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Context Existing studies focusing on the effects of nonalcoholic fatty liver disease (NAFLD) combined with normal prepregnant weight on pregnancy outcomes are limited. Objective This study aimed to explore the relationship between maternal NAFLD and adverse pregnancy outcomes in different body mass index (BMI) groups. Methods Using an antenatal care and delivery database, we retrospectively analyzed women who delivered in Minhang Hospital affiliated to Fudan University, Shanghai, China from January 1, 2013, to June 30, 2020. NAFLD was confirmed by ultrasound in early pregnancy. A logistic regression model with adjustment for confounders was used to examine potential associations between NAFLD and pregnancy outcomes. Results A total of 14 708 pregnant women (mean prepregnant BMI 21.0 [SD, 2.8] kg/m2) were included in our final study, of whom 554 (3.8%) had NAFLD. After fully adjusting for potential confounders, NAFLD significantly increased the risk of gestational diabetes mellitus (adjusted odds ratio 2.477; 95% CI, 1.885-3.254), gestational hypertension (3.054; 2.191-4.257), preeclampsia/eclampsia (3.994; 2.591-6.005), cesarean section (1.569; 1.315-1.872), preterm births (1.831; 1.229-2.727), and macrosomia (1.691; 1.300-2.198). It is notable that 83.9% (12 338) of women were of normal weight at the start of pregnancy (prepregnant 18.5 ≤ BMI < 24 kg/m2), and they still had higher odds of adverse pregnancy outcomes. Conclusion Women with NAFLD and a normal weight have a higher risk for adverse pregnancy outcomes. Pregnant women with NAFLD, regardless of obesity status, should be offered a more qualified surveillance to optimize pregnancy outcomes.

Ovarian cancer is one of the most aggressive and heterogeneous female tumors in the world, and serous ovarian cancer (SOC) is of particular concern for being the leading cause of ovarian cancer death. Due to its clinical and biological complexities, ovarian cancer is still considered one of the most difficult tumors to diagnose and manage. In this study, three datasets were assembled, including 30 cases of serous cystadenoma (SCA), 30 cases of serous borderline tumor (SBT), and 45 cases of serous adenocarcinoma (SAC). Mueller matrix microscopy is used to obtain the polarimetry basis parameters (PBPs) of each case, combined with a machine learning (ML) model to derive the polarimetry feature parameters (PFPs) for distinguishing serous ovarian tumor (SOT). The correlation between the mean values of PBPs and the clinicopathological features of serous ovarian cancer was analyzed. The accuracies of PFPs obtained from three types of SOT for identifying dichotomous groups (SCA versus SAC, SCA versus SBT, and SBT versus SAC) were 0.91, 0.92, and 0.8, respectively. The accuracy of PFP for identifying triadic groups (SCA versus SBT versus SAC) was 0.75. Correlation analysis between PBPs and the clinicopathological features of SOC was performed. There were correlations between some PBPs ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], rqcross, [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text]) and clinicopathological features, including the International Federation of Gynecology and Obstetrics (FIGO) stage, pathological grading, preoperative ascites, malignant ascites, and peritoneal implantation. The research showed that PFPs extracted from polarization images have potential applications in quantitatively differentiating the SOTs. These polarimetry basis parameters related to the clinicopathological features of SOC can be used as prognostic factors.

Background Endometrial cancer (EC) is one of the most common gynecological tumors. The prognosis of EC is seriously affected by the degree of tissue infiltration and distant metastasis by tumor cells. Approximately 15–20% of patients are at high risk of distant metastasis, which carries a poor prognosis. Lamellipodia are related to the invasion and migration of tumor cells, and cortactin (CTTN) can regulate the formation of lamellipodia. Methods Quantitative PCR (qPCR) and immunohistochemical staining (IHC) were used to detect the mRNA and protein of Ras-associated C3 botulinum toxin substrate 1 (Rac1) and CTTN in type I endometrial cancer tissues and normal endometrial tissues. The relationship between the expression of the two genes and the prognostic factors was analyzed. The expression of CTTN in four endometrial cancer cell lines (Ishikawa, AN3CA, HEC-1-A, and HEC-1-B) was detected by quantitative PCR, and the two cell lines with the highest expression levels (HEC-1-A and HEC-1-B) were selected for follow-up study. A CTTN-RNA interference lentiviral system was constructed and transfected into HEC-1-A and HEC-1-B cells. The migration and invasion abilities of the cells in each group were evaluated by scratch assay and transwell migration and invasion assays. Pseudopodia formation was observed using immunofluorescence staining. Western blot was used to detect Rac1 protein expression. Results The mRNA and protein expression of Rac1 and CTTN in EC group were significantly higher than those in normal endometrial group (P < 0.05). In EC group, there was correlation between the mRNA and protein expression of Rac1 and CTTN. The protein expression of Rac1 was related to lymph-vascular space invasion (LVSI), myometrial invasion and FIGO stage (P P > 0.05). The protein expression of CTTN was related to myometrial invasion and FIGO stage (P P > 0.05). After CTTN knockdown, the migration rate, invasion ability, and migration ability of HEC-1-A and HEC-1-B cells decreased significantly. A decrease in the number of lamellipodia, accompanied by a compensatory increase in the number of blebs, was also observed. Rac1 protein expression also decreased after CTTN knockdown. Conclusion CTTN may promote the invasion and migration abilities of EC by increasing the number of lamellipodia. This effect may be related to the regulation of Rac1 by CTTN.

