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At least 1,711 records · Page 95
All sourcesNASA NTRSDOE OSTI
DOE OSTI2015

AgI/Ag{sub 3}PO{sub 4} hybrids with highly efficient visible-light driven photocatalytic activity

Highlights: • AgI/Ag{sub 3}PO{sub 4} hybrid was prepared via an in situ anion-exchange method. • AgI/Ag{sub 3}PO{sub 4} displays the excellent photocatalytic activity under visible light. • AgI/Ag{sub 3}PO{sub 4} readily transforms to be Ag@AgI/Ag{sub 3}PO{sub 4} system. • h{sup +} and O{sub 2}{sup ·−} play the major role in the AO 7 decolorization over AgI/Ag{sub 3}PO{sub 4}. • The activity enhancement is ascribed to a Z-scheme system composed of Ag{sub 3}PO{sub 4}, Ag and AgI. - Abstract: Highly efficient visible-light-driven AgI/Ag{sub 3}PO{sub 4} hybrid photocatalysts with different mole ratios of AgI were prepared via an in situ anion-exchange method and characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), UV–vis diffuse reflectance spectroscopy (DRS) and photoluminescence (PL) technique. Under visible light irradiation (>420 nm), the AgI/Ag{sub 3}PO{sub 4} photocatalysts displayed the higher photocatalytic activity than pure Ag{sub 3}PO{sub 4} and AgI for the decolorization of acid orange 7 (AO 7). Among the hybrid photocatalysts, AgI/Ag{sub 3}PO{sub 4} with 80% of AgI exhibited the highest photocatalytic activity for the decolorization of AO 7. X-ray photoelectron spectroscopy (XPS) results revealed that AgI/Ag{sub 3}PO{sub 4} readily transformed to be Ag@AgI/Ag{sub 3}PO{sub 4} system while the photocatalytic activity of AgI/Ag{sub 3}PO{sub 4} remained after 5 recycling runs. In addition, the quenching effects of different scavengers displayed that the reactive h{sup +} and O{sub 2}{sup ·−} play the major role in the AO 7 decolorization. The photocatalytic activity enhancement of AgI/Ag{sub 3}PO{sub 4} hybrids can be ascribed to the efficient separation of electron–hole pairs through a Z-scheme system composed of Ag{sub 3}PO{sub 4}, Ag and AgI, in which Ag nanoparticles act as the charge separation center.

36 MATERIALS SCIENCE↗
DOE OSTI2015

BiPO{sub 4}/BiOBr p–n junction photocatalysts: One-pot synthesis and dramatic visible light photocatalytic activity

Highlights: • BiPO{sub 4}/BiOBr p–n junction photocatalysts were synthesized by a solvothermal method. • BiPO{sub 4}/BiOBr composites were constructed by inlaying BiPO{sub 4} particles into BiOBr microspheres. • BiPO{sub 4}/BiOBr photocatalysts exhibited the enhanced photocatalytic activity. • ·O{sub 2}{sup −} and h{sup +} were the main active species responsible for the degradation of RhB. - Abstract: BiPO{sub 4}/BiOBr p–n junction photocatalysts were successfully synthesized via a facile one-pot solvothermal method. The products were characterized by XRD, FE-SEM, HRTEM, XPS, DRS, PL and EIS. The obtained BiPO{sub 4}/BiOBr composites were constructed by inlaying BiPO{sub 4} nanoparticles into BiOBr hierarchical microspheres. Compared with BiPO{sub 4} and BiOBr, they exhibited significantly enhanced visible light photocatalytic activity towards the degradation of Rhodamine B (RhB). Among them, 10% BiPO{sub 4}/BiOBr showed the maximum value of the activity, whose degradation rate was about three times higher than that of pure BiOBr. The enhanced photocatalytic activity could be attributed to the formation of the BiPO{sub 4}/BiOBr p–n junction, which resulted in the effective separation and transfer of photogenerated electron–hole pairs. Moreover, the trapping experiments confirmed that ·O{sub 2}{sup −} and h{sup +} were the main active species responsible for the degradation of RhB.

