Immunomodulatory effects of black cohosh (Actaea racemosa) extract in female B6C3F1/N mice

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Smith, Matthew J.; Germolec, Dori R.; Frawley, Rachel P.; White, Kimber L.

2013-01-01

Black cohosh extracts (BCE; Actaea racemosa) are being used worldwide as an alternative to hormone replacement therapy for the management of menstrual and menopausal symptoms, yet the effects of BCE on the immune system are largely unknown. Female B 6 C 3 F 1 /N mice were treated daily with BCE (0, 62.5, 125, 250, 500, or 1000 mg/kg) for 28 days by oral gavage. Liver weights were significantly increased (26–32%) at the 1000 mg/kg dose. Dose-related increases in mean corpuscular volume and mean corpuscular hemoglobin were observed. Decreasing trends were observed in all thymic T cell populations, with the most notable dose-responsive effects on immature thymocytes. In the spleen, dose-related decreases were observed in all cell phenotypes evaluated, reaching the level of statistical significance at the 1000 mg/kg BCE dose. Splenic natural killer (NK) cell numbers were significantly decreased at all BCE doses, with the exception of absolute NK numbers at the 125 mg/kg dose. No effects were observed on T-dependent antibody responses of the humoral immune system, including the antibody-forming cell response to sheep erythrocytes (sRBC) and IgM antibody levels to both sRBC and keyhole limpet hemocyanin. Cytotoxic T cell (T CTL ) activity was increased, as was the mixed leukocyte response in one of two studies. Anti-CD3 mediated proliferation and the delayed-type hypersensitivity response were unaffected. No effects were observed on innate immunity or on bone marrow cellularity and colony-forming units. Overall, BCE exposure in B 6 C 3 F 1 /N mice for 28 days at doses up to 1000 mg/kg had minimal immune effects, with the exception of an increased T CTL response

Pathology of Serially Sacrificed Female B6C3F1 Mice Continuously Exposed to Very Low-Dose-Rate Gamma Rays.

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Tanaka, I B; Komura, J; Tanaka, S

2017-03-01

We have previously reported on life span shortening as well as increased incidence rates in several neoplasms in B6C3F1 mice that were continuously exposed to 21 mGy/day of gamma rays for 400 days. To clarify whether the life shortening was due to early appearance of neoplasms (shortened latency) or increased promotion/progression, 8-week-old female specific-pathogen-free B6C3F1 mice were gamma-ray irradiated at a low dose rate of 20 mGy/day for 400 days. At 100 days postirradiation, 60-90 mice were sacrificed, and thereafter every 100 days alongside the age-matched nonirradiated controls, for 700 days. Additional groups were allowed to live out their natural life span. Pathological examination was performed on all mice to identify lesions, non-neoplastic and neoplastic, as well as to determine the cause of death. Body weights were significantly increased in irradiated mice from sacrifice days 200-500. Incidence rates for spontaneously occurring non-neoplastic lesions, such as adrenal subcapsular cell hyperplasia, fatty degeneration of the liver, atrophy and tubulostromal hyperplasia of the ovaries, were significantly increased in irradiated mice. Significantly increased incidence rates with no shortening of latency periods were observed in irradiated mice for malignant lymphomas, hepatocellular adenomas/carcinomas, bronchioloalveolar adenomas, harderian gland adenoma/adenocarcinoma. Shortened latencies with significantly increased incidence rates were observed for adrenal subcapsular cell adenomas and ovarian neoplasms (tubulostromal adenoma, granulosa cell tumors) in irradiated mice. Life span shortening in mice exposed to 20 mGy/day was mostly due to malignant lymphomas. Multiple primary neoplasms were significantly increased in mice exposed to 20 mGy/day from sacrifice days 400-700 and in the life span group. Our results confirm that continuous low-dose-rate gamma-ray irradiation of female B6C3F1 mice causes both cancer induction (shortened latency) and

Toxicology study of senna (CAS No. 8013-11-4) in C57BL/6NTAC Mice and toxicology and carcinogenesis study of senna in genetically modified C3B6.129F1/Tac-Trp53tm1Brd haploinsufficient mice (Feed Studies).

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2012-04-01

Senna is used as a stimulant laxative in the management of constipation resulting from opioid use or when treatment with bulking or osmotic agents has failed. Increased use of senna was expected due to the removal of the stimulant laxatives danthron and phenolphthalein from the market. Senna was nominated for study by the Center for Drug Evaluation and Research, United States Food and Drug Administration (FDA) due to the wide use of laxative preparations, positive genotoxicity in vitro for some senna components or metabolites, and unknown carcinogenic potential. Because a 2-year rat study was ongoing by the manufacturer, the FDA requested that the NTP conduct a senna study in the p53(+/-) mouse. In this study, the potential for carcinogenic effects of senna was studied in the C3B6.129F1/Tac-Trp53tm1Brd N12 haploinsufficient (heterozygous F1 p53(+/-)) mouse model as an ongoing goal of the NTP to develop and test model systems for toxicology and carcinogenesis studies, especially those that can provide mechanistic information relative to understanding an agents mode of action. C57BL/6NTac mice were exposed to senna in feed for 5 weeks; heterozygous F1 p53(+/-) mice were exposed to senna in feed for 40 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes.

In vitro metabolism studies of 18F-labeled 1-phenylpiperazine using mouse liver S9 fraction

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Ryu, Eun Kyoung; Choe, Yearn Seong; Kim, Dong Hyun; Ko, Bong-Ho; Choi, Yong; Lee, Kyung-Han; Kim, Byung-Tae

2006-01-01

The in vitro metabolism of 1-(4-[ 18 F]fluoromethylbenzyl)-4-phenylpiperazine ([ 18 F]1) and 1-(4-[ 18 F]fluorobenzyl)-4-phenylpiperazine ([ 18 F]2) was investigated using mouse liver S9 fraction. Results were compared to those of in vivo metabolism using mouse blood and bone and to in vitro metabolism using mouse liver microsomes. Defluorination was the main metabolic pathway for [ 18 F]1 in vitro and in vivo. Based on TLC, HPLC and LC-MS data, [ 18 F]fluoride ion and less polar radioactive metabolites derived from aromatic ring oxidation were detected in vitro, and the latter metabolites were rapidly converted into the former with time, whereas only the [ 18 F]fluoride ion was detected in vivo. Similarly, the in vitro metabolism of [ 18 F]2 using either S9 fraction or microsomes showed the same pattern as the in vivo method using blood; however, the radioactive metabolites derived from aromatic ring oxidation were not detected in vivo. These results demonstrate that liver S9 fraction can be widely used to investigate the intermediate radioactive metabolites and to predict the in vivo metabolism of radiotracers

Exacerbating effects of human parvovirus B19 NS1 on liver fibrosis in NZB/W F1 mice.

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Tsai-Ching Hsu

Full Text Available Systemic lupus erythematosus (SLE is an autoimmune disorder with unknown etiology that impacts various organs including liver. Recently, human parvovirus B19 (B19 is recognized to exacerbate SLE. However, the effects of B19 on liver in SLE are still unclear. Herein we aimed to investigate the effects of B19 on liver in NZB/W F1 mice by injecting subcutaneously with PBS, recombinant B19 NS1, VP1u or VP2, respectively. Our experimental results revealed that B19 NS1 protein significantly enhanced the TGF-β/Smad fibrotic signaling by increasing the expressions of TGF-β, Smad2/3, phosphorylated Smad2/3, Smad4 and Sp1. The consequent fibrosis-related proteins, PAI-1 and α-SMA, were also significantly induced in livers of NZB/W F1 mice receiving B19 NS1 protein. Accordingly, markedly increased collagen deposition was also observed in livers of NZB/W F1 mice receiving B19 NS1 protein. However, no significant difference was observed in livers of NZB/W F1 mice receiving B19 VP1u or VP2 as compared to the controls. These findings indicate that B19 NS1 plays a crucial role in exacerbating liver fibrosis in NZB/W F1 mice through enhancing the TGF-â/Smad fibrotic signaling.

Exacerbating Effects of Human Parvovirus B19 NS1 on Liver Fibrosis in NZB/W F1 Mice

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Hsu, Tsai-Ching; Tsai, Chun-Chou; Chiu, Chun-Ching; Hsu, Jeng-Dong; Tzang, Bor-Show

2013-01-01

Systemic lupus erythematosus (SLE) is an autoimmune disorder with unknown etiology that impacts various organs including liver. Recently, human parvovirus B19 (B19) is recognized to exacerbate SLE. However, the effects of B19 on liver in SLE are still unclear. Herein we aimed to investigate the effects of B19 on liver in NZB/W F1 mice by injecting subcutaneously with PBS, recombinant B19 NS1, VP1u or VP2, respectively. Our experimental results revealed that B19 NS1 protein significantly enhanced the TGF-β/Smad fibrotic signaling by increasing the expressions of TGF-β, Smad2/3, phosphorylated Smad2/3, Smad4 and Sp1. The consequent fibrosis-related proteins, PAI-1 and α-SMA, were also significantly induced in livers of NZB/W F1 mice receiving B19 NS1 protein. Accordingly, markedly increased collagen deposition was also observed in livers of NZB/W F1 mice receiving B19 NS1 protein. However, no significant difference was observed in livers of NZB/W F1 mice receiving B19 VP1u or VP2 as compared to the controls. These findings indicate that B19 NS1 plays a crucial role in exacerbating liver fibrosis in NZB/W F1 mice through enhancing the TGF-â/Smad fibrotic signaling. PMID:23840852

[Inhibition of glycogen synthase kinase 3b activity regulates Toll-like receptor 4-mediated liver inflammation].

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Ren, Feng; Zhang, Hai-yan; Piao, Zheng-fu; Zheng, Su-jun; Chen, Yu; Chen, De-xi; Duan, Zhong-ping

2012-09-01

To determine the mechanism underlying the therapeutic activities of glycogen synthase kinase 3b (GSK3b) against hepatic ischemia-reperfusion (H-IR) injury by investigating the inhibitive effects of GSK3b on inflammation mediated by Toll-like receptor 4 (TLR4). C57BL/6 male mice were subjected to 90 min of warm liver cephalad lobe ischemia, followed by reperfusion for various lengths of time. The mice were divided into three groups: the H-IR untreated model (control group), and the H-IR inflammation-induced models that received an intraperitoneal injection of purified lipopolysaccharide (LPS) endotoxin alone (inflammation group) or with pretreatment of the SB216763 GSK3b-specific inhibitor (intervention group). To create a parallel isolated cell system for detailed investigations of macrophages, marrow-derived stem cells were isolated from femurs of the H-IR control group of mice and used to derive primary macrophages. The cells were then divided into the same three groups as the whole mouse system: control, LPS-induced inflammation model, and inflammation model with SB216763 intervention. Differential expressions of inflammation-related proteins and genes were detected by Western blotting and real-time quantitative PCR, respectively. The phosphorylation levels of ERK, JNK and p38 MAPK were induced in liver at 1 h after reperfusion, but then steadily decreased and returned to baseline levels by 4 h after reperfusion. In addition, the phosphorylation levels of ERK and JNK were induced in macrophages at 15 min after LPS stimulation, while the phosphorylation level of p38 MAPK was induced at 1 h; SB216763 pretreatment suppressed the LPS-stimulated ERK, JNK and p38 phosphorylation in macrophages. In the mouse model, GSK3b activity was found to promote the gene expression of anti-inflammatory cytokine IL-10 (control: 0.21 ± 0.08, inflammation: 0.83 ± 0.21, intervention: 1.76 ± 0.67; F = 3.16, P = 0.027) but to significantly inhibit the gene expression of pro

Toxicology and carcinogenesis studies of acrylamide (CASRN 79-06-1) in F344/N rats and B6C3F1 mice (feed and drinking water studies).

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2012-07-01

Acrylamide, a water-soluble α,β-unsaturated amide, is a contaminant in baked and fried starchy foods, including french fries, potato chips, and bread, as a result of Maillard reactions involving asparagine and reducing sugars. Additional sources of acrylamide exposure include cigarettes, laboratory procedures involving polyacrylamide gels, and various occupations (e.g, monomer production and polymerization processes). Acrylamide is carcinogenic in experimental animals. To obtain data for developing quantitative risk assessments for dietary exposures to acrylamide, the Food and Drug Administration nominated acrylamide for an in-depth toxicological evaluation by the National Toxicology Program. As part of this evaluation, male and female B6C3F1/Nctr (C57BL/6N x C3H/HeN MTV-) mice and male and female F344/N Nctr rats were exposed to acrylamide (at least 99.4% pure) in drinking water for 2 years. 2-WEEK STUDY IN RATS: Groups of four male and four female F344/N rats were administered 0, 0.14, 0.35, 0.70, 1.41, 3.52, or 7.03 mM acrylamide in the drinking water (0, 10, 25, 50, 100, 250, or 500 ppm acrylamide) or 0.0, 7.4, 18.5, 37, 74, 185, or 370 mg acrylamide per kg diet for 14 days. One male rat administered 7.03 mM acrylamide in the drinking water died on day 14. Male and female rats receiving 7.03 mM acrylamide weighed 56% and 64% of controls, respectively. Male and female rats fed 370 mg acrylamide per kg diet weighed 74% and 83% of controls, respectively. Female rats receiving 3.52 mM acrylamide in drinking water and male rats fed 185 mg acrylamide per kg diet weighed 85% and 89% of controls, respectively. Rats receiving 7.03 mM acrylamide in drinking water or 370 mg acrylamide per kg diet exhibited hind-leg paralysis on day 14. Mild to moderate dilatation of the urinary bladder was observed in all rats given 370 mg acrylamide per kg diet, and in three of four male rats and all four female rats given 7.03 mM acrylamide in drinking water, and in one of four male

T cell progenitors in the mouse fetal liver

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Rabinowich, H.; Umiel, T.; Globerson, A.

1983-01-01

Fourteen-day mouse fetal liver was found to contain cells capable of giving rise to T as well as B cell functions. The experimental system consisted of congenic C3H/DiSn and (C3H/DiSn X C3H.SW)F1 lethally irradiated (900 R) mice reconstituted with C3H/DiSn fetal liver or bone marrow cells. Assays included thyroid allograft rejection as well as in vitro measurement of reactivity to phytohemagglutinin (PHA) and concanavalin A (Con A) and in a mixed lymphocyte culture (MLC) system in spleen, lymph node, and thymus cells. The fetal liver chimeras were found to become as capable as the bone marrow chimeras in responding in these various assays. The T cell responses lagged behind the responses to the B cell mitogens dextran sulfate (DXS) and lipopolysaccharide (LPS) (30 days after reconstitution, as compared with 14 days for DXS and 21 for LPS). The reacting cells were of the donor genotype, as revealed after treatment with C3H/DiSn (H-2k) anti-C3H.SW (H-2b) congenic sera. T cell responses were not manifest in thymectomized (TX) chimeras. Hence, the liver seems to contain cells capable of developing into T cell lineages in a thymus-dependent process

NTP Toxicology and Carcinogenesis of 1,2,3-Trichloropropane (CAS No. 96-18-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

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1993-08-01

1,2,3-Trichloropropane is a colorless liquid used as a paint and varnish remover, solvent, and degreasing agent, and as a crosslinking agent in the synthesis of polysulfides and hexafluoropropylene. 1,2,3-Trichloropropane may be found as an impurity in certain nematocides and soil fumigants and as a contaminant of drinking and ground water. Studies on the toxic and carcinogenic effects of 1,2,3-trichloropropane were initiated because of the close structural relationship of this chemical to other short-chain halogenated compounds that were demonstrated to be carcinogenic in experimental animals, and because of the potential for human exposure. Toxicology and carcinogenicity studies were conducted by administering 1,2,3-trichloropropane (greater than 99% pure) in corn oil by gavage to groups of F344/N rats and B6C3FI mice for 17 weeks and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium strains, mouse lymphoma cells, and Chinese hamster ovary cells. 17-Week Studies: Groups of 20 male and 20 female rats received 1,2,3-trichloropropane in corn oil by gavage at doses of 8, 16, 32, 63, 125, or 250 mg/kg body weight 5 days per week for up to 17 weeks; 30 male and 30 female rats received corn oil alone and served as controls. Animals were evaluated at 8 or 17 weeks. All rats in the 250 mg/kg groups died by week 5. One male and four female rats in the 125 mg/kg groups died during the study. The mean body weight gains and final mean body weights of males receiving 63 mg/kg and of males and females receiving 125 mg/kg were lower than those of the controls. Hematocrit values, hemoglobin concentrations, and erythrocyte counts decreased with dose in males and females. Serum alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase activities were significantly increased in some female rats receiving 125 mg/kg. Serum pseudocholinesterase activity decreased with dose in females. Increases in kidney and liver weights were related

The OsO(3)F(+) and mu-F(OsO(3)F)(2)(+) cations: their syntheses and study by Raman and (19)F NMR spectroscopy and electron structure calculations and X-ray crystal structures of [OsO(3)F][PnF(6)] (Pn = As, Sb), [OsO(3)F][HF](2)[AsF(6)], [OsO(3)F][HF][SbF(6)], and [OsO(3)F][Sb(3)F(16)].

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Gerken, Michael; Dixon, David A; Schrobilgen, Gary J

2002-01-28

The fluoride ion donor properties of OsO(3)F(2) have been investigated. The salts [OsO(3)F][AsF(6)], [OsO(3)F][HF](2)[AsF(6)], mu-F(OsO(3)F)(2)[AsF(6)], [OsO(3)F][HF](2)[SbF(6)], and [OsO(3)F][HF][SbF(6)] have been prepared by reaction of OsO(3)F(2) with AsF(5) and SbF(5) in HF solvent and have been characterized in the solid state by Raman spectroscopy. The single-crystal X-ray diffraction studies of [OsO(3)F][AsF(6)] (P2(1)/n, a = 7.0001(11) A, c = 8.8629(13) A, beta = 92.270(7) degrees, Z = 4, and R(1) = 0.0401 at -126 degrees C), [OsO(3)F][SbF(6)] (P2(1)/c, a = 5.4772(14) A, b = 10.115(3) A, c = 12.234(3) A, beta = 99.321(5) degrees, Z = 4, and R(1) = 0.0325 at -173 degrees C), [OsO(3)F][HF](2)[AsF(6)] (P2(1)/n, a = 5.1491(9) A, b = 8.129(2) A, c = 19.636(7) A, beta = 95.099(7) degrees, Z = 4, and R(1) = 0.0348 at -117 degrees C), and [OsO(3)F][HF][SbF(6)] (Pc, a = 5.244(4) A, b = 9.646(6) A, c = 15.269(10) A, beta = 97.154(13) degrees, Z = 4, and R(1) = 0.0558 at -133 degrees C) have shown that the OsO(3)F(+) cations exhibit strong contacts to the anions and HF solvent molecules giving rise to cyclic, dimeric structures in which the osmium atoms have coordination numbers of 6. The reaction of OsO(3)F(2) with neat SbF(5) yielded [OsO(3)F][Sb(3)F(16)], which has been characterized by (19)F NMR spectroscopy in SbF(5) and SO(2)ClF solvents and by Raman spectroscopy and single-crystal X-ray diffraction in the solid state (P4(1)m, a = 10.076(6) A, c = 7.585(8) A, Z = 2, and R(1) = 0.0858 at -113 degrees C). The weak fluoride ion basicity of the Sb(3)F(16)(-) anion resulted in an OsO(3)F(+) cation (C(3)(v) point symmetry) that is well isolated from the anion and in which the osmium is four-coordinate. The geometrical parameters and vibrational frequencies of OsO(3)F(+), ReO(3)F, mu-F(OsO(3)F)(2)(+), (FO(3)Os--FPnF(5))(2), and (FO(3)Os--(HF)(2)--FPnF(5))(2) (Pn = As, Sb) have been calculated using density functional theory methods.

Toxicology and carcinogenesis studies of p,p'-dichlorophenyl sulfone (CAS No. 80-07-9) in F344/N rats and B6C3F1 mice (feed studies).

Science.gov (United States)

2001-09-01

p,pN-Dichlorodiphenyl sulfone is used as a starting material in the production of polysulfones and polyethersulfones and as a component in reactive dyes in the textile industry; it is also a by-product of pesticide production. p,pN-Dichlorodiphenyl sulfone was nominated for study by the National Cancer Institute because of its history of high production and use, the prospect of increased production and use, and the absence of adequate toxicity testing. Male and female F344/N rats and B6C3F1 mice were exposed top,pN-dichlorodiphenyl sulfone (greater than 99% pure)in feed for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium,cultured Chinese hamster ovary cells, and mouse bone marrow. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 30, 100, 300, 1,000, or 3,000 ppm p,pN-dichlorodiphenyl sulfone (equivalent to average daily doses of approximately 2, 6, 19, 65, or 200 mgp,pN-dichlorodiphenyl sulfone/kg body weight) for 14 weeks. All rats survived until the end of the study. Mean body weights of groups exposed to 300 ppm or greater were significantly less than those of the controls. Liver weights of groups exposed to 100 ppm or greater and kidney weights of 1,000 and 3,000 ppm male rats were significantly greater than those of the controls. Centrilobular hepatocyte hypertrophy of the liver was observed in most male rats exposed to 100 ppm or greater and in all female rats exposed to 300 ppm or greater, and the severities were increased in 300 ppm males and 1,000 and 3,000 ppm males and females. The incidences of nephropathy in 1,000 and 3,000 ppm female rats were significantly increased. Dose-related increases in severity of nephropathy were observed in male rats. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were fed diets containing 0, 30, 100, 300, 1,000, or 3,000 ppm p,pN-dichlorodiphenyl sulfone (equivalent to average daily doses of approximately 3.5, 15, 50

Genistein modulation of streptozotocin diabetes in male B6C3F1 mice can be induced by diet

International Nuclear Information System (INIS)

Guo, Tai L.; Wang, Yunbiao; Xiong, Tao; Ling, Xiao; Zheng, Jianfeng

2014-01-01

Diet and phytoestrogens affect the development and progression of diabetes. The objective of the present study was to determine if oral exposure to phytoestrogen genistein (GE) by gavage changed blood glucose levels (BGL) through immunomodulation in streptozotocin (STZ)-induced diabetic male B6C3F1 mice fed with three different diets. These three diets were: NTP-2000 diet (NTP), soy- and alfalfa-free 5K96 diet (SOF) and high fat diet (HFD) with 60% of kcal from fat, primarily rendered fat of swine. The dosing regimen for STZ consisted of three 100 mg/kg doses (i.p.): the first dose was administered at approximately 2 weeks following the initiation of daily GE (20 mg/kg) gavage, and the second dose was on day 19 following the first dose, and the third dose was on day 57 following the first dose. In mice on the NTP diet, GE treatment decreased BGL with statistical significances observed on days 33 and 82 following the first STZ injection. In mice fed the HFD diet, GE treatment produced a significant decrease and a significant increase in BGL on days 15 and 89 following the first STZ injection, respectively. In mice fed the SOF diet, GE treatment had no significant effects on BGL. Although GE treatment affected phenotypic distributions of both splenocytes (T cells, B cells, natural killer cells and neutrophils) and thymocytes (CD4/CD8 and CD44/CD25), and their mitochondrial transmembrane potential and generation of reactive oxygen species, indicators of cell death (possibly apoptosis), GE modulation of neutrophils was more consistent with its diabetogenic or anti-diabetic potentials. The differential effects of GE on BGL in male B6C3F1 mice fed with three different diets with varied phytoestrogen contents suggest that the estrogenic properties of this compound may contribute to its modulation of diabetes. - Highlights: • Diets affected streptozotocin-induced diabetes in male B6C3F1 mice. • Genistein modulation of streptozotocin diabetes can be induced by diet. �

Genistein modulation of streptozotocin diabetes in male B6C3F1 mice can be induced by diet

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Guo, Tai L., E-mail: tlguo1@uga.edu [Department of Biosciences and Diagnostic Imaging, College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7382 (United States); Wang, Yunbiao [Department of Biosciences and Diagnostic Imaging, College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7382 (United States); Key Laboratory of Wetland Ecology and Environment, Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences, Changchun 130102 (China); Xiong, Tao [College of Animal Science, Yangtze University, Jingzhou City, Hubei Province 434025 (China); Ling, Xiao [Institute for Food and Drug Control of Shandong Province, Jinan City, Shandong 250012 (China); Zheng, Jianfeng [Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613 (United States)

2014-11-01

Diet and phytoestrogens affect the development and progression of diabetes. The objective of the present study was to determine if oral exposure to phytoestrogen genistein (GE) by gavage changed blood glucose levels (BGL) through immunomodulation in streptozotocin (STZ)-induced diabetic male B6C3F1 mice fed with three different diets. These three diets were: NTP-2000 diet (NTP), soy- and alfalfa-free 5K96 diet (SOF) and high fat diet (HFD) with 60% of kcal from fat, primarily rendered fat of swine. The dosing regimen for STZ consisted of three 100 mg/kg doses (i.p.): the first dose was administered at approximately 2 weeks following the initiation of daily GE (20 mg/kg) gavage, and the second dose was on day 19 following the first dose, and the third dose was on day 57 following the first dose. In mice on the NTP diet, GE treatment decreased BGL with statistical significances observed on days 33 and 82 following the first STZ injection. In mice fed the HFD diet, GE treatment produced a significant decrease and a significant increase in BGL on days 15 and 89 following the first STZ injection, respectively. In mice fed the SOF diet, GE treatment had no significant effects on BGL. Although GE treatment affected phenotypic distributions of both splenocytes (T cells, B cells, natural killer cells and neutrophils) and thymocytes (CD4/CD8 and CD44/CD25), and their mitochondrial transmembrane potential and generation of reactive oxygen species, indicators of cell death (possibly apoptosis), GE modulation of neutrophils was more consistent with its diabetogenic or anti-diabetic potentials. The differential effects of GE on BGL in male B6C3F1 mice fed with three different diets with varied phytoestrogen contents suggest that the estrogenic properties of this compound may contribute to its modulation of diabetes. - Highlights: • Diets affected streptozotocin-induced diabetes in male B6C3F1 mice. • Genistein modulation of streptozotocin diabetes can be induced by diet. �

Characterization of genetically engineered mouse hepatoma cells with inducible liver functions by overexpression of liver-enriched transcription factors.

Science.gov (United States)

Yamamoto, Hideaki; Tonello, Jane Marie; Sambuichi, Takanori; Kawabe, Yoshinori; Ito, Akira; Kamihira, Masamichi

2018-01-01

New cell sources for the research and therapy of organ failure could significantly alleviate the shortage of donor livers that are available to patients who suffer from liver disease. Liver carcinoma derived cells, or hepatoma cells, are the ideal cells for developing bioartificial liver systems. Such cancerous liver cells are easy to prepare in large quantities and can be maintained over long periods under standard culture conditions, unlike primary hepatocytes. However, hepatoma cells possess only a fraction of the functions of primary hepatocytes. In a previous study, by transducing cells with liver-enriched transcription factors that could be inducibly overexpressed-hepatocyte nuclear factor (HNF)1α, HNF1β, HNF3β [FOXA2], HNF4α, HNF6, CCAAT/enhancer binding protein (C/EBP)α, C/EBPβ and C/EBPγ-we created mouse hepatoma cells with high liver-specific gene expression called the Hepa/8F5 cell line. In the present study, we performed functional and genetic analyses to characterize the Hepa/8F5 cell line. Further, in three-dimensional cultures, the function of these cells improved significantly compared to parental cells. Ultimately, these cells might become a new resource that can be used in basic and applied hepatic research. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Exenatide Delays the Progression of Nonalcoholic Fatty Liver Disease in C57BL/6 Mice, Which May Involve Inhibition of the NLRP3 Inflammasome through the Mitophagy Pathway

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Ning Shao

2018-01-01

Full Text Available Objective. This study is aimed at investigating whether exenatide (Exe delays the progression of nonalcoholic fatty liver disease (NAFLD in C57BL/6 mice by targeting the NLRP3 inflammasome through the autophagy/mitophagy pathway. Methods. Thirty male C57BL/6 mice were randomly divided into three groups: control group (n=10, model group (n=10, and Exe (exenatide group (n=10. Mouse models of NAFLD and diabetes were established using a high-fat diet and streptozocin. Results. The levels of fasting blood glucose (FBG, total cholesterol (TC, and triglyceride (TG in the serum were significantly reduced after Exe treatment. The body weight, liver weight/body weight, and number of lipid droplets in the liver significantly decreased in Exe-treated mice. Treatment with Exe markedly reduced the levels of liver lipids, malondialdehyde (MDA, and alanine aminotransferase (ALT in serum and livers. The number of autophagosomes increased significantly in the Exe group. The expression of LC3A/B-II/I, Beclin-1, Parkin, and BNIP3L increased significantly, whereas NLRP3 and IL-1β proteins were suppressed after Exe treatment. Conclusion. We successfully established a mouse model of NAFLD and diabetes. Exe may reduce oxidative stress injury and inhibit the NLRP3 inflammasome by enhancing the autophagy/mitophagy pathway in liver, which has a protective effect on the liver in NAFLD and diabetes in C57BL/6 mice.

Pharmacokinetic analysis of trichloroethylene metabolism in male B6C3F1 mice: Formation and disposition of trichloroacetic acid, dichloroacetic acid, S-(1,2-dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-L-cysteine

Science.gov (United States)

Kim, Sungkyoon; Kim, David; Pollack, Gary M.; Collins, Leonard B.; Rusyn, Ivan

2009-01-01

Trichloroethylene (TCE) is a well-known carcinogen in rodents and concerns exist regarding its potential carcinogenicity in humans. Oxidative metabolites of TCE, such as dichloroacetic acid (DCA) and trichloroacetic acid (TCA), are thought to be hepatotoxic and carcinogenic in mice. The reactive products of glutathione conjugation, such as S-(1,2-dichlorovinyl)-L-cysteine (DCVC), and S-(1,2-dichlorovinyl) glutathione (DCVG), are associated with renal toxicity in rats. Recently, we developed a new analytical method for simultaneous assessment of these TCE metabolites in small-volume biological samples. Since important gaps remain in our understanding of the pharmacokinetics of TCE and its metabolites, we studied a time-course of DCA, TCA, DCVG and DCVG formation and elimination after a single oral dose of 2100 mg/kg TCE in male B6C3F1 mice. Based on systemic concentration-time data, we constructed multi-compartment models to explore the kinetic properties of the formation and disposition of TCE metabolites, as well as the source of DCA formation. We conclude that TCE-oxide is the most likely source of DCA. According to the best-fit model, bioavailability of oral TCE was ~74%, and the half-life and clearance of each metabolite in the mouse were as follows: DCA: 0.6 hr, 0.081 ml/hr; TCA: 12 hr, 3.80 ml/hr; DCVG: 1.4 hr, 16.8 ml/hr; DCVC: 1.2 hr, 176 ml/hr. In B6C3F1 mice, oxidative metabolites are formed in much greater quantities (~3600 fold difference) than glutathione-conjugative metabolites. In addition, DCA is produced to a very limited extent relative to TCA, while most of DCVG is converted into DCVC. These pharmacokinetic studies provide insight into the kinetic properties of four key biomarkers of TCE toxicity in the mouse, representing novel information that can be used in risk assessment. PMID:19409406

Pharmacokinetic analysis of trichloroethylene metabolism in male B6C3F1 mice: Formation and disposition of trichloroacetic acid, dichloroacetic acid, S-(1,2-dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-L-cysteine

International Nuclear Information System (INIS)

Kim, Sungkyoon; Kim, David; Pollack, Gary M.; Collins, Leonard B.; Rusyn, Ivan

2009-01-01

Trichloroethylene (TCE) is a well-known carcinogen in rodents and concerns exist regarding its potential carcinogenicity in humans. Oxidative metabolites of TCE, such as dichloroacetic acid (DCA) and trichloroacetic acid (TCA), are thought to be hepatotoxic and carcinogenic in mice. The reactive products of glutathione conjugation, such as S-(1,2-dichlorovinyl)-L-cysteine (DCVC), and S-(1,2-dichlorovinyl) glutathione (DCVG), are associated with renal toxicity in rats. Recently, we developed a new analytical method for simultaneous assessment of these TCE metabolites in small-volume biological samples. Since important gaps remain in our understanding of the pharmacokinetics of TCE and its metabolites, we studied a time-course of DCA, TCA, DCVG and DCVG formation and elimination after a single oral dose of 2100 mg/kg TCE in male B6C3F1 mice. Based on systemic concentration-time data, we constructed multi-compartment models to explore the kinetic properties of the formation and disposition of TCE metabolites, as well as the source of DCA formation. We conclude that TCE-oxide is the most likely source of DCA. According to the best-fit model, bioavailability of oral TCE was ∼ 74%, and the half-life and clearance of each metabolite in the mouse were as follows: DCA: 0.6 h, 0.081 ml/h; TCA: 12 h, 3.80 ml/h; DCVG: 1.4 h, 16.8 ml/h; DCVC: 1.2 h, 176 ml/h. In B6C3F1 mice, oxidative metabolites are formed in much greater quantities (∼ 3600 fold difference) than glutathione-conjugative metabolites. In addition, DCA is produced to a very limited extent relative to TCA, while most of DCVG is converted into DCVC. These pharmacokinetic studies provide insight into the kinetic properties of four key biomarkers of TCE toxicity in the mouse, representing novel information that can be used in risk assessment.

Rhythmic expression of miR-27b-3p targets the clock gene Bmal1 at the posttranscriptional level in the mouse liver.

Science.gov (United States)

Zhang, Wenxiang; Wang, Peng; Chen, Siyu; Zhang, Zhao; Liang, Tingming; Liu, Chang

2016-06-01

Circadian clocks orchestrate daily oscillations in mammalian behaviors, physiology, and gene expression. MicroRNAs (miRNAs) play a crucial role in fine-tuning of the circadian system. However, little is known about the direct regulation of the clock genes by specific miRNAs. In this study, we found that miR-27b-3p exhibits rhythmic expression in the metabolic tissues of the mice subjected to constant darkness. MiR-27b-3p's expression is induced in livers of unfed and ob/ob mice. In addition, the oscillation phases of miR-27b-3p can be reversed by restricted feeding, suggesting a role of peripheral clock in regulating its rhythmicity. Bioinformatics analysis indicated that aryl hydrocarbon receptor nuclear translocator-like (also known as Bmal1) may be a direct target of miR-27b-3p. Luciferase reporter assay showed that miR-27b-3p suppressed Bmal1 3' UTR activity in a dose-dependent manner, and mutagenesis of their binding site abolished this suppression. Furthermore, overexpression of miR-27b-3p dose-dependently reduced the protein expression levels of BMAL1 and impaired the endogenous BMAL1 and gluconeogenic protein rhythmicity. Collectively, our results suggest that miR-27b-3p plays an important role in the posttranscriptional regulation of BMAL1 protein in the liver. MiR-27b-3p may serve as a novel node to integrate the circadian clock and energy metabolism.-Zhang, W., Wang, P., Chen, S., Zhang, Z., Liang, T., Liu, C. Rhythmic expression of miR-27b-3p targets the clock gene Bmal1 at the posttranscriptional level in the mouse liver. © FASEB.

Upregulation of estrogen receptor expression in the uterus of ovariectomized B6C3F1 mice and Ishikawa cells treated with bromoethane

International Nuclear Information System (INIS)

Aoyama, Hiroaki; Couse, John F.; Hewitt, Sylvia C.; Haseman, Joseph K.; He, Hong; Zheng, Xiaolin; Majstoravich, Sonja; Korach, Kenneth S.; Dixon, D.

2005-01-01

In a 2-year NTP bioassay, Bromoethane (BE) was found to induce endometrial neoplasms in the uterus of B6C3F1 mice [; ]. In women, hormonal influences, such as 'unopposed' estrogenic stimulus, have been implicated as important etiologic factors in uterine cancer. BE, however, does not affect the serum concentrations of sex hormones in female B6C3F1 mice [] and the mechanism of BE-induced uterine carcinogenesis still remains unclear. In the present study, we examined the estrogenic effects of BE on the uterus of ovariectomized B6C3F1 mice and on Ishikawa cells. Groups of 6 mice were given daily s.c. injections of 0, 100, 500 or 1000 mg BE/kg for 3 consecutive days. Mice treated with 17β-estradiol served as positive controls. Mice were necropsied 24 h after the final injection, and uteri were weighed and examined histologically and immunohistochemically along with the vagina. Changes observed in the estrogen-treated mice included increased uterine weights, edema and inflammation of the endometrium, increased epithelial layers of the uterine and vaginal lumens and keratinization of the vaginal epithelium. In the BE-treated mice, no such changes occurred; however, immunohistochemical staining of the uterus revealed a significant increase in immunoexpression of the estrogen receptor alpha (ERα) in the two higher dose groups. Analysis of mRNA also showed slightly increased uterine ERα expression in these groups. Upregulated expression of ERα was confirmed in BE-treated Ishikawa cells, in which Western blotting analyses identified an intense signal at approximately 66 kDa, which is consistent with ERα. These data suggest that upregulated expression of ERα may be important in the induction of endometrial neoplasms in BE-treated mice

Human Parvovirus B19 NS1 Protein Aggravates Liver Injury in NZB/W F1 Mice

Science.gov (United States)

Tsai, Chun-Chou; Chiu, Chun-Ching; Hsu, Jeng-Dong; Hsu, Huai-Sheng; Tzang, Bor-Show; Hsu, Tsai-Ching

2013-01-01

Human parvovirus B19 (B19) has been associated with a variety of diseases. However, the influence of B19 viral proteins on hepatic injury in SLE is still obscure. To elucidate the effects of B19 viral proteins on livers in SLE, recombinant B19 NS1, VP1u or VP2 proteins were injected subcutaneously into NZB/W F1 mice, respectively. Significant expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were detected in NZB/W F1 mice receiving B19 NS1 as compared to those mice receiving PBS. Markedly hepatocyte disarray and lymphocyte infiltration were observed in livers from NZB/WF 1 mice receiving B19 NS1 as compared to those mice receiving PBS. Additionally, significant increases of Tumor Necrosis Factor –α (TNF-α), TNF-α receptor, IκB kinase –α (IKK-α), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (IκB) and nuclear factor-kappa B (NF-κB) were detected in livers from NZB/W F1 mice receiving B19 NS1 as compared to those mice receiving PBS. Accordingly, significant increases of matrix metalloproteinase-9 (MMP9) and U-plasminogen activator (uPA) were also detected in livers from NZB/W F1 mice receiving B19 NS1 as compared to those mice receiving PBS. Contrarily, no significant variation on livers from NZB/W F1 mice receiving B19 VP1u or VP2 was observed as compared to those mice receiving PBS. These findings firstly demonstrated the aggravated effects of B19 NS1 but not VP1u or VP2 protein on hepatic injury and provide a clue in understanding the role of B19 NS1 on hepatic injury in SLE. PMID:23555760

Sex-related differential susceptibility to doxorubicin-induced cardiotoxicity in B6C3F1 mice

International Nuclear Information System (INIS)

Jenkins, G. Ronald; Lee, Taewon; Moland, Carrie L.; Vijay, Vikrant; Herman, Eugene H.; Lewis, Sherry M.; Davis, Kelly J.; Muskhelishvili, Levan; Kerr, Susan; Fuscoe, James C.; Desai, Varsha G.