Diabetic cardiovascular complications contribute more than half of diabetes mortality. Endothelial damage and subsequent pathological changes play a key role in this process. Phloretin, a plant-derived dihydrochalcone compound, was reported to have the activities in regulating metabolism homeostasis and anti-inflammation. However, its effects and the mechanism on early stage endothelial injury caused by diabetes are not clear yet. In our present study, human umbilical vein endothelial cells (HUVECs) were stimulated by high glucose or advanced glycation end products (AGEs) to induce endothelial damage, and streptozotocin (STZ) -induced diabetes mouse model was used for in vivo study. Our results showed that phloretin effectively reduced endothelial damage marker monocyte chemotactic protein-1 (MCP1) as well as pro-calcification factors bone morphogenetic protein-2 (BMP2) and receptor activator of NF-κB ligand (RANKL) expression, reversed the increased vimentin and decreased CD31 dose-dependently in vitro and in vivo. Phloretin had no effect on blood glucose level. However, it ameliorated endothelial injury and vascular fibrosis in diabetic mice. Further experiments revealed that phloretin could enhance AMP activated protein kinase (AMPK) activation and upregulate peroxidase proliferator activated receptor-gamma coactivator-lα (PGC1α) level, and inhibit the activation of TGFβ-Smad2-Snail signalling pathway which was abrogated by AMPK inhibitor, providing a rational mechanism that AMPK activation was required for the effects of phloretin on endothelial injury and endothelial-mesenchymal transformation (EndMT). Our data reveal a new role of phloretin in protection of diabetic endothelial damage via AMPK-dependent anti-EndMT activation, and also provide a potential therapeutic way for diabetic endothelial damage and its subsequent cardiovascular complications.

In this study a quantitative

Background. Postmenopausal osteoporosis (PMOP) has a supernal morbidity rate in elderly females. Objective. To appraise the effects of oleuropein on bone densitometry, bone metabolic index, oxidative stress, and inflammatory index in PMOP. In addition, the mechanism of olive bittersweet preventing bone loss was explored. Methods. We grouped 80 salubrious female Sprague-Dawley rats into four teams: (1) sham operation team (sham, N = 20 ), (2) ovariectomy (OVX, N = 20 ), (3) castrated mice fed with oleuropein (OVX+ole, N = 20 ), and (4) castrated mice fed with estrogen (OVX+E2, N = 20 ). The ovariectomized SD rats were continuously raised with 200 μg/kg/dose of oleuropein. Bone mineral density and bone metabolism indexes were recorded. In order to assess the effectiveness of oleuropein on osteopenia, an enzyme-linked immunosorbent assay (ELISA) was devoted to examining the bone marrow indexes. The bone metabolism standards of PMOP rats were appraised by assessing serum levels of calcium, alkaline phosphatase (ALP), phosphorus, malondialdehyde (MDA), and nitrate content by experimental detection methods and levels of osteoclastogenesis inhibitory factor (OPG) and receptor activator for nuclear factor-κB ligand (RANKL) by ELISA. The OPG-RANK-RANKL signal passage was examined by Western blot (WB). We measured bone mineral density using dual-energy X-rays. Results. Our animal experimental results indicated that oleuropein could significantly improve the bone mineral density of ovariectomized SD rats. In the meantime, it could reduce ending interleukin-6 (IL-6), malondialdehyde (MDA), nitrate, alkaline phosphatase (ALP), and phosphorus (P) serum concentration and would not affect Ca2+ concentration. In cell experiments, oleuropein also can promote the proliferation of osteoblasts. Furthermore, it can promote the expression of OPG protein and mRNA. In reverse, it inhibits the expression of RANKL protein and mRNA. Conclusion. Oleuropein can not only improve the inflammatory and oxidative indexes of castrated rats but also prevent osteoporosis. Oleuropein avoids bone resorption by regulating OPG/RANKL expression.

Introduction The incidence of cervical squamous cell carcinoma (CSCC) has expanded in recent years. However, the function of long non-coding RNA (lncRNA) MAGI2-AS3 in the occurrence and progression of CSCC remains unclear. Therefore, the role of lncRNA MAGI2-AS3 in cervical squamous cell carcinoma (CSCC) was investigated in our study. Methods We used qRT-PCR analysis to identify the level of MAGI2-AS3 mRNA expression in CSCC clinical samples and cell lines. We investigated cell migration and invasion of CSCC cells transfected with MAGI2-AS3, miR-233 mimic, or EPB41L3 with transwell assays. Bioinformatics analysis and a luciferase reporter assay were employed to predict the interaction between MAGI2-AS3 and miR-233. Results We found that MAGI2-AS3 and EPB41L3 were both downregulated in CSCC and the expression of this two was positively correlated. Bioinformatics analysis showed that MAGI2-AS3 might bind to miR-233, which could directly target EPB41L3. In CSCC cells, overexpression of MAGI2-AS3 led to upregulated, while overexpression of miRNA-233 led to downregulated expression of EPB41L3. However, MAGI2-AS3 and miR-233 did not affect the expression of each other. In addition, overexpression of MAGI2-AS3 and EPB41L3 led to inhibited cancer cell invasion and migration, while overexpression of miR-233 played an opposite role and attenuated the effects of overexpressing MAGI2-AS3. Conclusion MAGI2-AS3 may sponge miR-233 to upregulate EPB41L3, thereby inhibiting CSCC cell invasion and migration.