36 MATERIALS SCIENCE↗
DOE OSTI2016

A novel fabrication of Cu{sub 2}O@Cu{sub 7}S{sub 4} core-shell micro/nanocrystals from Cu{sub 2}O temples and enhanced photocatalytic activities

Highlights: • The Cu{sub 2}O@Cu{sub 7}S{sub 4} core-shell crystals maintained the same morphology with template. • The crystals exhibit enhanced photocatalytic activity than the pure Cu{sub 2}O crystals. • The photocatalytic activity of different R crystals is diverse from each other. • A possible formation mechanism has been proposed. - Abstract: Uniform and monodispersed Cu{sub 2}O@Cu{sub 7}S{sub 4} core-shell micro/nanocrystals have been synthesized successfully at room temperature via a simple chemical etching reaction, using Cu{sub 2}O as sacrificial template. The structure and properties of the crystals were characterized by X-ray diffraction (XRD), scanning electron microscope (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectra (XPS). The photocatalytic activity of the Cu{sub 2}O@Cu{sub 7}S{sub 4} crystals was evaluated by photocatalytic decolorization of MeO (methyl orange) aqueous solution at ambient temperature under visible-light irradiation. The results show that the as-prepared Cu{sub 2}O@Cu{sub 7}S{sub 4} crystals revealed core-shell structure, which maintained the same morphology with corresponding template and were composed of cuboctahedron Cu{sub 7}S{sub 4} shell and active Cu{sub 2}O core. Due to the unique Cu{sub 2}O@Cu{sub 7}S{sub 4} core-shell structure, the crystals exhibit enhanced photocatalytic activity than that of the pure Cu{sub 2}O crystals, and the photocatalytic activity of different R crystals is diverse from each other. A possible formation mechanism has been proposed.

36 MATERIALS SCIENCE↗
DOE OSTI2017

Remarkable improvement of visible light photocatalytic activity of TiO{sub 2} nanotubes doped sequentially with noble metals for removing of organic and microbial pollutants

Highlights: • Ordered TiO{sub 2} nanotubes (NTs) were synthesized using anodic oxidation. • TiO{sub 2} NTs were modified with Ag and Au NPs that settled separately to widen visible absorption. • TiO{sub 2} NTs modified with Ag and Au NPs is superior visible light photocatalyst. • TiO{sub 2} NTs modified with Ag and Au NPs shows superior antibacterial activity. • Annealing temperature played important role in photocatalytic activity of TiO{sub 2} NTs. - Abstract: The aim of this study was to show that Ag and Au nanoparticles (NPs) can have a synergistic effect on the photocatalytic and antibacterial activity of TiO{sub 2} nanotubes (NTs) under visible irradiation. TiO{sub 2} NTs were grown on Ti substrate by anodic oxidation and modified with Ag and Au NPs by dip coating and sputtering methods, respectively. The spherical 5–20 nm Ag and Au NPs were deposited on TiO{sub 2} NTs with diameter of 50–80 nm. In contrast to obtained results under UV irradiation, visible-light absorption range and visible photocatalytic activity of Ag and Au co-modified TiO{sub 2} NTs were much higher than TiO{sub 2} NTs without modification and TiO{sub 2} NTs modified with monometallic NPs. Photocatalytic activity of modified TiO{sub 2} NTs increased with increasing annealing temperature and appearing rutile phase. Antibacterial activity of Ag and Au-comodified TiO{sub 2} NTs against E. coli was noticeably more than that of TiO{sub 2} NTs modified with monometallic NPs.

36 MATERIALS SCIENCE↗
DOE OSTI2018

Core-shell structured α-Fe2O3@CeO2 heterojunction for the enhanced visible-light photocatalytic activity

Highlights: • CeO{sub 2}–coated α-Fe{sub 2}O{sub 3} sample was prepared via a hydrothermal route. • α-Fe{sub 2}O{sub 3}@CeO{sub 2} presented the excellent photocatalytic activity and stability. • The heterojunction interface facilitated the separation of electron-hole pairs. • Ce{sup 4+}/Ce{sup 3+} redox couple promoted the efficient electron transfer. - Abstract: CeO{sub 2}-coated α-Fe{sub 2}O{sub 3} nanoparticles (α-Fe{sub 2}O{sub 3}@CeO{sub 2}) with the enhanced photocatalytic activity were synthesized by a hydrothermal route and performed for the visible light driven photo-degradation of methylene blue (MB). The photocatalytic activity of α-Fe{sub 2}O{sub 3}@CeO{sub 2} is greatly affected by the thickness of CeO{sub 2} shell under the same conditions. The core-shell structured α-Fe{sub 2}O{sub 3}@CeO{sub 2} sample exhibited a narrower band gap energy in comparison to the pure α-Fe{sub 2}O{sub 3} and CeO{sub 2} bulks, leading to the excellent photocatalytic activity and stability for the degradation of MB under visible light irradiation after five cycle times. The core-shell structured α-Fe{sub 2}O{sub 3}@CeO{sub 2} sample presented higher degradation activity than that of the supported 8-Fe/CeO{sub 2} bulks with optimized α-Fe{sub 2}O{sub 3} loading of 8%. It can be ascribed to the Ce{sup 4+}/Ce{sup 3+} redox couple and the heterojunction interfaces of core-shell structured α-Fe{sub 2}O{sub 3}@CeO{sub 2} sample, which can promote the electrons transfer and restrain the photoexcited electron-hole recombination, leading to the excellent degradation activity under visible light irradiation.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗
DOE OSTI2018

