placental GCN2/ATF4 signaling via repressing ROS.•Activated mitophagy and reduced P4 synthesis occur in SGA placentae.
Context:
Vitamin D deficiency is common in pregnant women. Nevertheless, the association between maternal vitamin D status during pregnancy and the risk of having small for gestational age (SGA) and ...low birth weight (LBW) infants is uncertain.
Objective:
The objective of this study was to investigate whether there is a correlation between maternal vitamin D deficiency during pregnancy and the risk of having SGA and LBW infants in a Chinese population.
Design and Participants:
This was a population-based birth cohort study that recruited 3658 eligible mother-and-singleton-offspring pairs.
Main Outcome Measures:
Serum 25-hydroxyvitamin D was measured by RIA. The rate and relative risk (RR) for SGA and LBW infants were calculated among subjects with vitamin D deficiency and insufficiency during pregnancy.
Results:
There was a positive correlation between maternal serum 25-hydroxyvitamin D level and offspring birth weight (r = 0.477; P < .001). Further analysis showed that 4.98% of neonates were LBW infants among the subjects with vitamin D deficiency (RR, 12.00; 95% confidence interval CI, 4.37, 33.00) and 1.32% among the subjects with vitamin D insufficiency (RR, 3.18; 95% CI, 1.07, 9.48). After adjustment for confounders, the RR for LBW infants was 12.31 (95% CI, 4.47, 33.89) among subjects with vitamin D deficiency and 3.15 (95% CI, 1.06, 9.39) among subjects with vitamin D insufficiency. Moreover, 16.01% of neonates were SGA infants among subjects with vitamin D deficiency (RR, 5.72; 95% CI, 3.80, 8.59) and 5.59% among subjects with vitamin D insufficiency (RR, 1.99; 95% CI, 1.27, 3.13). After adjustment for confounders, the RR for SGA infants was 6.47 (95% CI, 4.30, 9.75) among subjects with vitamin D deficiency and 2.01 (95% CI, 1.28, 3.16) among subjects with vitamin D insufficiency.
Conclusion:
Maternal vitamin D deficiency during pregnancy elevates the risk of SGA and LBW infants in a Chinese population.
Oceanic moisture exports (OMEs) are considered the major moisture sources for precipitation over Mainland China during the boreal summer season. In this study, a Lagrangian particle dispersion and ...transport model FLEXible PARTicle dispersion model (FLEXPART) driven with European Centre for Medium-Range Weather Forecasts (ECMWF) reanalysis (ERA)-Interim data was used to conduct 35-year modeling of the summer season (May–August) for 1980–2014. Based on the 6-h output over 35 years, a relatively sophisticated approach was adopted that considers the change in specific humidity with trajectory tracking to diagnose OME-based precipitation during the summer season in China. We specifically explored the spatiotemporal structure of OME-based precipitation over Mainland China with a focus on quantifying the relative contributions of three specific oceanic sub-regions: the Arabian Sea (AS), the Bay of Bengal (BOB), and the South China Sea (SCS). The relevance of the OME anomalies from the three sub-regions and the observed precipitation changes on an interannual scale were also explored. The main research conclusions are summarized as follows: (1) The diagnosed OME-based precipitation and gauge observations exhibit similar spatial patterns in both seasonal and sub-seasonal scales, further evidencing the robustness of the approach used in this study. (2) Climatologically, the OMEs originating from the AS, the BOB, and the SCS made roughly equivalent contributions to the entire areal-averaged precipitation over Mainland China on a seasonal scale, but the preferred regions influenced by the three oceanic sources differ strongly from each other. (3) The relative contributions of OME from three specific subsections to precipitation varied significantly on the sub-seasonal scale. During the onset of summer monsoons, the AS region ranked first as an important oceanic source, followed by the BOB and the SCS, whereas during the withdrawal of summer monsoons, this order was reversed. (4) The interannual anomalies of OME-based precipitation from the SCS and the BOB regions are negatively correlated with those outside the AS region.
Several studies found that reduction of 5-hydroxymethylcytosine (5hmC), a marker of DNA hydroxymethylation highly enriched in developing brain, is associated with anxiety-like behaviors. This study ...aimed to investigate whether gestational arsenic (As) exposure induces anxiety-like behaviors in adult offspring by reducing DNA hydroxymethylation in the developing brain. The dams drank ultrapure water containing NaAsO2 (15 mg/L) throughout pregnancy. Anxiety-like behaviors were evaluated and developing brain 5hmC was detected. Results showed that anxiety-like behaviors were observed in As-exposed adult offspring. In addition, 5hmC content was reduced in As-exposed fetal brain. Despite no difference on Tet1, Tet2 and Tet3 expression, TET activity was suppressed in As-exposed fetal brain. Mechanistically, alpha-ketoglutarate (α-KG), a cofactor for TET dioxygenases, was reduced and Idh2, a key enzymatic gene for mitochondrial α-KG synthesis, was downregulated in As-exposed fetal brain. Of interest, ascorbic acid, a cofactor for TET dioxygenases, reversed As-induced suppression of TET activity. Moreover, ascorbic acid attenuated As-induced reduction of 5hmC in fetal brain. In addition, ascorbic acid alleviated As-induced anxiety-like behaviors in adult offspring. Taken together, these results suggest that gestational As exposure induces anxiety-like behaviors in adult offspring, possibly at part, by inhibiting DNA hydroxymethylation in developing brain.
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•Gestational As exposure induces anxiety-like behaviors in adult offspring.•Gestational As exposure reduces 5hmC in fetal brain.•Gestational As exposure inhibits TET activity by reducing α-KG content in fetal brain.•AA attenuates As-induced reduction of 5hmC and TET activity in fetal brain.•AA alleviated As-induced anxiety-like behaviors in adult offspring.
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