H-Abstraction reactions occurring during electron impact ionization processes in electron ionization mass spectrometry (EI-MS) are a long-standing and crucial topic in MS research. Yet, some critical relevant mechanisms are controversial and ambiguous, and information about the EI-induced H-abstraction reactions of halogenated organic compounds (HOCs) is completely in the dark. This study provides a systematic investigation of H-abstraction reactions of HOCs taking place in the EI source using 13C6-hexachlorobenzene (13C6-HCB) and 13C6-hexabromobenzene (13C6-HBB) as exemplary compounds by gas chromatography (GC)–high-resolution mass spectrometry (GC–HRMS). The H-abstraction efficiencies were evaluated with the MS signal intensity ratios of ions with H-abstraction relative to the corresponding original ions (without H-abstraction). Ion source temperatures, EI energies, and numbers of heavy isotope atoms (37Cl or 81Br) of isotopologues were investigated in terms of their effects on the H-abstraction efficiencies. The H-abstraction efficiencies of individual isotopologues generally decreased from the first to the last isotopologues of respective ions, and those of individual ions were different from each other, with the highest values of 0.017 and 0.444 for 13C6-HCB and 13C6-HBB, respectively. The overall H-abstraction efficiencies involving all measured ions of 13C6-HCB and 13C6-HBB were 0.004 and 0.128, respectively. With increasing ion source temperatures, the H-abstraction efficiencies first increased to a summit and then began to linearly decrease. EI energies and emission currents could impact the H-abstraction efficiencies but showed no certain tendency. The H-abstraction reactions were inferred to belong to ion–molecule reactions, and the siloxanes bleeding from the GC column might be a hydrogen source. Some strategies were proposed for eliminating or alleviating the interference triggered by the H-abstraction reactions in EI-MS in identification of halogenated organic pollutants (HOPs). Our findings provide a better understanding of the EI-induced H-abstraction reactions of HOCs and may benefit the identification of HOPs in environmental analysis, especially for novel HOPs.

Relative abundances of chlorine and carbon isotopologues of individual organochlorines (e.g. polychlorinated organic pollutants) are generally recognised to comply with stochastic distribution, and thus can be calculated by the binomial theorem. As a result, carbon isotope ratios derived from different chlorine-isotopologue pairs, e.g. 12C235Cl4 vs. 12C13C35Cl4, should be consistent. Yet this recognition may not exactly reflect the reality. This study investigated the consistency/inconsistency of carbon isotope compositions of chlorine-isotopologue pairs of individual organochlorines including two chloroethylenes, three polychlorinated biphenyls, methyl-triclosan and hexachlorobenzene. The raw carbon isotope ratios were measured by gas chromatography-high resolution mass spectrometry. Data simulations in terms of background subtraction, background addition, dual 13C-atoms substitution, deuterium substitution and hydrogen-transfer, along with measurements at different injection concentrations were conducted to confirm the validity of measured carbon isotope ratios and their differences. Inconsistent carbon isotope ratios derived from chlorine-isotopologue pairs of individual organochlorines were observed, and the isotopologues of each organochlorine were thus inferred to be non-randomly distributed. Mechanistic interpretation for these findings was tentatively proposed according to a basic principle in clumped-isotope geochemistry, reaction thermodynamics and kinetics, along with isotope effects occurring in electron ionisation mass spectrometry. This study sheds light on the actual carbon isotope compositions of chlorine-isotopologue pairs of organochlorines, and yields new insights into the real distributions of carbon and chlorine isotopologues. The inconsistent carbon isotope compositions of chlorine-isotopologue pairs are anticipated to benefit the exploration of formation conditions and source identification of organochlorine pollutants.

Revelation of chlorine and bromine isotope effects in fragmentation is crucial for compound-specific isotope analysis of chlorine/bromine (CSIA-Cl/Br) using gas chromatography-electron ionization mass spectrometry (GC-EI-MS), but theoretical fundamentals of the isotope effects remain unclear. Herein, this study provides a theoretical basis for elucidating the details and implications of chlorine and bromine isotope effects occurring in dehalogenation reactions in EI-MS. Inter-ion and intra-ion isotope effects can occur in dehalogenation reactions in EI-MS, and affect chlorine/bromine isotope ratios. In a dehalogenation reaction, inter-ion isotope effects increase the isotope ratio of a precursor ion but decrease that of its product ion. On the other hand, intra-ion isotope effects can only affect (increase) the isotope ratio of a product ion, and have no effect on its precursor ion. The chlorine/bromine isotopologue distributions of ions measured by EI-MS are deduced to be non-binomial (nonrandom), regardless of the initial isotopologue distributions prior to fragmentation. The bulk chlorine/bromine isotope ratio of an ion cannot be exactly achieved with a calculation scheme using an arbitrary pair or pairs of neighboring chlorine/bromine isotopologues, but can be calculated with complete isotopologues of the ion. The isotope ratio of a compound calculated with a pair/pairs of neighboring isotopologues could not accurately reflect the trueness, even though it has been calibrated with external isotopic standard(s), due to different isotopologue distributions of the analyte and external isotopic standard(s). The conclusions derived from theoretical derivation have been experimentally proven with the isotopically distinct standards of tetrachloroethylene and trichloroethylene from different manufacturers. The findings of this study are conducive to CSIA-Cl/Br using GC-EI-MS to obtain high-quality data, and provide new insights into the actual chlorine/bromine isotopologue distributions of chlorinated/brominated organic compounds.