Bi2O2(OH)NO3/AgI heterojunction with enhanced UV and visible-light responsive photocatalytic activity and mechanism investigation

Highlights: • Bi{sub 2}O{sub 2}(OH)NO{sub 3}/AgI heterojunction is obtained by in-situ crystallization method. • It shows a higher degradation activity than Bi{sub 2}O{sub 2}(OH)NO{sub 3} and AgI under UV light. • It shows a higher catalytic activity than Bi{sub 2}O{sub 2}(OH)NO{sub 3} and AgI under visible light. • Enhanced charge separation is responsible for the enhanced degradation activity. - Abstract: Fabricating heterojunction between a wide-band-gap semiconductor and a narrow-band-gap semiconductor has become an important strategy to simultaneously improve the photoabsorption and charge separation. In this work, a new heterojunction photocatalyst Bi{sub 2}O{sub 2}(OH)NO{sub 3}/AgI was prepared through a facile in-situ crystallization method under ambient atmosphere. The crystal morphology, surface structure and element distribution were investigated by scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive X-ray (EDX) mapping and X-ray photoelectron spectroscopy (XPS). Compared with the pristine Bi{sub 2}O{sub 2}(OH)NO{sub 3} and AgI, Bi{sub 2}O{sub 2}(OH)NO{sub 3}/AgI shows much enhanced degradation performance for eliminating MO regardless of UV or visible light. Photocurrent, electrochemical impedance spectra (EIS) and photoluminescence (PL) demonstrated that the enhanced photocatalytic activity is ascribed to the greatly promoted charge separation and transfer resulted from the matchable band energy levels of Bi{sub 2}O{sub 2}(OH)NO{sub 3} and AgI, favoring the formation of heterojunction. In addition, according to the active species trapping experiment, the main active species are superoxide radicals (O{sub 2}{sup −}) and holes (h{sup +}) during the degradation process.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗
DOE OSTI2017

Improved lithium iodide neutron scintillator with Eu 2+ activation: The elimination of Suzuki-Phase precipitates

Monovalent alkali halides such as NaI, CsI, and LiI are widely used as inorganic scintillators for radiation detection due to their light yield, the capability for the growth of large single crystals, relatively low cost, and other favorable characteristics. These materials are frequently activated through the addition of small amounts (e.g., a few hundred ppm) of elements such as thallium - or sodium in the case of CsI. The monovalent alkali halide scintillators can also be activated with low concentrations of Eu 2+ , however Eu activation has previously not been widely employed due to the non-uniform segregation of the divalent Eu dopant that leads to the formation of unwanted phases during Bridgman or other solidification crystal-growth methods. Specifically, for Eu concentrations near and above ~0.5%, Suzuki Phase precipitates form in the course of the melt-growth process, and these Suzuki Phase particles scatter the scintillation light. This adversely affects the scintillator performance via reduction in the optical transmission of the material, and depending on the crystal thickness and precipitated-particle concentration, this reduction can occur up to the point of opacity. Here we describe a post-growth process for the removal of Suzuki Phase precipitates from single crystals of the neutron scintillator LiI activated with Eu 2+ at concentrations up to and in excess of 3 wt.%, and we correlate the resulting neutron-detection performance with the thermal processing methods used to remove the Suzuki Phase particles. Furthermore, the resulting improved scintillator properties using increased Eu activator levels are applicable to neutron imaging and active interrogation systems, and pulse-height gamma-ray spectroscopy rather than pulse-shape discrimination can be used to discriminate between gamma ray and neutron interaction events.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
DOE OSTI2014

