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Numerous studies have shown that exposure to micro- or nano-plastics led to the cell viability and function of macrophages in the intestine tissue might be one possible mechanism. This study investigated the cytotoxicity and pro-inflammatory effect of 80 nm polystyrene-nano-plastic (PS-NP) and 3 µm PS-micro-plastic (PS-MP) on mouse macrophages RAW264.7 cells. Our results showed that exposure to PS-NP or PS-MP induced apoptosis of cells at 5 or 10 μg/mL, respectively. Besides, PS-NP enhanced the secretion of inflammatory cytokines (Tumor necrosis factor-α, Interleukin-6 and Interleukin-10) with the lowest effective concentration (LOEC) of 1, 0.01, and 0.01 μg/mL, respectively. PS-MP enhanced secretion of TNF-α and IL-10 with the LOEC of 1 and 0.01 μg/mL, respectively. We further studied the possible mechanisms of the effects of PS-NP or PS-MP on RAW264.7 cells. We found they might cause cytotoxicity and inflammatory effects by producing reactive oxygen species and nitric oxide in the cells. Accordingly, our results demonstrated that PS-NP and PS-MP had cytotoxicity and pro-inflammatory effect on macrophages, which might further lead to intestinal inflammation. Moreover, we revealed that the PS-NP had more potent adverse impacts on macrophages than PS-MP.

With the deepening of China's medical reform, the scale of hospital equipment assets at all levels is also expanding. In the face of large-scale and various equipment assets, the traditional single machine statistical management method not only has a single interface, poor data accuracy and is not compatible with other systems, but also is difficult to achieve "full life cycle" management. In order to solve above problems, the Ninth People's Hospital Affiliated to Shanghai Jiao Tong University of Medicine aims to use the Internet of Things to build a medical equipment management information platform, realize the whole hospital area, whole subject and whole process management of medical materials, and achieve the objectives of business linkage, information connectivity and data sharing between management departments and clinical departments.

Triclosan (TCS) and triclocarban (TCC) have become ubiquitous pollutants detected in human body with concentrations up to hundreds of nanomolar levels. Previous studies about the hepatic lipid accumulation induced by TCS and TCC were focused on pollutant itself, which showed weak or no effects. High-fat diet (HFD), as a known environmental factor contributing to lipid metabolism-related disorders, its synergistic action with environmental pollutants deserves concern. The present study aimed to demonstrate the combined effects and potential molecular mechanisms of TCS and TCC with HFD at cellular and animal levels. The in vitro studies showed that TCC and TCS alone had negligible impact on lipid accumulation in HepG2 cells but induced lipid deposition at nanomolar levels when co-exposure with fatty acid. TCC exhibited much higher induction effects than TCS, which was related to their differential regulatory roles in adipogenic-related genes expression. The in vivo studies showed that TCC had little influence on hepatic lipid accumulation in mice fed with normal diet (ND) but could exacerbate the lipid accumulation in mice fed with HFD. Meanwhile, TCC-induced dyslipidemia in mice fed with HFD was more significant than that fed with ND. Therefore, we speculated that TCC might increase the risk of nonalcoholic fatty liver disease (NAFLD) and atherosclerosis in HFD humans. Molecular mechanism studies showed that TCC and TCS could bind to and activate estrogen-related receptor α (ERRα) and ERRγ as well as regulate their expression. TCC had higher activity on ERRα and ERRγ than TCS, which explained partly the differential regulatory roles of two receptors in the lipid accumulation induced by TCC and TCS. This work revealed synergistic effects and molecular mechanisms of TCC and TCS with excessive fatty acid on the hepatic lipid metabolism, which provided a novel insight into the toxic mechanism of pollutants from the perspective of dietary habits.

Benzotriazole ultraviolet stabilizers (BUVSs) are ubiquitous emerging pollutants that have been reported to show estrogenic disruption effects through interaction with the classic estrogen receptors (ERs) in the fashion of low activity. The present study aims at revealing the potential disruption mechanism via estrogen-related receptors α and γ (ERRα and ERRγ) pathways. By the competitive binding assay, we first found that BUVSs bond to ERRγ ligand binding domain (ERRγ-LBD) with

Triclosan (TCS) and triclocarban (TCC) are two widely used antimicrobial agents that have been reported to be estrogenic disruptors. Previous researches have shown that TCC and TCS exhibit weak or ...

Per- and polyfluoroalkyl substances (PFAS) are found to have multiple adverse outcomes on human health. Recently, epidemiological and toxicological studies showed that exposure to PFAS had adverse impacts on pancreas and showed association with insulin abnormalities. To explore how PFAS may contribute to diabetes, we studied impacts of perfluorooctane sulfonate (PFOS) on cell viability and insulin release capacity of pancreatic β cells by using in vivo and in vitro methods. We found that 28-day administration with PFOS (10 mg/(kg body weight•day)) caused reductions of pancreas weight and islet size in male mice. PFOS administration also led to lower serum insulin level both in fasting state and after glucose infusion among male mice. For cell-based in vitro bioassay, we used mouse β-TC-6 cancer cells and found 48-hr exposure to PFOS decreased the cell viability at 50 μmol/L. By measuring insulin content in supernatant, 48-hr pretreatment of PFOS (100 μmol/L) decreased the insulin release capacity of β-TC-6 cells after glucose stimulation. Although these concentrations were higher than the environmental concentration of PFOS, it might be reasonable for high concentration of PFOS to exert observable toxic effects in mice considering mice had a faster removal efficiency of PFOS than human. PFOS exposure (50 μmol/L) to β-TC-6 cells induced intracellular accumulation of reactive oxidative specie (ROS). Excessive ROS induced the reactive toxicity of cells, which eventually invoke apoptosis and necrosis. Results in this study provide evidence for the possible causal link of exposure to PFOS and diabetes risk.

There has been long-standing evidence that the lower-chlorinated polychlorinated biphenyls (LC-PCBs) can be metabolized to hydroxylated metabolites (OH-PCBs), which play important roles in the LC-PCBs induced toxicity. Recently, multiple studies have demonstrated the further metabolic transformation of OH-PCBs to LC-PCB sulfates in vitro and in vivo. Several studies found LC-PCB sulfates could bind with thyroid hormone (TH) transport proteins in the serum, indicating the potential relevance of these metabolites in the TH system disruption effects. However, the interaction of LC-PCB sulfates with the TH nuclear receptor (TR), another kind of important functional protein in the TH system, has not been explored. Here, by using a fluorescence competitive binding assay, we demonstrated that LC-PCB sulfates could bind with TRα. Moreover, the LC-PCB sulfates had higher binding potency than their corresponding OH-PCB precursors. By using a luciferase reporter gene assay, we found the LC-PCB sulfates showed agonistic activity towards the TRα signaling pathway. Molecular docking simulation showed all the tested LC-PCB sulfates could fit into the ligand binding pocket of the TRα. The LC-PCB sulfates formed hydrogen bond interaction with arginine 228 residue of TRα by their sulfate groups, which might facilitate the TR binding and agonistic activity. The present study suggests that interaction with the TR might be another possible mechanism by which LC-PCB sulfate induce TH system disruption effects.

