Several reports indicate that melatonin alleviates bleomycin (BLM)-induced pulmonary fibrosis in rodent animals. Nevertheless, the exact mechanism remains obscure. The present study investigated the ...effects of melatonin on endoplasmic reticulum (ER) stress and epithelial-mesenchymal transition (EMT) during BLM-induced lung fibrosis. For the induction of pulmonary fibrosis, mice were intratracheally injected with a single dose of BLM (5.0 mg/kg). Some mice were intraperitoneally injected with melatonin (5 mg/kg) daily for a period of 3 wk. Twenty-one days after BLM injection, lung fibrosis was evaluated. As expected, melatonin significantly alleviated BLM-induced pulmonary fibrosis, as evidenced by Sirius red staining. Moreover, melatonin significantly attenuated BLM-induced EMT to myofibroblasts, as determined by its repression of α-SMA expression. Further analysis showed that melatonin markedly attenuated BLM-induced GRP78 up-regulation and elevation of the cleaved ATF6 in the lungs. Moreover, melatonin obviously attenuated BLM-induced activation of pulmonary eIF2α, a downstream target of the PERK pathway. Finally, melatonin repressed BLM-induced pulmonary IRE1α phosphorylation. Correspondingly, melatonin inhibited BLM-induced activation of XBP-1 and JNK, two downstream targets of the IRE1 pathway. Taken together, these results suggest that melatonin alleviates ER stress and ER stress-mediated EMT in the process of BLM-induced pulmonary fibrosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Tibet Plateau (TP) is a key region that imposes profound impacts on the atmospheric water cycle and energy budget of Asia, even the global climate. In this work, we develop a climatology of ...origin (destination) of air mass and moisture transported to (from) the TP using a Lagrangian moisture diagnosis combined with the forward and backward atmospheric tracking schemes. The climatology is derived from 6-h particle positions based on 5-year (2005–2009) seasonal summer trajectory dataset from the Lagrangian particle dispersion model FLEXPART using NCEP/GFS data as input, where the regional model atmosphere was globally filled with particles. The results show that (1) the dominant origin of the moisture supplied to the TP is a narrow tropical–subtropical band in the extended Arabian Sea covering a long distance from the Indian subcontinent to the Southern Hemisphere. Two additional moisture sources are located in the northwestern part of TP and the Bay of Bengal and play a secondary role. This result indicates that the moisture transporting to the TP more depends on the Indian summer monsoon controlled by large-scale circulation. (2) The moisture departing from the TP can be transported rapidly to East Asia, including East China, Korea, Japan, and even East Pacific. The qualitative similarity between the regions of diagnosed moisture loss and the pattern of the observed precipitation highlights the robustness of the role of the TP on precipitation over East Asia. (3) In contrast to the moisture origin confined in the low level, the origin and fate of whole column air mass over the TP is largely controlled by a strong high-level Asian anticyclone. The results show that the TP is a crossroad of air mass where air enters mainly from the northwest and northeast and continues in two separate streams: one goes southwestwards over the Indian Ocean and the other southeastwards through western North Pacific. Both of them partly enter the trade wind zone, which manifests the influence of the air mass transport over the TP on the budget of global atmosphere compositions.
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•Gestational exposure to human relevant dose of PFHxS induces developmental toxicity.•Increased fetal death incidence were observed at delivery.•PFHxS reached & crossed the placental ...barrier with tendency to accumulate in fetus.•Lipidomic and transcriptomic data showed disruption in placental lipid homeostasis.•Placental lipid disruption may be mediated by disruption in lipid transporters.