Coactivation of the PI3K/Akt and ERK signaling pathways in PCB153-induced NF-κB activation and caspase inhibition

Polychlorinated biphenyls (PCBs) are a group of persistent and widely distributed environmental pollutants that have various deleterious effects, e.g., neurotoxicity, endocrine disruption and reproductive abnormalities. In order to verify the hypothesis that the PI3K/Akt and MAPK pathways play important roles in hepatotoxicity induced by PCBs, Sprague–Dawley (SD) rats were dosed with PCB153 intraperitoneally at 0, 4, 16 and 32 mg/kg for five consecutive days; BRL cells (rat liver cell line) were treated with PCB153 (0, 1, 5, and 10 μM) for 24 h. Results indicated that the PI3K/Akt and ERK pathways were activated in vivo and in vitro after exposure to PCB153, and protein levels of phospho-Akt and phospho-ERK were significantly increased. Nuclear factor-κB (NF-κB) activation and caspase-3, -8 and -9 inhibition caused by PCB153 were also observed. Inhibiting the ERK pathway significantly attenuated PCB153-induced NF-κB activation, whereas inhibiting the PI3K/Akt pathway hardly influenced phospho-NF-κB level. However, inhibiting the PI3K/Akt pathway significantly elevated caspase-3, -8 and -9 activities, while the ERK pathway only synergistically regulated caspase-9. Proliferating cell nuclear antigen (PCNA), a reliable indicator of cell proliferation, was also induced. Moreover, PCB153 led to hepatocellular hypertrophy and elevated liver weight. Taken together, PCB153 leads to aberrant proliferation and apoptosis of hepatocytes through NF-κB activation and caspase inhibition, and coactivated PI3K/Akt and ERK pathways play critical roles in PCB153-induced hepatotoxicity. - Highlights: • PCB153 led to hepatotoxicity through NF-κB activation and caspase inhibition. • The PI3K/Akt and ERK pathways were coactivated in vivo and in vitro by PCB153. • The ERK pathway regulated levels of phospho-NF-κB and caspase-9. • The PI3K/Akt pathway regulated levels of caspase-3, -8 and -9.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Curcumin attenuates glutamate neurotoxicity in the hippocampus by suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in a manner dependent on AMPK

Curcumin is a natural polyphenolic compound in Curcuma longa with beneficial effects on neuronal protection. This study aims to investigate the action of curcumin in the hippocampus subjected to glutamate neurotoxicity. Glutamate stimulation induced reactive oxygen species (ROS), endoplasmic reticulum stress (ER stress) and TXNIP/NLRP3 inflammasome activation, leading to damage in the hippocampus. Curcumin treatment in the hippocampus or SH-SY5Y cells inhibited IRE1α and PERK phosphorylation with suppression of intracellular ROS production. Curcumin increased AMPK activity and knockdown of AMPKα with specific siRNA abrogated its inhibitory effects on IRE1α and PERK phosphorylation, indicating that AMPK activity was essential for the suppression of ER stress. As a result, curcumin reduced TXNIP expression and inhibited NLRP3 inflammasome activation by downregulation of NLRP3 and cleaved caspase-1 induction, and thus reduced IL-1β secretion. Specific fluorescent probe and flow cytometry analysis showed that curcumin prevented mitochondrial malfunction and protected cell survival from glutamate neurotoxicity. Moreover, oral administration of curcumin reduced brain infarct volume and attenuated neuronal damage in rats subjected to middle cerebral artery occlusion. Immunohistochemistry showed that curcumin inhibited p-IRE1α, p-PERK and NLRP3 expression in hippocampus CA1 region. Together, these results showed that curcumin attenuated glutamate neurotoxicity by inhibiting ER stress-associated TXNIP/NLRP3 inflammasome activation via the regulation of AMPK, and thereby protected the hippocampus from ischemic insult. - Highlights: • Curcumin attenuates glutamate neurotoxicity in the hippocampus. • Curcumin suppresses ER stress in glutamate-induced hippocampus slices. • Curcumin inhibits TXNIP/NLRP3 inflammasome activation. • Regulation of AMPK by curcumin contributes to suppressing ER stress.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