Tissue distributions and body-size dependent and species-specific bioaccumulation of 12 organic ultraviolet absorbents (UVAs) were investigated in 9 species of wildlife freshwater fish from the Pearl River catchment, South China. The concentrations of the 12 UVAs were from 109 to 2320 ng/g lipid weight in the fish tissue samples. The UVAs 2-hydroxy-4-methoxybenzophenone (BP-3), octocrylene (OCR), UV531, and 5 benzotriazole UV stabilizers (UVP, UV329, UV234, UV328, and UV327) were detected in more than half of the fish tissue samples. The UVA UV531 showed an obvious potential for bioaccumulation in the wild freshwater fish, with an estimated bioaccumulation factor (log BAF) and a biota-sediment accumulation factor (BSAF) of 4.54 ± 0.55 and 4.88 ± 6.78, respectively. Generally, liver (989 ± 464 ng/g lipid wt) contained the highest level of UVAs, followed in decreasing order by belly fat (599 ± 318 ng/g lipid wt), swimming bladder (494 ± 282 ng/g lipid wt), dorsal muscle (470 ± 240 ng/g lipid wt), and egg (442 ± 238 ng/g lipid wt). The bioaccumulation of UVAs in the freshwater wild fish was species specific and compound dependent. Bottom-dwelling detritus-ingesting omnivorous fish contained obviously higher UVA concentrations, suggesting that detritus/sediment ingestion is a significant pathway for exposure of the wild freshwater fish to the UVAs. The UVAs UV531 and BP-3 demonstrated a potential for growth dilution. Metabolism might play a significant role in elimination of the UVAs in the fish tissues, with the highest rate of metabolism in the liver. The UVAs did not demonstrate obvious trophic magnification in the freshwater ecosystem of the Pearl River catchment. More research is warranted to elucidate maternal transfer of the UVAs. Environ Toxicol Chem 2020;39:343-351. © 2019 SETAC.

Methimazole (MMI), the first-line anti-thyroid agent used in clinical practice is known to induce hepatotoxicity in patients with Grave's disease (GD), although its exact mechanism remains largely unclear. This cohort study aimed to examine the mechanism of MMI-induced hepatotoxicity using metabolomic approach. A total of 40 GD patients with MMI-induced hepatotoxicity (responders) and 80 GD patients without MMI-induced hepatotoxicity (non-responders) were included in this study and their plasma metabolomics was profiled with targeted gas chromatography-tandem mass spectrometry (GC-MS/MS). The plasma levels of 42 metabolites, including glucuronic acid, some amino acids, fatty acids, ethanolamine and octopamine were found to be significantly different between responders and non-responders. In agreement with our previous genotyping data, the genetic polymorphism of uridine 5'-diphospho-glucuronosyltransferase (UGT)1A1*6, which affects the glucuronidation activity and circulating glucuronic acid level was identified as one of the determinants of MMI-induced hepatotoxicity. Plasma level of ethanolamine has a significant correlation with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. The pathway analyses further revealed that monoamine oxidase (MAO) inhibition, reactive oxygen species (ROS) production, mitochondria dysfunction, and DNA disruption might contribute to MMI-induced hepatotoxicity. Interestingly, the metabolomic data further suggested the responders had a higher risk of developing osteoporosis and fatty liver disease in comparison to the non-responders. This mechanistic study sheds light on the pathogenesis of MMI-induced hepatotoxicity and prompts personalized prescription of MMI based on UGT1A1*6 genotype in the management of GD.

High-grade squamous intraepithelial lesion (HSIL) is regarded as a serious precancerous state of cervix, and it is easy to progress into cervical invasive carcinoma which highlights the importance of earlier diagnosis and treatment of cervical lesions. Pathologists examine the biopsied cervical epithelial tissue through a microscope. The pathological examination will take a long time and sometimes results in high inter- and intra-observer variability in outcomes. Polarization imaging techniques have broad application prospects for biomedical diagnosis such as breast, liver, colon, thyroid and so on. In our team, we have derived polarimetry feature parameters (PFPs) to characterize microstructural features in histological sections of breast tissues, and the accuracy for PFPs ranges from 0.82 to 0.91. Therefore, the aim of this paper is to distinguish automatically microstructural features between HSIL and cervical squamous cell carcinoma (CSCC) by means of polarization imaging techniques, and try to provide quantitative reference index for pathological diagnosis which can alleviate the workload of pathologists. Polarization images of the H&E stained histological slices were obtained by Mueller matrix microscope. The typical pathological structure area was labeled by two experienced pathologists. Calculate the polarimetry basis parameter (PBP) statistics for this region. The PBP statistics (stat_PBPs) are screened by mutual information (MI) method. The training method is based on a linear discriminant analysis (LDA) classifier which finds the most simplified linear combination from these stat_PBPs and the accuracy remains constant to characterize the specific microstructural feature quantitatively in cervical squamous epithelium. We present results from 37 clinical patients with analysis regions of cervical squamous epithelium. The accuracy of PFP for recognizing HSIL and CSCC was 83.8% and 87.5%, respectively. This work demonstrates the ability of PFP to quantitatively characterize the cervical squamous epithelial lesions in the H&E pathological sections. Significance: Polarization detection technology provides an efficient method for digital pathological diagnosis and points out a new way for automatic screening of pathological sections.