Perfluorohexyl sulfonate (PFHxS) is the third most abundant per- and polyfluoroalkyl substances and its developmental toxicity remains very poorly understood. Here, pregnant mice exposed to PFHxS at human relevant dose showed increased fetal death incidence in the high-dose PFHxS-H group (P < 0.01). Body distribution analyses suggested that PFHxS crossed the placental barrier reaching the fetus in a dose-dependent manner. Histopathological data demonstrated impairment in the placenta with reduced blood sinus volume, placental labyrinth area as well as thickness of labyrinthine layer. Further lipidomic and transcriptomic data together showed that PFHxS exposure caused significant disruption in placental lipid homeostasis, including total lipid accumulation in the placenta, and dysregulation in phospholipid and glycerol lipid metabolism. Gene expression analyses uncovered elevation in key placental fatty acid transporters including fabp2, whereas protein expression showed transporter specific disruptions following exposure. Together, gestational exposure to human relevant level of PFHxS may increase the incidence of fetal deaths and caused placental dysplasia via disruption in lipid metabolism homeostasis. These findings raise the concern regarding the highly prevalent and persistent chemical towards early sensitive developing stages and provide basis for further understanding of its effects on lipid metabolism and underlying mechanisms.
Environmental cadmium (Cd) is positively associated with placental impairment and fetal growth retardation. Nevertheless, its potential mechanisms remain unclear. microRNAs (miRNAs) are known to ...influence placental development and fetal growth. This work was aimed to determine which miRNAs are involved in Cd-impaired placental and fetal development based on the mRNA and miRNA expression profiles analysis. As a result, gestational Cd exposure deceased fetal and placental weight, and reduced the protein level of PCNA in human and mouse placentae. Furthermore, the results of mRNA microarray showed that Cd-downregulated mRNAs were predictively correlated with several biological processes, including cell proliferation, differentiation and motility. In addition, the results of miRNA microarray and qPCR assay demonstrated that Cd significantly increased the level of miR-6769b-5p, miR-146b-5p and miR-452–5p. Integrated analysis of Cd-upregulated miRNAs predicted target genes and Cd-downregulated mRNAs found that overlapping mRNAs, such as CCND1, CDK13, RINT1 and CDC26 were also significantly associated with cell proliferation. Further experiments showed that miR-6769b-5p inhibitor, but not miR-146b-5p and miR-452–5p, markedly reversed Cd-downregulated the expression of proliferation-related mRNAs, and thereby restored Cd-decreased the proteins level of CCND1 and PCNA in human placental trophoblasts. Dual luciferase reporter assay further revealed that miR-6769b-5p directly targets CCND1. Finally, the case-control study demonstrated that increased miR-6769b-5p level and impaired cell proliferation were observed in small-for-gestational-age human placentae. In conclusion, miR-6769b-5p targets CCND-1 to regulate proliferation in Cd-treated placental trophoblasts, which is associated with the impairment of fetal growth. Our findings imply that placental miR-6769b-5p may be used as an epigenetic marker for environmental pollutants-caused fetal growth restriction and its late-onset chronic diseases.
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•Cadmium exposure impairs placental and fetal development.•Cadmium induces dysregulated expression of proliferation-related mRNAs and miRNAs in placental trophoblasts.•MiR-6769b-5p inhibitor markedly reverses Cd-inhibited cell proliferation in human placental trophoblasts.•Impaired cell proliferation and increased miR-6769b-5p level are observed in human SGA placenta.
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•Gestational DEHP exposure causes fetal IUGR in a dose-dependent manner.•Gestational DEHP exposure disturbs placental THR signaling.•Gestational DEHP exposure disturbs placental ...angiogenesis.•Placental microvessels density is lower in SGA cases from MABC Birth Cohort.•THRs protein abundance is reduced in SGA cases.
Previous study reported that gestational Di-(2-ethylhexyl) phthalate (DEHP) exposure caused fetal intrauterine growth restriction (IUGR). We aimed to investigate the role of placental thyroid hormone receptor (THR) signaling in DEHP-induced IUGR. Dams were treated with DEHP (50 or 200 mg/kg) by gavage daily throughout pregnancy. As expected, gestational DEHP exposure dose-dependently caused fetal IUGR. The mRNA levels of placental Thrα1 and Thrβ1 were reduced and nuclear translocation of placental THRα1 and THRβ1 were suppressed in DEHP-exposed mice even though thyroid hormones in maternal and fetal sera were unaffected. Correspondingly, Vegf, Pgf, Igf1 and Igf2, several THR downstream genes essential for placental angiogenesis, were down-regulated in placenta of DEHP-exposed mice. Histopathology showed that vascular space in the labyrinthine region was shrunken in placenta of DEHP-treated mice. The microvessel density in labyrinthine region was reduced in DEHP-treated mice. A nested case-control study based on MABC suggested that microvessel density was decreased in placenta of SGA cases. Moreover, protein abundance of placental THRα1 and THRβ1 were lower in SGA cases. In conclusion, gestational DEHP exposure increases fetal IUGR incidence through disturbing placental THR signaling. The present study, at least partially, elucidate the underlying mechanism of DEHP-induced fetal IUGR.