CPT-11 activates NLRP3 inflammasome through JNK and NF-κB signalings

CPT-11 is widely used for cancer therapy as a chemotherapeutic agent. Despite its good efficacy, a large number of side effects appeared during decades of clinical application. Delayed diarrhea, at dose limiting toxicity, happens after 24 h of treatment and the rate of occurrence is up to 90%. Although many investments have been made on this negative impact, the real molecular mechanism of delayed diarrhea is poorly understood. In this study, we have discovered that CPT-11 promotes macrophage infiltration into intestinal tissues and activates the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, resulting in a robust IL-1β response and colonic inflammation similar to DSS (dextran sodium sulfate) induced experimental colitis. CPT-11 plus LPS primed mouse bone marrow-derived macrophages (BMDMs) and human acute monocytic leukemia cells (THP-1 cells) staying in a highly activated status, showing increased caspase-1 activity and releasing great amounts of IL-1β and IL-18 as detected by ELISA and western blot. A further mechanism showed that JNK and NF-κB signaling pathways participated in inflammatory responses activated by CPT-11. These results prompted us to suggest that the NLRP3-IL-1β signaling pathway might play an important role in CPT11-induced colitis. Our findings provide a basis for developing novel strategies that improve clinical implications of CPT-11. - Highlights: • CPT-11 induced experimental colitis in vivo. • CPT-11 induced intestine injury and macrophage infiltration. • CPT-11 significantly elevated levels of macrophage derived inflammatory cytokines in mice intestines. • CPT-11 activated NLRP3 inflammasome in vitro and in vivo. • CPT-11 activated JNK and NF-κB signalings in THP-1 and BMDMs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

PFOS induces adipogenesis and glucose uptake in association with activation of Nrf2 signaling pathway

PFOS is a chemical of nearly ubiquitous exposure in humans. Recent studies have associated PFOS exposure to adipose tissue-related effects. The present study was to determine whether PFOS alters the process of adipogenesis and regulates insulin-stimulated glucose uptake in mouse and human preadipocytes. In murine-derived 3T3-L1 preadipocytes, PFOS enhanced hormone-induced differentiation to adipocytes and adipogenic gene expression, increased insulin-stimulated glucose uptake at concentrations ranging from 10 to 100 μM, and enhanced Glucose transporter type 4 and Insulin receptor substrate-1 expression. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), NAD(P)H dehydrogenase, quinone 1 and Glutamate-cysteine ligase, catalytic subunit were significantly induced in 3T3-L1 cells treated with PFOS, along with a robust induction of Antioxidant Response Element (ARE) reporter in mouse embryonic fibroblasts isolated from ARE-hPAP transgenic mice by PFOS treatment. Chromatin immunoprecipitation assays further illustrated that PFOS increased Nrf2 binding to ARE sites in mouse Nqo1 promoter, suggesting that PFOS activated Nrf2 signaling in murine-derived preadipocytes. Additionally, PFOS administration in mice (100 μg/kg/day) induced adipogenic gene expression and activated Nrf2 signaling in epididymal white adipose tissue. Moreover, the treatment on human visceral preadipocytes illustrated that PFOS (5 and 50 μM) promoted adipogenesis and increased cellular lipid accumulation. It was observed that PFOS increased Nrf2 binding to ARE sites in association with Nrf2 signaling activation, induction of Peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein α expression, and increased adipogenesis. This study points to a potential role of PFOS in dysregulation of adipose tissue expandability, and warrants further investigations on the adverse effects of persistent pollutants on human health. - Highlights: • PFOS induces adipogenesis in association with increased Pparγ and Cebpα mRNA expression. • PFOS increases ARE binding activity and activates Nrf2 signaling. • PFOS increases insulin-stimulated glucose uptake.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

PTP1B confers liver fibrosis by regulating the activation of hepatic stellate cells