2016-01-01

Sex is a risk factor for development of cardiotoxicity, induced by the anti-cancer drug, doxorubicin (DOX), in humans. To explore potential mechanisms underlying differential susceptibility to DOX between sexes, 8-week old male and female B6C3F 1 mice were dosed with 3 mg/kg body weight DOX or an equivalent volume of saline via tail vein once a week for 6, 7, 8, and 9 consecutive weeks, resulting in 18, 21, 24, and 27 mg/kg cumulative DOX doses, respectively. At necropsy, one week after each consecutive final dose, the extent of myocardial injury was greater in male mice compared to females as indicated by higher plasma concentrations of cardiac troponin T at all cumulative DOX doses with statistically significant differences between sexes at the 21 and 24 mg/kg cumulative doses. A greater susceptibility to DOX in male mice was further confirmed by the presence of cytoplasmic vacuolization in cardiomyocytes, with left atrium being more vulnerable to DOX cardiotoxicity. The number of TUNEL-positive cardiomyocytes was mostly higher in DOX-treated male mice compared to female counterparts, showing a statistically significant sex-related difference only in left atrium at 21 mg/kg cumulative dose. DOX-treated male mice also had an increased number of γ-H2A.X-positive (measure of DNA double-strand breaks) cardiomyocytes compared to female counterparts with a significant sex effect in the ventricle at 27 mg/kg cumulative dose and right atrium at 21 and 27 mg/kg cumulative doses. This newly established mouse model provides a means to identify biomarkers and access potential mechanisms underlying sex-related differences in DOX-induced cardiotoxicity. - Highlights: • Doxorubicin caused greater heart injury in male mice than females. • Doxorubicin caused vacuolization in cardiomyocytes only in male mice. • TUNEL-positive cardiomyocytes was higher in DOX-treated male mice. • γ-H2A.X-positive cardiomyocytes was greater in DOX-treated male mice.

Short-term carcinogenicity testing of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f] quinoline (IQ) in E mu-pim-1 transgenic mice

DEFF Research Database (Denmark)

Sørensen, Ilona Kryspin; Mortensen, Alicja; Kristiansen, E.

1996-01-01

The usefulness of transgenic E mu-pim-1 mice over-expressing the pim-1 oncogene in lymphoid tissues, as sensitive test organisms was studied in a short-term carcinogenicity study. The mice were fed standard diet Altromin 1314 supplemented either with 0.03% 2-amino-1-methyl-6-phenylimidazo[4,5-b......]pyridine (PhIP) for 7 months or with 0.03% 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) for 6 months, PhIP and IQ are heterocyclic amines formed during cooking of meat and fish and are mutagenic to bacteria and cultured mammalian cells, PhIP is a potent mouse lymphomagen, while IQ is a liver carcinogen...... to non-transgenic mice. Our results suggest that the transgenic E mu-pim-1 mouse may be a useful model for short-term carcinogenicity screening of potential genotoxic carcinogens having the lymphoid system as target tissue, The carcinogen IQ which does not have the lymphoid system as a target...

Establishment of c-myc-immortalized Kupffer cell line from a C57BL/6 mouse strain

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Hiroshi Kitani

2014-01-01

Full Text Available We recently demonstrated in several mammalian species, a novel procedure to obtain liver-macrophages (Kupffer cells in sufficient numbers and purity using a mixed primary culture of hepatocytes. In this study, we applied this method to the C57BL/6 mouse liver and established an immortalized Kupffer cell line from this mouse strain. The hepatocytes from the C57BL/6 adult mouse liver were isolated by a two-step collagenase perfusion method and cultured in T25 culture flasks. Similar to our previous studies, the mouse hepatocytes progressively changed their morphology into a fibroblastic appearance after a few days of culture. After 7–10 days of culture, Kupffer-like cells, which were contaminants in the hepatocyte fraction at the start of the culture, actively proliferated on the mixed fibroblastic cell sheet. At this stage, a retroviral vector containing the human c-myc oncogene and neomycin resistance gene was introduced into the mixed culture. Gentle shaking of the culture flask, followed by the transfer and brief incubation of the culture supernatant, resulted in a quick and selective adhesion of Kupffer cells to a plastic dish surface. After selection with G418 and cloning by limiting dilutions, a clonal cell line (KUP5 was established. KUP5 cells displayed typical macrophage morphology and were stably passaged at 4–5 days intervals for more than 5 months, with a population doubling time of 19 h. KUP5 cells are immunocytochemically positive for mouse macrophage markers, such as Mac-1, F4/80. KUP5 cells exhibited substantial phagocytosis of polystyrene microbeads and the release of inflammatory cytokines upon lipopolysaccharide stimulation. Taken together, KUP5 cells provide a useful means to study the function of Kupffer cells in vitro.

Measurement of the figure of merit M for 1-C3F6/SF6 mixtures

DEFF Research Database (Denmark)

Christensen, Jørn Erik Berril; McAllister, Iain Wilson

1997-01-01

High precision measurements of the linear part of the Paschen curve are reported for 1-C3F6/SF6 mixtures. From these measurements, values for the pressure-reduced limiting electric field strength (E/p)lim and the associated figure of merit M are derived. These two parameters can be used to charac......High precision measurements of the linear part of the Paschen curve are reported for 1-C3F6/SF6 mixtures. From these measurements, values for the pressure-reduced limiting electric field strength (E/p)lim and the associated figure of merit M are derived. These two parameters can be used...

gamma-Glutamyl transpeptidase overexpression increases metastatic growth of B16 melanoma cells in the mouse liver.

Science.gov (United States)

Obrador, Elena; Carretero, Julian; Ortega, Angel; Medina, Ignacio; Rodilla, Vicente; Pellicer, José A; Estrela, José M

2002-01-01

B16 melanoma (B16M) cells with high glutathione (GSH) content show rapid proliferation in vitro and high metastatic activity in the liver in vivo. gamma-Glutamyl transpeptidase (GGT)-mediated extracellular GSH cleavage and intracellular GSH synthesis were studied in vitro in B16M cells with high (F10) and low (F1) metastatic potential. GGT activity was modified by transfection with the human GGT gene (B16MF1/Tet-GGT cells) or by acivicin-induced inhibition. B16MF1/Tet-GGT and B16MF10 cells exhibited higher GSH content (35 +/- 6 and 40 +/- 5 nmol/10(6) cells, respectively) and GGT activity (89 +/- 9 and 37 +/- 7 mU/10(6) cells, respectively) as compared (P <.05) with B16MF1 cells (10 +/- 3 nmol GSH and 4 mU GGT/10(6) cells). Metastasis (number of foci/100 mm(3) of liver) increased in B16MF1 cells pretreated with GSH ester ( approximately 3-fold, P <.01), and decreased in B16MF1/Tet-GGT and B16MF10 cells pretreated with the GSH synthesis inhibitor L-buthionine (S,R)-sulphoximine ( approximately 5-fold and 2-fold, respectively, P <.01). Liver, kidney, brain, lung, and erythrocyte GSH content in B16MF1/Tet-GGT- or B16MF10-bearing mice decreased as compared with B16MF1- and non-tumor-bearing mice. Organic anion transporting polypeptide 1-independent sinusoidal GSH efflux from hepatocytes increased in B16MF1/Tet-GGT- or B16MF10-bearing mice ( approximately 2-fold, P <.01) as compared with non-tumor-bearing mice. Our results indicate that tumor GGT activity and an intertissue flow of GSH can regulate GSH content of melanoma cells and their metastatic growth in the liver.

Sex-related differential susceptibility to doxorubicin-induced cardiotoxicity in B6C3F{sub 1} mice

Energy Technology Data Exchange (ETDEWEB)

Jenkins, G. Ronald [Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Lee, Taewon [Department of Mathematics, Korea University, Sejong (Korea, Republic of); Moland, Carrie L.; Vijay, Vikrant [Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Herman, Eugene H. [Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, The National Cancer Institute, Rockville, MD 20850-9734 (United States); Lewis, Sherry M. [Office of Scientific Coordination, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Davis, Kelly J.; Muskhelishvili, Levan [Toxicologic Pathology Associates, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Kerr, Susan [Arkansas Heart Hospital, Little Rock, AR 72211 (United States); Fuscoe, James C. [Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Desai, Varsha G., E-mail: varsha.desai@fda.hhs.gov [Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States)

2016-11-01

Sex is a risk factor for development of cardiotoxicity, induced by the anti-cancer drug, doxorubicin (DOX), in humans. To explore potential mechanisms underlying differential susceptibility to DOX between sexes, 8-week old male and female B6C3F{sub 1} mice were dosed with 3 mg/kg body weight DOX or an equivalent volume of saline via tail vein once a week for 6, 7, 8, and 9 consecutive weeks, resulting in 18, 21, 24, and 27 mg/kg cumulative DOX doses, respectively. At necropsy, one week after each consecutive final dose, the extent of myocardial injury was greater in male mice compared to females as indicated by higher plasma concentrations of cardiac troponin T at all cumulative DOX doses with statistically significant differences between sexes at the 21 and 24 mg/kg cumulative doses. A greater susceptibility to DOX in male mice was further confirmed by the presence of cytoplasmic vacuolization in cardiomyocytes, with left atrium being more vulnerable to DOX cardiotoxicity. The number of TUNEL-positive cardiomyocytes was mostly higher in DOX-treated male mice compared to female counterparts, showing a statistically significant sex-related difference only in left atrium at 21 mg/kg cumulative dose. DOX-treated male mice also had an increased number of γ-H2A.X-positive (measure of DNA double-strand breaks) cardiomyocytes compared to female counterparts with a significant sex effect in the ventricle at 27 mg/kg cumulative dose and right atrium at 21 and 27 mg/kg cumulative doses. This newly established mouse model provides a means to identify biomarkers and access potential mechanisms underlying sex-related differences in DOX-induced cardiotoxicity. - Highlights: • Doxorubicin caused greater heart injury in male mice than females. • Doxorubicin caused vacuolization in cardiomyocytes only in male mice. • TUNEL-positive cardiomyocytes was higher in DOX-treated male mice. • γ-H2A.X-positive cardiomyocytes was greater in DOX-treated male mice.

Toxicology and carcinogenesis studies of nitrofurantoin (CAS No. 67-20-9) in F344/n rats and B6C3F1 mice (feed studies). Technical report

Energy Technology Data Exchange (ETDEWEB)

French, J.E.

1989-09-01

Two-year toxicology and carcinogenesis studies were conducted by administering diets containing 0, 600, or 1,300 ppm nitrofurantoin to groups of 50 female rats for 103 weeks. Groups of 50 male rats and 50 mice of each sex were fed diets containing 0, 1,300 or 2,500 ppm for 103 weeks. Under the conditions of these 2-year feed studies, there was some evidence of carcinogenic activity of nitrofurantoin for male F344/N rats as shown by increased incidences of uncommon kidney tubular cell neoplasms. Uncommon osteosarcomas of the bone and neoplasms of the subcutaneous tissue were observed in dosed male rats. Incidences of interstitial cell adenomas of the testis and neoplasms of the preputial gland were decreased in the 2,500-ppm group of male rats. There was no evidence of carcinogenic activity of nitrofurantoin for female F344/N rats fed diets containing 600 ppm or 1,300 ppm for 2 years. Female rats may have been able to tolerate higher doses. There was no evidence of carcinogenic activity of nitrofurantoin for male B6C3F(1) mice fed diets containing 1,300 ppm or 2,500 ppm for 2 years. There was clear evidence of carcinogenic activity of nitrofurantoin for female B6C3F(1) mice as shown by increased incidences of tubular adenomas, benign mixed tumors, and granulosa cell tumors of the ovary.

Immunotoxicological profile of chloramine in female B6C3F1 mice when administered in the drinking water for 28 days.

Science.gov (United States)

Guo, Tai L; Germolec, Dori R; Collins, Bradley J; Luebke, Robert W; Auttachoat, Wimolnut; Smith, Matthew J; White, Kimber L

2011-01-01

Monochloramine has been used to provide a disinfecting residual in water distribution systems where it is difficult to maintain an adequate free-chlorine residual or where disinfection by-product formation is of concern. The goal of this study was to characterize the immunotoxic effects of chloramine in female B(6)C(3)F(1) mice when administered via the drinking water. Mice were exposed to chloramine-containing deionized tap water at 2, 10, 20, 100, or 200 ppm for 28 days. No statistically significant differences in drinking water consumption, body weight, body weight gain, organ weights, or hematological parameters between the exposed and control animals were noted during the experimental period. There were no changes in the percentages and numbers of total B-lymphocytes, T-lymphocytes, CD4(+) and CD8(+) T-lymphocytes, natural killer (NK) cells, and macrophages in the spleen. Exposure to chloramine did not affect the IgM antibody-forming cell response to sheep red blood cells (SRBC) or anti-SRBC IgM antibody production. Minimal effects, judged to be biologically insignificant, were observed in the mixed-leukocyte response and NK activity. In conclusion, chloramine produced no toxicological and immunotoxic effects in female B(6)C(3)F(1) mice when administered for 28 days in the drinking water at concentrations ranging from 2-200 ppm.

F1 hybrids of BALB/c and C57BL/6 mouse strains respond differently ...

Indian Academy of Sciences (India)

cross was decided between C57BL/6 female and BALB/c ... on the mouse 7.4k cDNA microarray slide (University Health ... The ratio of two-fold increase (2.0) or decrease (−2.0) in ... were carried out to validate data from the cDNA micror- ray.

The Metabolism of Separase Inhibitor Sepin-1 in Human, Mouse, and Rat Liver Microsomes

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Feng Li

2018-05-01

Full Text Available Separase, a known oncogene, is widely overexpressed in numerous human tumors of breast, bone, brain, blood, and prostate. Separase is an emerging target for cancer therapy, and separase enzymatic inhibitors such as sepin-1 are currently being developed to treat separase-overexpressed tumors. Drug metabolism plays a critical role in the efficacy and safety of drug development, as well as possible drug–drug interactions. In this study, we investigated the in vitro metabolism of sepin-1 in human, mouse, and rat liver microsomes (RLM using metabolomic approaches. In human liver microsomes (HLM, we identified seven metabolites including one cysteine–sepin-1 adduct and one glutathione–sepin-1 adduct. All the sepin-1 metabolites in HLM were also found in both mouse and RLM. Using recombinant CYP450 isoenzymes, we demonstrated that multiple enzymes contributed to the metabolism of sepin-1, including CYP2D6 and CYP3A4 as the major metabolizing enzymes. Inhibitory effects of sepin-1 on seven major CYP450s were also evaluated using the corresponding substrates recommended by the US Food and Drug Administration. Our studies indicated that sepin-1 moderately inhibits CYP1A2, CYP2C19, and CYP3A4 with IC50 < 10 μM but weakly inhibits CYP2B6, CYP2C8/9, and CYP2D6 with IC50 > 10 μM. This information can be used to optimize the structures of sepin-1 for more suitable pharmacological properties and to predict the possible sepin-1 interactions with other chemotherapeutic drugs.

Influence of dietary selenium on the disposition of arsenate in the female B6C3F{sub 1} mouse

Energy Technology Data Exchange (ETDEWEB)

Kenyon, E.M.; Hughes, M.F. [Environmental Protection Agency, Research Triangle Park, NC (United States); Levander, O.A. [Nutrient Requirements and Functions Lab., Beltsville, MD (United States)

1997-06-27

Interactions between arsenic (As) and selenium (Se) at the metabolic level are multifaceted and complex. These interactions are of practical significance because populations in various parts of the world are simultaneously exposed to inorganic As in drinking water and Se mainly in the diet at varying levels. The primary goal of this study was to investigate whether differing dietary Se status would alter the profile of urinary metabolites or their time course for elimination after exposure to arsenate [As(V)]. Weanling female 86C3F, mice were maintained for 28 d on either a control diet of powdered rodent meal sufficient in Se (A 0.2 ppm) or Torula yeast-based (TYB) diets deficient (B, 0.02 ppm Se), sufficient (C, 0.2 ppm Se), or excessive (D, 2.0 ppm Se) in Se; mice then received by oral gavage 5 mg (As)/kg as sodium [{sup 73}As] arsenate. The time course for elimination of total arsenic and metabolites in urine was measured over a 48-h period, and total arsenic was determined in feces and tissues at 48 h. Mice on the Se excess diet excreted a significantly higher percentage of urinary As as inorganic As, with a significantly decreased ratio of organic to inorganic As compared to Se-sufficient mice, suggesting that As methylation was decreased. Mice on the Se-deficient diet appeared to eliminate As(V), arsenite, and dimethylarsinic acid (DMA) in urine more slowly than Se-sufficient mice; however, further studies are required to confirm this finding. Mice on the Se-sufficient meal diet (A) excreted significantly less (by percent) arsenate-derived radioactivity in urine and more in feces compared to mice on the Se-sufficient TYB diet (C), with total elimination being similar for both groups. This indicates that mice on the meal diet absorbed significantly less As(V) than mice on the TYB diet, and this may be due to more fiber or {open_quotes}bulk{close_quotes} in the meal diet. 35 refs., 6 figs., 6 tabs.

Phase stability, crystal structure and magnetism in (U1-xNbx)2 Ni21B6 and (UyNb1-y)3Ni20B6

Science.gov (United States)

Provino, Alessia; Bhattacharya, Amitava; Dhar, Sudesh K.; Pani, Marcella; Gatti, Flavio; Paudyal, Durga; Manfrinetti, Pietro

Ternary phases with composition T2M21X6 and T3M20X6 (T = transition metal; M = 3 d metal; X = B, C, P) are reported to crystallize with the W2Cr21C6-type and Mg3Ni20B6-type, respectively (ternary ordered derivatives of the cubic Cr23C6-type, cF116). They attract interest due to their refractory, mechanical, and peculiar magnetic properties. Literature data on these compounds only concern apparently stoichiometric 2:21:6 and 3:20:6 phases. Often only nominal composition has been reported, with few structural refinements and no measurements of physical properties. Lack of detailed stoichiometry and crystallographic data does not allow sufficient understanding of the crystal chemistry and properties of these compounds. We studied stability, crystal structure and magnetism of (U1-xNbx)2 Ni21B6 and (UyNb1-y)3Ni20B6; stable phases are U2Ni21B6 and Nb3Ni20B6, as also confirmed by theoretical calculations. The two pristine compounds solubilize Nb and U, respectively, up to a given extent. The substitution of U by Nb leads to a structural change from the W2Cr21C6- to the Mg3Ni20B6-type. While U2Ni21B6 is a Pauli paramagnet (itinerant non-magnetic state of U-5 f electrons), in agreement with literature, magnetization data for (UyNb1-y)3 Ni20B6 show itinerant ferromagnetism with TC >300 K.

Reactivity of Amine/E(C6F53 (E = B, Al Lewis Pairs toward Linear and Cyclic Acrylic Monomers: Hydrogenation vs. Polymerization

Directory of Open Access Journals (Sweden)

Jiawei Chen

2015-05-01

Full Text Available This work reveals the contrasting reactivity of amine/E(C6F53 (E = B, Al Lewis pairs toward linear and cyclic acrylic monomers, methyl methacrylate (MMA and biorenewable γ-methyl-α-methylene-γ-butyrolactone (γMMBL. While mixing of 2,2,6,6-tetramethylpiperidine (TMP and B(C6F53 leads to a frustrated Lewis pair (FLP, Et3N reacts with B(C6F53 to form disproportionation products, ammonium hydridoborate ionic pair and iminium zwitterion. On the other hand, the stoichiometric reaction of either TMP or Et3N with Al(C6F53 leads to clean formation of a classic Lewis adduct (CLA. Neither TMP nor Et3N, when paired with E(C6F53, polymerizes MMA, but the Et3N/2B(C6F53 pair promotes transfer hydrogenation of MMA to form methyl isobutyrate. In contrast, the amine/E(C6F53 pairs promote rapid polymerization of γMMBL carrying the more reactive exocyclic methylene moiety, achieving full conversion in less than 3 min even at a low catalyst loading of 0.0625 mol %. TMP is more effective than Et3N for the polymerization when paired with either the borane or the alane, while the alane exhibits higher polymerization activity than the borane when paired with Et3N. Overall, the TMP/Al(C6F53 system exhibits the highest polymerization activity, achieving a maximum turn-over frequency of 96,000 h−1 at 0.125 mol % of catalyst loading, producing high molecular weight PγMMBL with Mn = 1.29 × 105 g∙mol−1.

Study on parameters of L-[1-13C] phenylalanine breath test for quantitative assessment of liver function in healthy subjects and patients with hepatitis B virus-related liver disease

International Nuclear Information System (INIS)

Yan Weili; Fudan Univ., Shanghai; Lin Xiangtong; Jiang Yibin; Sun Su; Sun Dayu

2005-01-01

The aims of this study are to investigate the feasibility and validity of the L-[1- 13 C] phenylalanine breath test ( 13 C-PheBT) which has been used to measure hepatocyte functional capacity in hepatitis B virus-related liver disease patients and to propose validity parameters of the test in 12 healthy volunteer, 8 chronic hepatitis and 26 liver cirrhotic patients. 100mg/body nonradiative L-[1- 13 C] phenylalanine ( 13 C-Phe) was administered orally to all subjects. Breath samples were taken before and different intervals within 360 min after administration. The 13 CO 2 / 12 CO 2 enrichment was assessed by isotope ratio mass spectrometer( The parameter percentage 13 C excretion rate 13 CERt (% 13 C dose/h) all peaked within 10-30 min after oral 13 C-Phe application)The parameters such as maximum value of 13 C excretion rate, 13 CER max (% 13 C dose/h) (controls: 18.0±3.3; Child A: 11.0±3.8; Child B: 5.0±0.5; Child C: 3.6±1.2), 13 C excretion rate at 30 min, 13 CER 30 (% dose/h) (controls: 11.9±2.1; Child A: 8.1±0.4; Child B: 6.1±0.9; Child C: 3.2±1.2), 13 C cumulative excretion of first 60 min, 13 C cum60 (% 13 C dose) (controls: 9.3±1.4; Child A: 6.6±0.7; Child B: 4.1±0.3; Child C: 2.6±0.9) and half time of 13 C excretion rate, T 1 / 2 (minutes) (controls: 40.4±4.4; chronic hepatitis: 53.4±4.4; Child A: 59.8±4.5; Child B: 102.0±17.3; Child C: 212.1±87.9) were effective indexes which could be employed to stage hepatocyte impairment and liver functional reserve of advanced HBV-related cirrhotic patients (i.e. healthy subjects, Child A, B, C); T 1/2 was also useful for distinguishing mild HBV-related liver injure. (authors)

Studies on a transplantable C57BL/6 mouse lymphoma

International Nuclear Information System (INIS)

Kendall, C.E.

1977-01-01

A C57BL/6 mouse lymphoma was demonstrated to be of T cell origin by treating the lymphoma cells with anti-Thy 1.2 antisera in a complement-dependent cytotoxicity test. The lymphoma's growth pattern was described using flow microfluorometric determinations and spleen weight progression. C-type particles were identified in electron micrographs of the lymphoma. C57BL/6 mice were immunized against the lymphoma by injecting x-ray inactivated lymphoma cells into the mice. Protection of immunized mice against live lymphoma cells demonstrated tumor antigens on the lymphoma cells. The success of immunization was found to depend on: route of injection, antigen dosage, state of the antigen, number of injections and the vaccination-challenge interval. Attempts were made to passively transfer immunity from immunized C57BL/6 mice which had survived lymphoma challenge to non-treated, syngeneic mice. The route of immunization in the donors influenced the success of passively transferred immunity in the recipients. Serum from days 1 to 3 and days 11 to death (day 17) had an enhancing effect on lymphoma growth. However, sera from days 5 to 9 retarded lymphoma growth. The C57BL/6 lymphoma cells were injected into rabbits and other strains of mice to demonstrate tumor specificity. The lymphoma did not grow in rabbits and only grew in one mouse strain. This strain had the same major histocompatibility loci as C57BL/6 mice. Crosses were made between C57BL/6 mice and a resistant strain of mice (DBA/2 mice). The F 1 hybrids were found to be less susceptible to the lymphoma than the C57BL/6 strain. Sublethal x-irradiation of the F 1 mice decreased its ability to resist the C57BL/6 lymphoma. Immunization with x-ray inactivated C57BL/6 lymphoma cells increased survival after challenge with lymphoma in the F 1 mice

Curcumin ameliorates liver damage and progression of NASH in NASH-HCC mouse model possibly by modulating HMGB1-NF-κB translocation.

Science.gov (United States)

Afrin, Rejina; Arumugam, Somasundaram; Rahman, Azizur; Wahed, Mir Imam Ibne; Karuppagounder, Vengadeshprabhu; Harima, Meilei; Suzuki, Hiroshi; Miyashita, Shizuka; Suzuki, Kenji; Yoneyama, Hiroyuki; Ueno, Kazuyuki; Watanabe, Kenichi

2017-03-01

Curcumin, a phenolic compound, has a wide spectrum of therapeutic effects such as antitumor, anti-inflammatory, anti-cancer and so on. The study aimed to investigate the underlying mechanisms of curcumin to protect liver damage and progression of non-alcoholic steatohepatitis (NASH) in a novel NASH-hepatocellular carcinoma (HCC) mouse model. To induce this model neonatal C57BL/6J male mice were exposed to low-dose streptozotocin and were fed a high-fat diet (HFD) from the age of 4weeks to 14weeks. Curcumin was given at 100mg/kg dose daily by oral gavage started at the age of 10weeks and continued until 14weeks along with HFD feeding. We found that curcumin improved the histopathological changes of the NASH liver via reducing the level of steatosis, fibrosis associated with decreasing serum aminotransferases. In addition, curcumin treatment markedly reduced the hepatic protein expression of oxidative stress, pro-inflammatory cytokines, and chemokines including interferon (IFN) γ, interleukin-1β and IFNγ-inducible protein 10, in NASH mice. Furthermore, curcumin treatment significantly reduced the cytoplasmic translocation of high mobility group box 1 (HMGB1) and the protein expression of toll like receptor 4. Nuclear translocation of nuclear factor kappa B (NF-κB) was also dramatically attenuated by the curcumin in NASH liver. Curcumin treatment effectively reduced the progression of NASH to HCC by suppressing the protein expression of glypican-3, vascular endothelial growth factor, and prothrombin in the NASH liver. Our data suggest that curcumin reduces the progression of NASH and liver damage, which may act via inhibiting HMGB1-NF-κB translocation. Copyright © 2017 Elsevier B.V. All rights reserved.

NTP Toxicology and Carcinogenesis Studies of Molybdenum Trioxide (CAS No. 1313-27-5) in F344 Rats and B6C3F1 Mice (Inhalation Studies).

Science.gov (United States)

1997-04-01

body weights of male and female mice exposed to 300 mg/m(3) were significantly lower than those of the control groups. Male mice exposed to 300 mg/m(3) lost weight during the study. There were no clinical findings related to exposure to molybdenum trioxide. No chemical-related lesions were observed. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were exposed to molybdenum trioxide by inhalation at concentrations of 0, 1, 3, 10, 30, or 100 mg/m(3) for 6.5 hours per day, 5 days per week, for 13 weeks. All rats survived to the end of the study. The final mean body weights of exposed rats were similar to those of the control groups. No clinical findings related to molybdenum trioxide exposure were observed. There were no significant chemical-related differences in absolute or relative organ weights, hematology or clinical chemistry parameters, sperm counts or motility, or liver copper concentrations between control and exposed rats. No chemical-related lesions were observed. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to molybdenum trioxide by inhalation at concentrations of 0, 1, 3, 10, 30, or 100 mg/m(3) for 6.5 hours per day, 5 days per week, for 13 weeks. All mice survived to the end of the study. The final mean body weights of exposed mice were similar to those of the control groups. There were no chemical-related clinical findings. There were no significant differences in absolute or relative organ weights or sperm counts or motility between control and exposed mice. There were significant increases in liver copper concentrations in female mice exposed to 30 mg/m(3) and in male and female mice exposed to 100 mg/m(3) compared to those of the control groups. No chemical-related lesions were observed. 2-YEAR STUDIES IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to molybdenum trioxide by inhalation at concentrations of 0, 10, 30, or 100 mg/m(3). Rats were exposed for 6 hours per day, 5 days per

BROMOETHANE, CHLOROETHANE AND ETHYLENE OXIDE INDUCED UTERINE NEOPLASMS IN B6C3F1 MICE FROM 2-YEAR NTP INHALATION BIOASSAYS: PATHOLOGY AND INCIDENCE DATA REVISITED

Science.gov (United States)

SUMMARY: Chloroethane, bromoethane and etjulene oxide represent a unique set of three chemicals that induce endometrial neoplasms in the uterus of B6C3F1 mice following an inhalation route of exposure. The results of the NTP's chronic bioassays with these three compounds resu...

Synergistic Effect of Radiation and Interleukin-6 on Hepatitis B Virus Reactivation in Liver Through STAT3 Signaling Pathway

International Nuclear Information System (INIS)

Chou, C.H.; Chen, P.-J.; Jeng, Y.-M.; Cheng, A.-L.; Huang, L.-R.; Cheng, J.C.-H.

2009-01-01

Purpose: Hepatitis B virus (HBV) reactivation can occur after radiotherapy (RT) for hepatobiliary malignancies. Our previous in vitro culture study identified interleukin-6 (IL-6) as the main bystander mediator of RT-induced HBV replication. We attempted to examine the molecular mechanism in HBV-transgenic mice. Methods and materials: HBV transgenic mice were treated with whole liver RT (4 Gy daily for 5 days) with or without administration of IL-6 (400 ng twice daily for 15 days). The serum level of HBV DNA was measured using real-time polymerase chain reaction, and the IL-6 concentration was measured using enzyme-linked immunosorbent assay. The intensity of immunostaining with antibodies to HBV core protein and phosphorylated signal transducer and activator of transcription (STAT)3 in the mouse liver was qualitatively analyzed. HepG2.2.15 cells (a human hepatoblastoma cell line that persistently produces HBV DNA) were used to investigate the molecular role of IL-6 plus RT in HBV reactivation. Results: HBV reactivation was induced in vivo with IL-6 plus RT (5.58-fold) compared with RT alone (1.31-fold, p = .005), IL-6 alone (1.31-fold, p = .005), or sham treatment (1.22-fold, p = .004). HBV core protein staining confirmed augmentation of intrahepatic HBV replication. IL-6 plus RT-induced HBV DNA replication in HepG2.2.15 cells was suppressed by the STAT3 inhibitor AG490 and by transfection with dominant-negative STAT3 plasmid. Phosphorylated STAT3 staining was strongest in liver tissue from mice treated with IL-6 plus RT. The mobility shift assay demonstrated that reactivation was mediated through the interaction of phosphorylated STAT3/hepatocyte nuclear factor-3 complex with HBV enhancer 1. Conclusion: RT to the liver and longer sustained IL-6 induced HBV reactivation through the STAT3 signal transduction pathway.

Atmospheric CO2 promoted synthesis of N-containing heterocycles over B(C6F5)3 catalyst

International Nuclear Information System (INIS)

Xiang Gao; Bo Yu; Qingqing Mei; Zhenzhen Yang; Yanfei Zhao; Hongye Zhang; Leiduan Hao, Zhimin Liu

2016-01-01

B(C 6 F 5 ) 3 combined with atmospheric CO 2 was found to be highly effective for the cyclization of ortho substituted aniline derivatives with N,N-dimethylformamide (DMF), and a series of N-containing heterocycles including benzothiazoles, benzimidazoles, quinazolinone and benzoxazole were obtained in good to excellent yields. (authors)

Structure determination of two structural analogs, named 3-[1-(2-fluoro-4-biphenyl)ethyl]-6-(4-fluorophenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (C23H16F2N4S) and 3-[1-(2-fluoro-4-biphenyl)ethyl]-6-(4-chlorophenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (C23H16ClFN4S) by synchrotron X-ray powder diffraction

Energy Technology Data Exchange (ETDEWEB)

Gündoğdu, Gülsüm; Aytaç, Sevim Peri; Müller, Melanie; Tozkoparan, Birsen; Kaynak, Filiz Betül

2017-12-01

Two novel compounds, 3-[1-(2-fluoro-4-biphenyl)ethyl]-6-(4-fluorophenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (C₂₃H₁₆F₂N₄S) (1) and 3-[1-(2-fluoro-4-biphenyl)ethyl]-6-(4-chlorophenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (C₂₃H₁₆ClFN₄S) (2), have been designed and synthesized as cytotoxic agents. The compounds were characterized by infrared, proton nuclear magnetic resonance, mass spectral data, elemental analysis and X-ray powder diffraction. The present study comprises spectral data and crystal structures of these novel compounds determined from synchrotron X-ray powder diffraction data. The structure solutions were obtained by simulated annealing. The final structures were achieved by Rietveld refinement using soft restraints for all bond lengths, bond angles, and planar groups. Both compounds crystallize in space group1' mime-subtype='gif' type='simple'/>$P\\bar 1$,Z= 2, with the unit-cell parametersa= 6.37433(9),b= 11.3641(2),c= 14.09115(19) Å,α= 80.1740(8)°,β= 85.1164(8)°,γ= 80.9831(10)°,V= 991.55(3) ųof compound (1) anda= 6.53736(6),b= 11.55725(15),c= 14.01373(13) Å,α= 80.3323(7)°,β= 84.8939(6)°,γ= 79.3954(8)°,V= 1024.08(2) ųof compound (2). Structural analyses reveal that the title compounds are isostructural.

Modification of nanocellulose by poly-lysine can inhibit the effect of fumonisin B1 on mouse liver cells.

Science.gov (United States)

Jebali, Ali; Yasini Ardakani, Seyed Ali; Shahdadi, Hossein; Balal Zadeh, Mohammad Hossein; Hekmatimoghaddam, Seyedhossein

2015-02-01

Fumonisin B1 is an important mycotoxin, mainly produced by Fusarium verticillioides. It has toxic effects on liver, brain, and kidney cells. The first aim of this study was to synthesize nanocellulose modified with poly-lysine (NMPL), and the second aim was to evaluate the adsorption of fumonisin B1 by NMPL. As third aim, the function of mouse liver cells was investigated after exposure to fumonisin B1, and fumonisin B1+ NMPL. In this study, NMPL was prepared using cross-linker, and then incubated with fumonisin B1 at controlled conditions. After incubation, the adsorption and release of fumonisin B1 were evaluated in each condition. Next, mouse liver cells were separately exposed to fumonisin B1, NMPL, and (fumonisin B1+NMPL). Then, the level of aniline aminotransferase (ALT) and aspartate aminotransferase (AST) was evaluated. It was found that both adsorption and release of fumonisin B1 were not affected by temperature and incubation time, but affected by pH and concentration of NMPL. Also, this study showed NMPL could adsorb fumonisin B1 in different foodstuffs. Importantly, although the levels of ALT and AST were increased when the cells were treated with fumonisin B1 alone, they were not affected when exposed to NMPL or (fumonisin B1+NMPL). The authors suggest that NMPL is a good adsorbent to remove and inhibit fumonisin B1. Copyright © 2015 Elsevier B.V. All rights reserved.

Linkage of genes for laminin B1 and B2 subunits on chromosome 1 in mouse.

Science.gov (United States)

Elliott, R W; Barlow, D; Hogan, B L

1985-08-01

We have used cDNA clones for the B1 and B2 subunits of laminin to find restriction fragment length DNA polymorphisms for the genes encoding these polypeptides in the mouse. Three alleles were found for LamB2 and two for LamB1 among the inbred mouse strains. The segregation of these polymorphisms among recombinant inbred strains showed that these genes are tightly linked in the central region of mouse Chromosome 1 between Sas-1 and Ly-m22, 7.4 +/- 3.2 cM distal to the Pep-3 locus. There is no evidence in the mouse for pseudogenes for these proteins.

Metabolism of ginger component [6]-shogaol in liver microsomes from mouse, rat, dog, monkey, and human.

Science.gov (United States)

Chen, Huadong; Soroka, Dominique; Zhu, Yingdong; Sang, Shengmin

2013-05-01

There are limited data on the metabolism of [6]-shogaol (6S), a major bioactive component of ginger. This study demonstrates metabolism of 6S in liver microsomes from mouse, rat, dog, monkey, and human. The in vitro metabolism of 6S was compared among five species using liver microsomes from mouse, rat, dog, monkey, and human. Following incubations with 6S, three major reductive metabolites 1-(4'-hydroxy-3'-methoxyphenyl)-4-decen-3-ol (M6), 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-ol (M9), and 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-one (M11), as well as two new oxidative metabolites (1E,4E)-1-(4'-hydroxy-3'-methoxyphenyl)-deca-1,4-dien-3-one (M14) and (E)-1-(4'-hydroxy-3'-methoxyphenyl)-dec-1-en-3-one (M15) were found in all species. The kinetic parameters of M6 in liver microsomes from each respective species were quantified using Michaelis-Menten theory. A broad CYP-450 inhibitor, 1-aminobenzotriazole, precluded the formation of oxidative metabolites, M14 and M15, and 18β-glycyrrhetinic acid, an aldo-keto reductase inhibitor, eradicated the formation of the reductive metabolites M6, M9, and M11 in all species. Metabolites M14 and M15 were tested for cancer cell growth inhibition and induction of apoptosis and both showed substantial activity, with M14 displaying greater potency than 6S. We conclude that 6S is metabolized extensively in mammalian species mouse, rat, dog, monkey, and human, and that there are significant interspecies differences to consider when planning preclinical trials toward 6S chemoprevention. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Bridging Binding Modes of Phosphine-Stabilized Nitrous Oxide to Zn(C6F5)2

NARCIS (Netherlands)

Neu, Rebecca C.; Otten, Edwin; Stephan, Douglas W.