As alternatives to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide (HFPO) homologues, including hexafluoropropylene oxide dimer acid (HFPO-DA), hexafluoropropylene oxide trimer acid (HFPO-TA), and hexafluoropropylene oxide tetramer acid (HFPO-TeA), have been used in the fluoropolymer industry for a long period of time. These compounds have attracted widespread attention in recent years due to their environmental ubiquity and high bioaccumulation capability, as well as their toxicity. In our study, we evaluated the potential estrogenic effects of HFPOs in comparison to PFOA by ligand binding, transcriptional activity, and in vivo assays. Fluorescence ligand binding assays showed that both HFPO-TA and HFPO-TeA exhibited higher binding affinity to estrogen receptor ligand binding domains (ER-LBDs) than PFOA, with 2.5- and 57.5-fold higher affinity to ERα-LBD and 2.6- and 41.8-fold higher affinity to ERβ-LBD, respectively, whereas HFPO-DA exhibited weaker binding affinity than PFOA. Unlike PFOA, HFPO-TA and HFPO-TeA exhibited antagonistic activity toward the ERs' signaling pathway, with HFPO-TeA displaying the strongest potency. In silico study revealed that while PFOA binds with ERs in a similar fashion as 17β-estradiol, the HFPOs display an antagonistic binding mode. Using a zebrafish model, we further found that exposure to HFPO homologues significantly altered the levels of sex steroid hormones and vitellogenin. In general, both in vivo and in vitro results indicate that HFPO homologues might exert higher estrogenic effects than PFOA.

Background: Tetrabromobisphenol A (TBBPA) mono-ether structural analogs, identified as the by-products or transformation products of commercial TBBPA bis-ether derivatives, have been identified as emerging widespread pollutants. However, there is very little information regarding their toxicological effects. Objective: We aimed to explore the potential thyroid hormone (TH) system–disrupting effect of TBBPA mono-ether structural analogs. Methods: The binding potencies of chemicals toward human TH transport proteins [transthyretin (TTR) and thyroxine-binding globulin (TBG)] and receptors [TRα ligand-binding domain (LBD) and TRβ-LBD] were determined by fluorescence competitive binding assays. Molecular docking was used to simulate the binding modes of the chemicals with the proteins. The cellular TR-disrupting potencies of chemicals were assessed by a GH3 cell proliferation assay. The intracellular concentrations of the chemicals were measured by high-performance liquid chromatography and mass spectrometry. Results: TBBPA mono-ether structural analogs bound to TTR with half maximal inhibitory concentrations ranging from 0.1μM to 1.0μM but did not bind to TBG. They also bound to both subtypes of TR-LBDs with 20% maximal inhibitory concentrations ranging from 4.0μM to 50.0μM. The docking results showed that the analogs fit into the ligand-binding pockets of TTR and TR-LBDs with binding modes similar to that of TBBPA. These compounds likely induced GH3 cell proliferation via TR [with the lowest effective concentrations (LOECs) ranging from 0.3μM to 2.5μM] and further enhanced TH-induced GH3 cell proliferation (with LOECs ranging from 0.3μM to 1.2μM). Compared with TBBPA, TBBPA-mono(2,3-dibromopropyl ether) showed a 4.18-fold higher GH3 cell proliferation effect and 105-fold higher cell membrane transportation ability. Conclusion: This study provided a possible mechanism underlying the difference in TTR or TR binding by novel TBBPA structural analogs. These compounds might exert TH system–disrupting effects by disrupting TH transport in circulation and TR activity in TH-responsive cells. https://doi.org/10.1289/EHP6498

Tetrabromobisphenol A (TBBPA), the most widely used brominated flame retardant, is reported to potentially possess risks in inducing obesity or obesity-related metabolic diseases. Considering the increasing environmental contamination of TBBPA analogues and their high structural similarities to the parent compound, whether they could influence adipogenesis or not remains to be elucidated. In this study, two of the most prevalent TBBPA derivatives [i.e., TBBPA bis(allyl ether) (TBBPA-BAE) and TBBPA bis(2,3-dibromopropyl ether) (TBBPA-BDBPE)] and their byproducts [i.e., TBBPA mono(allyl ether) (TBBPA-MAE) and TBBPA mono(2,3-dibromopropyl ether) (TBBPA-MDBPE)], together with TBBPA, were screened for their capacities in activating peroxisome proliferator-activated receptor-γ (PPARγ) and glucocorticoid receptor (GR), the key nuclear receptors involved in adipogenesis, and their structure-related effects on differentiation of 3T3-L1 preadipocytes were explored. The results indicated that the binding affinities of TBBPA and its analogues for the PPARγ ligand-binding domain (PPARγ-LBD) and GR, as well as their effects on PPARγ transactivation, followed the order of TBBPA > TBBPA-MAE > TBBPA-MDBPE > TBBPA-BAE, TBBPA-BDBPE. Nevertheless, TBBPA-MAE and TBBPA-MDBPE showed higher potentials in promoting adipogenesis in 3T3-L1 cells than did TBBPA, as evidenced by intracellular triglyceride contents and adipogenic biomarkers at both protein and transcriptional levels. The etherified group at position 4 of TBBPA phenolic rings was crucial in chemical-induced adipogenic effects, which was related with the recruitment of PPARγ and GR-mediated networks and some other unidentified signaling pathways. The findings on the disturbance of TBBPA analogues on adipogenesis revealed their potential risk in causing obesity and other lipid metabolism-related human health concerns.

To investigate the clinical features, pathogenesis, diagnosis and scrotal reconstruction in the treatment of idiopathic scrotal calcinosis (ISC).From March 2007 to October 2018, 10 ISC patients, aged 28－79 (mean 45) years and with a disease course of 6－497 (mean 128.4) months, were treated in our hospital. We retrospectively analyzed their clinical data and reviewed related literature.All the patients underwent physical examination and biochemical and parathyroid function tests. None of them had a history of endocrine or metabolic disease, or trauma, or a family member with similar diseases, and none had subjective symptoms except local pruritus in 1 case. All were treated surgically and post-operative follow-up revealed no recurrence. Histopathological examination of the excised lesion confirmed it to be ISC.ISC is a rare localized benign disease, of which surgery seems an effective option for the definite diagnosis and treatment. Occasionally scrotal reconstruction may be required in case of extensive involvement of the scrotal skin.