In this study, we investigated the distribution of brominated and organophosphate flame retardants (BFRs and OPFRs) in the paired gaseous and nine size-segregated particulate samples collected from 8 typical indoor compartments and monthly outdoor in Xinxiang, China, respectively. For the indoor environments, total concentrations of FRs (Σ

Exploration of multiple sources of brominated (BFRs) and organophosphate flame retardants (OPFRs) for children promotes the understanding of exposure pathways and health risk. 10 BFRs and 9 OPFRs were measured in skin wipes from hands, forehead, and arms of 30 children, and surface wipe samples from sills, toys, desks and floors, and indoor air samples of kindergartens from Xinxiang, China. Higher ∑9OPFRs concentrations were observed in the forehead (1840 ng/m2), followed by hand (1420 ng/m2) and arm wipes (1130 ng/m2), and the ∑8BFRs concentrations in forehead, hand and arm wipes were 116, 315 and 165 ng/m2, respectively. The total concentration of OPFRs and BFRs in floor wipes (66.1 and 24.5 ng/m2) were lower than those in toy (205 and 535 ng/m2), sill (227 and 30.1 ng/m2) and desk (84.4 and 139 ng/m2) wipes. Concentrations of FRs in forehead wipes were significantly correlated with those in gaseous air (p

Objective. SLC16a genes encode H + -coupled monocarboxylate transporters (MCTs). MCTs are involved in maintaining interstitial fluids’ pH and regulating insulin’s binding affinity to its receptor, which is a potential mechanism for the onset of diabetes. In this research, we make explorations of the association between the rs312457 genotype of the SLC16a13 gene and diabetes in the Chinese population. Methods. It included 384 type 2 diabetes patients and 1,468 healthy control subjects in total. We measured the anthropometric parameters, glycaemic index, homeostasis model assessment-B cell (HOMA-%B), lipid profile, and homeostasis model assessment-insulin resistance (HOMA-IR). The associations between the rs312457 genotype and type 2 diabetes were analyzed. Results. The rs312457 genotype was markedly in relation to type 2 diabetes ( P = 0.002 ). The frequency of the rs312457 risk allele (G) was 4.8%, higher than that of the wild-type allele (A) in patients of type 2 diabetes, indicating that allele (G)’s presence seemed to make the risk of type 2 diabetes go up. Compared to the GA and AA genotypes, the GG genotype of rs312457 significantly increased the risk of contracting diabetes mellitus ( P ≤ 0.001 ). Moreover, the rs312457 genotype was associated with HOMA-%B. Subjects harbored the GG genotype of rs312457, whose HOMA-%B level went down in comparison with that in subjects harboring the AA genotype ( P = 0.023 ). Conclusion. Our results revealed that the rs312457 genotype of the SLC16a13 gene was correlated with the development of diabetes mellitus in the Chinese population.

Objective The present study aimed to evaluate the effects of cluster of differentiation (CD)4+CD25+ forkhead box p3 (Foxp3)+ regulatory T cells (Tregs) on unexplained recurrent spontaneous abortion (URSA) and the associated mechanisms. Methods The proportion of CD4+CD25+Foxp3+ Tregs and inflammatory cytokine concentrations in the peripheral blood of women with URSA were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. CBA/JxDBA/2J mating was used to establish an abortion-prone mouse model and the model mice were treated with the Toll-like receptor 4 (TLR4) antagonist E5564 and the TLR4 agonist lipopolysaccharide. Results The proportion of CD4+CD25+Foxp3+ Tregs was decreased and the inflammatory response was increased in women with URSA. In the abortion-prone mouse model, E5564 significantly increased the proportion of CD4+CD25+Foxp3+ Tregs, decreased the inflammatory response, and increased Foxp3 mRNA and protein expression. Lipopolysaccharide had adverse effects on the abortion-prone model. Conclusions These data suggest that CD4+CD25+Foxp3+ Tregs regulate immune homeostasis in URSA via the TLR4/nuclear factor-κB pathway, and that the TLR4 antagonist E5564 may be a novel and potential drug for treating URSA.

Objective The present study aimed to evaluate the effects of cluster of differentiation (CD)4+CD25+ forkhead box p3 (Foxp3)+ regulatory T cells (Tregs) on unexplained recurrent spontaneous abortion (URSA) and the associated mechanisms. Methods The proportion of CD4+CD25+Foxp3+ Tregs and inflammatory cytokine concentrations in the peripheral blood of women with URSA were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. CBA/JxDBA/2J mating was used to establish an abortion-prone mouse model and the model mice were treated with the Toll-like receptor 4 (TLR4) antagonist E5564 and the TLR4 agonist lipopolysaccharide. Results The proportion of CD4+CD25+Foxp3+ Tregs was decreased and the inflammatory response was increased in women with URSA. In the abortion-prone mouse model, E5564 significantly increased the proportion of CD4+CD25+Foxp3+ Tregs, decreased the inflammatory response, and increased Foxp3 mRNA and protein expression. Lipopolysaccharide had adverse effects on the abortion-prone model. Conclusions These data suggest that CD4+CD25+Foxp3+ Tregs regulate immune homeostasis in URSA via the TLR4/nuclear factor-κB pathway, and that the TLR4 antagonist E5564 may be a novel and potential drug for treating URSA.