2009-01-01

Reaction of [tBu3PN2O(B(C6H4F)3)] with 1, 1.5, or 2 equivalents of Zn(C6F5)2 affords the species [{tBu3PN2OZn(C6F5)2}2], [{tBu3PN2OZn(C6F5)2}2Zn(C6F5)2], and [tBu3PN2O{Zn(C6F5)2}2] displaying unique binding modes of Zn to the phosphine-stabilized N2O fragment.

SREBP-1c overactivates ROS-mediated hepatic NF-κB inflammatory pathway in dairy cows with fatty liver.

Science.gov (United States)

Li, Xinwei; Huang, Weikun; Gu, Jingmin; Du, Xiliang; Lei, Lin; Yuan, Xue; Sun, Guoquan; Wang, Zhe; Li, Xiaobing; Liu, Guowen

2015-10-01

Dairy cows with fatty liver are characterized by hepatic lipid accumulation and a severe inflammatory response. Sterol receptor element binding protein-1c (SREBP-1c) and nuclear factor κB (NF-κB) are components of the main pathways for controlling triglyceride (TG) accumulation and inflammatory levels, respectively. A previous study demonstrated that hepatic inflammatory levels are positively correlated with hepatic TG content. We therefore speculated that SREBP-1c might play an important role in the overactivation of the hepatic NF-κB inflammatory pathway in cows with fatty liver. Compared with healthy cows, cows with fatty liver exhibited severe hepatic injury and high blood concentrations of the inflammatory cytokines TNF-α, IL-6 and IL-1β. Hepatic SREBP-1c-mediated lipid synthesis and the NF-κB inflammatory pathway were both overinduced in cows with fatty liver. In vitro, treatment with non-esterified fatty acids (NEFA) further increased SREBP-1c expression and NF-κB pathway activation, which then promoted TG and inflammatory cytokine synthesis. SREBP-1c overexpression overactivated the NF-κB inflammatory pathway in hepatocytes by increasing ROS content and not through TLR4. Furthermore, SREBP-1c silencing decreased ROS content and further attenuated the activation of the NEFA-induced NF-κB pathway, thereby decreasing TNF-α, IL-6 and IL-1β synthesis. SREBP-1c-overexpressing mice exhibited hepatic steatosis and an overinduced hepatic NF-κB pathway. Taken together, these results indicate that SREBP-1c enhances the NEFA-induced overactivation of the NF-κB inflammatory pathway by increasing ROS in cow hepatocytes, thereby further increasing hepatic inflammatory injury in cows with fatty liver. Copyright © 2015. Published by Elsevier Inc.

Mouse models of aerosol-acquired tularemia caused by Francisella tularensis types A and B.

Science.gov (United States)

Fritz, David L; England, Marilyn J; Miller, Lynda; Waag, David M

2014-10-01

After preliminary assessment of virulence in AKR/J, DBA/1, BALB/c, and C57BL/6 mice, we investigated histopathologic changes in BALB/c and C57BL/6 mice infected with type A (strain SCHU S4) or type B (strain 425) Francisella tularensis by aerosol exposure. In mice exposed to type A infection, changes in histologic presentation were not apparent until day 3 after infection, when pyogranulomatous inflammation was detected in spleens and livers of BALB/c mice, and in lungs and spleens of C57BL/6 mice. Histopathologic changes were most severe and widespread in both mouse strains on day 5 after infection and seemed to completely resolve within 22 d of challenge. BALB/c mice were more resistant than C57BL/6 mice in lethal-dose calculations, but C57BL/6 mice cleared the infection more rapidly. Mice similarly challenged with type B F. tularensis also developed histopathologic signs of infection beginning on day 3. The most severe changes were noted on day 8 and were characterized by granulomatous or pyogranulomatous infiltrations of the lungs. Unlike type A infection, lesions due to type B did not resolve over time and remained 3 wk after infection. In type B, but not type A, infection we noted extensive inflammation of the heart muscle. Although no microorganisms were found in tissues of type A survivors beyond 9 d after infection, mice surviving strain 425 infection had a low level of residual infection at 3 wk after challenge. The histopathologic presentation of tularemia caused by F. tularensis types A and B in BALB/c and C57BL/6 mice bears distinct similarities to tularemia in humans.

Anomalous electron-attachment properties of perfluoropropylene (1-C3F6) and their effect on the breakdown strength of this gas

International Nuclear Information System (INIS)

Hunter, S.R.; Christophorou, L.G.; McCorkle, D.L.; Sauers, I.; Ellis, H.W.; James, D.R.

1982-01-01

Electron attachment to perfluoropropylene (1-C 3 F 6 ) in 1-C 3 F 6 /buffer gas mixtures has been found to be anomalously dependent on both the 1-C 3 F 6 and buffer gas pressures, as well as on the gas temperature. We have found also that the uniform field breakdown strength of pure 1-C 3 F 6 is dependent on gas pressure but not on the gas temperature. A mass spectrometer study of the negative ions formed in a moderately high pressure corona discharge has been made, and the principal negative ions formed by electron attachment to 1-C 3 F 6 have been identified. Based on these studies, a reaction scheme for electron attachment to 1-C 3 F 6 is proposed which results in stable negative ion clusters but does not involve pre-existing dimers. Further, we propose that the observed pressure dependence in the breakdown strength of this gas is due to the large pressure dependence of the electron attachment process we observed

Comparison of [(11)C]Choline ([(11)C]CHO) and [(18)F]Bombesin (BAY 86-4367) as Imaging Probes for Prostate Cancer in a PC-3 Prostate Cancer Xenograft Model.

Science.gov (United States)

Schwarzenböck, Sarah Marie; Schmeja, Philipp; Kurth, Jens; Souvatzoglou, Michael; Nawroth, Roman; Treiber, Uwe; Kundt, Guenther; Berndt, Sandra; Graham, Keith; Senekowitsch-Schmidtke, Reingard; Schwaiger, Markus; Ziegler, Sibylle I; Dinkelborg, Ludger; Wester, Hans-Jürgen; Krause, Bernd Joachim

2016-06-01

Carbon-11- and fluorine-18-labeled choline derivatives are commonly used in prostate cancer imaging in the clinical setting for staging and re-staging of prostate cancer. Due to a limited detection rate of established positron emission tomography (PET) tracers, there is a clinical need for innovative tumor-specific PET compounds addressing new imaging targets. The aim of this study was to compare the properties of [(18)F]Bombesin (BAY 86-4367) as an innovative biomarker for prostate cancer imaging targeting the gastrin-releasing peptide receptor and [(11)C]Choline ([(11)C]CHO) in a human prostate tumor mouse xenograft model by small animal PET/X-ray computed tomography (CT). We carried out a dual-tracer small animal PET/CT study comparing [(18)F]Bombesin and [(11)C]CHO. The androgen-independent human prostate tumor cell line PC-3 was implanted subcutaneously in the flanks of nu/nu NMRI mice (n = 10) (PET/CT measurements of two [(11)C]Choline mice could not be analyzed due to technical reasons). [(18)F]Bombesin and [(11)C]CHO PET/CT imaging was performed about 3-4 weeks after the implantation of PC-3 cells on two separate days. After the intravenous tail vein injection of 14 MBq [(18)F]Bombesin and 37 MBq [(11)C]CHO, respectively, a dynamic study over 60 min was acquired in list mode using an Inveon animal PET/CT scanner (Siemens Medical Solutions). The sequence of [(18)F]Bombesin and [(11)C]CHO was randomized. Image analysis was performed using summed images as well as dynamic data. To calculate static and dynamic tumor-to-muscle (T/M), tumor-to-blood (T/B), liver-to-blood (L/B), and kidney-to-blood (K/B) ratios, 4 × 4 × 4 mm(3) volumes of interest (VOIs) of tumor, muscle (thigh), liver, kidney, and blood derived from transversal slices were used. The mean T/M ratio of [(18)F]Bombesin and [(11)C]CHO was 6.54 ± 2.49 and 1.35 ± 0.30, respectively. The mean T/B ratio was 1.83 ± 0.79 for [(18)F]Bombesin and 0.55 ± 0.10 for [(11)C

NTP Toxicology and Carcinogenesis Studies of Benzene (CAS No. 71-43-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Science.gov (United States)

1986-04-01

Benzene ranks 16th in production volume for chemicals produced in the United States, with approximately 9.9 billion pounds being produced in 1984, 9.1 billion pounds in 1983, and 7.8 billion pounds in 1982. This simplest aromatic chemical in used in the synthesis of styrene (polystyrene plastics and synthetic rubber), phenol (phenolic resins), cyclohexane (nylon), aniline, maleic anhydride (polyester resins), alkylbenzenes (detergents), chlorobenzenes, and other products used in the production of drugs, dyes, insecticides, and plastics. Benzene, along with other light, high-octane aromatic hydrocarbons, such as toluene and xylenes, is a component of motor gasoline. Benzene is also used as a solvent, but for most applications, it has been replaced by less hazardous solvents. During the 17-week studies, groups of 10 or 15 male and female F344/N rats and B6C3F1 mice were gavaged 5 days per week with benzene in corn oil (5 ml/kg) at doses of 0 to 600 mg/kg. No benzene-related deaths occurred; in rats that received benzene, final mean body weights were 14%-22% lower compared with vehicle controls and in mice, slight dose-related reductions were observed (less than 10% differences). Doses for the 2-year studies were selected based on clinical observations (tremors in higher dosed mice), on clinical pathologic findings (lymphoid depletion in rats and leukopenia in mice), and on body weight effects. Two-year toxicology and carcinogenesis studies of benzene (greater than 99.7% pure) were conducted in groups of 50 F344/N rats and 50 B6C3F1 mice of each sex and for each dose. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil (5 ml/kg) were administered by gavage to male rats, 5 days per week, for 103 weeks. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 weeks. Ten additional animals in each of the 16 groups were killed at 12 months and necropsies were performed. Hematologic

Peptidase-3 (Pep-3), dipeptidase variant in the rat homologous to mouse pep-3 (Dip-1) and human PEP-c.

Science.gov (United States)

Womack, J E; Cramer, D V

1980-10-01

Starch gel electrophoresis and histochemical staining with L-leucyl-L-tyrosine have revealed genetic variation for dipeptidase in Rattus norvegicus. The tissue distribution, substrate specificity, and heterozygous expression as a monmeric protein suggest homology of the variant peptidase to human PEP-C and mouse Pep-3 (Dip-1). We propose Peptidase-3 (Pep-3) as a name for this autosomal locus in the rat. The allele responsible for slower (less anodal) electrophoretic migration is designated Pep-3a and is characteristic of strain ACI/Pit. A faster (more anodal) electrophoretic mobility is the product of the Pep-3b allele in strain F344/Pit. Twenty-five additional inbred strains carry Pep-3a and 16 others carry Pep-3b. Wild rats trapped in Pittsburgh were polymorphic for this locus. Alleles at Pep-3 segregated independently of c (linkage group I), a (linkage group IV), RT2 and Es-1 (linkage group V), h (linkage group VI), and RTI (linkage group VIII).

An Increased Ratio of Glycated Albumin to HbA1c Is Associated with the Degree of Liver Fibrosis in Hepatitis B Virus-Positive Patients

Directory of Open Access Journals (Sweden)

Hirayuki Enomoto

2014-01-01

Full Text Available Background. In hepatitis B virus- (HBV- positive patients, the relationship between the metabolic variables and histological degree of liver fibrosis has been poorly investigated. Methods. A total of 176 HBV-positive patients were assessed in whom the ratios of glycated albumin-to-glycated hemoglobin (GA/HbA1c were calculated in order to investigate the relationship with the degree of liver fibrosis. Results. The GA/HbA1c ratio increased in association with the severity of fibrosis (METAVIR scores: F0-1: 2.61 ± 0.24, F2: 2.65 ± 0.24, F3: 2.74 ± 0.38, and F4: 2.91 ± 0.63. The GA/HbA1c ratios were inversely correlated with four variables of liver function: the prothrombin time (PT percentage (P<0.0001, platelet count (P<0.0001, albumin value (P<0.0001, and cholinesterase value (P<0.0001. The GA/HbA1c ratio was positively correlated with two well-known markers of liver fibrosis, FIB-4 (P<0.0001 and the AST-to-platelet ratio index (APRI (P<0.0001. Furthermore, the GA/HbA1c showed better correlations with two variables of liver function (PT percentage and cholinesterase value than did FIB-4 and with all four variables than did the APRI. Conclusion. The GA/HbA1c ratio is associated with the degree of liver fibrosis in HBV-positive patients.

Differential expression patterns of Nqo1, AKR1B8 and Ho-1 in the liver and small intestine of C57BL/6 mice treated with sulforaphane

Directory of Open Access Journals (Sweden)

Lin Luo

2015-12-01

Full Text Available This data article contains complementary figures and results related to the research article entitled “butylated hydroxyanisole induces distinct expression patterns of Nrf2 and detoxification enzymes in the liver and small intestine of C57BL/6 mice” (Luo et al., 2015 [1], which defined the basal and butylated hydroxyanisole (BHA-induced expression patterns of Phase II enzymes Nqo1, AKR1B8, and Ho-1 in the liver and small intestine of C57BL/6 mice. Sulforaphane [1-isothiocyanato-4-(methylsulfinylbutane] (SFN, a naturally occurring isothiocyanate derived from cruciferous vegetables, is a highly potent inducer of phase II cytoprotective enzymes. This dataset reports the histological changes of Nqo1, AKR1B8, and Ho-1 in wild-type (WT and Nrf2-/- mice induced by SFN. The mice were given a 25 mg/kg single oral dose of SFN for 24 h and 48 h. Immunohistochemistry revealed that, in the liver from WT mice, SFN increased Nqo1 staining in hepatocytes with slight higher staining in the pericentral region. The induction of AKR1B8 appeared mostly in hepatocytes in the periportal region. The basal and inducible Ho-1 was located predominately in Kupffer cells. In the small intestine from WT mice, the inducible expression of Nqo1 and AKR1B8 appeared more obvious in the villus than that in the crypt.

Atmospheric histories and growth trends of C4F10, C5F12, C6F14, C7F16 and C8F18

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R. F. Weiss

2012-05-01

Full Text Available Atmospheric observations and trends are presented for the high molecular weight perfluorocarbons (PFCs: decafluorobutane (C4F10, dodecafluoropentane (C5F12, tetradecafluorohexane (C6F14, hexadecafluoroheptane (C7F16 and octadecafluorooctane (C8F18. Their atmospheric histories are based on measurements of 36 Northern Hemisphere and 46 Southern Hemisphere archived air samples collected between 1973 to 2011 using the Advanced Global Atmospheric Gases Experiment (AGAGE "Medusa" preconcentration gas chromatography-mass spectrometry systems. A new calibration scale was prepared for each PFC, with estimated accuracies of 6.8% for C4F10, 7.8% for C5F12, 4.0% for C6F14, 6.6% for C7F16 and 7.9% for C8F18. Based on our observations the 2011 globally averaged dry air mole fractions of these heavy PFCs are: 0.17 parts-per-trillion (ppt, i.e., parts per 1012 for C4F10, 0.12 ppt for C5F12, 0.27 ppt for C6F14, 0.12 ppt for C7F16 and 0.09 ppt for C8F18. These atmospheric mole fractions combine to contribute to a global average radiative forcing of 0.35 mW m−2, which is 6% of the total anthropogenic PFC radiative forcing (Montzka and Reimann, 2011; Oram et al., 2012. The growth rates of the heavy perfluorocarbons were largest in the late 1990s peaking at 6.2 parts per quadrillion (ppq, i.e., parts per 1015 per year (yr for C4F10, at 5.0 ppq yr−1 for C5F12 and 16.6 ppq yr−1 for C6F14 and in the early 1990s for C7F16 at 4.7 ppq yr−1 and in the mid 1990s for C8F18 at 4.8 ppq yr−1. The 2011 globally averaged mean atmospheric growth rates of these PFCs are subsequently lower at 2.2 ppq yr−1 for C4F10, 1.4 ppq yr−1 for C5F12, 5.0 ppq yr−1 for C6F14, 3.4 ppq yr−1 for C7F16 and 0.9 ppq yr−1 for C8F18. The more recent slowdown in the growth rates suggests that emissions are declining as compared to the 1980s and 1990s.

Prospective evaluation of FibroTest®, FibroMeter®, and HepaScore® for staging liver fibrosis in chronic hepatitis B: comparison with hepatitis C.

Science.gov (United States)

Leroy, Vincent; Sturm, Nathalie; Faure, Patrice; Trocme, Candice; Marlu, Alice; Hilleret, Marie-Noëlle; Morel, Françoise; Zarski, Jean-Pierre

2014-07-01

Fibrosis blood tests have been validated in chronic hepatitis C. Their diagnostic accuracy is less documented in hepatitis B. The aim of this study was to describe the diagnostic performance of FibroTest®, FibroMeter®, and HepaScore® for liver fibrosis in hepatitis B compared to hepatitis C. 510 patients mono-infected with hepatitis B or C and matched on fibrosis stage were included. Blood tests were performed the day of the liver biopsy. Histological lesions were staged according to METAVIR. Fibrosis stages were distributed as followed: F0 n=76, F1 n=192, F2 n=132, F3 n=54, F4 n=56. Overall diagnostic performance of blood tests were similar between hepatitis B and C with AUROC ranging from 0.75 to 0.84 for significant fibrosis, 0.82 to 0.85 for extensive fibrosis and 0.84 to 0.87 for cirrhosis. Optimal cut-offs were consistently lower in hepatitis B compared to hepatitis C, especially for the diagnosis of extensive fibrosis and cirrhosis, with decreased sensitivity and negative predictive values. More hepatitis B than C patients with F ⩾3 were underestimated: FibroTest®: 47% vs. 26%, FibroMeter®: 24% vs. 6%, HepaScore®: 41% vs. 24%, pfibrosis underestimation. Overall the diagnostic performance of blood tests is similar in hepatitis B and C. The risk of underestimating significant fibrosis and cirrhosis is however greater in hepatitis B and cannot be entirely corrected by the use of more stringent cut-offs. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Protectin D1 reduces concanavalin A-induced liver injury by inhibiting NF-κB-mediated CX3CL1/CX3CR1 axis and NLR family, pyrin domain containing 3 inflammasome activation.

Science.gov (United States)

Ren, Jun; Meng, Shanshan; Yan, Bingdi; Yu, Jinyan; Liu, Jing

2016-04-01

Protectin D1 (PD1) is a bioactive product generated from docosahexaenoic acid, which may exert anti-inflammatory effects in various inflammatory diseases. However, the underlying molecular mechanism of its anti‑inflammatory activity on concanavalin A (Con A)-induced hepatitis remains unknown. The aim of the present study was to investigate the protective effects of PD1 against Con A‑induced liver injury and the underlying mechanisms via intravenous injection of PD1 prior to Con A administration. C57BL/6 mice were randomly divided into four experimental groups as follows: Control group, Con A group (30 mg/kg), 20 µg/kg PD1 + Con A (30 mg/kg) group and 10 µg/kg PD1 + Con A (30 mg/kg) group. PD1 pretreatment was demonstrated to significantly inhibit elevated plasma aminotransferase levels, high mobility group box 1 and liver necrosis, which were observed in Con A‑induced hepatitis. Furthermore, compared with the Con A group, PD1 pretreatment prevented the production of pro‑inflammatory cytokines, including tumor necrosis factor‑α, interferon‑γ and interleukin‑2, ‑1β and ‑6. In addition, pretreatment with PD1 markedly downregulated cluster of differentiation (CD)4+, CD8+ and natural killer T (NKT) cell infiltration in the liver. PD1 pretreatment was observed to suppress the messenger RNA and protein expression levels of NLR family, pyrin domain containing 3 and Toll‑like receptor (TLR) 4 in liver tissue samples. Further data indicated that PD1 pretreatment inhibited the activation of the nuclear factor κ‑light‑chain‑enhancer of activated B cells (NF‑κB) signaling pathway and chemokine (C‑X3‑C motif) ligand 1 (CX3CL1)/chemokine (C-X3-C motif) receptor 1 (CX3CR1) axis by preventing phosphorylation of nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor, α and NF‑κB in Con A‑induced liver injury. Therefore, these results suggest that PD1 administration protects mice against Con A‑induced liver injury via

NTP Toxicology and Carcinogenesis Studies of Dimethyl Methylphosphonate (CAS No. 756-79-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Science.gov (United States)

1987-11-01

Dimethyl methylphosphonate (98% pure) is one of four chemicals nominated by the U.S. Army for toxicology and carcinogenesis studies because it was being considered for use to simulate the physical and spectroscopic (but not the biologic) properties of anticholinesterase (nerve) agents. Dimethyl methylphosphonate is also used as a flame retardant, a preignition additive for gasoline, an antifoam agent, a plasticizer and stabilizer, a textile conditioner and antistatic agent, and an additive for solvents and low-temperature hydraulic fluids. The United States produces 0.2-2 million pounds (91,000-910,000 kg) of per year. Gavage was chosen as the route of administration for all four candidate "simulants" to mimic potential exposure. Experimental Design: Dimethyl methylphosphonate was administered in corn oil by gavage to male and female F344/N rats and B6C3F1 mice in single-administration, 15-day, and 13-week studies to obtain toxicity data, to establish dose levels for the 2-year studies, and to identify target tissues. Additional studies were also performed to determine toxicity to the reproductive system of male F344/N rats and B6C3F1 mice and to study the potential for genetic damage in bacteria, mammalian cells, and Drosophila. Single-Administration Studies: In the single-administration studies, dimethyl methylphosphonate was given to rats and mice at doses up to 6,810 mg/kg body weight. No compound-related deaths were seen in male or female rats or male mice; two high dose female mice died. Rats exhibited inactivity, unsteady gait, and prostration after dosing; mice were inactive after dosing. Fifteen-Day Studies: Rats and mice received doses of 0, 1,250, 2,500, 5,000, 10,000, or 15,000 mg/kg dimethyl methylphosphonate per day. Compound-related deaths occurred in the three highest dose groups of rats and the two highest dose groups of mice. Rats receiving doses of 2,500 mg/kg or higher were inactive and at 5,000 or 10,000 mg/kg had an unsteady gait after dosing

Heteroaromatization with 4-Hydroxycoumarin Part II: Synthesis of Some New Pyrano[2,3-d]pyrimidines, [1,2,4]triazolo[1,5-c]pyrimidines and Pyrimido[1,6-b]-[1,2,4]triazine Derivatives

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A. H. Bedair

2001-05-01

Full Text Available A variety of novel [1,2,4]triazolo[1,5-c]pyrimidine-13-ones (4a-f and (5b-d could be obtained via reaction of 9-amino-7-(4’-chlorophenyl-8,9-dihydro-8-imino-6H,7H-[1]benzopyrano[3`,4`:5,6]pyrano[2,3-d]pyrimidine-6-one (3 with a variety of reagents. Pyrano[2,3-d]pyrimidine-6-ones 5a, 8a-c and pyrimido[1,6-b][1,2,4]-triazine-3,14-dione (6 were also prepared. The antimicrobial activity of some of the synthesized compounds was tested.

Centrosymmetric [N(CH3)4]2TiF6 vs. noncentrosymmetric polar [C(NH2)3]2TiF6: A hydrogen-bonding effect on the out-of-center distortion of TiF6 octahedra

International Nuclear Information System (INIS)

Kim, Eun-ah; Lee, Dong Woo; Ok, Kang Min

2012-01-01

The syntheses, structures, and characterization of organically templated zero-dimensional titanium fluoride materials, A 2 TiF 6 (A=[N(CH 3 ) 4 ] or [C(NH 2 ) 3 ]), are reported. Phase pure samples of A 2 TiF 6 were synthesized by either solvothermal reaction method or a simple mixing method. While [N(CH 3 ) 4 ] 2 TiF 6 crystallizes in a centrosymmetric space group, R-3, [C(NH 2 ) 3 ] 2 TiF 6 crystallizes in a noncentrosymmetric polar space group, Cm. The asymmetric out-of-center distortion of TiF 6 octahedra in polar [C(NH 2 ) 3 ] 2 TiF 6 are attributable to the hydrogen-bonding interactions between the fluorine atoms in TiF 6 octahedra and the nitrogen atoms in the [C(NH 2 ) 3 ] + cation. Powder second-harmonic generation (SHG) measurements on the [C(NH 2 ) 3 ] 2 TiF 6 , using 1064 nm radiation, indicate the material has SHG efficiency of 25× that of α-SiO 2 , which indicates an average nonlinear optical susceptibility, 〈d eff 〉 exp of 2.8 pm/V. Additional SHG measurements reveal that the material is not phase-matchable (Type 1). The magnitudes of out-of-center distortions and dipole moment calculations for TiF 6 octahedra will be also reported. - Graphical abstract: The out-of-center distortion of TiF 6 octahedron in the polar noncentrosymmetric [C(NH 2 ) 3 ] 2 TiF 6 is attributable to the hydrogen-bonding interactions between the F in TiF 6 octahedron and the H–N in the [C(NH 2 ) 3 ] + . Highlights: ► Two titanium fluorides materials have been synthesized in high yields. ► Hydrogen-bonds are crucial for the out-of-center distortion of TiF 6 octahedra. ► [C(NH 2 ) 3 ] 2 TiF 6 has a SHG efficiency of 25× that of α-SiO 2 .

Lrit3 deficient mouse (nob6): a novel model of complete congenital stationary night blindness (cCSNB).

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Neuillé, Marion; El Shamieh, Said; Orhan, Elise; Michiels, Christelle; Antonio, Aline; Lancelot, Marie-Elise; Condroyer, Christel; Bujakowska, Kinga; Poch, Olivier; Sahel, José-Alain; Audo, Isabelle; Zeitz, Christina

2014-01-01

Mutations in LRIT3, coding for a Leucine-Rich Repeat, immunoglobulin-like and transmembrane domains 3 protein lead to autosomal recessive complete congenital stationary night blindness (cCSNB). The role of the corresponding protein in the ON-bipolar cell signaling cascade remains to be elucidated. Here we genetically and functionally characterize a commercially available Lrit3 knock-out mouse, a model to study the function and the pathogenic mechanism of LRIT3. We confirm that the insertion of a Bgeo/Puro cassette in the knock-out allele introduces a premature stop codon, which presumably codes for a non-functional protein. The mouse line does not harbor other mutations present in common laboratory mouse strains or in other known cCSNB genes. Lrit3 mutant mice exhibit a so-called no b-wave (nob) phenotype with lacking or severely reduced b-wave amplitudes in the scotopic and photopic electroretinogram (ERG), respectively. Optomotor tests reveal strongly decreased optomotor responses in scotopic conditions. No obvious fundus auto-fluorescence or histological retinal structure abnormalities are observed. However, spectral domain optical coherence tomography (SD-OCT) reveals thinned inner nuclear layer and part of the retina containing inner plexiform layer, ganglion cell layer and nerve fiber layer in these mice. To our knowledge, this is the first time that SD-OCT technology is used to characterize an animal model for CSNB. This phenotype is noted at 6 weeks and at 6 months. The stationary nob phenotype of mice lacking Lrit3, which we named nob6, confirms the findings previously reported in patients carrying LRIT3 mutations and is similar to other cCSNB mouse models. This novel mouse model will be useful for investigating the pathogenic mechanism(s) associated with LRIT3 mutations and clarifying the role of LRIT3 in the ON-bipolar cell signaling cascade.

Lrit3 deficient mouse (nob6: a novel model of complete congenital stationary night blindness (cCSNB.

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Marion Neuillé

Full Text Available Mutations in LRIT3, coding for a Leucine-Rich Repeat, immunoglobulin-like and transmembrane domains 3 protein lead to autosomal recessive complete congenital stationary night blindness (cCSNB. The role of the corresponding protein in the ON-bipolar cell signaling cascade remains to be elucidated. Here we genetically and functionally characterize a commercially available Lrit3 knock-out mouse, a model to study the function and the pathogenic mechanism of LRIT3. We confirm that the insertion of a Bgeo/Puro cassette in the knock-out allele introduces a premature stop codon, which presumably codes for a non-functional protein. The mouse line does not harbor other mutations present in common laboratory mouse strains or in other known cCSNB genes. Lrit3 mutant mice exhibit a so-called no b-wave (nob phenotype with lacking or severely reduced b-wave amplitudes in the scotopic and photopic electroretinogram (ERG, respectively. Optomotor tests reveal strongly decreased optomotor responses in scotopic conditions. No obvious fundus auto-fluorescence or histological retinal structure abnormalities are observed. However, spectral domain optical coherence tomography (SD-OCT reveals thinned inner nuclear layer and part of the retina containing inner plexiform layer, ganglion cell layer and nerve fiber layer in these mice. To our knowledge, this is the first time that SD-OCT technology is used to characterize an animal model for CSNB. This phenotype is noted at 6 weeks and at 6 months. The stationary nob phenotype of mice lacking Lrit3, which we named nob6, confirms the findings previously reported in patients carrying LRIT3 mutations and is similar to other cCSNB mouse models. This novel mouse model will be useful for investigating the pathogenic mechanism(s associated with LRIT3 mutations and clarifying the role of LRIT3 in the ON-bipolar cell signaling cascade.

Remarkable Enhancement of the Hole Mobility in Several Organic Small-Molecules, Polymers, and Small-Molecule:Polymer Blend Transistors by Simple Admixing of the Lewis Acid p-Dopant B(C6F5)3

KAUST Repository

Panidi, Julianna; Paterson, Alexandra F.; Khim, Dongyoon; Fei, Zhuping; Han, Yang; Tsetseris, Leonidas; Vourlias, George; Patsalas, Panos A.; Heeney, Martin; Anthopoulos, Thomas D.

2017-01-01

Improving the charge carrier mobility of solution-processable organic semiconductors is critical for the development of advanced organic thin-film transistors and their application in the emerging sector of printed electronics. Here, a simple method is reported for enhancing the hole mobility in a wide range of organic semiconductors, including small-molecules, polymers, and small-molecule:polymer blends, with the latter systems exhibiting the highest mobility. The method is simple and relies on admixing of the molecular Lewis acid B(C6F5)(3) in the semiconductor formulation prior to solution deposition. Two prototypical semiconductors where B(C6F5)(3) is shown to have a remarkable impact are the blends of 2,8-difluoro-5,11-bis(triethylsilylethynyl)anthradithiophene:poly(triarylamine) (diF-TESADT:PTAA) and 2,7-dioctyl[1]-benzothieno[3,2-b][1]benzothiophene:poly(indacenodithiophene-co-benzothiadiazole) (C8-BTBT:C16-IDTBT), for which hole mobilities of 8 and 11 cm(2) V-1 s(-1), respectively, are obtained. Doping of the 6,13-bis(triisopropylsilylethynyl)pentacene:PTAA blend with B(C6F5)(3) is also shown to increase the maximum hole mobility to 3.7 cm(2) V-1 s(-1). Analysis of the single and multicomponent materials reveals that B(C6F5)(3) plays a dual role, first acting as an efficient p-dopant, and secondly as a microstructure modifier. Semiconductors that undergo simultaneous p-doping and dopant-induced long-range crystallization are found to consistently outperform transistors based on the pristine materials. Our work underscores Lewis acid doping as a generic strategy towards high performance printed organic microelectronics.

Remarkable Enhancement of the Hole Mobility in Several Organic Small-Molecules, Polymers, and Small-Molecule:Polymer Blend Transistors by Simple Admixing of the Lewis Acid p-Dopant B(C6F5)3.

Science.gov (United States)

Panidi, Julianna; Paterson, Alexandra F; Khim, Dongyoon; Fei, Zhuping; Han, Yang; Tsetseris, Leonidas; Vourlias, George; Patsalas, Panos A; Heeney, Martin; Anthopoulos, Thomas D

2018-01-01

Improving the charge carrier mobility of solution-processable organic semiconductors is critical for the development of advanced organic thin-film transistors and their application in the emerging sector of printed electronics. Here, a simple method is reported for enhancing the hole mobility in a wide range of organic semiconductors, including small-molecules, polymers, and small-molecule:polymer blends, with the latter systems exhibiting the highest mobility. The method is simple and relies on admixing of the molecular Lewis acid B(C 6 F 5 ) 3 in the semiconductor formulation prior to solution deposition. Two prototypical semiconductors where B(C 6 F 5 ) 3 is shown to have a remarkable impact are the blends of 2,8-difluoro-5,11-bis(triethylsilylethynyl)anthradithiophene:poly(triarylamine) (diF-TESADT:PTAA) and 2,7-dioctyl[1]-benzothieno[3,2-b][1]benzothiophene:poly(indacenodithiophene-co-benzothiadiazole) (C8-BTBT:C16-IDTBT), for which hole mobilities of 8 and 11 cm 2 V -1 s -1 , respectively, are obtained. Doping of the 6,13-bis(triisopropylsilylethynyl)pentacene:PTAA blend with B(C 6 F 5 ) 3 is also shown to increase the maximum hole mobility to 3.7 cm 2 V -1 s -1 . Analysis of the single and multicomponent materials reveals that B(C 6 F 5 ) 3 plays a dual role, first acting as an efficient p-dopant, and secondly as a microstructure modifier. Semiconductors that undergo simultaneous p-doping and dopant-induced long-range crystallization are found to consistently outperform transistors based on the pristine materials. Our work underscores Lewis acid doping as a generic strategy towards high performance printed organic microelectronics.

Remarkable Enhancement of the Hole Mobility in Several Organic Small-Molecules, Polymers, and Small-Molecule:Polymer Blend Transistors by Simple Admixing of the Lewis Acid p-Dopant B(C6F5)3

KAUST Repository

Panidi, Julianna

2017-10-05

Improving the charge carrier mobility of solution-processable organic semiconductors is critical for the development of advanced organic thin-film transistors and their application in the emerging sector of printed electronics. Here, a simple method is reported for enhancing the hole mobility in a wide range of organic semiconductors, including small-molecules, polymers, and small-molecule:polymer blends, with the latter systems exhibiting the highest mobility. The method is simple and relies on admixing of the molecular Lewis acid B(C6F5)(3) in the semiconductor formulation prior to solution deposition. Two prototypical semiconductors where B(C6F5)(3) is shown to have a remarkable impact are the blends of 2,8-difluoro-5,11-bis(triethylsilylethynyl)anthradithiophene:poly(triarylamine) (diF-TESADT:PTAA) and 2,7-dioctyl[1]-benzothieno[3,2-b][1]benzothiophene:poly(indacenodithiophene-co-benzothiadiazole) (C8-BTBT:C16-IDTBT), for which hole mobilities of 8 and 11 cm(2) V-1 s(-1), respectively, are obtained. Doping of the 6,13-bis(triisopropylsilylethynyl)pentacene:PTAA blend with B(C6F5)(3) is also shown to increase the maximum hole mobility to 3.7 cm(2) V-1 s(-1). Analysis of the single and multicomponent materials reveals that B(C6F5)(3) plays a dual role, first acting as an efficient p-dopant, and secondly as a microstructure modifier. Semiconductors that undergo simultaneous p-doping and dopant-induced long-range crystallization are found to consistently outperform transistors based on the pristine materials. Our work underscores Lewis acid doping as a generic strategy towards high performance printed organic microelectronics.

Carcinogenicity study of 3-monochloropropane-1, 2-diol (3-MCPD) administered by drinking water to B6C3F1 mice showed no carcinogenic potential.

Science.gov (United States)

Jeong, Jayoung; Han, Beom Seok; Cho, Wan-Seob; Choi, Mina; Ha, Chang-Su; Lee, Byoung-Seok; Kim, Yong-Bum; Son, Woo-Chan; Kim, Choong-Yong

2010-09-01

3-Monochloropropane-1, 2-diol (or 3-chloro-1,2-propanediol, 3-MCPD) is a well-known food processing contaminant found in a wide range of foods and ingredients. It has been classified as non-genotoxic carcinogen but its carcinogenic potential in the rodents has been controversial. The carcinogenicity to B6C3F1 mice by drinking water administration was assessed over a period of 104 weeks. Three groups, each comprising 50 male and 50 female mice received 3-MCPD at dosages of 30, 100 or 300 ppm up to Day 100 and 200 ppm onward (4.2, 14.3 and 33.0 mg/kg for males; 3.7, 12.2, and 31.0 mg/kg for females), were allocated. Survival was good, with at least 80% of males and 72% of females in each group surviving 104 weeks. Body weights and body weight gain were decreased in males and females receiving 200 ppm. Water and food consumptions of both sexes at 300/200 ppm were lowered. Emaciated or crouching position was observed for animals of both sexes exposed to 200 ppm. There were some differences in hematology and serum biochemistry compared with controls, although there was no histopathological evidence to support those changes. Histopathological examination did not reveal any neoplastic or non-neoplastic findings attributable to treatment with 3-MCPD. It is concluded that drinking water administration of 3-MCPD for 104 weeks revealed no evidence of carcinogenic potential.

NTP technical report on the toxicity studies of Castor Oil (CAS No. 8001-79-4) in F344/N Rats and B6C3F1 Mice (Dosed Feed Studies).