ABSTRACT
The Sichuan Basin (SCB), in southwest China, is characterized by a high frequency of heavy precipitation (HP) events in the boreal summer. In this study, the top 50 HP events that occurred ...in the SCB were selected, based on daily precipitation gauge data during 1980–2013, and the moisture sources for these events have been identified. Taking advantage of the Lagrangian approach, we particularly examined the spatiotemporal structure of the moisture sources, both in their magnitude and temporal sequence. The results of this study can be summarized as follows: (1) the quantification of the contribution of the moisture sources indicated that the remote sources of moisture originating from the Tibetan Plateau, Indian Peninsula, Bay of Bengal and the Arabian Sea made considerable contributions to the moisture in the HP events; however, these areas were only the third most important factor in climatology, following the stronger influence of moisture uptake from the SCB local regions and the nearby Indo‐China Peninsula and South China Sea regions; (2) the time that moisture involved in the HP events varies between a few hours to more than a week before the HP events. Most of the moisture uptakes happened 1–5 days before the events, with maximum uptake occurring about 1 day before; (3) individual event‐to‐event variability of moisture sources was apparent. However, in contrast to the primary moisture contributors, this event‐to‐event variation depended largely on the externally imported moisture, particularly water vapor conveyed by both dominant southwest circulations and the moisture exported from the Tibetan Plateau, rather than the local SCB region. These results have established the atmospheric flow patterns that are prerequisites for HP events; meanwhile, regional moisture availability over the SCB region could also be an essential component of forecasting the HP events and needs to be better understood.
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Whilst certain environmental organochlorine pesticide exposure may still pose significant burden, the associations between dichloro-diphenyl-trichloroethane (DDT) and chronic kidney ...disease (CKD) remain disputable notwithstanding the potentially inaccurate disease definition between age groups. National DDT exposure burden atlas was depicted from 92,061 participants by measuring their serum concentrations of DDT congeners and major metabolite in the US from 1999 to 2016. Temporal analyses of these toxicant exposure suggested that although serum DDT concentrations exhibited recent decline, the detection rates remain up to 99.8% every year, posing great concern for exposure risk. A total of 3,039 US adults were further included from these participants demonstrating the weighted CKD prevalence of 40.2% using the new age-adapted CKD-EPI40 model compared to 28.0% using the current CKD-EPI method. After adjustment for covariates, logistic regression model results showed individual metabolites and total DDT burden were positively, yet monotonically, associated with risk of CKD incidence (P-trend for all < 0.05), particularly among adults 40 years of age and older. Much heightened renal disease risk was also observed with high DDT exposure (OR, 1.55; 95 % CI, 1.11–2.15) in those who were hypertensive (P for heterogeneity < 0.001) but not with diabetes. The current high DDT exposure risk combined with elevated probability for CKD incidence call for health concerns and management for the environmentally persistent pollutants.