To fully understand the characteristics of particulate matter (PM) retained on plant leaves (PMR) and the effect of vegetation on haze on a large spatial scale, we investigated needle samples collected from 78 parks and campuses in 31 cities (30 provincial cities) of China and developed a comprehensive method to characterise PMR. Both the PMR load (including water-insoluble particulate matter (WIPM), water-soluble inorganic ions (WSIS) and water-soluble organic matter (WSOM)), with a mean value of 554 ± 345 mg m−2 leaf area, and component profiles of PMR showed obvious spatial variation across the cities. Though haze pollution levels vary greatly among the 31 cities, the PM retention capacity of needles does not depend on haze level because PMR generally reaches saturation before precipitation in winter. The water-soluble component (WSC, the sum of WSIS and WSOM) accounted for 52.3% of PMR on average, among which WSIS and WSOM contributed 21.4% and 30.9% to PMR, respectively. The dominant ions of WSIS in PMR in the cities were Ca2+, K+ and NO3−, indicating that raised dust, biomass combustion and traffic exhaust are significant sources of PM in China. Compared with previous reports, the particle size distributions of PMR and PM across China were consistent, with fine PM (PM2.5) constituting a substantial proportion (43.8 ± 17.0%) of PMR. These results prove that trees can effectively remove fine particles from the air, thereby reducing human exposure to inhalable PM. We proposed a method to estimate the annual amount of PMR on Cedrus deodara, with an average value of 11.9 ± 9.6 t km−2 canopy yr−1 in China. Compared with the load of dust fall (atmospheric particles naturally falling on the ground, average of 138 ± 164 t km−2 land area yr−1 in China), we conclude that trees play a significant role in mitigating haze pollution.

Background Atherosclerosis-related cardiovascular diseases are among the leading causes of mortality worldwide. Uptake of modified lipoproteins by monocyte-derived macrophages leads to the formation of foam cells, which by secreting pro-inflammatory cytokines accelerate plaque development. Sorting Nexin 10 (SNX10) plays a critical role in the regulation of macrophage functions as well as in the lipid metabolism. This study aims to explore the precise effects and the underlying molecular mechanisms of SNX10 mediated processes in atherosclerotic diseases. Methods SNX10 knockout mice were generated and bone marrow-derived macrophages (BMDMs) were studied in vitro. Mice were crossed with apolipoprotein E-deficient (ApoE-/-) mice and atherogenesis was monitored for 16 weeks. Results Expression of SNX10 was increased in atherosclerotic plaques from both humans and ApoE-/- mice. SNX10 deficiency decreased foam cell abundance and alleviated atherosclerotic plaque progression in ApoE-/- mice. In addition, high fat, high cholesterol diet fed ApoE-/- mice contained more Ly6ChiCX3CR1lo monocytes than ApoE-/- SNX10-/- (DKO) littermates. ApoE-/- mice showed a higher level of inflammatory macrophages infiltrating into atherosclerotic lesions. SNX10 deficiency reduced the interactions between CD36 and Lyn, thus inhibiting CD36-mediated lipoprotein uptake and foam cell formation. Conclusions Our findings demonstrate CD36-Lyn dependent non-redundant atherogenic role for SNX10 in diet-induced atherogenesis. We propose SNX10 as a potential therapeutic target for the prevention and treatment of atherosclerosis.

Parabens, bisphenol A (BPA), triclosan, and triclocarban are recognized endocrine-disrupting contaminants (EDCs); and their occurrence in the environment has attracted increasing concern. Body size-dependent bioaccumulation, tissue distribution, trophic magnification, and maternal transfer of methyl-, ethyl-, propyl-, and butylparabens; 2-phenylphenol (PHP); BPA; triclosan; and triclocarban were investigated in freshwater fish of the Pearl River catchment, China. Most of the EDCs were detected in more than half of the biota samples, ranging from not detected to 6750 ng g-1 lipid weight, with median concentrations of 5 to 72 ng g-1 lipid weight. Livers generally contained the highest EDC levels (1609 ± 1860 ng g-1 lipid wt, mean ± standard deviation), followed in decreasing order by eggs (842 ± 1317 ng g-1 lipid wt), belly fats (488 ± 465 ng g-1 lipid wt), and dorsal muscles (240 ± 239 ng g-1 lipid wt) of the wildlife. Body size-dependent bioaccumulation of the EDCs was observed in the freshwater fish, which varied according to species, tissue, and compound. The concentrations of triclosan, PHP, and BPA usually showed decreasing trends, whereas parabens mostly demonstrated increasing tendency with increasing fish weights, indicating effects of growth dilution and bioaccumulation, respectively. Potential biomagnification was shown by triclosan with trophic magnification factors of 3.0, 4.3, and 4.0 in liver, belly fat, and dorsal muscle, respectively. In addition, the potential of maternal transfer in the fish was primarily revealed for methyl- and propylparabens, PHP, triclosan, and BPA. Presence of the EDCs in the freshwater organisms of the Pearl River catchment warrants more attention considering the potential of trophic magnification and maternal transfer. Environ Toxicol Chem 2018;37:1811-1823. © 2018 SETAC.

Murine double minute 2 (MDM2) is an oncoprotein mediating the degradation of the tumor suppressor p53 protein. The physiological levels of MDM2 protein are closely related to malignant transformation and tumor growth. In this work, the simultaneous and label-free determination of free and p53-bound MDM2 proteins from sarcoma tissue extracts was conducted using a dual-channel surface plasmon resonance (SPR) instrument. Free MDM2 protein was measured in one fluidic channel covered with the consensus double-stranded (ds)-DNA/p53 conjugate, while MDM2 bound to p53 was captured by the consensus ds-DNA immobilized onto the other channel. To achieve higher sensitivity and to confirm specificity, an MDM2-specific monoclonal antibody (2A10) was used to recognize both the free and p53-bound MDM2 proteins. The resultant method afforded a detection limit of 0.55 pM of MDM2. The amenability of the method to the analysis of free and p53-bound MDM2 proteins was demonstrated for normal and sarcoma tissue extracts from three patients. Our data reveal that both free and total MDM2 (free and bound forms combined) proteins from sarcoma tissue extracts are of much higher concentrations than those from normal tissue extracts and the p53-bound MDM2 protein only constitutes a small fraction of the total MDM2 concentration. In comparison with enzyme-linked immunosorbent assay (ELISA), the proposed method possesses higher sensitivity, is more cost-effective, and is capable of determining free and p53-bound MDM2 proteins in clinical samples.