Science.gov (United States)

Irwin, R

1992-03-01

Castor oil is a natural oil derived from the seeds of the castor bean, Ricinus communis. It is comprised largely of triglycerides with a high ricinolin content. Toxicity studies with castor oil were performed by incorporating the material at concentrations as high as 10% in diets given to F344/N rats and B6C3F1 mice of both sexes for 13 weeks. Genetic toxicity studies also were performed and were negative for mutation induction in Salmonella typhimurium, for induction of sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells, and for induction of micronuclei in the peripheral blood erythrocytes of mice evaluated at the end of the 13-week studies. Exposure to castor oil at dietary concentrations as high as 10% in 13-week studies did not affect survival or body weight gains of rats or mice (10 per sex and dose). There were no biologically significant effects noted in hematologic analyses in rats. Mild increases in total bile acids and in serum alkaline phosphatase were noted at various times during the studies in rats receiving the higher dietary concentrations of castor oil. Liver weights were increased in male rats receiving the 10% dietary concentration and in male and female mice receiving diets containing 5% or 10% castor oil. However, there were no histopathologic lesions associated with these liver changes, nor were there any compound-related morphologic changes in any organ in rats or mice. No significant changes were noted in a screening for male reproductive endpoints, including sperm count and motility, and no changes were observed in the length of estrous cycles of rats or mice given diets containing castor oil. Thus, no significant adverse effects of castor oil administration were noted in these studies. Synonyms: Ricinus Oil, oil of Palma Christi, tangantangan oil, phorboyl, Neoloid.

Usefulness of [18F]-DA and [18F]-DOPA for PET imaging in a mouse model of pheochromocytoma

International Nuclear Information System (INIS)

Martiniova, Lucia; Cleary, Susannah; Lai, Edwin W.; Kiesewetter, Dale O.; Seidel, Jurgen; Dawson, Linda F.; Phillips, Jacqueline K.; Thomasson, David; Chen Xiaoyuan; Eisenhofer, Graeme; Powers, James F.; Kvetnansky, Richard

2012-01-01

Purpose: To evaluate the usefulness of [ 18 F]-6-fluorodopamine ([ 18 F]-DA) and [ 18 F]-L-6-fluoro-3,4-dihydroxyphenylalanine ([ 18 F]-DOPA) positron emission tomography (PET) in the detection of subcutaneous (s.c.) and metastatic pheochromocytoma in mice; to assess the expression of the norepinephrine transporter (NET) and vesicular monoamine transporters 1 and 2 (VMAT1 and VMAT2), all important for [ 18 F]-DA and [ 18 F]-DOPA uptake. Furthermore, to compare tumor detection by micro-computed tomography (microCT) to magnetic resonance imaging (MRI) in individual mouse. Methods: SUV max values were calculated from [ 18 F]-DA and [ 18 F]-DOPA PET, tumor-to-liver ratios (TLR) were obtained and expression of NET, VMAT1 and VMAT2 was evaluated. Results: [ 18 F]-DA detected less metastatic lesions compared to [ 18 F]-DOPA. TLR values for liver metastases were 2.26–2.71 for [ 18 F]-DOPA and 1.83–2.83 for [ 18 F]-DA. A limited uptake of [ 18 F]-DA was found in s.c. tumors (TLR=0.22-0.27) compared to [ 18 F]-DOPA (TLR=1.56-2.24). Overall, NET and VMAT2 were expressed in all organ and s.c. tumors. However, s.c. tumors lacked expression of VMAT1. We confirmed [ 18 F]-DA's high affinity for the NET for its uptake and VMAT1 and VMAT2 for its storage and retention in pheochromocytoma cell vesicles. In contrast, [ 18 F]-DOPA was found to utilize only VMAT2. Conclusion: MRI was superior in the detection of all organ tumors compared to microCT and PET. [ 18 F]-DOPA had overall better sensitivity than [ 18 F]-DA for the detection of metastases. Subcutaneous tumors were localized only with [ 18 F]-DOPA, a finding that may reflect differences in expression of VMAT1 and VMAT2, perhaps similar to some patients with pheochromocytoma where [ 18 F]-DOPA provides better visualization of lesions than [ 18 F]-DA.

1,3-Diphenyl-3,4-dihydrobenzo[b][1,6]naphthyridine

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Werner Seebacher

2010-05-01

Full Text Available The title compound, C24H18N2, is the first structural example containing the 3,4-dihydrobenzo[b][1,6]naphthyridine fragment. It was synthesized from 2,4,6,8-tetraphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one and was crystallized from a methanol–ethanol solution over two years as a racemate. The C=N double bond [1.2868 (15 Å] is bent significantly out of the plane of the aromatic bicyclic ring system [N—C—C—C = −157.63 (12°] and out of the plane of the phenyl ring bonded at the 1-position [N—C—C—C = 41.15 (16°].

Identification of Combined Genetic Determinants of Liver Stiffness within the SREBP1c-PNPLA3 Pathway

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Frank Lammert

2013-10-01

Full Text Available The common PNPLA3 (adiponutrin variant, p.I148M, was identified as a genetic determinant of liver fibrosis. Since the expression of PNPLA3 is induced by sterol regulatory element binding protein 1c (SREBP1c, we investigate two common SREBP1c variants (rs2297508 and rs11868035 for their association with liver stiffness. In 899 individuals (aged 17–83 years, 547 males with chronic liver diseases, hepatic fibrosis was non-invasively phenotyped by transient elastography (TE. The SREBP1c single nucleotide polymorphisms (SNPs were genotyped using PCR-based assays with 5'-nuclease and fluorescence detection. The SREBP1c rs11868035 variant affected liver fibrosis significantly (p = 0.029: median TE levels were 7.2, 6.6 and 6.0 kPa in carriers of (TT (n = 421, (CT (n = 384 and (CC (n = 87 genotypes, respectively. Overall, the SREBP1c SNP was associated with low TE levels (5.0–8.0 kPa. Carriers of both PNPLA3 and SREBP1c risk genotypes displayed significantly (p = 0.005 higher median liver stiffness, as compared to patients carrying none of these variants. The common SREBP1c variant may affect early stages of liver fibrosis. Our study supports a role of the SREBP1c-PNPLA3 pathway as a “disease module” that promotes hepatic fibrogenesis.

Nonstructural 5A Protein of Hepatitis C Virus Interferes with Toll-Like Receptor Signaling and Suppresses the Interferon Response in Mouse Liver.

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Takeya Tsutsumi

Full Text Available The hepatitis C virus nonstructural protein NS5A is involved in resistance to the host immune response, as well as the viral lifecycle such as replication and maturation. Here, we established transgenic mice expressing NS5A protein in the liver and examined innate immune responses against lipopolysaccharide (LPS in vivo. Intrahepatic gene expression levels of cytokines such as interleukin-6, tumor necrosis factor-α, and interferon-γ were significantly suppressed after LPS injection in the transgenic mouse liver. Induction of the C-C motif chemokine ligand 2, 4, and 5 was also suppressed. Phosphorylation of the signal transducer and activator of transcription 3, which is activated by cytokines, was also reduced, and expression levels of interferon-stimulated genes, 2'-5' oligoadenylate synthase, interferon-inducible double-stranded RNA-activated protein kinase, and myxovirus resistance 1 were similarly suppressed. Since LPS binds to toll-like receptor 4 and stimulates the downstream pathway leading to induction of these genes, we examined the extracellular signal-regulated kinase and IκB-α. The phosphorylation levels of these molecules were reduced in transgenic mouse liver, indicating that the pathway upstream of the molecules was disrupted by NS5A. Further analyses revealed that the interaction between interleukin-1 receptor-associated kinase-1 and tumor necrosis factor receptor associated factor-6 was dispersed in transgenic mice, suggesting that NS5A may interfere with this interaction via myeloid differentiation primary response gene 88, which was shown to interact with NS5A. Since the gut microbiota, a source of LPS, is known to be associated with pathological conditions in liver diseases, our results suggest the involvement of NS5A in the pathogenesis of HCV infected-liver via the suppression of innate immunity.

Identification of CTLA2A, DEFB29, WFDC15B, SERPINA1F and MUP19 as Novel Tissue-Specific Secretory Factors in Mouse.

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Jibin Zhang

Full Text Available Secretory factors in animals play an important role in communication between different cells, tissues and organs. Especially, the secretory factors with specific expression in one tissue may reflect important functions and unique status of that tissue in an organism. In this study, we identified potential tissue-specific secretory factors in the fat, muscle, heart, lung, kidney and liver in the mouse by analyzing microarray data from NCBI's Gene Expression Omnibus (GEO public repository and searching and predicting their subcellular location in GeneCards and WoLF PSORT, and then confirmed tissue-specific expression of the genes using semi-quantitative PCR reactions. With this approach, we confirmed 11 lung, 7 liver, 2 heart, 1 heart and muscle, 7 kidney and 2 adipose and liver-specific secretory factors. Among these genes, 1 lung-specific gene--CTLA2A (cytotoxic T lymphocyte-associated protein 2 alpha, 3 kidney-specific genes--SERPINA1F (serpin peptidase inhibitor, Clade A, member 1F, WFDC15B (WAP four-disulfide core domain 15B and DEFB29 (defensin beta 29 and 1 liver-specific gene--MUP19 (major urinary protein 19 have not been reported as secretory factors. These genes were tagged with hemagglutinin at the 3'end and then transiently transfected to HEK293 cells. Through protein detection in cell lysate and media using Western blotting, we verified secretion of the 5 genes and predicted the potential pathways in which they may participate in the specific tissue through data analysis of GEO profiles. In addition, alternative splicing was detected in transcripts of CTLA2A and SERPINA1F and the corresponding proteins were found not to be secreted in cell culture media. Identification of novel secretory factors through the current study provides a new platform to explore novel secretory factors and a general direction for further study of these genes in the future.

Novel (1E,3E,5E-1,6-bis(Substituted phenylhexa-1,3,5-triene Analogs Inhibit Melanogenesis in B16F10 Cells and Zebrafish

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Jisun Oh

2018-04-01

Full Text Available The present study aimed to evaluate the anti-melanogenic activity of 1,6-diphenyl-1,3,5-hexatriene and its derivatives in B16F10 murine melanoma cells and zebrafish embryos. Twenty five (1E,3E,5E-1,6-bis(substituted phenylhexa-1,3,5-triene analogs were synthesized and their non-cytotoxic effects were predictively analyzed using three-dimensional quantitative structure-activity relationship approach. Inhibitory activities of these synthetic compounds against melanin synthesis were determined by evaluating melanin content and melanogenic regulatory enzyme expression in B16F10 cells. The anti-melanogenic activity was verified by observing body pigmentation in zebrafishes treated with these compounds. Compound #2, #4, and #6 effectively decreased melanogenesis induced by α-melanocyte-stimulating hormone. In particular, compound #2 remarkably lowered the mRNA and protein expression levels of microphthalmia-associated transcription factor (MITF, tyrosinase (TYR, tyrosinase-related protein 1 (TYRP1, and TYRP2 in B16F10 cells and substantially reduced skin pigmentation in the developed larvae of zebrafish. These findings suggest that compound #2 may be used as an anti-melanogenic agent for cosmetic purpose.

NMR-based Metabolomics Analysis of Liver from C57BL/6 Mouse Exposed to Ionizing Radiation

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Xiao, Xiongjie [Pacific Northwest National Laboratory, Richland, Washington 99352; State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, the Chinese Academy of Sciences, Wuhan, 430071, PR China; University of Chinese Academy of Sciences, Beijing 100049, China; Hu, Mary [Pacific Northwest National Laboratory, Richland, Washington 99352; Zhang, Xu [State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, the Chinese Academy of Sciences, Wuhan, 430071, PR China; Hu, Jian Zhi [Pacific Northwest National Laboratory, Richland, Washington 99352

2017-07-01

The health effects of exposing to ionizing radiation are attracting great interest in the space exploration community and patients considering radiotherapy. However, the impact to metabolism after exposure to high dose radiation has not yet been clearly defined in livers. In the present study, 1H nuclear magnetic resonance (NMR) based metabolomics combined with multivariate data analysis are applied to study the changes of metabolism in the liver of C57BL/6 mouse after whole body exposure to either gamma (3.0 and 7.8 Gy) or proton (3.0 Gy) radiation. Principal component analysis (PCA) and orthogonal projection to latent structures analysis (OPLS) are employed for classification and identification of potential biomarkers associated with gamma and proton irradiation. The results show that the radiation exposed groups can be well separated from the control group. At the same radiation dosage, the group exposed to proton radiation is well separated from the group exposed to gamma radiation, indicating different radiation sources induce different alterations based on metabolic profiling. Common to both gamma and proton radiation at the high radiation doses studied in this work, compared with the control groups the concentrations of choline, O-phosphocholine and trimethylamine N-oxide are decreased statistically, while those of glutamine, glutathione, malate, creatinine, phosphate, betaine and 4-hydroxyphenylacetate are statistically and significantly elevated after exposure to radiation. Since these altered metabolites are associated with multiple biological pathways, the changes suggest that the exposure to radiation induce abnormality in multiple biological pathways. In particular, metabolites such as 4-hydroxyphenylacetate, betaine, glutamine, choline and trimethylamine N-oxide may be good candidates of pre-diagnose biomarkers for ionizing radiation in liver.

Toxicokinetics of chloral hydrate in ad libitum-fed, dietary-controlled, and calorically restricted male B6C3F1 mice following short-term exposure

International Nuclear Information System (INIS)

Seng, John E.; Agrawal, Nalini; Horsley, Elizabeth T.M.; Leakey, Tatiana I.; Scherer, Erin M.; Xia, Shijun; Allaben, William T.; Leakey, Julian E.A.

2003-01-01

Chloral hydrate is widely used as a sedative in pediatric medicine and is a by-product of water chlorination and a metabolic intermediate in the biotransformation of trichloroethylene. Chloral hydrate and its major metabolite, trichloroacetic acid, induce liver tumors in B6C3F 1 mice, a strain that can exhibit high rates of background liver tumor incidence, which is associated with increased body weight. This report describes the influence of diet and body weight on the acute toxicity, hepatic enzyme response, and toxickinetics of chloral hydrate as part of a larger study investigating the carcinogenicity of chloral hydrate in ad libitum-fed and dietary controlled mice. Dietary control involves moderate food restriction to maintain the test animals at an idealized body weight. Mice were dosed with chloral hydrate at 0, 50, 100, 250, 500, and 1000 mg/kg daily, 5 days/week, by aqueous gavage for 2 weekly dosing cycles. Three diet groups were used: ad libitum, dietary control, and 40% caloric restriction. Both dietary control and caloric restriction slightly reduced acute toxicity of high doses of chloral hydrate and potentiated the induction of hepatic enzymes associated with peroxisome proliferation. Chloral hydrate toxicokinetics were investigated using blood samples obtained by sequential tail clipping and a microscale gas chromatography technique. It was rapidly cleared from serum within 3 h of dosing. Trichloroacetate was the major metabolite in serum in all three diet groups. Although the area under the curve values for serum trichloroacetate were slightly greater in the dietary controlled and calorically restricted groups than in the ad libitum-fed groups, this increase did not appear to completely account for the potentiation of hepatic enzyme induction by dietary restriction

and Epigenetic Dysregulation in Diabetes-prone Bicongenic B6.NODC11bxC1tb Mice

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Erin Garrigan

2015-01-01

Full Text Available In Type 1 diabetic (T1D human monocytes, STAT5 aberrantly binds to epigenetic regulatory sites of two proinflammatory genes, CSF2 (encoding granulocyte–macrophage colony-stimulating factor and PTGS2 (encoding prostaglandin synthase 2/cyclooxygenase 2. Bicongenic B6.NOD C11bxC1tb mice re-create this phenotype of T1D monocytes with only two nonobese diabetic (NOD Idd subloci (130.8 Mb–149.7 Mb, of Idd5 on Chr 1 and 32.08–53.85 Mb of Idd4.3 on Chr11 on C57BL/6 genetic background. These two Idd loci interact through STAT5 binding at upstream regulatory regions affecting Csf2 ( Chr 11 and Ptgs2 ( Chr 1 expression. B6.NODC11bxC1tb mice exhibited hyperglycemia and immune destruction of pancreatic islets between 8 and 30 weeks of age, with 12%–22% penetrance. Thus, B6.NODC11bxC1tb mice embody NOD epigenetic dysregulation of gene expression in myeloid cells, and this defect appears to be sufficient to impart genetic susceptibility to diabetes in an otherwise genetically nonautoimmune mouse.

DX5+NKT cells display phenotypical and functional differences between spleen and liver as well as NK1.1-Balb/c and NK1.1+ C57Bl/6 mice.

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Werner, Jens M; Busl, Elisabeth; Farkas, Stefan A; Schlitt, Hans J; Geissler, Edward K; Hornung, Matthias

2011-04-29

Natural killer T cells represent a linkage between innate and adaptive immunity. They are a heterogeneous population of specialized T lymphocytes composed of different subsets. DX5+NKT cells are characterized by expression of the NK cell marker DX5 in the context of CD3. However, little is known about the phenotype and functional capacity of this unique cell population. Therefore, we investigated the expression of several T cell and NK cell markers, as well as functional parameters in spleen and liver subsets of DX5+NKT cells in NK1.1- Balb/c mice and compared our findings to NK1.1+ C57Bl/6 mice. In the spleen 34% of DX5+NKT cells expressed CD62L and they up-regulated the functional receptors CD154 as well as CD178 upon activation. In contrast, only a few liver DX5+NKT cells expressed CD62L, and they did not up-regulate CD154 upon activation. A further difference between spleen and liver subsets was observed in cytokine production. Spleen DX5+NKT cells produced more Th1 cytokines including IL-2, IFN-γ and TNF-α, while liver DX5+NKT cells secreted more Th2 cytokines (e.g. IL-4) and even the Th17 cytokine, IL-17a. Furthermore, we found inter-strain differences. In NK1.1+ C57Bl/6 mice DX5+NKT cells represented a distinct T cell population expressing less CD4 and more CD8. Accordingly, these cells showed a CD178 and Th2-type functional capacity upon activation. These results show that DX5+NKT cells are a heterogeneous population, depending on the dedicated organ and mouse strain, that has diverse functional capacity.

Oral toxicity study of tragacanth gum in B6C3F1 mice: development of squamous-cell hyperplasia in the forestomach and its reversibility.

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Hagiwara, A; Tanaka, H; Tiwawech, D; Shirai, T; Ito, N

1991-10-01

Tragacanth gum was administered at dietary levels of 0 (control), 0.625, 1.25, 2.5, and 5.0% to groups of 10 male and 10 female B6C3F1 mice for 13 wk. There were no treatment-associated effects regarding clinical signs, body or organ weights, and urinalysis or hematology data. Significant dose-related, but slight, elevations of plasma gamma-glutamyl transpeptidase (GGT) level were observed in all treated animals except the 0.625% females. Single or small numbers of tiny nodules were observed on the luminal surface of the forestomach in 4 males of the 5.0% group, 2 males of the 2.5% group, and 1 male each from the 1.25 and 0.625% groups. Histopathologically, they were diagnosed as squamous-cell hyperplasia. To investigate the nature of these gross lesions, tragacanth gum was fed to groups of 30 male mice at the dietary level of 5.0% for periods of up to 48 wk; 20 males served as controls. There were no treatment-related increases of plasma GGT levels at wk 24 and 48. Although squamous-cell hyperplasias were seen in 2 out of 10 mice at wk 24, none of these proliferative lesions were apparent at wk 48, after either chronic exposure or 24 wk on basal diet. Furthermore, the levels of DNA synthesis in forestomach epithelium as measured by 5-bromo-2-deoxyuridine (BrdU) immunohistochemistry were comparable to control values at wk 24 and 48. Thus, the oral toxicity of tragacanth gum to B6C3F1 mice was concluded to be negligible.

Crystal structure of cyclo-tris(μ-3,4,5,6-tetrafluoro-o-phenylene-κ2C1:C2trimercury–tetracyanoethylene (1/1

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Raúl Castañeda

2015-11-01

Full Text Available The title compound, [Hg3(C6F43]·C6N4, contains one molecule of tetracyanoethylene B per one molecule of mercury macrocycle A, i.e., A•B, and crystallizes in the monoclinic space group C2/c. Macrocycle A and molecule B both occupy special positions on a twofold rotation axis and the inversion centre, respectively. The supramolecular unit [A•B] is built by the simultaneous coordination of one of the nitrile N atoms of B to the three mercury atoms of the macrocycle A. The Hg...N distances range from 2.990 (4 to 3.030 (4 Å and are very close to those observed in the related adducts of the macrocycle A with other nitrile derivatives. The molecule of B is almost perpendicular to the mean plane of the macrocycle A at the dihedral angle of 88.20 (5°. The donor–acceptor Hg...N interactions do not affect the C[triple-bond]N bond lengths [1.136 (6 and 1.140 (6 Å]. The trans nitrile group of B coordinates to another macrocycle A, forming an infinite mixed-stack [A•B]∞ architecture toward [101]. The remaining N atoms of two nitrile groups of B are not engaged in any donor–acceptor interactions. In the crystal, the mixed stacks are held together by intermolecular C—F...C[triple-bond]N secondary interactions [2.846 (5–2.925 (5 Å].

In vivo 13C MRS in the mouse brain at 14.1 Tesla and metabolic flux quantification under infusion of [1,6-13C2]glucose.

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Lai, Marta; Lanz, Bernard; Poitry-Yamate, Carole; Romero, Jackeline F; Berset, Corina M; Cudalbu, Cristina; Gruetter, Rolf

2017-01-01

In vivo 13 C magnetic resonance spectroscopy (MRS) enables the investigation of cerebral metabolic compartmentation while, e.g. infusing 13 C-labeled glucose. Metabolic flux analysis of 13 C turnover previously yielded quantitative information of glutamate and glutamine metabolism in humans and rats, while the application to in vivo mouse brain remains exceedingly challenging. In the present study, 13 C direct detection at 14.1 T provided highly resolved in vivo spectra of the mouse brain while infusing [1,6- 13 C 2 ]glucose for up to 5 h. 13 C incorporation to glutamate and glutamine C4, C3, and C2 and aspartate C3 were detected dynamically and fitted to a two-compartment model: flux estimation of neuron-glial metabolism included tricarboxylic acid cycle (TCA) flux in astrocytes (V g  = 0.16 ± 0.03 µmol/g/min) and neurons (V TCA n  = 0.56 ± 0.03 µmol/g/min), pyruvate carboxylase activity (V PC  = 0.041 ± 0.003 µmol/g/min) and neurotransmission rate (V NT  = 0.084 ± 0.008 µmol/g/min), resulting in a cerebral metabolic rate of glucose (CMR glc ) of 0.38 ± 0.02 µmol/g/min, in excellent agreement with that determined with concomitant 18 F-fluorodeoxyglucose positron emission tomography ( 18 FDG PET).We conclude that modeling of neuron-glial metabolism in vivo is accessible in the mouse brain from 13 C direct detection with an unprecedented spatial resolution under [1,6- 13 C 2 ]glucose infusion.

Stress hormones promote growth of B16-F10 melanoma metastases: an interleukin 6- and glutathione-dependent mechanism.

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Valles, Soraya L; Benlloch, María; Rodriguez, María L; Mena, Salvador; Pellicer, José A; Asensi, Miguel; Obrador, Elena; Estrela, José M

2013-03-22

Interleukin (IL)-6 (mainly of tumor origin) activates glutathione (GSH) release from hepatocytes and its interorgan transport to B16-F10 melanoma metastatic foci. We studied if this capacity to overproduce IL-6 is regulated by cancer cell-independent mechanisms. Murine B16-F10 melanoma cells were cultured, transfected with red fluorescent protein, injected i.v. into syngenic C57BL/6J mice to generate lung and liver metastases, and isolated from metastatic foci using high-performance cell sorting. Stress hormones and IL-6 levels were measured by ELISA, and CRH expression in the brain by in situ hybridization. DNA binding activity of NF-κB, CREB, AP-1, and NF-IL-6 was measured using specific transcription factor assay kits. IL-6 expression was measured by RT-PCR, and silencing was achieved by transfection of anti-IL-6 small interfering RNA. GSH was determined by HPLC. Cell death analysis was distinguished using fluorescence microscopy, TUNEL labeling, and flow cytometry techniques. Statistical analyses were performed using Student's t test. Plasma levels of stress-related hormones (adrenocorticotropin hormone, corticosterone, and noradrenaline) increased, following a circadian pattern and as compared to non-tumor controls, in mice bearing B16-F10 lung or liver metastases. Corticosterone and noradrenaline, at pathophysiological levels, increased expression and secretion of IL-6 in B16-F10 cells in vitro. Corticosterone- and noradrenaline-induced transcriptional up-regulation of IL-6 gene involves changes in the DNA binding activity of nuclear factor-κB, cAMP response element-binding protein, activator protein-1, and nuclear factor for IL-6. In vivo inoculation of B16-F10 cells transfected with anti-IL-6-siRNA, treatment with a glucocorticoid receptor blocker (RU-486) or with a β-adrenoceptor blocker (propranolol), increased hepatic GSH whereas decreased plasma IL-6 levels and metastatic growth. Corticosterone, but not NORA, also induced apoptotic cell death in

Remarkable Enhancement of the Hole Mobility in Several Organic Small‐Molecules, Polymers, and Small‐Molecule:Polymer Blend Transistors by Simple Admixing of the Lewis Acid p‐Dopant B(C6F5)3

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Panidi, Julianna; Paterson, Alexandra F.; Khim, Dongyoon; Fei, Zhuping; Han, Yang; Tsetseris, Leonidas; Vourlias, George; Patsalas, Panos A.; Heeney, Martin

2017-01-01

Abstract Improving the charge carrier mobility of solution‐processable organic semiconductors is critical for the development of advanced organic thin‐film transistors and their application in the emerging sector of printed electronics. Here, a simple method is reported for enhancing the hole mobility in a wide range of organic semiconductors, including small‐molecules, polymers, and small‐molecule:polymer blends, with the latter systems exhibiting the highest mobility. The method is simple and relies on admixing of the molecular Lewis acid B(C6F5)3 in the semiconductor formulation prior to solution deposition. Two prototypical semiconductors where B(C6F5)3 is shown to have a remarkable impact are the blends of 2,8‐difluoro‐5,11‐bis(triethylsilylethynyl)anthradithiophene:poly(triarylamine) (diF‐TESADT:PTAA) and 2,7‐dioctyl[1]‐benzothieno[3,2‐b][1]benzothiophene:poly(indacenodithiophene‐co‐benzothiadiazole) (C8‐BTBT:C16‐IDTBT), for which hole mobilities of 8 and 11 cm2 V−1 s−1, respectively, are obtained. Doping of the 6,13‐bis(triisopropylsilylethynyl)pentacene:PTAA blend with B(C6F5)3 is also shown to increase the maximum hole mobility to 3.7 cm2 V−1 s−1. Analysis of the single and multicomponent materials reveals that B(C6F5)3 plays a dual role, first acting as an efficient p‐dopant, and secondly as a microstructure modifier. Semiconductors that undergo simultaneous p‐doping and dopant‐induced long‐range crystallization are found to consistently outperform transistors based on the pristine materials. Our work underscores Lewis acid doping as a generic strategy towards high performance printed organic microelectronics. PMID:29375962

UDP-Glucuronosyltransferase Expression in Mouse Liver Is Increased in Obesity- and Fasting-Induced Steatosis

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Xu, Jialin; Kulkarni, Supriya R.; Li, Liya

2012-01-01

UDP-glucuronosyltransferases (Ugt) catalyze phase II conjugation reactions with glucuronic acid, which enhances chemical polarity and the elimination from the body. Few studies have addressed whether Ugt expression and activity are affected by liver disease, such as steatosis. The purpose of this study was to determine whether steatosis induced by obesity or fasting could affect liver Ugt mRNA expression and activity. Male C57BL/6J and Lepob/ob (ob/ob) mice were fed ad libitum or food was withheld for 24 h. In steatotic livers of ob/ob mice, Ugt1a1, -1a6, -1a9, -2a3, -3a1, and -3a2 mRNA expression increased. Fasting, which also induced steatosis, increased hepatic Ugt1a1, -1a6, -1a7, -1a9, -2b1, -2b5, -2a3, -3a1, and -3a2 mRNA expression in mouse liver. Likewise, acetaminophen glucuronidation increased by 47% in hepatic microsomes from ob/ob mice compared with that in C57BL/6J mice, but not after fasting. In both steatosis models, Ugt induction was accompanied by increased aryl hydrocarbon receptor, constitutive androstane receptor (CAR), peroxisome proliferator-activated receptor (PPAR)-α, pregnane X receptor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and peroxisome proliferator-activated receptor-γ coactivator-1α mRNA expression. In addition, fasting increased CAR, PPAR, and Nrf2 binding activity. The work points to hepatic triglyceride concentrations corresponding with nuclear receptor and Ugt expression. The findings indicate that steatosis significantly alters hepatic Ugt expression and activity, which could have a significant impact on determining circulating hormone levels, drug efficacy, and environmental chemical clearance. PMID:22031624

UDP-glucuronosyltransferase expression in mouse liver is increased in obesity- and fasting-induced steatosis.

Science.gov (United States)

Xu, Jialin; Kulkarni, Supriya R; Li, Liya; Slitt, Angela L

2012-02-01

UDP-glucuronosyltransferases (Ugt) catalyze phase II conjugation reactions with glucuronic acid, which enhances chemical polarity and the elimination from the body. Few studies have addressed whether Ugt expression and activity are affected by liver disease, such as steatosis. The purpose of this study was to determine whether steatosis induced by obesity or fasting could affect liver Ugt mRNA expression and activity. Male C57BL/6J and Lep(ob/ob) (ob/ob) mice were fed ad libitum or food was withheld for 24 h. In steatotic livers of ob/ob mice, Ugt1a1, -1a6, -1a9, -2a3, -3a1, and -3a2 mRNA expression increased. Fasting, which also induced steatosis, increased hepatic Ugt1a1, -1a6, -1a7, -1a9, -2b1, -2b5, -2a3, -3a1, and -3a2 mRNA expression in mouse liver. Likewise, acetaminophen glucuronidation increased by 47% in hepatic microsomes from ob/ob mice compared with that in C57BL/6J mice, but not after fasting. In both steatosis models, Ugt induction was accompanied by increased aryl hydrocarbon receptor, constitutive androstane receptor (CAR), peroxisome proliferator-activated receptor (PPAR)-α, pregnane X receptor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and peroxisome proliferator-activated receptor-γ coactivator-1α mRNA expression. In addition, fasting increased CAR, PPAR, and Nrf2 binding activity. The work points to hepatic triglyceride concentrations corresponding with nuclear receptor and Ugt expression. The findings indicate that steatosis significantly alters hepatic Ugt expression and activity, which could have a significant impact on determining circulating hormone levels, drug efficacy, and environmental chemical clearance.

Ab initio dynamics trajectory study of the heterolytic cleavage of H2 by a Lewis acid [B(C6F5)3] and a Lewis base [P(tBu)3

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Pu, Maoping; Privalov, Timofei

2013-04-01

Activation of H2 by a "frustrated Lewis pair" (FLP) composed of B(C6F5)3 and P(tBu)3 species has been explored with high level direct ab initio molecular dynamics (AIMD) simulations at finite temperature (T = 300 K) in gas phase. The initial geometrical conditions for the AIMD trajectory calculations, i.e., the near attack conformations of FLP + H2, were devised using the host-guest model in which suitable FLP conformations were obtained from the dynamics of the B(C6F5)3/P(tBu)3 pair in gas phase. AIMD trajectory calculations yielded microscopic insight into effects which originate from nuclear motion in the reacting complex, e.g., the alternating compression/elongation of the boron-phosphorous distance and the change of the pyramidality of boron in B(C6F5)3. The ensemble averaged trajectory analysis has been compared with the minimum energy path (MEP) description of the reaction. Similar to MEP, AIMD shows that an attack of the acid/base pair on the H-H bond gives rise to the polarization of the H2 molecule and as a consequence generates a large dipole moment of the reacting complex. The MEP and AIMD portrayals of the reaction are fundamentally different in terms of the magnitude of the motion of nuclei in B(C6F5)3 and P(tBu)3 during the H2 cleavage. In the AIMD trajectory simulations, geometries of B(C6F5)3 and P(tBu)3 appear as nearly "frozen" on the short time scale of the H2 cleavage. This is contrary to the MEP picture. Several of the concepts which arise from this work, e.g., separation of time scales of nuclear motion and the time-dependence of the donor-acceptor interactions in the reacting complex, are important for the understanding of chemical reactivity and catalysis.

Benzene metabolite levels in blood and bone marrow of B6C3F{sub 1} mice after low-level exposure

Energy Technology Data Exchange (ETDEWEB)

Bechtold, W.E.; Strunk, M.R.; Thornton-Manning, J.R. [and others

1995-12-01

Studies at the Inhalation Toxicology Research Institute (ITRI) have explored the species-specific uptake and metabolism of benzene. Results have shown that metabolism is dependent on both dose and route of administration. Of particular interest were shifts in the major metabolic pathways as a function of exposure concentration. In these studies, B6C3F{sub 1} mice were exposed to increasing levels of benzene by either gavage or inhalation. As benzene internal dose increased, the relative amounts of muconic acid and hydroquinone decreased. In contrast, the relative amount of catechol increased with increasing exposure. These results show that the relative levels of toxic metabolites are a function of exposure level. Based on these results and assuming a linear relationship between exposure concentration and levels of bone marrow metabolites, it would be difficult to detect an elevation of any phenolic metabolites above background after occupational exposures to the OSHA Permissible Exposure Limit of 1 ppm benzene.

New organic superconductors beta-(BDA-TTP)2X [BDA-TTP + 2,5-bis(1,3-dithian-2ylidene)-1,3,4,6-tetrathiapentalene; X(-) = SbF6(-), AsF6(-), and PF6(-)].

Science.gov (United States)

Yamada, J; Watanabe, M; Akutsu, H; Nakatsuji, S; Nishikawa, H; Ikemoto, I; Kikuchi, K

2001-05-09

The synthesis, electrochemical properties, and molecular structure of a new pi-electron donor, 2,5-bis(1,3-dithian-2-ylidene)-1,3,4,6-tetrathiapentalene (BDA-TTP), is described. In contrast to the hitherto-known tetrachalcogenafulvalene pi-donors providing organic superconductors, this donor contains only the bis-fused 1,3-dithiole-2-ylidene unit as a pi-electron system, yet produces a series of ambient-pressure superconductors beta-(BDA-TTP)2X [X = SbF6 (magnetic T(c) = 6.9 K, resistive T(c) = 7.5 K), AsF6 (magnetic T(c) = 5.9 K, resistive T(c) = 5.8 K), and PF6 (magnetic T(c) = 5.9 K)], which are isostructural. The values of the intermolecular overlap integrals calculated on the donor layers of these superconductors suggest a two-dimensional (2D) electronic structure with loose donor packing. Tight-binding band calculations also indicate that these superconductors have the 2D band dispersion relations and closed Fermi surfaces.

Diagnostic Usefulness of Real-Time Elastography for Liver Fibrosis in Chronic Viral Hepatitis B and C

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Young Woon Kim

2014-01-01

Full Text Available The aim of this study was to investigate the diagnostic usefulness of real-time elastography (RTE for liver fibrosis in chronic viral hepatitis B (CHB and C (CHC. Fifty-one and thirty-two of the patients were diagnosed with CHB and CHC, respectively. Enrolled patients underwent liver biopsy and RTE. The FIB-4 index and aspartate transaminase-to-platelet ratio index (APRI were also measured. The liver fibrosis index (LFI by RTE increased significantly with the Knodell fibrosis stage: 3.14±0.62 for F0, 3.28 ± 0.42 for F1, 3.43 ± 0.53 for F3, and 4.09 ± 1.03 for F4 (P=0.000. LFI as well as APRI, FIB-4, platelet, albumin, and prothrombin time showed the difference in patients with advanced fibrosis (≥F3 and those with mild fibrosis (≤F1. In addition, RTE had better discrimination power between ≥F3 and F4 than between FIB-4 and APRI. In CHC patients, the area under receiver operating characteristic curves of RTE for advanced fibrosis was higher than that in CHB patients (0.795 versus 0.641. RTE is useful for the assessment of advanced fibrosis in patients with CHB and CHC and has better discrimination power than other serologic markers.

Phenobarbital induces cell cycle transcriptional responses in mouse liver humanized for constitutive androstane and pregnane x receptors.

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Luisier, Raphaëlle; Lempiäinen, Harri; Scherbichler, Nina; Braeuning, Albert; Geissler, Miriam; Dubost, Valerie; Müller, Arne; Scheer, Nico; Chibout, Salah-Dine; Hara, Hisanori; Picard, Frank; Theil, Diethilde; Couttet, Philippe; Vitobello, Antonio; Grenet, Olivier; Grasl-Kraupp, Bettina; Ellinger-Ziegelbauer, Heidrun; Thomson, John P; Meehan, Richard R; Elcombe, Clifford R; Henderson, Colin J; Wolf, C Roland; Schwarz, Michael; Moulin, Pierre; Terranova, Rémi; Moggs, Jonathan G

2014-06-01

The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcinogenesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CAR(KO)-PXR(KO)), double humanized CAR and PXR (CAR(h)-PXR(h)), and wild-type C57BL/6 mice. Wild-type and CAR(h)-PXR(h) mouse livers exhibited temporally and quantitatively similar transcriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1) and the proliferation-related nuclear antigen Mki67 were observed with peak expression occurring between 1 and 7 days PB exposure. All these transcriptional responses were absent in CAR(KO)-PXR(KO) mouse livers and largely reversible in wild-type and CAR(h)-PXR(h) mouse livers following 91 days of PB exposure and a subsequent 4-week recovery period. Furthermore, PB-mediated upregulation of the noncoding RNA Meg3, which has recently been associated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CAR(h)-PXR(h) mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB.