The potential causal relationship between exposure to environmental contaminants and diabetes is troubling. Exposure of perfluoroalkyl substances (PFASs) is found to be associated with hyperinsulinemia and the enhancement of insulin secretion by islet β cells in humans, but the underlying mechanism is still unclear. Here, by combining in vivo studies with both wild type and gene knockout mice and in vitro studies with mouse islet β cells (β-TC-6), we demonstrated clearly that 1 h exposure of perfluorooctanesulfonate (PFOS) stimulated insulin secretion and intracellular calcium level by activating G protein-coupled receptor 40 (GPR40), a vital free fatty acid regulated membrane receptor on islet β cells. We further showed that the observed effects of PFASs on the mouse model may also exist in humans by investigating the molecular binding interaction of PFASs with human GPR40. We thus provided evidence for a novel mechanism for how insulin-secretion is disrupted by PFASs in humans.

Perfluorooctane sulfonate (PFOS) has been widely used as a surface coating for household products. It still exists in living environments despite being restricted, due to its bioaccumulation and long half-life. Studies have shown that PFOS has the ability to induce adipogenic differentiation of human cells. Human mesenchymal stem cells (hMSCs) distributed within the adipose tissue might be a potential target of accumulated PFOS. However, traditional end-point toxicity assays failed to examine the subtle changes of cellular function exposed to low-dose persistent organic pollutants in real time. In the present work, highly sensitive and long-retained (more than 30 days) fluorescence based polymeric nanosensors were developed and employed for real-time assessment of cellular functions. hMSCs were engineered with sensor molecules encapsulated poly (lactic-co-glycolic acid) (PLGA) particles. Once internalized by hMSCs, PLGA particles continuously release and replenish sensor molecules to cytoplasm, resulting in prolonged fluorescence signal against photo bleaching and dilution by exocytosis. With this method, the dynamic changes of viability, ROS induction, and adipogenic differentiation related mRNA expression of hMSCs were monitored. PFOS with the concentration as low as 0.1 μM can induce cellular ROS and enhance the PPARγ and ap2 mRNA expression, suggesting the effect on promoting adipogenic differentiation of hMSCs.

Obesity has become a very large concern worldwide, reaching pandemic proportions over the past several decades. Lifestyle factors, such as excess caloric intake and decreased physical activity, together with genetic predispositions, are well-known factors related to obesity. There is accumulating evidence suggesting that exposure to some environmental chemicals during critical windows of development may contribute to the rapid increase in the incidence of obesity. Agrochemicals are a class of chemicals extensively used in agriculture, which have been widely detected in human. There is now considerable evidence linking human exposure to agrochemicals with obesity. This review summarizes human epidemiological evidence and experimental animal studies supporting the association between agrochemical exposure and obesity and outlines possible mechanistic underpinnings for this link.

Background Previous studies have suggested that exogenous hydrogen sulfide can alleviate the development of diabetic cardiomyopathy (DCM) by inhibiting oxidative stress, inflammation, and apoptosis. However, the underlying mechanism is not fully understood. Nuclear expression and function of the transcription factor Forkhead box protein O (FoxO1) have been associated with cardiovascular diseases, and thus, the importance of FoxO1 in DCM has gained increasing attention. This study was designed to investigate the interactions between hydrogen sulfide (H2 S) and nuclear FoxO1 in DCM. Methods Diabetes was induced in adult male C57BL/6J mice by intraperitoneal injection of streptozotocin and was treated with H2 S donor sodium hydrosulfide for 12 weeks. The H9C2 cardiomyoblast cell line and neonatal rat cardiomyocytes (NRCMs) were treated with the slow-releasing H2 S donor GYY4137 before high-glucose (HG) exposure with or without pretreatment with the Akt inhibitor MK-2206 2HCl. Changes in FoxO1 protein phosphorylation and subcellular localization were determined in H9C2 cells, NRCMs, and cardiac tissues from normal and diabetic mice. Cardiac structure and function in the diabetic mice were evaluated by echocardiography and histological analysis and compared with those in control animals. Results The echocardiographic and histopathological data indicated that exogenous H2 S improved cardiac function and attenuated cardiac hypertrophy and myocardial fibrosis in diabetic mice. H2 S also improved HG-induced oxidative stress and apoptosis in cardiac tissue and NRCMs. In addition, H2 S induced FoxO1 phosphorylation and nuclear exclusion in vitro and in vivo, and this function was not inhibited by MK-2206 2HCl. Alanine substitution mutation of three sites in FoxO1-enhanced FoxO1 transcriptional activity, and subsequent treatment with exogenous H2 S could not prevent HG-induced nuclear retention. Conclusions Our data indicate that H2 S is a novel regulator of FoxO1 in cardiac cells and provide evidence supporting the potential of H2 S in inhibiting the progression of DCM.

Chlorinated polyfluoroalkylether sulfonates (Cl-PFAESs) have been used as perfluorooctanesulfonate (PFOS) alternatives in the chrome plating industry for years. Although Cl-PFAESs have become ubiquitous environmental contaminants, knowledge on their toxicological mechanism remains very limited. We compared potential thyroid hormone (TH) disruption effects of Cl-PFAESs and PFOS via the mechanisms of competitive binding to TH transport proteins and activation of TH receptors (TRs). Fluorescence binding assays revealed that 6:2 Cl-PFAES, 8:2 Cl-PFAES and F-53B (a mixture of 6:2 and 8:2 Cl-PFAES) all interacted with a TH transport protein transthyretin (TTR), with 6:2 Cl-PFAES showing the highest affinity. It was also found that the chemicals interacted with TRs, with the affinity following the order of 6:2 Cl-PFAES > PFOS > 8:2 Cl-PFAES. In reporter gene assays the chemicals exhibited agonistic activity toward TRs, with the potency of 6:2 Cl-PFAES comparable to that of PFOS. The chemicals also promoted GH3 cell proliferation, with 6:2 Cl-PFAES displaying the highest potency. Molecular docking and molecular dynamic simulation revealed that both Cl-PFAESs fit into the ligand binding pockets of TTR and TRs with the binding modes similar to PFOS. Collectively, our results demonstrate that Cl-PFAESs might cause TH disruption effects through competitive binding to transport proteins and activation of TRs.