Liver fibrosis is a reversible wound-healing response to chronic hepatic injuries. Activation of hepatic stellate cells (HSCs) plays a pivotal role in the development of hepatic fibrosis. The currently accepted mechanism for the resolution of liver fibrosis is the apoptosis and inactivation of activated HSCs. Protein tyrosine phosphatase 1B (PTP1B), a prototype of non-receptor protein tyrosine phosphatase, is proved to be a vital modulator in cardiac fibrogenesis. However, the precise role of PTP1B on liver fibrosis and HSC activation is still unclear. Our study showed that the expression of PTP1B was elevated in fibrotic liver but reduced after spontaneous recovery. Moreover, stimulation of HSC-T6 cells with transforming growth factor-β1 (TGF-β1) resulted in a dose/time-dependent increase of PTP1B mRNA and protein. Co-incubation of HSC-T6 cells with PTP1B-siRNA inhibited the cell proliferation and activation induced by TGF-β1. Additionally, both mRNA and protein of PTP1B were dramatically decreased in inactivated HSCs after treated with adipogenic differentiation mixture (MDI). Over-expression of PTP1B hindered the inactivation of HSC-T6 cells induced by MDI. These observations revealed a regulatory role of PTP1B in liver fibrosis and implied PTP1B as a potential therapeutic target. - Highlights: • The expression of PTP1B in the fibrotic livers and recovery livers • The expression of PTP1B in activated and inactivated HSCs • Blockade of PTP1B inhibited the TGF-β1-induced proliferation and activation of HSCs. • Over-expression of PTP1B abolished the inactivation of HSCs induced by MDI.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1

Obesity is an increasingly urgent global problem, yet, little is known about its causes and less is known how obesity can be effectively treated. We showed previously that the aryl hydrocarbon receptor (AHR) plays a role in the regulation of body mass in mice fed Western diet. The AHR is a ligand-activated nuclear receptor that regulates genes involved in a number of biological pathways, including xenobiotic metabolism and T cell polarization. This study was an investigation into whether inhibition of the AHR prevents Western diet-based obesity. Male C57Bl/6J mice were fed control and Western diets with and without the AHR antagonist α-naphthoflavone or CH-223191, and a mouse hepatocyte cell line was used to delineate relevant cellular pathways. Studies are presented showing that the AHR antagonists α-naphthoflavone and CH-223191 significantly reduce obesity and adiposity and ameliorates liver steatosis in male C57Bl/6J mice fed a Western diet. Mice deficient in the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) were also resistant to obesity. Using an AHR-directed, luciferase-expressing mouse hepatocyte cell line, we show that the transforming growth factor β1 (TGFβ1) signaling pathway via PI3K and NF-κB and the toll-like receptor 2/4 (TLR2/4) signaling pathway stimulated by oxidized low-density lipoproteins via NF-κB, each induce luciferase expression; however, TLR2/4 signaling was significantly reduced by inhibition of IDO1. At physiological levels, kynurenine but not kynurenic acid (both tryptophan metabolites and known AHR agonists) activated AHR-directed luciferase expression. We propose a hepatocyte-based model, in which kynurenine production is increased by enhanced IDO1 activity stimulated by TGFβ1 and TLR2/4 signaling, via PI3K and NF-κB, to perpetuate a cycle of AHR activation to cause obesity; and inhibition of the AHR, in turn, blocks the cycle's output to prevent obesity. The AHR with its broad ligand binding specificity is a promising candidate for a potentially simple therapeutic approach for the prevention and treatment of obesity and associated complications. - Highlights: • The AHR acts as a hub in Western diet-based obesity. • Inhibition of AHR signaling by antagonists prevents obesity and liver steatosis. • ox-LDL stimulates AHR activity via a TLR2/4, NF-kB, IDO1, kynurenine axis. • TGFβ stimulates AHR activity in Hepa-1c1c7 cells via PI3K and NF-kB. • The AHR offers a simple and promising approach for treating obesity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SHP-1 is directly activated by the aryl hydrocarbon receptor and regulates BCL-6 in the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a strong AHR agonist, causes significant suppression of human B cell activation and differentiation. The current studies describe the identification of Src homology phosphatase 1 (SHP-1) encoded by the gene PTPN6 as a putative regulator of TCDD-mediated suppression of B cell activation. Shp-1 was initially identified through a genome-wide analysis of AHR binding in mouse B cells in the presence of TCDD. The binding of AHR to the PTPN6 promoter was further confirmed using electrophoretic mobility shift assays in which, specific binding of AHR was detected at four putative DRE sites within PTPN6 promoter. Time-course measurements performed in human B cells highlighted a significant increase in SHP-1 mRNA and protein levels in the presence of TCDD. The changes in the protein levels of SHP-1 were also observed in a TCDD concentration-dependent manner. The increase in SHP-1 levels was also seen to occur due to a change in early signaling events in the presence of TCDD. We have shown that BCL-6 regulates B cell activation by repressing activation marker CD80 in the presence of TCDD. TCDD-treatment led to a significant increase in the double positive (SHP-1{sup hi} BCL-6{sup hi}) population. Interestingly, treatment of naïve human B cells with SHP-1 inhibitor decreased BCL-6 protein levels suggesting possible regulation of BCL-6 by SHP-1 for the first time. Collectively, these results suggest that SHP-1 is regulated by AHR in the presence of TCDD and may, in part through BCL-6, regulate TCDD-mediated suppression of human B cell activation. - Highlights: • SHP-1 encoded by the gene PTPN6 is directly activated by the AHR. • AHR binds to dioxin response elements within the SHP-1 promoter in a TCDD-inducible manner. • TCDD-mediated increase in SHP-1 levels is observed in primary human B cells. • Higher SHP-1 levels help in maintaining high BCL-6 levels in the presence of TCDD. • In the presence of SHP-1 inhibitor, decreased BCL-6 levels are observed.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