First report of an HIV-1 triple recombinant of subtypes B, C and F in Buenos Aires, Argentina

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Weissenbacher Mercedes

2006-09-01

Full Text Available Abstract We describe the genetic diversity of currently transmitted strains of HIV-1 in men who have sex with men (MSM in Buenos Aires, Argentina between 2000 and 2004. Nearly full-length sequence analysis of 10 samples showed that 6 were subtype B, 3 were BF recombinant and 1 was a triple recombinant of subtypes B, C and F. The 3 BF recombinants were 3 different unique recombinant forms. Full genome analysis of one strain that was subtype F when sequenced in pol was found to be a triple recombinant. Gag and pol were predominantly subtype F, while gp120 was subtype B; there were regions of subtype C interspersed throughout. The young man infected with this strain reported multiple sexual partners and sero-converted between May and November of 2004. This study reported for the first time the full genome analysis of a triple recombinant between subtypes B, C and F, that combines in one virus the three most common subtypes in South America.

Decreased expression of insulin-like growth factor binding protein-related protein-1 (IGFBP-rP1) in radiation-induced mouse hepatocellular carcinoma

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Teishima, Jun [Hiroshima Univ. (Japan). Research Inst. for Radiation Biology and Medicine

2002-04-01

Insulin-like growth factor binding protein-related protein-1 (IGFBP-rP1) is a member of the IGFBP family, which was called IGFBP-7 or mac25 previously. Decreased expression of IGFBP-rP1 has been shown in breast cancer and prostatic cancer, and tumor suppressive effects of IGFBP-rP1 have been reported in prostatic cancer and osteosarcoma cell lines. In the present study, we investigated whether expression levels of IGFBP-rP1 were related to the development and the growth of radiation-induced hepatomas of B6C3F1 mice. In northern blot analysis, decreased expressions of IGFBP-rP1 gene were shown in radiation-induced mouse hepatomas compared to normal livers. In hepatoma cell lines established from these hepatomas, decreased expressions of IGFBP-rP1 were strongly related to the grade of anchorage-independent growth. In cell lines which were transfected with IGFBP-rP1cDNA, the doubling time of cell growth was increased, and the number and the size of colony formation in soft agar culture were decreased. In tumor formation assay by injecting these cells to B6C3F1 mice subcutaneously, the volume of tumors were decreased. Furthermore, the decreased expression of IGFBP-rP1 gene was observed in human hepatomas by northern blot analysis. These results may suggest that the suppression of IGFBP-rP1 is related to development and progression of mouse and human hepatomas. (author)

Nuclear receptor CAR (NR1I3) is essential for DDC-induced liver injury and oval cell proliferation in mouse liver.

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Yamazaki, Yuichi; Moore, Rick; Negishi, Masahiko

2011-11-01

The liver is endowed with the ability to regenerate hepatocytes in response to injury. When this regeneration ability is impaired during liver injury, oval cells, which are considered to be postnatal hepatic progenitors, proliferate and differentiate into hepatocytes. Here we have demonstrated that 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) activates the nuclear receptor constitutive active/androstane receptor (CAR), resulting in proliferation of oval cells in mouse liver. Activation of CAR by DDC was shown by hepatic nuclear CAR accumulation and cytochrome P450 (CYP)2B10 mRNA induction after feeding a 0.1% DDC-containing diet to Car(+/+) mice. After being fed the DDC diet, Car(+/+), but not Car(-/-) mice, developed severe liver injury and an A6 antibody-stained ductular reaction in an area around the portal tract. Oval cell proliferation was confirmed by laser capture microdissection and real-time PCR; mRNAs for the two oval cell markers epithelial cell adhesion molecule and TROP2 were specifically induced in the periportal region of DDC diet-fed Car(+/+), but not Car(-/-) mice. Although rates of both hepatocyte growth and death were initially enhanced only in DDC diet-fed Car(+/+) mice, growth was attenuated when oval cells proliferated, whereas death continued unabated. DDC-induced liver injury, which differs from other CAR activators such as phenobarbital, occurred in the periportal region where cells developed hypertrophy, accumulated porphyrin crystals and inflammation developed, all in association with the proliferation of oval cells. Thus, CAR provides an excellent experimental model for further investigations into its roles in liver regeneration, as well as the development of diseases such as hepatocellular carcinoma.

Stress hormones promote growth of B16-F10 melanoma metastases: an interleukin 6- and glutathione-dependent mechanism

OpenAIRE

Valles, Soraya L; Benlloch, Mar?a; Rodriguez, Mar?a L; Mena, Salvador; Pellicer, Jos? A; Asensi, Miguel; Obrador, Elena; Estrela, Jos? M

2013-01-01

[EN] Background: Interleukin (IL)-6 (mainly of tumor origin) activates glutathione (GSH) release from hepatocytes and its interorgan transport to B16-F10 melanoma metastatic foci. We studied if this capacity to overproduce IL-6 is regulated by cancer cell-independent mechanisms. Methods: Murine B16-F10 melanoma cells were cultured, transfected with red fluorescent protein, injected i.v. into syngenic C57BL/6J mice to generate lung and liver metastases, and isolated from metastatic f...

Potent inhibition of cytochrome P450 2B6 by sibutramine in human liver microsomes.

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Bae, Soo Hyeon; Kwon, Min Jo; Choi, Eu Jin; Zheng, Yu Fen; Yoon, Kee Dong; Liu, Kwang-Hyeon; Bae, Soo Kyung

2013-09-05

The present study was performed to evaluate the potency and specificity of sibutramine as an inhibitor of the activities of nine human CYP isoforms in liver microsomes. Using a cocktail assay, the effects of sibutramine on specific marker reactions of the nine CYP isoforms were measured in human liver microsomes. Sibutramine showed potent inhibition of CYP2B6-mediated bupropion 6-hydroxylation with an IC50 value of 1.61μM and Ki value of 0.466μM in a competitive manner at microsomal protein concentrations of 0.25mg/ml; this was 3.49-fold more potent than the typical CYP2B6 inhibitor thio-TEPA (Ki=1.59μM). In addition, sibutramine slightly inhibited CYP2C19 activity (Ki=16.6μM, noncompetitive inhibition) and CYP2D6 activity (Ki=15.7μM, noncompetitive inhibition). These observations indicated 35.6- and 33.7-fold decreases in inhibition potency, respectively, compared with that of CYP2B6 by sibutramine. However, no inhibition of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6, or CYP2E1 activities was observed. In addition, the CYP2B6 inhibitory potential of sibutramine was enhanced at a lower microsomal protein concentration of 0.05mg/ml. After 30min preincubation of human liver microsomes with sibutramine in the presence of NADPH, no shift in IC50 was observed in terms of inhibition of the activities of the nine CYPs, suggesting that sibutramine is not a time-dependent inactivator. These observations suggest that sibutramine is a selective and potent inhibitor of CYP2B6 in vitro, whereas inhibition of other CYPs is substantially lower. These in vitro data support the use of sibutramine as a well-known inhibitor of CYP2B6 for routine screening of P450 reversible inhibition when human liver microsomes are used as the enzyme source. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Toxicity and carcinogenicity of methyl isobutyl ketone in F344N rats and B6C3F1 mice following 2-year inhalation exposure

International Nuclear Information System (INIS)

Stout, Matthew D.; Herbert, Ronald A.; Kissling, Grace E.; Suarez, Fernando; Roycroft, Joseph H.; Chhabra, Rajendra S.; Bucher, John R.

2008-01-01

Methyl isobutyl ketone (MIBK) is primarily used as a denaturant for rubbing alcohol, as a solvent and in the manufacture of methyl amyl alcohol. Inhalation of vapors is the most likely route of exposure in the work place. In order to evaluate the potential of MIBK to induce toxic and carcinogenic effects following chronic exposure, groups of 50 male and 50 female F344/N rats and B6C3F1 mice were exposed to MIBK at concentrations of 0, 450, 900, or 1800 ppm by inhalation, 6 h/day, 5 days per week for 2 years. Survival was decreased in male rats at 1800 ppm. Body weight gains were decreased in male rats at 900 and 1800 ppm and in female mice at 1800 ppm. The primary targets of MIBK toxicity and carcinogenicity were the kidney in rats and the liver in mice. In male rats, there was increased mineralization of the renal papilla at all exposure concentrations. The incidence of chronic progressive nephropathy (CPN) was increased at 1800 ppm and the severity was increased in all exposed groups. There were also increases in renal tubule hyperplasia at all exposure concentrations, and in adenoma and adenoma or carcinoma (combined) at 1800 ppm; these lesions are thought to represent a continuum in the progression of proliferative lesions in renal tubule epithelium. These increases may have resulted from the increased severity of CPN, either through α2μ-globulin-dependent or -independent mechanisms. An increase in mononuclear cell leukemia at 1800 ppm was an uncertain finding. Adrenal medulla hyperplasia was increased at 1800 ppm, and there was a positive trend for increases in benign or malignant pheochromocytomas (combined). In female rats, there were increases in the incidence of CPN in all exposure concentrations and in the severity at 1800 ppm, indicating that CPN was increased by mechanisms in addition to those related to α2μ-globulin. There were renal mesenchymal tumors, which have not been observed in historical control animals, in two female rats at 1800 ppm. The

NTP Toxicology and Carcinogenesis Studies of Chloroprene (CAS No. 126-99-8) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Science.gov (United States)

1998-09-01

Chloroprene is used almost exclusively in the manufacture of neoprene (polychloroprene). Chloroprene was chosen for study because it is a high-volume production chemical with limited information on its carcinogenic potential and because it is the 2-chloro analogue of 1,3-butadiene, a potent, multi-species, multi-organ carcinogen. Male and female F344/N rats and B6C3F1 mice were exposed to chloroprene (greater than 96% pure) by inhalation for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Drosophila melanogaster, and B6C3F1 mice (bone marrow cells and peripheral blood erythrocytes). 16-Day Study in Rats: Groups of 10 male and 10 female F344/N rats were exposed to 0, 32, 80, 200, or 500 ppm chloroprene by inhalation, 6 hours per day, 5 days per week, for 16 days. Three 500 ppm males died on day 2 or 3 of the study. Mean body weight gains of 200 ppm males and females and 500 ppm females were significantly less than those of the chamber control groups. On the first day of exposure, rats exposed to 500 ppm were hypoactive and unsteady and had rapid shallow breathing. These effects were also observed to some degree in animals exposed to 200 ppm. After the second day of exposure, the effects in these groups worsened, and hemorrhage from the nose was observed. A normocytic, normochromic, responsive anemia; thrombocytopenia; and increases in serum activities of alanine aminotransferase, glutamate dehydrogenase, and sorbitol dehydrogenase occurred on day 4 in 200 ppm females and 500 ppm males. Kidney weights of 80 and 500 ppm females were significantly greater than those of the chamber control group, as were the liver weights of 200 and 500 ppm females. The incidences of minimal to mild olfactory epithelial degeneration of the nose in all exposed groups of males and females were significantly greater than those in the chamber control groups. The incidence of squamous metaplasia of the respiratory epithelium was

Influence of hepatitis C virus and IL28B genotypes on liver stiffness.

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Lene Fogt Lundbo

Full Text Available Liver fibrosis has been associated with hepatitis C virus (HCV genotype and genetic variation near the interleukin 28B (IL28B gene, but the relative contribution is unknown. We aimed to investigate the relation between HCV genotypes, IL28B and development of liver stiffness.This cross-sectional study consists of 369 patients with chronic hepatitis C (CHC. Liver stiffness was evaluated using transient elastograhy (TE. Factors associated with development of liver fibrosis were identified by logistic regression analysis.We identified 369 patients with CHC. 235 were male, 297 Caucasians, and 223 had been exposed to HCV through intravenous drug use. The overall median TE value was 7.4 kPa (interquartile range (IQR 5.7-12.1. HCV replication was enhanced in patients carrying the IL28B CC genotype compared to TT and TC (5.8 vs. 5.4 log10 IU/mL, p = 0.03. Patients infected with HCV genotype 3 had significantly higher TE values (8.2 kPa; IQR, 5.9-14.5 compared to genotype 1 (6.9 kPa; IQR, 5.4-10.9 and 2 (6.7 kPa; IQR, 4.9-8.8 (p = 0.02. Within patients with genotype 3, IL28B CC genotype had the highest TE values (p = 0.04. However, in multivariate logistic regression, using various cut-off values for fibrosis and cirrhosis, only increasing age (odds ratio (OR 1.09 (95% confidence interval (CI, 1.05-1.14 per year increment, ALT (OR 1.01 (95% CI, 1.002-1.011, per unit increment and HCV genotype 3 compared to genotype 1 (OR 2.40 (95% CI, 1.19-4.81, were consistently associated with cirrhosis (TE>17.1 kPa.Age, ALT and infection with HCV genotype 3 were associated with cirrhosis assessed by TE. However, IL28B genotype was not an independent predictor of fibrosis in our study.

Clinical Chemistry Reference Intervals for C57BL/6J, C57BL/6N, and C3HeB/FeJ Mice (Mus musculus).

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Otto, Gordon P; Rathkolb, Birgit; Oestereicher, Manuela A; Lengger, Christoph J; Moerth, Corinna; Micklich, Kateryna; Fuchs, Helmut; Gailus-Durner, Valérie; Wolf, Eckhard; Hrabě de Angelis, Martin

2016-01-01

Although various mouse inbred strains are widely used to investigate disease mechanisms and to establish new therapeutic strategies, sex-specific reference intervals for laboratory diagnostic analytes that are generated from large numbers of animals have been unavailable. In this retrospective study, we screened data from more than 12,000 mice phenotyped in the German Mouse Clinic from January 2006 through June 2014 and selected animals with the genetic background of C57BL/6J, C57BL/6N, or C3HeB/FeJ. In addition, we distinguished between the C57BL/6NTac substrain and C57BL/6N mice received from other vendors. The corresponding data sets of electrolytes (sodium, potassium, calcium, chloride, inorganic phosphate), lipids (cholesterol, triglyceride), and enzyme activities (ALT, AST, ALP, α-amylase) and urea, albumin, and total protein levels were analyzed. Significant effects of age and sex on these analytes were identified, and strain- or substrain- and sex-specific reference intervals for 90- to 135-d-old mice were calculated. In addition, we include an overview of the literature that reports clinical chemistry values for wild-type mice of different strains. Our results support researchers interpreting clinical chemistry values from various mouse mutants and corresponding wild-type controls based on the examined strains and substrains.

Hinokitiol, a tropolone derivative, inhibits mouse melanoma (B16-F10) cell migration and in vivo tumor formation.

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Huang, Chien-Hsun; Lu, Shing-Hwa; Chang, Chao-Chien; Thomas, Philip Aloysius; Jayakumar, Thanasekaran; Sheu, Joen-Rong

2015-01-05

Invasion and metastasis are the major causes of treatment failure in patients with cancer. Hinokitiol, a natural bioactive compound found in Chamacyparis taiwanensis, has been used in hair tonics, cosmetics, and food as an antimicrobial agent. In this study, we investigated the effects and possible mechanisms of action of hinokitiol on migration by the metastatic melanoma cell line, B16-F10, in which matrix metalloproteinase-1 (MMP-1) is found to be highly- expressed. Treatment with hinokitiol revealed a concentration-dependent inhibition of migration of B16-F10 melanoma cells. Hinokitiol appeared to achieve this effect by reducing the expression of MMP-1 and by suppressing the phosphorylation of mitogen- activated protein kinase (MAPK) signaling molecules such as extracellular signal-regulated kinase (ERK) 1/2, p38 MAPK and c-Jun N-terminal kinases (JNK). On the other hand, hinokitiol treatment reversed IκB-α degradation and inhibited the phosphorylation of p65 nuclear factor kappa B (NF-κB) and cJun in B16-F10 cells. In addition, hinokitiol suppressed the translocation of p65 NF-κB from the cytosol to the nucleus, suggesting reduced NF-κB activation. Consistent with these in vitro findings, our in vivo study demonstrated that hinokitiol treatment significantly reduced the total number of mouse lung metastatic nodules and improved histological alterations in B16-F10 injected C57BL/6 mice. These findings suggest that treatment of B16-F10 cells with hinokitiol significantly inhibits metastasis, possibly by blocking MMP-1 activation, MAPK signaling pathways and inhibition of the transcription factors, NF-κB and c-Jun, involved in cancer cell migration. These results may accelerate the development of novel therapeutic agents for the treatment of malignant cancers. Copyright © 2014 Elsevier B.V. All rights reserved.

Metabolic fate of 18F-FDG in mice bearing either SCCVII squamous cell carcinoma or C3H mammary carcinoma

DEFF Research Database (Denmark)

Kaarstad, Katrin; Bender, Dirk; Bentzen, Lise

2002-01-01

in mice. METHODS: 18F-FDG was given intravenously to mice with either SCCVII squamous cell carcinoma or C3H mammary carcinoma grown on the back. 18F-Labeled metabolites were determined by radio-high-performance liquid chromatography in tumor tissue biopsies, in a time course of 180 min (12 mice of each...... tumor type), and in liver tissue biopsies 80 min after tracer injection (2 mice of each type). RESULTS: After the tracer injection, not only 18F-FDG and 18F-FDG-6-P but also 18F-FD-PG1 and 2-18F-fluoro-2-deoxy-1,6-biphosphate were detected in both tumors, relatively more in SCCVII carcinoma than in C3H...... carcinoma. Both tumors accumulated radioactivity throughout the 180-min measurement period, 4-fold more in SCCVII carcinoma than in C3H carcinoma. At 80 min, the radioactivity was approximately 6 and 1.2 times higher in the respective tumors than in liver tissue. CONCLUSION: Our results agree...

Assessment of immunotoxicity in female Fischer 344/N and Sprague Dawley rats and female B6C3F1 mice exposed to hexavalent chromium via the drinking water.

Science.gov (United States)

Shipkowski, Kelly A; Sheth, Christopher M; Smith, Matthew J; Hooth, Michelle J; White, Kimber L; Germolec, Dori R

2017-12-01

Sodium dichromate dihydrate (SDD), an inorganic compound containing hexavalent chromium (Cr(VI)), is a common environmental contaminant of groundwater sources due to widespread industrial use. There are indications in the literature that Cr(VI) may induce immunotoxic effects following dermal exposure, including acting as both an irritant and a sensitizer; however, the potential immunomodulatory effects of Cr(VI) following oral exposure are relatively unknown. Following the detection of Cr(VI) in drinking water sources, the National Toxicology Program (NTP) conducted extensive evaluations of the toxicity and carcinogenicity of SDD following drinking water exposure, including studies to assess the potential for Cr(VI) to modulate immune function. For the immunotoxicity assessments, female Fischer 344/N (F344/N) and Sprague Dawley (SD) rats and female B 6 C 3 F 1 mice were exposed to SDD in drinking water for 28 consecutive days and evaluated for alterations in cellular and humoral immune function as well as innate immunity. Rats were exposed to concentrations of 0, 14.3, 57.3, 172, or 516 ppm SDD while mice were exposed to concentrations of 0, 15.6, 31.3, 62.5, 125, or 250 ppm SDD. Final mean body weight and body weight gain were decreased relative to controls in 250 ppm B 6 C 3 F 1 mice and 516 ppm SD rats. Water consumption was significantly decreased in F344/N and SD rats exposed to 172 and 516 ppm SDD; this was attributed to poor palatability of the SDD drinking water solutions. Several red blood cell-specific parameters were significantly (5-7%) decreased in 250 ppm mice; however, these parameters were unaffected in rats. Sporadic increases in the spleen IgM antibody response to sheep red blood cells (SRBC) were observed, however, these increases were not dose-dependent and were not reproducible. No significant effects were observed in the other immunological parameters evaluated. Overall, exposure to Cr(VI) in drinking water had limited effects on

Changes in the expression of Hepatic Cytochrome P450 Isoenzymes 2E1, 2B1/2, 4A, and 2C6 in mice infected with different levels of Schistosoma Mansoni Cercariae

International Nuclear Information System (INIS)

Sheweita, Salah A.

2005-01-01

Most xenobiotic agents are metabolized by cytochrome P450 system. In the present study, Western blotting was used to investigate the effect of different levels of Schistosoma Mansoni infection on the expression of somr cytochrome P450 isozymes (CYP 2E1, 2B1/2, 2C6, 4A) and to enzyme assay their related metabolic functions in mouse liver microsomes. Male mice were infected with 60, 120, 180, 300 and 600 Schistosoma Mansoni cercariae per mouse for 33 days and 60, 120, 180 and 300 cercariae/mouse with no change at the last level of Schistosoma Mansoni infection. Also the expression of CYP 4A was potentially induced at all levels of Schistosoma Mansoni infection. A significant induction of CYP 2B1/2 expression was observed at all levels of Schistosoma Mansoni infection with loss of signal at 180 cercariaea/mouse. In contrast, CYP 2C6 expression was induced at the first two levels and such expression was decreased at the last three levels. In addition, the infection of the mouse with 60, 120 and 180 cercariae/mouse decreased; [1] 7-methoxycoumarin O-demethylase activity by 36, 54 and 58% respectively; [2] 7-ethoxycoumarin O-deethylase activity by 33, 40 and 57% respectively; [3] coumarin hydroxlase activity by 33, 45 and 55% respectively. However, 300 and 600 cercariae/mouse induced: [1] 7-methoxycoumarin O-demethylase activity by 45 and 97% respectively: [2] 7-ethoxycoumarin O-deethylase activity by 26 and 90% respectively; [3] coumarin hydroxylase activity by 100 and 200% respectively. In addition, all levels of Schistosoma Mansoni infection decreased the sleeping time caused by hexobarital. It is concluded that different levels of Schistosoma Mansoni infection change the expression of different CYPisozymes and that these alterations could enhance the carcinogenicity of N-nitrosamines which is mainly dependent on CYP 2E1. The alterations in the expression of CYP 2E1, 4A and 2B1/2 isozymes as a result of Schistosoma Mansoni infection may change the therapeutic actions

Enzyme Kinetics and Molecular Docking Studies on Cytochrome 2B6, 2C19, 2E1, and 3A4 Activities by Sauchinone

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Eun Chae Gong

2018-03-01

Full Text Available Sauchinone, an active lignan isolated from the aerial parts of Saururus chinensis (Saururaceae, exhibits anti-inflammatory, anti-obesity, anti-hyperglycemic, and anti-hepatic steatosis effects. As herb–drug interaction (HDI through cytochrome P450s (CYPs-mediated metabolism limits clinical application of herbs and drugs in combination, this study sought to explore the enzyme kinetics of sauchinone towards CYP inhibition in in vitro human liver microsomes (HLMs and in vivo mice studies and computational molecular docking analysis. In in vitro HLMs, sauchinone reversibly inhibited CYP2B6, 2C19, 2E1, and 3A4 activities in non-competitive modes, showing inhibition constant (Ki values of 14.3, 16.8, 41.7, and 6.84 μM, respectively. Also, sauchinone time-dependently inhibited CYP2B6, 2E1 and 3A4 activities in vitro HLMs. Molecular docking study showed that sauchinone could be bound to a few key amino acid residues in the active site of CYP2B6, 2C19, 2E1, and 3A4. When sibutramine, clopidogrel, or chlorzoxazone was co-administered with sauchinone to mice, the systemic exposure of each drug was increased compared to that without sauchinone, because sauchinone reduced the metabolic clearance of each drug. In conclusion, when sauchinone was co-treated with drugs metabolized via CYP2B6, 2C19, 2E1, or 3A4, sauchinone–drug interactions occurred because sauchinone inhibited the CYP-mediated metabolic activities.

Inefficient binding of IgM immune complexes to erythrocyte C3b-C4b receptors (CR1) and weak incorporation of C3b-iC3b into the complexes

DEFF Research Database (Denmark)

Kávai, M; Rasmussen, J M; Baatrup, G

1988-01-01

, but the binding was low (2-3%) when compared to the binding of the corresponding IgG-IC (50-60%). Solid phase IC were prepared by coating microwells with heat-aggregated bovine serum albumin (BSA) followed by incubation with rabbit IgM anti-BSA antibody. The IC were reacted with human serum at 37 degrees C....... The binding of C3b-iC3b was determined by use of biotinylated F(ab')2 antibodies to C3b-C3c and avidin-coupled alkaline phosphatase. The incorporation of C3b-iC3b into solid-phase IgM-IC increased when increasing amounts of IgM antibody were reacted with the antigen. The binding reaction was slow, reaching...

Cordycepin (3'-deoxyadenosine) inhibits the growth of B16-BL6 mouse melanoma cells through the stimulation of adenosine A3 receptor followed by glycogen synthase kinase-3beta activation and cyclin D1 suppression.

Science.gov (United States)

Yoshikawa, Noriko; Yamada, Shizuo; Takeuchi, Chihiro; Kagota, Satomi; Shinozuka, Kazumasa; Kunitomo, Masaru; Nakamura, Kazuki

2008-06-01

Cordyceps sinensis, a parasitic fungus on the larvae of Lepidoptera, has been used as a traditional Chinese medicine. We previously reported that the growth of B16-BL6 mouse melanoma (B16-BL6) cells was inhibited by cordycepin (3'-deoxyadenosine), an active ingredient of C. sinensis, and its effect was antagonized by MRS1191, a selective adenosine A3 receptor antagonist. In this study, the radioligand binding assay using [125I]-AB-MECA (a selective adenosine A3 receptor agonist) has shown that B16-BL6 cells express adenosine A3 receptors and that cordycepin binds to these receptors. We also confirmed the involvement of adenosine A3 receptors in the action of cordycepin using MRS1523 and MRS1220, specific adenosine A3 receptor antagonists. Next, indirubin, a glycogen synthase kinase-3beta (GSK-3beta) inhibitor, antagonized the growth suppression induced by cordycepin. Furthermore, the level of cyclin D1 protein in B16-BL6 cells was decreased by cordycepin using Western blot analysis. In conclusion, this study demonstrated that cordycepin inhibits the proliferation of B16-BL6 cells by stimulating adenosine A3 receptors followed by the Wnt signaling pathway, including GSK-3beta activation and cyclin D1 inhibition.

Evaluation of an in vitro toxicogenetic mouse model for hepatotoxicity

International Nuclear Information System (INIS)

Martinez, Stephanie M.; Bradford, Blair U.; Soldatow, Valerie Y.; Kosyk, Oksana; Sandot, Amelia; Witek, Rafal; Kaiser, Robert; Stewart, Todd; Amaral, Kirsten; Freeman, Kimberly; Black, Chris; LeCluyse, Edward L.; Ferguson, Stephen S.; Rusyn, Ivan

2010-01-01

Numerous studies support the fact that a genetically diverse mouse population may be useful as an animal model to understand and predict toxicity in humans. We hypothesized that cultures of hepatocytes obtained from a large panel of inbred mouse strains can produce data indicative of inter-individual differences in in vivo responses to hepato-toxicants. In order to test this hypothesis and establish whether in vitro studies using cultured hepatocytes from genetically distinct mouse strains are feasible, we aimed to determine whether viable cells may be isolated from different mouse inbred strains, evaluate the reproducibility of cell yield, viability and functionality over subsequent isolations, and assess the utility of the model for toxicity screening. Hepatocytes were isolated from 15 strains of mice (A/J, B6C3F1, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/EiJ, DBA/2J, FVB/NJ, BALB/cByJ, AKR/J, MRL/MpJ, NOD/LtJ, NZW/LacJ, PWD/PhJ and WSB/EiJ males) and cultured for up to 7 days in traditional 2-dimensional culture. Cells from B6C3F1, C57BL/6J, and NOD/LtJ strains were treated with acetaminophen, WY-14,643 or rifampin and concentration-response effects on viability and function were established. Our data suggest that high yield and viability can be achieved across a panel of strains. Cell function and expression of key liver-specific genes of hepatocytes isolated from different strains and cultured under standardized conditions are comparable. Strain-specific responses to toxicant exposure have been observed in cultured hepatocytes and these experiments open new opportunities for further developments of in vitro models of hepatotoxicity in a genetically diverse population.

Construction and evaluation of quantitative small-animal PET probabilistic atlases for [¹⁸F]FDG and [¹⁸F]FECT functional mapping of the mouse brain.

Directory of Open Access Journals (Sweden)

Cindy Casteels

Full Text Available UNLABELLED: Automated voxel-based or pre-defined volume-of-interest (VOI analysis of small-animal PET data in mice is necessary for optimal information usage as the number of available resolution elements is limited. We have mapped metabolic ([(18F]FDG and dopamine transporter ([(18F]FECT small-animal PET data onto a 3D Magnetic Resonance Microscopy (MRM mouse brain template and aligned them in space to the Paxinos co-ordinate system. In this way, ligand-specific templates for sensitive analysis and accurate anatomical localization were created. Next, using a pre-defined VOI approach, test-retest and intersubject variability of various quantification methods were evaluated. Also, the feasibility of mouse brain statistical parametric mapping (SPM was explored for [(18F]FDG and [(18F]FECT imaging of 6-hydroxydopamine-lesioned (6-OHDA mice. METHODS: Twenty-three adult C57BL6 mice were scanned with [(18F]FDG and [(18F]FECT. Registrations and affine spatial normalizations were performed using SPM8. [(18F]FDG data were quantified using (1 an image-derived-input function obtained from the liver (cMRglc, using (2 standardized uptake values (SUVglc corrected for blood glucose levels and by (3 normalizing counts to the whole-brain uptake. Parametric [(18F]FECT binding images were constructed by reference to the cerebellum. Registration accuracy was determined using random simulated misalignments and vectorial mismatch determination. RESULTS: Registration accuracy was between 0.21-1.11 mm. Regional intersubject variabilities of cMRglc ranged from 15.4% to 19.2%, while test-retest values were between 5.0% and 13.0%. For [(18F]FECT uptake in the caudate-putamen, these values were 13.0% and 10.3%, respectively. Regional values of cMRglc positively correlated to SUVglc measured within the 45-60 min time frame (spearman r = 0.71. Next, SPM analysis of 6-OHDA-lesioned mice showed hypometabolism in the bilateral caudate-putamen and cerebellum, and an

Phosphatase of Regenerating Liver-3 Promotes Motility and Metastasis of Mouse Melanoma Cells

Science.gov (United States)

Wu, Xiaopeng; Zeng, Hu; Zhang, Xianming; Zhao, Ying; Sha, Haibo; Ge, Xiaomei; Zhang, Minyue; Gao, Xiang; Xu, Qiang

2004-01-01

Recent reports suggested that phosphatase of regenerating liver (PRL)-3 might be involved in colorectal carcinoma metastasis with an unknown mechanism. Here we demonstrated that PRL-3 expression was up-regulated in human liver carcinoma compared with normal liver. PRL-3 was also highly expressed in metastatic melanoma B16-BL6 cells but not in its lowly metastatic parental cell line, B16 cells. B16 cells transfected with PRL-3 cDNA displayed morphological transformation from epithelial-like shape to fibroblast-like shape. PRL-3-overexpressed cells showed much higher migratory ability, which could be reversed by specific anti-sense oligodeoxynucleotide and the phosphatase inhibitors sodium orthovanadate or potassium bisperoxo oxovanadate V. Meanwhile, the expression of the catalytically inactive PRL-3 mutations (D72A or C104S) significantly reduced the cell migratory capability. In addition, PRL-3 transfectants demonstrated altered extracellular matrix adhesive property and up-regulated integrin-mediated cell spreading efficiency. Furthermore, we confirmed that PRL-3 could facilitate lung and liver metastasis of B16 cells in an experimental metastasis model in mice, consistent with accelerated proliferation and growth rate both in vitro and in vivo. Together, these observations provide convincing evidence that PRL-3 truly plays a causal role in tumor metastasis. PMID:15161639

Peroxiredoxin 6 expression is inversely correlated with nuclear factor-κB activation during Clonorchis sinensis infestation.

Science.gov (United States)

Pak, Jhang Ho; Son, Woo Chan; Seo, Sang-Beom; Hong, Sung-Jong; Sohn, Woon-Mok; Na, Byoung-Kuk; Kim, Tong-Soo

2016-10-01

Clonorchis sinensis is a carcinogenic human liver fluke. Its infection promotes persistent oxidative stress and chronic inflammation environments in the bile duct and surrounding liver tissues owing to direct contact with worms and their excretory-secretory products (ESPs), provoking epithelial hyperplasia, periductal fibrosis, and cholangiocarcinogenesis. We examined the reciprocal regulation of two ESP-induced redox-active proteins, NF-κB and peroxiredoxin 6 (Prdx6), during C. sinensis infection. Prdx6 overexpression suppressed intracellular free-radical generation by inhibiting NADPH oxidase2 and inducible nitric oxide synthase activation in the ESP-treated cholangiocarcinoma cells, substantially attenuating NF-κB-mediated inflammation. NF-κB overexpression decreased Prdx6 transcription levels by binding to two κB sites within the promoter. This transcriptional repression was compensated for by other ESP-induced redox-active transcription factors, including erythroid 2-related factor 2 (Nrf2), hypoxia inducible factor 1α (HIF1α), and CCAAT/enhancer-binding protein β (C/EBPβ). Distribution of immunoreactive Prdx6 and NF-κB was distinct in the early stages of infection in mouse livers but shared concomitant localization in the later stages. The intensity and extent of their immunoreactive staining in infected mouse livers are proportional to lesion severity and infection duration. The constitutive elevations of Prdx6 and NF-κB during C. sinensis infection may be associated with more severe persistent hepatobiliary abnormalities mediated by clonorchiasis. Copyright © 2016 Elsevier Inc. All rights reserved.

Impact of calcium ion on cytotoxic effect of the boroxine derivative, K2[B3O3F4OH].

Science.gov (United States)

Ivankovic, Sinisa; Stojkovic, Ranko; Maksimovic, Milka; Galic, Borivoj; Milos, Mladen

2016-01-01

The effect of Ca 2+ ions on the cytotoxic ability of boron heterocyclic compound dipotassium-trioxohydroxytetrafluorotriborate (K 2 [B 3 O 3 F 4 OH]), on in vitro tumor cells (mammary adenocarcinoma 4T1, melanoma B16F10 and squamous cell carcinoma SCCVII) and non-tumoral fibroblast cells (mouse dermal L929 and hamster lung V79) was examined. At small concentrations of Ca 2+ ions (0.42 mM), K 2 [B 3 O 3 F 4 OH] (3.85 mM) has a very strong cytotoxic effect on all cancer cells tested (89.1, 85.6 and 84.6%) and significantly less effect on normal cells (19.5 and 24.2%), respectively. Applying larger concentrations of Ca 2+ ions (9.42-72.42 mM), at the same concentration of K 2 [B 3 O 3 F 4 OH], no significant cytotoxic effect was detected on cancer cells and normal cells investigated. The selective ability of K 2 [B 3 O 3 F 4 OH], in the medium with a low concentration of Ca 2+ ions has a strong cytotoxic effect on cancer cells and very weak effect in normal cells, opens up the possibility of its application in antitumor therapy.

IL-6 modulates hepatocyte proliferation via induction of HGF/p21cip1: Regulation by SOCS3

International Nuclear Information System (INIS)

Sun Rui; Jaruga, Barbara; Kulkarni, Shailin; Sun Haoyu; Gao Bin

2005-01-01

The precise role of IL-6 in liver regeneration and hepatocyte proliferation is controversial and the role of SOCS3 in liver regeneration remains unknown. Here we show that in vitro treatment with IL-6 inhibited primary mouse hepatocyte proliferation. IL-6 induced p21 cip1 protein expression in primary mouse hepatocytes. Disruption of the p21 cip1 gene abolished the inhibitory effect of IL-6 on cell proliferation. Co-culture with nonparenchymal liver cells diminished IL-6 inhibition of hepatocyte proliferation, which was likely due to IL-6 stimulation of nonparenchymal cells to produce HGF. Finally, IL-6 induced higher levels of p21 cip1 protein expression and a slightly stronger inhibition of cell proliferation in SOCS3 +/- mouse hepatocytes compared to wild-type hepatocytes, while liver regeneration was enhanced and prolonged in SOCS3 +/- mice. Our findings suggest that IL-6 directly inhibits hepatocyte proliferation via a p21 cip1 -dependent mechanism and indirectly enhances hepatocyte proliferation via stimulating nonparenchymal cells to produce HGF. SOCS3 negatively regulates liver regeneration

Effect of diphenyl ether herbicides and oxadiazon on porphyrin biosynthesis in mouse liver, rat primary hepatocyte culture and HepG2 cells.

Science.gov (United States)

Krijt, J; van Holsteijn, I; Hassing, I; Vokurka, M; Blaauboer, B J

1993-01-01

The effects of the herbicides fomesafen, oxyfluorfen, oxadiazon and fluazifop-butyl on porphyrin accumulation in mouse liver, rat primary hepatocyte culture and HepG2 cells were investigated. Ten days of herbicide feeding (0.25% in the diet) increased the liver porphyrins in male C57B1/6J mice from 1.4 +/- 0.6 to 4.8 +/- 2.1 (fomesafen) 16.9 +2- 2.9 (oxyfluorfen) and 25.9 +/- 3.1 (oxadiazon) nmol/g wet weight, respectively. Fluazifop-butyl had no effect on liver porphyrin metabolism. Fomesafen, oxyfluorfen and oxadiazon increased the cellular porphyrin content of rat hepatocytes after 24 h of incubation (control, 3.2 pmol/mg protein, fomesafen, oxyfluorfen and oxadiazon at 0.125 mM concentration 51.5, 54.3 and 44.0 pmol/mg protein, respectively). The porphyrin content of HepG2 cells increased from 1.6 to 18.2, 10.6 and 9.2 pmol/mg protein after 24 h incubation with the three herbicides. Fluazifop-butyl increased hepatic cytochrome P450 levels and ethoxy- and pentoxyresorufin O-dealkylase (EROD and PROD) activity, oxyfluorfen increased PROD activity. Peroxisomal palmitoyl CoA oxidation increased after fomesafen and fluazifop treatment to about 500% of control values both in mouse liver and rat hepatocytes. Both rat hepatocytes and HepG2 cells can be used as a test system for the porphyrogenic potential of photobleaching herbicides.