Estrogen-related receptor γ (ERRγ) is an orphan nuclear receptor having functional cross-talk with classical estrogen receptors. Here, we investigated whether ERRγ is a potential target of polybrominated diphenyl ethers (PBDEs) and their hydroxylated metabolites (OH-PBDEs). By using a fluorescence competitive binding method established in our laboratory, the binding potencies of 30 PBDEs/OH-PBDEs with ERRγ were determined for the first time. All of the tested OH-PBDEs and some PBDEs bound to ERRγ with K

The wide use of the alternatives to bisphenol A (BPA) has raised concerns about their potential toxicities. Considering the disrupting activity of BPA on thyroid hormone (TH) signaling, we investigated whether bisphenol S (BPS) and bisphenol F (BPF), two leading alternatives, could interfere with TH signaling pathway using a series of assays in vitro and in vivo. In the fluorescence competitive binding assay, we found BPS and BPF, like BPA, bound to TH receptors (TRα and TRβ), with the binding potencies an order of magnitude lower than BPA (BPA > BPF > BPS). Molecular docking data also show their binding potencies to TRs. In the coactivator recruitment assay, BPS and BPF recruited coactivator to TRβ but not TRα, with weaker potencies than BPA. Correspondingly, agonistic actions of the three bisphenols in the absence or presence of T3 were observed in the TR-mediated reporter gene transcription assay. Also, all the three bisphenols induced TH-dependent GH3 cell proliferation, whereas BPA and BPF inhibited T3 induction in the presence of T3. As for in vivo assay, the three bisphenols like T3 induced TH-response gene transcription in Pelophylax nigromaculatus tadpoles, but in the presence of T3 altered T3-induced gene transcription in a biphasic concentration-response manner. These results for the first time demonstrate that BPS and BPF, like BPA, have potential to interfere with TH signaling pathway, i.e., they generally activate TH signaling in the absence of T3, but in the presence of TH, display agonistic or/and antagonistic actions under certain condition. Our study highlights the potential risks of BPS and BPF as BPA alternatives.

The optimal strategy of antithrombotic therapy for patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention remains to be a question to be answered. The major challenge in such population is the balance between the benefit of reduced stroke and coronary ischemic events, against the risk of increased bleeding complications. Thus, both thrombotic and bleeding risk assessments should be included into clinical decision-making process for such patients. Currently, there is limited evidence based on randomized trials with adequate power to show the superiority of any strategy in the beneficial profile of safety and efficacy, thus limited recommendations are provided by clinical guidelines. Given the recent advancement in this field, our review provided an overview of the available risk stratification schemes for stroke and bleeding risk for AF patients, discussed the multiple questions in the optimal regimens of oral antiplatelet and anticoagulation therapy, and summarized evidence and recommendations related to long-term antithrombotic therapy for AF patients receiving stent implications.

Chlorinated polyfluorinated ether sulfonates (Cl-PFAESs) are the alternative products of perfluorooctanesulfonate (PFOS) in the metal plating industry in China. The similarity in chemical structures between Cl-PFAESs and PFOS makes it reasonable to assume they possess similar biological activities. In the present study, we investigated whether Cl-PFAESs could induce cellular effects through peroxisome proliferator-activated receptors (PPARs) signaling pathways like PFOS. By using fluorescence competitive binding assay, we found two dominant Cl-PFAESs (6:2 Cl-PFAES and 8:2 Cl-PFAES) bound to PPARs with affinity higher than PFOS. Based on the luciferase reporter gene transcription assay, the two Cl-PFAESs also showed agonistic activity toward PPARs signaling pathways with potency similar to (6:2 Cl-PFAES) or higher than (8:2 Cl-PFAES) PFOS. Molecular docking simulation showed the two Cl-PFAESs fitted into the ligand binding pockets of PPARs with very similar binding mode as PFOS. The cell function results showed Cl-PFAESs promoted the process of adipogenesis in 3T3-L1 cells with potency higher than PFOS. Taken together, we found for the first time that Cl-PFAESs have the ability to interfere with PPARs signaling pathways, and current exposure level of 6:2 Cl-PFAES in occupational workers has exceeded the margin of safety. Our study highlights the potential health risks of Cl-PFAESs as PFOS alternatives.

Organophosphate esters (OPEs) have been reported to induce endocrine disruption effects, and several well-known nuclear receptors have been investigated as cellular targets of OPEs in their mode of action. Here, we demonstrated for the first time that an orphan nuclear receptor estrogen-related receptor γ (ERRγ) is another possible target of OPEs. Using the fluorescence competitive binding assays that we established, we measured the binding affinity of nine OPEs with different substitution groups, including aromatic rings, chlorinated alkyl chains, and alkyl chains. Seven of the OPEs were found to bind to ERRγ, with tri-m-cresyl phosphate (TCrP) showing the highest binding affinity (Kd, 0.34 μM). By using an ERRγ-mediated luciferase reporter gene assay, we found seven OPEs showed inhibitory effects toward ERRγ. Both the binding affinity and the inhibitory effect of the OPEs correlate positively with the hydrophobicity of their substitution groups in the following rank order: aromatic rings > chlorinated a...

Numerous studies have indicated estrogenic disruption effects of bisphenol A (BPA) analogues. Previous mechanistic studies were mainly focused on their genomic activities on nuclear estrogen receptor pathway. However, their nongenomic effects through G protein-coupled estrogen receptor (GPER) pathway remain poorly understood. Here, using a SKBR3 cell-based fluorescence competitive binding assay, we found six BPA analogues bound to GPER directly, with bisphenol AF (BPAF) and bisphenol B (BPB) displaying much higher (∼9-fold) binding affinity than BPA. Molecular docking also demonstrated the binding of these BPA analogues to GPER. By measuring calcium mobilization and cAMP production in SKBR3 cells, we found the binding of these BPA analogues to GPER lead to the activation of subsequent signaling pathways. Consistent with the binding results, BPAF and BPB presented higher agonistic activity than BPA with the lowest effective concentration (LOEC) of 10 nM. Moreover, based on the results of Boyden chamber and wound-healing assays, BPAF and BPB displayed higher activity in promoting GPER mediated SKBR3 cell migration than BPA with the LOEC of 100 nM. Overall, we found two BPA analogues BPAF and BPB could exert higher estrogenic effects than BPA via GPER pathway at nanomolar concentrations.

1D loop chain copper(I) cluster, [Cu 2 I 2 L 2 ] n , can be obtained based upon 9-(3-phenylselanyl-2-phenylselanylmethylpropyl)anthracene ( L ) and CuI. A facile in situ surface assembly strategy was designed to construct polymeric [Cu 2 I 2 L 2 ] n on the surface of TiO 2 nanoparticles. The visible-light photocatalytic property of core-shell TiO 2 -[Cu 2 I 2 L 2 ] n was confirmed by effective reduction of aqueous chromium(VI), showing a clear correlation to optical absorption ( E g = 2.8 eV). The key points of this strategy include high reactivity between copper(I) and soft selenium atom, efficient charge-transfer through polymeric cluster shell, and visible-light photoactivity of copper(I) halogen clusters.