The role of PTEN in regulation of hepatic macrophages activation and function in progression and reversal of liver fibrosis

Activation of Kupffer cells (KCs) plays a pivotal role in the pathogenesis of liver fibrosis. The progression and reversal of CCl{sub 4}-induced mouse liver fibrosis showed a mixed induction of hepatic classical (M1) and alternative (M2) macrophage markers. Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in modulating myeloid cell activation has recently been identified, its function in macrophage activation during hepatic fibrosis remains to be fully appreciated. In our study, PTEN expression of KCs was remarkably decreased in CCl{sub 4}-induced mice but increased to a near-normal level in reversed mice. Moreover, PTEN was significantly decreased in IL4-induced RAW 264.7 cells in vitro and lower expression of PTEN was observed in M2 macrophages in vivo. In addition, loss- and gain-of-function studies suggested that PTEN regulates M2 macrophages polarization via activation of PI3K/Akt/STAT6 signaling, but had a limited effect on M1 macrophages polarization in vitro. Additionally, Ly294002, a chemical inhibitor of PI3K/Akt, could dramatically down-regulate the hallmarks of M2 macrophages. In conclusion, PTEN mediates macrophages activation by PI3K/Akt/STAT6 signaling pathway, which provides novel compelling evidences on the potential of PTEN in liver injury and opens new cellular target for the pharmacological therapy of liver fibrosis. - Highlights: • CCl{sub 4} treatment triggered a mixed M1/M2 macrophage phenotype in fibrosis. • Lower expression of PTEN in murine M2 macrophages in vivo and vitro. • PTEN modulates M2 macrophages activation via PI3K/Akt/STAT6 signaling. • Provide a new cellular target modulate macrophage mediated hepatic fibrosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Ultrafine carbon particles promote rotenone-induced dopamine neuronal loss through activating microglial NADPH oxidase

Background: Atmospheric ultrafine particles (UFPs) and pesticide rotenone were considered as potential environmental risk factors for Parkinson's disease (PD). However, whether and how UFPs alone and in combination with rotenone affect the pathogenesis of PD remains largely unknown. Methods: Ultrafine carbon black (ufCB, a surrogate of UFPs) and rotenone were used individually or in combination to determine their roles in chronic dopaminergic (DA) loss in neuron-glia, and neuron-enriched, mix-glia cultures. Immunochemistry using antibody against tyrosine hydroxylase was performed to detect DA neuronal loss. Measurement of extracellular superoxide and intracellular reactive oxygen species (ROS) were performed to examine activation of NADPH oxidase. Genetic deletion and pharmacological inhibition of NADPH oxidase and MAC-1 receptor in microglia were employed to examine their role in DA neuronal loss triggered by ufCB and rotenone. Results: In rodent midbrain neuron-glia cultures, ufCB and rotenone alone caused neuronal death in a dose-dependent manner. In particularly, ufCB at doses of 50 and 100 μg/cm{sup 2} induced significant loss of DA neurons. More importantly, nontoxic doses of ufCB (10 μg/cm{sup 2}) and rotenone (2 nM) induced synergistic toxicity to DA neurons. Microglial activation was essential in this process. Furthermore, superoxide production from microglial NADPH oxidase was critical in ufCB/rotenone-induced neurotoxicity. Studies in mix-glia cultures showed that ufCB treatment activated microglial NADPH oxidase to induce superoxide production. Firstly, ufCB enhanced the expression of NADPH oxidase subunits (gp91{sup phox}, p47{sup phox} and p40{sup phox}); secondly, ufCB was recognized by microglial surface MAC-1 receptor and consequently promoted rotenone-induced p47{sup phox} and p67{sup phox} translocation assembling active NADPH oxidase. Conclusion: ufCB and rotenone worked in synergy to activate NADPH oxidase in microglia, leading to oxidative damage to DA neurons. Our findings delineated the potential role of ultrafine particles alone and in combination with pesticide rotenone in the pathogenesis of PD. - Graphical abstract: Ultrafine particles and rotenone synergistically induce the assembly of active form NADPH oxidase complex in microglia inducing oxidative damage to dopamine neurons. - Highlights: • Ultrafine carbon black promotes dopaminergic neuronal loss induced by rotenone. • The role and underlying mechanism of ultrafine particles in the pathogenesis of PD • NADPH oxidase is a potential therapeutic target of Parkinson's disease.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Perinatal exposure to organohalogen pollutants decreases vasopressin content and its mRNA expression in magnocellular neuroendocrine cells activated by osmotic stress in adult rats

Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are environmental pollutants that produce neurotoxicity and neuroendocrine disruption. They affect the vasopressinergic system but their disruptive mechanisms are not well understood. Our group reported that rats perinatally exposed to Aroclor-1254 (A1254) and DE-71 (commercial mixtures of PCBs and PBDEs) decrease somatodendritic vasopressin (AVP) release while increasing plasma AVP responses to osmotic activation, potentially emptying AVP reserves required for body-water balance. The aim of this research was to evaluate the effects of perinatal exposure to A1254 or DE-71 (30 mg kg/day) on AVP transcription and protein content in the paraventricular and supraoptic hypothalamic nuclei, of male and female rats, by in situ hybridization and immunohistochemistry. cFOS mRNA expression was evaluated in order to determine neuroendocrine cells activation due to osmotic stimulation. Animal groups were: vehicle (control); exposed to either A1254 or DE-71; both, control and exposed, subjected to osmotic challenge. The results confirmed a physiological increase in AVP-immunoreactivity (AVP-IR) and gene expression in response to osmotic challenge as reported elsewhere. In contrast, the exposed groups did not show this response to osmotic activation, they showed significant reduction in AVP-IR neurons, and AVP mRNA expression as compared to the hyperosmotic controls. cFOS mRNA expression increased in A1254 dehydrated groups, suggesting that the AVP-IR decrease was not due to a lack of the response to the osmotic activation. Therefore, A1254 may interfere with the activation of AVP mRNA transcript levels and protein, causing a central dysfunction of vasopressinergic system. - Highlights: • Perinatal exposure to A1254 and DE-71 disrupts the vasopressin system of adult rats. • Exposure to organohalogens reduces AVP responses to osmotic stress in PVN and SON. • Perinatal exposure to A1254 fails to increase AVP mRNA in the hyperosmotic challenge. • Hyperosmotic stress and A1254 exposure activate cFOS gene in PVN and SON neurons. • Perinatal exposure to A1254 disrupts the AVP system similarly in Wistar and SD rats.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Determination of the protease cleavage site repertoire—The RNase H but not the RT domain is essential for foamy viral protease activity

In contrast to orthoretroviruses, the foamy virus protease is only active as a protease-reverse transcriptase fusion protein and requires viral RNA for activation. Maturation of foamy viral proteins seems to be restricted to a single cleavage site in Gag and Pol. We provide evidence that unprocessed Gag is required for optimal infectivity, which is unique among retroviruses. Analyses of the cleavage site sequences of the Gag and Pol cleavage sites revealed a high similarity compared to those of Lentiviruses. We show that positions P2' and P2 are invariant and that Gag and Pol cleavage sites are processed with similar efficiencies. The RNase H domain is essential for protease activity, but can functionally be substituted by RNase H domains of other retroviruses. Thus, the RNase H domain might be involved in the stabilization of the protease dimer, while the RT domain is essential for RNA dependent protease activation. - Highlights: • Unprocessed Gag is required for optimal infectivity of foamy viruses. • Positions P2 and P2' are invariant in the foamy viral cleavage sites. • The RNaseH domain is essential for protease activity. • The RNaseH domains of other retroviruses support foamy viral protease activity.

60 APPLIED LIFE SCIENCES↗