Plastic pollution has been a growing global issue. Various plastic additives may enter the environment with plastic debris, which could also become contaminants. Lifetime bioaccumulation, gender difference, tissue distribution, and parental transfer potential of commonly applied organophosphorus plastic additives (OPPAs) were investigated in wildlife fish of the Pearl River system, China. The OPPAs were widely detected in 7 consumable fish species. Tris (2-chloropropyl) phosphate was the predominant compound, with a median concentration of 18.8 ng/g lipid weight. The total OPPA concentrations (ΣOPPAs) were higher in the livers and swimming bladders, suggesting important roles of lipophilicity on the OPPAs accumulation in the fish. Besides, the livers were more abundant in the non-chlorinated OPPAs relative to the other tissues, indicating potentially stronger metabolism of the chlorinated OPPAs in the livers. Redbelly tilapia contained obviously lower ΣOPPAs than the other species. On the other hand, proportions of the chlorinated OPPAs were obviously lower in barbel chub and Guangdong black bream. For an individual species, higher ΣOPPAs were usually detected in the female than in the male fish. Furthermore, the females contained higher proportions of the non-chlorinated OPPAs. These results suggested potentially more accumulation of the OPPAs, particularly the non-chlorinated OPPAs in the female than in the male fish. Body weight dependence of the OPPAs accumulation showed varied patterns depending on species, tissue, and compound. Species-specific characteristics affected by both ecology and organisms’ physiology should be considered in combination in assessing bioaccumulation of the OPPAs. The OPPAs were slightly bioaccumulative with LogBAFs of 1.2–3.3. The OPPAs did not show obvious inclination to be partitioned to biota from sediment. Omnipresence of the OPPAs in both egg/ovary and testis of the fish suggested potential transgenerational transfer of these chemicals, which can be a serious ecological issue and warrants further research.

A variety of personal care products have been classified as emerging contaminants (ECs). Occurrence, fate, spatial and vertical profiles of 13 ultraviolet absorbents, triclocarban (TCC) and its dechlorinated products, triclosan (TCS), 2-phenylphenol and parabens were investigated in riverine and estuarine sediment of the Pearl River catchment, China. Bisphenol A (BPA), a widely applied plasticizer, was also investigated. The ECs were widely present in the bed sediment. TCC was the most abundant with a maximum concentration of 332ngg-1 dry weight. The other prominent ECs included BPA, TCS, octocrylene, and benzotriazole UV stabilizers UV326 and UV328. Treated wastewater effluent was the major source of the ECs in the riverine sediment. TCC, BPA, TCS, methyparaben, UV531, UV326, and UV328 were also detected throughout the estuarine sediment cores, indicating their persistence in the sediment. Temporal trends of the ECs in the sediment cores reflected a combined effect of industrial development, population growth, human life quality improvement, and waste treatment capacity in the Pearl River Delta over the last decades. TCC dechlorination products were frequently detected in the bed sediment with higher levels near treated effluent outlets but only occasionally observed in the sediment cores, suggesting insignificant in-situ TCC dechlorination in the sediment.

Methimazole (MMI) has been used for the treatment of Graves’ Disease (GD) for more than half a century. The MMI treatment has been reported to be associated with hepatotoxicity. Previous studies have demonstrated that human leukocyte antigen (HLA) genetic polymorphisms were associated with many drugs-induced liver injuries. To investigate HLA genetic susceptibility to MMI-induced liver injury (MMI-DILI), we characterized both HLA class I and class Ⅱ in a well-characterized phenotypic cohort with 40 MMI-DILI cases and 118 MMI-tolerant controls. Among the 40 MMI-DILI cases, 57.5% were women and 50% were cholestatic liver damage with occurring time from days to months after MMI dosing. The frequency of HLA-C*03:02 was 6.7% (5/75) in the MMI-DILI case patients and 6.4% (4/62) in MMI-induced cholestatic/mixed liver damage, which were significantly different from the percentage of 0.4% (1/231) in the MMI-tolerant patients (odds ratio (OR) = 15.4, 95% confidence interval (CI) = 1.77–133.9, adjusted P = 0.0292; OR=14.9, 95% CI=2.38–182.9, adjusted P = 0.0323; respectively). HLA-A*02:01 was also found to be associated with MMI-induced cholestatic/mixed liver injury (OR = 3.13, 95%CI=1.45–6.91, adjusted P = 0.0464). The present study demonstrated that individuals carrying HLA-C*03:02 allele are at increased risk of developing MMI-induced DILI. These results may assist doctors to prevent the occurrence of hepatotoxicity in GD patients receiving MMI.