Coexistence of nanomaterials and environmental pollutants requires in-depth understanding of combined toxicity and underlying mechanism. In this work, we found that coexposure to the mixture of noncytotoxic level of single-walled carbon nanotubes (SWCNTs) (10 μg/mL) and Ni2+ (20 μM) induced significant cytotoxicity in macrophages. However, almost equal amount of intracellular Ni2+ was detected after Ni2+/SWCNT coexposure or Ni2+ single exposure, indicating no enhanced cellular uptake of Ni2+ occurred. SDS-PAGE analysis revealed 50% more SWCNTs retained in Ni2+/SWCNT exposed cells than that with SWCNT exposure alone, regardless of the exposure sequence (coexposure, Ni2+ pre- or post-treatment), suggesting inhibited SWCNT exocytosis by Ni2+. The increased cellular dose of SWCNTs could quantitatively account for the elevated toxicity of Ni2+/SWCNT mixture to cells. It was then found that agonist (ATP) and antagonist (o-ATP) of P2X7R could regulate intracellular SWCNT amount and the cytotoxicity accordingly. ...

Previously, perfluoroalkyl substances (PFASs) have been found to be associated with many adverse effects mediated by the peroxisome proliferator-activated receptor α (PPARα) and PPARγ. Here, we found another subtype of the peroxisome proliferator-activated receptors (PPARs); the PPARβ/δ mediated pathway might also be a potential adverse outcome pathway for PFASs. We investigated the direct binding and transcriptional activity of PFASs toward human PPARβ/δ, and further revealed the structure-binding and structure–activity relationship between PFASs and PPARβ/δ. The receptor binding experiment showed that their binding potency was dependent on the carbon chain length and the terminal functional group. For twelve perfluoroalkyl carboxylic acids (PFCAs), an inverted U-shaped relationship existed between the PPARβ/δ binding potency and the carbon chain length, with perfluorododecanoc acid (C12) showing the highest binding potency. The three perfluoroalkane sulfonic acids (PFSAs) exhibited a stronger binding potency than their PFCA counterparts. The two fluorotelomer alcohols (FTOHs) showed no binding potency. In receptor transcriptional activity assays, they enhanced the PPARβ/δ transcriptional activity. Their transcriptional activity was also related to the carbon chain length and the terminal functional group. Molecular docking analysis showed the PFASs fitted into the ligand binding pocket of PPARβ/δ with a binding geometry similar to a fatty acid.

Diabetic cardiomyopathy, which refers to the destruction of the structure and function of the heart, is the primary cause of heart failure due to diabetes. LCZ696 is the first angiotensin receptor-neprilysin inhibitor (ARNi) to be used clinically. Our study investigated the role played by LCZ696 during diabetic cardiomyopathy and explored the potential mechanisms underlying these effects. Diabetes was induced by injecting streptozotocin intraperitoneally into mice, and the mice were then divided randomly into two groups: one group was treated with LCZ696 (60 mg/kg/d) for 16 weeks, and the other received no treatment. The H9C2 cardiomyoblast cell line was treated with LCZ696 under high-glucose (HG) conditions. The levels of apoptotic (Bax, Bcl-2 and cleaved caspase-3) and pro-inflammatory factors [nuclear factor (NF)-κB, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated kinase (MAPK)] were assessed in heart tissues from diabetic and normal mice and in H9C2 cells. The heart tissue structures and cardiac functions of diabetic mice were compared with those of normal mice, using histological and echocardiographic analyses. The results showed that LCZ696 inhibits the nuclear transfer of NF-κB and JNK/p38MAPK phosphorylation, and mitigates inflammation and apoptosis in diabetic mice and H9C2 cardiomyocytes under HG conditions. The histological and echocardiographic data showed that compared with untreated diabetic mice, diabetic mice treated with LCZ696 exhibited improved ventricular remodeling and cardiac function. LCZ696 also ameliorated oxidative stress in both vivo and vitro. In conclusion, LCZ696 improved diabetic cardiomyopathy by reducing cardiac inflammation, oxidative stress, and apoptosis. Impact statement Diabetic cardiomyopathy (DCM) is an important cause of heart failure in patients with diabetes, resulting in increased morbidity and mortality. LCZ696, which was studied here, is a novel drug for the treatment of heart failure. The latest research reports that LCZ696 is more effective for preventing heart failure than valsartan alone. However, little research has been performed examining the effects of LCZ696 on DCM. This study was designed to examine the role played by LCZ696 during DCM and the potential mechanisms underlying these effects, which may provide the basis for a new therapeutic strategy for DCM.

Polybrominated diphenyl ethers (PBDEs) can be metabolized to hydroxylated PBDEs (OH-PBDEs), which play important roles in their disruption effects on the thyroid hormone (TH) system. Recently, multiple in vitro studies suggested that OH-PBDEs might be further metabolically transformed to PBDE sulfates. However, information about the bioactivity of PBDE sulfate metabolites is limited. In the present study, we explored the possible disruption effects of PBDE sulfates to the TH system by studying their binding and activity towards TH transport proteins and nuclear receptors. We found PBDE sulfates could bind to two major TH transport proteins (thyroxine-binding globulin and transthyretin). Besides, PBDE sulfates could also bind to two subtypes of TH nuclear receptors (TRα and TRβ) and showed agonistic activity towards the subsequent signaling pathway. Moreover, the PBDE sulfates showed higher binding potency to TH transport proteins and TRs compared with their corresponding OH-PBDE precursors. Molecular docking results showed that replacement of hydroxyl groups with sulfate groups might lead to more hydrogen bond interactions with these proteins. Overall, our study suggested that PBDE sulfates might disturb the TH system by binding to TH transport proteins or TRs. Our finding indicated a possible mechanism for the TH system disruption effects of PBDEs through their sulfate metabolites.

Hexafluoropropylene oxide trimer acid (HFPO-TA) and hexafluoropropylene oxide dimer acid (HFPO-DA) have been used as perfluorooctanoic acid (PFOA) alternatives in the fluoropolymer industry for years. Their widespread environmental distribution, high bioaccumulation capability, and human exposure have caused great concern. Nevertheless, their potential toxicity and health risk remain largely unknown. In the present study, we compared potential disruption effects of HFPO-TA, HFPO-DA, and PFOA on peroxisome proliferator-activated receptor γ (PPARγ) via the investigation of receptor binding, receptor activity, and cell adipogenesis effects. The receptor binding experiment showed HFPO-TA exhibited 4.8-7.5 folds higher binding affinity with PPARγ than PFOA, whereas HFPO-DA exhibited weaker binding affinity than PFOA. They also showed agonistic activity toward PPARγ signaling pathway in HEK 293 cells in the order of HFPO-TA > PFOA > HFPO-DA. Molecular docking simulation indicated HFPO-TA formed more hydrogen bonds than PFOA, whereas HFPO-DA formed fewer hydrogen bonds than PFOA. HFPO-TA promoted adipogenic differentiation and lipid accumulation in both mouse and human preadipocytes with potency higher than PFOA. Adipogenesis in human preadipocytes is a more sensitive end point than mouse preadipocytes. Collectively, HFPO-TA exerts higher binding affinity, agonistic activity, and adipogenesis activity than PFOA. The potential health risk of HFPO-TA should be of concern.