Heavy metal cadmium (Cd), a classical environmental pollutant, causes placental apoptosis and fetal growth restriction (FGR), whereby the mechanism remains unclear. Here, our human case-control study ...firstly showed that there was a positive association of Parkin mitochondrial translocation, MCL-1 reduction, placental apoptosis, and all-cause FGR. Subsequently, Cd was administered to establish in vitro and in vivo models of placental apoptosis or FGR. Our models demonstrated that Parkin mitochondrial translocation was observed in Cd-administrated placental trophoblasts. Meaningfully, Parkin siRNA (siR) dramatically mitigated Cd-triggered apoptosis in placental trophoblasts. Mdivi-1 (M-1), an inhibitor for Parkin mitochondrial translocation, mitigated Cd-induced apoptosis in placental trophoblasts, which further ameliorated the effect of attenuated placental sizes in Cd-exposed mice. Furthermore, the interaction of MCL-1 with Parkin or Ub in Cd-stimulated cells was stronger than that in controls. MG132, an inhibitor for proteasome, abolished MCL-1 degradation in Cd-stimulated cells. Importantly, Parkin siR and M-1 memorably abolished the ubiquitin-dependent degradation of MCL-1 in placental trophoblasts. Interestingly, mito-TEMPO and melatonin, two mitochondria-targeted antioxidants, obviously rescued Cd-caused mitochondrial membrane potential (MMP) decrease, Parkin mitochondrial translocation, MCL-1 degradation, and apoptosis in placental trophoblasts. In conclusion, cadmium induces placental apoptosis and FGR via mtROS-mediated Parkin-modulated degradation of MCL-1.
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•Parkin mitochondrial translocation and apoptosis occur in SGA placentae.•Cadmium promotes placental apoptosis via MCL-1 degradation.•Cadmium causes MCL-1 degradation by Parkin mitochondrial translocation.•Cadmium promotes Parkin mitochondrial translocation via mtROS release.
Long noncoding RNAs (lncRNAs) regulate tumor development and progression by promoting proliferation, invasion, and metastasis. The oncogenic role of lncRNA SNHG16 in hepatocellular carcinoma (HCC) ...has not been revealed. LncRNA SNHG16 is upregulated in HCC and correlates with poorer prognosis. Patients with high SNHG16 expression showed lower rates of overall and disease‐free survival than patients with low SNHG16 expression. Multivariate Cox regression revealed that SNHG16 expression was an independent predictor of poor overall and disease‐free survival. In vitro, SNHG16 promoted HCC cell proliferation, migration, and invasion while inhibiting apoptosis; in vivo, it accelerated tumor development. Altering SNHG16 expression altered levels of miR‐17‐5p, which in turn modified expression of p62, which has been shown to regulate the mTOR and NF‐κB pathways. Indeed, altering SNHG16 expression in HCC cells activated mTOR and NF‐κB signaling. These results reveal a potential mechanism for the oncogenic role of SNHG16 in HCC. SNHG16 may therefore be a promising diagnostic marker as well as therapeutic target in HCC.
A schematic hypothetical model shows how SNHG16 acts as an oncogenic long noncoding RNA that promotes hepatocarcinogenesis by acting as a competing endogenous RNA that binds to miR‐17‐5p, thereby de‐repressing expression of p62 and its signal pathways AFB1, aflatoxin B1.
Despite the reported efficacy of osimertinib, central nervous system (CNS) progression is still frequent in EGFR-mutated NSCLC. This study aimed to reveal site-specific resistant mechanisms to ...osimertinib and investigate subsequent treatments for leptomeningeal metastases (LM).
EGFR-mutated NSCLC with LM who progressed on osimertinib were included. Molecular analysis of cerebrospinal fluid (CSF) at osimertinib progression was performed. Subsequent treatments of LM were collected and analyzed.
A total of 246 patients were identified. Only those with LM as a progression site on osimertinib were included (n=81). In 58 CSF-plasma pairs, more alterations were uniquely detected in CSF (77%) than in plasma (7%). These mechanisms led to 22 patients receiving matched targeted therapy. Among them, 16 (72.7%) had a clinical response. The median overall survival was 7.2 months. For non-matched therapy (n=59), the osimertinib combination had a longer median overall survival than the regimen switch in CNS-only progression (15.3 vs. 7 months, p=0.03). Finally, serial monitoring by CSF revealed the potential evolution of LM.
Private resistant mechanisms in CSF might match osimertinib-resistant LM for targeted therapy. Besides, continuing osimertinib with intensification strategy might prolong survival, especially for those with CNS-only progression. Prospective exploration is needed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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