Introduction The incidence of cervical squamous cell carcinoma (CSCC) has expanded in recent years. However, the function of long non-coding RNA (lncRNA) MAGI2-AS3 in the occurrence and progression of CSCC remains unclear. Therefore, the role of lncRNA MAGI2-AS3 in cervical squamous cell carcinoma (CSCC) was investigated in our study. Methods We used qRT-PCR analysis to identify the level of MAGI2-AS3 mRNA expression in CSCC clinical samples and cell lines. We investigated cell migration and invasion of CSCC cells transfected with MAGI2-AS3, miR-233 mimic, or EPB41L3 with transwell assays. Bioinformatics analysis and a luciferase reporter assay were employed to predict the interaction between MAGI2-AS3 and miR-233. Results We found that MAGI2-AS3 and EPB41L3 were both downregulated in CSCC and the expression of this two was positively correlated. Bioinformatics analysis showed that MAGI2-AS3 might bind to miR-233, which could directly target EPB41L3. In CSCC cells, overexpression of MAGI2-AS3 led to upregulated, while overexpression of miRNA-233 led to downregulated expression of EPB41L3. However, MAGI2-AS3 and miR-233 did not affect the expression of each other. In addition, overexpression of MAGI2-AS3 and EPB41L3 led to inhibited cancer cell invasion and migration, while overexpression of miR-233 played an opposite role and attenuated the effects of overexpressing MAGI2-AS3. Conclusion MAGI2-AS3 may sponge miR-233 to upregulate EPB41L3, thereby inhibiting CSCC cell invasion and migration.

Methimazole (MMI) has been used in the therapy of Grave's disease (GD) since 1954, and drug-induced liver injury (DILI) is one of the most deleterious side effects. Genetic polymorphisms of drug-metabolizing enzymes and drug transporters have been associated with drug-induced hepatotoxicity in many cases. The aim of this study was to investigate genetic susceptibility of the drug-metabolizing enzymes and drug transporters to the MMI-DILI. A total of 44 GD patients with MMI-DILI and 118 GD patients without MMI-DILI development were included in the study. Thirty-three single nucleotide polymorphisms (SNPs) in twenty candidate genes were genotyped. We found that rs12422149 of SLCO2B1, rs2032582_AT of ABCB1, rs2306283 of SLCO1B1 and rs4148323 of UGT1A1 exhibited a significant association with MMI-DILI; however, no significant difference existed after Bonferroni correction. Haplotype analysis showed that the frequency of SLCO1B1*1a (388A521T) was significantly higher in MMI-DILI cases than that in the control group (OR = 2.21, 95% CI = 1.11-4.39, P = 0.023), while the frequency of SLCO1B1*1b (388G521T) was significantly higher in the control group (OR = 0.52, 95% CI = 0.29-0.93, P = 0.028). These results suggested that genetic polymorphisms of SLCO1B1 were associated with susceptibility to MMI-DILI. The genetic polymorphism of SLCO1B1 may be important predisposing factors for MMI-induced hepatotoxicity.

Hexa-mix-chlorinated/brominated benzenes (HXBs), a group of newly found analogues of hexachlorobenzene (HCB) and hexabromobenzene (HBB), may exhibit similar environmental risks and toxicities as HCB and HBB, and therefore possess high interests in environmental and toxicological research. Yet information regarding HXBs in the environment remains scarce. In this study, we developed an isotope dilution method for quantitative and semiquantitative determination of five HXBs in fly ash, soil and air using gas chromatography high resolution mass spectrometry (GC-HRMS) in multiple ion detection mode. The samples were Soxhlet-extracted and purified with multilayer composite silica gel-alumina columns, followed by GC-HRMS detection. Identification of HXBs was conducted by the comparison between theoretical and detected mass spectra using paired-samples T test and cosine similarity analysis. Two HXBs (C6BrCl5 and C6Br4Cl2) with reference standards were quantitatively determined while the rest three (C6Br2Cl4, C6Br3Cl3 and C6Br5Cl) without reference standards were semiquantitatively analyzed by sharing the calibration curves of C6BrCl5 and C6Br4Cl2 in cooperation with isotopologue distribution computation. The accuracies for C6BrCl5 and C6Br4Cl2 were 87.3–107.8% with relative standard deviations (RSD) of 2.8–5.0%. The method limits of quantification of the HXBs were 0.10 ng/g in fly ash and soil samples and 0.09 pg/m3 in ambient air samples. The recoveries ranged from 42.7% to 102.1% with RSD of 3.7–13.9%. This method has been successfully applied to the analysis of the HXBs in the environmental samples. The total concentrations of HXBs in the fly ash, soil and ambient air samples were 19.48 ng/g, 10.44 ng/g and 5.13 pg/m3, respectively, which accounted for 10.6%, 0.4% and 10.8% of the corresponding total concentrations of HCB and HBB. This study provides a reference method for quantitative and/or semiquantitative analyses of novel mix-halogenated organic compounds, and sheds light on the full picture of HXBs pollution in the environment.

This study aimed to investigate the role of lncRNA terminal differentiation-induced ncRNA (TINCR) in cervical squamous cell carcinoma (CSCC). By informatics analysis, we found that miR-302 may bind TINCR. Expression analysis showed that miR-302 was downregulated, while TINCR was upregulated in CSCC. Correlation analysis showed that they were not significantly correlated. In CSCC cells, miR-302 and TINCR failed to affect the expression of each other. However, miR-302 overexpression led to downregulated and TINCR overexpression led to upregulated cyclin D1 expression in CSCC cells. Interestingly, overexpression of cyclin D1 led to upregulated miR-302 and TINCR. Cell proliferation analysis showed that TINCR and cyclin D1 overexpression led to increased, while miR-302 overexpression led to decreased rate of cell proliferation. Moreover, miR-302 overexpression reduced the effects of TINCR overexpression. Therefore, TINCR sponges miR-302 to upregulate cyclin D1 in CSCC, thereby promoting cell proliferation.