Hyperglycemia-induced apoptosis plays a critical role in the pathogenesis of diabetic cardiomyopathy (DCM). Our previous study demonstrated that ivabradine, a selective If current antagonist, significantly attenuated myocardial apoptosis in diabetic mice, but the underlying mechanisms remained unknown. This study investigated the underlying mechanisms by which ivabradine exerts anti-apoptotic effects in experimental DCM. Pretreatment with ivabradine, but not ZD7288 (an established If current blocker), profoundly inhibited high glucose-induced apoptosis via inactivation of nuclear factor (NF)-κB signaling in neonatal rat cardiomyocytes. The effect was abolished by transfection of an siRNA targeting protein phosphatase 2A catalytic subunit (PP2Ac). In streptozotocin-induced diabetic mice, ivabradine treatment significantly inhibited left ventricular hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) and HCN4 (major components of the If current), activated PP2Ac, and attenuated NF-κB signaling activation and apoptosis, in line with improved histological abnormalities, fibrosis, and cardiac dysfunction without affecting hyperglycemia. These effects were not observed in diabetic mice with virus-mediated knockdown of HCN2 or HCN4 after myocardial injection, but were alleviated by knockdown of PP2Acα. Molecular docking and phosphatase activity assay confirmed direct binding of ivabradine to, and activation of, PP2Ac. In conclusion, ivabradine may directly activate PP2Ac, leading to inhibition of NF-κB signaling activation, myocardial apoptosis, and fibrosis, and eventually improving cardiac function in experimental DCM. Taken together, the present findings suggest that ivabradine may be a promising drug for treatment of DCM.

Exocytosis of single-walled carbon nanotubes (SWCNTs) determines therapeutic efficiency and toxicity of nanoproducts but its underlying mechanism remains elusive. In this study, it is found that the exocytosis mechanism of SWCNTs is mediated mainly through the activation of P2X7 receptor (P2X7 R), an ATP-gated membrane receptor highly expressed in macrophages. Inhibition of P2X7 R signaling by either a specific inhibitor (oxidized ATP) or small interfering RNA targeting P2X7 R largely prevents the exocytosis of SWCNTs from Raw264.7 cells, resulting in significant accumulation of SWCNTs within cells. In contrast, activation of P2X7 R with ATP promotes exocytosis of SWCNTs. Specifically, it is elucidated that internalized SWCNTs are accumulated in lysosomes and induce transitional release of ATP into extracellular space, which further activates P2X7 R, leading to the influx of calcium ions, phosphorylation of protein kinase C, ERK1/2, p38, and JNK, as well as alkalization of lysosomes. SWCNTs exposure also induces microtubules reorganization that facilitates the secretion of SWCNTs-containing lysosomes. It is also found that P2X7 R simultaneously mediates secretion of IL-1β from Raw264.7 cells during the process of SWCNTs exocytosis. The combined data reveals that P2X7 R-mediated pathway is the predominant molecular mechanism for exocytosis of SWCNTs in Raw264.7 cells. Moreover, SWCNT-induced inflammation is closely coupled with the exocytosis of SWCNTs through P2X7 R.

Vascular endothelial growth factor receptor-2 (VEGFR-2), which is a key determinant of the angiogenecic response, is decreased in diabetic mice under oxidative stress. β-transduction repeat-containing protein (β-TrCP) has been reported to participate in VEGFR-2 degradation in thyroid cancer cells. Additionally, glycogen synthase kinase-3β (GSK‑3β) acts as a mediator in the β-TrCP-induced degradation of several proteins. However, the role played by β-TrCP and GSK‑3β in the degradation of VEGFR-2 in endothelial cells where hyperglycemia had been induced was not fully understood. In the present study, we aimed to analyze the mechanisms of VEGFR-2 degradation by studying excess reactive oxygen species (ROS) induced by hyperglycemia or glucose oxidase (GO). Human umbilical vein endothelial cells (HUVECs) were treated with different concentrations of glucose (6.6, 19.8 and 33 mM), mannitol (33 mM) and GO (1 U/ml). Angiogenic function, ROS levels, the co-location of VEGFR-2 and β-TrCP were evaluated. Cells were collected for RT-qPCR and western blot analysis. We noted that angiogenesis was impaired upon increasing the glucose concentration. When HUVECs were in a hyperglycemic state, ROS production increased, comparable to exposure to GO; GO catalyzes oxidation of glucose into H2O2 and D-glucono-δ-lactone. Phosphorylated VEGFR-2 was reduced by hyperglycemia while total VEGFR-2 was almost unaltered. However, VEGFR-2 was reduced when directly exposed to ROS, with resultant co-location of β-TrCP and VEGFR-2. Through a co-immunoprecipitation assay, we noted that ubiquitinated VEGFR-2 was significantly augmented by excess ROS. Decreased VEGFR-2 caused by ROS was ameliorated by β-TrCP siRNA, proteasome inhibitor MG132 and GSK‑3β activity inhibitor (lithium chloride and SB216763). We suggest that redundant ROS reduces VEGFR-2 through β-TrCP-mediated VEGFR-2 degradation, which is postulated to be regulated by GSK-3β.

Biotransformation of 8:2 fluorotelomer alcohol (8:2 FTOH) can form potentially more toxic metabolites. However, the responsible cytochrome P450 (CYP) isoform(s) and phase II metabolism have not been studied in humans. Here, we characterized the in vitro metabolism of 8:2 FTOH by recombinant human CYPs, human liver microsomes, and human liver cytosol. The results showed that among the 11 isoforms investigated, CYP2C19 was the only enzyme capable of catalyzing 8:2 FTOH with Km and Vmax values of 18.8 μM and 8.52 pmol min−1 pmol−1 P450, respectively. The phase I metabolite was identified as 8:2 fluorotelomer aldehyde (8:2 FTAL). HLMs also catalyzed 8:2 FTOH transformation, with the Vmax and intrinsic clearance (CLint) values similar to those of CYP2C19 after the protein content is taken into account. Molecular docking showed that the hydroxyl group of 8:2 FTOH accesses the heme iron-oxo of CYP2C19 in an energetically favored orientation. 8:2 FTOH was also transformed by phase II enzymes to form O-glucuronide and O-sulfate conjugates. The CLint values follow the order of sulfation > oxidation > glucuronidation, suggesting that conjugation is the major metabolic pathway, which explains the low yield of perfluoroalkyl acids (PFCAs). These results provide new insight into fluorotelomer alcohol biotransformation and indirect human exposure to PFCAs.

Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant that is used worldwide and is continuously being detected in biota and the environment, thus presenting potential threats to the ecosystem and human health. Although PFOS is highly immunotoxic, its underlying molecular mechanisms remain largely unknown. The present study examined PFOS-induced immunotoxicity in the mouse spleen and explored its underlying mechanisms by gene expression profiling. Oral exposure of male BALB/c mice for three weeks followed by one-week recovery showed that a 10 mg/kg/day PFOS exposure damaged the splenic architecture, inhibited T-cell proliferation in response to mitogen, and increased the percentages of T helper (CD3(+)CD4(+)) and cytotoxic T (CD3(+)CD8(+)) cells, despite the decrease in the absolute number of these cells. A delayed type of PFOS immunotoxicity was observed, which mainly occurred during the recovery period. Global gene expression profiling of mouse spleens and QRT-PCR analyses suggest that PFOS inhibited the expression of genes involved in cell cycle regulation and NRF2-mediated oxidative stress response, and upregulated those in TCR signaling, calcium signaling, and p38/MAPK signaling pathways. Western blot analysis confirmed that the expressions of CAMK4, THEMIS, and CD3G, which were involved in the upregulated pathways, were induced upon PFOS exposure. Acute PFOS exposure modulated calcium homoeostasis in splenocytes. These results indicate that PFOS exposure can activate TCR signaling and calcium ion influx, which provides a clue for the potential mechanism of PFOS immunotoxicity. The altered signaling pathways by PFOS treatment as revealed in the present study might facilitate in better understanding PFOS immunotoxicity and explain the association between immune disease and PFOS exposure.

As a class of widely used ultraviolet filters, hydroxylated benzophenones (BPs) have been detected in various environmental and human samples, raising concerns about their ecological and health effects. BPs were found to impair reproductive functions, and their disruption effects on estrogen receptor, G protein-coupled estrogen receptor, and androgen receptor were investigated as possible mechanisms of action. In the present study, we investigated the binding and activation of estrogen related receptor γ (ERRγ) as an alternative mechanism of BPs reproductive toxicity. In competitive fluorescence binding assays, all of the 8 tested BPs were found to bind to the ligand-binding domain of ERRγ but with varying binding affinity. Molecular dock analysis indicated that binding of BPs to ERRγ in the agonistic conformation is preferred. In luciferase reporter gene assays in HepG2 cells, all the 8 BPs activated the transcription of ERRγ in a concentration-dependent manner in the range of 3–100 μM,consistent with the docking result. Hazard quotient calculation revealed a high risk on the BP-type personal care products users. The combined in vitro and in silico results suggest that binding and activation of ERRγ might be the molecular initiating events of an alternative mechanism of BPs endocrine disruption toxicity.

Airborne lower-chlorinated PCBs are vulnerable to metabolization to PCB sulfates through further sulfation of the hydroxylated metabolites (OH-PCBs). However, studies on the toxic effects and mechanisms of PCB sulfates are still very limited. Here, we investigated for the first time the potential endocrine disruption effects of PCB sulfates through estrogen-related receptor γ (ERRγ) in comparison with their OH-PCBs precursors and PCB parent compounds. The binding affinity of thirteen PCBs/OH-PCBs/PCB sulfates was measured by using fluorescence competitive binding assays based on fluorescence polarization (FP). All of the tested chemicals could bind to ERRγ with the Kd (dissociation constant) values ranging from not available (NA) to 3.2 μM 4′–OH–PCB 12 showed the highest binding affinity with Kd value of 3.2 μM, which was comparable to that of a synthetic ERRγ agonist GSK4716. The effects of the thirteen chemicals on the ERRγ transcriptional activity were determined by using the luciferase reporter gene assay. We found the PCBs/OH-PCBs/PCB sulfates acted as agonists for ERRγ, with the lowest observed effective concentration reaching 3 μM. The binding affinity and agonistic activity of PCBs towards ERRγ were both enhanced after hydroxylation, while further sulfation of OH-PCBs decreased the activity instead. Molecular docking simulation showed that OH-PCBs had lower binding energy than the corresponding PCBs and PCB sulfates, indicating that OH-PCBs had higher binding affinity theoretically. In addition, OH-PCBs could form hydrogen bonds with amino acids Glu316 and Arg247 while PCBs and PCB sulfates could not, which might be the main factor impacting the binding affinity and agonistic activity. Overall, ERRγ is a novel target for lower-chlorinated PCBs and their metabolites.

To explore the temporal and spatial variations and the process of trace element migration in the karst critical zone, continuous fixed-point monitoring and sampling analysis was applied to measure each cave system component, which includes rainfall, soils, bedrock, drip waters, and their aerial sediment. Approximately 650 experimental data were obtained from October 2009 to May 2015 in a typical karst critical zone in north China-an interactive zone of the Jiguan Cave in the west Henan Province. The variations in and the migration rules of Ca, Mg, Ba, Sr, and δ

Background: Numerous studies have indicated the estrogenic effects of polybrominated diphenyl ethers (PBDEs) and hydroxylated PBDEs (OH-PBDEs). However, the previous mechanistic studies focused on ...

Background: Numerous studies have indicated the estrogenic effects of polybrominated diphenyl ethers (PBDEs) and hydroxylated PBDEs (OH-PBDEs). However, the previous mechanistic studies focused on their estrogenic effects through genomic transcriptional activation of estrogen receptors. Objective: The present study aimed to investigate the estrogenic effects of PBDEs and OH-PBDEs via nongenomic G protein–coupled estrogen receptor (GPER) pathways. Methods: The binding affinities of 12 PBDEs and 18 OH-PBDEs with GPER were determined by a fluorescence competitive binding assay in a human breast cancer cell line (SKBR3). Molecular docking was performed to simulate the interactions. Their activities on GPER pathways were investigated by detecting calcium mobilization and cyclic adenosine monophosphate (cAMP) accumulation in SKBR3 cells. The effects on SKBR3 cell migration were investigated using Boyden chamber and wound-healing assays. Results: Our results showed that 11 of the OH-PBDEs but none of the PBDEs bound to GPER directly. Relative binding affinities ranged from 1.3% to 20.0% compared to 17β-estradiol. Docking results suggested that the hydroxyl group played an essential role in the binding of OH-PBDEs to GPER by forming hydrogen bond interactions. Most of the OH-PBDEs activated subsequent GPER signaling pathways. Among them, 4ʹ-OH-BDE-049, 5ʹ-OH-BDE-099, and 3ʹ-OH-BDE-154 displayed the highest activity with lowest effective concentrations (LOECs) of 10–100 nM. These three OH-PBDEs also promoted SKBR3 cell migration via GPER pathways with LOECs of 0.1–1μM. Conclusion: OH-PBDEs could bind to GPER, activate the subsequent signaling pathways, and promote SKBR3 cell migration via GPER pathways. OH-PBDEs might exert estrogenic effects by a novel nongenomic mechanism involving the activation of GPER at nanomolar concentrations. https://doi.org/10.1289/EHP2387

