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.
The goal of this study was to analyze whether mitochondria-associated endoplasmic reticulum membrane (MAMs) dysfunction mediated arsenic (As)-evoked pulmonary ferroptosis and acute lung injury (ALI). ...As exposure led to alveolar structure damage, inflammatory cell infiltration and pulmonary function decline in mice. Ferritin, the marker of iron overload, was increased, GPX4, the index of lipid peroxidation, was decreased in As-exposed lungs and pulmonary epithelial cells (MLE-12). Pretreatment with ferrostatin-1 (Fer-1), the inhibitor of ferroptosis, alleviated As-evoked ALI. In addition, As-induced non-heme iron deposition was inhibited in Fer-1 pretreated-mice. Moreover, As-triggered mitochondria damage and ferroptosis were mitigated in Fer-1 pretreated-MLE-12 cells. Mechanistically, PERK phosphorylation and mitofusin-2 (Mfn-2) reduction was observed in As-exposed MLE-12 cells and mice lungs. Additionally, the interaction between PERK and Mfn-2 was downregulated and MAMs dysfunction was observed in As-exposed MLE-12 cells. Intriguingly, PERK inhibitor and Mfn-2-overexpression all mitigated As-induced ferroptosis in MLE-12 cells. Additionally, CLPP and mtHSP70, the markers of mitochondrial stress, were upregulated, mitochondrial ROS (mtROS) was elevated, mitochondrial membrane potential (MMP) and ATP were decreased in As-exposed MLE-12 cells. Mitoquinone mesylate (MitoQ), a novel mitochondrial-targeted antioxidant, alleviated As-induced excess mtROS, mitochondrial stress, MAMs dysfunction in pulmonary epithelial cells. Similarly, in vivo experiments indicated that MitoQ pretreatment countered As-induced pulmonary ferroptosis and ALI. These data indicated that mtROS-initiated MAMs dysfunction is, at least partially, implicated in As-evoked ferroptosis and ALI.
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•Acute As exposure induced pulmonary function decline and ALI in mice.•Acute As exposure caused ferroptosis, MAMs dysfunction and mitochondrial stress in mice lungs and pulmonary epithelial cells.•Pretreatment with ferrostatin-1 alleviated As-induced pulmonary function decline and ALI.•PERK inhibitor and Mfn-2-overexpression inhibited As-evoked ferroptosis in pulmonary epithelial cells.•MitoQ neutralized As-mediated MAMs dysfunction, mtROS production and ferroptosis in pulmonary epithelial cells.•MitoQ abolished As-induced decline of the interaction between PERK and Mfn-2 in pulmonary epithelial cells.•MitoQ attenuated As-caused ferroptosis and ALI in mice.
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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.
Vitamin D deficiency is associated with increased risks of chronic obstructive pulmonary disease (COPD). Nevertheless, the mechanisms remain unknown. This study analyzed the correlations between ...vitamin D levels and inflammation in COPD patients. One hundred and one patients with COPD and 202 control subjects were enrolled. Serum 25(OH)D level and inflammatory cytokines were detected. Serum 25(OH)D was decreased and inflammatory cytokines were increased in COPD patients. According to forced expiratory volume in 1 s, COPD patients were divided into three grades. Furthermore, serum 25(OH)D was gradually decreased in COPD patients ranging from grade 1-2 to 4. Serum 25(OH)D was inversely associated with inflammatory cytokines in COPD patients. Further analysis found that NF-κB and AP-1 signaling were activated in COPD patients. Besides, inflammatory signaling was gradually increased in parallel with the severity of COPD. By contrast, pulmonary nuclear vitamin D receptor was decreased in COPD patients. In vitro experiments showed that 1,25(OH)
D
inhibited LPS-activated inflammatory signaling in A549 cells (human lung adenocarcinoma cell). Mechanically, 1,25(OH)
D
reinforced physical interactions between vitamin D receptor with NF-κB p65 and c-Jun. Our results indicate that vitamin D is inversely correlated with inflammatory signaling in COPD patients. Inflammation may be a vital mediator of COPD progress in patients with low vitamin D levels.
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.
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.
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.
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