Dicty_cDB: Contig-U03991-1 [Dicty_cDB

Lifescience Database Archive (English)

Full Text Available 32 5.2 2 ( AZ306413 ) 1M0007B05R Mouse 10kb plasmid UUGC1M library Mus ... 38 5.2 2 ( BJ824535 ) Misgurnus anguillicaudatu...us visual cortex cDNA, RIKEN full-lengt... 32 6.7 2 ( AZ500970 ) 1M0339B10R Mouse 10kb plasmid UUGC1M library...7 2 ( AZ845402 ) 2M0145M09F Mouse 10kb plasmid UUGC1M library Mus ... 32 1.7 2 ( AZ990102 ) 2M0273L11R Mouse 10kb plasmid UUGC2M libr...07.... 44 2.5 1 ( AP009510 ) Uncultured Termite group 1 bacterium phylotype Rs...... cl... 32 6.5 2 ( AZ364702 ) 1M0110P21R Mouse 10kb plasmid UUGC1M library Mus ... 32 6.5 2 ( BH053767 ) R

The low-temperature structures of Hgsub(3-delta)SbF6 and Hgsub(3-delta)TaF6

International Nuclear Information System (INIS)

Tun, Z.; Brown, I.D.

1986-01-01

The Hg chains in both Hgsub(3-delta)SbF 6 and Hgsub(3-delta)TaF 6 order below room temperature. Down to about 190 K the ordering results from the interaction between parallel chains. It is short range and is different for the two compounds. Below 190 K both compounds transform to an isostructural long-range-ordered phase which is driven by the interaction between perpendicular chains. The structure of this phase in both compounds has been determined. Hgsub(3-delta)SbF 6 at 173 K, delta=0.134(1), Msub(r)=810.6(2). It is monoclinic but pseudotetragonal with I4 1 /amd, a=7.655(1), c=12.558(1) A, V=735.9(2) A 3 , Z=4, Dsub(x)=7.314(3) Mg m -3 , graphite-monochromated Mo Kα radiation, lambda=0.71069 A, μ=64.8 mm -1 , F(000)=1337.1(3). Hgsub(3-delta)TaF 6 at 150 K is isostructural but has delta=0.142(1), Msub(r)=868.2(2), a=7.634(1), c=12.610(2) A, V=734.9(2) A, Dsub(x)=7.844(3) Mg m -3 , μ=76.4 mm -1 , F(000)=1422.6(3). Comparison of the low-temperature structures with those at room temperature shows that the thermal contraction results from the shortening of interatomic distances associated with the weak bonds, with the result that the MF 6 (M=Sb, Ta) host lattice shrinks more than the Hg chains. Variation of the atomic displacement parameters with temperature indicates that the large librational displacements of the MF 6 ion result from thermal motion rather than static disorder. (orig.)

Dichlorodiphenyltrichloroethane technical mixture regulates cell cycle and apoptosis genes through the activation of CAR and ERα in mouse livers

Energy Technology Data Exchange (ETDEWEB)

Kazantseva, Yuliya A.; Yarushkin, Andrei A. [Institute of Molecular Biology and Biophysics SB RAMS, Novosibirsk, Timakova str., 2, 630117 (Russian Federation); Pustylnyak, Vladimir O., E-mail: pustylnyak@ngs.ru [Institute of Molecular Biology and Biophysics SB RAMS, Novosibirsk, Timakova str., 2, 630117 (Russian Federation); Novosibirsk State University, Novosibirsk, Pirogova str., 2, 630090 (Russian Federation)

2013-09-01

Dichlorodiphenyltrichloroethane (DDT) is a widely used organochlorine pesticide and a xenoestrogen that promotes rodent hepatomegaly and tumours. A recent study has shown significant correlation between DDT serum concentration and liver cancer incidence in humans, but the underlying mechanisms remain elusive. We hypothesised that a mixture of DDT isomers could exert effects on the liver through pathways instead of classical ERs. The acute effects of a DDT mixture containing the two major isomers p,p′-DDT (85%) and o,p′-DDT (15%) on CAR and ERα receptors and their cell cycle and apoptosis target genes were studied in mouse livers. ChIP results demonstrated increased CAR and ERα recruitment to their specific target gene binding sites in response to the DDT mixture. The results of real-time RT-PCR were consistent with the ChIP data and demonstrated that the DDT was able to activate both CAR and ERα in mouse livers, leading to target gene transcriptional increases including Cyp2b10, Gadd45β, cMyc, Mdm2, Ccnd1, cFos and E2f1. Western blot analysis demonstrated increases in cell cycle progression proteins cMyc, Cyclin D1, CDK4 and E2f1 and anti-apoptosis proteins Mdm2 and Gadd45β. In addition, DDT exposure led to Rb phosphorylation. Increases in cell cycle progression and anti-apoptosis proteins were accompanied by a decrease in p53 content and its transcriptional activity. However, the DDT was unable to stimulate the β-catenin signalling pathway, which can play an important role in hepatocyte proliferation. Thus, our results indicate that DDT treatment may result in cell cycle progression and apoptosis inhibition through CAR- and ERα-mediated gene activation in mouse livers. These findings suggest that the proliferative and anti-apoptotic conditions induced by CAR and ERα activation may be important contributors to the early stages of hepatocarcinogenesis as produced by DDT in rodent livers. - Highlights: • DDT activated both CAR and ERα and their cell

Dichlorodiphenyltrichloroethane technical mixture regulates cell cycle and apoptosis genes through the activation of CAR and ERα in mouse livers

International Nuclear Information System (INIS)

Kazantseva, Yuliya A.; Yarushkin, Andrei A.; Pustylnyak, Vladimir O.

2013-01-01

Dichlorodiphenyltrichloroethane (DDT) is a widely used organochlorine pesticide and a xenoestrogen that promotes rodent hepatomegaly and tumours. A recent study has shown significant correlation between DDT serum concentration and liver cancer incidence in humans, but the underlying mechanisms remain elusive. We hypothesised that a mixture of DDT isomers could exert effects on the liver through pathways instead of classical ERs. The acute effects of a DDT mixture containing the two major isomers p,p′-DDT (85%) and o,p′-DDT (15%) on CAR and ERα receptors and their cell cycle and apoptosis target genes were studied in mouse livers. ChIP results demonstrated increased CAR and ERα recruitment to their specific target gene binding sites in response to the DDT mixture. The results of real-time RT-PCR were consistent with the ChIP data and demonstrated that the DDT was able to activate both CAR and ERα in mouse livers, leading to target gene transcriptional increases including Cyp2b10, Gadd45β, cMyc, Mdm2, Ccnd1, cFos and E2f1. Western blot analysis demonstrated increases in cell cycle progression proteins cMyc, Cyclin D1, CDK4 and E2f1 and anti-apoptosis proteins Mdm2 and Gadd45β. In addition, DDT exposure led to Rb phosphorylation. Increases in cell cycle progression and anti-apoptosis proteins were accompanied by a decrease in p53 content and its transcriptional activity. However, the DDT was unable to stimulate the β-catenin signalling pathway, which can play an important role in hepatocyte proliferation. Thus, our results indicate that DDT treatment may result in cell cycle progression and apoptosis inhibition through CAR- and ERα-mediated gene activation in mouse livers. These findings suggest that the proliferative and anti-apoptotic conditions induced by CAR and ERα activation may be important contributors to the early stages of hepatocarcinogenesis as produced by DDT in rodent livers. - Highlights: • DDT activated both CAR and ERα and their cell

Comparison of the cytokine immune response to pathogenic Yersinia enterocolitica bioserotype 1B/O:8 and 2/O:9 in susceptible BALB/C and resistant C57BL/6 mice.

Science.gov (United States)

Wang, Xin; Gu, Wenpeng; Qiu, Haiyan; Xia, Shengli; Zheng, Han; Xiao, Yuchun; Liang, Junrong; Jing, Huaiqi

2013-10-01

We investigated the lethality of pathogenic Yersinia enterocolitica bioserotypes 1B/O:8 and 2/O:9 in susceptible BALB/C and resistant C57BL/6 mice; the cytokine alterations and histopathological changes were observed comparing the two strains in BALB/C mice. The data showed the 50% lethal dose (LD50) for the pathogenic Y. enterocolitica bioserotype 1B/O:8 was 10³ cfu in both BALB/C and C57BL/6 mice; while the LD50 for the 2/O:9 was 10⁸ cfu in BALB/C mice and 10⁹ cfu in C57BL/6 mice, a large difference. After infection with the two strains in BALB/C mice, GM-CSF (granulocyte-macrophage colony stimulating factor), IFN-γ (interferon-γ), IL-1β (interleukin-1β), IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, and TNF-α (tumor necrosis factor-α) appeared as a cytokine storm in a short period, reached peak values, and then quickly decreased. This appeared important for the immune response and cytokine immunopathogenesis in pathogenic Y. enterocolitica infections. In the initial infection stage, GM-CSF, IL-6, and TNF-α of 2/O:9 were higher than 1B/O:8; and subsequently the status was reversed. However, levels of IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-10, IL-12 following infection with 1B/O:8 were always higher than with 2/O:9. The histopathological changes in the liver and spleen in BALB/C mice infected with the two strains were similar at different times and doses. These observations show the different immunological effects and changes for pathogenic Y. enterocolitica 1B/O:8 and 2/O:9 infections using the mouse model. Copyright © 2013 Elsevier Ltd. All rights reserved.

Crystal structures of KM(AsF6)3 (M2+ = Mg, Co, Mn, Zn), KCu(SbF6)3 and [Co(HF)2]Sr[Sr(HF)]2-[Sr(HF)2]2[AsF6]12

International Nuclear Information System (INIS)

Mazej, Zoran; Goreshnik, Evgeny

2015-01-01

The KM(AsF 6 ) 3 (M 2+ = Mg, Co, Mn, Zn) and KCu(SbF 6 ) 3 compounds crystallize isotypically to previously known KNi(AsF 6 ) 3 . The main features of the structure of these compounds are rings of MF 6 octahedra sharing apexes with AsF 6 octahedra connected into infinite tri-dimensional frameworks. In this arrangement cavities are formed where K + cations are placed. Single crystals of CoSr 5 (AsF 6 ) 12 .8HF were obtained as one of the products after the crystallization of 3KF/CoF 2 /SrF 2 mixture in the presence of AsF 5 in anhydrous HF. The CoSr 5 (AsF 6 ) 12 .8HF is monoclinic, C/2c (No.15), with a = 26.773(5) Aa, b = 10.087(2) Aa, c = 21.141(5) Aa, β = 93.296(13) circle , V = 5699.9(19) Aa 3 at 200 K, and Z = 4. There are three crystallographically non-equivalent Sr 2+ cations in the crystal structure of CoSr 5 (AsF 6 ) 12 .8HF. The Sr1 is coordinated by ten fluorine atoms from eight different [AsF 6 ]- anions, meanwhile Sr2 and Sr3 are bound to nine fluorine atoms provided by one HF and eight AsF 6 units or by two HF and six AsF 6 units, respectively. The Co 2+ is coordinated distorted-octahedrally by six fluorine atoms from two HF molecules and four different AsF 6 units. All those moieties in the crystal structure of [Co(HF) 2 ]Sr[Sr(HF)] 2 [Sr(HF) 2 ] 2 [AsF 6 ] 12 are connected into tridimensional framework. The CoSr 5 (AsF 6 ) 12 .8HF is a unique example of compound where HF molecules are directly bound via fluorine atoms to two different metal centres.

EBI3 regulates the NK cell response to mouse cytomegalovirus infection

DEFF Research Database (Denmark)

Jensen, Helle; Chen, Shih-Yu; Folkersen, Lasse Westergaard

2017-01-01

Natural killer (NK) cells are key mediators in the control of cytomegalovirus infection. Here, we show that Epstein-Barr virus-induced 3 (EBI3) is expressed by human NK cells after NKG2D or IL-12 plus IL-18 stimulation and by mouse NK cells during mouse cytomegalovirus (MCMV) infection. The induc......Natural killer (NK) cells are key mediators in the control of cytomegalovirus infection. Here, we show that Epstein-Barr virus-induced 3 (EBI3) is expressed by human NK cells after NKG2D or IL-12 plus IL-18 stimulation and by mouse NK cells during mouse cytomegalovirus (MCMV) infection....... The induction of EBI3 protein expression in mouse NK cells is a late activation event. Thus, early activation events of NK cells, such as IFNγ production and CD69 expression, were not affected in EBI3-deficient (Ebi3-/-) C57BL/6 (B6) mice during MCMV infection. Furthermore, comparable levels of early viral...... replication in spleen and liver were observed in MCMV-infected Ebi3-/- and wild-type (WT) B6 mice. Interestingly, the viral load in salivary glands and oral lavage was strongly decreased in the MCMV-infected Ebi3-/- B6 mice, suggesting that EBI3 plays a role in the establishment of MCMV latency. We detected...

Molecular profiling of early stage liver fibrosis in patients with chronic hepatitis C virus infection

International Nuclear Information System (INIS)

Bieche, Ivan; Asselah, Tarik; Laurendeau, Ingrid; Vidaud, Dominique; Degot, Claude; Paradis, Valerie; Bedossa, Pierre; Valla, Dominique-Charles; Marcellin, Patrick; Vidaud, Michel

2005-01-01

The molecular mechanisms of acute hepatitis C virus (HCV) infection, end-stage hepatitis (cirrhosis), and hepatocellular carcinoma have been extensively studied, but little is known of the changes in liver gene expression during the early stages of liver fibrosis associated with chronic HCV infection, that is, the transition from normal liver (NL) of uninfected patients to the first stage of liver fibrosis (F1-CH-C). To obtain insight into the molecular pathogenesis of F1-CH-C, we used real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) to study the mRNA expression of 240 selected genes in liver tissue with F1-CH-C, in comparison with NL. The expression of 54 (22.5%) of the 240 genes was significantly different between F1-CH-C and NL; 46 genes were upregulated and 8 were downregulated in F1-CH-C. The most noteworthy changes in gene expression mainly affected the transcriptional network regulated by interferons (IFNs), including both IFN-α/β-inducible genes (STAT1, STAT2, ISGF3G/IRF9, IFI27, G1P3, G1P2, OAS2, MX1) and IFN-γ-inducible genes (CXCL9, CXCL10, CXCL11). Interesting, upregulation of IFN-α/β-inducible genes (but not IFN-γ-inducible genes) was independent of histological scores (grade and stage of fibrosis) and HCV characteristics (hepatic HCV mRNA levels and the HCV genotype), and was specific to HCV (as compared to hepatitis B virus (HBV)). Other genes dysregulated in F1-CH-C, albeit less markedly than IFN-α/β- and IFN-γ-inducible genes, were mainly involved in the activation of lymphocytes infiltrating the liver (IFNG, TNF, CXCL6, IL6, CCL8, CXCR3, CXCR4, CCR2), cell proliferation (p16/CDKN2A, MKI67, p14/ARF), extracellular matrix remodeling (MMP9, ITGA2), lymphangiogenesis (XLKD1/LYVE), oxidative stress (CYP2E1), and cytoskeleton microtubule organization (STMN2/SCG10). Thus, a limited number of signaling pathways, and particularly the transcriptional network regulated by interferons, are dysregulated in the first

Crystal structure of difluorochloronium hexafluoroniobate and hexafluorotantalate, ClF2NbF6 and ClF2TaF6

International Nuclear Information System (INIS)

Ehllern, A.M.; Antipin, M.Yu.; Sharabarin, A.V.; Struchkov, Yu.T.

1991-01-01

Crystal structure of ClF 2 NbF 6 (1) and ClF 2 TaF 6 (2) were investigated by the method of X-ray diffraction analysis. Salts 1 and 2 are isostructural, crystals are rhombic: a = 9.981(2) and 10.049(2), b = 5.781(1) and 5.775(1), c = 10.552(2) and 10.670(2) A, V = 608.9(3) and 619.2(3) A 3 , Z = 4, d calcd 3.058 and 3.952 g/cm 3 , sp. gr. Pcca. Both salts are characterized by ionic structure. Bond lengths and valent angles, general view of 1 crystal structure are presented

Synthesis of binuclear rhodacarboranes from dianions 1,4- and 1,3-C6H4(CH2-9-C2H2B9H9-7,8-nido)22- and (Ph3P)3RhCl

International Nuclear Information System (INIS)

Zakharkin, L.I.; Zhigareva, G.G.

1996-01-01

Dianions 1,4 and 1,3-C 6 H 4 (CH 2 -9-C 2 H 2 B 9 H 9 -7,8-nido) 2 2- obtained from nido 7,8-dicarbollide-ion and 1,4-bis(bromomethyl) and 1,3-bis(bromomethyl)benzenes react with (Ph 3 P) 3 RhCl to give binuclear rhodacarboranes, 1,4- and 1,3-[3,3-(Ph 3 P) 2 -3-H-3,1,2-RhC 2 B 9 H 10 -4-CH 2 ] 2 C 6 H 6 with chemical reaction yield 85% and 87% respectively. 7 refs., 1 fig., 1 tab

Expression, crystallization and preliminary X-ray analysis of the extracellular Ig modules I–IV and F3 modules I–III of the neural cell-adhesion molecule L1

International Nuclear Information System (INIS)

Kulahin, Nikolaj; Kasper, Christina; Kristensen, Ole; Kastrup, Jette Sandholm; Berezin, Vladimir; Bock, Elisabeth; Gajhede, Michael

2005-01-01

Mouse L1 modules Ig I–IV and F3 I–III were crystallized. The crystals diffracted X-rays to 3.5 and 2.8 Å resolution, respectively. Four amino-terminal immunoglobulin (Ig) modules and three fibronectin type III (F3) modules of the mouse neural cell-adhesion molecule L1 have been expressed in Drosophila S2 cells. The Ig modules I–IV of L1 crystallized in a trigonal space group, with unit-cell parameters a = b = 239.6, c = 99.3 Å, and the crystals diffracted X-rays to a resolution of about 3.5 Å. The F3 modules I–III of L1 crystallized in a tetragonal space group, with unit-cell parameters a = b = 80.1, c = 131 Å, and the crystals diffracted X-rays to 2.8 Å resolution. This is a step towards the structure determination of the multimodular constructs of the neural cell-adhesion molecule L1 in order to understand the function of L1 on a structural basis

Synthesis and Molecular Structure of 6-Amino-3-benzylmercapto-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H-one

Directory of Open Access Journals (Sweden)

Gene-Hsiang Lee

2006-03-01

Full Text Available The title compound 6-amino-3-benzylmercapto-1,2,4-triazolo[3,4-f][1,2,4]-triazin-8(7H-one (4, molecular formula C11H10N6OS, was obtained by the reaction of3-amino-2-benzyl-6-hydrazino-1,2,4-triazin-5(2H-one (3 with carbon disulfide in awater/pyridine mixture. Compound 4 can also be synthesized by reacting6-amino-3(2Hmercapto-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H-one (7 with benzylbromide in methanolic ammonia water. The compound crystallizes in the monoclinicspace group P21/c with a = 7.2926(15, b = 14.456(2, c = 11.436(2 å, β = 105.30(2°, V= 1162.9(4 å3 and Z = 4, resulting in a density Dcalc of 1.567 g/cm3. Molecules of 4 arelinked by extensive intermolecular N-H···N and N-H···O hydrogen bonding [graph set R22 (9]. The structure is further stabilized by π-π stacking interactions. 2

(C2N2H10)[Fe xV1-x(HPO3)F3] (x = 0.44, 0.72): Two new organically templated phosphites

International Nuclear Information System (INIS)

Cisneros, Jose L.; Fernandez-Armas, Sergio; Mesa, Jose L.; Pizarro, Jose L.; Arriortua, Maria I.; Rojo, Teofilo

2006-01-01

(C 2 N 2 H 10 )[Fe x V 1-x (HPO 3 )F 3 ] (x = 0.44, 0.72) have been synthesized using mild solvothermal conditions under autogenous pressure and the ethylenediamine molecule as templating agent. The crystal structures have been determined from X-ray single-crystal diffraction data. The compounds crystallize in the orthorhombic P2 1 2 1 2 1 space group with Z = 4 and unit-cell parameters a = 12.8494(9), b = 9.5430(6), c = 6.4372(5) A, and a = 12.8578(1), b = 9.5342(1), c = 6.4370(7) A for (C 2 N 2 H 10 )[Fe 0.44 V 0.56 (HPO 3 )F 3 ] and (C 2 N 2 H 10 )[Fe 0.72 V 0.28 (HPO 3 )F 3 ] (1) and (2), respectively. These isostructural compounds exhibit a monodimensional crystal structure formed by pillared double anionic chains with the formula [M(HPO 3 )F 3 ] 2- , extended along the [0 0 1] direction. These doubled ionic chains are the result of the linking of two simple chains in which there are alternating octahedral [MO 3 F 3 ] and tetrahedral groups [HPO 3 ]. The ethylendiammonium cations are placed in the space delimited by three different chains. The metallic ions are interconnected by the pseudo-pyramidal (HPO 3 ) 2- phosphite oxoanions, adopting a slightly distorted octahedral geometry. The IR spectra show bands corresponding to the phosphite oxoanion and the ethylendiamonium cation at 2400 and 1600 cm -1 , respectively. The thermogravimetric analyses show that these phases are stable up to ca. 280 deg. C, at higher temperatures, the decomposition of the crystal structure begins by calcination of the organic cation and the elimination of the fluoride anions. The diffuse reflectance spectra show bands of the V 3+ ion (d 2 ) in octahedral symmetry. The values of the Dq (1540, 1540 cm -1 ), and Racah parameters, B (560, 535 cm -1 ) and C (3055, 3140 cm -1 ) for (1) and (2), respectively, correspond with those usually found for octahedrically coordinated V(III) compounds. Magnetic measurements, performed on a powered sample from 5.0 to 300 K at 1000 G, in the ZFC and

Electroluminescent TCC, C3dg and fB/Bb epitope assays for profiling complement cascade activation in vitro using an activated complement serum calibration standard.

Science.gov (United States)

van Vuuren, B Jansen; Bergseth, G; Mollnes, T E; Shaw, A M

2014-01-15

Electroluminescent assays for epitopes on the complement components C3dg, terminal complement complex (TCC) and factor B/Bb (fB/Bb) have been developed with capture and detection antibodies to produce detection limits C3dg=91±9ng/mL, TCC=3±0.1ng/mL and fB=55.7±0.1ng/mL. The assay performance was assessed against a series of zymosan and heat aggregated IgG (HAIgG) in vitro activations of complement using a calibrated activated complement serum (ACS) as calibration standard. The ACS standard was stable within 20% accuracy over a 6-month period with freeze-thaw cycles as required. Differential activation of the complement cascade was observed for TCC showing a pseudo-first order formation half-life of 3.5h after activation with zymosan. The C3dg activation fragment indicates a 10% total activation for both activation agents. The kinetic-epitope analysis for fB indicates that the capture epitope is on the fB/Bb protein fragment which can then become covered by the formation of C3bBb or C3bBbP complexes during the time course of the cascade. Copyright © 2013 Elsevier B.V. All rights reserved.

5-[(3-Fluorophenyl(2-hydroxy-6-oxocyclohex-1-en-1-ylmethyl]-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H-dione

Directory of Open Access Journals (Sweden)

Assem Barakat

2016-09-01

Full Text Available 5-[(3-Fluorophenyl(2-hydroxy-6-oxocyclohex-1-en-1-yl-methyl]-6-hydroxy-1,3-di-methylpyrimidine-2,4(1H,3H-dione 3 was synthesized via a multicomponent reaction. The Aldol–Michael addition reactions of N,N-dimethylbarbituric acid, cyclohexane-1,3-dione, and 3-fluorobenzaldehyde in aqueous solution gave the product in high yield. The molecular structure of the compound was confirmed by spectroscopic methods and X-ray crystallography. The title compound (C19H19FN2O5·H2O crystallizes in the Monoclinic form, P21/c, a = 7.8630 (5 Å, b = 20.0308 (13 Å, c = 11.3987 (8 Å, β = 104.274 (3°, V = 1739.9 (2° Å3, Z = 4, Rint = 0.117, wR(F2 = 0.124, T = 100 K.

A Revised Mechanism for the Activation of Complement C3 to C3b

Science.gov (United States)

Rodriguez, Elizabeth; Nan, Ruodan; Li, Keying; Gor, Jayesh; Perkins, Stephen J.

2015-01-01

The solution structure of complement C3b is crucial for the understanding of complement activation and regulation. C3b is generated by the removal of C3a from C3. Hydrolysis of the C3 thioester produces C3u, an analog of C3b. C3b cleavage results in C3c and C3d (thioester-containing domain; TED). To resolve functional questions in relation to C3b and C3u, analytical ultracentrifugation and x-ray and neutron scattering studies were used with C3, C3b, C3u, C3c, and C3d, using the wild-type allotype with Arg102. In 50 mm NaCl buffer, atomistic scattering modeling showed that both C3b and C3u adopted a compact structure, similar to the C3b crystal structure in which its TED and macroglobulin 1 (MG1) domains were connected through the Arg102–Glu1032 salt bridge. In physiological 137 mm NaCl, scattering modeling showed that C3b and C3u were both extended in structure, with the TED and MG1 domains now separated by up to 6 nm. The importance of the Arg102–Glu1032 salt bridge was determined using surface plasmon resonance to monitor the binding of wild-type C3d(E1032) and mutant C3d(A1032) to immobilized C3c. The mutant did not bind, whereas the wild-type form did. The high conformational variability of TED in C3b in physiological buffer showed that C3b is more reactive than previously thought. Because the Arg102-Glu1032 salt bridge is essential for the C3b-Factor H complex during the regulatory control of C3b, the known clinical associations of the major C3S (Arg102) and disease-linked C3F (Gly102) allotypes of C3b were experimentally explained for the first time. PMID:25488663

Limited value of 18F-FDG PET/CT and S-100B tumour marker in the detection of liver metastases from uveal melanoma compared to liver metastases from cutaneous melanoma

International Nuclear Information System (INIS)

Strobel, K.; Veit-Haibach, P.; Fischer, D.R.; Steinert, Hans C.; Schulthess, G.K. von; Bode, B.; Dummer, R.; Imhof, L.; Goldinger, S.

2009-01-01

The objective of this study was to evaluate the value of 18 F-FDG PET/CT and S-100B tumour marker for the detection of liver metastases from uveal melanoma in comparison to liver metastases from cutaneous melanoma. A retrospective evaluation was conducted of 27 liver metastases in 13 patients with uveal melanoma (UM) (mean age: 56.8, range: 30-77) and 43 liver metastases in 14 patients (mean age: 57.9, range: 40-82) with cutaneous melanoma (CM) regarding size and FDG uptake by measuring the maximum standardized uptake value (SUV max ). S-100B serum tumour markers were available in 20 patients. Cytology, histology, additional morphological imaging and follow-up served as reference standard. In nine patients liver metastases were further evaluated histologically regarding GLUT-1 and S-100 receptor expression and regarding epithelial or spindle cell growth pattern. Of 27 liver metastases in 6 of 13 patients (46%) with UM, 16 (59%) were FDG negative, whereas all liver metastases from CM were positive. Liver metastases from UM showed significantly (p max (mean: 3.5, range: 1.5-13.4) compared with liver metastases from CM (mean: 6.6, range: 2.3-15.3). In four of six (66.7%) patients with UM and liver metastases S-100B was normal and in two (33.3%) increased. All PET-negative liver metastases were detectable by morphological imaging (CT or MRI). S-100B was abnormal in 13 of 14 patients with liver metastases from CM. S-100B values were significantly higher (p = 0.007) in the CM patient group (mean S-100B: 10.9 μg/l, range: 0.1-115 μg/l) compared with the UM patients (mean: 0.2 μg/l, range: 0.0-0.5 μg/l). Histological work-up of the liver metastases showed no obvious difference in GLUT-1 or S-100 expression between UM and CM liver metastases. The minority (36%) of patients with UM had extrahepatic metastases and the majority (86%) of patients with CM had extrahepatic metastases, respectively. There was a close to significant trend to better survival of UM patients

Centrosymmetric [N(CH{sub 3}){sub 4}]{sub 2}TiF{sub 6} vs. noncentrosymmetric polar [C(NH{sub 2}){sub 3}]{sub 2}TiF{sub 6}: A hydrogen-bonding effect on the out-of-center distortion of TiF{sub 6} octahedra

Energy Technology Data Exchange (ETDEWEB)

Kim, Eun-ah [Department of Chemistry Education, Chung-Ang University, Seoul 156-756 (Korea, Republic of); Lee, Dong Woo [Department of Chemistry, Chung-Ang University, Seoul 156-756 (Korea, Republic of); Ok, Kang Min, E-mail: kmok@cau.ac.kr [Department of Chemistry, Chung-Ang University, Seoul 156-756 (Korea, Republic of)

2012-11-15

The syntheses, structures, and characterization of organically templated zero-dimensional titanium fluoride materials, A{sub 2}TiF{sub 6} (A=[N(CH{sub 3}){sub 4}] or [C(NH{sub 2}){sub 3}]), are reported. Phase pure samples of A{sub 2}TiF{sub 6} were synthesized by either solvothermal reaction method or a simple mixing method. While [N(CH{sub 3}){sub 4}]{sub 2}TiF{sub 6} crystallizes in a centrosymmetric space group, R-3, [C(NH{sub 2}){sub 3}]{sub 2}TiF{sub 6} crystallizes in a noncentrosymmetric polar space group, Cm. The asymmetric out-of-center distortion of TiF{sub 6} octahedra in polar [C(NH{sub 2}){sub 3}]{sub 2}TiF{sub 6} are attributable to the hydrogen-bonding interactions between the fluorine atoms in TiF{sub 6} octahedra and the nitrogen atoms in the [C(NH{sub 2}){sub 3}]{sup +} cation. Powder second-harmonic generation (SHG) measurements on the [C(NH{sub 2}){sub 3}]{sub 2}TiF{sub 6}, using 1064 nm radiation, indicate the material has SHG efficiency of 25 Multiplication-Sign that of {alpha}-SiO{sub 2}, which indicates an average nonlinear optical susceptibility, Left-Pointing-Angle-Bracket d{sub eff} Right-Pointing-Angle-Bracket {sub exp} of 2.8 pm/V. Additional SHG measurements reveal that the material is not phase-matchable (Type 1). The magnitudes of out-of-center distortions and dipole moment calculations for TiF{sub 6} octahedra will be also reported. - Graphical abstract: The out-of-center distortion of TiF{sub 6} octahedron in the polar noncentrosymmetric [C(NH{sub 2}){sub 3}]{sub 2}TiF{sub 6} is attributable to the hydrogen-bonding interactions between the F in TiF{sub 6} octahedron and the H-N in the [C(NH{sub 2}){sub 3}]{sup +}. Highlights: Black-Right-Pointing-Pointer Two titanium fluorides materials have been synthesized in high yields. Black-Right-Pointing-Pointer Hydrogen-bonds are crucial for the out-of-center distortion of TiF{sub 6} octahedra. Black-Right-Pointing-Pointer [C(NH{sub 2}){sub 3}]{sub 2}TiF{sub 6} has a SHG efficiency of 25

Toxicology and carcinogenesis studies of tetralin (CAS No. 119-64-2) in F344/N rats and B6C3F1 mice (inhalation studies).

Science.gov (United States)

2011-04-01

Tetralin is used as an industrial solvent primarily for naphthalene, fats, resins, oils, and waxes; as a solvent and stabilizer for shoe polishes and floor waxes; as a solvent for pesticides, rubber, asphalt, and aromatic hydrocarbons (e.g., anthracene); as a dye solvent carrier in the textile industry; as a substitute for turpentine in lacquers, paints, and varnishes; in paint thinners and as a paint remover; in alkali-resistant lacquers for cleaning printing ink from rollers and type; as a constituent of motor fuels and lubricants; for the removal of naphthalene in gas distribution systems; and as an insecticide for clothes moths. Tetralin was nominated by the National Cancer Institute for carcinogenicity and disposition studies because of its structure, high production volume, and high potential for worker and consumer exposure. Male and female F344/N rats and B6C3F1 mice were exposed to tetralin (at least 97% pure) by inhalation for 2 weeks, 3 months, or 2 years; male NCI Black Reiter (NBR) rats were exposed to tetralin by inhalation for 2 weeks. Male NBR rats do not produce 2u-globulin; the NBR rats were included to study the relationship of 2u-globulin and renal lesion induction. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male (F344/N and NBR) and five female (F344/N) rats were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 12 exposures. All rats survived to the end of the studies. The final mean body weight of female rats exposed to 120 ppm and mean body weight gains of female rats exposed to 30 ppm or greater were significantly less than those of the chamber controls. Final mean body weights of exposed groups of male NBR rats and mean body weight gains of all exposed groups of male rats were significantly less than those of the chamber controls. Dark

Complement C3a binding to its receptor as a negative modulator of Th2 response in liver injury in trichloroethylene-sensitized mice.

Science.gov (United States)

Wang, Feng; Zha, Wan-sheng; Zhang, Jia-xiang; Li, Shu-long; Wang, Hui; Ye, Liang-ping; Shen, Tong; Wu, Chang-hao; Zhu, Qi-xing

2014-08-17

Trichloroethylene (TCE) is a major occupational health hazard and causes occupational medicamentosa-like dermatitis (OMLDT) and liver damage. Recent evidence suggests immune response as a distinct mode of action for TCE-induced liver damage. This study aimed to explore the role of the key complement activation product C3a and its receptor C3aR in TCE-induced immune liver injury. A mouse model of skin sensitization was induced by TCE in the presence and absence of the C3aR antagonist SB 290157. Liver function was evaluated by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in conjunction with histopathological characterizations. C3a and C3aR were detected by immunohistochemistry and C5b-9 was assessed by immunofluorescence. IFN-γ and IL4 expressions were determined by flow cytometry and ELISA. The total sensitization rate was 44.1%. TCE sensitization caused liver cell necrosis and inflammatory infiltration, elevated serum ALT and AST, expression of C3a and C3aR, and deposition of C5b-9 in the liver. IFN-γ and IL-4 expressions were up-regulated in spleen mononuclear cells and their serum levels were also increased. Pretreatment with SB 290157 resulted in more inflammatory infiltration in the liver, higher levels of AST, reduced C3aR expression on Kupffer cells, and decreased IL-4 levels while IFN-γ remained unchanged. These data demonstrate that blocking of C3a binding to C3aR reduces IL4, shifts IFN-γ and IL-4 balance, and aggravates TCE-sensitization induced liver damage. These findings reveal a novel mechanism whereby modulation of Th2 response by C3a binding to C3a receptor contributes to immune-mediated liver damage by TCE exposure. Copyright © 2014. Published by Elsevier Ireland Ltd.

Synthesis and structure of a 1,6-hexyldiamine heptaborate, [H3N(CH2)6NH3][B7O10(OH)3

International Nuclear Information System (INIS)

Yang Sihai; Li Guobao; Tian Shujian; Liao Fuhui; Xiong Ming; Lin Jianhua

2007-01-01

A new 1,6-hexyldiamine heptaborate, [H 3 N(CH 2 ) 6 NH 3 ][B 7 O 10 (OH) 3 ] (1), has been solvothermally synthesized and characterized by single-crystal X-ray diffraction, FTIR, elemental analysis, and thermogravimetric analysis. Compound 1 crystallizes in monoclinic system, space group P2 1 /n with a=8.042(2) A, b=20.004(4) A, c=10.103(2) A, and β=90.42(3) deg. The anionic [B 7 O 10 (OH) 3 ] n 2n- layers are interlinked via hydrogen bonding to form a 3D supramolecular network containing large channels, in which the templated [H 3 N(CH 2 ) 6 NH 3 ] 2+ cations are located. - Graphical abstract: A layered 1,6-hexyldiamine heptaborate, [H 3 N(CH 2 ) 6 NH 3 ][B 7 O 10 (OH) 3 ], was solvothermally synthesized at 150 deg. C. It is a layer borate and crystallized in monoclinic space group P2 1 /n with a=8.042(2) A, b=20.004(4) A, c=10.103(2) A, β=90.42(3) deg

Superconductivity of Hg3NbF6 and Hg3TaF6

International Nuclear Information System (INIS)

Datars, W.R.; Morgan, K.R.; Gillespie, R.J.

1983-01-01

Low-temperature ac susceptibility measurements show that two new metallic compounds, Hg 3 TaF 6 and Hg 3 NbF 6 , are superconductors with a critical temperature of 7.0 K. Critical fields are 20% higher in Hg 3 TaF 6 but the temperature dependence of the critical field of the compounds is very similar down to 1.35 K. The critical field extrapolated to T = 0 K is 0.17 T for Hg 3 TaF 6 and 0.13 T for Hg 3 NbF 6

Solvothermal indium fluoride chemistry: Syntheses and crystal structures of K5In3F14, β-(NH4)3InF6 and [NH4]3[C6H21N4]2[In4F21

International Nuclear Information System (INIS)

Jayasundera, Anil C.A.; Goff, Richard J.; Li Yang; Finch, Adrian A.; Lightfoot, Philip

2010-01-01

The solvothermal syntheses and crystal structures of three indium fluorides are presented. K 5 In 3 F 14 (1) and β-(NH 4 ) 3 InF 6 (2) are variants on known inorganic structure types chiolite and cryolite, respectively, with the latter exhibiting a complex and apparently novel structural distortion. [NH 4 ] 3 [C 6 H 21 N 4 ] 2 [In 4 F 21 ] (3) represents a new hybrid composition displaying a unique trimeric metal fluoride building unit. - Graphical abstract: Solvothermal synthesis has been used to prepare three indium fluorides, including a novel hybrid material containing a unique [In 3 F 15 ] trimer templated by tren.

EphrinB1/EphB3b Coordinate Bidirectional Epithelial-Mesenchymal Interactions Controlling Liver Morphogenesis and Laterality

DEFF Research Database (Denmark)

Cayuso, Jordi; Dzementsei, Aliaksandr; Fischer, Johanna C

2016-01-01

Positioning organs in the body often requires the movement of multiple tissues, yet the molecular and cellular mechanisms coordinating such movements are largely unknown. Here, we show that bidirectional signaling between EphrinB1 and EphB3b coordinates the movements of the hepatic endoderm...... and adjacent lateral plate mesoderm (LPM), resulting in asymmetric positioning of the zebrafish liver. EphrinB1 in hepatoblasts regulates directional migration and mediates interactions with the LPM, where EphB3b controls polarity and movement of the LPM. EphB3b in the LPM concomitantly repels hepatoblasts...