We have investigated the effect of surface dangling bonds and molecular passivation on the doping of GaAs nanowires by first-principles calculations. Results show that the positively charged surface dangling bond on Ga atom is the most stable defect for both ultrathin and large size GaAs nanowires. It can form the trap centers of holes and then prefer to capture the holes from p-type doping. Thus it could obviously reduce the efficiency of the p-type doping. We also found that the NO2 molecule is electronegative enough to capture the unpaired electrons of surface dangling bonds, which is an ideal passivation material for the Zn-doped GaAs nanowires.

a Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China b Sheffield Teaching Hospitals and the University of Sheffield, Sheffield, United Kingdom c Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands d Department of Cardiology, University College London Hospital, London, United Kingdom e Department of Cardiology, Fu Wai Hospital, National Center for Cardiovascular Diseases, Beijing 100037, China f International Centre for Circulatory Health, Imperial College London, London, United Kingdom

O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) plays a critical role in modulating protein function in many cellular processes and human diseases such as Alzheimer's disease and type II diabetes, and has emerged as a promising new target. Specific inhibitors of OGT could be valuable tools to probe the biological functions of O-GlcNAcylation, but a lack of robust nonradiometric assay strategies to detect glycosylation, has impeded efforts to identify such compounds. Here we have developed a novel label-free electrochemical biosensor for the detection of peptide O-GlcNAcylation using protease-protection strategy and electrocatalytic oxidation of tyrosine mediated by osmium bipyridine as a signal reporter. There is a large difference in the abilities of proteolysis of the glycosylated and the unglycosylated peptides by protease, thus providing a sensing mechanism for OGT activity. When the O-GlcNAcylation is achieved, the glycosylated peptides cannot be cleaved by proteinase K and result in a high current response on indium tin oxide (ITO) electrode. However, when the O-GlcNAcylation is successfully inhibited using a small molecule, the unglycosylated peptides can be cleaved easily and lead to low current signal. Peptide O-GlcNAcylation reaction was performed in the presence of a well-defined small-molecule OGT inhibitor. The results indicated that the biosensor could be used to screen the OGT inhibitors effectively. Our label-free electrochemical method is a promising candidate for protein glycosylation pathway research in screening small-molecule inhibitors of OGT.

Perfluorinated compounds (PFCs) have been shown to disrupt lipid metabolism and even induce cancer in rodents through activation of peroxisome proliferator-activated receptors (PPARs). Lines of evidence showed that PPARα was activated by PFCs. However, the information on the binding interactions between PPARγ and PFCs and subsequent alteration of PPARγ activity is still limited and sometimes inconsistent. In the present study, in vitro binding of 16 PFCs to human PPARγ ligand binding domain (hPPARγ-LBD) and their activity on the receptor in cells were investigated. The results showed that the binding affinity was strongly dependent on their carbon number and functional group. For the eleven perfluorinated carboxylic acids (PFCAs), the binding affinity increased with their carbon number from 4 to 11, and then decreased slightly. The binding affinity of the three perfluorinated sulfonic acids (PFSAs) was stronger than their PFCA counterparts. No binding was detected for the two fluorotelomer alcohols (FTOHs). Circular dichroim spectroscopy showed that PFC binding induced distinctive structural change of the receptor. In dual luciferase reporter assays using transiently transfected Hep G2 cells, PFCs acted as hPPARγ agonists, and their potency correlated with their binding affinity with hPPARγ-LBD. Molecular docking showed that PFCs with different chain length bind with the receptor in different geometry, which may contribute to their differences in binding affinity and transcriptional activity.

Perfluoroalkyl compounds (PFCs) have been shown to disrupt thyroid functions through thyroid hormone receptor (TR)-mediated pathways, but direct binding of PFCs with TR has not been demonstrated. We investigated the binding interactions of 16 structurally diverse PFCs with human TR, their activities on TR in cells, and the activity of perfluorooctane sulfonate (PFOS) in vivo. In fluorescence competitive binding assays, most of the 16 PFCs were found to bind to TR with relative binding potency in the range of 0.0003-0.05 compared with triiodothyronine (T3). A structure-binding relationship for PFCs was observed, where fluorinated alkyl chain length longer than ten, and an acid end group were optimal for TR binding. In thyroid hormone (TH)-responsive cell proliferation assays, PFOS, perfluorohexadecanoic acid, and perfluorooctadecanoic acid exhibited agonistic activity by promoting cell growth. Furthermore, similar to T3, PFOS exposure promoted expression of three TH upregulated genes and inhibited three TH downregulated genes in amphibians. Molecular docking analysis revealed that most of the tested PFCs efficiently fit into the T3-binding pocket in TR and formed a hydrogen bond with arginine 228 in a manner similar to T3. The combined in vitro, in vivo, and computational data strongly suggest that some PFCs disrupt the normal activity of TR pathways by directly binding to TR.

We theoretically analyze the electrical properties of GaAs substrate-nanowire p-n junction using Technology Computer Aided Design (TCAD). The results show that GaAs nanowire-substrate p-n junction exhibits clear diode behavior which has been confirmed in some experiments. Increasing NWs doping concentration and diameter or shortening NWs length can enlarge the total current after the diode is conducted. Total current through p-n junction is approximately linearly proportional to NWs growth density. The substrate-nanowires p-n junction has smaller current than that of substrate-layer p-n junction, which implies the superiority of NW structure. These results constitute an important progress for experimental researches on nanowire-integrated devices.

Surface-enhanced Raman scattering (SERS) is an effective spectral analysis technique as its advantage of molecular fingerprint, ultra-sensitivity and non-contact. It is the most popular and easiest method to create SERS metal nanoparticles (NPs) combining magnetron sputtering deposition of noble metal with rapid annealing. In this study, we have demonstrated an approach to improve the SERS effect by using graphene oxide (GO) Au NPs composite structure. Here, we obtain the Au NPs coated SOI substrate prepared by magnetron sputtering 4 nm Au film and followed by rapid annealing treatment. The experimental results indicate that the SERS intensity is maximum of the Au NPs coated SOI substrate with the average particle diameter of 20 nm when the rapid annealing time is 30s and temperature is 500 degrees. Then, graphene oxide solution is spin coated on the Au NPs to form the GO-Au NPs composite structure. The morphology of GO-Au NPs have been characterized by scanning electron microscope (SEM). Rhodamine 6G (R6G) is used as the probe molecule to detect the SERS intensity. The GO-Au NPs has an excellent SERS effect which can detect R6G as low as 10 -9 M. Besides, compared to the Au NPs without GO the GO-Au NPs has two times Raman intensity enhancement of bands at 774 cm -1 because of the GO improving the SERS properties through strong ability of adsorption the probe molecule and chemical enhancement effect. Therefore, the GO-Au NPs composite structure shows a promising future to detect low concentration material.