Measurement of F_2^{c\\bar{c}} and F_2^{b\\bar{b}} at Low Q^2 and x using the H1 Vertex Detector at HERA

CERN Document Server

Aktas, A.; Anthonis, T.; Aplin, S.; Asmone, A.; Astvatsatourov, A.; Babaev, A.; Backovic, S.; Bahr, J.; Baghdasaryan, A.; Baranov, P.; Barrelet, E.; Bartel, W.; Baudrand, S.; Baumgartner, S.; Becker, J.; Beckingham, M.; Behnke, O.; Behrendt, O.; Belousov, A.; Berger, Ch.; Berger, N.; Bizot, J.C.; Boenig, M.-O.; Boudry, V.; Bracinik, J.; Brandt, G.; Brisson, V.; Brown, D.P.; Bruncko, D.; Busser, F.W.; Bunyatyan, A.; Buschhorn, G.; Bystritskaya, L.; Campbell, A.J.; Caron, S.; Cassol-Brunner, F.; Cerny, K.; Cerny, V.; Chekelian, V.; Contreras, J.G.; Coughlan, J.A.; Cox, B.E.; Cozzika, G.; Cvach, J.; Dainton, J.B.; Dau, W.D.; Daum, K.; de Boer, Y.; Delcourt, B.; De Roeck, A.; Desch, K.; De Wolf, E.A.; Diaconu, C.; Dodonov, V.; Dubak, A.; Eckerlin, Guenter; Efremenko, V.; Egli, S.; Eichler, R.; Eisele, F.; Ellerbrock, M.; Erdmann, W.; Essenov, S.; Falkewicz, A.; Faulkner, P.J.W.; Favart, L.; Fedotov, A.; Felst, R.; Ferencei, J.; Finke, L.; Fleischer, M.; Fleischmann, P.; Fleming, Y.H.; Flucke, G.; Fomenko, A.; Foresti, I.; Franke, G.; Frisson, T.; Gabathuler, E.; Garutti, E.; Gayler, J.; Gerlich, C.; Ghazaryan, Samvel; Ginzburgskaya, S.; Glazov, A.; Glushkov, I.; Goerlich, L.; Goettlich, M.; Gogitidze, N.; Gorbounov, S.; Goyon, C.; Grab, C.; Greenshaw, T.; Gregori, M.; Grell, B.R.; Grindhammer, Guenter; Gwilliam, C.; Haidt, D.; Hajduk, L.; Hansson, M.; Heinzelmann, G.; Henderson, R.C.W.; Henschel, H.; Henshaw, O.; Herrera, G.; Hildebrandt, M.; Hiller, K.H.; Hoffmann, D.; Horisberger, R.; Hovhannisyan, A.; Hreus, T.; Hussain, S.; Ibbotson, M.; Ismail, M.; Jacquet, M.; Janauschek, L.; Janssen, X.; Jemanov, V.; Jonsson, L.; Johnson, D.P.; Jung, Andreas Werner; Jung, H.; Kapichine, M.; Katzy, J.; Keller, N.; Kenyon, I.R.; Kiesling, Christian M.; Klein, M.; Kleinwort, C.; Klimkovich, T.; Kluge, T.; Knies, G.; Knutsson, A.; Korbel, V.; Kostka, P.; Krastev, K.; Kretzschmar, J.; Kropivnitskaya, A.; Kruger, K.; Kuckens, J.; Landon, M.P.J.; Lange, W.; Lastovicka, T.; Lastovicka-Medin, G.; Laycock, P.; Lebedev, A.; Leibenguth, G.; Lendermann, V.; Levonian, S.; Lindfeld, L.; Lipka, K.; Liptaj, A.; List, B.; Lobodzinska, E.; Loktionova, N.; Lopez-Fernandez, R.; Lubimov, V.; Lucaci-Timoce, A.-I.; Lueders, H.; Luke, D.; Lux, T.; Lytkin, L.; Makankine, A.; Malden, N.; Malinovski, E.; Mangano, S.; Marage, P.; Marshall, R.; Martisikova, M.; Martyn, H.-U.; Maxeld, S.J.; Meer, D.; Mehta, A.; Meier, K.; Meyer, A.B.; Meyer, H.; Meyer, J.; Mikocki, S.; Milcewicz-Mika, I.; Milstead, D.; Mladenov, D.; Mohamed, A.; Moreau, F.; Morozov, A.; Morris, J.V.; Mozer, Matthias Ulrich; Muller, K.; Murin, P.; Nankov, K.; Naroska, B.; Naumann, Th.; Newman, Paul R.; Niebuhr, C.; Nikiforov, A.; Nikitin, D.; Nowak, G.; Nozicka, M.; Oganezov, R.; Olivier, B.; Olsson, J.E.; Osman, S.; Ozerov, D.; Palichik, V.; Panagoulias, I.; Papadopoulou, T.; Pascaud, C.; Patel, G.D.; Peez, M.; Perez, E.; Perez-Astudillo, D.; Perieanu, A.; Petrukhin, A.; Pitzl, D.; Placakyte, R.; Portheault, B.; Povh, B.; Prideaux, P.; Raicevic, N.; Reimer, P.; Rimmer, A.; Risler, C.; Rizvi, E.; Robmann, P.; Roland, B.; Roosen, R.; Rostovtsev, A.; Rurikova, Z.; Rusakov, S.; Salvaire, F.; Sankey, D.P.C.; Sauvan, E.; Schatzel, S.; Schilling, F.-P.; Schmidt, S.; Schmitt, S.; Schmitz, C.; Schoeffel, L.; Schoning, A.; Schultz-Coulon, H.-C.; Sedlak, K.; Sefkow, F.; Shaw-West, R.N.; Sheviakov, I.; Shtarkov, L.N.; Sloan, T.; Smirnov, P.; Soloviev, Y.; South, D.; Spaskov, V.; Specka, Arnd E.; Stella, B.; Stiewe, J.; Strauch, I.; Straumann, U.; Tchoulakov, V.; Thompson, Graham; Thompson, P.D.; Tomasz, F.; Traynor, D.; Truoel, Peter; Tsakov, I.; Tsipolitis, G.; Tsurin, I.; Turnau, J.; Tzamariudaki, E.; Urban, Marcel; Usik, A.; Utkin, D.; Valkar, S.; Valkarova, A.; Vallee, C.; Van Mechelen, P.; Vargas Trevino, A.; Vazdik, Y.; Veelken, C.; Vest, A.; Vinokurova, S.; Volchinski, V.; Vujicic, B.; Wacker, K.; Wagner, J.; Weber, G.; Weber, R.; Wegener, D.; Werner, C.; Werner, N.; Wessels, M.; Wessling, B.; Wigmore, C.; Wissing, Ch.; Wolf, R.; Wunsch, E.; Xella, S.; Yan, W.; Yeganov, V.; Zacek, J.; Zalesak, J.; Zhang, Z.; Zhelezov, A.; Zhokin, A.; Zhu, Y.C.; Zimmermann, J.; Zimmermann, T.; Zohrabyan, H.; Zomer, F.

2006-01-01

Measurements are presented of inclusive charm and beauty cross sections in e^+p collisions at HERA for values of photon virtuality 12 \\le Q^2 \\le 60 GeV^2 and of the Bjorken scaling variable 0.0002 \\le x \\le 0.005. The fractions of events containing charm and beauty quarks are determined using a method based on the impact parameter, in the transverse plane, of tracks to the primary vertex, as measured by the H1 vertex detector. Values for the structure functions F_2^{c\\bar{c}} and F_2^{b\\bar{b}} are obtained. This is the first measurement of F_2^{b\\bar{b}} in this kinematic range. The results are found to be compatible with the predictions of perturbative quantum chromodynamics and withprevious measurements of F_2^{c\\bar{c}}.

Dimethylarsinic acid: Results of chronic toxicity/oncogenicity studies in F344 rats and in B6C3F1 mice

International Nuclear Information System (INIS)

Arnold, Lora L.; Eldan, Michal; Nyska, Abraham; Gemert, Marcia van; Cohen, Samuel M.

2006-01-01

Dimethylarsinic acid (DMA V , cacodylic acid), a foliar herbicide, was administered in the diet to B6C3F1 mice (at dose levels of 0, 8, 40, 200, and 500 ppm) and to F344 rats (at dose levels of 0, 2, 10, 40, and 100 ppm) for 2 years, according to US EPA guidelines. In mice, there were no treatment-related tumors observed at any site. Treatment-related progressive glomerulonephropathy and nephrocalcinosis were observed in the kidneys in both sexes. The incidence of vacuolation of the epithelium in the urinary bladder was increased in both sexes, but was not associated with cytotoxicity, necrosis or hyperplasia. Based on non-neoplastic lesions found in the urinary bladder, the NOEL for mice was assessed to be 40 ppm in males and 8 ppm in females. In rats, treatment-related mortality occurred early in the study in five males in the 100 ppm group and in one male in the 40 ppm group. Papillomas and carcinomas with degeneration of the urothelium, necrosis and urothelial cell hyperplasia, were found in the urinary bladders of both sexes. In male rats, one papilloma was found in each of the 10 and 40 ppm groups; one urothelial cell carcinoma was found in the 2 ppm group and two in the 100 ppm group. Four papillomas and six urothelial cell carcinomas were found in the female 100 ppm group. Non-neoplastic treatment-related kidney lesions were confined to the 40 and 100 ppm levels and included necrosis, pyelonephritis, medullary nephrocalcinosis and tubular cystic dilation, hyperplasia of the epithelial lining of the papilla, and pelvic urothelial cell hyperplasia. All of these kidney changes appear to be related to an increase in the aging nephropathy of the rat. Dose-related increases in the height of the thyroid follicular epithelium were also noted in males and females, however, such changes reflect an adaptive response of the thyroid to decreased levels of circulating thyroid hormone, rather than an adverse effect. Based on the kidney and bladder lesions, the NOEL for

Morphological Lesions in Mouse Liver and Lungs After Lung Exposure to Carbon Nanotubes

DEFF Research Database (Denmark)

Szarek, J.; Mortensen, Alicja; Jackson, P.

2013-01-01

Introduction: Engineered nanoparticles are smaller than 100 nm in at least one direction and designed to improve or achieve new physicochemical properties. Consequently, toxicological properties may also change. Carbon nanotubes have attracted industrial interest due to their unique properties....... Materials and Methods: One day before mating, 30 mice (C57BL/6BomTac, Taconic Europe, Denmark) were given 67 μg multi-walled carbon nanotubes (NM-400, Nanocyl, Belgium) intratracheally (group A). A further 30 control mice (group B) received vehicle (Millipore water with 2% mouse serum). Lungs and liver were...... taken from six animals from each group for histopathological examination (haematoxylin and eosin staining) 6 weeks (A1, B1 group) and 4 months (A2, B2) after exposure. Results: Lungs in A1 mice showed bronchiolar subepithelial oedema and perivascular oedema and sporadic hyperaemia and the presence...

Neutron diffraction analysis of HRh[P(C6H5)3]4

International Nuclear Information System (INIS)

Bau, R.; Stevens, R.C.; McLean, M.; Koetzle, T.F.

1987-01-01

We have collected neutron diffraction data on a large single crystal of the title compound. The most surprising result is an extremely short Rh-H distance of 1.31(8) A, presumably caused by steric interactions involving the bulky triphenyl phosphine ligands. Crystallographic details: HRh[P(C 6 H 5 ) 3 ] 4 . 1 / 2 C 6 H 6 crystallizes in the space group Pa3, with a = b = c = 22.776(3) A, Z = 8. Data were collected at the Brookhaven High Flux Beam reactor at a temperature of -23 0 C, λ = 1.15882(7) A -1 . Least-squares refinement (in which the phenyl rings were treated as rigid groups) resulted in an R factor [based on data with f > 4σ(F)] of 0.12 for 914 reflections and 95 parameters. 10 refs

Synthesis and Spectral Analysis of 3,4,5-trichloro-6-(dibenzo[d,f][1,3]diazepin-5-yl-[1,2]-benzoquinones

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Mohsen A. M. Gomaa

2011-01-01

Full Text Available Reaction of N1,N2-di-(4-methoxyphenyl- or N1,N2-di-(4-hydroxyphenyl -amidines (1a-d with 3,4,5,6-tetrachloro-1,2-benzoquinone (2 in ethyl acetate at room temperature led to formation of new 3,4,5-trichloro-6-(2-hydroxy-6-methyldibenzo[d,f][1,3]diazepin-5-yl[1,2]-benzoquinones (3a-d in addition to N-aryl-N'-(6,7,8,9-tetrachloro-4-hydroxydibenzo-[1,4]dioxin-2-ylacetamidines (4a,b. The rational of formation of products 3a-d and 4a,b was discussed and structures were confirmed on the basis of elemental analysis and spectral data.

Silyl Ketene Acetals/B(C6F53 Lewis Pair-Catalyzed Living Group Transfer Polymerization of Renewable Cyclic Acrylic Monomers

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Lu Hu

2018-03-01

Full Text Available This work reveals the silyl ketene acetal (SKA/B(C6F53 Lewis pair-catalyzed room-temperature group transfer polymerization (GTP of polar acrylic monomers, including methyl linear methacrylate (MMA, and the biorenewable cyclic monomers γ-methyl-α-methylene-γ-butyrolactone (MMBL and α-methylene-γ-butyrolactone (MBL as well. The in situ NMR monitored reaction of SKA with B(C6F53 indicated the formation of Frustrated Lewis Pairs (FLPs, although it is sluggish for MMA polymerization, such a FLP system exhibits highly activity and living GTP of MMBL and MBL. Detailed investigations, including the characterization of key reaction intermediates, polymerization kinetics and polymer structures have led to a polymerization mechanism, in which the polymerization is initiated with an intermolecular Michael addition of the ester enolate group of SKA to the vinyl group of B(C6F53-activated monomer, while the silyl group is transferred to the carbonyl group of the B(C6F53-activated monomer to generate the single-monomer-addition species or the active propagating species; the coordinated B(C6F53 is released to the incoming monomer, followed by repeated intermolecular Michael additions in the subsequent propagation cycle. Such neutral SKA analogues are the real active species for the polymerization and are retained in the whole process as confirmed by experimental data and the chain-end analysis by matrix-assisted laser desorption/ionization time of flight mass spectroscopy (MALDI-TOF MS. Moreover, using this method, we have successfully synthesized well-defined PMMBL-b-PMBL, PMMBL-b-PMBL-b-PMMBL and random copolymers with the predicated molecular weights (Mn and narrow molecular weight distribution (MWD.

Serum level of IL-6 in liver cirrhosis patients

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Rey, I.; Effendi-YS, R.; Dairi, L. B.; Siregar, G. A.; Zain, L. H.

2018-03-01

Cytokines are polypeptides that have a wide spectrum of inflammatory, metabolic, hematopoietic and immunologic regulatory properties. The liver represents an important site of synthesis and clearance organ for several cytokines. This study aimed to evaluate serum IL-6 in liver cirrhosis with the type of underlying disease, child pugh group and various clinical and laboratory parameter. This cross-sectional study was at Adam Malik General Hospital and Pirngadi General Hospital from July - December 2016. We examine 75 patients with liver cirrhosis. The exclusion criteria were hepatoma, sepsis and renal impairment. There were 28 (37.3%), 8 (10.6%) and 39 (52%) for HBV-positive; HCV-positive and HBV- HCV negative liver cirrhosis patients, respectively were 14 (18.7 %), 15 (20 %) and 46 (61.3%) for Child- Pugh A, B and C respectively. There was no significant difference value of IL-6 between HBV positive, HCV positive, and HBV-HCV negative group (7.7/6.1/10.9). There was no significant difference value of IL-6 between child pugh A, B, and C group (4.2/11.0/7.9).

Moderate activation of IKK2-NF-kB in unstressed adult mouse liver induces cytoprotective genes and lipogenesis without apparent signs of inflammation or fibrosis.

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Lu, Hong; Lei, Xiaohong; Zhang, Qinghao

2015-07-30

The NF-kB signaling, regulated by IKK1-p52/RelB and IKK2-p65, is activated by various stresses to protect or damage the liver, in context-specific manners. Two previous studies of liver-specific expression of constitutive active IKK2 (IKK2ca) showed that strong activation of IKK2-NF-kB in mouse livers caused inflammation, insulin resistance, and/or fibrosis. The purpose of this study was to understand how moderate activation of IKK2-NF-kB in adult mouse livers alters hepatic gene expression and pathophysiology. We generated mice with adult hepatocyte-specific activation of Ikk2 (Liv-Ikk2ca) using Alb-cre mice and Ikk2ca Rosa26 knockin mice in which a moderate expression of Ikk2ca transgene was driven by the endogenous Rosa26 promoter. Surprisingly, compared to wild-type mice, adult male Liv-Ikk2ca mice had higher hepatic mRNA expression of Ikk2 and classical NF-kB targets (e.g. Lcn2 and A20), as well as IKK1, NIK, and RelB, but no changes in markers of inflammation or fibrosis. Blood levels of IL-6 and MCP-1 remained unchanged, and histology analysis showed a lack of injury or infiltration of inflammatory cells in livers of Liv-Ikk2ca mice. Moreover, Liv-Ikk2ca mice had lower mRNA expression of prooxidative enzymes Cyp2e1 and Cyp4a14, higher expression of antioxidative enzymes Sod2, Gpx1, and Nqo1, without changes in key enzymes for fatty acid oxidation, glucose utilization, or gluconeogenesis. In parallel, Liv-Ikk2ca mice and wild-type mice had similar levels of hepatic reduced glutathione, endogenous reactive oxygen species, and lipid peroxidation. Additionally, Liv-Ikk2ca mice had higher Cyp3a11 without down-regulation of most drug processing genes. Regarding nuclear proteins of NF-kB subunits, Liv-Ikk2ca mice had moderately higher p65 and p50 but much higher RelB. Results of ChIP-qPCR showed that the binding of p50 to multiple NF-kB-target genes was markedly increased in Liv-Ikk2ca mice. Additionally, Liv-Ikk2ca mice had moderate increase in triglycerides in

Borders and Comparative Cytoarchitecture of the Perirhinal and Postrhinal Cortices in an F1 Hybrid Mouse

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Beaudin, Stephane A.; Singh, Teghpal; Agster, Kara L.

2013-01-01

We examined the cytoarchitectonic and chemoarchitectonic organization of the cortical regions associated with the posterior rhinal fissure in the mouse brain, within the framework of what is known about these regions in the rat. Primary observations were in a first-generation hybrid mouse line, B6129PF/J1. The F1 hybrid was chosen because of the many advantages afforded in the study of the molecular and cellular bases of learning and memory. Comparisons with the parent strains, the C57BL6/J and 129P3/J are also reported. Mouse brain tissue was processed for visualization of Nissl material, myelin, acetyl cholinesterase, parvalbumin, and heavy metals. Tissue stained for heavy metals by the Timm’s method was particularly useful in the assignment of borders and in the comparative analyses because the patterns of staining were similar across species and strains. As in the rat, the areas examined were parcellated into 2 regions, the perirhinal and the postrhinal cortices. The perirhinal cortex was divided into areas 35 and 36, and the postrhinal cortex was divided into dorsal (PORd) and ventral (PORv) subregions. In addition to identifying the borders of the perirhinal cortex, we were able to identify a region in the mouse brain that shares signature features with the rat postrhinal cortex. PMID:22368084

Evaluation of 11C-Acetate and 18 F-FDG PET/CT in mouse multidrug resistance gene-2 deficient mouse model of hepatocellular carcinoma

International Nuclear Information System (INIS)

Territo, Paul R.; Maluccio, Mary; Riley, Amanda A.; McCarthy, Brian P.; Fletcher, James; Tann, Mark; Saxena, Romil; Skill, Nicholas J.

2015-01-01

Hepatocellular carcinoma (HCC) remains a global health problem with unique diagnostic and therapeutic challenges, including difficulties in identifying the highest risk patients. Previous work from our lab has established the murine multidrug resistance-2 mouse (MDR2) model of HCC as a reasonable preclinical model that parallels the changes seen in human inflammatory associated HCC. The purpose of this study is to evaluate modalities of PET/CT in MDR2 −/− mice in order to facilitate therapeutic translational studies from bench to bedside. 18 F-FDG and 11 C-acetate PET/CT was performed on 12 m MDR2 −/− mice (n = 3/tracer) with HCC and 12 m MDR2 −/+ control mice (n = 3/tracer) without HCC. To compare PET/CT to biological markers of HCC and cellular function, serum alpha-fetoprotein (AFP), lysophosphatidic acid (LPA), cAMP and hepatic tumor necrosis factor α (TNFα) were quantified in 3-12 m MDR2 −/− (n = 10) mice using commercially available ELISA analysis. To translate results in mice to patients 11 C-acetate PET/CT was also performed in 8 patents suspected of HCC recurrence following treatment and currently on the liver transplant wait list. Hepatic 18 F-FDG metabolism was not significantly increased in MDR2 −/− mice. In contrast, hepatic 11 C-acetate metabolism was significantly elevated in MDR2 −/− mice when compared to MDR2 −/+ controls. Serum AFP and LPA levels increased in MDR2 −/− mice contemporaneous with the emergence of HCC. This was accompanied by a significant decrease in serum cAMP levels and an increase in hepatic TNFα. In patients suspected of HCC recurrence there were 5 true positives, 2 true negatives and 1 suspected false 11 C-acetate negative. Hepatic 11 C-acetate PET/CT tracks well with HCC in MDR2 −/− mice and patients with underlying liver disease. Consequently 11 C-acetate PET/CT is well suited to study 1) HCC emergence/progression in patients and 2) reduce animal numbers required to study new

NS3 protease resistance-associated substitutions in liver tissue and plasma samples from patients infected by hepatitis C virus genotype 1A or 1B.

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Morsica, Giulia; Andolina, Andrea; Merli, Marco; Messina, Emanuela; Hasson, Hamid; Lazzarin, Adriano; Uberti-Foppa, Caterina; Bagaglio, Sabrina

2017-08-01

The presence of naturally occurring resistance-associated substitutions (RASs) in the HCV-protease domain has been poorly investigated in the liver, the main site of HCV replication. We evaluated the natural resistance of the virus to NS3 protease inhibitors in liver tissue and plasma samples taken from HCV-infected patients. RASs were investigated by means of viral population sequencing in liver tissue samples from 18 HCV-infected patients harbouring genotype 1a or genotype 1b; plasma samples from 12 of these patients were also available for virological investigation. A discordant genotype was found in two of the 12 patients (16.6%) who provided samples from both compartments. Sequence analysis of the NS3 protease domain showed the presence of RASs in four of the 18 liver tissue samples (22.2%), two of which showed cross-resistance to protease inhibitors in clinical use or phase 2-3 trials. The analysis of the 12 paired tissues and plasma samples excluded the presence of RASs in the plasma compartment. The dominance of discordant genotypes in the paired liver and plasma samples of some HCV-infected patients suggests mixed infection possibly leading to the selective advantage of different genotype in the two compartments. The presence of RASs at intra-hepatic level is not uncommon and may lead to the early emergence of cross-resistant strains.

Toxicology and Carcinogenesis Studies of Furfuryl Alcohol (CAS No. 98-00-0) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Science.gov (United States)

1999-02-01

Furfuryl alcohol-based resins are used as binding agents in foundry sand and as corrosion inhibitors in mortar, grout, and cement. Because of their heat resistance, furan resins are used in the manufacture of fiberglass-reinforced plastic equipment. Furfuryl alcohol was selected for evaluation because of the absence of data on its carcinogenic potential and its large production volume, widespread use in manufacturing, and ubiquitous presence in consumer goods. Male and female F344/N rats and B6C3F1 mice were exposed to furfuryl alcohol (greater than 98% pure) by inhalation for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse bone marrow cells. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to concentrations of 0, 16, 31, 63, 125, or 250 ppm furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 16 days. All male and female rats exposed to 250 ppm died by day 2 of the study, and one male rat exposed to 125 ppm died on day 5. Final mean body weights of male and female rats exposed to 125 ppm were significantly less than those of the chamber control groups. Male rats exposed to 31, 63, or 125 ppm and female rats exposed to 125 ppm gained less weight than the chamber control groups. Clinical findings included dyspnea, hypoactivity, and nasal and ocular discharge in males and females exposed to 63, 125, or 250 ppm. All exposed animals developed lesions in the nasal respiratory epithelium and olfactory epithelium, and the severities of these lesions generally increased with increasing exposure concentration. 16-DAY STUDY IN MICE: Groups of five male and five female mice were exposed to concentrations of 0, 16, 31, 63, 125, or 250 ppm furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 16 days. All male and female mice exposed to 250 ppm died by day 4 of the study, and one female mouse exposed to 125 ppm died on day

Recruitment of Gr1(+)CD11b (+)F4/80 (+) population in the bone marrow and spleen by irradiation-induced pulmonary damage.

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Thanasegaran, Suganya; Ito, Sachiko; Nishio, Naomi; Uddin, Mohammad Nizam; Sun, Yang; Isobe, Ken-ichi

2015-04-01

Radiation-induced lung injury is a kind of sterile inflammation, which may lead to morbidity and mortality. The mechanism by which ionizing radiation activate the immune system is not well understood. In the present study, we have investigated the immunological responses induced by local irradiation-induced damage in mouse lung. The left lungs of C57BL/6 mice were irradiated at a high dose of 100 Gy. The histology of the lungs and spleen showed evidences of alveolar inflammation and congestion at 2 weeks after X-ray treatment. Also, prominent increase in cells expressing the cell surface markers, Gr(+)CD11b(+)F4/80(+) and Ly6C(+) Ly6G(+) were observed 2 weeks after X-ray treatment (100 Gy). Gr1(+)CD11b(+)F4/80(+) cell depletion by clodronate treatment reversed the histological effects and also failed to recruit Gr(+)CD11b(+) cells or F4/80(+) cells caused by irradiation. The origin of recruited Gr1(+)CD11b(+) cells was found to be a mixed resident and recruited phenotype.

Complement and alcoholic liver disease: role of C1q in the pathogenesis of ethanol-induced liver injury in mice.

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Cohen, Jessica I; Roychowdhury, Sanjoy; McMullen, Megan R; Stavitsky, Abram B; Nagy, Laura E

2010-08-01

Complement is involved in the development of alcoholic liver disease in mice; however, the mechanisms for complement activation during ethanol exposure have not been identified. C1q, the recognition subunit of the first complement component, binds to apoptotic cells, thereby activating the classical complement pathway. Because ethanol exposure increases hepatocellular apoptosis, we hypothesized that ethanol-induced apoptosis would lead to activation of complement via the classical pathway. Wild-type and C1qa-/- mice were allowed free access to ethanol-containing diets or pair-fed control diets for 4 or 25 days. Ethanol feeding for 4 days increased apoptosis of Kupffer cells in both wild-type and C1qa-/- mice. Ethanol-induced deposition of C1q and C3b/iC3b/C3c was colocalized with apoptotic Kupffer cells in wild-type, but not C1qa-/-, mice. Furthermore, ethanol-induced increases in tumor necrosis factor-alpha and interleukin-6 expression at this early time point were suppressed in C1q-deficient mice. Chronic ethanol feeding (25 days) increased steatosis, hepatocyte apoptosis, and activity of serum alanine and aspartate aminotransferases in wild-type mice. These markers of hepatocyte injury were attenuated in C1qa-/- mice. In contrast, chronic ethanol (25 days)-induced increases in cytochrome P450 2E1 expression and oxidative stress did not differ between wild-type and C1qa-/- mice. For the first time, these data indicate that ethanol activates the classical complement pathway via C1q binding to apoptotic cells in the liver and that C1q contributes to the pathogenesis of ethanol-induced liver injury. Copyright (c) 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

MEK kinase 1 activity is required for definitive erythropoiesis in the mouse fetal liver

DEFF Research Database (Denmark)

Bonnesen, Barbara; Ørskov, Cathrine; Rasmussen, Susanne

2005-01-01

for MEKK1 in definitive mouse erythropoiesis. Although Mekk1(DeltaKD) mice are alive and fertile on a 129 x C57/BL6 background, the frequency of Mekk1(DeltaKD) embryos that develop past embryonic day (E) 14.5 is dramatically reduced when backcrossed into the C57/BL6 background. At E13.5, Mekk1(Delta......KD) embryos have normal morphology but are anemic due to failure of definitive erythropoiesis. When Mekk1(DeltaKD) fetal liver cells were transferred to lethally irradiated wild-type hosts, mature red blood cells were generated from the mutant cells, suggesting that MEKK1 functions in a non......-cell-autonomous manner. Based on immunohistochemical and hemoglobin chain transcription analysis, we propose that the failure of definitive erythropoiesis is due to a deficiency in enucleation activity caused by insufficient macrophage-mediated nuclear DNA destruction....

1H, 15N and 13C NMR Assignments of Mouse Methionine Sulfoxide Reductase B2

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Breivik, Åshild S.; Aachmann, Finn L.; Sal, Lena S.; Kim, Hwa-Young; Del Conte, Rebecca; Gladyshev, Vadim N.; Dikiy, Alexander

2011-01-01

A recombinant mouse methionine-r-sulfoxide reductase 2 (MsrB2ΔS) isotopically labeled with 15N and 15N/13C was generated. We report here the 1H, 15N and 13C NMR assignments of the reduced form of this protein. PMID:19636904

Cytochrome c6B of Synechococcus sp. WH 8102 – Crystal structure and basic properties of novel c6-like family representative

International Nuclear Information System (INIS)

Zatwarnicki, Pawel; Barciszewski, Jakub; Krzywda, Szymon; Jaskolski, Mariusz; Kolesinski, Piotr; Szczepaniak, Andrzej

2014-01-01

Highlights: • Crystal structure of cytochrome c 6B from Synechococcus sp. WH 8102 was solved. • Basic biophysical properties of cytochrome c 6B were determined. • Cytochrome c 6B exhibits similar architecture to cytochrome c 6 . • Organization of heme binding pocket of cytochrome c 6B differs from that of c 6 . • Midpoint potential of cytochrome c 6B is significantly lower than of cytochrome c 6 . - Abstract: Cytochromes c are soluble electron carriers of relatively low molecular weight, containing single heme moiety. In cyanobacteria cytochrome c 6 participates in electron transfer from cytochrome b 6 f complex to photosystem I. Recent phylogenetic analysis revealed the existence of a few families of proteins homologous to the previously mentioned. Cytochrome c 6A from Arabidopsis thaliana was identified as a protein responsible for disulfide bond formation in response to intracellular redox state changes and c 550 is well known element of photosystem II. However, function of cytochromes marked as c 6B , c 6C and c M as well as the physiological process in which they take a part still remain unidentified. Here we present the first structural and biophysical analysis of cytochrome from the c 6B family from mesophilic cyanobacteria Synechococcus sp. WH 8102. Purified protein was crystallized and its structure was refined at 1.4 Å resolution. Overall architecture of this polypeptide resembles typical I-class cytochromes c. The main features, that distinguish described protein from cytochrome c 6 , are slightly red-shifted α band of UV–Vis spectrum as well as relatively low midpoint potential (113.2 ± 2.2 mV). Although, physiological function of cytochrome c 6B has yet to be determined its properties probably exclude the participation of this protein in electron trafficking between b 6 f complex and photosystem I

Crystals structure of Na3Li(TiF6)2

International Nuclear Information System (INIS)

Popov, D.Yu.; Antokhina, T.F.; Gerasimenko, A.V.; Kajdalova, T.A.; Sergienko, V.I.

2004-01-01

Crystals of Na 3 Li(TiF 6 ) 2 (1) were synthesized in aqueous solution and characterized by the elementary and X-ray phase analysis methods. According to X-ray diffraction analysis data compound 1 is crystallized in a tetragonal crystal system with the following parameters: a=5.130(1), c=18.046(4) A, Z=2, space group P4-bar2 1 c. Alternating layers on the basis of dimers made up by octahedrons of TiF 6 and Na(1)F 6 constitute the frame of compound 1 crystal structure. The dimer layers are joined in a continuous frame by Na(2) and Li cations. Coordination polyhedron of Li atom is tetrahedron (Li-F 1.898(3) A) [ru

Postnatal liver growth and regeneration are independent of c-myc in a mouse model of conditional hepatic c-myc deletion

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Sanders Jennifer A

2012-03-01

Full Text Available Abstract Background The transcription factor c-myc regulates genes involved in hepatocyte growth, proliferation, metabolism, and differentiation. It has also been assigned roles in liver development and regeneration. In previous studies, we made the unexpected observation that c-Myc protein levels were similar in proliferating fetal liver and quiescent adult liver with c-Myc displaying nucleolar localization in the latter. In order to investigate the functional role of c-Myc in adult liver, we have developed a hepatocyte-specific c-myc knockout mouse, c-mycfl/fl;Alb-Cre. Results Liver weight to body weight ratios were similar in control and c-myc deficient mice. Liver architecture was unaffected. Conditional c-myc deletion did not result in compensatory induction of other myc family members or in c-Myc's binding partner Max. Floxed c-myc did have a negative effect on Alb-Cre expression at 4 weeks of age. To explore this relationship further, we used the Rosa26 reporter line to assay Cre activity in the c-myc floxed mice. No significant difference in Alb-Cre activity was found between control and c-mycfl/fl mice. c-myc deficient mice were studied in a nonproliferative model of liver growth, fasting for 48 hr followed by a 24 hr refeeding period. Fasting resulted in a decrease in liver mass and liver protein, both of which recovered upon 24 h of refeeding in the c-mycfl/fl;Alb-Cre animals. There was also no effect of reducing c-myc on recovery of liver mass following 2/3 partial hepatectomy. Conclusions c-Myc appears to be dispensable for normal liver growth during the postnatal period, restoration of liver mass following partial hepatectomy and recovery from fasting.

Polymorphisms of cytochrome P450 2B6 (CYP2B6) in cynomolgus and rhesus macaques.

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Uno, Yasuhiro; Uehara, Shotaro; Yamazaki, Hiroshi

2018-02-22

Cytochrome P450 2B6 (CYP2B6) is an important drug-metabolizing enzyme and is expressed in liver. Although human CYP2B6 variants account for variable enzyme properties among individuals and populations, CYP2B6 genetic variants have not been investigated in cynomolgus macaques, widely used in drug metabolism studies. CYP2B6 was resequenced in 120 cynomolgus macaques and 23 rhesus macaques by direct sequencing. Twenty-three non-synonymous variants were found, of which 12 and 3 were unique to cynomolgus macaques and rhesus macaques, respectively. By functional characterization using the 14 variant proteins, 8 variants (V114I, R253C, M435I, V459M, L465P, C475S, R487C, and R487H) showed different rate (>1.5-fold) of testosterone 16β-hydroxylation to wild type. However, the four variants (M435I, L465P, C475S, and R487H) were analyzed in liver microsomes, and the catalytic rates were not substantially different from wild type. Macaque CYP2B6 was polymorphic, and the genotype could partly account for variable enzyme activities of macaque CYP2B6. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A 4-week study of four 3-monochloropropane-1,2-diol diesters on lipid metabolism in C57BL/6J mice.

Science.gov (United States)

Lu, Jing; Wang, Zhenning; Ren, Mengrou; Feng, Guangxin; Ye, Beining; Wang, Yi; Fang, Baochen; Deng, Xuming; Guan, Shuang

2015-09-01

3-Monochloropropane-1,2-diol (3-MCPD) esters have been detected in many foods, which have become a new safety issue worldwide. In the study, we investigated the effect of four 3-MCPD diesters (palmitate diester: CDP; stearate diester: CDS; oleate diester: CDO; linoleate diester: CDL) on lipid metabolism in C57BL/6J mice. The results showed that CDP, CDS, CDO and CDL significantly increased the serum TC, LDL-C levels and liver TG, TC levels at dose of 16.5μmol/kg/day. These results indicated that 3-MCPD diesters could potentially cause hyperlipidemia in C57BL/6J mice. Moreover, oil red O staining confirmed fat accumulation in liver induced by 3-MCPD diesters. Our work will provide more information for safety evaluation of 3-MCPD diesters. However, whether free 3-MCPD or free fatty acids or combined action compensates for the hyperlipidemia effects should be elucidated in the future. Copyright © 2015 Elsevier B.V. All rights reserved.

CLEC4F is an inducible C-type lectin in F4/80-positive cells and is involved in alpha-galactosylceramide presentation in liver.

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Chih-Ya Yang

Full Text Available CLEC4F, a member of C-type lectin, was first purified from rat liver extract with high binding affinity to fucose, galactose (Gal, N-acetylgalactosamine (GalNAc, and un-sialylated glucosphingolipids with GalNAc or Gal terminus. However, the biological functions of CLEC4F have not been elucidated. To address this question, we examined the expression and distribution of murine CLEC4F, determined its binding specificity by glycan array, and investigated its function using CLEC4F knockout (Clec4f-/- mice. We found that CLEC4F is a heavily glycosylated membrane protein co-expressed with F4/80 on Kupffer cells. In contrast to F4/80, CLEC4F is detectable in fetal livers at embryonic day 11.5 (E11.5 but not in yolk sac, suggesting the expression of CLEC4F is induced as cells migrate from yolk cells to the liver. Even though CLEC4F is not detectable in tissues outside liver, both residential Kupffer cells and infiltrating mononuclear cells surrounding liver abscesses are CLEC4F-positive upon Listeria monocytogenes (L. monocytogenes infection. While CLEC4F has strong binding to Gal and GalNAc, terminal fucosylation inhibits CLEC4F recognition to several glycans such as Fucosyl GM1, Globo H, Bb3∼4 and other fucosyl-glycans. Moreover, CLEC4F interacts with alpha-galactosylceramide (α-GalCer in a calcium-dependent manner and participates in the presentation of α-GalCer to natural killer T (NKT cells. This suggests that CLEC4F is a C-type lectin with diverse binding specificity expressed on residential Kupffer cells and infiltrating monocytes in the liver, and may play an important role to modulate glycolipids presentation on Kupffer cells.

Predominant modifier of extreme liver cancer susceptibility in C57BR/cdJ female mice localized to 6 Mb on chromosome 17

Science.gov (United States)

Peychal, Stephanie E.-M.; Bilger, Andrea; Pitot, Henry C.; Drinkwater, Norman R.

2009-01-01

Sex hormones influence the susceptibility of inbred mice to liver cancer. C57BR/cdJ (BR) females are extremely susceptible to spontaneous and chemically induced liver tumors, in part due to a lack of protection against hepatocarcinogenesis normally offered by ovarian hormones. BR males are also moderately susceptible, and the susceptibility of both sexes of BR mice to liver tumors induced with N,N-diethylnitrosamine relative to the resistant C57BL/6J (B6) strain is caused by two loci designated Hcf1 and Hcf2 (hepatocarcinogenesis in females) located on chromosomes 17 and 1, respectively. The Hcf1 locus on chromosome 17 is the predominant modifier of liver cancer in BR mice. To validate the existence of this locus and investigate its potential interaction with Hcf2, congenic mice for each region were generated. Homozygosity for the B6.BR(D17Mit164-D17Mit2) region resulted in a 4-fold increase in liver tumor multiplicity in females and a 4.5-fold increase in males compared with B6 controls. A series of 16 recombinants covering the entire congenic region was developed to further narrow the area containing Hcf1. Susceptible heterozygous recombinants demonstrated a 3- to 7-fold effect in females and a 1.5- to 2-fold effect in males compared with B6 siblings. The effect in susceptible lines completely recapitulated the susceptibility of heterozygous full-length chromosome 17 congenics and furthermore narrowed the location of the Hcf1 locus to a single region of the chromosome from 30.05 to 35.83 Mb. PMID:19255062

NF-κB mediates the transcription of mouse calsarcin-1 gene, but not calsarcin-2, in C2C12 cells

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Mu Yulian

2007-03-01

Full Text Available Abstract Background The calsarcins comprise a novel family of muscle-specific calcineurin-interaction proteins that play an important role in modulating both the function and substrate specificity of calcineurin in muscle cells. The expression of calsarcin-1 (CS-1 is restricted to slow-twitch skeletal muscle fibres, whereas that of both calsarcin-2 (CS-2 and calsarcin-3 (CS-3 is enriched in fast-twitch fibres. However, the transcriptional control of this selective expression has not been previously elucidated. Results Our real-time RT-PCR analyses suggest that the expression of CS-1 and CS-2 is increased during the myogenic differentiation of mouse C2C12 cells. Promoter deletion analysis further suggests that an NF-κB binding site within the CS-1 promoter is responsible for the up-regulation of CS-1 transcription, but no similar mechanism was evident for CS-2. These findings are further supported by the results of EMSA analysis, as well as by overexpression and inhibition experiments in which NF-κB function was blocked by treatment with its inhibitor, PDTC. In addition, the overexpression of NFATc4 induces both the CS-1 and CS-2 promoters, whereas MEF2C only activates CS-1. Conclusion Our present data suggest that NF-κB is required for the transcription of mouse CS-1 but not CS-2, and that the regulation of the calsarcins is mediated also by the NFAT and MEF2 transcription factors. These results provide new insights into the molecular mechanisms governing transcription in specific muscle fibre cells. The calsarcins may also serve as a valuable mechanistic tool to better understand the regulation of calcineurin signalling during muscle differentiation.

Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1.

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Dmitriy Zamarin

2005-09-01

Full Text Available The influenza virus PB1-F2 is an 87-amino acid mitochondrial protein that previously has been shown to induce cell death, although the mechanism of apoptosis induction has remained unclear. In the process of characterizing its mechanism of action we found that the viral PB1-F2 protein sensitizes cells to apoptotic stimuli such as tumor necrosis factor alpha, as demonstrated by increased cleavage of caspase 3 substrates in PB1-F2-expressing cells. Moreover, treatment of purified mouse liver mitochondria with recombinant PB1-F2 protein resulted in cytochrome c release, loss of the mitochondrial membrane potential, and enhancement of tBid-induced mitochondrial permeabilization, suggesting a possible mechanism for the observed cellular sensitization to apoptosis. Using glutathione-S-transferase pulldowns with subsequent mass spectrometric analysis, we identified the mitochondrial interactors of the PB1-F2 protein and showed that the viral protein uniquely interacts with the inner mitochondrial membrane adenine nucleotide translocator 3 and the outer mitochondrial membrane voltage-dependent anion channel 1, both of which are implicated in the mitochondrial permeability transition during apoptosis. Consistent with this interaction, blockers of the permeability transition pore complex (PTPC inhibited PB1-F2-induced mitochondrial permeabilization. Based on our findings, we propose a model whereby the proapoptotic PB1-F2 protein acts through the mitochondrial PTPC and may play a role in the down-regulation of the host immune response to infection.

Formation of DNA adducts in mouse tissues after 1-nitropyrene administration

International Nuclear Information System (INIS)

Mitchell, C.E.

1986-01-01

DNA adducts were isolated and characterized in mouse lung, liver and kidney after intratracheal instillation of [ 3 H]-1-nitropyrene (1-NP). HPLC analysis of the enzymatically digested DNA indicated the presence of multiple DNA adducts in mouse lung, liver and kidney. These results indicate that DNA adducts of 1-NP are formed in mouse lung, liver and kidney after intratracheal instillation of 1-NP; the HPLC profiles of the multiple adducts suggests that adducts may be formed via metabolic pathways that involve both nitroreduction and ring-oxidation. 6 references, 1 figure

Natively oxidized amino acid residues in the spinach cytochrome b 6 f complex.

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Taylor, Ryan M; Sallans, Larry; Frankel, Laurie K; Bricker, Terry M

2018-01-29

The cytochrome b 6 f complex of oxygenic photosynthesis produces substantial levels of reactive oxygen species (ROS). It has been observed that the ROS production rate by b 6 f is 10-20 fold higher than that observed for the analogous respiratory cytochrome bc 1 complex. The types of ROS produced (O 2 •-, 1 O 2 , and, possibly, H 2 O 2 ) and the site(s) of ROS production within the b 6 f complex have been the subject of some debate. Proposed sources of ROS have included the heme b p , PQ p •- (possible sources for O 2 •- ), the Rieske iron-sulfur cluster (possible source of O 2 •- and/or 1 O 2 ), Chl a (possible source of 1 O 2 ), and heme c n (possible source of O 2 •- and/or H 2 O 2 ). Our working hypothesis is that amino acid residues proximal to the ROS production sites will be more susceptible to oxidative modification than distant residues. In the current study, we have identified natively oxidized amino acid residues in the subunits of the spinach cytochrome b 6 f complex. The oxidized residues were identified by tandem mass spectrometry using the MassMatrix Program. Our results indicate that numerous residues, principally localized near p-side cofactors and Chl a, were oxidatively modified. We hypothesize that these sites are sources for ROS generation in the spinach cytochrome b 6 f complex.

Bifidobacterium breve B-3 exerts metabolic syndrome-suppressing effects in the liver of diet-induced obese mice: a DNA microarray analysis.

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Kondo, S; Kamei, A; Xiao, J Z; Iwatsuki, K; Abe, K

2013-09-01

We previously reported that supplementation with Bifidobacterium breve B-3 reduced body weight gain and accumulation of visceral fat in a dose-dependent manner, and improved serum levels of total cholesterol, glucose and insulin in a mouse model of diet-induced obesity. In this study, we investigated the expression of genes in the liver using DNA microarray analysis and q-PCR to reveal the mechanism of these anti-obesity effects in this mouse model. Administration of B. breve B-3 led to regulated gene expression of pathways involved in lipid metabolism and response to stress. The results indicate that these regulations in the liver are related to the anti-metabolic syndrome effects of B. breve B-3.

Ordering effects in benzo[1,2-b:4,5-b']difuran-thieno[3,4-c]pyrrole-4,6- dione polymers with >7% solar cell efficiency

KAUST Repository

Warnan, Julien; Cabanetos, Clement; El Labban, Abdulrahman; Hansen, Michael Ryan; Tassone, Christopher J.; Toney, Michael F.; Beaujuge, Pierre

2014-01-01

Benzo[1,2-b:4,5-b']difuran-thieno[3,4-c]pyrrole-4,6-dione (PBDFTPD) polymers prepared by microwave-assisted synthesis can achieve power conversion efficiencies (PCEs) >7% in bulk-heterojunction solar cells with phenyl-C61/71-butyric acid methyl

Morphometric studies with attached mouse C3H/10T 1/2 cells

International Nuclear Information System (INIS)

Geard, C.R.; Harding, T.

1981-01-01

Studies of in vitro transformation using the Syrian hamster embryo cell system and the mouse C3H/10T 1/2 cell system form an integral part of this laboratory's activities. As part of the studies with the mouse cell line we have monitored the behavior of these cells in culture in order to ascertain those variables which might influence the expression of transformation. The study of transformed cells versus normal cells could lead to insight into an earlier definition of transformation that the clonal morphological change currently in use. This present report details the changes in cellular morphology with time in culture of normal mouse C3H/10T 1/2 cells from early passages (9 to 13) and x-ray transformed cells which have been maintained in culture for three years

Identification, synthesis, and biological evaluation of the metabolites of 3-amino-6-(3'-aminopropyl)-5H-indeno[1,2-c]isoquinoline-5,11-(6H)dione (AM6-36), a promising rexinoid lead compound for the development of cancer chemotherapeutic and chemopreventive agents.

Science.gov (United States)

Chen, Lian; Conda-Sheridan, Martin; Reddy, P V Narasimha; Morrell, Andrew; Park, Eun-Jung; Kondratyuk, Tamara P; Pezzuto, John M; van Breemen, Richard B; Cushman, Mark

2012-06-28

Activation of the retinoid X receptor (RXR), which is involved in cell proliferation, differentiation, and apoptosis, is a strategy for cancer chemotherapy and chemoprevention, and 3-amino-6-(3'-aminopropyl)-5H-indeno[1,2-c]isoquinoline-5,11-(6H)dione (AM6-36) (3) is among the few RXR ligands known. The presently reported studies of 3 include its binding to human plasma proteins, metabolic stability using human liver microsomes, metabolism by human liver microsomes and hepatocytes, and in vivo disposition in rat serum, liver, and mammary tissue. Compound 3 was 75% bound to human plasma proteins, and its metabolic stability was much greater than propranolol. One phase I metabolite was formed by human liver microsomes, seven phase I and II metabolites were formed by human hepatocytes, and five metabolites were detected in rat serum and liver after oral administration. The putative metabolites predicted using LC-MS-MS were synthesized to confirm their structures and to provide sufficient material for investigation of induction of RXRE transcriptional activity and inhibition of NFκB.

Discordance between liver biopsy and Fibroscan® in assessing liver fibrosis in chronic hepatitis b: risk factors and influence of necroinflammation.

Directory of Open Access Journals (Sweden)

Seung Up Kim

Full Text Available BACKGROUND: Few studies have investigated predictors of discordance between liver biopsy (LB and liver stiffness measurement (LSM using FibroScan®. We assessed predictors of discordance between LB and LSM in chronic hepatitis B (CHB and investigated the effects of necroinflammatory activity. METHODS: In total, 150 patients (107 men, 43 women were prospectively enrolled. Only LSM with ≥ 10 valid measurements was considered reliable. Liver fibrosis was evaluated using the Laennec system. LB specimens <15 mm in length were considered ineligible. Reference cutoff LSM values to determine discordance were calculated from our cohort (6.0 kPa for ≥ F2, 7.5 kPa for ≥ F3, and 9.4 kPa for F4. RESULTS: A discordance, defined as a discordance of at least two stages between LB and LSM, was identified in 21 (14.0% patients. In multivariate analyses, fibrosis stages F3-4 and F4 showed independent negative associations with discordance (P = 0.002; hazard ratio [HR], 0.073; 95% confidence interval [CI], 0.014-0.390 for F3-4 and P = 0.014; HR, 0.067; 95% CI, 0.008-0.574 for F4. LSM values were not significantly different between maximal activity grades 1-2 and 3-4 in F1 and F2 fibrosis stages, whereas LSM values were significantly higher in maximal activity grade 3-4 than 1-2 in F3 and F4 fibrosis stage (median 8.6 vs. 11.3 kPa in F3, P = 0.049; median 11.9 vs. 19.2 kPa in F4, P = 0.009. CONCLUSION: Advanced fibrosis stage (F3-4 or cirrhosis (F4 showed a negative correlation with discordance between LB and LSM in patients with CHB, and maximal activity grade 3-4 significantly influenced LSM values in F3 and F4.

Inhibition of Cyclic Adenosine Monophosphate (cAMP-response Element-binding Protein (CREB-binding Protein (CBP/β-Catenin Reduces Liver Fibrosis in Mice

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Yosuke Osawa

2015-11-01

Full Text Available Wnt/β-catenin is involved in every aspect of embryonic development and in the pathogenesis of many human diseases, and is also implicated in organ fibrosis. However, the role of β-catenin-mediated signaling on liver fibrosis remains unclear. To explore this issue, the effects of PRI-724, a selective inhibitor of the cAMP-response element-binding protein-binding protein (CBP/β-catenin interaction, on liver fibrosis were examined using carbon tetrachloride (CCl4- or bile duct ligation (BDL-induced mouse liver fibrosis models. Following repetitive CCl4 administrations, the nuclear translocation of β-catenin was observed only in the non-parenchymal cells in the liver. PRI-724 treatment reduced the fibrosis induced by CCl4 or BDL. C-82, an active form of PRI-724, inhibited the activation of isolated primary mouse quiescent hepatic stellate cells (HSCs and promoted cell death in culture-activated HSCs. During the fibrosis resolution period, an increase in F4/80+ CD11b+ and Ly6Clow CD11b+ macrophages was induced by CCl4 and was sustained for two weeks thereafter, even after having stopped CCl4 treatment. PRI-724 accelerated the resolution of CCl4-induced liver fibrosis, and this was accompanied by increased matrix metalloproteinase (MMP-9, MMP-2, and MMP-8 expression in intrahepatic leukocytes. In conclusion, targeting the CBP/β-catenin interaction may become a new therapeutic strategy in treating liver fibrosis.

Crystal structures of LiCsTiF6 and Cs2TiF6 and interval mobility of complex anions

International Nuclear Information System (INIS)

Popov, D.Yu.; Kavun, V.Ya.; Gerasimenko, A.V.; Sergienko, V.I.; Antokhina, T.F.

2002-01-01

The structure of LiCsTiF 6 (1) and Cs 2 TiF 6 (2) monocrystals was studied by the method of X-ray diffraction analysis. Crystal lattice parameters for compound 1 are: a = 9.251 (1), b = 11.920 (1), c = 10.271 (1), sp.gr. Pbcn, Z = 8; for compound 2: a = 6.213 (1), c = 5.004 (1), sp.gr. P3-bar m1, Z = 1. Three-dimensional frame of bound titanium octahedrons and slightly distorted lithium tetragonal pyramids with Li-F distance ranging from 1.86 to 2.24 A is the crystal structure base of compound 1. The structure of compound 2 is made of dose-packed CsF 3 layers and TiF 6 2- octahedrons located between the layers. The types of internal motion of the complex anions were determined by 10 F NMR method, their activation energy in crystals 1 and 2 in the temperature range of 200-500 K being estimated [ru

Deleterious effect of n-3 polyunsaturated fatty acids in non-alcoholic steatohepatitis in the fat-1 mouse model

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Diana Shefer-Weinberg

2017-04-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD represents a spectrum of pathologies, ranging from hepatocellular steatosis to non-alcoholic steatohepatitis (NASH, fibrosis and cirrhosis. It has been suggested that fish oil containing n-3 polyunsaturated fatty acids (n-3 PUFA induce beneficial effects in NAFLD. However, n-3 PUFA are sensitive to peroxidation that generate free radicals and reactive aldehydes. We aimed at determining whether changing the tissue ratio of n-3 to n-6 PUFA may be beneficial or alternatively harmful to the etiology of NAFLD. The transgenic Fat-1 mouse model was used to determine whether n-3 PUFA positively or negatively affect the development of NAFLD. fat-1mice express the fat-1 gene of Caenorhabditis elegans, which encodes an n-3 fatty-acid desaturase that converts n-6 to n-3 fatty acids. Wild-type C57BL/6 mice served as the control group. Both groups of mice were fed methionine and choline deficient (MCD diet, which induces NASH within 4 weeks. The study shows that NASH developed faster and was more severe in mice from the fat-1 group when compared to control C57BL/6 mice. This was due to enhanced lipid peroxidation of PUFA in the liver of the fat-1 mice as compared to the control group. Results of our mice study suggest that supplementing the diet of individuals who develop or have fatty livers with n-3 PUFA should be carefully considered and if recommended adequate antioxidants should be added to the diet in order to reduce such risk.

Human parvovirus B19 VP1u Protein as inflammatory mediators induces liver injury in naïve mice.

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Hsu, Tsai-Ching; Chiu, Chun-Ching; Chang, Shun-Chih; Chan, Hsu-Chin; Shi, Ya-Fang; Chen, Tzy-Yen; Tzang, Bor-Show

2016-01-01

Human parvovirus B19 (B19V) is a human pathogen known to be associated with many non-erythroid diseases, including hepatitis. Although B19V VP1-unique region (B19-VP1u) has crucial roles in the pathogenesis of B19V infection, the influence of B19-VP1u proteins on hepatic injury is still obscure. This study investigated the effect and possible inflammatory signaling of B19-VP1u in livers from BALB/c mice that were subcutaneously inoculated with VP1u-expressing COS-7 cells. The in vivo effects of B19-VP1u were analyzed by using live animal imaging system (IVIS), Haematoxylin-Eosin staining, gel zymography, and immunoblotting after inoculation. Markedly hepatocyte disarray and lymphocyte infiltration, enhanced matrix metalloproteinase (MMP)-9 activity and increased phosphorylation of p38, ERK, IKK-α, IκB and NF-κB (p-p65) proteins were observed in livers from BALB/c mice receiving COS-7 cells expressing B19-VP1u as well as the significantly increased CRP, IL-1β and IL-6. Notably, IFN-γ and phosphorylated STAT1, but not STAT3, were also significantly increased in the livers of BALB/c mice that were subcutaneously inoculated with VP1u-expressing COS-7 cells. These findings revealed the effects of B19-VP1u on liver injury and suggested that B19-VP1u may have a role as mediators of inflammation in B19V infection.

IPCC IS92 Emissions Scenarios (A, B, C, D, E, F) Dataset Version 1.1

Data.gov (United States)

National Aeronautics and Space Administration — The Intergovernmental Panel on Climate Change (IPCC) IS92 Emissions Scenarios (A, B, C, D, E, F) Dataset Version 1.1 consists of six global and regional greenhouse...

Nido-Carborane building-block reagents. 2. Bulky-substituent (alkyl)2C2B4H6 derivatives and (C6H5)2C2B4H6: synthesis and properties

International Nuclear Information System (INIS)

Boyter, H.A. Jr.; Grimes, R.N.

1988-01-01

The preparation and chemistry of nido-2,3-R 2 C 2 C 2 B 4 H 6 carboranes in which R is n-butyl, isopentyl, n-hexyl, and phenyl was investigated in order to further assess the steric and electronic influence of the R groups on the properties of the nido-C 2 B 4 cage, especially with respect to metal complexation at the C 2 B 3 face and metal-promoted oxidative fusion. The three dialkyl derivatives were prepared from the corresponding dialkylacetylenes via reaction with B 5 H 9 and triethylamine, but the diphenyl compound could not be prepared in this manner and was obtained instead in a thermal reaction of B 5 H 9 with diphenylacetylene in the absence of amine. All four carboranes are readily bridge-deprotonated by NaH in THF, and the anions of the dialkyl species, on treatment with FeCl 2 and air oxidation, generate the respective R 4 C 4 B 8 H 8 carborane fusion products were R = n-C 4 H 9 , i-C 5 H 11 or n-C 6 H 13 . The diphenylcarborane anion Ph 2 C 2 B 4 H 5 - did not form detectable metal complexes with Fe 2+ , Co 2+ , or Ni 2+ , and no evidence of a Ph 4 C 4 B 8 H 8 fusion product has been found. Treatment of Ph 2 C 2 B 4 H 6 with Cr(CO) 6 did not lead to metal coordination of the phenyl rings, unlike (PhCH 2 ) 2 C 2 B 4 H 6 , which had previously been shown to form mono- and bis(tricarbonylchromium) complexes. However, the reaction of Ph 2 C 2 B 4 H 5 - , CoCl 2 , and (PhPCH 2 ) 2 did give 1,1-(Ph 2 PCH 2 ) 2 -1-Cl-1,2,3-Co(Ph 2 C 2 B 4 H 4 ), the only case in which metal complexation of the diphenylcarborane was observed. 14 references, 3 figures, 3 tables

Complement activation and liver impairment in trichloroethylene-sensitized BALB/c mice.

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Zhang, Jiaxiang; Zha, Wansheng; Wang, Feng; Jiang, Tao; Xu, Shuhai; Yu, Junfeng; Zhou, Chengfan; Shen, Tong; Wu, Changhao; Zhu, Qixing

2013-01-01

Our recent studies have shown that trichloroethylene (TCE) was able to induce multisystem injuries in the form of occupational medicamentosa-like dermatitis, including skin, kidney, and liver damages. However, the role of complement activation in the immune-mediated liver injury is not known. This study examined the role of complement activation in the liver injury in a mouse model of TCE-induced sensitization. Treatment of female BALB/c mice with TCE under specific dosing protocols resulted in skin inflammation and sensitization. Skin edema and erythema occurred in TCE-sensitized groups. Trichloroethylene sensitization produced liver histopathological lesions, increased serum alanine aminotransferase, aspartate transaminase activities, and the relative liver weight. The concentrations of serum complement components C3a-desArg, C5a-desArg, and C5b-9 were significantly increased in 24-hour, 48-hour, and 72-hour sensitization-positive groups treated with TCE and peaked in the 72-hour sensitization-positive group. Depositions of C3a, C5a, and C5b-9 into the liver tissue were also revealed by immunohistochemistry. Immunofluorescence further verified high C5b-9 expression in 24-hour, 48-hour, and 72-hour sensitization-positive groups in response to TCE treatment. Reverse transcription-polymerase chain reaction detected C3 messenger RNA expression in the liver, and this was significantly increased in 24-hour and 48-hour sensitization-positive groups with a transient reduction at 72 hours. These results provide the first experimental evidence that complement activation may play a key role in the generation and progression of immune-mediated hepatic injury by exposure to TCE.

Immunogenicity and safety of concomitant administration of meningococcal serogroup B (4CMenB) and serogroup C (MenC-CRM) vaccines in infants: A phase 3b, randomized controlled trial.

Science.gov (United States)

P Safadi, Marco Aurelio; Martinon-Torres, Federico; Weckx, Lily Yin; Moreira, Edson Duarte; da Fonseca Lima, Eduardo Jorge; Mensi, Ilhem; Calabresi, Marco; Toneatto, Daniela

2017-04-11

After implementation of routine infant MenC vaccination, MenB remains a serious cause of meningococcal disease, yet to be targeted by vaccination programs in several countries. This study (NCT01339923) investigated the immunogenicity and safety of MenC CRM-conjugated vaccine (MenC-CRM) concomitantly administered with MenB vaccine (4CMenB). Infants (N=251) were randomised 1:1 to receive 4CMenB and MenC-CRM (Group 1) or MenC-CRM alone (Group 2) at 3 and 5months (M3, M5) and a booster at 12months of age (M12), and pneumococcal vaccine at M3, M5, M7, M12. Antibody responses to meningococcal vaccines were measured at M3, M6, M12, and M13. Non-inferiority of MenC-CRM response in Group 1 vs Group 2 was demonstrated at M6 and M13, if the lower limit of the 95% confidence interval (LL95%CI) of the difference in percentage of infants with hSBA titres ≥1:8 was >-10%. Sufficiency of MenB response was achieved if LL95%CI of the percentage of infants with hSBA titres ≥1:4 against fHbp, NadA and PorA strains was ≥70% at M6 or ≥75% at M13. Adverse events (AEs) were collected for 7days post-vaccination, and serious AEs (SAEs) and medically attended AEs throughout the study. Non-inferiority of MenC response in Group 1 vs Group 2 (LL95%CI -6.4% [M6]; -5.2% [M13]) and sufficiency of MenB response in Group 1 (LL95%CI 92%, 90%, 89% [M6]; 97%, 92%, 93% [M13] against fHbp, NadA, PorA, respectively) were demonstrated. Higher rates of mild to moderate solicited AEs were reported in Group 1. Unsolicited AEs and SAEs incidences were similar across groups. Concomitant administration of MenC-CRM and 4CMenB in infants was immunogenic, resulting in non-inferior responses against MenC compared to MenC-CRM alone and demonstration of sufficient immune response to MenB, after primary and booster vaccination. Reactogenicity was higher for concomitant vaccines administration, but no safety concerns were identified. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

A CHRONIC INHALATION STUDY OF METHYL BROMIDE TOXICITY IN B6C3F1 MICE. (FINAL REPORT TO THE NATIONAL TOXICOLOGY PROGRAM)

Energy Technology Data Exchange (ETDEWEB)

HABER, S.B.

1987-06-26

This report provides a detailed account of a two year chronic inhalation study of methyl bromide toxicity in B6C3Fl mice conducted for the National Toxicology Program. Mice were randomized into three dose groups (10, 33 and 100 ppm methyl bromide) and one control group (0 ppm) per sex and exposed 5 days/week, 6 hours/day, for a total of 103 weeks. Endpoints included body weight; clinical signs and mortality, and at 6, 15 and 24 months of exposure, animals were sacrificed for organ weights, hematology and histopathology. In addition, a subgroup of animals in each dosage group was monitored for neurobehavioral and neuropathological changes. After only 20 weeks of exposure, 48% of the males and 12% of the females in the 100 ppm group had died. Exposures were terminated in that group and the surviving mice were observed for the duration of the study. Exposure of B6C3Fl mice to methyl bromide, even for only 20 weeks, produced significant changes in growth rate, mortality, organ weights and neurobehavioral functioning. These changes occurred in both males and females, but were more pronounced in males.

Failure of catalase to protect against aflatoxin B1-induced mouse lung tumorigenicity

International Nuclear Information System (INIS)

Guindon, Katherine A.; Foley, Julie F.; Maronpot, Robert R.; Massey, Thomas E.

2008-01-01

The carcinogenic mycotoxin aflatoxin B 1 (AFB 1 ) induces 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation in mouse lung, an effect that can be prevented by treatment with polyethylene glycol-conjugated catalase (PEG-CAT). G → T transversion mutation in K-ras, an early event in AFB 1 -induced mouse lung carcinogenesis, is thought to result from AFB 1 -8,9-exo-epoxide binding to DNA to form AFB 1 -N 7 -guanine, but may also result from formation of 8-OHdG. Therefore, oxidative DNA damage may be important in AFB 1 carcinogenicity. The objective of this study was to determine whether PEG-CAT would prevent AFB 1 tumorigenicity. Mouse lung tumorigenesis was assessed following treatment of female A/J mice with 300 kU/kg PEG-CAT ip and/or 50 mg/kg AFB 1 . Mice were killed 7 months post-treatment and tumors greater than 1 mm in diameter were excised. Unexpectedly, the mean number of tumors per mouse in the PEG-CAT + AFB 1 group (8.81 ± 3.64, n = 47) was greater than that of the group treated with AFB 1 alone (7.05 ± 3.45, n = 42) (P 1 were larger than those from mice treated with AFB 1 alone (P 1 and PEG-CAT + AFB 1 groups (P > 0.05). In vitro incubation with mouse liver catalase (CAT) resulted in conversion of [ 3 H]AFB 1 into a DNA-binding species, a possible explanation for the results observed in vivo. These results demonstrate that PEG-CAT is not protective against AFB 1 carcinogenicity in mouse lung despite preventing DNA oxidation

Trapping of cis-2-butene-1,4-dial to measure furan metabolism in human liver microsomes by cytochrome P450 enzymes.

Science.gov (United States)

Gates, Leah A; Lu, Ding; Peterson, Lisa A

2012-03-01

Furan is a liver toxicant and carcinogen in rodents. It is classified as a possible human carcinogen, but the human health effects of furan exposure remain unknown. The oxidation of furan by cytochrome P450 (P450) enzymes is necessary for furan toxicity. The product of this reaction is the reactive α,β-unsaturated dialdehyde, cis-2-butene-1,4-dial (BDA). To determine whether human liver microsomes metabolize furan to BDA, a liquid chromatography/tandem mass spectrometry method was developed to detect and quantify BDA by trapping this reactive metabolite with N-acetyl-l-cysteine (NAC) and N-acetyl-l-lysine (NAL). Reaction of NAC and NAL with BDA generates N-acetyl-S-[1-(5-acetylamino-5-carboxypentyl)-1H-pyrrol-3-yl]-l-cysteine (NAC-BDA-NAL). Formation of NAC-BDA-NAL was quantified in 21 different human liver microsomal preparations. The levels of metabolism were comparable to that observed in F-344 rat and B6C3F1 mouse liver microsomes, two species known to be sensitive to furan-induced toxicity. Studies with recombinant human liver P450s indicated that CYP2E1 is the most active human liver furan oxidase. The activity of CYP2E1 as measured by p-nitrophenol hydroxylase activity was correlated to the extent of NAC-BDA-NAL formation in human liver microsomes. The formation of NAC-BDA-NAL was blocked by CYP2E1 inhibitors but not other P450 inhibitors. These results suggest that humans are capable of oxidizing furan to its toxic metabolite, BDA, at rates comparable to those of species sensitive to furan exposure. Therefore, humans may be susceptible to furan's toxic effects.

Hepatic protein phosphatase 1 regulatory subunit 3B (Ppp1r3b) promotes hepatic glycogen synthesis and thereby regulates fasting energy homeostasis.

Science.gov (United States)

Mehta, Minal B; Shewale, Swapnil V; Sequeira, Raymond N; Millar, John S; Hand, Nicholas J; Rader, Daniel J

2017-06-23

Maintenance of whole-body glucose homeostasis is critical to glycemic function. Genetic variants mapping to chromosome 8p23.1 in genome-wide association studies have been linked to glycemic traits in humans. The gene of known function closest to the mapped region, PPP1R3B (protein phosphatase 1 regulatory subunit 3B), encodes a protein (G L ) that regulates glycogen metabolism in the liver. We therefore sought to test the hypothesis that hepatic PPP1R3B is associated with glycemic traits. We generated mice with either liver-specific deletion ( Ppp1r3b Δ hep ) or liver-specific overexpression of Ppp1r3b The Ppp1r3b deletion significantly reduced glycogen synthase protein abundance, and the remaining protein was predominantly phosphorylated and inactive. As a consequence, glucose incorporation into hepatic glycogen was significantly impaired, total hepatic glycogen content was substantially decreased, and mice lacking hepatic Ppp1r3b had lower fasting plasma glucose than controls. The concomitant loss of liver glycogen impaired whole-body glucose homeostasis and increased hepatic expression of glycolytic enzymes in Ppp1r3b Δ hep mice relative to controls in the postprandial state. Eight hours of fasting significantly increased the expression of two critical gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, above the levels in control livers. Conversely, the liver-specific overexpression of Ppp1r3b enhanced hepatic glycogen storage above that of controls and, as a result, delayed the onset of fasting-induced hypoglycemia. Moreover, mice overexpressing hepatic Ppp1r3b upon long-term fasting (12-36 h) were protected from blood ketone-body accumulation, unlike control and Ppp1r3b Δ hep mice. These findings indicate a major role for Ppp1r3b in regulating hepatic glycogen stores and whole-body glucose/energy homeostasis. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Noscapinoids bearing silver nanocrystals augmented drug delivery, cytotoxicity, apoptosis and cellular uptake in B16F1, mouse melanoma skin cancer cells.

Science.gov (United States)

Soni, Naina; Jyoti, Kiran; Jain, Upendra Kumar; Katyal, Anju; Chandra, Ramesh; Madan, Jitender

2017-06-01

Noscapine (Nos) and reduced brominated analogue of noscapine (Red-Br-Nos) prevent cellular proliferation and induce apoptosis in cancer cells either alone or in combination with other chemotherapeutic drugs. However, owing to poor physicochemical properties, Nos and Red-Br-Nos have demonstrated their anticancer activity at higher and multiple doses. Therefore, in present investigation, silver nanocrystals of noscapinoids (Nos-Ag 2+ nanocrystals and Red-Br-Nos-Ag 2+ nanocrystals) were customized to augment drug delivery, cytotoxicity, apoptosis and cellular uptake in B16F1 mouse melanoma cancer cells. Nos-Ag 2+ nanocrystals and Red-Br-Nos-Ag 2+ nanocrystals were prepared separately by precipitation method. The mean particle size of Nos-Ag 2+ nanocrystals was measured to be 25.33±3.52nm, insignificantly (P>0.05) different from 27.43±4.51nm of Red-Br-Nos-Ag 2+ nanocrystals. Furthermore, zeta-potential of Nos-Ag 2+ nanocrystals was determined to be -25.3±3.11mV significantly (Pcellular uptake. The Nos-Ag 2+ nanocrystals and Red-Br-Nos-Ag 2+ nanocrystals exhibited an IC 50 of 16.6μM and 6.5μM, significantly (Pcellular morphological alterations in B16F1 cells upon internalization of Nos-Ag 2+ nanocrystals and Red-Br-Nos-Ag 2+ nanocrystals provided the evidences for accumulation within membrane-bound cytoplasmic vacuoles and in enlarged lysosomes and thus triggered mitochondria mediated apoptosis via caspase activation. Preliminary investigations substantiated that Nos-Ag 2+ nanocrystals and Red-Br-Nos-Ag 2+ nanocrystals must be further explored and utilized for the delivery of noscapinoids to melanoma cancer cells. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

"Send & Hold" Clinical Decision Support Rules improvement to reduce unnecessary testing of vitamins A, E, K, B1, B2, B3, B6 and C.

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Rodriguez-Borja, Enrique; Corchon-Peyrallo, Africa; Barba-Serrano, Esther; Villalba Martínez, Celia; Carratala Calvo, Arturo

2018-02-03

We assessed the impact of several "send & hold" clinical decision support rules (CDSRs) within the electronical request system for vitamins A, E, K, B1, B2, B3, B6 and C for all outpatients at a large health department. When ordered through electronical request, providers (except for all our primary care physicians who worked as a non-intervention control group) were always asked to answer several compulsory questions regarding main indication, symptomatology, suspected diagnosis, vitamin active treatments, etc., for each vitamin test using a drop-down list format. After samples arrival, tests were later put on hold internally by our laboratory information system (LIS) until review for their appropriateness was made by two staff pathologists according to the provided answers and LIS records (i.e. "send & hold"). The number of tests for each analyte was compared between the 10-month period before and after CDSRs implementation in both groups. After implementation, vitamins test volumes decreased by 40% for vitamin A, 29% for vitamin E, 42% for vitamin K, 37% for vitamin B1, 85% for vitamin B2, 68% for vitamin B3, 65% for vitamin B6 and 59% for vitamin C (all p values 0.03 or lower except for vitamin B3), whereas in control group, the majority increased or remained stable. In patients with rejected vitamins, no new requests and/or adverse clinical outcome comments due to this fact were identified. "Send & hold" CDSRs are a promising informatics tool that can support in utilization management and enhance the pathologist's leadership role as tests specialist.

Dicty_cDB: Contig-U14329-1 [Dicty_cDB

Lifescience Database Archive (English)

Full Text Available 2 0.41 3 ( DV113252 ) CV03005B1A12.f1 CV03-normalized library Euphorbia... 32 0.42 3 ( CB610770 ) ALBEDO0002_IaF_C05 Mature...NA non acclimated Bluecrop library Vaccin... 34 0.057 3 ( AL645532 ) Mouse DNA sequence from clone RP23-295E...formis cDNA, cleaving embryo clone:m... 38 0.085 2 ( CF811518 ) NA72 cDNA non acclimated Bluecrop library...TTEAF92THC Tetrahymena thermophila EST library, c... 44 0.22 2 ( AC096661 ) Homo sapiens BAC clone RP11-61G2...4425 ) TTEAV71THB Tetrahymena thermophila EST library, c... 44 0.27 2 ( CQ870098 ) Sequence 519 from Patent

CAR-mediated repression of Foxo1 transcriptional activity regulates the cell cycle inhibitor p21 in mouse livers

International Nuclear Information System (INIS)

Kazantseva, Yuliya A.; Yarushkin, Andrei A.; Pustylnyak, Vladimir O.

2014-01-01

Highlights: • CAR activation decreased the level of Foxo1 in mouse livers. • CAR activation decreased the level of p21 in mouse livers. • CAR activation inhibited Foxo1 transcriptional activity in mouse livers. - Abstract: 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), an agonist of constitutive androstane receptor (CAR), is a well-known strong primary chemical mitogen for the mouse liver. Despite extensive investigation of the role of CAR in the regulation of cell proliferation, our knowledge of the intricate mediating mechanism is incomplete. In this study, we demonstrated that long-term CAR activation by TCPOBOP increased liver-to-body weight ratio and decreased tumour suppressor Foxo1 expression and transcriptional activity, which were correlated with reduced expression of genes regulated by Foxo1, including the cell-cycle inhibitor Cdkn1a(p21), and upregulation of the cell-cycle regulator Cyclin D1. Moreover, we demonstrated the negative regulatory effect of TCPOBOP-activated CAR on the association of Foxo1 with the target Foxo1 itself and Cdkn1a(p21) promoters. Thus, we identified CAR-mediated repression of cell cycle inhibitor p21, as mediated by repression of FOXO1 expression and transcriptional activity. CAR-FOXO1 cross-talk may provide new opportunities for understanding liver diseases and developing more effective therapeutic approaches to better drug treatments